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Expression of trophinin and bystin identifies distinct cell types in the germinal zones of adult rat brain.
Ma, Liping; Yin, Min; Wu, Xuefei; Wu, Chunhua; Yang, Shuo; Sheng, Jiansong; Ni, Hengjian; Fukuda, Michiko N; Zhou, Jiawei
In the adult brain, the subventricular zone (SVZ) is one of the regions where active neurogenesis occurs. Relatively few specific markers are available to distinguish different types of cells in the SVZ and rostral migratory stream (RMS) of adult brain. Here, we showed that trophinin and bystin, both of which are required for early embryo implantation during development, were expressed in the SVZ and RMS of the adult rat brain, but not in the brain of embryos and early postnatal animals. Trophinin-expressing cells were immunopositive for both Ki-67 and nestin in the SVZ. Some of the trophinin-positive cells did not express either the type A cell marker polysialylated weakly adhesive form of the neural cell adhesion molecule (PSA-NCAM) or the type B cell marker glial fibrillary acidic protein (GFAP). Double-label immunohistochemistry revealed that bystin-positive cells co-expressed GFAP, Ki-67 and nestin, but not PSA-NCAM, suggesting that they are likely type B cells. Intracerebroventricular infusion of cytosine-beta-d-arabiofuranoside (Ara-C) eliminated trophinin-positive cells in the SVZ. Following its depletion, however, the remaining bystin-positive cells continued to divide and generate actively dividing trophinin-positive cells that were negative for PSA-NCAM, leading to reconstruction of SVZ network. These characteristics indicate that this subset of trophinin-positive cells in the SVZ is type C cells. Conversely in the RMS, trophinin co-localized with nestin and PSA-NCAM, suggesting that it is expressed in neuroblasts. Cultured neural precursor cells derived from the adult SVZ also expressed both trophinin and bystin. These findings provide insight into the molecular basis of adult neurogenesis in the SVZ and RMS. PMID:16706835
Gingival Tissue Transcriptomes Identify Distinct Periodontitis Phenotypes
Kebschull, M.; Demmer, R.T.; Gr³n, B.; Guarnieri, P.; Pavlidis, P.; Papapanou, P.N.
The currently recognized principal forms of periodontitisŚchronic and aggressiveŚlack an unequivocal, pathobiology-based foundation. We explored whether gingival tissue transcriptomes can serve as the basis for an alternative classification of periodontitis. We used cross-sectional whole-genome gene expression data from 241 gingival tissue biopsies obtained from sites with periodontal pathology in 120 systemically healthy nonsmokers with periodontitis, with available data on clinical periodontal status, subgingival microbial profiles, and serum IgG antibodies to periodontal microbiota. Adjusted model-based clustering of transcriptomic data using finite mixtures generated two distinct clusters of patients that did not align with the current classification of chronic and aggressive periodontitis. Differential expression profiles primarily related to cell proliferation in cluster 1 and to lymphocyte activation and unfolded protein responses in cluster 2. Patients in the two clusters did not differ with respect to age but presented with distinct phenotypes (statistically significantly different whole-mouth clinical measures of extent/severity, subgingival microbial burden by several species, and selected serum antibody responses). Patients in cluster 2 showed more extensive/severe disease and were more often male. The findings suggest that distinct gene expression signatures in pathologic gingival tissues translate into phenotypic differences and can provide a basis for a novel classification. PMID:24646639
Neural precursor lineages specify distinct neocortical pyramidal neuron types.
Tyler, William A; Medalla, Maria; Guillamon-Vivancos, Teresa; Luebke, Jennifer I; Haydar, Tarik F
Several neural precursor populations contemporaneously generate neurons in the developing neocortex. Specifically, radial glial stem cells of the dorsal telencephalon divide asymmetrically to produce excitatory neurons, but also indirectly to produce neurons via three types of intermediate progenitor cells. Why so many precursor types are needed to produce neurons has not been established; whether different intermediate progenitor cells merely expand the output of radial glia or instead generate distinct types of neurons is unknown. Here we use a novel genetic fate mapping technique to simultaneously track multiple precursor streams in the developing mouse brain and show that layer 2 and 3 pyramidal neurons exhibit distinctive electrophysiological and structural properties depending upon their precursor cell type of origin. These data indicate that individual precursor subclasses synchronously produce functionally different neurons, even within the same lamina, and identify a primary mechanism leading to cortical neuronal diversity. PMID:25878286
Distinct meteoroid families identified on the lunar seismograms
NASA Technical Reports Server (NTRS)
Oberst, Jurgen; Nakamura, Yosio
The meteoroid impact-seismic activity data recorded by the Apollo lunar seismic network is examined. The study investigates the difference in temporal distribution between large and small impacts, clustering of impacts in a two-dimensional space of the time of the year and the time of the month, and the relationship of these observations with terrestrial observations. Several distinct families of meteoroids impacting the moon are identified. Most meteoroids producing small impact-seismic events, including ones associated with cometary showers, appear to approach from retrograde heliocentric orbits. In contrast, most meteoroids associated with large impact-seismic events appear to approach from prograde orbits; the observation is consistent with a hypothesis that many of them represent stony asteroidal material. It is suggested that the previously reported discrepancy between lunar and terrestrial meteoroid-flux estimates may be due to the differences in lunar and terrestrial detection efficiency among various families of meteoroids.
Brain networks for exploration decisions utilizing distinct modeled information types during contextual learning.
Wang, Jane X; Voss, Joel L
Exploration permits acquisition of the most relevant information during learning. However, the specific information needed, the influences of this information on decision making, and the relevant neural mechanisms remain poorly understood. We modeled distinct information types available during contextual association learning and used model-based fMRI in conjunction with manipulation of exploratory decision making to identify neural activity associated with information-based decisions. We identified hippocampal-prefrontal contributions to advantageous decisions based on immediately available novel information, distinct from striatal contributions to advantageous decisions based on the sum total available (accumulated) information. Furthermore, network-level interactions among these regions during exploratory decision making were related to learning success. These findings link strategic exploration decisions during learning to quantifiable information and advance understanding of adaptive behavior by identifying the distinct and interactive nature of brain-network contributions to decisions based on distinct information types. PMID:24908493
Brain networks for exploration decisions utilizing distinct modeled information types during contextual learning
Wang, Jane X.; Voss, Joel L.
Summary Exploration permits acquisition of the most relevant information during learning. However, the specific information needed, the influences of this information on decision-making, and the relevant neural mechanisms remain poorly understood. We modeled distinct information types available during contextual association learning and used model-based fMRI in conjunction with manipulation of exploratory decision-making to identify neural activity associated with information-based decisions. We identified hippocampal-prefrontal contributions to advantageous decisions based on immediately available novel information, distinct from striatal contributions to advantageous decisions based on the sum total available (accumulated) information. Furthermore, network-level interactions among these regions during exploratory decision-making were related to learning success. These findings link strategic exploration decisions during learning to quantifiable information and advance understanding of adaptive behavior by identifying the distinct and interactive nature of brain-network contributions to decisions based on distinct information types. PMID:24908493
Identifying elemental genomic track types and representing them uniformly
Background With the recent advances and availability of various high-throughput sequencing technologies, data on many molecular aspects, such as gene regulation, chromatin dynamics, and the three-dimensional organization of DNA, are rapidly being generated in an increasing number of laboratories. The variation in biological context, and the increasingly dispersed mode of data generation, imply a need for precise, interoperable and flexible representations of genomic features through formats that are easy to parse. A host of alternative formats are currently available and in use, complicating analysis and tool development. The issue of whether and how the multitude of formats reflects varying underlying characteristics of data has to our knowledge not previously been systematically treated. Results We here identify intrinsic distinctions between genomic features, and argue that the distinctions imply that a certain variation in the representation of features as genomic tracks is warranted. Four core informational properties of tracks are discussed: gaps, lengths, values and interconnections. From this we delineate fifteen generic track types. Based on the track type distinctions, we characterize major existing representational formats and find that the track types are not adequately supported by any single format. We also find, in contrast to the XML formats, that none of the existing tabular formats are conveniently extendable to support all track types. We thus propose two unified formats for track data, an improved XML format, BioXSD 1.1, and a new tabular format, GTrack 1.0. Conclusions The defined track types are shown to capture relevant distinctions between genomic annotation tracks, resulting in varying representational needs and analysis possibilities. The proposed formats, GTrack 1.0 and BioXSD 1.1, cater to the identified track distinctions and emphasize preciseness, flexibility and parsing convenience. PMID:22208806
Ferroan anorthosite - A widespread and distinctive lunar rock type
NASA Technical Reports Server (NTRS)
Dowty, E.; Prinz, M.; Keil, K.
Eight of eleven Apollo 16 rake-sample anorthosites are very similar to each other, to hand-specimen Apollo 16 anorthosites, and to Apollo 15 anorthosites. They have feldspar An-96.6, both high- and low-Ca pyroxene with a restricted range of (low-magnesium) composition, minor olivine, traces of ilmenite and chromite, and originally coarse-grained, but now cataclastic texture. Such ferroan anorthosite is evidently a coherent, distinctive and widespread lunar rock type of cumulate origin which may not necessarily be very closely related genetically to other highland rock types.
The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations
Capecchi, Mario R.
The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations (sent for review October 28, 2011) The small intestine epithelium undergoes rapid and continuous regeneration supported by crypt intestinal stem cells (ISCs). Bmi1 and Lgr5 have been independently identified
Two distinct types of noisy oscillators in electroreceptors of paddlefish.
Neiman, Alexander B; Russell, David F
Our computational analyses and experiments demonstrate that ampullary electroreceptors in paddlefish (Polyodon spathula) contain 2 distinct types of continuously active noisy oscillators. The spontaneous firing of afferents reflects both rhythms, and as a result is stochastically biperiodic (quasiperiodic). The first type of oscillator resides in the sensory epithelia, is recorded as approximately 26 Hz and +/-70 microV voltage fluctuations at the canal skin pores, and gives rise to a noisy peak at f(e) approximately 26 Hz in power spectra of spontaneous afferent firing. The second type of oscillator resides in afferent terminals, is seen as a noisy peak at f(a) approximately 30-70 Hz that dominates the power spectra of spontaneous afferent firing, and corresponds to the mean spontaneous firing rate. Sideband peaks at frequencies of f(a) +/- f(e) are consistent with epithelia-to-afferent unidirectional synaptic coupling or, alternatively, nonlinear mixing of the 2 oscillatory processes. External stimulation affects the frequency of only the afferent oscillator, not the epithelial oscillators. Application of temperature gradients localized the f(e) and f(a) oscillators to different depths below the skin. Having 2 distinct types of internal oscillators is a novel form of organization for peripheral sensory receptors, of relevance for other hair cell sensory receptors. PMID:14573556
Identifying Clinically Distinct Subgroups of Self-Injurers among Young Adults: A Latent Class Analysis
ERIC Educational Resources Information Center
Klonsky, E. David; Olino, Thomas M.
High rates of nonsuicidal self-injury (NSSI; 14%-17%) in adolescents and young adults suggest that some self-injurers may exhibit more or different psychiatric problems than others. In the present study, the authors utilized a latent class analysis to identify clinically distinct subgroups of self-injurers. Participants were 205 young adults withģ
Whole-genome screening identifies proteins localized to distinct nuclear bodies
Fong, Ka-wing; Li, Yujing; Wang, Wenqi; Ma, Wenbin; Li, Kunpeng; Qi, Robert Z.; Liu, Dan; Songyang, Zhou
The nucleus is a unique organelle that contains essential genetic materials in chromosome territories. The interchromatin space is composed of nuclear subcompartments, which are defined by several distinctive nuclear bodies believed to be factories of DNA or RNA processing and sites of transcriptional and/or posttranscriptional regulation. In this paper, we performed a genome-wide microscopy-based screening for proteins that form nuclear foci and characterized their localizations using markers of known nuclear bodies. In total, we identified 325 proteins localized to distinct nuclear bodies, including nucleoli (148), promyelocytic leukemia nuclear bodies (38), nuclear speckles (27), paraspeckles (24), Cajal bodies (17), Sam68 nuclear bodies (5), Polycomb bodies (2), and uncharacterized nuclear bodies (64). Functional validation revealed several proteins potentially involved in the assembly of Cajal bodies and paraspeckles. Together, these data establish the first atlas of human proteins in different nuclear bodies and provide key information for research on nuclear bodies. PMID:24127217
Long noncoding RNA profiles identify five distinct molecular subtypes of colorectal cancer with clinical relevance.
Chen, Haoyan; Xu, Jie; Hong, Jie; Tang, Ruqi; Zhang, Xi; Fang, Jing-Yuan
Colorectal cancer (CRC) is a heterogeneous disease in terms of clinical behavior and response to therapy. Increasing evidence suggests that long noncoding RNAs (lncRNAs) are frequently aberrantly expressed in cancers, and some of them have been implicated in CRC biogenesis and prognosis. Using an lncRNA-mining approach, we constructed lncRNAs expression profiles in approximately 888 CRC samples. By applying unsupervised consensus clustering to LncRNA expression profiles, we identified five distinct molecular subtypes of CRC with different biological pathways and phenotypically distinct in their clinical outcome in both univariate and multivariate analysis. The prognostic significance of the lncRNA-based classifier was confirmed in independent patient cohorts. Further analysis revealed that most of the signature lncRNAs positively correlated with somatic copy number alterations (SCNAs). This lncRNAs-based classification schema thus provides a molecular classification applicable to individual tumors that has implications to influence treatment decisions. PMID:24954858
Driver somatic mutations identify distinct disease entities within myeloid neoplasms with myelodysplasia.
Malcovati, Luca; Papaemmanuil, Elli; Ambaglio, Ilaria; Elena, Chiara; Gallņ, Anna; Della Porta, Matteo G; Travaglino, Erica; Pietra, Daniela; Pascutto, Cristiana; Ubezio, Marta; Bono, Elisa; Da ViÓ, Matteo C; Brisci, Angela; Bruno, Francesca; Cremonesi, Laura; Ferrari, Maurizio; Boveri, Emanuela; Invernizzi, Rosangela; Campbell, Peter J; Cazzola, Mario
Our knowledge of the genetic basis of myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) has considerably improved. To define genotype/phenotype relationships of clinical relevance, we studied 308 patients with MDS, MDS/MPN, or acute myeloid leukemia evolving from MDS. Unsupervised statistical analysis, including the World Health Organization classification criteria and somatic mutations, showed that MDS associated with SF3B1-mutation (51 of 245 patients, 20.8%) is a distinct nosologic entity irrespective of current morphologic classification criteria. Conversely, MDS with ring sideroblasts with nonmutated SF3B1 segregated in different clusters with other MDS subtypes. Mutations of genes involved in DNA methylation, splicing factors other than SF3B1, and genes of the RAS pathway and cohesin complex were independently associated with multilineage dysplasia and identified a distinct subset (51 of 245 patients, 20.8%). No recurrent mutation pattern correlated with unilineage dysplasia without ring sideroblasts. Irrespective of driver somatic mutations, a threshold of 5% bone marrow blasts retained a significant discriminant value for identifying cases with clonal evolution. Comutation of TET2 and SRSF2 was highly predictive of a myeloid neoplasm characterized by myelodysplasia and monocytosis, including but not limited to, chronic myelomonocytic leukemia. These results serve as a proof of concept that a molecular classification of myeloid neoplasms is feasible. PMID:24970933
Coronal type II bursts and interplanetary type II bursts: Distinct shock drivers
NASA Astrophysics Data System (ADS)
Suryanarayana, G. S.
We study solar radio type II bursts combining with Wind/WAVES type II bursts and coronal mass ejections (CMEs). The aim of the present work is to investigate the effectiveness of shocks to cause type II bursts in the solar corona and the interplanetary space. We consider the following findings. The distribution of the cessation heights of type II emission is confined to a rather narrow range of height than the distribution of the heights of start frequencies. This is suggestive of the presence of a gradient for the Alfvķn speed from the heliocentric height of ś1.4 solar radii. The range of the kinetic energy of CMEs associated with coronal type II emission taken together with the suggested computation method and the Alfvķn speed gradient, indicates the limit to the height up to which type II emission could be expected. This height is ś2 solar radii from the center of the Sun. Further, the large time gap between the cessation time and heights of coronal type II emission and the commencement time and heights of most of the IP type II bursts do not account for the difference between the two heights and the average shock speed. Also, there is clear difference in the magnitude of the kinetic energies and the distinct characteristics of the CMEs associated with coronal and IP type II bursts. Hence, we suggest that in most instances the coronal type II bursts and IP type II bursts occur due to distinct shocks. We also address the question of the origin of type II bursts and discuss the possible explanation of observed results.
Identifying land cover variability distinct from land cover change: Cheatgrass in the Great Basin
Bradley, Bethany
that ecosystems dominated by non-native cheatgrass (Bromus tectorum) show an inter-annual amplified response Basin; Cheatgrass; Bromus tectorum; Invasive species; Time series; NDVI; Inter-annual variability 1 is prominent in land cover types dominated by cheatgrass (Bromus tectorum). Correctly identifying
Multiparameter Analysis of Human Bone Marrow Stromal Cells Identifies Distinct Immunomodulatory and Differentiation-Competent Subtypes
James, Sally; Fox, James; Afsari, Farinaz; Lee, Jennifer; Clough, Sally; Knight, Charlotte; Ashmore, James; Ashton, Peter; Preham, Olivier; Hoogduijn, Martin; Ponzoni, RaquelĀDeĀAlmeidaĀRocha; Hancock, Y.; Coles, Mark; Genever, Paul
Summary Bone marrow stromal cells (BMSCs, also called bone-marrow-derived mesenchymal stromal cells) provide hematopoietic support and immunoregulation and contain a stem cell fraction capable of skeletogenic differentiation. We used immortalized human BMSC clonal lines for multi-level analysis of functional markers for BMSC subsets. All clones expressed typical BMSC cell-surface antigens; however, clones with trilineage differentiation capacity exhibited enhanced vascular interaction gene sets, whereas non-differentiating clones were uniquely CD317 positive with significantly enriched immunomodulatory transcriptional networks and high IL-7 production. IL-7 lineage tracing and CD317 immunolocalization confirmed the existence of a rare non-differentiating BMSC subtype, distinct from Cxcl12-DsRed+ perivascular stromal cells inĀvivo. Colony-forming CD317+ IL-7hi cells, identified at ?1%¢3% frequency in heterogeneous human BMSC fractions, were found to have the same biomolecular profile as non-differentiating BMSC clones using Raman spectroscopy. Distinct functional identities can be assigned to BMSC subpopulations, which are likely to have specific roles in immune control, lymphopoiesis, and bone homeostasis. PMID:26070611
Multiparameter Analysis of Human Bone Marrow Stromal Cells Identifies Distinct Immunomodulatory and Differentiation-Competent Subtypes.
James, Sally; Fox, James; Afsari, Farinaz; Lee, Jennifer; Clough, Sally; Knight, Charlotte; Ashmore, James; Ashton, Peter; Preham, Olivier; Hoogduijn, Martin; Ponzoni, Raquel De Almeida Rocha; Hancock, Y; Coles, Mark; Genever, Paul
Bone marrow stromal cells (BMSCs, also called bone-marrow-derived mesenchymal stromal cells) provide hematopoietic support and immunoregulation and contain a stem cell fraction capable of skeletogenic differentiation. We used immortalized human BMSC clonal lines for multi-level analysis of functional markers for BMSC subsets. All clones expressed typical BMSC cell-surface antigens; however, clones with trilineage differentiation capacity exhibited enhanced vascular interaction gene sets, whereas non-differentiating clones were uniquely CD317 positive with significantly enriched immunomodulatory transcriptional networks and high IL-7 production. IL-7 lineage tracing and CD317 immunolocalization confirmed the existence of a rare non-differentiating BMSC subtype, distinct from Cxcl12-DsRed(+) perivascular stromal cells inĀvivo. Colony-forming CD317(+) IL-7(hi) cells, identified at ?1%-3% frequency in heterogeneous human BMSC fractions, were found to have the same biomolecular profile as non-differentiating BMSC clones using Raman spectroscopy. Distinct functional identities can be assigned to BMSC subpopulations, which are likely to have specific roles in immune control, lymphopoiesis, and bone homeostasis. PMID:26070611
Burkholderia pseudomallei sequencing identifies genomic clades with distinct recombination, accessory, and epigenetic profiles
Nandi, Tannistha; Holden, Matthew T.G.; Didelot, Xavier; Mehershahi, Kurosh; Boddey, Justin A.; Beacham, Ifor; Peak, Ian; Harting, John; Baybayan, Primo; Guo, Yan; Wang, Susana; How, Lee Chee; Sim, Bernice; Essex-Lopresti, Angela; Sarkar-Tyson, Mitali; Nelson, Michelle; Smither, Sophie; Ong, Catherine; Aw, Lay Tin; Hoon, Chua Hui; Michell, Stephen; Studholme, David J.; Titball, Richard; Chen, Swaine L.; Parkhill, Julian
Burkholderia pseudomallei (Bp) is the causative agent of the infectious disease melioidosis. To investigate population diversity, recombination, and horizontal gene transfer in closely related Bp isolates, we performed whole-genome sequencing (WGS) on 106 clinical, animal, and environmental strains from a restricted Asian locale. Whole-genome phylogenies resolved multiple genomic clades of Bp, largely congruent with multilocus sequence typing (MLST). We discovered widespread recombination in the Bp core genome, involving hundreds of regions associated with multiple haplotypes. Highly recombinant regions exhibited functional enrichments that may contribute to virulence. We observed clade-specific patterns of recombination and accessory gene exchange, and provide evidence that this is likely due to ongoing recombination between clade members. Reciprocally, interclade exchanges were rarely observed, suggesting mechanisms restricting gene flow between clades. Interrogation of accessory elements revealed that each clade harbored a distinct complement of restriction-modification (RM) systems, predicted to cause clade-specific patterns of DNA methylation. Using methylome sequencing, we confirmed that representative strains from separate clades indeed exhibit distinct methylation profiles. Finally, using an E. coli system, we demonstrate that Bp RM systems can inhibit uptake of non-self DNA. Our data suggest that RM systems borne on mobile elements, besides preventing foreign DNA invasion, may also contribute to limiting exchanges of genetic material between individuals of the same species. Genomic clades may thus represent functional units of genetic isolation in Bp, modulating intraspecies genetic diversity. PMID:25236617
Propionibacterium acnes Types I and II Represent Phylogenetically Distinct Groups
Andrew McDowell; Susanna Valanne; Gordon Ramage; Michael M. Tunney; Josephine V. Glenn; Gregory C. McLorinan; Ajay Bhatia; Jean-Francois Maisonneuve; Michael Lodes; David H. Persing; Sheila Patrick
Although two phenotypes of the opportunistic pathogen Propionibacterium acnes (types I and II) have been described, epidemiological investigations of their roles in different infections have not been widely reported. Using immunofluorescence microscopy with monoclonal antibodies (MAbs) QUBPa1 and QUBPa2, specific for types I and II, respectively, we investigated the prevalences of the two types among 132 P. acnes isolates. Analysis
A Systematic Approach to Identify Markers of Distinctly Activated Human Macrophages
Sudan, Bayan; Wacker, Mark A.; Wilson, Mary E.; Graff, Joel W.
Polarization has been a useful concept for describing activated macrophage phenotypes and gene expression profiles. However, macrophage activation status within tumors and other settings are often inferred based on only a few markers. Complicating matters for relevance to human biology, many macrophage activation markers have been best characterized in mice and sometimes are not similarly regulated in human macrophages. To identify novel markers of activated human macrophages, gene expression profiles for human macrophages of a single donor subjected to 33 distinct activating conditions were obtained and a set of putative activation markers were subsequently evaluated in macrophages from multiple donors using integrated fluidic circuit (IFC)-based RT-PCR. Using unsupervised hierarchical clustering of the microarray screen, highly altered transcripts (>4-fold change in expression) sorted the macrophage transcription profiles into two major and 13 minor clusters. Among the 1874 highly altered transcripts, over 100 were uniquely altered in one major or two related minor clusters. IFC PCR-derived data confirmed the microarray results and determined the kinetics of expression of potential macrophage activation markers. Transcripts encoding chemokines, cytokines, and cell surface were prominent in our analyses. The activation markers identified by this study could be used to better characterize tumor-associated macrophages from biopsies as well as other macrophage populations collected from human clinical samples. PMID:26074920
Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes.
Cristescu, Razvan; Lee, Jeeyun; Nebozhyn, Michael; Kim, Kyoung-Mee; Ting, Jason C; Wong, Swee Seong; Liu, Jiangang; Yue, Yong Gang; Wang, Jian; Yu, Kun; Ye, Xiang S; Do, In-Gu; Liu, Shawn; Gong, Lara; Fu, Jake; Jin, Jason Gang; Choi, Min Gew; Sohn, Tae Sung; Lee, Joon Ho; Bae, Jae Moon; Kim, Seung Tae; Park, Se Hoon; Sohn, Insuk; Jung, Sin-Ho; Tan, Patrick; Chen, Ronghua; Hardwick, James; Kang, Won Ki; Ayers, Mark; Hongyue, Dai; Reinhard, Christoph; Loboda, Andrey; Kim, Sung; Aggarwal, Amit
Gastric cancer, a leading cause of cancer-related deaths, is a heterogeneous disease. We aim to establish clinically relevant molecular subtypes that would encompass this heterogeneity and provide useful clinical information. We use gene expression data to describe four molecular subtypes linked to distinct patterns of molecular alterations, disease progression and prognosis. The mesenchymal-like type includes diffuse-subtype tumors with the worst prognosis, the tendency to occur at an earlier age and the highest recurrence frequency (63%) of the four subtypes. Microsatellite-unstable tumors are hyper-mutated intestinal-subtype tumors occurring in the antrum; these have the best overall prognosis and the lowest frequency of recurrence (22%) of the four subtypes. The tumor protein 53 (TP53)-active and TP53-inactive types include patients with intermediate prognosis and recurrence rates (with respect to the other two subtypes), with the TP53-active group showing better prognosis. We describe key molecular alterations in each of the four subtypes using targeted sequencing and genome-wide copy number microarrays. We validate these subtypes in independent cohorts in order to provide a consistent and unified framework for further clinical and preclinical translational research. PMID:25894828
bodies [4, 12]. In honeybee queens, several types of glands have been identified [6, 15,
Paris-Sud XI, Universitķ de
bodies [4, 12]. In honeybee queens, several types of glands have been identified [6, 15, 17, 28 no differences in gland location or structure in the honeybee queens of both races. However capen- sis workers further emphasises the distinctiveness of Cape honeybees. A. m. capensis / A. m. scutellata / tergal gland
SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts.
Malcovati, Luca; Karimi, Mohsen; Papaemmanuil, Elli; Ambaglio, Ilaria; Jõdersten, Martin; Jansson, Monika; Elena, Chiara; Gallņ, Anna; Walldin, Gunilla; Della Porta, Matteo G; Raaschou-Jensen, Klas; Travaglino, Erica; Kallenbach, Klaus; Pietra, Daniela; Ljungstr÷m, Viktor; Conte, Simona; Boveri, Emanuela; Invernizzi, Rosangela; Rosenquist, Richard; Campbell, Peter J; Cazzola, Mario; Hellstr÷m Lindberg, Eva
Refractory anemia with ring sideroblasts (RARS) is a myelodysplastic syndrome (MDS) characterized by isolated erythroid dysplasia and 15% or more bone marrow ring sideroblasts. Ring sideroblasts are found also in other MDS subtypes, such as refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). A high prevalence of somatic mutations of SF3B1 was reported in these conditions. To identify mutation patterns that affect disease phenotype and clinical outcome, we performed a comprehensive mutation analysis in 293 patients with myeloid neoplasm and 1% or more ring sideroblasts. SF3B1 mutations were detected in 129 of 159 cases (81%) of RARS or RCMD-RS. Among other patients with ring sideroblasts, lower prevalence of SF3B1 mutations and higher prevalence of mutations in other splicing factor genes were observed (P < .001). In multivariable analyses, patients with SF3B1 mutations showed significantly better overall survival (hazard ratio [HR], .37; P = .003) and lower cumulative incidence of disease progression (HR = 0.31; P = .018) compared with SF3B1-unmutated cases. The independent prognostic value of SF3B1 mutation was retained in MDS without excess blasts, as well as in sideroblastic categories (RARS and RCMD-RS). Among SF3B1-mutated patients, coexisting mutations in DNA methylation genes were associated with multilineage dysplasia (P = .015) but had no effect on clinical outcome. TP53 mutations were frequently detected in patients without SF3B1 mutation, and were associated with poor outcome. Thus, SF3B1 mutation identifies a distinct MDS subtype that is unlikely to develop detrimental subclonal mutations and is characterized by indolent clinical course and favorable outcome. PMID:25957392
A Focused Small-Molecule Screen Identifies 14 Compounds with Distinct Effects on Toxoplasma gondii
Kamau, Edwin T.; Srinivasan, Ananth R.; Brown, Mark J.; Fair, Matthew G.; Caraher, Erin J.
Toxoplasma gondii is a globally ubiquitous pathogen that can cause severe disease in immunocompromised humans and the developing fetus. Given the proven role of Toxoplasma-secreted kinases in the interaction of Toxoplasma with its host cell, identification of novel kinase inhibitors could precipitate the development of new anti-Toxoplasma drugs and define new pathways important for parasite survival. We selected a small (n = 527) but diverse set of putative kinase inhibitors and screened them for effects on the growth of Toxoplasma in vitro. We identified and validated 14 noncytotoxic compounds, all of which had 50% effective concentrations in the nanomolar to micromolar range. We further characterized eight of these compounds, four inhibitors and four enhancers, by determining their effects on parasite motility, invasion, and the likely cellular target (parasite or host cell). Only two compounds had an effect on parasite motility and invasion. All the inhibitors appeared to target the parasite, and interestingly, two of the enhancers appeared to rather target the host cell, suggesting modulation of host cell pathways beneficial for parasite growth. For the four inhibitors, we also tested their efficacy in a mouse model, where one compound proved potent. Overall, these 14 compounds represent a new and diverse set of small molecules that are likely targeting distinct parasite and host cell pathways. Future work will aim to characterize their molecular targets in both the host and parasite. PMID:22908155
INTRODUCTION Two distinct types of hydromedusan propulsion are well known
Mohseni, Kamran
, 2002). Prolate species such as Sarsia tubulosa primarily use a jetting type of propulsion with large and energy efficiency. For jetting propulsion, the force necessary for propulsion increases faster with size propulsion technologies for underwater vehicles. Recently, jet and vortex propulsion have become a focus
Adenovirus vectors targeting distinct cell types in the retina.
Sweigard, J Harry; Cashman, Siobhan M; Kumar-Singh, Rajendra
Purpose. Gene therapy for a number of retinal diseases necessitates efficient transduction of photoreceptor cells. Whereas adenovirus (Ad) serotype 5 (Ad5) does not transduce photoreceptors efficiently, previous studies have demonstrated improved photoreceptor transduction by Ad5 pseudotyped with Ad35 (Ad5/F35) or Ad37 (Ad5/F37) fiber or by the deletion of the RGD domain in the Ad5 penton base (Ad5DeltaRGD). However, each of these constructs contained a different transgene cassette, preventing the evaluation of the relative performance of these vectors, an important consideration before the use of these vectors in the clinic. The aim of this study was to evaluate these vectors in the retina and to attempt photoreceptor-specific transgene expression. Methods. Three Ad5-based vectors containing the same expression cassette were generated and injected into the subretinal space of adult mice. Eyes were analyzed for green fluorescence protein expression in flat-mounts, cross-sections, quantitative RT-PCR, and a modified stereological technique. A 257-bp fragment derived from the mouse opsin promoter was analyzed in the context of photoreceptor-specific transgene expression. Results. Each virus tested efficiently transduced the retinal pigment epithelium. The authors found no evidence that Ad5/F35 or Ad5/F37 transduced photoreceptors. Instead, they found that Ad5/F37 transduced M³ller cells. Robust photoreceptor transduction by Ad5DeltaRGD was detected. Photoreceptor-specific transgene expression from the 257-bp mouse opsin promoter in the context of Ad5DeltaRGD vectors was found. Conclusions. Adenovirus vectors may be designed with tropism to distinct cell populations. Robust photoreceptor-specific transgene expression can be achieved in the context of Ad5DeltaRGD vectors. PMID:19892875
Tryptophan Scanning Mutagenesis Identifies the Molecular Determinants of Distinct Barttin Functions.
Wojciechowski, Daniel; Fischer, Martin; Fahlke, Christoph
CLC-K chloride channels are expressed in the kidney and in the inner ear and require the accessory subunit barttin for proper function and membrane insertion. Barttin exerts multiple functions on CLC-proteins: it modifies protein stability and intracellular trafficking as well as channel activity, ion conduction, and gating. So far, the molecular determinants of these distinct barttin functions have remained elusive. Here we performed serial perturbation mutagenesis to identify the sequence determinants of barttin function. Barttin consists of two transmembrane helices followed by a long intracellular carboxyl terminus, and earlier work demonstrated that the transmembrane core of barttin suffices for most effects on the ?-subunit. We individually substituted every amino acid of the predicted transmembrane core (amino acids 9-26 and 35-55) with tryptophan, co-expressed mutant barttin with hClC-Ka or V166E rClC-K1, and characterized CLC-K/barttin channels by patch clamp techniques, biochemistry, and confocal microscopy. The majority of mutations left the chaperone function of barttin, i.e. the effects on endoplasmic reticulum exit and surface membrane insertion, unaffected. In contrast, tryptophan insertion at multiple positions resulted in impaired activity of hClC-Ka/barttin and changes in gating of V166E rClC-K1/barttin. These results demonstrate that mutations in a cluster of hydrophobic residues within transmembrane domain 1 affect barttin-CLC-K interaction and impair gating modification by the accessory subunit. Whereas tight interaction is necessary for functional modification, even impaired association of barttin and CLC-K suffices for normal intracellular trafficking. Our findings allow definition of a likely interaction surface and clarify the mechanisms underlying CLC-K channel modification by barttin. PMID:26063802
Single-cell quantitative HER2 measurement identifies heterogeneity and distinct subgroups within traditionally defined HER2-positive patients.
Onsum, Matthew D; Geretti, Elena; Paragas, Violette; Kudla, Arthur J; Moulis, Sharon P; Luus, Lia; Wickham, Thomas J; McDonagh, Charlotte F; Macbeath, Gavin; Hendriks, Bart S
Human epidermal growth factor receptor 2 (HER2) is an important biomarker for breast and gastric cancer prognosis and patient treatment decisions. HER2 positivity, as defined by IHC or fluorescent in situ hybridization testing, remains an imprecise predictor of patient response to HER2-targeted therapies. Challenges to correct HER2 assessment and patient stratification include intratumoral heterogeneity, lack of quantitative and/or objective assays, and differences between measuring HER2 amplification at the protein versus gene level. We developed a novel immunofluorescence method for quantitation of HER2 protein expression at the single-cell level on FFPE patient samples. Our assay uses automated image analysis to identify and classify tumor versus non-tumor cells, as well as quantitate the HER2 staining for each tumor cell. The HER2 staining level is converted to HER2 protein expression using a standard cell pellet array stained in parallel with the tissue sample. This approach allows assessment of HER2 expression and heterogeneity within a tissue section at the single-cell level. By using this assay, we identified distinct subgroups of HER2 heterogeneity within traditional definitions of HER2 positivity in both breast and gastric cancers. Quantitative assessment of intratumoral HER2 heterogeneity may offer an opportunity to improve the identification of patients likely to respond to HER2-targeted therapies. The broad applicability of the assay was demonstrated by measuring HER2 expression profiles on multiple tumor types, and on normal and diseased heart tissues. PMID:24035511
Evidence for two distinct populations of type Ia supernovae.
Wang, Xiaofeng; Wang, Lifan; Filippenko, Alexei V; Zhang, Tianmeng; Zhao, Xulin
Type Ia supernovae (SNe Ia) have been used as excellent standardizable candles for measuring cosmic expansion, but their progenitors are still elusive. Here, we report that the spectral diversity of SNe Ia is tied to their birthplace environments. We found that those with high-velocity ejecta are substantially more concentrated in the inner and brighter regions of their host galaxies than are normal-velocity SNe Ia. Furthermore, the former tend to inhabit larger and more luminous hosts. These results suggest that high-velocity SNe Ia likely originate from relatively younger and more metal-rich progenitors than do normal-velocity SNe Ia and are restricted to galaxies with substantial chemical evolution. PMID:23470733
Two Types of Alpha Satellite DNA in Distinct Chromosomal Locations in Azara's Owl Monkey
Prakhongcheep, Ornjira; Hirai, Yuriko; Hara, Toru; Srikulnath, Kornsorn; Hirai, Hirohisa; Koga, Akihiko
Alpha satellite DNA is a repetitive sequence known to be a major DNA component of centromeres in primates (order Primates). New World monkeys form one major taxon (parvorder Platyrrhini) of primates, and their alpha satellite DNA is known to comprise repeat units of around 340 bp. In one species (Azara's owl monkey Aotus azarae) of this taxon, we identified two types of alpha satellite DNA consisting of 185- and 344-bp repeat units that we designated as OwlAlp1 and OwlAlp2, respectively. OwlAlp2 exhibits similarity throughout its entire sequence to the alpha satellite DNA of other New World monkeys. The chromosomal locations of the two types of sequence are markedly distinct: OwlAlp1 was observed at the centromeric constrictions, whereas OwlAlp2 was found in the pericentric regions. From these results, we inferred that OwlAlp1 was derived from OwlAlp2 and rapidly replaced OwlAlp2 as the principal alpha satellite DNA on a short time scale at the speciation level. A less likely alternative explanation is also discussed. PMID:23477842
Hippocampal pyramidal neurons comprise two distinct cell types that are countermodulated by metabotropic receptors.
Graves, Austin R; Moore, Shannon J; Bloss, Erik B; Mensh, Brett D; Kath, William L; Spruston, Nelson
Relating the function of neuronal cell types to information processing and behavior is a central goal of neuroscience. In the hippocampus, pyramidal cells in CA1 and the subiculum process sensory and motor cues to form a cognitive map encoding spatial, contextual, and emotional information, which they transmit throughout the brain. Do these cells constitute a single class or are there multiple cell types with specialized functions? Using unbiased cluster analysis, we show that there are two morphologically and electrophysiologically distinct principal cell types that carry hippocampal output. We show further that these two cell types are inversely modulated by the synergistic action of glutamate and acetylcholine acting on metabotropic receptors that are central to hippocampal function. Combined with prior connectivity studies, our results support a model of hippocampal processing in which the two pyramidal cell types are predominantly segregated into two parallel pathways that process distinct modalities of information. PMID:23177962
Sequence Analysis of 96 Genomic Regions Identifies Distinct Evolutionary Lineages within CC156, the Largest Streptococcus pneumoniae Clonal Complex in the MLST Database
Moschioni, Monica; Lo Sapio, Morena; Crisafulli, Giovanni; Torricelli, Giulia; Guidotti, Silvia; Muzzi, Alessandro; Barocchi, MichĶle A.; Donati, Claudio
Multi-Locus Sequence Typing (MLST) of Streptococcus pneumoniae is based on the sequence of seven housekeeping gene fragments. The analysis of MLST allelic profiles by eBURST allows the grouping of genetically related strains into Clonal Complexes (CCs) including those genotypes with a common descent from a predicted ancestor. However, the increasing use of MLST to characterize S. pneumoniae strains has led to the identification of a large number of new Sequence Types (STs) causing the merger of formerly distinct lineages into larger CCs. An example of this is the CC156, displaying a high level of complexity and including strains with allelic profiles differing in all seven of the MLST loci, capsular type and the presence of the Pilus Islet-1 (PI-1). Detailed analysis of the CC156 indicates that the identification of new STs, such as ST4945, induced the merging of formerly distinct clonal complexes. In order to discriminate the strain diversity within CC156, a recently developed typing schema, 96-MLST, was used to analyse 66 strains representative of 41 different STs. Analysis of allelic profiles by hierarchical clustering and a minimum spanning tree identified ten genetically distinct evolutionary lineages. Similar results were obtained by phylogenetic analysis on the concatenated sequences with different methods. The identified lineages are homogenous in capsular type and PI-1 presence. ST4945 strains were unequivocally assigned to one of the lineages. In conclusion, the identification of new STs through an exhaustive analysis of pneumococcal strains from various laboratories has highlighted that potentially unrelated subgroups can be grouped into a single CC by eBURST. The analysis of additional loci, such as those included in the 96-MLST schema, will be necessary to accurately discriminate the clonal evolution of the pneumococcal population. PMID:23593373
Sequence analysis of 96 genomic regions identifies distinct evolutionary lineages within CC156, the largest Streptococcus pneumoniae clonal complex in the MLST database.
Moschioni, Monica; Lo Sapio, Morena; Crisafulli, Giovanni; Torricelli, Giulia; Guidotti, Silvia; Muzzi, Alessandro; Barocchi, MichĶle A; Donati, Claudio
Multi-Locus Sequence Typing (MLST) of Streptococcus pneumoniae is based on the sequence of seven housekeeping gene fragments. The analysis of MLST allelic profiles by eBURST allows the grouping of genetically related strains into Clonal Complexes (CCs) including those genotypes with a common descent from a predicted ancestor. However, the increasing use of MLST to characterize S. pneumoniae strains has led to the identification of a large number of new Sequence Types (STs) causing the merger of formerly distinct lineages into larger CCs. An example of this is the CC156, displaying a high level of complexity and including strains with allelic profiles differing in all seven of the MLST loci, capsular type and the presence of the Pilus Islet-1 (PI-1). Detailed analysis of the CC156 indicates that the identification of new STs, such as ST4945, induced the merging of formerly distinct clonal complexes. In order to discriminate the strain diversity within CC156, a recently developed typing schema, 96-MLST, was used to analyse 66 strains representative of 41 different STs. Analysis of allelic profiles by hierarchical clustering and a minimum spanning tree identified ten genetically distinct evolutionary lineages. Similar results were obtained by phylogenetic analysis on the concatenated sequences with different methods. The identified lineages are homogenous in capsular type and PI-1 presence. ST4945 strains were unequivocally assigned to one of the lineages. In conclusion, the identification of new STs through an exhaustive analysis of pneumococcal strains from various laboratories has highlighted that potentially unrelated subgroups can be grouped into a single CC by eBURST. The analysis of additional loci, such as those included in the 96-MLST schema, will be necessary to accurately discriminate the clonal evolution of the pneumococcal population. PMID:23593373
Two Types of Human Mast Cells That Have Distinct Neutral Protease Compositions
A. A. Irani; N. M. Schechter; S. S. Craig; G. Deblois; L. B. Schwartz
Two human mast cell types were identified by immunohistochemical techniques in skin, lung, and small intestine. One type contains the neutral proteases, tryptase and chymotryptic proteinase, and is termed the TC mast cell. The second type contains only tryptase and is termed the T mast cell. Both types are fixed better by Carnoy's fluid than by formalin. The percentage of
Porcine Skin-Derived Progenitor (SKP) Spheres and Neurospheres: Distinct ōStemnessö Identified by Microarray Analysis
Zhao, Ming-Tao; Whitworth, Kristin M.; Lin, Hui; Zhang, Xia; Isom, S. Clay; Dobbs, Kyle B.; Bauer, Bethany; Zhang, Yong
Abstract Skin-derived progenitors (SKP) are neural crest derived and can generate neural and mesodermal progeny in vitro, corresponding to the multipotency of neural crest stem cells. Likewise, neural stem/progenitor cells (displaying as neurospheres) have the capacity of self-renewing, and can produce most phenotypes in the nervous system. Both form spheres when cultured with epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). Although the ōstemnessö of neural stem/progenitor cells has been extensively investigated, the molecular comparison of SKP spheres and neurospheres has not been elucidated. Here, SKP spheres and neurospheres from the same individual porcine fetuses were isolated with the same culture medium, and the multipotency was tested by in vitro differentiation assays. Microarray analysis was used to illustrate the ōstemnessö of SKP spheres and neurospheres. The upregulated genes that were in common in the SKP spheres and neurospheres are involved in ribosome, tight junction, gap junction, cell communication, calcium signaling, ErbB signaling, JAK¢STAT signaling, MAPK signaling, etc. The differentially expressed genes between SKP spheres and neurospheres are mainly involved in ECM¢receptor interaction and the transforming growth factor-beta (TGF-?) signaling pathway. Finally, treatment with leukemia inhibitory factor (LIF) or MEK inhibitor results in a distinctive impact on the ōstemnessö and differentiation genes of SKP spheres and neurospheres. Thus, the cell-intrinsic genetic program may contribute to the innate ōstemnessö of SKP spheres and neurospheres in a similar local microenvironment. PMID:20694160
A novel split kinesin assay identifies motor proteins that interact with distinct vesicle populations.
Jenkins, Brian; Decker, Helena; Bentley, Marvin; Luisi, Julie; Banker, Gary
Identifying the kinesin motors that interact with different vesicle populations is a longstanding and challenging problem with implications for many aspects of cell biology. Here we introduce a new live-cell assay to assess kinesin-vesicle interactions and use it to identify kinesins that bind to vesicles undergoing dendrite-selective transport in cultured hippocampal neurons. We prepared a library of "split kinesins," comprising an axon-selective kinesin motor domain and a series of kinesin tail domains that can attach to their native vesicles; when the split kinesins were assembled by chemical dimerization, bound vesicles were misdirected into the axon. This method provided highly specific results, showing that three Kinesin-3 family members-KIF1A, KIF13A, and KIF13B-interacted with dendritic vesicle populations. This experimental paradigm allows a systematic approach to evaluate motor-vesicle interactions in living cells. PMID:22908316
Hyaluronan Binding Identifies a Functionally Distinct Alveolar Macrophage-like Population in Bone Marrow-Derived Dendritic Cell Cultures.
Poon, Grace F T; Dong, Yifei; Marshall, Kelsey C; Arif, Arif; Deeg, Christoph M; Dosanjh, Manisha; Johnson, Pauline
Although classical dendritic cells (DCs) arise from distinct progenitors in the bone marrow, the origin of inflammatory DCs and the distinction between monocyte-derived DCs and macrophages is less clear. In vitro culture of mouse bone marrow cells with GM-CSF is a well-established method to generate DCs, but GM-CSF has also been used to generate bone marrow-derived macrophages. In this article, we identify a distinct subpopulation of cells within the GM-CSF bone marrow-derived DC culture based on their ability to bind hyaluronan (HA), a major component of the extracellular matrix and ligand for CD44. HA identified a morphologically distinct subpopulation of cells within the immature DC population (CD11c(+) MHC II(mid/low)) that were CCR5(+)/CCR7(-) and proliferated in response to GM-CSF, but, unlike immature DCs, did not develop into mature DCs expressing CCR7 and high levels of MHC II, even after stimulation with LPS. The majority of these cells produced TNF-? in response to LPS but were unable to activate naive T cells, whereas the majority of mature DCs produced IL-12 and activated naive T cells. This HA binding population shared many characteristics with alveolar macrophages and was retained in the alveolar space after lung instillation even after LPS stimulation, whereas the MHC II(high) mature DCs were found in the draining lymph node. Thus, HA binding in combination with MHC II expression can be used to identify alveolar-like macrophages from GM-CSF-treated bone marrow cultures, which provides a useful in vitro model to study alveolar macrophages. PMID:26085682
In silico molecular comparisons of C. elegans and mammalian pharmacology identify distinct targets that regulate feeding.
Lemieux, George A; Keiser, Michael J; Sassano, Maria F; Laggner, Christian; Mayer, Fahima; Bainton, Roland J; Werb, Zena; Roth, Bryan L; Shoichet, Brian K; Ashrafi, Kaveh
Phenotypic screens can identify molecules that are at once penetrant and active on the integrated circuitry of a whole cell or organism. These advantages are offset by the need to identify the targets underlying the phenotypes. Additionally, logistical considerations limit screening for certain physiological and behavioral phenotypes to organisms such as zebrafish and C. elegans. This further raises the challenge of elucidating whether compound-target relationships found in model organisms are preserved in humans. To address these challenges we searched for compounds that affect feeding behavior in C. elegans and sought to identify their molecular mechanisms of action. Here, we applied predictive chemoinformatics to small molecules previously identified in a C. elegans phenotypic screen likely to be enriched for feeding regulatory compounds. Based on the predictions, 16 of these compounds were tested in vitro against 20 mammalian targets. Of these, nine were active, with affinities ranging from 9 nM to 10 ĄM. Four of these nine compounds were found to alter feeding. We then verified the in vitro findings in vivo through genetic knockdowns, the use of previously characterized compounds with high affinity for the four targets, and chemical genetic epistasis, which is the effect of combined chemical and genetic perturbations on a phenotype relative to that of each perturbation in isolation. Our findings reveal four previously unrecognized pathways that regulate feeding in C. elegans with strong parallels in mammals. Together, our study addresses three inherent challenges in phenotypic screening: the identification of the molecular targets from a phenotypic screen, the confirmation of the in vivo relevance of these targets, and the evolutionary conservation and relevance of these targets to their human orthologs. PMID:24260022
Comparative genomic analysis of Helicobacter pylori from Malaysia identifies three distinct lineages suggestive of differential evolution
Kumar, Narender; Mariappan, Vanitha; Baddam, Ramani; Lankapalli, Aditya K.; Shaik, Sabiha; Goh, Khean-Lee; Loke, Mun Fai; Perkins, Tim; Benghezal, Mohammed; Hasnain, Seyed E.; Vadivelu, Jamuna; Marshall, Barry J.; Ahmed, Niyaz
The discordant prevalence of Helicobacter pylori and its related diseases, for a long time, fostered certain enigmatic situations observed in the countries of the southern world. Variation in H. pylori infection rates and disease outcomes among different populations in multi-ethnic Malaysia provides a unique opportunity to understand dynamics of host¢pathogen interaction and genome evolution. In this study, we extensively analyzed and compared genomes of 27 Malaysian H. pylori isolates and identified three major phylogeographic lineages: hspEastAsia, hpEurope and hpSouthIndia. The analysis of the virulence genes within the core genome, however, revealed a comparable pathogenic potential of the strains. In addition, we identified four genes limited to strains of East-Asian lineage. Our analyses identified a few strain-specific genes encoding restriction modification systems and outlined 311 core genes possibly under differential evolutionary constraints, among the strains representing different ethnic groups. The cagA and vacA genes also showed variations in accordance with the host genetic background of the strains. Moreover, restriction modification genes were found to be significantly enriched in East-Asian strains. An understanding of these variations in the genome content would provide significant insights into various adaptive and host modulation strategies harnessed by H. pylori to effectively persist in a host-specific manner. PMID:25452339
Parallel circuits mediating distinct emotional coping reactions to different types of stress
Kevin A. Keay; Richard Bandler
All animals, including humans, react with distinct emotional coping strategies to different types of stress. Active coping strategies (e.g. confrontation, fight, escape) are evoked if the stressor is controllable or escapable. Passive coping strategies (e.g. quiescence, immobility, decreased responsiveness to the environment) are usually elicited if the stressor is inescapable and help to facilitate recovery and healing. Neural substrates mediating
Burkholderia Type VI Secretion Systems Have Distinct Roles in Eukaryotic and Bacterial Cell Interactions
Schwarz, Sandra; West, T. Eoin; Boyer, Frķdķric; Chiang, Wen-Chi; Carl, Mike A.; Hood, Rachel D.; Rohmer, Laurence; Tolker-Nielsen, Tim; Skerrett, Shawn J.; Mougous, Joseph D.
Bacteria that live in the environment have evolved pathways specialized to defend against eukaryotic organisms or other bacteria. In this manuscript, we systematically examined the role of the five type VI secretion systems (T6SSs) of Burkholderia thailandensis (B. thai) in eukaryotic and bacterial cell interactions. Consistent with phylogenetic analyses comparing the distribution of the B. thai T6SSs with well-characterized bacterial and eukaryotic cell-targeting T6SSs, we found that T6SS-5 plays a critical role in the virulence of the organism in a murine melioidosis model, while a strain lacking the other four T6SSs remained as virulent as the wild-type. The function of T6SS-5 appeared to be specialized to the host and not related to an in vivo growth defect, as ?T6SS-5 was fully virulent in mice lacking MyD88. Next we probed the role of the five systems in interbacterial interactions. From a group of 31 diverse bacteria, we identified several organisms that competed less effectively against wild-type B. thai than a strain lacking T6SS-1 function. Inactivation of T6SS-1 renders B. thai greatly more susceptible to cell contact-induced stasis by Pseudomonas putida, Pseudomonas fluorescens and Serratia proteamaculansŚleaving it 100- to 1000-fold less fit than the wild-type in competition experiments with these organisms. Flow cell biofilm assays showed that T6S-dependent interbacterial interactions are likely relevant in the environment. B. thai cells lacking T6SS-1 were rapidly displaced in mixed biofilms with P. putida, whereas wild-type cells persisted and overran the competitor. Our data show that T6SSs within a single organism can have distinct functions in eukaryotic versus bacterial cell interactions. These systems are likely to be a decisive factor in the survival of bacterial cells of one species in intimate association with those of another, such as in polymicrobial communities present both in the environment and in many infections. PMID:20865170
Chemical similarities among physically distinct spring types in a karst terrain
NASA Astrophysics Data System (ADS)
Scanlon, B. R.; Thrailkill, J.
In karst regions where correlations between physical characteristics of springs and temporal variations in spring water chemistry have been found, spring water chemistry has been used to infer physical attributes of karst systems. Possible correlations between chemical and physical characteristics of springs were tested in the Inner Bluegrass Karst Region of central Kentucky where previous dye-tracing studies have identified two physically distinct spring types: local high-level springs discharging from shallow flow paths and major low-level springs discharging from a deep integrated conduit system. Representative high-level and major springs were sampled over a 16-month period and analyzed for major dissolved components. Both spring types showed similar variations in temperature, calcium, magnesium, bicarbonate, and hardness. No systematic differences in ionic concentrations or in saturation indices with respect to calcite and dolomite were apparent between the two spring types. Chemical similarities between high-level and major springs during low flow are attributed to recharge of major springs by percolation and by high-level springs and to the occurrence of most chemical reactions near the recharge zone rather than in the deep conduit system. During high discharge, however, most recharge to the major springs is surface runoff which produces low ionic concentrations. Similarly low ionic concentrations in the high-level springs are thought to result from rapid flow through the soil-rock zone and short flow distances. These relationships indicate that spring water chemistry is not only a function of conduit size but also an indicator of recharge type and amount and flow path length. Differing flow path lengths to major and high-level springs counteract the effect of varying conduit size between the two spring types and result in similar ionic concentrations. These data indicate that spring water chemistry cannot be used to predict physical characteristics of karst aquifers in the Inner Bluegrass Region. The physical and chemical attributes of springs in the Inner Bluegrass were compared to those of springs in the Nittany Valley of Pennsylvania. A reported high correlation between physical and chemical characteristics of springs in the Pennsylvania karst system reflects geological and structural controls not present in the Inner Bluegrass Region.
X-linked intellectual disability type Nascimento is a clinically distinct, probably underdiagnosed entity
X-linked intellectual disability type Nascimento (MIM #300860), caused by mutations in UBE2A (MIM *312180), is characterized by craniofacial dysmorphism (synophrys, prominent supraorbital ridges, deep-set, almond-shaped eyes, depressed nasal bridge, prominent columella, hypoplastic alae nasi, and macrostomia), skin anomalies (hirsutism, myxedematous appearance, onychodystrophy), micropenis, moderate to severe intellectual disability (ID), motor delay, impaired/absent speech, and seizures. Hitherto only five familial point mutations and four different deletions including UBE2A have been reported in the literature. We present eight additional individuals from five families with UBE2A associated ID - three males from a consanguineous family, in whom we identified a small deletion of only 7.1Ākb encompassing the first three exons of UBE2A, two related males with a UBE2A missense mutation in exon 4, a patient with a de novo nonsense mutation in exon 6, and two sporadic males with larger deletions including UBE2A. All affected male individuals share the typical clinical phenotype, all carrier females are unaffected and presented with a completely skewed X inactivation in blood. We conclude that 1.) X-linked intellectual disability type Nascimento is a clinically very distinct entity that might be underdiagnosed to date. 2.) So far, all females carrying a familial UBE2A aberration have a completely skewed X inactivation and are clinically unaffected. This should be taken in to account when counselling those families. 3.) The coverage of an array should be checked carefully prior to analysis since not all arrays have a sufficient resolution at specific loci, or alternative quantitative methods should be applied not to miss small deletions. PMID:24053514
Genetically distinct pathways guide effector export through the type VI secretion system
Whitney, John C.; Beck, Christina M.; Goo, Young Ah; Russell, Alistair B.; Harding, Brittany; De Leon, Justin A.; Cunningham, David A.; Tran, Bao Q.; Low, David A.; Goodlett, David R.; Hayes, Christopher S.; Mougous, Joseph D.
Summary Bacterial secretion systems often employ molecular chaperones to recognize and facilitate export of their substrates. Recent work demonstrated that a secreted component of the type VI secretion system (T6SS), hemolysin co-regulated protein (Hcp), binds directly to effectors, enhancing their stability in the bacterial cytoplasm. Herein, we describe a quantitative cellular proteomics screen for T6S substrates that exploits this chaperone-like quality of Hcp. Application of this approach to the Hcp secretion island I-encoded T6SS (H1-T6SS) of Pseudomonas aeruginosa led to the identification of a novel effector protein, termed Tse4 (type VI secretion exported 4), subsequently shown to act as a potent intra-specific H1-T6SS-delivered antibacterial toxin. Interestingly, our screen failed to identify two predicted H1-T6SS effectors, Tse5 and Tse6, which differ from Hcp-stabilized substrates by the presence of toxin-associated PAAR-repeat motifs and genetic linkage to members of the valine-glycine repeat protein G (vgrG) genes. Genetic studies further distinguished these two groups of effectors: Hcp-stabilized effectors were found to display redundancy in interbacterial competition with respect to the requirement for the two H1-T6SS-exported VgrG proteins, whereas Tse5 and Tse6 delivery strictly required a cognate VgrG. Together, we propose that interaction with either VgrG or Hcp defines distinct pathways for T6S effector export. PMID:24589350
Differential expression of vesicular glutamate transporters 1 and 2 may identify distinct modes of glutamatergic transmission in the macaque visual system
Balaram, Pooja; Hackett, Troy A.; Kaas, Jon H.
Glutamate is the primary neurotransmitter utilized by the mammalian visual system for excitatory neurotransmission. The sequestration of glutamate into synaptic vesicles, and the subsequent transport of filled vesicles to the presynaptic terminal membrane, is regulated by a family of proteins known as vesicular glutamate transporters (VGLUTs). Two VGLUT proteins, VGLUT1 and VGLUT2, characterize distinct sets of glutamatergic projections between visual structures in rodents and prosimian primates, yet little is known about their distributions in the visual system of anthropoid primates. We have examined the mRNA and protein expression patterns of VGLUT1 and VGLUT2 in the visual system of macaque monkeys, an Old World anthropoid primate, in order to determine their relative distributions in the superior colliculus, lateral geniculate nucleus, pulvinar complex, V1 and V2. Distinct expression patterns for both VGLUT1 and VGLUT2 identified architectonic boundaries in all structures, as well as anatomical subdivisions of the superior colliculus, pulvinar complex, and V1. These results suggest that VGLUT1 and VGLUT2 clearly identify regions of glutamatergic input in visual structures, and may identify common architectonic features of visual areas and nuclei across the primate radiation. Additionally, we find that VGLUT1 and VGLUT2 characterize distinct subsets of glutamatergic projections in the macaque visual system; VGLUT2 predominates in driving or feedforward projections from lower order to higher order visual structures while VGLUT1 predominates in modulatory or feedback projections from higher order to lower order visual structures. The distribution of these two proteins suggests that VGLUT1 and VGLUT2 may identify class 1 and class 2 type glutamatergic projections within the primate visual system (Sherman and Guillery, 2006). PMID:23524295
Identifying Essential Cell Types and Circuits in Autism Spectrum Disorders
Maloney, Susan E.; Rieger, Michael A.; Dougherty, Joseph D.
Autism spectrum disorder (ASD) is highly genetic in its etiology, with potentially hundreds of genes contributing to risk. Despite this heterogeneity, these disparate genetic lesions may result in the disruption of a limited number of key cell types or circuits ¢information which could be leveraged for the design of therapeutic interventions. While hypotheses for cellular disruptions can be identified by postmortem anatomical analysis and expression studies of ASD risk genes, testing these hypotheses requires the use of animal models. In this review, we explore the existing evidence supporting the contribution of different cell types to ASD, specifically focusing on rodent studies disrupting serotonergic, GABAergic, cerebellar and striatal cell types, with particular attention to studies of the sufficiency of specific cellular disruptions to generate ASD-related behavioral abnormalities. This evidence suggests multiple cellular routes can create features of the disorder, though it is currently unclear if these cell types converge on a final common circuit. We hope that in the future, systematic studies of cellular sufficiency and genetic interaction will help to classify patients into groups by type of cellular disruptions which suggest tractable therapeutic targets. PMID:24290383
Diffusion-weighted MRI derived apparent diffusion coefficient identifies prognostically distinct subgroups of pediatric diffuse intrinsic pontine glioma.
Lober, Robert M; Cho, Yoon-Jae; Tang, Yujie; Barnes, Patrick D; Edwards, Michael S; Vogel, Hannes; Fisher, Paul G; Monje, Michelle; Yeom, Kristen W
While pediatric diffuse intrinsic pontine gliomas (DIPG) remain fatal, recent data have shown subgroups with distinct molecular biology and clinical behavior. We hypothesized that diffusion-weighted MRI can be used as a prognostic marker to stratify DIPG subsets with distinct clinical behavior. Apparent diffusion coefficient (ADC) values derived from diffusion-weighted MRI were computed in 20 consecutive children with treatment-na've DIPG tumors. The median ADC for the cohort was used to stratify the tumors into low and high ADC groups. Survival, gender, therapy, and potential steroid effects were compared between the ADC groups. Median age at diagnosis was 6.6 (range 2.3-13.2) years, with median follow-up seven (range 1-36) months. There were 14 boys and six girls. Seventeen patients received radiotherapy, five received chemotherapy, and six underwent cerebrospinal fluid diversion. The median ADC of 1,295 ū 10(-6) mm(2)/s for the cohort partitioned tumors into low or high diffusion groups, which had distinct median survivals of 3 and 13 months, respectively (log-rank p < 0.001). Low ADC tumors were found only in boys, whereas high ADC tumors were found in both boys and girls. Available tissue specimens in three low ADC tumors demonstrated high-grade histology, whereas one high ADC tumor demonstrated low-grade histology with a histone H3.1 K27M mutation and high-grade metastatic lesion at autopsy. ADC derived from diffusion-weighted MRI may identify prognostically distinct subgroups of pediatric DIPG. PMID:24522717
Individual neural cell types express immunologically distinct N-CAM forms
The neural cell adhesion molecules, or N-CAMs, are a group of structurally and immunologically related glycoproteins found in vertebrate neural tissues. Adult brain N-CAMs have apparent molecular weights of 180,000, 140,000, and 120,000. In this article we identify, using monoclonal antibody (Mab) 3G6.41, an immunologically distinct adult rat N-CAM form and show that this form is selectively expressed by some
Ovarian atypical proliferative (borderline) mucinous tumors: gastrointestinal and seromucinous (endocervical-like) types are immunophenotypically distinctive.
Vang, Russell; Gown, Allen M; Barry, Todd S; Wheeler, Darren T; Ronnett, Brigitte M
Ovarian atypical proliferative (borderline) mucinous tumors of gastrointestinal and seromucinous types are considered subtypes within the mucinous tumor category despite the presence of distinctive clinicopathologic features that seromucinous tumors share with pure serous tumors. Immunophenotypic differences have not been extensively investigated. Immunohistochemical studies were performed to compare the expression patterns of cytokeratins 7 and 20 (CK7, CK 20), estrogen and progesterone receptors (ER, PR), CA-125, mesothelin, and WT-1 in 28 tumors of gastrointestinal type and 12 tumors of seromucinous type. Both gastrointestinal and seromucinous type tumors had a high frequency of CK7 expression (93% and 100%, respectively). The gastrointestinal type tumors were characterized by frequent expression of CK20 (86%) and CDX2 (39%), infrequent expression of CA-125 (11%) and mesothelin (7%), and lack of expression of ER, PR, and WT-1. In contrast, the seromucinous type tumors were characterized by frequent expression of ER (100%), PR (67%), CA-125 (92%), and mesothelin (83%), infrequent expression of WT-1 (8%), and lack of expression of CK20 and CDX2. The gastrointestinal and seromucinous types of atypical proliferative mucinous tumors are immunophenotypically distinctive tumors. The former are characterized by expression of markers of gastrointestinal-type differentiation (CK20 and CDX2), whereas the latter are characterized by expression of "m³llerian-type" markers (ER, PR, CA-125, and mesothelin). Expression of the latter markers in the seromucinous tumors, which also are expressed in pure serous tumors, and lack of expression of gastrointestinal-type markers, combined with the clinicopathologic features these tumors share with pure serous tumors, support the concept that this subtype is more closely related to serous than gastrointestinal type mucinous tumors and justify the designation "seromucinous." PMID:16306790
ON IDENTIFYING THE PROGENITORS OF Type Ia SUPERNOVAE
Livio, Mario; Pringle, J. E., E-mail: firstname.lastname@example.com [Space Telescope Science Institute, Baltimore, MD (United States)
We propose two new means of identifying the main class of progenitors of Type Ia supernovae-single or double degenerate: (1) if the range of supernova properties is significantly determined by the range of viewing angles of non-spherically symmetric explosions, then the nature of the correlation between polarization and another property (for example, the velocity gradient) can be used to determine the geometry of the asymmetry and hence the nature of the progenitor, and (2) in the double- but not in the single-degenerate case, the range in the observed properties (e.g., velocity gradients) is likely to increase with the amount of carbon seen in the ejecta.
Congenital fibrosis of the extraocular muscles type 1, distinctive conjunctival changes and intrapapillary disc colobomata.
Flaherty, Maree P; Balachandran, Chandra; Jamieson, Robyn; Engle, Elizabeth C
A 6-month-old boy presented with a congenital eye movement disorder consistent with congenital fibrosis of the extraocular muscles type 1 (CFEOM1). Mutational analysis confirmed the most common mutation in the CFEOM1 gene KIF21A. In addition to the typical findings in CFEOM1, distinctive conjunctival changes and small bilateral optic disc colobomata were also noted. It is suggested that optic disc colobomata represent a new association of CFEOM1. PMID:19373680
Identifying patients at risk of type 2 diabetes.
Savill, Peter
At present there are nearly 3 million people with diabetes in the UK. It is predicted that this number will almost double by 2025. Nine out of ten of these individuals will have type 2 diabetes. It is estimated that one in seven adults have impaired glucose regulation and up to 12% of these will develop type 2 diabetes each year. The impact of obesity on the development of type 2 diabetes cannot be overemphasised, with a 1 kg/m2 increase in BMI raising the risk of impaired fasting glycaemia by 9.5% and of developing new-onset type 2 diabetes by 8.4%. A 1 cm increase in waist circumference increases the risks by 3.2% and 3.5% respectively. NICE advises using a validated risk assessment tool to identify patients at risk of diabetes. Risk factors used by such tools include: age; ethnicity; weight; first-degree relative with type 2 diabetes; low birthweight and sedentary lifestyle. Certain comorbidities increase the risk of type 2 diabetes, these include: cardiovascular and cerebrovascular disease; polycystic ovary syndrome; a history of gestational diabetes; and mental health problems. The initial screening blood test could be a fasting plasma glucose, HbA1c, or an oral glucose tolerance test, according to WHO criteria. NICE recommends that high-risk patients should be offered a programme encouraging them to undertake a minimum of 150 minutes of moderate intensity physical activity a week, gradually lose weight to reach and maintain a BMI within the healthy range, increase consumption of whole grains, vegetables, and other foods that are high in dietary fibre, reduce the total amount of fat in their diet and eat less saturated fat. PMID:22988703
Anti-MDA5 autoantibodies in juvenile dermatomyositis identify a distinct clinical phenotype: a prospective cohort study
Introduction The aim of this study was to define the frequency and associated clinical phenotype of anti-MDA5 autoantibodies in a large UK based, predominantly Caucasian, cohort of patients with juvenile dermatomyositis (JDM). Methods Serum samples and clinical data were obtained from 285 patients with JDM recruited to the UK Juvenile Dermatomyositis Cohort and Biomarker Study. The presence of anti-MDA5 antibodies was determined by immunoprecipitation and confirmed by ELISA using recombinant MDA5 protein. Results were compared with matched clinical data, muscle biopsies (scored by an experienced paediatric neuropathologist) and chest imaging (reviewed by an experienced paediatric radiologist). Results Anti-MDA5 antibodies were identified in 7.4% of JDM patients and were associated with a distinct clinical phenotype including skin ulceration (P?=?0.03) oral ulceration (P?=?0.01), arthritis (P <0.01) and milder muscle disease both clinically (as determined by Childhood Myositis Assessment Score (P?=?0.03)) and histologically (as determined by a lower JDM muscle biopsy score (P <0.01)) than patients who did not have anti-MDA5 antibodies. A greater proportion of children with anti-MDA5 autoantibodies achieved disease inactivity at two years post-diagnosis according to PRINTO criteria (P?=?0.02). A total of 4 out of 21 children with anti-MDA5 had interstitial lung disease; none had rapidly progressive interstitial lung disease. Conclusions Anti-MDA5 antibodies can be identified in a small but significant proportion of patients with JDM and identify a distinctive clinical sub-group. Screening for anti-MDA5 autoantibodies at diagnosis would be useful to guide further investigation for lung disease, inform on prognosis and potentially confirm the diagnosis, as subtle biopsy changes could otherwise be missed. PMID:24989778
Multilocus Sequence Typing of Streptococcus pyogenes Representing Most Known emm Types and Distinctions among Subpopulation Genetic Structures
Karen F. McGregor; Brian G. Spratt; Awdhesh Kalia; Alicia Bennett; Nicole Bilek; Bernard Beall; Debra E. Bessen
A long-term goal is to characterize the full range of genetic diversity within Streptococcus pyogenes as it exists in the world today. Since the emm locus is subject to strong diversifying selection, emm type was used as a guide for identifying a genetically diverse set of strains. This report contains a description of multilocus sequence typing based on seven housekeeping
Identifying Mycobacterium species and strain typing using a microfluidic labchip instrument.
Cooksey, Robert C; Limor, Josef; Morlock, Glenn P; Crawford, Jack T
We developed schemes for rapid identification of Mycobacterium species and strain typing using a microfluidic labchip instrument. A 439-bp region of the gene that codes for the 65-kDa heat shock protein (hsp65), which has sequence polymorphisms specific for most mycobacterial species, was examined using PCR-restriction analysis (PRA). We performed PRA in duplicate, using 2 strains each of 12 species, and observed that fragment sizes (bp) determined automatically by the instrument were consistently smaller than the correct sizes for each of the species as determined by sequence analysis (mean variance, < 7 bp). Mycobacterium tuberculosis isolates were typed with the labchip instrument using mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) typing, which determines the number of copies of repeated units at 12 loci in the genome based on product size after PCR amplification. Seven strains with one to six repeat copies at each locus were examined. Sizes were smaller by a mean of 13.47 bp compared with correct sizes predicted by sequence analysis, but could be used to correctly identify all strains types. Isolates of Mycobacterium chelonae and Mycobacterium abscessus were typed using randomly amplified polymorphic DNA (RAPD) electrophoresis, and patterns obtained using the labchip instrument were compared with multilocus enzyme electrophoresis (MEE) types. Patterns were distinct and reproducible for all strains except those with closely related MEE types. The labchip instrument is a versatile alternative for sizing mycobacterial DNA fragments. PMID:14579744
Improvement of the Owner Distinction Method for Healing-Type Pet Robots
NASA Astrophysics Data System (ADS)
Nambo, Hidetaka; Kimura, Haruhiko; Hara, Mirai; Abe, Koji; Tajima, Takuya
In order to decrease human stress, Animal Assisted Therapy which applies pets to heal humans is attracted. However, since animals are insanitary and unsafe, it is difficult to practically apply animal pets in hospitals. For the reason, on behalf of animal pets, pet robots have been attracted. Since pet robots would have no problems in sanitation and safety, they are able to be applied as a substitute for animal pets in the therapy. In our previous study where pet robots distinguish their owners like an animal pet, we used a puppet type pet robot which has pressure type touch sensors. However, the accuracy of our method was not sufficient to practical use. In this paper, we propose a method to improve the accuracy of the distinction. The proposed method can be applied for capacitive touch sensors such as installed in AIBO in addition to pressure type touch sensors. Besides, this paper shows performance of the proposed method from experimental results and confirms the proposed method has improved performance of the distinction in the conventional method.
Novel Human Embryonic Stem Cell Regulators Identified by Conserved and Distinct CpG Island Methylation State
Pells, Steve; Koutsouraki, Eirini; Morfopoulou, Sofia; Valencia-Cadavid, Sara; Tomlinson, Simon R.; Kalathur, Ravi; Futschik, Matthias E.; De Sousa, Paul A.
Human embryonic stem cells (hESCs) undergo epigenetic changes in vitro which may compromise function, so an epigenetic pluripotency ōsignatureö would be invaluable for line validation. We assessed Cytosine-phosphate-Guanine Island (CGI) methylation in hESCs by genomic DNA hybridisation to a CGI array, and saw substantial variation in CGI methylation between lines. Comparison of hESC CGI methylation profiles to corresponding somatic tissue data and hESC mRNA expression profiles identified a conserved hESC-specific methylation pattern associated with expressed genes. Transcriptional repressors and activators were over-represented amongst genes whose associated CGIs were methylated or unmethylated specifically in hESCs, respectively. Knockdown of candidate transcriptional regulators (HMGA1, GLIS2, PFDN5) induced differentiation in hESCs, whereas ectopic expression in fibroblasts modulated iPSC colony formation. Chromatin immunoprecipitation confirmed interaction between the candidates and the core pluripotency transcription factor network. We thus identify novel pluripotency genes on the basis of a conserved and distinct epigenetic configuration in human stem cells. PMID:26151932
Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.
Speliotes, Elizabeth K; Yerges-Armstrong, Laura M; Wu, Jun; Hernaez, Ruben; Kim, Lauren J; Palmer, Cameron D; Gudnason, Vilmundur; Eiriksdottir, Gudny; Garcia, Melissa E; Launer, Lenore J; Nalls, Michael A; Clark, Jeanne M; Mitchell, Braxton D; Shuldiner, Alan R; Butler, Johannah L; Tomas, Marta; Hoffmann, Udo; Hwang, Shih-Jen; Massaro, Joseph M; O'Donnell, Christopher J; Sahani, Dushyant V; Salomaa, Veikko; Schadt, Eric E; Schwartz, Stephen M; Siscovick, David S; Voight, Benjamin F; Carr, J Jeffrey; Feitosa, Mary F; Harris, Tamara B; Fox, Caroline S; Smith, Albert V; Kao, W H Linda; Hirschhorn, Joel N; Borecki, Ingrid B
Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (?26%-27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n?=?880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ?2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5ū10(-8)) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT-assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits. PMID:21423719
Genome-Wide Association Analysis Identifies Variants Associated with Nonalcoholic Fatty Liver Disease That Have Distinct Effects on Metabolic Traits
Palmer, Cameron D.; Gudnason, Vilmundur; Eiriksdottir, Gudny; Garcia, Melissa E.; Launer, Lenore J.; Nalls, Michael A.; Clark, Jeanne M.; Mitchell, Braxton D.; Shuldiner, Alan R.; Butler, Johannah L.; Tomas, Marta; Hoffmann, Udo; Hwang, Shih-Jen; Massaro, Joseph M.; O'Donnell, Christopher J.; Sahani, Dushyant V.; Salomaa, Veikko; Schadt, Eric E.; Schwartz, Stephen M.; Siscovick, David S.; Voight, Benjamin F.; Carr, J. Jeffrey; Feitosa, Mary F.; Harris, Tamara B.; Fox, Caroline S.
Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (?26%¢27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n?=?880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ?2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5ū10?8) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT¢assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits. PMID:21423719
Distinct Pseudomonas type-III effectors use a cleavable transit peptide to target chloroplasts.
Li, Guangyong; Froehlich, John E; Elowsky, Christian; Msanne, Joseph; Ostosh, Andrew C; Zhang, Chi; Awada, Tala; Alfano, James R
The pathogen Pseudomonas syringae requires a type-III protein secretion system and the effector proteins it injects into plant cells for pathogenesis. The primary role for P.Āsyringae type-III effectors is the suppression of plant immunity. The P.Āsyringae pv. tomato DC3000 HopK1 type-III effector was known to suppress the hypersensitive response (HR), a programmed cell death response associated with effector-triggered immunity. Here we show that DC3000 hopK1 mutants are reduced in their ability to grow in Arabidopsis, and produce reduced disease symptoms. Arabidopsis transgenically expressing HopK1 are reduced in PAMP-triggered immune responses compared with wild-type plants. An N-terminal region of HopK1 shares similarity with the corresponding region in the well-studied type-III effector AvrRps4; however, their C-terminal regions are dissimilar, indicating that they have different effector activities. HopK1 is processed inĀplanta at the same processing site found in AvrRps4. The processed forms of HopK1 and AvrRps4 are chloroplast localized, indicating that the shared N-terminal regions of these type-III effectors represent a chloroplast transit peptide. The HopK1 contribution to virulence and the ability of HopK1 and AvrRps4 to suppress immunity required their respective transit peptides, but the AvrRps4-induced HR did not. Our results suggest that a primary virulence target of these type-III effectors resides in chloroplasts, and that the recognition of AvrRps4 by the plant immune system occurs elsewhere. Moreover, our results reveal that distinct type-III effectors use a cleavable transit peptide to localize to chloroplasts, and that targets within this organelle are important for immunity. PMID:24299018
Identifying Aerosol Type/Mixture from Aerosol Absorption Properties Using AERONET
NASA Technical Reports Server (NTRS)
Giles, D. M.; Holben, B. N.; Eck, T. F.; Sinyuk, A.; Dickerson, R. R.; Thompson, A. M.; Slutsker, I.; Li, Z.; Tripathi, S. N.; Singh, R. P.; Zibordi, G.
Aerosols are generated in the atmosphere through anthropogenic and natural mechanisms. These sources have signatures in the aerosol optical and microphysical properties that can be used to identify the aerosol type/mixture. Spectral aerosol absorption information (absorption Angstrom exponent; AAE) used in conjunction with the particle size parameterization (extinction Angstrom exponent; EAE) can only identify the dominant absorbing aerosol type in the sample volume (e.g., black carbon vs. iron oxides in dust). This AAE/EAE relationship can be expanded to also identify non-absorbing aerosol types/mixtures by applying an absorption weighting. This new relationship provides improved aerosol type distinction when the magnitude of absorption is not equal (e.g, black carbon vs. sulfates). The Aerosol Robotic Network (AERONET) data provide spectral aerosol optical depth and single scattering albedo - key parameters used to determine EAE and AAE. The proposed aerosol type/mixture relationship is demonstrated using the long-term data archive acquired at AERONET sites within various source regions. The preliminary analysis has found that dust, sulfate, organic carbon, and black carbon aerosol types/mixtures can be determined from this AAE/EAE relationship when applying the absorption weighting for each available wavelength (Le., 440, 675, 870nm). Large, non-spherical dust particles absorb in the shorter wavelengths and the application of 440nm wavelength absorption weighting produced the best particle type definition. Sulfate particles scatter light efficiently and organic carbon particles are small near the source and aggregate over time to form larger less absorbing particles. Both sulfates and organic carbon showed generally better definition using the 870nm wavelength absorption weighting. Black carbon generation results from varying combustion rates from a number of sources including industrial processes and biomass burning. Cases with primarily black carbon showed improved definition in the 870nm wavelength absorption weighting due to the increased absorption in the near-infrared wavelengths, while the 440nm wavelength provided better definition when black carbon mixed with dust. Utilization of this particle type scheme provides necessary information for remote sensing applications, which needs a priori knowledge of aerosol type to model the retrieved properties especially over semi-bright surfaces. In fact, this analysis reveals that the aerosol types occurred in mixtures with varying magnitudes of absorption and requires the use of more than one assumed aerosol mixture model. Furthermore, this technique will provide the aerosol transport model community a data set for validating aerosol type.
A Targeted UAS-RNAi Screen in Drosophila Larvae Identifies Wound Closure Genes Regulating Distinct Cellular Processes
Lesch, Christine; Jo, Juyeon; Wu, Yujane; Fish, Greg S.; Galko, Michael J.
Robust mechanisms for tissue repair are critical for survival of multicellular organisms. Efficient cutaneous wound repair requires the migration of cells at the wound edge and farther back within the epidermal sheet, but the genes that control and coordinate these migrations remain obscure. This is in part because a systematic screening approach for in vivo identification and classification of postembryonic wound closure genes has yet to be developed. Here, we performed a proof-of-principle reporter-based in vivo RNAi screen in the Drosophila melanogaster larval epidermis to identify genes required for normal wound closure. Among the candidate genes tested were kinases and transcriptional mediators of the Jun N-terminal kinase (JNK) signaling pathway shown to be required for epithelial sheet migration during development. Also targeted were genes involved in actin cytoskeletal remodeling. Importantly, RNAi knockdown of both canonical and noncanonical members of the JNK pathway caused open wounds, as did several genes involved in actin cytoskeletal remodeling. Our analysis of JNK pathway components reveals redundancy among the upstream activating kinases and distinct roles for the downstream transcription factors DJun and DFos. Quantitative and qualitative morphological classification of the open wound phenotypes and evaluation of JNK activation suggest that multiple cellular processes are required in the migrating epidermal cells, including functions specific to cells at the wound edge and others specific to cells farther back within the epidermal sheet. Together, our results identify a new set of conserved wound closure genes, determine putative functional roles for these genes within the migrating epidermal sheet, and provide a template for a broader in vivo RNAi screen to discover the full complement of genes required for wound closure during larval epidermal wound healing. PMID:20813879
The Co-Expression Pattern of Odorant Binding Proteins and Olfactory Receptors Identify Distinct Trichoid Sensilla on the Antenna of the Malaria Mosquito Anopheles gambiae
Schultze, Anna; Pregitzer, Pablo; Walter, Marika F.; Woods, Daniel F.; Marinotti, Osvaldo; Breer, Heinz; Krieger, J³rgen
The initial steps of odorant recognition in the insect olfactory system involve odorant binding proteins (OBPs) and odorant receptors (ORs). While large families of OBPs have been identified in the malaria vector A. gambiae, little is known about their expression pattern in the numerous sensory hairs of the female antenna. We applied whole mount fluorescence in Situ hybridization (WM-FISH) and fluorescence immunohistochemistry (WM-FIHC) to investigate the sensilla co-expression of eight A. gambiae OBPs (AgOBPs), most notably AgOBP1 and AgOBP4, which all have abundant transcripts in female antenna. WM-FISH analysis of female antennae using AgOBP-specific probes revealed marked differences in the number of cells expressing each various AgOBPs. Testing combinations of AgOBP probes in two-color WM-FISH resulted in distinct cellular labeling patterns, indicating a combinatorial expression of AgOBPs and revealing distinct AgOBP requirements for various functional sensilla types. WM-FIHC with antisera to AgOBP1 and AgOBP4 confirmed expression of the respective proteins by support cells and demonstrated a location of OBPs within sensilla trichodea. Based on the finding that AgOBP1 and AgOBP4 as well as the receptor type AgOR2 are involved in the recognition of indole, experiments were performed to explore if the AgOBP-types and AgOR2 are co-expressed in distinct olfactory sensilla. Applying two-color WM-FISH with AgOBP-specific probes and probes specific for AgOR2 revealed a close association of support cells bearing transcripts for AgOBP1 and AgOBP4 and neurons with a transcript for the receptor AgOR2. Moreover, combined WM-FISH/-FIHC approaches using an AgOR2-specific riboprobe and AgOBP-specific antisera revealed the expression of the ōligand-matchedö AgOBP1, AgOBP4 and AgOR2 to single trichoid hairs. This result substantiates the notion that a specific response to indole is mediated by an interplay of the proteins. PMID:23861970
Duck Hepatitis A Virus Possesses a Distinct Type IV Internal Ribosome Entry Site Element of Picornavirus
Pan, Meng; Yang, Xiaorong; Zhou, Lei; Ge, Xinna; Guo, Xin; Liu, Jinhua
Sequence analysis of duck hepatitis virus type 1 (DHV-1) led to its classification as the only member of a new genus, Avihepatovirus, of the family Picornaviridae, and so was renamed duck hepatitis A virus (DHAV). The 5? untranslated region (5? UTR) plays an important role in translation initiation and RNA synthesis of the picornavirus. Here, we provide evidence that the 651-nucleotide (nt)-long 5? UTR of DHAV genome contains an internal ribosome entry site (IRES) element that functions efficiently in vitro and within BHK cells. Comparative sequence analysis showed that the 3? part of the DHAV 5? UTR is similar to the porcine teschovirus 1 (PTV-1) IRES in sequence and predicted secondary structure. Further mutational analyses of the predicted domain IIId, domain IIIe, and pseudoknot structure at the 3? end of the DHAV IRES support our predicted secondary structure. However, unlike the case for the PTV-1 IRES element, analysis of various deletion mutants demonstrated that the optimally functional DHAV IRES element with a size of approximately 420 nt is larger than that of PTV-1 and contains other peripheral domains (Id and Ie) that do not exist within the type IV IRES elements. The domain Ie, however, could be removed without significant loss of activity. Surprisingly, like the hepatitis A virus (HAV) IRES element, the activity of DHAV IRES could be eliminated by expression of enterovirus 2A protease. These findings indicate that the DHAV IRES shares common features with type IV picornavirus IRES elements, whereas it exhibits significant differences from type IV IRESs. Therefore, we propose that DHAV possesses a distinct type IV IRES element of picornavirus. PMID:22090106
Mucinous carcinoma of the breast is genomically distinct from invasive ductal carcinomas of no special type.
Lacroix-Triki, Magali; Suarez, Paula H; MacKay, Alan; Lambros, Maryou B; Natrajan, Rachael; Savage, Kay; Geyer, Felipe C; Weigelt, Britta; Ashworth, Alan; Reis-Filho, Jorge S
Mucinous carcinomas are a rare entity accounting for up to 2% of all breast cancers, which have been shown to display a gene expression profile distinct from that of invasive ductal carcinomas of no special type (IDC-NSTs). Here, we have defined the genomic aberrations that are characteristic of this special type of breast cancer and have investigated whether mucinous carcinomas might constitute a genomic entity distinct from IDC-NSTs. Thirty-five pure and 11 mixed mucinous breast carcinomas were assessed by immunohistochemistry using antibodies against oestrogen receptor (ER), progesterone receptor, HER2, Ki67, cyclin D1, cortactin, Bcl-2, p53, E-cadherin, basal markers, neuroendocrine markers, and WT1. Fifteen pure mucinous carcinomas and 30 grade- and ER-matched IDC-NSTs were microdissected and subjected to high-resolution microarray-based comparative genomic hybridization (aCGH). In addition, the distinct components of seven mixed mucinous carcinomas were microdissected separately and subjected to aCGH. Pure mucinous carcinomas consistently expressed ER (100%), lacked HER2 expression (97.1%), and showed a relatively low level of genetic instability. Unsupervised hierarchical cluster analysis revealed that pure mucinous carcinomas were homogeneous and preferentially clustered together, separately from IDC-NSTs. They less frequently harboured gains of 1q and 16p and losses of 16q and 22q than grade- and ER-matched IDC-NSTs, and no pure mucinous carcinoma displayed concurrent 1q gain and 16q loss, a hallmark genetic feature of low-grade IDC-NSTs. Finally, both components of all but one mixed mucinous carcinoma displayed similar patterns of genetic aberrations and preferentially clustered together with pure mucinous carcinomas on unsupervised clustering analysis. Our results demonstrate that mucinous carcinomas are more homogeneous between themselves at the genetic level than IDC-NSTs. Both components of mixed mucinous tumours are remarkably similar at the molecular level to pure mucinous cancers, suggesting that mixed mucinous carcinomas may be best classified as variants of mucinous cancers rather than of IDC-NSTs. PMID:20815046
Galanin-immunoreactivity identifies a distinct population of inhibitory interneurons in laminae I-III of the rat spinal cord
Background Inhibitory interneurons constitute 30-40% of neurons in laminae I-III and have an important anti-nociceptive role. However, because of the difficulty in classifying them we know little about their organisation. Previous studies have identified 3 non-overlapping groups of inhibitory interneuron, which contain neuropeptide Y (NPY), neuronal nitric oxide synthase (nNOS) or parvalbumin, and have shown that these differ in postsynaptic targets. Some inhibitory interneurons contain galanin and the first aim of this study was to determine whether these form a different population from those containing NPY, nNOS or parvalbumin. We also estimated the proportion of neurons and GABAergic axons that contain galanin in laminae I-III. Results Galanin cells were concentrated in laminae I-IIo, with few in laminae IIi-III. Galanin showed minimal co-localisation with NPY, nNOS or parvalbumin in laminae I-II, but most galanin-containing cells in lamina III were nNOS-positive. Galanin cells constituted ~7%, 3% and 2% of all neurons in laminae I, II and III, and we estimate that this corresponds to 26%, 10% and 5% of the GABAergic neurons in these laminae. However, galanin was only found in ~6% of GABAergic boutons in laminae I-IIo, and ~1% of those in laminae IIi-III. Conclusions These results show that galanin, NPY, nNOS and parvalbumin can be used to define four distinct neurochemical populations of inhibitory interneurons. Together with results of a recent study, they suggest that the galanin and NPY populations account for around half of the inhibitory interneurons in lamina I and a quarter of those in lamina II. PMID:21569622
Comparison of odor-active compounds from six distinctly different rice flavor types.
Yang, Dong Sik; Shewfelt, Robert L; Lee, Kyu-Seong; Kays, Stanley J
Using a dynamic headspace system with Tenax trap, GC-MS, GC-olfactometry (GC-O), and multivariate analysis, the aroma chemistry of six distinctly different rice flavor types (basmati, jasmine, two Korean japonica cultivars, black rice, and a nonaromatic rice) was analyzed. A total of 36 odorants from cooked samples were characterized by trained assessors. Twenty-five odorants had an intermediate or greater intensity (odor intensity >or= 3) and were considered to be major odor-active compounds. Their odor thresholds in air were determined using GC-O. 2-Acetyl-1-pyrroline (2-AP) had the lowest odor threshold (0.02 ng/L) followed by 11 aldehydes (ranging from 0.09 to 3.1 ng/L), guaiacol (1.5 ng/L), and 1-octen-3-ol (2.7 ng/L). On the basis of odor thresholds and odor activity values (OAVs), the importance of each major odor-active compound was assessed. OAVs for 2-AP, hexanal, ( E)-2-nonenal, octanal, heptanal, and nonanal comprised >97% of the relative proportion of OAVs from each rice flavor type, even though the relative proportion varied among samples. Thirteen odor-active compounds [2-AP, hexanal, ( E)-2-nonenal, octanal, heptanal, nonanal, 1-octen-3-ol, ( E)-2-octenal, ( E, E)-2,4-nonadienal, 2-heptanone, ( E, E)-2,4-decadienal, decanal, and guaiacol] among the six flavor types were the primary compounds explaining the differences in aroma. Multivariate analysis demonstrated that the individual rice flavor types could be separated and characterized using these compounds, which may be of potential use in rice-breeding programs focusing on flavor. PMID:18363355
Distinct mutations led to inactivation of type 1 fimbriae expression in Shigella spp.
Bravo, Ver¾nica; Puhar, Andrea; Sansonetti, Philippe; Parsot, Claude; Toro, Cecilia S
Shigella spp. are responsible for bacillary dysentery in humans. The acquisition or the modification of the virulence plasmid encoding factors promoting entry of bacteria into and dissemination within epithelial cells was a critical step in the evolution of these bacteria from their Escherichia coli ancestor(s). Incorporation of genomic islands (GI) and gene inactivation also shaped interactions between these pathogens and their human host. Sequence analysis of the GI inserted next to the leuX tRNA gene in S. boydii, S. dysenteriae, S. flexneri, S. sonnei and enteroinvasive E. coli (EIEC) suggests that this region initially carried the fec, yjhATS and fim gene clusters. The fim cluster encoding type I fimbriae is systematically inactivated in both reference strains and clinical isolates and distinct mutations are responsible for this inactivation in at least three phylogenetic groups. To investigate consequences of the presence of fimbriae on the outcome of the interaction of Shigella with host cells, we used a S. flexneri strain harboring a plasmid encoding the E. coli fim operon. Production of fimbriae by this recombinant strain increased the ability of bacteria to adhere to and enter into epithelial cells and had no effect on their ability to disseminate from cell to cell. The observations that production of type I fimbriae increases invasion of epithelial cells and that independent mutations abolish fimbriae production in Shigella suggest that these mutations correspond to pathoadaptive events. PMID:25811616
Identifying Cell Types from Spatially Referenced Single-Cell Expression Datasets
Achim, Kaia; Richardson, Sylvia; Azizi, Lamiae; Marioni, John
Complex tissues, such as the brain, are composed of multiple different cell types, each of which have distinct and important roles, for example in neural function. Moreover, it has recently been appreciated that the cells that make up these sub-cell types themselves harbour significant cell-to-cell heterogeneity, in particular at the level of gene expression. The ability to study this heterogeneity has been revolutionised by advances in experimental technology, such as Wholemount in Situ Hybridizations (WiSH) and single-cell RNA-sequencing. Consequently, it is now possible to study gene expression levels in thousands of cells from the same tissue type. After generating such data one of the key goals is to cluster the cells into groups that correspond to both known and putatively novel cell types. Whilst many clustering algorithms exist, they are typically unable to incorporate information about the spatial dependence between cells within the tissue under study. When such information exists it provides important insights that should be directly included in the clustering scheme. To this end we have developed a clustering method that uses a Hidden Markov Random Field (HMRF) model to exploit both quantitative measures of expression and spatial information. To accurately reflect the underlying biology, we extend current HMRF approaches by allowing the degree of spatial coherency to differ between clusters. We demonstrate the utility of our method using simulated data before applying it to cluster single cell gene expression data generated by applying WiSH to study expression patterns in the brain of the marine annelid Platynereis dumereilii. Our approach allows known cell types to be identified as well as revealing new, previously unexplored cell types within the brain of this important model system. PMID:25254363
J. Non-Newtonian Fluid Mech. 96 (2001) 405425 On two distinct types of drag-reducing fluids, diameter
Aguilar, Guillermo
J. Non-Newtonian Fluid Mech. 96 (2001) 405Ł425 On two distinct types of drag-reducing fluids;406 K. Gasljevic et al. / J. Non-Newtonian Fluid Mech. 96 (2001) 405Ł425 Nomenclature CF = 2w/V 2 to predict the diameter effect for different types of drag-reducing fluids. The first one, which correlates
Meta-analysis of several gene lists for distinct types of cancer: A simple way to reveal common prognostic markers
Yang, Xinan; Sun, Xiao
Background Although prognostic biomarkers specific for particular cancers have been discovered, microarray analysis of gene expression profiles, supported by integrative analysis algorithms, helps to identify common factors in molecular oncology. Similarities of Ordered Gene Lists (SOGL) is a recently proposed approach to meta-analysis suitable for identifying features shared by two data sets. Here we extend the idea of SOGL to the detection of significant prognostic marker genes from microarrays of multiple data sets. Three data sets for leukemia and the other six for different solid tumors are used to demonstrate our method, using established statistical techniques. Results We describe a set of significantly similar ordered gene lists, representing outcome comparisons for distinct types of cancer. This kind of similarity could improve the diagnostic accuracies of individual studies when SOGL is incorporated into the support vector machine algorithm. In particular, we investigate the similarities among three ordered gene lists pertaining to mesothelioma survival, prostate recurrence and glioma survival. The similarity-driving genes are related to the outcomes of patients with lung cancer with a hazard ratio of 4.47 (p = 0.035). Many of these genes are involved in breakdown of EMC proteins regulating angiogenesis, and may be used for further research on prognostic markers and molecular targets of gene therapy for cancers. Conclusion The proposed method and its application show the potential of such meta-analyses in clinical studies of gene expression profiles. PMID:17411443
FAMA is an essential component for the differentiation of two distinct cell types, myrosin cells and guard cells, in Arabidopsis.
Shirakawa, Makoto; Ueda, Haruko; Nagano, Atsushi J; Shimada, Tomoo; Kohchi, Takayuki; Hara-Nishimura, Ikuko
Brassicales plants, including Arabidopsis thaliana, have an ingenious two-compartment defense system, which sequesters myrosinase from the substrate glucosinolate and produces a toxic compound when cells are damaged by herbivores. Myrosinase is stored in vacuoles of idioblast myrosin cells. The molecular mechanism that regulates myrosin cell development remains elusive. Here, we identify the basic helix-loop-helix transcription factor FAMA as an essential component for myrosin cell development along Arabidopsis leaf veins. FAMA is known as a regulator of stomatal development. We detected FAMA expression in myrosin cell precursors in leaf primordia in addition to stomatal lineage cells. FAMA deficiency caused defects in myrosin cell development and in the biosynthesis of myrosinases THIOGLUCOSIDE GLUCOHYDROLASE1 (TGG1) and TGG2. Conversely, ectopic FAMA expression conferred myrosin cell characteristics to hypocotyl and root cells, both of which normally lack myrosin cells. The FAMA interactors ICE1/SCREAM and its closest paralog SCREAM2/ICE2 were essential for myrosin cell development. DNA microarray analysis identified 32 candidate genes involved in myrosin cell development under the control of FAMA. This study provides a common regulatory pathway that determines two distinct cell types in leaves: epidermal guard cells and inner-tissue myrosin cells. PMID:25304202
Modeling autosomal recessive cutis laxa type 1C in mice reveals distinct functions for Ltbp-4 isoforms.
Bultmann-Mellin, Insa; Conradi, Anne; Maul, Alexandra C; Dinger, Katharina; Wempe, Frank; Wohl, Alexander P; Imhof, Thomas; Wunderlich, F Thomas; Bunck, Alexander C; Nakamura, Tomoyuki; Koli, Katri; Bloch, Wilhelm; Ghanem, Alexander; Heinz, Andrea; von Melchner, Harald; Sengle, Gerhard; Sterner-Kock, Anja
Recent studies have revealed an important role for LTBP-4 in elastogenesis. Its mutational inactivation in humans causes autosomal recessive cutis laxa type 1C (ARCL1C), which is a severe disorder caused by defects of the elastic fiber network. Although the human gene involved in ARCL1C has been discovered based on similar elastic fiber abnormalities exhibited by mice lacking the short Ltbp-4 isoform (Ltbp4S(-/-)), the murine phenotype does not replicate ARCL1C. We therefore inactivated both Ltbp-4 isoforms in the mouse germline to model ARCL1C. Comparative analysis of Ltbp4S(-/-) and Ltbp4-null (Ltbp4(-/-)) mice identified Ltbp-4L as an important factor for elastogenesis and postnatal survival, and showed that it has distinct tissue expression patterns and specific molecular functions. We identified fibulin-4 as a previously unknown interaction partner of both Ltbp-4 isoforms and demonstrated that at least Ltbp-4L expression is essential for incorporation of fibulin-4 into the extracellular matrix (ECM). Overall, our results contribute to the current understanding of elastogenesis and provide an animal model of ARCL1C. PMID:25713297
Four distinct types of dehydration stress memory genes in Arabidopsis thaliana
Background How plants respond to dehydration stress has been extensively researched. However, how plants respond to multiple consecutive stresses is virtually unknown. Pre-exposure to various abiotic stresses (including dehydration) may alter plantsÆ subsequent responses by improving resistance to future exposures. These observations have led to the concept of æstress memoryÆ implying that during subsequent exposures plants provide responses that are different from those during their first encounter with the stress. Genes that provide altered responses in a subsequent stress define the æmemory genesÆ category; genes responding similarly to each stress form the ænon-memoryÆ category. Results Using a genome-wide RNA-Seq approach we determine the transcriptional responses of Arabidopsis plants that have experienced multiple exposures to dehydration stress and compare them with the transcriptional behavior of plants encountering the stress for the first time. The major contribution of this study is the revealed existence of four distinct, previously unknown, transcription memory response patterns of dehydration stress genes in A.thaliana. The biological relevance for each of the four memory types is considered in the context of four overlapping strategies employed by a plant to improve its stress tolerance and/or survival: 1) increased synthesis of protective, damage-repairing, and detoxifying functions; 2) coordinating photosynthesis and growth under repetitive stress; 3) re-adjusting osmotic and ionic equilibrium to maintain homeostasis; and 4) re-adjusting interactions between dehydration and other stress/hormone regulated pathways. Conclusions The results reveal the unknown, hitherto, existence of four distinct transcription memory response types in a plant and provide genome-wide characterization of memory and non-memory dehydration stress response genes in A.thaliana. The transcriptional responses during repeated exposures to stress are different from known responses occurring during a single exposure. GO analyses of encoded proteins suggested implications for the cellular/organismal protective, adaptive, and survival functions encoded by the memory genes. The results add a new dimension to our understanding of plantsÆ responses to dehydration stress and to current models for interactions between different signaling systems when adjusting to repeated spells of water deficits. PMID:24377444
Method for identifying type I diabetes mellitus in humans
Metz, Thomas O [Kennewick, WA; Qian, Weijun [Richland, WA; Jacobs, Jon M [Pasco, WA
A method and system for classifying subject populations utilizing predictive and diagnostic biomarkers for type I diabetes mellitus. The method including determining the levels of a variety of markers within the serum or plasma of a target organism and correlating this level to general populations as a screen for predisposition or progressive monitoring of disease presence or predisposition.
Identifying chaotic systems via a Wiener-type cascade model
Guanrong Chen; Ying Chen; Haluk Ogmen
In this article we first show a theory that the Wiener-type cascade dynamical model, in which a simple linear plant is used as the dynamic subsystem and a three-layer feedforward artificial neural network is employed as the nonlinear static subsystem, can uniformly approximate a continuous trajectory of a general nonlinear dynamical system with arbitrarily high precision on a compact time
Digital morphometry of rat cerebellar climbing fibers reveals distinct branch and bouton types
Brown, Kerry M.; Sugihara, Izumi; Shinoda, Yoshikazu; Ascoli, Giorgio A.
Cerebellar climbing fibers provide powerful excitatory input to Purkinje cells, which represent the sole output of the cerebellar cortex. Recent discoveries suggest that climbing fibers have information-rich signaling properties important for cerebellar function, beyond eliciting the well-known all-or-none Purkinje cell complex spike. Climbing fiber morphology has not been quantitatively analyzed at the same level of detail as their biophysical properties. Because morphology can greatly influence function, including the capacity for information processing, it is important to understand climbing fiber branching structure in detail, as well as its variability across and within arbors. We have digitally reconstructed 68 rat climbing fibers labeled using biotinylated dextran amine (BDA) injected into the inferior olive and comprehensively quantified their morphology. Climbing fiber structure was considerably diverse even within the same anatomical regions. Distinctly identifiable primary, tendril, and distal branches could be operationally differentiated by the relative size of the subtrees at their initial bifurcations. Additionally, primary branches were more directed toward the cortical surface and had fewer and less pronounced synaptic boutons, suggesting they prioritize efficient and reliable signal propagation. Tendril and distal branches were spatially segregated and bouton dense, indicating specialization in signal transmission. Furthermore, climbing fibers systematically targeted molecular layer interneuron cell bodies, especially at terminal boutons, potentially instantiating feed-forward inhibition on Purkinje cells. This study offers the most detailed and comprehensive characterization of climbing fiber morphology to date. The reconstruction files and metadata are publicly distributed at NeuroMorpho.Org. PMID:23077053
A comparative genetic study of serologically distinct Haemophilus influenzae type 1 immunoglobulin A1 proteases.
Poulsen, K; Reinholdt, J; Kilian, M
The bacterial immunoglobulin A1 (IgA1) proteases are putative virulence factors secreted by a number of human pathogens capable of penetrating the mucosal barrier. Among Haemophilus influenzae strains, the IgA1 protease is found in several allelic forms with different serological neutralizing properties. A comparison of the primary structures of four serologically distinct H. influenzae IgA1 proteases suggests that this variation is caused by epitopes of the discontinuous conformational type. Analysis of the homologies among the four iga genes indicates that the variation results from transformation and subsequent homologous recombination in the iga gene region among H. influenzae strains. We find evidence for gene rearrangements, including transpositions in the iga gene region encoding the secretory part of the IgA1 preprotease. The amino acid sequence of the C terminus of the preprotease (the beta-core), which is assumed to be involved in secretion of the protease by forming a pore in the outer membrane, is highly conserved. In contrast to conserved areas in the protease domain, the nucleotide sequence encoding the beta-core showed a striking paucity of synonymous site variation. Images PMID:1373717
Distinct structural elements dictate the specificity of the type III pentaketide synthase from Neurospora crassa.
Rubin-Pitel, Sheryl B; Zhang, Houjin; Vu, Trang; Brunzelle, Joseph S; Zhao, Huimin; Nair, Satish K
The fungal type III polyketide synthase 2'-oxoalkylresorcylic acid synthase (ORAS) primes with a range of acyl-Coenzyme A thioesters (C4-C20) and extends using malonyl-Coenzyme A to produce pyrones, resorcinols, and resorcylic acids. To gain insight into this unusual substrate specificity and product profile, we have determined the crystal structures of ORAS to 1.75 A resolution, the Phe-252-->Gly site-directed mutant to 2.1 A resolution, and a binary complex of ORAS with eicosanoic acid to 2.0 A resolution. The structures reveal a distinct rearrangement of structural elements near the active site that allows accommodation of long-chain fatty acid esters and a reorientation of the gating mechanism that controls cyclization and polyketide chain length. The roles of these structural elements are further elucidated by characterization of various structure-based site-directed variants. These studies establish an unexpected plasticity to the PKS fold, unanticipated from structural studies of other members of this enzyme family. PMID:18940668
Invasive micropapillary carcinoma: a distinct type of adenocarcinomas in the gastrointestinal tract.
Guzi?ska-Ustymowicz, Katarzyna; Niewiarowska, Katarzyna; Pryczynicz, Anna
Invasive micropapillary carcinoma (IMPC) is a rare histological type of tumor, first described in invasive ductal breast cancer, than in malignancies in other organs such as lungs, urinary bladder, ovaries or salivary glands. Recent literature data shows that this histological lesion has also been found in cancers of the gastrointestinal system. The micropapillary components are clusters of neoplastic cells that closely adhere to each other and are located in distinct empty spaces. Moreover, clusters of neoplastic cells do not have a fibrous-vascular core. The IMPC cells show reverse polarity resulting in typical ''inside-out'' structures that determines secretary properties, disturbs adhesion and conditions grade of malignancy in gastrointestinal (GI) tract. Invasive micropapillary carcinoma in this location is associated with metastases to local lymph nodes and lymphovascular invasion. IMPC can be a prognostic factor for patients with cancers of the stomach, pancreas and with colorectal cancer since it is related with disease-free and overall survival. The purpose of this review is to present the characterization of invasive micropapillary carcinoma in colon, rectum, stomach and others site of GI tract, and to determine the immunohistological indentification of IMPC in those localization. PMID:24782612
Variability in soil CO2 efflux across distinct urban land cover types
NASA Astrophysics Data System (ADS)
Weissert, Lena F.; Salmond, Jennifer A.; Schwendenmann, Luitgard
As a main source of greenhouse gases urban areas play an important role in the global carbon cycle. To assess the potential role of urban vegetation in mitigating carbon emissions we need information on the magnitude of biogenic CO2 emissions and its driving factors. We examined how urban land use types (urban forest, parklands, sportsfields) vary in their soil CO2 efflux. We measured soil CO2 efflux and its isotopic signature, soil temperature and soil moisture over a complete growing season in Auckland, New Zealand. Soil physical and chemical properties and vegetation characteristics were also measured. Mean soil CO2 efflux ranged from 4.15 to 12 ?mol m-2 s-1. We did not find significant differences in soil CO2 efflux among land cover types due to high spatial variability in soil CO2 efflux among plots. Soil (soil carbon and nitrogen density, texture, soil carbon:nitrogen ratio) and vegetation characteristics (basal area, litter carbon density, grass biomass) were not significantly correlated with soil CO2 efflux. We found a distinct seasonal pattern with significantly higher soil CO2 efflux in autumn (Apr/May) and spring (Oct). In urban forests and sportsfields over 80% of the temporal variation was explained by soil temperature and soil water content. The ?13C signature of CO2 respired from parklands and sportsfields (-20 permil - -25 permil) were more positive compared to forest plots (-29 permil) indicating that parkland and sportsfields had a considerable proportion of C4 grasses. Despite the large intra-urban variability, our results compare to values reported from other, often climatically different cities, supporting the hypothesis of homogenization across urban areas as a result of human management practices.
Comparative Analysis of Type III Secreted Effector Genes Reflects Divergence of Acidovorax citrulli Strains into Three Distinct Lineages.
Eckshtain-Levi, Noam; Munitz, Tamar; Zivanovi?, Marija; Traore, Sy M; Spr÷er, Cathrin; Zhao, Bingyu; Welbaum, Gregory; Walcott, Ron; Sikorski, Johannes; Burdman, Saul
ABSTRACT Acidovorax citrulli causes bacterial fruit blotch of cucurbits, a serious economic threat to watermelon (Citrullus lanatus) and melon (Cucumis melo) production worldwide. Based on genetic and biochemical traits, A. citrulli strains have been divided into two distinct groups: group I strains have been mainly isolated from various non-watermelon hosts, while group II strains have been generally isolated from and are highly virulent on watermelon. The pathogen depends on a functional type III secretion system for pathogenicity. Annotation of the genome of the group II strain AAC00-1 revealed 11 genes encoding putative type III secreted (T3S) effectors. Due to the crucial role of type III secretion for A. citrulli pathogenicity, we hypothesized that group I and II strains differ in their T3S effector repertoire. Comparative analysis of the 11 effector genes from a collection of 22 A. citrulli strains confirmed this hypothesis. Moreover, this analysis led to the identification of a third A. citrulli group, which was supported by DNA:DNA hybridization, DNA fingerprinting, multilocus sequence analysis of conserved genes, and virulence assays. The effector genes assessed in this study are homologous to effectors from other plant-pathogenic bacteria, mainly belonging to Xanthomonas spp. and Ralstonia solanacearum. Analyses of the effective number of codons and gas chromatography content of effector genes relative to a representative set of housekeeping genes support the idea that these effector genes were acquired by lateral gene transfer. Further investigation is required to identify new T3S effectors of A. citrulli and to determine their contribution to virulence and host preferential association. PMID:24848275
Distinct behavioural and network correlates of two interneuron types in prefrontal cortex
Kvitsiani, D.; Ranade, S.; Hangya, B.; Taniguchi, H.; Huang, JZ.; Kepecs, A.
Neurons in prefrontal cortex exhibit diverse behavioural correlates1¢4, an observation that has been attributed to cell-type diversity. To link identified neuron types with network and behavioural functions, we recorded from the two largest genetically-defined inhibitory interneuron classes, the perisomatically-targeting parvalbumin (Pv) and the dendritically-targeting somatostatin (Som) neurons5¢8 in anterior cingulate cortex (ACC) of mice performing a reward foraging task. Here we show that Pv and a subtype of Som neurons form functionally homogeneous populations showing a double dissociation between both their inhibitory impact and behavioural correlates. Out of a number of events pertaining to behaviour, a subtype of Som neurons selectively responded at reward approach, while Pv neurons responded at reward leaving encoding preceding stay duration. These behavioural correlates of Pv and Som neurons defined a behavioural epoch and a decision variable important for foraging (whether to stay or to leave), a crucial function attributed to ACC9¢11. Furthermore, Pv neurons could fire in millisecond synchrony exerting fast and powerful inhibition on principal cell firing, while the inhibitory impact of Som neurons on firing output was weak and more variable, consistent with the idea that they respectively control the outputs of and inputs to principal neurons12¢16. These results suggest a connection between the circuit-level function of different interneuron-types in regulating the flow of information, and the behavioural functions served by the cortical circuits. Moreover these observations bolster the hope that functional response diversity during behaviour can in part be explained by cell-type diversity. PMID:23708967
Sources and Types of Confidence Identified by World Class Sport Performers
Kate Hays; Ian Maynard; Owen Thomas; Mark Bawden
This study identified the sources and types of confidence salient to 14 (7 male, 7 female) successful World Class athletes. Nine sources of confidence were identified: Preparation, performance accomplishments, coaching, innate factors, social support, experience, competitive advantage, self-awareness, and trust. A testament to the multi-dimensional nature of sport confidence, six types of sport confidence were also identified: skill execution, achievement,
Distinct genetic interactions between multiple Vegf receptors are required for development of different blood vessel types in zebrafish
Covassin, L. D.; Villefranc, J. A.; Kacergis, M. C.; Weinstein, B. M.; Lawson, N. D.
Recent evidence indicates a specific role for vascular endothelial growth factor a (Vegfa) during artery development in both zebrafish and mouse embryos, whereas less is known about signals that govern vein formation. In zebrafish, loss of vegfa blocks segmental artery formation and reduces artery-specific gene expression, whereas veins are largely unaffected. Here, we describe a mutation in the zebrafish vegf receptor-2 homolog, kdra, which eliminates its kinase activity and leads to specific defects in artery development. We further find that Flt4, a receptor for Vegfc, cooperates with Kdr during artery morphogenesis, but not differentiation. We also identify an additional zebrafish vegfr-2 ortholog, referred to as kdrb, which can partially compensate for loss of kdra but is dispensable for vascular development in wild-type embryos. Interestingly, we find that these Vegf receptors are also required for formation of veins but in distinct genetic interactions that differ from those required for artery development. Taken together, our results indicate that formation of arteries and veins in the embryo is governed in part by different Vegf receptor combinations and suggest a genetic mechanism for generating blood vessel diversity during vertebrate development. PMID:16617120
Tectonically Undulating Terrestrial Geospheres and Concordant Development of Two Distinct Somatic Types of Man
NASA Astrophysics Data System (ADS)
Kochemasov, G. G.
The human organisms in microgravity conditions loss Ca or become less dense. But variously dense men also develop on Earth due to varying tectonics. As any celestial body, Earth is not a billiard-ball but is complexly warped by a number of standing waves imprinted in the geoid shape. The fundamental wave (long 2? R, R- planet radius) makes tectonic dichotomy (an opposition of the eastern and western oceanic hemispheres), the first overtone (? R) makes sectoring: on the continental eastern hemisphere, for example, around the Pamirs-Hindukush converge 4 sectors. They are 2 opposed differently uplifted (African ++, Asian +) separated by 2 opposed differently subsided (Eurasian -, Indoceanic - -). In rotating Earth the alternating uplifts (++, +) and subsidences (- -, -) require materials of different densities: less dense for uplifts and denser for subsidences. This requirement concerns all geospheres including anthroposphere. The long development of Homo sapiens adapting to graviconditions of uplifting and subsiding blocks produced two distinct somatic types of man: long and narrow (slim) leptosomes and short and broad eirisomes. As shows F. Weidenreich [1], this fundamental division appeared very early in the human history and is observed in all great human races and even in apes. A block uplifting (an increase of the planetary radius) requires diminishing density. This is achieved by distributing the man's weight by the longer stature. Thus appears long and slim leptosome. On the contrary, a block subsidence (diminishing radius) requires increasing density: man is shorter and broader (eirisome). A long existence on intensively moving (up or down) blocks makes these somatic types characteristic of races. Thus, many African tribes developing on intensively moving up continent (more than one kilometer in a few mln. y. ) are leptosomatic; on the contrary, Indians of subsiding western hemisphere are typically eirisomatic with high Rohrer's index; Polynesians of Pacific are high but corpulent, the Rohrer' index is also high. Short in time cosmic experiments (abrupt uplifting) with a sharp drop in gravity produce noticeable effect of Ca leaching out of organism making it less dense. Sure, changing gravity influences not only bones but also flesh, blood, hairs and eventually genes. The frequencies of genetic markers of Rh-system in blood of inhabitants of 4 variously leveled sectors and subsided western hemisphere are clearly different. References: [1] F. Weidenreich. Rasse und K÷rperbau (in Russian translation, State Publishing House, Moscow-Leningrad, 1929, 271 pp.).
Steady state or non-steady state? Identifying driving mechanisms of oxygen isotope signatures of leaf transpiration in functionally distinct plant species
NASA Astrophysics Data System (ADS)
Dubbert, Maren; K³bert, Angelika; Cuntz, Matthias; Werner, Christiane
Isotope techniques are widely applied in ecosystem studies. For example, isoflux models are used to separate soil evaporation from transpiration in ecosystems. These models often assume that plant transpiration occurs at isotopic steady state, i.e. that the transpired water shows the same isotopic signature as the source water. Yet, several studies found that transpiration did not occur at isotopic steady state, under both controlled and field conditions. Here we focused on identifying the internal and external factors which drive the isotopic signature of leaf transpiration. Using cavity ring-down spectroscopy (CRDS), the effect of both environmental variables and leaf physiological traits on ?18OT was investigated under controlled conditions. Six plant species with distinct leaf physiological traits were exposed to step changes in relative air humidity (RH), their response in ?18OT and gas exchange parameters and their leaf physiological traits were assessed. Moreover, two functionally distinct plant types (tree, i.e. Quercus suber, and grassland) of a semi-arid Mediterranean oak-woodland where observed under natural conditions throughout an entire growth period in the field. The species differed substantially in their leaf physiological traits and their turn-over times of leaf water. They could be grouped in species with fast (<60 min.), intermediate (ca. 120 min.) and slow (>240 min.) turn-over times, mostly due to differences in stomatal conductance, leaf water content or a combination of both. Changes in RH caused an immediate response in ?18OT, which were similarly strong in all species, while leaf physiological traits affected the subsequent response in ?18OT. The turn-over time of leaf water determined the speed of return to the isotopic steady or a stable ?18OT value (Dubbert & K³bert et al., in prep.). Under natural conditions, changes in environmental conditions over the diurnal cycle had a huge impact on the diurnal development of ?18OT in both observed plant functional types. However, in accordance with our findings in the lab, species specific differences in the leaf water turn over time, significantly influenced the amount of time plants transpired at non-steady state during the day (Dubbert et al., 2013, 2014). Our results emphasize the significance of considering isotopic non-steady state of transpiration and specifically to account for the specific differences of plant species resulting from distinct physiological traits of their leaves when applying isoflux models in ecosystem studies. Dubbert, M; Cuntz, M; Piayda, A; Maguas, C; Werner, C: Partitioning evapotranspiration - Testing the Craig and Gordon model with field measurements of oxygen isotope ratios of evaporative fluxes. J Hydrol (2013) Dubbert, M; Piayda, A; Cuntz, M; Correia, AC; Costa e Silva, F; Pereira, JS; Werner, C: Stable oxygen isotope and flux partitioning demonstrates understory of an oak savanna contributes up to half of ecosystem carbon and water exchange, Frontiers in Plant Science (2014a)
Wisconsin Card Sorting Revisited: Distinct Neural Circuits Participating in Different Stages of the Task Identified by Event Related Functional Magnetic Resonance Imaging
Oury Monchi; Michael Petrides; Valentina Petre; Keith Worsley; Alain Dagher
The Wisconsin Card Sorting Task (WCST) has been used to assess dysfunction of the prefrontal cortex and basal ganglia. Previous brain imaging studies have focused on identifying activity related to the set-shifting requirement of the WCST. The present study used event-related functional magnetic reso- nance imaging (fMRI) to study the pattern of activation during four distinct stages in the performance
Essential role of EBF1 in the generation and function of distinct mature B cell types
Vilagos, Bojan; Hoffmann, Mareike; Souabni, Abdallah; Sun, Qiong; Werner, Barbara; Medvedovic, Jasna; Bilic, Ivan; Minnich, Martina; Axelsson, Elin; Jaritz, Markus
The transcription factor EBF1 is essential for lineage specification in early B cell development. In this study, we demonstrate by conditional mutagenesis that EBF1 is required for B cell commitment, pro¢B cell development, and subsequent transition to the pre¢B cell stage. Later in B cell development, EBF1 was essential for the generation and maintenance of several mature B cell types. Marginal zone and B-1 B cells were lost, whereas follicular (FO) and germinal center (GC) B cells were reduced in the absence of EBF1. Activation of the B cell receptor resulted in impaired intracellular signaling, proliferation and survival of EBF1-deficient FO B cells. Immune responses were severely reduced upon Ebf1 inactivation, as GCs were formed but not maintained. ChIP- and RNA-sequencing of FO B cells identified EBF1-activated genes that encode receptors, signal transducers, and transcriptional regulators implicated in B cell signaling. Notably, ectopic expression of EBF1 efficiently induced the development of B-1 cells at the expense of conventional B cells. These gain- and loss-of-function analyses uncovered novel important functions of EBF1 in controlling B cell immunity. PMID:22473956
A Distinctive Microsatellite Locus That Differentiates Ocean-Type from Stream-Type Chinook Salmon in the Interior Columbia River Basin
Shawn R. Narum; Madison S. Powell; Andrķ J. Talbot
Chinook salmon Oncorhynchus tshawytscha display two life history strategies that are referred to as ocean type and stream type. Ocean-type Chinook salmon typically differ from stream-type fish in juvenile migration timing, adult spawning location, and run timing. Spatial and temporal separation during spawning can lead to reproductive isolation and genetic divergence between the two life history strategies. We identified a
A genome-wide RNAi screen identifies factors required for distinct stages of C. elegans piRNA biogenesis
Goh, Wee-Siong Sho; Seah, Jun Wen Eugene; Harrison, Emily J.; Chen, Caifu; Hammell, Christopher M.; Hannon, Gregory J.
In animals, piRNAs and their associated Piwi proteins guard germ cell genomes against mobile genetic elements via an RNAi-like mechanism. In Caenorhabditis elegans, 21U-RNAs comprise the piRNA class, and these collaborate with 22G RNAs via unclear mechanisms to discriminate self from nonself and selectively and heritably silence the latter. Recent work indicates that 21U-RNAs are post-transcriptional processing products of individual transcription units that produce ?26-nucleotide capped precursors. However, nothing is known of how the expression of precursors is controlled or how primary transcripts give rise to mature small RNAs. We conducted a genome-wide RNAi screen to identify components of the 21U biogenesis machinery. Screening by direct, quantitative PCR (qPCR)-based measurements of mature 21U-RNA levels, we identified 22 genes important for 21U-RNA production, termed TOFUs (Twenty-One-u Fouled Ups). We also identified seven genes that normally repress 21U production. By measuring mature 21U-RNA and precursor levels for the seven strongest hits from the screen, we assigned factors to discrete stages of 21U-RNA production. Our work identifies for the first time factors separately required for the transcription of 21U precursors and the processing of these precursors into mature 21U-RNAs, thereby providing a resource for studying the biogenesis of this important small RNA class. PMID:24696458
Full Genome Sequencing and Genetic Characterization of Eubenangee Viruses Identify Pata Virus as a Distinct Species within the Genus Orbivirus
Manjunatha N. Belaganahalli; Sushila Maan; Narender S. Maan; Kyriaki Nomikou; Ian Pritchard; Ross Lunt; Peter D. Kirkland; Houssam Attoui; Joe Brownlie; Peter P. C. Mertens
Eubenangee virus has previously been identified as the cause of Tammar sudden death syndrome (TSDS). Eubenangee virus (EUBV), Tilligery virus (TILV), Pata virus (PATAV) and Ngoupe virus (NGOV) are currently all classified within the Eubenangee virus species of the genus Orbivirus, family Reoviridae. Full genome sequencing confirmed that EUBV and TILV (both of which are from Australia) show high levels
A genome-wide RNAi screen identifies factors required for distinct stages of C. elegans piRNA biogenesis.
Goh, Wee-Siong Sho; Seah, Jun Wen Eugene; Harrison, Emily J; Chen, Caifu; Hammell, Christopher M; Hannon, Gregory J
In animals, piRNAs and their associated Piwi proteins guard germ cell genomes against mobile genetic elements via an RNAi-like mechanism. In Caenorhabditis elegans, 21U-RNAs comprise the piRNA class, and these collaborate with 22G RNAs via unclear mechanisms to discriminate self from nonself and selectively and heritably silence the latter. Recent work indicates that 21U-RNAs are post-transcriptional processing products of individual transcription units that produce ? 26-nucleotide capped precursors. However, nothing is known of how the expression of precursors is controlled or how primary transcripts give rise to mature small RNAs. We conducted a genome-wide RNAi screen to identify components of the 21U biogenesis machinery. Screening by direct, quantitative PCR (qPCR)-based measurements of mature 21U-RNA levels, we identified 22 genes important for 21U-RNA production, termed TOFUs (Twenty-One-u Fouled Ups). We also identified seven genes that normally repress 21U production. By measuring mature 21U-RNA and precursor levels for the seven strongest hits from the screen, we assigned factors to discrete stages of 21U-RNA production. Our work identifies for the first time factors separately required for the transcription of 21U precursors and the processing of these precursors into mature 21U-RNAs, thereby providing a resource for studying the biogenesis of this important small RNA class. PMID:24696458
Multilocus sequence typing identifies epidemic clones of Flavobacterium psychrophilum in Nordic countries.
Nilsen, Hanne; Sundell, Krister; Duchaud, Eric; Nicolas, Pierre; Dalsgaard, Inger; Madsen, Lone; Aspßn, Anna; Jansson, Eva; Colquhoun, Duncan J; Wiklund, Tom
Flavobacterium psychrophilum is the causative agent of bacterial cold water disease (BCWD), which affects a variety of freshwater-reared salmonid species. A large-scale study was performed to investigate the genetic diversity of F. psychrophilum in the four Nordic countries: Denmark, Finland, Norway, and Sweden. Multilocus sequence typing of 560 geographically and temporally disparate F. psychrophilum isolates collected from various sources between 1983 and 2012 revealed 81 different sequence types (STs) belonging to 12 clonal complexes (CCs) and 30 singleton STs. The largest CC, CC-ST10, which represented almost exclusively isolates from rainbow trout and included the most predominant genotype, ST2, comprised 65% of all isolates examined. In Norway, with a shorter history (<10 years) of BCWD in rainbow trout, ST2 was the only isolated CC-ST10 genotype, suggesting a recent introduction of an epidemic clone. The study identified five additional CCs shared between countries and five country-specific CCs, some with apparent host specificity. Almost 80% of the singleton STs were isolated from non-rainbow trout species or the environment. The present study reveals a simultaneous presence of genetically distinct CCs in the Nordic countries and points out specific F. psychrophilum STs posing a threat to the salmonid production. The study provides a significant contribution toward mapping the genetic diversity of F. psychrophilum globally and support for the existence of an epidemic population structure where recombination is a significant driver in F. psychrophilum evolution. Evidence indicating dissemination of a putatively virulent clonal complex (CC-ST10) with commercial movement of fish or fish products is strengthened. PMID:24561585
John von Neumann Institute for Computing Different Types of Protein Folding Identified with
Janke, Wolfhard
John von Neumann Institute for Computing Different Types of Protein Folding Identified://www.fz-juelich.de/nic-series/volume40 #12;Different Types of Protein Folding Identified with a Coarse-Grained Heteropolymer Model Stefan The identification of folding channels is one of the key tasks of protein folding studies. While secondary structures
Genome-Wide Association Analysis Identifies Variants Associated with Nonalcoholic Fatty Liver Disease That Have Distinct Effects on Metabolic Traits
Elizabeth K. Speliotes; Laura M. Yerges-Armstrong; Jun Wu; Ruben Hernaez; Lauren J. Kim; Cameron D. Palmer; Vilmundur Gudnason; Gudny Eiriksdottir; Melissa E. Garcia; Lenore J. Launer; Michael A. Nalls; Jeanne M. Clark; Braxton D. Mitchell; Alan R. Shuldiner; Johannah L. Butler; Marta Tomas; Udo Hoffmann; Shih-Jen Hwang; Joseph M. Massaro; Christopher J. ODonnell; Dushyant V. Sahani; Veikko Salomaa; Eric E. Schadt; Stephen M. Schwartz; David S. Siscovick; Benjamin F. Voight; J. Jeffrey Carr; Mary F. Feitosa; Tamara B. Harris; Caroline S. Fox; Albert V. Smith; W. H. Linda Kao; Joel N. Hirschhorn; Ingrid B. Borecki; M. den Heijer; J. J. Hottenga; G. Willemsen; Geus de E. J. C; D. I. Boomsma
Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic
In vivo electrophysiological recordings in amygdala subnuclei reveal selective and distinct responses to a behaviorally identified predator odor.
Govic, Antonina; Paolini, Antonio G
Chemosensory cues signaling predators reliably stimulate innate defensive responses in rodents. Despite the well-documented role of the amygdala in predator odor-induced fear, evidence for the relative contribution of the specific nuclei that comprise this structurally heterogeneous structure is conflicting. In an effort to clarify this we examined neural activity, via electrophysiological recordings, in amygdala subnuclei to controlled and repeated presentations of a predator odor: cat urine. Defensive behaviors, characterized by avoidance, decreased exploration, and increased risk assessment, were observed in adult male hooded Wistar rats (n = 11) exposed to a cloth impregnated with cat urine. Electrophysiological recordings of the amygdala (777 multiunit clusters) were subsequently obtained in freely breathing anesthetized rats exposed to cat urine, distilled water, and eugenol via an air-dilution olfactometer. Recorded units selectively responded to cat urine, and frequencies of responses were distributed differently across amygdala nuclei; medial amygdala (MeA) demonstrated the greatest frequency of responses to cat urine (51.7%), followed by the basolateral and basomedial nuclei (18.8%) and finally the central amygdala (3.0%). Temporally, information transduction occurred primarily from the cortical amygdala and MeA (ventral divisions) to other amygdala nuclei. Interestingly, MeA subnuclei exhibited distinct firing patterns to predator urine, potentially revealing aspects of the underlying neurocircuitry of predator odor processing and defensiveness. These findings highlight the critical involvement of the MeA in processing olfactory cues signaling predator threat and converge with previous studies to indicate that amygdala regulation of predator odor-induced fear is restricted to a particular set of subnuclei that primarily include the MeA, particularly the ventral divisions. PMID:25475347
Cluster Analysis in the COPDGene Study Identifies Subtypes of Smokers with Distinct Patterns of Airway Disease and Emphysema
Castaldi, Peter J; Dy, Jennifer; Ross, James; Chang, Yale; Washko, George R; Curran-Everett, Douglas; Williams, Andre; Lynch, David A; Make, Barry J; Crapo, James D; Bowler, Russ P; Regan, Elizabeth A; Hokanson, John E; Kinney, Greg L; Han, Meilan K; Soler, Xavier; Ramsdell, Joseph W; Barr, R Graham; Foreman, Marilyn; van Beek, Edwin; Casaburi, Richard; Criner, Gerald J; Lutz, Sharon M; Rennard, Steven I; Santorico, Stephanie; Sciurba, Frank C; DeMeo, Dawn L; Hersh, Craig P; Silverman, Edwin K; Cho, Michael H
Background There is notable heterogeneity in the clinical presentation of patients with COPD. To characterize this heterogeneity, we sought to identify subgroups of smokers by applying cluster analysis to data from the COPDGene Study. Methods We applied a clustering method, k-means, to data from 10,192 smokers in the COPDGene Study. After splitting the sample into a training and validation set, we evaluated three sets of input features across a range of k (user-specified number of clusters). Stable solutions were tested for association with four COPD-related measures and five genetic variants previously associated with COPD at genome-wide significance. The results were confirmed in the validation set. Findings We identified four clusters that can be characterized as 1) relatively resistant smokers (i.e. no/mild obstruction and minimal emphysema despite heavy smoking), 2) mild upper zone emphysema predominant, 3) airway disease predominant, and 4) severe emphysema. All clusters are strongly associated with COPD-related clinical characteristics, including exacerbations and dyspnea (p<0.001). We found strong genetic associations between the mild upper zone emphysema group and rs1980057 near HHIP, and between the severe emphysema group and rs8034191 in the chromosome 15q region (p<0.001). All significant associations were replicated at p<0.05 in the validation sample (12/12 associations with clinical measures and 2/2 genetic associations). Interpretation Cluster analysis identifies four subgroups of smokers that show robust associations with clinical characteristics of COPD and known COPD-associated genetic variants. PMID:24563194
Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia
Ladroue, Charline; Hoogewijs, David; Gad, Sophie; Carcenac, Romain; Storti, Federica; Barrois, Michel; Gimenez-Roqueplo, Anne-Paule; Leporrier, Michel; Casadevall, Nicole; Hermine, Olivier; Kiladjian, Jean-Jacques; Baruchel, Andrķ; Fakhoury, Fadi; Bressac-de Paillerets, Brigitte; Feunteun, Jean; Mazure, Nathalie; Pouyssķgur, Jacques; Wenger, Roland H.; Richard, Stķphane; Gardie, Betty
Background Congenital secondary erythrocytoses are due to deregulation of hypoxia inducible factor resulting in overproduction of erythropoietin. The most common germline mutation identified in the hypoxia signaling pathway is the Arginine 200-Tryptophan mutant of the von Hippel-Lindau tumor suppressor gene, resulting in Chuvash polycythemia. This mutant displays a weak deficiency in hypoxia inducible factor ? regulation and does not promote tumorigenesis. Other von Hippel-Lindau mutants with more deleterious effects are responsible for von Hippel-Lindau disease, which is characterized by the development of multiple tumors. Recently, a few mutations in gene for the prolyl hydroxylase domain 2 protein (PHD2) have been reported in cases of congenital erythrocytosis not associated with tumor formation with the exception of one patient with a recurrent extra-adrenal paraganglioma. Design and Methods Five PHD2 variants, four of which were novel, were identified in patients with erythrocytosis. These PHD2 variants were functionally analyzed and compared with the PHD2 mutant previously identified in a patient with polycythemia and paraganglioma. The capacity of PHD2 to regulate the activity, stability and hydroxylation of hypoxia inducible factor ? was assessed using hypoxia-inducible reporter gene, one-hybrid and in vitro hydroxylation assays, respectively. Results This functional comparative study showed that two categories of PHD2 mutants could be distinguished: one category with a weak deficiency in hypoxia inducible factor ? regulation and a second one with a deleterious effect; the mutant implicated in tumor occurrence belongs to the second category. Conclusions As observed with germline von Hippel-Lindau mutations, there are functional differences between the PHD2 mutants with regards to hypoxia inducible factor regulation. PHD2 mutation carriers do, therefore, need careful medical follow-up, since some mutations must be considered as potential candidates for tumor predisposition. PMID:21933857
Rabies virus glycoprotein can fold in two alternative, antigenically distinct conformations depending on membrane-anchor type
Antoine P. Maillard; Yves Gaudin
Rabies virus glycoprotein (G) is a trimeric type I transmembrane glycoprotein that mediates both receptor recognition and low pH-induced membrane fusion. We have previously demonstrated that a soluble form of the ectodomain of G (G1-439), although secreted, is folded in an alternative conformation, which is monomeric and antigenically distinct from the native state of the complete, membrane-anchored glycoprotein. This has
Observation of two distinct phase states in a self-phase-locked type II phase-matched optical parametric oscillator.
Mason, E J; Wong, N C
We demonstrate self-phase locking in a type II phase-matched optical parametric oscillator by mutual injection locking. An intracavity quarter-wave plate provides polarization mixing between the orthogonally polarized signal and idler that induces signal-idler self-phase locking when their frequency difference is within the capture range. We observed two distinct phase states that differ in their oscillator thresholds and their signal-idler phase differences, in good agreement with theory. PMID:18091897
Promoter Hypermethylation Profiling Identifies Subtypes of Head and Neck Cancer with Distinct Viral, Environmental, Genetic and Survival Characteristics
Choudhury, Javed Hussain; Ghosh, Sankar Kumar
Background Epigenetic and genetic alteration plays a major role to the development of head and neck squamous cell carcinoma (HNSCC). Consumption of tobacco (smoking/chewing) and human papilloma virus (HPV) are also associated with an increase the risk of HNSCC. Promoter hypermethylation of the tumor suppression genes is related with transcriptional inactivation and loss of gene expression. We investigated epigenetic alteration (promoter methylation of tumor-related genes/loci) in tumor tissues in the context of genetic alteration, viral infection, and tobacco exposure and survival status. Methodology The study included 116 tissue samples (71 tumor and 45 normal tissues) from the Northeast Indian population. Methylation specific polymerase chain reaction (MSP) was used to determine the methylation status of 10 tumor-related genes/loci (p16, DAPK, RASSF1, BRAC1, GSTP1, ECAD, MLH1, MINT1, MINT2 and MINT31). Polymorphisms of CYP1A1, GST (M1 & T1), XRCC1and XRCC2 genes were studied by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and multiplex-PCR respectively. Principal Findings Unsupervised hierarchical clustering analysis based on methylation pattern had identified two tumor clusters, which significantly differ by CpG island methylator phenotype (CIMP), tobacco, GSTM1, CYP1A1, HPV and survival status. Analyzing methylation of genes/loci individually, we have found significant higher methylation of DAPK, RASSF1, p16 and MINT31genes (P = 0.031, 0.013, 0.031 and 0.015 respectively) in HPV (+) cases compared to HPV (-). Furthermore, a CIMP-high and Cluster-1 characteristic was also associated with poor survival. Conclusions Promoter methylation profiles reflecting a correlation with tobacco, HPV, survival status and genetic alteration and may act as a marker to determine subtypes and patient outcome in HNSCC. PMID:26098903
Phenotypic Variation of Helicobacter pylori Isolates from Geographically Distinct Regions Detected by Lectin Typing
Sean O. Hynes; Nathalie Broutet; Torkel Wadstrom; Marika Mikelsaar; Paul W. O'Toole; John Telford; Lars Engstrand; Shigeru Kamiya; Andreas F. Mentis; Anthony P. Moran
A total of 309 Helicobacter pylori isolates from 18 different countries were analyzed with a previously developed lectin typing system. The system was developed by using a proteolytic pretreatment to enhance the carbohydrate fraction of the sample. Four lectins from Ulex europaeus, Lotus tetragonolobus, Erythrina cristigali, and Triticum vulgaris were used to type the strains. The lectins were chosen for
Distinct Functional Types of Associative Long-Term Potentiation in Neocortical and Hippocampal Pyramidal Neurons
Buonomano, Dean
we examine how long- term potentiation (LTP) and short-term plasticity (STP) interact in two different cell types that exhibit NMDA-dependent LTP: neocortical L-II/III and hippocampal CA1 pyramidal of LTP. In both cell types, the same pairing protocol was used to induce LTP in the presence
Mapping character types onto space: the urban-rural distinction in early statistical writings.
Bayatrizi, Zohreh
This article investigates the construction of urban/rural binary distinctions in 18th- and 19th-century social scientific literature, and in particular in the writings of the statistical societies in England. The 18th-century writers were primarily concerned with the spread of luxury, vice, and effeminacy among the upper social strata in large cities. Later on, statisticians began to focus on moral hazards among the urban working poor. These writings are significant in several respects: they contributed to the spatial mapping of moral character, played a role in the development of quantitative social scientific techniques, and foreshadowed later sociological debates over the nature and consequences of social evolution from simpler to more complex societies. PMID:21789837
The two types of 3-dehydroquinase have distinct structures but catalyze the same overall reactionĀ
Gourley, David G; Shrive, Annette K; Polikarpov, Igor; Krell, Tino; Coggins, John R; Hawkins, Alastair R; Isaacs, Neil W; Sawyer, Lindsay
The structures of enzymes catalyzing the reactions in central metabolic pathways are generally well conserved as are their catalytic mechanisms. The two types of 3-dehydroquinate dehydratase (DHQase) are therefore most ...
Characterization of Staphylococcus aureus from Distinct Geographic Locations in China: An Increasing Prevalence of spa-t030 and SCCmec Type III
Duo, Libo; Xiong, Jie; Gong, Yanwen; Yang, Jiyong; Wang, Zhanke; Wu, Xuqin; Lu, Zhongyi; Meng, Xiangzhao; Zhao, Jingya; Zhang, Changjian; Wang, Fang; Zhang, Yulong; Zhang, Mengqiang; Han, Li
Staphylococcus aureus belongs to one of the most common bacteria causing healthcare and community associated infections in China, but their molecular characterization has not been well studied. From May 2011 to June 2012, a total of 322 non-duplicate S. aureus isolates were consecutively collected from seven tertiary care hospitals in seven cities with distinct geographical locations in China, including 171 methicillin sensitive S. aureus (MSSA) and 151 MRSA isolates. All isolates were characterized by spa typing. The presence of virulence genes was tested by PCR. MRSA were further characterized by SCCmec typing. Seventy four and 16 spa types were identified among 168 MSSA and 150 MRSA, respectively. One spa type t030 accounted for 80.1% of all MRSA isolates, which was higher than previously reported, while spa-t037 accounted for only 4.0% of all MRSA isolates. The first six spa types (t309, t189, t034, t377, t078 and t091) accounted for about one third of all MSSA isolates. 121 of 151 MRSA isolates (80.1%) were identified as SCCmec type III. pvl gene was found in 32 MSSA (18.7%) and 5 MRSA (3.3%) isolates, with ST22-MSSA-t309 as the most commonly identified strain. Compared with non-epidemic MRSA clones, epidemic MRSA clones (corresponding to ST239) exhibited a lower susceptibility to rifampin, ciprofloxacin, gentamicin and trimethoprim-sulfamethoxazole, a higher prevalence of sea gene and a lower prevalence of seb, sec, seg, sei and tst genes. The increasing prevalence of multidrug resistant spa-t030 MRSA represents a major public health problem in China. PMID:24763740
Variance of the Boundary Layer Structure in Dependence of distinct Circulation Types
NASA Astrophysics Data System (ADS)
Philipp, Andreas; Beck, Christoph; Jacobeit, Jucundus
Variability of local climate features is related on the one hand to large scale circulation patterns, but is modified additionally by regional or local influences. This is true for basic climate variables like temperature and precipitation but also for more complex environmental conditions like air quality, e.g. PM10 concentration. Regional and local influences are to a large extend represented by the atmosperic boundary structure, i.e. the height of the mixed layer or its stability determining fluxes of temperature and impulse as well as water vapor etc. The presented study focusses on the interaction between the boundary layer structure and large scale circulation types for selected radiosonde stations. Crculation is described by a k-means cluster analysis of European circulation fields, retrieved from the NCEP/NCAR reanalysis. The boundary layer structure is derived from European radiosonde data collected in the Integrated Global Radiosonde Archive (IGRA). Here the mixed layer heigth and stability indices are anaylsed for within-type variance in a first step for different circulation types created independently from any other information. In a second step circulation types are created including boundary layer information. Both kinds of types are then realted to local impact variables in order to achieve conclusions about the interdependence of both, the large scale circulation and the boundary layer structure in modifying local climate variables.
Privacy: Gone with the Typing! Identifying Web Users by Their Typing Patterns
Hengartner, Urs
protection for Internet users has been identified as a major problem in modern web browsers. Despite poten, most browsers allow user to delete cookies, and a privacy-conscious user might choose to do so after sophisticated network surveillance or traffic analysis, the Tor network1 needs to be utilized. In spite of all
Two distinct types of the inhibition of vasculogenesis by different species of charged particles
Background Charged particle radiation is known to be more biologically effective than photon radiation. One example of this is the inhibition of the formation of human blood vessels. This effect is an important factor influencing human health and is relevant to space travel as well as to cancer radiotherapy. We have previously shown that ion particles with a high energy deposition, or linear energy transfer (LET) are more than four times more effective at disrupting mature vessel tissue models than particles with a lower LET. For vasculogenesis however, the relative biological effectiveness between particles is the same. This unexpected result prompted us to investigate whether the inhibition of vasculogenesis was occurring by distinct mechanisms. Methods Using 3-Dimensional human vessel models, we developed assays that determine at what stage angiogenesis is inhibited. Vessel morphology, the presence of motile tip structures, and changes in the matrix architecture were assessed. To confirm that the mechanisms are distinct, stimulation of Protein Kinase C (PKC) with phorbol ester (PMA) was employed to selectively restore vessel formation in cultures where early motile tip activity was inhibited. Results Endothelial cells in 3-D culture exposed to low LET protons failed to make connections with other cells but eventually developed a central lumen. Conversely, cells exposed to high LET Fe charged particles extended cellular processes and made connections to other cells but did not develop a central lumen. The microtubule and actin cytoskeletons indicated that motility at the extending tips of endothelial cells is inhibited by low LET but not high LET particles. Actin-rich protrusive structures that contain bundled microtubules showed a 65% decrease when exposed to low LET particles but not high LET particles, with commensurate changes in the matrix architecture. Stimulation of PKC with PMA restored tip motility and capillary formation in low but not high LET particle treated cultures. Conclusion Low LET charged particles inhibit the early stages of vasculogenesis when tip cells have motile protrusive structures and are creating pioneer guidance tunnels through the matrix. High LET charged particles do not affect the early stages of vasculogenesis but they do affect the later stages when the endothelial cells migrate to form tubes. PMID:24044765
Functional genomics identifies neural stem cell sub-type expression profiles and genes regulating neuroblast homeostasis
Carney, Travis D.; Miller, Michael R.; Robinson, Kristin J.; Bayraktar, Omer A.; Osterhout, Jessica A.; Doe, Chris Q.
The Drosophila larval central brain contains about 10,000 differentiated neurons and 200 scattered neural progenitors (neuroblasts), which can be further subdivided into ~95 type I neuroblasts and eight type II neuroblasts per brain lobe. Only type II neuroblasts generate self-renewing intermediate neural progenitors (INPs), and consequently each contributes more neurons to the brain, including much of the central complex. We characterized six different mutant genotypes that lead to expansion of neuroblast numbers; some preferentially expand type II or type I neuroblasts. Transcriptional profiling of larval brains from these mutant genotypes versus wild-type allowed us to identify small clusters of transcripts enriched in type II or type I neuroblasts, and we validated these clusters by gene expression analysis. Unexpectedly, only a few genes were found to be differentially expressed between type I/II neuroblasts, suggesting that these genes play a large role in establishing the different cell types. We also identified a large group of genes predicted to be expressed in all neuroblasts but not neurons. We performed a neuroblast-specific, RNAi-based functional screen and identified 84 genes that are required to maintain proper neuroblast numbers; all have conserved mammalian orthologs. These genes are excellent candidates for regulating neural progenitor self-renewal in Drosophila and mammals. PMID:22061480
Type III secretion system in Chlamydia species: identified members and candidates
Agathe Subtil; Ariel Blocker; Alice Dautry-Varsat
Chlamydia trachomatis and Chlamydia pneumoniae genomes contain genes coding for type III secretion apparatuses. Like other pathogens, Chlamydia probably uses this system to secrete proteins in the host cell. With the aim of identifying such proteins, we analyzed the organization of Chlamydia type III secretion genes.
Arcavi, Iair; Gal-Yam, Avishay; Yaron, Ofer [Department of Particle Physics and Astrophysics, Weizmann Institute of Science, Rehovot 76100 (Israel); Cenko, S. Bradley; Becker, Adam B. [Department of Astronomy, University of California, Berkeley, CA 94720-3411 (United States); Fox, Derek B. [Department of Astronomy and Astrophysics, Pennsylvania State University, University Park, PA 16802 (United States); Leonard, Douglas C. [Department of Astronomy, San Diego State University, San Diego, CA 92182 (United States); Moon, Dae-Sik [Department of Astronomy and Astrophysics, University of Toronto, Toronto, ON M5S 3H4 (Canada); Sand, David J. [Las Cumbres Observatory Global Telescope Network, Santa Barbara, CA 93117 (United States); Soderberg, Alicia M. [Harvard-Smithsonian Center for Astrophysics, Cambridge, MA 02138 (United States); Kiewe, Michael [Department of Physics, University of Wisconsin, Madison, WI 53706 (United States); Scheps, Raphael [King's College, University of Cambridge, Cambridge CB2 1ST (United Kingdom); Birenbaum, Gali [12 Amos St, Ramat Chen, Ramat Gan 52233 (Israel); Chamudot, Daniel [20 Chen St, Petach Tikvah 49520 (Israel); Zhou, Jonathan, E-mail: firstname.lastname@example.com [101 Dunster Street, Box 398, Cambridge, MA 02138 (United States)
We present R-band light curves of Type II supernovae (SNe) from the Caltech Core-Collapse Project (CCCP). With the exception of interacting (Type IIn) SNe and rare events with long rise times, we find that most light curve shapes belong to one of three apparently distinct classes: plateau, slowly declining, and rapidly declining events. The last class is composed solely of Type IIb SNe which present similar light curve shapes to those of SNe Ib, suggesting, perhaps, similar progenitor channels. We do not find any intermediate light curves, implying that these subclasses are unlikely to reflect variance of continuous parameters, but rather might result from physically distinct progenitor systems, strengthening the suggestion of a binary origin for at least some stripped SNe. We find a large plateau luminosity range for SNe IIP, while the plateau lengths seem rather uniform at approximately 100 days. As analysis of additional CCCP data goes on and larger samples are collected, demographic studies of core-collapse SNe will likely continue to provide new constraints on progenitor scenarios.
Microbial community composition and in silico predicted metabolic potential reflect biogeochemical gradients between distinct peatland types.
Urbanovß, Zuzana; Bßrta, Ji?Ē
It is not well understood how the ecological status and microbial community composition of spruce swamp forests (SSF) relate to those found in bogs and fens. To clarify this, we investigated biogeochemical parameters and microbial community composition in a bog, a fen and two SSF using high throughput barcoded sequencing of the small ribosomal subunit (SSU) variable region V4. The results demonstrated that the microbial community of SSF is positioned between those of bogs and fens, and this was confirmed by in silico predicted metabolic potentials. This corresponds well with the position of SSF on the trophic gradient and reflects distinct responses of microbial communities to environmental variables. Species richness and microbial diversity increased significantly from bog to fen, with SSF in between, reflecting the variation in pH, nutrient availability and peat decomposability. The archaeal community, dominated by hydrogenotrophic methanogens, was more similar in SSF and the bog compared with the fen. The composition of the bacterial community of SSF was intermediate between those of bog and fen. However, the production of CO2 (an indicator of peat decomposability) did not differ between SSF and bog, suggesting the limiting effect of low pH and poor litter quality on the functioning of the bacterial community in SSF. These results help to clarify the transitional position of SSF between bogs and fens and showed the strong effect of environmental conditions on microbial community composition and functioning. PMID:25195805
The distinction of 'psychosomatogenic family types' based on parents' self reported questionnaire information: a cluster analysis.
Rousseau, Sofie; Grietens, Hans; Vanderfaeillie, Johan; Ceulemans, Eva; Hoppenbrouwers, Karel; Desoete, Annemie; Van Leeuwen, Karla
The theory of 'psychosomatogenic family types' is often used in treatment of somatizing adolescents. This study investigated the validity of distinguishing 'psychosomatogenic family types' based on parents' self-reported family features. The study included a Flemish general population sample of 12-year olds (n = 1428). We performed cluster analysis on 3 variables concerning parents' self-reported problems in family functioning. The distinguished clusters were examined for differences in marital problems, parental emotional problems, professional help for family members, demographics, and adolescents' somatization. Results showed the existence of 5 family types: 'chaotic family functioning,' 'average amount of family functioning problems,' 'few family functioning problems,' 'high amount of support and communication problems,' and 'high amount of sense of security problems' clusters. Membership of the 'chaotic family functioning' and 'average amount of family functioning problems' cluster was significantly associated with higher levels of somatization, compared with 'few family functioning problems' cluster membership. Among additional variables, only marital and parental emotional problems distinguished somatization relevant from non relevant clusters: parents in 'average amount of family functioning problems' and 'chaotic family functioning' clusters reported higher problems. The data showed that 'apparently perfect' or 'enmeshed' patterns of family functioning may not be assessed by means of parent report as adopted in this study. In addition, not only adolescents from 'extreme' types of family functioning may suffer from somatization. Further, professionals should be careful assuming that families in which parents report average to high amounts of family functioning problems also show different demographic characteristics. PMID:24749676
A new multi-label classifier in identifying the functional types of human membrane proteins.
Zou, Hong-Liang; Xiao, Xuan
Membrane proteins were found to be involved in various cellular processes performing various important functions, which are mainly associated to their type. Given a membrane protein sequence, how can we identify its type(s)? Particularly, how can we deal with the multi-type problem since one membrane protein may simultaneously belong to two or more different types? To address these problems, which are obviously very important to both basic research and drug development, a new multi-label classifier was developed based on pseudo amino acid composition with multi-label k-nearest neighbor algorithm. The success rate achieved by the new predictor on the benchmark dataset by jackknife test is 73.94%, indicating that the method is promising and the predictor may become a very useful high-throughput tool, or at least play a complementary role to the existing predictors in identifying functional types of membrane proteins. PMID:25433431
Mutations at Ser331 in the HSN type I gene SPTLC1 are associated with a distinct syndromic phenotype
Auer-Grumbach, Michaela; Bode, Heiko; Pieber, Thomas R.; Schabh³ttl, Maria; Fischer, Dirk; Seidl, Rainer; Graf, Elisabeth; Wieland, Thomas; Schuh, Reinhard; Vacariu, Gerda; Grill, Franz; Timmerman, Vincent; Strom, Tim M.; Hornemann, Thorsten
Mutations in the serine palmitoyltransferase subunit 1 (SPTLC1) gene are the most common cause of hereditary sensory neuropathy type 1 (HSN1). Here we report the clinical and molecular consequences of a particular mutation (p.S331Y) in SPTLC1 affecting a patient with severe, diffuse muscle wasting and hypotonia, prominent distal sensory disturbances, joint hypermobility, bilateral cataracts and considerable growth retardation. Normal plasma sphingolipids were unchanged but 1-deoxy-sphingolipids were significantly elevated. In contrast to other HSN patients reported so far, our findings strongly indicate that mutations at amino acid position Ser331 of the SPTLC1 gene lead to a distinct syndrome. PMID:23454272
Distinct Functional Properties of Isoamylase-Type Starch Debranching Enzymes in Monocot and Dicot Leaves1[C][W][OPEN
Facon, Maud; Lin, Qiaohui; Azzaz, Abdelhamid M.; Hennen-Bierwagen, Tracie A.; Myers, Alan M.; Putaux, Jean-Luc; Roussel, Xavier; DÆHulst, Christophe; Wattebled, Fabrice
Isoamylase-type starch debranching enzymes (ISA) play important roles in starch biosynthesis in chloroplast-containing organisms, as shown by the strict conservation of both catalytically active ISA1 and the noncatalytic homolog ISA2. Functional distinctions exist between species, although they are not understood yet. Numerous plant tissues require both ISA1 and ISA2 for normal starch biosynthesis, whereas monocot endosperm and leaf exhibit nearly normal starch metabolism without ISA2. This study took in vivo and in vitro approaches to determine whether organism-specific physiology or evolutionary divergence between monocots and dicots is responsible for distinctions in ISA function. Maize (Zea mays) ISA1 was expressed in Arabidopsis (Arabidopsis thaliana) lacking endogenous ISA1 or lacking both native ISA1 and ISA2. The maize protein functioned in Arabidopsis leaves to support nearly normal starch metabolism in the absence of any native ISA1 or ISA2. Analysis of recombinant enzymes showed that Arabidopsis ISA1 requires ISA2 as a partner for enzymatic function, whereas maize ISA1 was active by itself. The electrophoretic mobility of recombinant and native maize ISA differed, suggestive of posttranslational modifications in vivo. Sedimentation equilibrium measurements showed recombinant maize ISA1 to be a dimer, in contrast to previous gel permeation data that estimated the molecular mass as a tetramer. These data demonstrate that evolutionary divergence between monocots and dicots is responsible for the distinctions in ISA1 function. PMID:24027240
Multilocus sequence typing reveals that Bacillus cereus strains isolated from clinical infections have distinct phylogenetic origins.
Barker, Margaret; Thakker, Bishan; Priest, Fergus G
Eight strains of Bacillus cereus isolated from bacteremia and soft tissue infections were assigned to seven sequence types (STs) by multilocus sequence typing (MLST). Two strains from different locations had identical STs. The concatenated sequences of the seven STs were aligned with 65 concatenated sequences from reference STs and a neighbor-joining tree was constructed. Two strains were distantly related to all reference STs. Three strains were recovered in a clade that included Bacillus anthracis, B. cereus and rare Bacillus thuringiensis strains while the other three strains were assigned to two STs that were more closely affiliated to most of the B. thuringiensis STs. We conclude that invasive B. cereus strains do not form a single clone or clonal complex of highly virulent strains. PMID:15796996
Distinct Microbial Communities within the Endosphere and Rhizosphere of Populus deltoides Roots across Contrasting Soil Types ?å
Gottel, Neil R.; Castro, Hector F.; Kerley, Marilyn; Yang, Zamin; Pelletier, Dale A.; Podar, Mircea; Karpinets, Tatiana; Uberbacher, Ed; Tuskan, Gerald A.; Vilgalys, Rytas; Doktycz, Mitchel J.; Schadt, Christopher W.
The root-rhizosphere interface of Populus is the nexus of a variety of associations between bacteria, fungi, and the host plant and an ideal model for studying interactions between plants and microorganisms. However, such studies have generally been confined to greenhouse and plantation systems. Here we analyze microbial communities from the root endophytic and rhizospheric habitats of Populus deltoides in mature natural trees from both upland and bottomland sites in central Tennessee. Community profiling utilized 454 pyrosequencing with separate primers targeting the V4 region for bacterial 16S rRNA and the D1/D2 region for fungal 28S rRNA genes. Rhizosphere bacteria were dominated by Acidobacteria (31%) and Alphaproteobacteria (30%), whereas most endophytes were from the Gammaproteobacteria (54%) as well as Alphaproteobacteria (23%). A single Pseudomonas-like operational taxonomic unit (OTU) accounted for 34% of endophytic bacterial sequences. Endophytic bacterial richness was also highly variable and 10-fold lower than in rhizosphere samples originating from the same roots. Fungal rhizosphere and endophyte samples had approximately equal amounts of the Pezizomycotina (40%), while the Agaricomycotina were more abundant in the rhizosphere (34%) than endosphere (17%). Both fungal and bacterial rhizosphere samples were highly clustered compared to the more variable endophyte samples in a UniFrac principal coordinates analysis, regardless of upland or bottomland site origin. Hierarchical clustering of OTU relative abundance patterns also showed that the most abundant bacterial and fungal OTUs tended to be dominant in either the endophyte or rhizosphere samples but not both. Together, these findings demonstrate that root endophytic communities are distinct assemblages rather than opportunistic subsets of the rhizosphere. PMID:21764952
Distinct Structural Elements Dictate the Specificity of the Type III Pentaketide Synthase from Neurospora crassa
Sheryl B. Rubin-Pitel; Houjin Zhang; Trang Vu; Joseph S. Brunzelle; Huimin Zhao; Satish K. Nair
SUMMARY The fungal type III polyketide synthase 20-oxoalkylre- sorcylic acid synthase (ORAS) primes with a range of acyl-Coenzyme A thioesters (C4-C20) and extends using malonyl-Coenzyme A to produce pyrones, res- orcinols, and resorcylic acids. To gain insight into this unusual substrate specificity and product profile, we have determined the crystal structures of ORAS to 1.75 A ¹ resolution, the Phe-252\\/Gly
Distinctive Higgs signals of a type II two-Higgs-doublet model at the LHC
Kanemura, Shinya; Mukai, Yuki; Yagyu, Kei [Department of Physics, University of Toyama, 3190 Gofuku, Toyama 930-8555 (Japan); Moretti, Stefano; Santos, Rui [School of Physics and Astronomy, University of Southampton, Highfield, Southampton SO17 1BJ (United Kingdom)
We perform a numerical analysis of Higgs-to-Higgs decays within a type II two-Higgs-doublet model (2HDM), highlighting several channels that cannot occur in its supersymmetric version, thereby allowing one to possibly distinguish between these two scenarios. Our results are compliant with all available experimental bounds from both direct and indirect Higgs searches and with theoretical constraints from vacuum stability and perturbative unitarity.
Two Distinct Types of Cusp-Like Regions Observed by POLAR
NASA Astrophysics Data System (ADS)
Niehof, J. T.; Fritz, T.; Friedel, R. H.; Chen, J.
We examine POLAR data for several cusp crossings, observing two different types of cusp-like regions. We apply the label "quiet cusp" to the traditional cusp of high-density, stagnant solar wind plasma. "Cusp Diamagnetic Cavities", described previously, are similar but show a strongly depressed and turbulent field and are colocated with "Cusp Energetic Particle" observations. Within the CDC's, field depressions are strongly correlated to enhancements in the local plasma density.
A Distinct Perisynaptic Glial Cell Type Forms Tripartite Neuromuscular Synapses in the Drosophila Adult
Strauss, Alexandra L.; Kawasaki, Fumiko; Ordway, Richard W.
Previous studies of Drosophila flight muscle neuromuscular synapses have revealed their tripartite architecture and established an attractive experimental model for genetic analysis of glial function in synaptic transmission. Here we extend these findings by defining a new Drosophila glial cell type, designated peripheral perisynaptic glia (PPG), which resides in the periphery and interacts specifically with fine motor axon branches forming neuromuscular synapses. Identification and specific labeling of PPG was achieved through cell type-specific RNAi-mediated knockdown (KD) of a glial marker, Glutamine Synthetase 2 (GS2). In addition, comparison among different Drosophila neuromuscular synapse models from adult and larval developmental stages indicated the presence of tripartite synapses on several different muscle types in the adult. In contrast, PPG appear to be absent from larval body wall neuromuscular synapses, which do not exhibit a tripartite architecture but rather are imbedded in the muscle plasma membrane. Evolutionary conservation of tripartite synapse architecture and peripheral perisynaptic glia in vertebrates and Drosophila suggests ancient and conserved roles for glia-synapse interactions in synaptic transmission. PMID:26053860
Modular transcriptional repertoire analyses of adults with systemic lupus erythematosus reveal distinct type I and type II interferon signatures
Chiche, Laurent; Jourde-Chiche, Noķmie; Whalen, Elizabeth; Presnell, Scott; Gersuk, Vivian; Dang, Kristen; Anguiano, Esperanza; Quinn, Charlie; Burtey, Stķphane; Berland, Yvon; Kaplanski, Gilles; Harle, Jean-Robert; Pascual, Virginia; Chaussabel, Damien
Objective The role for interferon (IFN)-? in systemic lupus erythematosus (SLE) pathogenesis is strongly supported by gene expression studies. The aim of this study was to improve characterization of the blood-IFN signature in adult SLE patients. Methods Consecutive patients were enrolled and followed-up prospectively. Microarray data were generated using Illumina beadchips. A modular transcriptional repertoire was employed as a framework for the analysis. Results Our repertoire of 260 modules, which consist of co-clustered gene sets, included 3 IFN-annotated modules (M1.2, M3.4 and M5.12) that were strongly up-regulated in SLE patients. A modular IFN signature (mIS) was observed in 54/62 (87%) patients or 131/157 (83%) longitudinal samples. The IFN signature was more complex than expected with each module displaying a distinct activation threshold (M1.2
Desorption of water from distinct step types on a curved silver crystal.
Janlamool, Jakrapan; Bashlakov, Dima; Berg, Otto; Praserthdam, Piyasan; Jongsomjit, Bunjerd; Juurlink, Ludo B F
We have investigated the adsorption of H2O onto the A and B type steps on an Ag single crystal by temperature programmed desorption. For this study, we have used a curved crystal exposing a continuous range of surface structures ranging from [5(111) ū (100)] via (111) to [5(111) ū (110)]. LEED and STM studies verify that the curvature of our sample results predominantly from monoatomic steps. The sample thus provides a continuous array of step densities for both step types. Desorption probed by spatially-resolved TPD of multilayers of H2O shows no dependence on the exact substrate structure and thus confirms the absence of thermal gradients during temperature ramps. In the submonolayer regime, we observe a small and linear dependence of the desorption temperature on the A and B step density. We argue that such small differences are only observable by means of a single curved crystal, which thus establishes new experimental benchmarks for theoretical calculation of chemically accurate binding energies. We propose an origin of the observed behavior based on a "two state" desorption model. PMID:25068782
Satellite tracking reveals distinct movement patterns for Type B and Type C killer whales in the southern Ross Sea, Antarctica
Russel D. Andrews; Robert L. Pitman; Lisa T. Ballance
During January\\/February 2006, we satellite-tracked two different ecotypes of killer whales (Orcinus orca) in McMurdo Sound, Ross Sea, Antarctica, using surface-mounted tags attached with sub-dermal darts. A single Type B whale\\u000a (pinniped prey specialist), tracked for 27Ādays, traveled an average net distance of 56.8Ā▒Ā32.8ĀkmĀday?1, a maximum of 114ĀkmĀday?1, and covered an estimated area of 49,351Ākm2. It spent several days near
The hippocampal CA3 region can generate two distinct types of sharp wave-ripple complexes, in vitro.
Hofer, Katharina T; Kandrßcs, ┴gnes; Ulbert, Istvßn; Pßl, Ildik¾; Szab¾, Csilla; Hķja, Lßszl¾; Wittner, Lucia
Hippocampal sharp wave-ripples (SPW-Rs) occur during slow wave sleep and behavioral immobility and are thought to play an important role in memory formation. We investigated the cellular and network properties of SPW-Rs with simultaneous laminar multielectrode and intracellular recordings in a rat hippocampal slice model, using physiological bathing medium. Spontaneous SPW-Rs were generated in the dentate gyrus (DG), CA3, and CA1 regions. These events were characterized by a local field potential gradient (LFPg) transient, increased fast oscillatory activity and increased multiple unit activity (MUA). Two types of SPW-Rs were distinguished in the CA3 region based on their different LFPg and current source density (CSD) pattern. Type 1 (T1) displayed negative LFPg transient in the pyramidal cell layer, and the associated CSD sink was confined to the proximal dendrites. Type 2 (T2) SPW-Rs were characterized by positive LFPg transient in the cell layer, and showed CSD sinks involving both the apical and basal dendrites. In both types, consistent with the somatic CSD source, only a small subset of CA3 pyramidal cells fired, most pyramidal cells were hyperpolarized, while most interneurons increased firing rate before the LFPg peak. Different neuronal populations, with different proportions of pyramidal cells and distinct subsets of interneurons were activated during T1 and T2 SPW-Rs. Activation of specific inhibitory cell subsets-with the possible leading role of perisomatic interneurons-seems to be crucial to synchronize distinct ensembles of CA3 pyramidal cells finally resulting in the expression of different SPW-R activities. This suggests that the hippocampus can generate dynamic changes in its activity stemming from the same excitatory and inhibitory circuits, and so, might provide the cellular and network basis for an input-specific and activity-dependent information transmission. PMID:25209976
Narrow-Host-Range Bacteriophages That Infect Rhizobium etli Associate with Distinct Genomic Types
SantamarĒa, Rosa Isela; Bustos, Patricia; Sep·lveda-Robles, Omar; Lozano, Luis; RodrĒguez, Cķsar; Fernßndez, Josķ Luis; Jußrez, Soledad; Kameyama, Luis; Guarneros, Gabriel; Dßvila, Guillermo
In this work, we isolated and characterized 14 bacteriophages that infect Rhizobium etli. They were obtained from rhizosphere soil of bean plants from agricultural lands in Mexico using an enrichment method. The host range of these phages was narrow but variable within a collection of 48 R. etli strains. We obtained the complete genome sequence of nine phages. Four phages were resistant to several restriction enzymes and in vivo cloning, probably due to nucleotide modifications. The genome size of the sequenced phages varied from 43 kb to 115 kb, with a median size of ?45 to 50 kb. A large proportion of open reading frames of these phage genomes (65 to 70%) consisted of hypothetical and orphan genes. The remainder encoded proteins needed for phage morphogenesis and DNA synthesis and processing, among other functions, and a minor percentage represented genes of bacterial origin. We classified these phages into four genomic types on the basis of their genomic similarity, gene content, and host range. Since there are no reports of similar sequences, we propose that these bacteriophages correspond to novel species. PMID:24185856
A Distinct Type of Heterochromatin at the Telomeric Region of the Drosophila melanogaster Y Chromosome
Wang, Sidney H.; Nan, Ruth; Accardo, Maria C.; Sentmanat, Monica; Dimitri, Patrizio; Elgin, Sarah C. R.
Heterochromatin assembly and its associated phenotype, position effect variegation (PEV), provide an informative system to study chromatin structure and genome packaging. In the fruit fly Drosophila melanogaster, the Y chromosome is entirely heterochromatic in all cell types except the male germline; as such, Y chromosome dosage is a potent modifier of PEV. However, neither Y heterochromatin composition, nor its assembly, has been carefully studied. Here, we report the mapping and characterization of eight reporter lines that show male-specific PEV. In all eight cases, the reporter insertion sites lie in the telomeric transposon array (HeT-A and TART-B2 homologous repeats) of the Y chromosome short arm (Ys). Investigations of the impact on the PEV phenotype of mutations in known heterochromatin proteins (i.e., modifiers of PEV) show that this Ys telomeric region is a unique heterochromatin domain: it displays sensitivity to mutations in HP1a, EGG and SU(VAR)3-9, but no sensitivity to Su(z)2 mutations. It appears that the endo-siRNA pathway plays a major targeting role for this domain. Interestingly, an ectopic copy of 1360 is sufficient to induce a piRNA targeting mechanism to further enhance silencing of a reporter cytologically localized to the Ys telomere. These results demonstrate the diversity of heterochromatin domains, and the corresponding variation in potential targeting mechanisms. PMID:24475122
Using wearable cameras to categorise type and context of accelerometer-identified episodes of physical activity
Background Accelerometers can identify certain physical activity behaviours, but not the context in which they take place. This study investigates the feasibility of wearable cameras to objectively categorise the behaviour type and context of participantsÆ accelerometer-identified episodes of activity. Methods Adults were given an Actical hip-mounted accelerometer and a SenseCam wearable camera (worn via lanyard). The onboard clocks on both devices were time-synchronised. Participants engaged in free-living activities for 3 days. Actical data were cleaned and episodes of sedentary, lifestyle-light, lifestyle-moderate, and moderate-to-vigorous physical activity (MVPA) were identified. Actical episodes were categorised according to their social and environmental context and Physical Activity (PA) compendium category as identified from time-matched SenseCam images. Results There were 212 days considered from 49 participants from whom SenseCam images and associated Actical data were captured. Using SenseCam images, behaviour type and context attributes were annotated for 386 (out of 3017) randomly selected episodes (such as walking/transportation, social/not-social, domestic/leisure). Across the episodes, 12 categories that aligned with the PA Compendium were identified, and 114 subcategory types were identified. Nineteen percent of episodes could not have their behaviour type and context categorized; 59% were outdoors versus 39% indoors; 33% of episodes were recorded as leisure time activities, with 33% transport, 18% domestic, and 15% occupational. 33% of the randomly selected episodes contained direct social interaction and 22% were in social situations where the participant wasnÆt involved in direct engagement. Conclusion Wearable camera images offer an objective method to capture a spectrum of activity behaviour types and context across 81% of accelerometer-identified episodes of activity. Wearable cameras represent the best objective method currently available to categorise the social and environmental context of accelerometer-defined episodes of activity in free-living conditions. PMID:23406270
Mercury dynamics in groundwater across three distinct riparian zone types of the US Midwest.
Vidon, Philippe G; Mitchell, Carl P J; Jacinthe, Pierre-Andrķ; Baker, Matthew E; Liu, Xiaoqiang; Fisher, Katelin R
Although the intense biogeochemical gradients present in riparian zones have the potential to affect mercury (Hg) cycling, Hg dynamics in riparian zones has received relatively little attention in the literature. Our study investigated groundwater filtered total mercury (THg) and methylmercury (MeHg) dynamics in three riparian zones with contrasting hydrogeomorphic (HGM) characteristics (till, alluvium, outwash) in the US Midwest. Despite high Hg deposition rates (>16 ?g m(-2)) in the region, median THg (<1.05 ng L(-1)) and MeHg (<0.05 ng L(-1)) concentrations were low at the study sites. Methylmercury concentrations were significantly (p < 0.05) correlated to THg (R = 0.82), temperature (R = 0.55), and dissolved organic carbon (DOC) (R = 0.62). THg also correlated with groundwater DOC (R = 0.59). The proportion of MeHg in THg (%MeHg) was significantly correlated to temperature (R = 0.58) and MeHg (R = 0.50). Results suggest that HGM characteristics, the presence of tile drains, and the propensity for overbank flooding at a riparian site determined the extent to which stream water Hg concentrations influenced riparian groundwater Hg levels or vice versa. Differences in hydrogeomorphic characteristics between sites did not translate however in significant differences in groundwater MeHg or %MeHg. Overall, widespread Hg contamination in the most common riparian hydrogeomorphic types of the US Midwest is unlikely to be a major concern. However, for frequently flooded riparian zones located downstream from a potentially large source of Hg (e.g., concentrated urban development), Hg concentrations are likely to be higher than at other sites. PMID:24113840
Analysis of the type II-A CRISPR-Cas system of Streptococcus agalactiae reveals distinctive features according to genetic lineages
Lier, Clķment; Baticle, Elodie; Horvath, Philippe; Haguenoer, Eve; Valentin, Anne-Sophie; Glaser, Philippe; Mereghetti, Laurent; Lanotte, Philippe
CRISPR-Cas systems (clustered regularly interspaced short palindromic repeats/CRISPR-associated proteins) are found in 90% of archaea and about 40% of bacteria. In this original system, CRISPR arrays comprise short, almost unique sequences called spacers that are interspersed with conserved palindromic repeats. These systems play a role in adaptive immunity and participate to fight non-self DNA such as integrative and conjugative elements, plasmids, and phages. In Streptococcus agalactiae, a bacterium implicated in colonization and infections in humans since the 1960s, two CRISPR-Cas systems have been described. A type II-A system, characterized by proteins Cas9, Cas1, Cas2, and Csn2, is ubiquitous, and a type I¢C system, with the Cas8c signature protein, is present in about 20% of the isolates. Unlike type I¢C, which appears to be non-functional, type II-A appears fully functional. Here we studied type II-A CRISPR-cas loci from 126 human isolates of S. agalactiae belonging to different clonal complexes that represent the diversity of the species and that have been implicated in colonization or infection. The CRISPR-cas locus was analyzed both at spacer and repeat levels. Major distinctive features were identified according to the phylogenetic lineages previously defined by multilocus sequence typing, especially for the sequence type (ST) 17, which is considered hypervirulent. Among other idiosyncrasies, ST-17 shows a significantly lower number of spacers in comparison with other lineages. This characteristic could reflect the peculiar virulence or colonization specificities of this lineage.
Unique functions of the type II interleukin 4 receptor identified in mice lacking the interleukin 13 receptor ?1 chain
Thirumalai R Ramalingam; John T Pesce; Faruk Sheikh; Allen W Cheever; Margaret M Mentink-Kane; Mark S Wilson; Sean Stevens; David M Valenzuela; Andrew J Murphy; George D Yancopoulos; Joseph F Urban; Raymond P Donnelly; Thomas A Wynn
The interleukin 4 receptor (IL-4R) is a central mediator of T helper type 2 (TH2)¢mediated disease and associates with either the common ?-chain to form the type I IL-4R or with the IL-13R ?1 chain (IL-13R?1) to form the type II IL-4R. Here we used Il13ra1?\\/? mice to characterize the distinct functions of type I and type II IL-4 receptors
Charge transport in C60-based dumbbell-type molecules: mechanically induced switching between two distinct conductance states.
Moreno-GarcĒa, Pavel; La Rosa, Andrea; KolivoÜka, Viliam; Bermejo, Daniel; Hong, Wenjing; Yoshida, Koji; Baghernejad, Masoud; Filippone, Salvatore; Broekmann, Peter; Wandlowski, Thomas; MartĒn, Nazario
Single molecule charge transport characteristics of buckminsterfullerene-capped symmetric fluorene-based dumbbell-type compound 1 were investigated by scanning tunneling microscopy break junction (STM-BJ), current sensing atomic force microscopy break junction (CS-AFM-BJ), and mechanically controlled break junction (MCBJ) techniques, under ambient conditions. We also show that compound 1 is able to form highly organized defect-free surface adlayers, allowing the molecules on the surface to be addressed specifically. Two distinct single molecule conductance states (called high G(H)(1) and low G(L)(1)) were observed, depending on the pressure exerted by the probe on the junction, thus allowing molecule 1 to function as a mechanically driven molecular switch. These two distinct conductance states were attributed to the electron tunneling through the buckminsterfullerene anchoring group and fully extended molecule 1, respectively. The assignment of conductance features to these configurations was further confirmed by control experiments with asymmetrically designed buckminsterfullerene derivative 2 as well as pristine buckminsterfullerene 3, both lacking the G(L) feature. PMID:25651069
Co-existence of Distinct Prion Types Enables Conformational Evolution of Human PrPSc by Competitive Selection*
Haldiman, Tracy; Kim, Chae; Cohen, Yvonne; Chen, Wei; Blevins, Janis; Qing, Liuting; Cohen, Mark L.; Langeveld, Jan; Telling, Glenn C.; Kong, Qingzhong; Safar, Jiri G.
The unique phenotypic characteristics of mammalian prions are thought to be encoded in the conformation of pathogenic prion proteins (PrPSc). The molecular mechanism responsible for the adaptation, mutation, and evolution of prions observed in cloned cells and upon crossing the species barrier remains unsolved. Using biophysical techniques and conformation-dependent immunoassays in tandem, we isolated two distinct populations of PrPSc particles with different conformational stabilities and aggregate sizes, which frequently co-exist in the most common human prion disease, sporadic Creutzfeldt-Jakob disease. The protein misfolding cyclic amplification replicates each of the PrPSc particle types independently and leads to the competitive selection of those with lower initial conformational stability. In serial propagation with a nonglycosylated mutant PrPC substrate, the dominant PrPSc conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to its lowest stability. Cumulatively, the data show that sporadic Creutzfeldt-Jakob disease PrPSc is not a single conformational entity but a dynamic collection of two distinct populations of particles. This implies the co-existence of different prions, whose adaptation and evolution are governed by the selection of progressively less stable, faster replicating PrPSc conformers. PMID:23974118
Experimentally-Derived Fibroblast Gene Signatures Identify Molecular Pathways Associated with Distinct Subsets of Systemic Sclerosis Patients in Three Independent Cohorts
Johnson, Michael E.; Mahoney, J. Matthew; Taroni, Jaclyn; Sargent, Jennifer L.; Marmarelis, Eleni; Wu, Ming-Ru; Varga, John; Hinchcliff, Monique E.; Whitfield, Michael L.
Genome-wide expression profiling in systemic sclerosis (SSc) has identified four æintrinsicÆ subsets of disease (fibroproliferative, inflammatory, limited, and normal-like), each of which shows deregulation of distinct signaling pathways; however, the full set of pathways contributing to this differential gene expression has not been fully elucidated. Here we examine experimentally derived gene expression signatures in dermal fibroblasts for thirteen different signaling pathways implicated in SSc pathogenesis. These data show distinct and overlapping sets of genes induced by each pathway, allowing for a better understanding of the molecular relationship between profibrotic and immune signaling networks. Pathway-specific gene signatures were analyzed across a compendium of microarray datasets consisting of skin biopsies from three independent cohorts representing 80 SSc patients, 4 morphea, and 26 controls. IFN? signaling showed a strong association with early disease, while TGF? signaling spanned the fibroproliferative and inflammatory subsets, was associated with worse MRSS, and was higher in lesional than non-lesional skin. The fibroproliferative subset was most strongly associated with PDGF signaling, while the inflammatory subset demonstrated strong activation of innate immune pathways including TLR signaling upstream of NF-?B. The limited and normal-like subsets did not show associations with fibrotic and inflammatory mediators such as TGF? and TNF?. The normal-like subset showed high expression of genes associated with lipid signaling, which was absent in the inflammatory and limited subsets. Together, these data suggest a model by which IFN? is involved in early disease pathology, and disease severity is associated with active TGF? signaling. PMID:25607805
Experimentally-derived fibroblast gene signatures identify molecular pathways associated with distinct subsets of systemic sclerosis patients in three independent cohorts.
Johnson, Michael E; Mahoney, J Matthew; Taroni, Jaclyn; Sargent, Jennifer L; Marmarelis, Eleni; Wu, Ming-Ru; Varga, John; Hinchcliff, Monique E; Whitfield, Michael L
Genome-wide expression profiling in systemic sclerosis (SSc) has identified four 'intrinsic' subsets of disease (fibroproliferative, inflammatory, limited, and normal-like), each of which shows deregulation of distinct signaling pathways; however, the full set of pathways contributing to this differential gene expression has not been fully elucidated. Here we examine experimentally derived gene expression signatures in dermal fibroblasts for thirteen different signaling pathways implicated in SSc pathogenesis. These data show distinct and overlapping sets of genes induced by each pathway, allowing for a better understanding of the molecular relationship between profibrotic and immune signaling networks. Pathway-specific gene signatures were analyzed across a compendium of microarray datasets consisting of skin biopsies from three independent cohorts representing 80 SSc patients, 4 morphea, and 26 controls. IFN? signaling showed a strong association with early disease, while TGF? signaling spanned the fibroproliferative and inflammatory subsets, was associated with worse MRSS, and was higher in lesional than non-lesional skin. The fibroproliferative subset was most strongly associated with PDGF signaling, while the inflammatory subset demonstrated strong activation of innate immune pathways including TLR signaling upstream of NF-?B. The limited and normal-like subsets did not show associations with fibrotic and inflammatory mediators such as TGF? and TNF?. The normal-like subset showed high expression of genes associated with lipid signaling, which was absent in the inflammatory and limited subsets. Together, these data suggest a model by which IFN? is involved in early disease pathology, and disease severity is associated with active TGF? signaling. PMID:25607805
Chitin activates parallel immune modules that direct distinct inflammatory responses via innate lymphoid type 2 (ILC2) and ?? T cells
Van Dyken, Steven J.; Mohapatra, Alexander; Nussbaum, Jesse C.; Molofsky, Ari B.; Thornton, Emily E.; Ziegler, Steven F.; McKenzie, Andrew N. J.; Krummel, Matthew F.; Liang, Hong-Erh; Locksley, Richard M.
SUMMARY Chitin, a polysaccharide constituent of many allergens and parasites, initiates innate type 2 lung inflammation through incompletely defined pathways. We show that inhaled chitin induced expression of three epithelial cytokines, interleukin-25 (IL-25), IL-33 and thymic stromal lymphopoietin (TSLP), which non-redundantly activated resident innate lymphoid type 2 cells (ILC2) to express IL-5 and IL-13 necessary for accumulation of eosinophils and alternatively activated macrophages (AAMs). In the absence of all three epithelial cytokines, ILC2 normally populated the lung but failed to increase IL-5 and IL-13. Although eosinophils and AAMs were attenuated, neutrophil influx remained normal without these epithelial cytokines. Genetic ablation of ILC2, however, enhanced IL-1?, TNF? and IL-23 expression, increased activation of IL-17A-producing ?? T cells, and prolonged neutrophil influx. Thus, chitin elicited patterns of innate cytokines that targeted distinct populations of resident lymphoid cells, revealing divergent but interacting pathways underlying the tissue accumulation of specific types of inflammatory myeloid cells. PMID:24631157
Human T-cell leukemia virus type 1 Tax protein transforms rat fibroblasts via two distinct pathways.
Matsumoto, K; Shibata, H; Fujisawa, J I; Inoue, H; Hakura, A; Tsukahara, T; Fujii, M
The human T-cell leukemia virus type 1 (HTLV-1) Tax protein activates the transcription of several cellular genes. This function is thought to play a critical role in the Tax-dependent transformation step in HTLV-1 leukemogenesis. Tax activates transcription via three enhancers: the cyclic AMP response element (CRE)-like sequence, the kappaB element, and the CArG box. Their involvement in the transformation of rat fibroblasts by Tax was examined by colony formation of Rat-1 cells in soft agar and Ras cooperative focus formation of rat embryo fibroblasts (REF). Among Tax mutants, those retaining activity for the CArG box transformed REF like wild-type Tax, while those inactive for the CArG box did not. Thus, the activation of the CArG box pathway is essential for the transformation of REF by Tax. In contrast, activation of the kappaB element correlated with the transformation of Rat-1 by Tax. These results show that Tax transforms rat fibroblasts via two distinct pathways. PMID:9151835
Identification and characterization of a new and distinct molecular subtype of human T-cell lymphotropic virus type 2.
Eiraku, N; Novoa, P; da Costa Ferreira, M; Monken, C; Ishak, R; da Costa Ferreira, O; Zhu, S W; Lorenco, R; Ishak, M; Azvedo, V; Guerreiro, J; de Oliveira, M P; Loureiro, P; Hammerschlak, N; Ijichi, S; Hall, W M
Molecular studies have demonstrated the existence of at least two major subtypes of human T-cell lymphotropic virus type 2 (HTLV-2), designated HTLV-2a and HTLV-2b. To further investigate the heterogeneity of this family of viruses, we have characterized the HTLV-2 subtypes present in several urban areas in Brazil. DNAs from peripheral blood mononuclear cells of a large number of infected individuals, the majority of whom were intravenous drug abusers, were analyzed by using PCR with restriction fragment length polymorphism and nucleotide sequencing analysis. Restriction fragment length polymorphism analysis of the env region suggested that all individuals were infected with the HTLV-2a subtype, and this was confirmed by nucleotide sequence analysis. In contrast, nucleotide sequence analysis of the long terminal repeat demonstrated that although the viruses were more related to the HTLV-2a than to the HTLV-2b subtype, they clustered in a distinct phylogenetic group, suggesting that they may represent a new and distinct molecular subtype of HTLV-2. This conclusion was supported by nucleotide sequence analysis of the pX region, which demonstrated that the Tax proteins of the Brazilian viruses differed from that of prototype HTLV-2a isolates but were more similar to that of HTLV-2b in that they would be expected to have an additional 25 amino acids at the carboxy terminus. In transient expression assays, the extended Tax protein of the prototype HTLV-2a subtype. The studies suggest that the Brazilian viruses analyzed in this study, while being phylogenetically related to the prototypic HTLV-2a seen in North America, are phenotypically more related to HTLV-2b and can be justifiably classified as a new molecular subtype, which has been tentatively designated HTLV-2c. PMID:8627666
Is nonsmall cell type high-grade neuroendocrine carcinoma of the tubular gastrointestinal tract a distinct disease entity?
Shia, Jinru; Tang, Laura H; Weiser, Martin R; Brenner, Baruch; Adsay, N Volkan; Stelow, Edward B; Saltz, Leonard B; Qin, Jing; Landmann, Ron; Leonard, Gregory D; Dhall, Deepti; Temple, Larissa; Guillem, Jose G; Paty, Philip B; Kelsen, David; Wong, W Douglas; Klimstra, David S
Although small cell carcinoma of the gastrointestinal (GI) tract is well-recognized, nonsmall cell type high-grade neuroendocrine carcinoma (HGNEC) of this site remains undefined. At the current time, neither the World Health Organization nor American Joint Committee on Cancer includes this condition in the histologic classifications, and consequently it is being diagnosed and treated inconsistently. In this study, we aimed at delineating the histologic and immunophenotypical spectrum of HGNECs of the GI tract with emphasis on histologic subtypes. Guided primarily by the World Health Organization/International Association for the Study of Lung Cancer criteria for pulmonary neuroendocrine tumors, we were able to classify 87 high-grade GI tract tumors that initially carried a diagnosis of either poorly differentiated carcinoma with or without any neuroendocrine characteristics, small cell carcinoma, or combined adenocarcinoma-neuroendocrine carcinoma into the following 4 categories. The first was small cell carcinoma (n=23), which had features typical of pulmonary small cell carcinoma, although the cells tended to have a more round nuclear contour. The second was large cell neuroendocrine carcinoma (n=31), which had a morphology similar to its pulmonary counterpart and showed positive immunoreactivity for either chromogranin (71%) or synaptophysin (94%) or both. The third was mixed neuroendocrine carcinoma (n=11), which had intermediate histologic features (eg, cells with an increased nuclear/cytoplasmic ratio but with apparent nucleoli), and positive immunoreactivity for at least 1 neuroendocrine marker. The fourth was poorly differentiated adenocarcinoma (n=17). In addition, 5 of the 87 tumors showed either nonsmall cell type neuroendocrine morphology (n=3) or immunohistochemical reactivity for neuroendocrine markers (n=2), but not both. Further analysis showed that most HGNECs arising in the squamous lined parts (esophagus and anal canal) were small cell type (78%), whereas most involving the glandular mucosa were large cell (53%) or mixed (82%) type; associated adenocarcinomas were more frequent in large cell (61%) or mixed (36%) type than in small cell type (26%); and focal intracytoplasmic mucin was seen only in large cell or mixed type. As a group, the 2-year disease-specific survival for patients with HGNEC was 25.4% (median follow-up time, 11.3 mo). No significant survival difference was observed among the different histologic subtypes. In conclusion, our study demonstrates the existence of both small cell and nonsmall cell types of HGNEC in the GI tract, and provides a detailed illustration of their morphologic spectrum. There are differences in certain pathologic features between small cell and nonsmall cell types, whereas the differences between the subtypes of nonsmall cell category (large cell versus mixed) are less distinct. Given the current uncertainty as to whether large cell neuroendocrine carcinoma is as chemosensitive as small cell carcinoma even in the lung, our data provide further evidence in favor of a dichotomous classification scheme (small cell vs. nonsmall cell) for HGNEC of the GI tract. Separation of nonsmall cell type into large cell and mixed subtypes may not be necessary. These tumors are clinically aggressive. Prospective studies using defined diagnostic criteria are needed to determine their biologic characteristics and optimal management. PMID:18360283
Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis
Benjamin F Voight; Laura J Scott; Valgerdur Steinthorsdottir; Andrew P Morris; Christian Dina; Ryan P Welch; Eleftheria Zeggini; Cornelia Huth; Yurii S Aulchenko; Gudmar Thorleifsson; Laura J McCulloch; Teresa Ferreira; Harald Grallert; Najaf Amin; Guanming Wu; Cristen J Willer; Soumya Raychaudhuri; Steve A McCarroll; Claudia Langenberg; Oliver M Hofmann; Josķe Dupuis; Lu Qi; Ayellet V SegrĶ; Mandy van Hoek; Pau Navarro; Kristin Ardlie; Beverley Balkau; Rafn Benediktsson; Amanda J Bennett; Roza Blagieva; Eric Boerwinkle; Lori L Bonnycastle; Kristina Bengtsson Bostr÷m; Bert Bravenboer; Suzannah Bumpstead; Noisļl P Burtt; Guillaume Charpentier; Peter S Chines; Marilyn Cornelis; David J Couper; Gabe Crawford; Alex S F Doney; Katherine S Elliott; Amanda L Elliott; Michael R Erdos; Caroline S Fox; Christopher S Franklin; Martha Ganser; Christian Gieger; Niels Grarup; Todd Green; Simon Griffin; Christopher J Groves; Candace Guiducci; Samy Hadjadj; Neelam Hassanali; Christian Herder; Bo Isomaa; Anne U Jackson; Paul R V Johnson; Torben J°rgensen; Wen H L Kao; Norman Klopp; Augustine Kong; Peter Kraft; Johanna Kuusisto; Torsten Lauritzen; Man Li; Aloysius Lieverse; Cecilia M Lindgren; Valeriya Lyssenko; Michel Marre; Thomas Meitinger; Kristian Midthjell; Mario A Morken; Narisu Narisu; Peter Nilsson; Katharine R Owen; Felicity Payne; John R B Perry; Ann-Kristin Petersen; Carl Platou; Christine Proenńa; Inga Prokopenko; Wolfgang Rathmann; N William Rayner; Neil R Robertson; Ghislain Rocheleau; Michael Roden; Michael J Sampson; Richa Saxena; Beverley M Shields; Peter Shrader; Gunnar Sigurdsson; Thomas Spars°; Klaus Strassburger; Heather M Stringham; Qi Sun; Amy J Swift; Barbara Thorand; Jean Tichet; Tiinamaija Tuomi; Rob M van Dam; Timon W van Haeften; Thijs van Herpt; Jana V van Vliet-Ostaptchouk; G Bragi Walters; Michael N Weedon; Cisca Wijmenga; Jacqueline Witteman; Richard N Bergman; Stephane Cauchi; Francis S Collins; Anna L Gloyn; Ulf Gyllensten; Torben Hansen; Winston A Hide; Graham A Hitman; Albert Hofman; David J Hunter; Kristian Hveem; Markku Laakso; Karen L Mohlke; Andrew D Morris; Colin N A Palmer; Peter P Pramstaller; Igor Rudan; Eric Sijbrands; Lincoln D Stein; Jaakko Tuomilehto; Andre Uitterlinden; Mark Walker; Nicholas J Wareham; Richard M Watanabe; Gonńalo R Abecasis; Bernhard O Boehm; Harry Campbell; Mark J Daly; Andrew T Hattersley; Frank B Hu; James B Meigs; James S Pankow; Oluf Pedersen; H-Erich Wichmann; InĻs Barroso; Jose C Florez; Timothy M Frayling; Leif Groop; Rob Sladek; Unnur Thorsteinsdottir; James F Wilson; Thomas Illig; Philippe Froguel; Cornelia M van Duijn; Kari Stefansson; David Altshuler; Michael Boehnke; Mark I McCarthy
By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P < 5 ū 10?8. These include a second independent signal at the KCNQ1 locus; the first
Targeting surface nucleolin with multivalent HB-19 and related Nucant pseudopeptides results in distinct inhibitory mechanisms depending on the malignant tumor cell type
Background Nucleolin expressed at the cell surface is a binding protein for a variety of ligands implicated in tumorigenesis and angiogenesis. By using a specific antagonist that binds the C-terminal RGG domain of nucleolin, the HB-19 pseudopeptide, we recently reported that targeting surface nucleolin with HB-19 suppresses progression of established human breast tumor cells in the athymic nude mice, and delays development of spontaneous melanoma in the RET transgenic mice. Methods By the capacity of HB-19 to bind stably surface nucleolin, we purified and identified nucleolin partners at the cell surface. HB-19 and related multivalent Nucant pseudopeptides, that present pentavalently or hexavalently the tripeptide Lys?(CH2N)-Pro-Arg, were then used to show that targeting surface nucleolin results in distinct inhibitory mechanisms on breast, prostate, colon carcinoma and leukemia cells. Results Surface nucleolin exists in a 500-kDa protein complex including several other proteins, which we identified by microsequencing as two Wnt related proteins, Ku86 autoantigen, signal recognition particle subunits SRP68/72, the receptor for complement component gC1q-R, and ribosomal proteins S4/S6. Interestingly, some of the surface-nucleolin associated proteins are implicated in cell signaling, tumor cell adhesion, migration, invasion, cell death, autoimmunity, and bacterial infections. Surface nucleolin in the 500-kDa complex is highly stable. Surface nucleolin antagonists, HB-19 and related multivalent Nucant pseudopeptides, exert distinct inhibitory mechanisms depending on the malignant tumor cell type. For example, in epithelial tumor cells they inhibit cell adhesion or spreading and induce reversion of the malignant phenotype (BMC cancer 2010, 10:325) while in leukemia cells they trigger a rapid cell death associated with DNA fragmentation. The fact that these pseudopeptides do not cause cell death in epithelial tumor cells indicates that cell death in leukemia cells is triggered by a specific signaling mechanism, rather than nonspecific cellular injury. Conclusions Our results suggest that targeting surface nucleolin could change the organization of the 500-kDa complex to interfere with the proper functioning of surface nucleolin and the associated proteins, and thus lead to distinct inhibitory mechanisms. Consequently, HB-19 and related Nucant pseudopeptides provide novel therapeutic opportunities in treatment of a wide variety of cancers and related malignancies. PMID:21812966
Using vertebrate prey capture locations to identify cover type selection patterns of nocturnally foraging Burrowing Owls.
Marsh, Alan; Bayne, Erin M; Wellicome, Troy I
Studies of habitat selection often measure an animal's use of space via radiotelemetry or GPS-based technologies. Such data tend to be analyzed using a resource selection function, despite the fact that the actual resources acquired are typically not recorded. Without explicit proof of resource use, conclusions from RSF models are based on assumptions regarding an animal's behavior and the resources gained. Conservation initiatives are often based on space-use models, and could be detrimental to the target species if these assumptions are incorrect. We used GPS dataloggers and digital video recorders to determine precise locations where nocturnally foraging Burrowing Owls acquired food resources (vertebrate prey). We compared land cover type selection patterns using a presence-only resource selection function (RSF) to a model that incorporated prey capture locations (CRSF). We also compared net prey returns in each cover type to better measure reward relative to foraging effort. The RSF method did not reflect prey capture patterns and cover-type rankings from this model were quite different from models that used only locations where prey was known to have been obtained. Burrowing Owls successfully foraged across all cover types; however, return vs. effort models indicate that different cover types were of higher quality than those identified using resource selection functions. Conclusions about the type of resources acquired should not be made from RSF-style models without evidence that the actual resource of interest was acquired. Conservation efforts based on RSF models alone may be ineffective or detrimental to the target species if the limiting resource and where it is acquired are not properly identified. PMID:25154089
On Identifying Clusters Within the C-type Asteroids of the Sloan Digital Sky Survey
NASA Astrophysics Data System (ADS)
Poole, Renae; Ziffer, J.; Harvell, T.
We applied AutoClass, a data mining technique based upon Bayesian Classification, to C-group asteroid colors in the Sloan Digital Sky Survey (SDSS). Previous taxonomic studies relied mostly on Principal Component Analysis (PCA) to differentiate asteroids within the C-group (e.g. B, G, F, Ch, Cg and Cb). AutoClass's advantage is that it calculates the most probable classification for us, removing the human factor from this part of the analysis. In our results, AutoClass divided the C-groups into two large classes and six smaller classes. The two large classes (n=4974 and 2033, respectively) display distinct regions with some overlap in color-vs-color plots. Each cluster's average spectrum is compared to 'typical' spectra of the C-group subtypes as defined by Tholen (1989) and each cluster's members are evaluated for consistency with previous taxonomies. Of the 117 asteroids classified as B-type in previous taxonomies, only 12 were found with SDSS colors that matched our criteria of having less than 0.1 magnitude error in u and 0.05 magnitude error in g, r, i, and z colors. Although this is a relatively small group, 11 of the 12 B-types were placed by AutoClass in the same cluster. By determining the C-group sub-classifications in the large SDSS database, this research furthers our understanding of the stratigraphy and composition of the main-belt.
Human T-lymphotropic virus type I Tax protein utilizes distinct pathways for p53 inhibition that are cell type-dependent.
Pise-Masison, C A; Mahieux, R; Radonovich, M; Jiang, H; Brady, J N
p53 plays a pivotal role in transmitting signals from many forms of genotoxic stress to genes and factors that control the cell cycle and apoptosis. We have previously shown that the human T-lymphotropic virus type I Tax protein can inhibit p53 function. Recently we reported that Tax inhibits p53 function in Jurkat cells and mouse embryo fibroblasts through a mechanism involving the nuclear factor kappa B pathway and correlates with phosphorylation on serines 15 and 392 of p53. However, several groups have also observed a mechanism that correlates with p300 binding of Tax. To address this controversy and to determine the mechanism by which Tax inhibits p53 function, we examined the activation functions of Tax required for p53 inhibition. In HeLa and H1299 cells the cAMP-response element-binding protein/activating transcription factor activation function is essential, as demonstrated by the Tax mutants M47 and K88A. In addition, expression of exogenous p300 in H1299 cells allows full recovery of p53 transactivation in the presence of Tax. Consistent with p300 being a limiting factor in H1299, Saos-2, and HeLa cells, we found that the level of endogenous p300 is relatively low in these cells compared with Jurkat cells or the human T-lymphotropic virus type I-infected C81 and MT2 cells. Thus our data suggests that Tax utilizes distinct mechanisms to inhibit p53 function that are cell type-dependent. PMID:11036071
The First Identified Nucleocytoplasmic Shuttling Herpesviral Capsid Protein: Herpes Simplex Virus Type 1 VP19C
Zhao, Lei; Zheng, Chunfu
VP19C is a structural protein of herpes simplex virus type 1 viral particle, which is essential for assembly of the capsid. In this study, a nuclear export signal (NES) of VP19C is for the first time identified and mapped to amino acid residues 342 to 351. Furthermore, VP19C is demonstrated to shuttle between the nucleus and the cytoplasm through the NES in a chromosomal region maintenance 1 (CRM1)-dependent manner involving RanGTP hydrolysis. This makes VP19C the first herpesviral capsid protein with nucleocytoplasmic shuttling property and adds it to the list of HSV-1 nucleocytoplasmic shuttling proteins. PMID:22927916
Identifying Mobility Types in Cognitively Heterogeneous Older Adults Based on GPS-Tracking: What Discriminates Best?
Wettstein, Markus; Wahl, Hans-Werner; Shoval, Noam; Auslander, Gail; Oswald, Frank; Heinik, Jeremia
Heterogeneity in older adults' mobility and its correlates have rarely been investigated based on objective mobility data and in samples including cognitively impaired individuals. We analyzed mobility profiles within a cognitively heterogeneous sample of N = 257 older adults from Israel and Germany based on GPS tracking technology. Participants were aged between 59 and 91 years (M = 72.9; SD = 6.4) and were either cognitively healthy (CH, n = 146), mildly cognitively impaired (MCI, n = 76), or diagnosed with an early-stage dementia of the Alzheimer's type (DAT, n = 35). Based on cluster analysis, we identified three mobility types ("Mobility restricted," "Outdoor oriented," "Walkers"), which could be predicted based on socio-demographic indicators, activity, health, and cognitive impairment status using discriminant analysis. Particularly demented individuals and persons with worse health exhibited restrictions in mobility. Our findings contribute to a better understanding of heterogeneity in mobility in old age. PMID:24652916
Human antibodies recognize multiple distinct type-specific and cross-reactive regions of the minor capsid proteins of human papillomavirus types 6 and 11.
Yaegashi, N; Jenison, S A; Batra, M; Galloway, D A
Human serum samples derived from a case-control study of patients with cervical carcinoma (n = 174) or condyloma acuminatum (n = 25) were tested for the presence of immunoglobulin G antibodies to human papillomavirus type 6 (HPV6) L2 and HPV11 L2 recombinant proteins in a Western immunoblot assay. Thirty-six samples (18%) were positive for HPV6 L2 antibodies alone, 25 (13%) were positive for HPV11 L2 antibodies alone, and 34 (17%) were positive for both HPV6 L2 and HPV11 L2 antibodies. Thirty samples that were positive for both antibodies were tested for the presence of HPV6-HPV11 L2 cross-reactive antibodies. Fifteen (50%) serum samples contained HPV6-HPV11 L2 cross-reactive antibodies, and 15 (50%) contained independent, type-specific HPV6 L2 and HPV11 L2 antibodies. Altogether, 82% of the HPV6 L2 and HPV11 L2 antibody reactivities were type specific and 18% were HPV6-HPV11 cross-reactive. There was no significant difference in the prevalence of antibody reactivities between samples from patients with cervical carcinoma and those with condyloma acuminatum. Deletion mapping identified five HPV6 L2 regions that reacted with HPV6 type-specific antibodies: 6U1 (amino acids [aa] 152 to 173), 6U2 (aa 175 to 191), 6U3 (aa 187 to 199), 6U4 (aa 201 to 217), and 6U5 (aa 351 to 367). Five HPV11 L2 regions that reacted with HPV11 type-specific antibodies were identified: 11U1 (aa 49 to 84), 11U2 (aa 147 to 162), 11U3 (aa 179 to 188), 11U4 (aa 180 to 200), and 11U5 (aa 355 to 367). Two HPV6-HPV11 cross-reactive regions were identified: 6CR1 (HPV6 L2 aa 106 to 128)/11CR1 (HPV11 L2 aa 103 to 127) and 6CR2 (HPV6 L2 aa 187 to 199)/11CR2 (HPV11 L2 aa 180 to 200). Images PMID:1312618
Schneider, Adam; Song, Inseok [Department of Physics and Astronomy, University of Georgia, Athens, GA 30602 (United States); Melis, Carl [Center for Astrophysics and Space Sciences, University of California, San Diego, CA 92093 (United States); Zuckerman, B. [Department of Physics and Astronomy, University of California, Los Angeles, CA, 90095 (United States); Bessell, Mike, E-mail: firstname.lastname@example.com, E-mail: firstname.lastname@example.com, E-mail: email@example.com, E-mail: firstname.lastname@example.com, E-mail: firstname.lastname@example.com [Research School of Astronomy and Astrophysics, The Australian National University, Weston Creek, ACT 2611 (Australia)
It has recently been shown that a significant fraction of late-type members of nearby, very young associations (age {approx}<10 Myr) display excess emission at mid-IR wavelengths indicative of dusty circumstellar disks. We demonstrate that the detection of mid-IR excess emission can be utilized to identify new nearby, young, late-type stars including two definite new members ('TWA 33' and 'TWA 34') of the TW Hydrae Association (TWA). Both new TWA members display mid-IR excess emission in the Wide-field Infrared Survey Explorer catalog and they show proper motion and youthful spectroscopic characteristics-namely, H{alpha} emission, strong lithium absorption, and low surface gravity features consistent with known TWA members. We also detect mid-IR excess-the first unambiguous evidence of a dusty circumstellar disk-around a previously identified UV-bright, young, accreting star (2M1337) that is a likely member of the Lower-Centaurus Crux region of the Scorpius-Centaurus Complex.
Genome-Wide Expression Profiling Identifies Type 1 Interferon Response Pathways in Active Tuberculosis
Ottenhoff, Tom H. M.; Zhang, Mingzi M.; Wong, Hazel E. E.; Sahiratmadja, Edhyana; Khor, Chiea Chuen; Alisjahbana, Bachti; van Crevel, Reinout; Marzuki, Sangkot; Seielstad, Mark; van de Vosse, Esther; Hibberd, Martin L.
Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), remains the leading cause of mortality from a single infectious agent. Each year around 9 million individuals newly develop active TB disease, and over 2 billion individuals are latently infected with M.tb worldwide, thus being at risk of developing TB reactivation disease later in life. The underlying mechanisms and pathways of protection against TB in humans, as well as the dynamics of the host response to M.tb infection, are incompletely understood. We carried out whole-genome expression profiling on a cohort of TB patients longitudinally sampled along 3 time-points: during active infection, during treatment, and after completion of curative treatment. We identified molecular signatures involving the upregulation of type-1 interferon (?/?) mediated signaling and chronic inflammation during active TB disease in an Indonesian population, in line with results from two recent studies in ethnically and epidemiologically different populations in Europe and South Africa. Expression profiles were captured in neutrophil-depleted blood samples, indicating a major contribution of lymphocytes and myeloid cells. Expression of type-1 interferon (?/?) genes mediated was also upregulated in the lungs of M.tb infected mice and in infected human macrophages. In patients, the regulated gene expression-signature normalized during treatment, including the type-1 interferon mediated signaling and a concurrent opposite regulation of interferon-gamma. Further analysis revealed IL15RA, UBE2L6 and GBP4 as molecules involved in the type-I interferon response in all three experimental models. Our data is highly suggestive that the innate immune type-I interferon signaling cascade could be used as a quantitative tool for monitoring active TB disease, and provide evidence that components of the patientÆs blood gene expression signature bear similarities to the pulmonary and macrophage response to mycobacterial infection. PMID:23029268
Identifying New Positives and Linkage to HIV Medical Care - 23 Testing Site Types, United States, 2013.
Seth, Puja; Wang, Guoshen; Collins, Nicoline T; Belcher, Lisa
Among the estimated 1.2 million persons living with human immunodeficiency virus (HIV) infection in the United States, approximately 14% have not had their HIV diagnosed. Certain populations, such as African Americans/blacks (in this report referred to as blacks), men who have sex with men (MSM), and Hispanics/Latinos (in this report referred to as Hispanics), are disproportionately affected by HIV. In areas where HIV prevalence is ?0.1%, CDC recommends routine HIV screening in health care settings for persons aged 13-64 years. Implementation of HIV screening as part of routine care can increase the number of HIV diagnoses, destigmatize HIV testing, and improve access to care for persons with new HIV infections. Additionally, targeted testing in non-health care settings might facilitate access to persons in at-risk populations (e.g., MSM, blacks, and Hispanics) who are unaware of their status and do not routinely seek care. CDC analyzed data for 23 testing site types submitted by 61 health departments and 151 CDC-funded community-based organizations to determine 1) the number of HIV tests conducted, 2) the percentage of persons with new diagnoses of HIV infection (in this report referred to as new positives), and 3) the percentage of persons who were linked to HIV medical care within 90 days after receiving diagnoses at specific site types within health care and non-health care settings. The results indicated that, in health care settings, primary care and sexually transmitted disease (STD) clinics accounted for substantially more HIV tests than did other sites, and STD clinics identified more new positives. In non-health care settings, HIV counseling and testing sites accounted for the most tests and identified the highest number of new positives. Examining program data by site type shows which sites performed better in diagnosing new positives and informs decisions about program planning and allocation of CDC HIV testing resources among and within settings. PMID:26110836
Brass, Stefan
, July 1998. . Tim BernersŁLee: Cool URIs don't change. [http://www.w3.org/Provider/Style/URI] . Uniform://archive.ncsa.uiuc.edu/demoweb/urlŁprimer.html] . T. BernersŁLee, R. Fielding, L. Masinter: Uniform Resource Identifiers (URI): Generic Syntax. RFC Names. RFC 1737, December 1994, 7 pages. . T. BernersŁLee, L. Masinter, M. McCahill: Uniform Resource
Brass, Stefan
, July 1998. . Tim BernersŁLee: Cool URIs don't change. [http://www.w3.org/Provider/Style/URI] Stefan://archive.ncsa.uiuc.edu/demoweb/urlŁprimer.html] . T. BernersŁLee, R. Fielding, L. Masinter: Uniform Resource Identifiers (URI): Generic Syntax. RFC Names. RFC 1737, December 1994, 7 pages. . T. BernersŁLee, L. Masinter, M. McCahill: Uniform Resource
Expression quantitative trait analyses to identify causal genetic variants for type 2 diabetes susceptibility
Das, Swapan Kumar; Sharma, Neeraj Kumar
Type 2 diabetes (T2D) is a common metabolic disorder which is caused by multiple genetic perturbations affecting different biological pathways. Identifying genetic factors modulating the susceptibility of this complex heterogeneous metabolic phenotype in different ethnic and racial groups remains challenging. Despite recent success, the functional role of the T2D susceptibility variants implicated by genome-wide association studies (GWAS) remains largely unknown. Genetic dissection of transcript abundance or expression quantitative trait (eQTL) analysis unravels the genomic architecture of regulatory variants. Availability of eQTL information from tissues relevant for glucose homeostasis in humans opens a new avenue to prioritize GWAS-implicated variants that may be involved in triggering a causal chain of events leading to T2D. In this article, we review the progress made in the field of eQTL research and knowledge gained from those studies in understanding transcription regulatory mechanisms in human subjects. We highlight several novel approaches that can integrate eQTL analysis with multiple layers of biological information to identify ethnic-specific causal variants and gene-environment interactions relevant to T2D pathogenesis. Finally, we discuss how the eQTL analysis mediated search for ōmissing heritabilityö may lead us to novel biological and molecular mechanisms involved in susceptibility to T2D. PMID:24748924
Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.
Saxena, Richa; Voight, Benjamin F; Lyssenko, Valeriya; Burtt, Noļl P; de Bakker, Paul I W; Chen, Hong; Roix, Jeffrey J; Kathiresan, Sekar; Hirschhorn, Joel N; Daly, Mark J; Hughes, Thomas E; Groop, Leif; Altshuler, David; Almgren, Peter; Florez, Jose C; Meyer, Joanne; Ardlie, Kristin; Bengtsson Bostr÷m, Kristina; Isomaa, Bo; Lettre, Guillaume; Lindblad, Ulf; Lyon, Helen N; Melander, Olle; Newton-Cheh, Christopher; Nilsson, Peter; Orho-Melander, Marju; RÕstam, Lennart; Speliotes, Elizabeth K; Taskinen, Marja-Riitta; Tuomi, Tiinamaija; Guiducci, Candace; Berglund, Anna; Carlson, Joyce; Gianniny, Lauren; Hackett, Rachel; Hall, Liselotte; Holmkvist, Johan; Laurila, Esa; Sj÷gren, Marketa; Sterner, Maria; Surti, Aarti; Svensson, Margareta; Svensson, Malin; Tewhey, Ryan; Blumenstiel, Brendan; Parkin, Melissa; Defelice, Matthew; Barry, Rachel; Brodeur, Wendy; Camarata, Jody; Chia, Nancy; Fava, Mary; Gibbons, John; Handsaker, Bob; Healy, Claire; Nguyen, Kieu; Gates, Casey; Sougnez, Carrie; Gage, Diane; Nizzari, Marcia; Gabriel, Stacey B; Chirn, Gung-Wei; Ma, Qicheng; Parikh, Hemang; Richardson, Delwood; Ricke, Darrell; Purcell, Shaun
New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single-nucleotide polymorphisms (SNPs) in 1464 patients with T2D and 1467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D), we identified and confirmed three loci associated with T2D-in a noncoding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1-and replicated associations near HHEX and in SLC30A8 found by a recent whole-genome association study. We identified and confirmed association of a SNP in an intron of glucokinase regulatory protein (GCKR) with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases. PMID:17463246
Genome-wide association study identifies three novel loci for type 2 diabetes.
Hara, Kazuo; Fujita, Hayato; Johnson, Todd A; Yamauchi, Toshimasa; Yasuda, Kazuki; Horikoshi, Momoko; Peng, Chen; Hu, Cheng; Ma, Ronald C W; Imamura, Minako; Iwata, Minoru; Tsunoda, Tatsuhiko; Morizono, Takashi; Shojima, Nobuhiro; So, Wing Yee; Leung, Ting Fan; Kwan, Patrick; Zhang, Rong; Wang, Jie; Yu, Weihui; Maegawa, Hiroshi; Hirose, Hiroshi; Kaku, Kohei; Ito, Chikako; Watada, Hirotaka; Tanaka, Yasushi; Tobe, Kazuyuki; Kashiwagi, Atsunori; Kawamori, Ryuzo; Jia, Weiping; Chan, Juliana C N; Teo, Yik Ying; Shyong, Tai E; Kamatani, Naoyuki; Kubo, Michiaki; Maeda, Shiro; Kadowaki, Takashi
Although over 60 loci for type 2 diabetes (T2D) have been identified, there still remains a large genetic component to be clarified. To explore unidentified loci for T2D, we performed a genome-wide association study (GWAS) of 6 209 637 single-nucleotide polymorphisms (SNPs), which were directly genotyped or imputed using East Asian references from the 1000 Genomes Project (June 2011 release) in 5976 Japanese patients with T2D and 20 829 nondiabetic individuals. Nineteen unreported loci were selected and taken forward to follow-up analyses. Combined discovery and follow-up analyses (30 392 cases and 34 814 controls) identified three new loci with genome-wide significance, which were MIR129-LEP [rs791595; risk allele = A; risk allele frequency (RAF) = 0.080; P = 2.55 ū 10(-13); odds ratio (OR) = 1.17], GPSM1 [rs11787792; risk allele = A; RAF = 0.874; P = 1.74 ū 10(-10); OR = 1.15] and SLC16A13 (rs312457; risk allele = G; RAF = 0.078; P = 7.69 ū 10(-13); OR = 1.20). This study demonstrates that GWASs based on the imputation of genotypes using modern reference haplotypes such as that from the 1000 Genomes Project data can assist in identification of new loci for common diseases. PMID:23945395
Identifying low-dimensional dynamics in type-I edge-localised-mode processes in JET plasmas
Calderon, F. A.; Chapman, S. C.; Nicol, R. M. [Department of Physics, Centre for Fusion, Space and Astrophysics, University of Warwick, Coventry CV4 7AL (United Kingdom); Dendy, R. O. [EURATOM/CCFE Fusion Association, Culham Science Centre, Abingdon, Oxfordshire OX14 3DB (United Kingdom); Department of Physics, Centre for Fusion, Space and Astrophysics, University of Warwick, Coventry CV4 7AL (United Kingdom); Webster, A. J.; Alper, B. [EURATOM/CCFE Fusion Association, Culham Science Centre, Abingdon, Oxfordshire OX14 3DB (United Kingdom); Collaboration: JET EFDA Contributors
Edge localised mode (ELM) measurements from reproducibly similar plasmas in the Joint European Torus (JET) tokamak, which differ only in their gas puffing rate, are analysed in terms of the pattern in the sequence of inter-ELM time intervals. It is found that the category of ELM defined empirically as type I-typically more regular, less frequent, and having larger amplitude than other ELM types-embraces substantially different ELMing processes. By quantifying the structure in the sequence of inter-ELM time intervals using delay time plots, we reveal transitions between distinct phase space dynamics, implying transitions between distinct underlying physical processes. The control parameter for these transitions between these different ELMing processes is the gas puffing rate.
Genogeography and Immune Epitope Characteristics of Hepatitis B Virus Genotype C Reveals Two Distinct Types: Asian and Papua-Pacific
Thedja, Meta Dewi; Muljono, David Handojo; Ie, Susan Irawati; Sidarta, Erick; Turyadi; Verhoef, Jan; Marzuki, Sangkot
Distribution of hepatitis B virus (HBV) genotypes/subgenotypes is geographically and ethnologically specific. In the Indonesian archipelago, HBV genotype C (HBV/C) is prevalent with high genome variability, reflected by the presence of 13 of currently existing 16 subgenotypes. We investigated the association between HBV/C molecular characteristics with host ethnicity and geographical distribution by examining various subgenotypes of HBV/C isolates from the Asia and Pacific region, with further analysis on the immune epitope characteristics of the core and surface proteins. Phylogenetic tree was constructed based on complete HBV/C genome sequences from Asia and Pacific region, and genetic distance between isolates was also examined. HBV/C surface and core immune epitopes were analyzed and grouped by comparing the amino acid residue characteristics and geographical origins. Based on phylogenetic tree and geographical origins of isolates, two major groups of HBV/C isolatesŚEast-Southeast Asia and Papua-PacificŚwere identified. Analysis of core and surface immune epitopes supported these findings with several amino acid substitutions distinguishing the East-Southeast Asia isolates from the Papua-Pacific isolates. A west-to-east gradient of HBsAg subtype distribution was observed with adrq+ prominent in the East and Southeast Asia and adrq- in the Pacific, with several adrq-indeterminate subtypes observed in Papua and Papua New Guinea (PNG). This study indicates that HBV/C isolates can be classified into two types, the Asian and the Papua-Pacific, based on the virus genome diversity, immune epitope characteristics, and geographical distribution, with Papua and PNG as the molecular evolutionary admixture region in the switching from adrq+ to adrq-. PMID:26162099
Integration of Hi-C and ChIP-seq data reveals distinct types of chromatin linkages.
Lan, Xun; Witt, Heather; Katsumura, Koichi; Ye, Zhenqing; Wang, Qianben; Bresnick, Emery H; Farnham, Peggy J; Jin, Victor X
We have analyzed publicly available K562 Hi-C data, which enable genome-wide unbiased capturing of chromatin interactions, using a Mixture Poisson Regression Model and a power-law decay background to define a highly specific set of interacting genomic regions. We integrated multiple ENCODE Consortium resources with the Hi-C data, using DNase-seq data and ChIP-seq data for 45 transcription factors and 9 histone modifications. We classified 12 different sets (clusters) of interacting loci that can be distinguished by their chromatin modifications and which can be categorized into two types of chromatin linkages. The different clusters of loci display very different relationships with transcription factor-binding sites. As expected, many of the transcription factors show binding patterns specific to clusters composed of interacting loci that encompass promoters or enhancers. However, cluster 9, which is distinguished by marks of open chromatin but not by active enhancer or promoter marks, was not bound by most transcription factors but was highly enriched for three transcription factors (GATA1, GATA2 and c-Jun) and three chromatin modifiers (BRG1, INI1 and SIRT6). To investigate the impact of chromatin organization on gene regulation, we performed ribonucleicacid-seq analyses before and after knockdown of GATA1 or GATA2. We found that knockdown of the GATA factors not only alters the expression of genes having a nearby bound GATA but also affects expression of genes in interacting loci. Our work, in combination with previous studies linking regulation by GATA factors with c-Jun and BRG1, provides genome-wide evidence that Hi-C data identify sets of biologically relevant interacting loci. PMID:22675074
Two Types of Functionally Distinct Fiber Containing Structural Protein Complexes Are Produced during Infection of Adenovirus Serotype 5
Zhang, Bo; Yan, Yuhua; Jin, Jie; Lin, Hongyu; Li, Zongyi; Zhang, Xiaoyan; Liu, Jin; Xi, Chao; Lieber, Andre; Fan, Xiaolong; Ran, Liang
Adenoviruses are common pathogens. The localization of their receptors coxsackievirus and adenovirus receptor, and desmoglein-2 in cell-cell junction complexes between polarized epithelial cells represents a major challenge for adenovirus infection from the apical surface. Structural proteins including hexon, penton base and fiber are excessively produced in serotype 5 adenovirus (Ad5)-infected cells. We have characterized the composition of structural protein complexes released from Ad5 infected cells and their capacity in remodeling cell-cell junction complexes. Using T84 cells as a model for polarized epithelium, we have studied the effect of Ad5 structural protein complexes in remodeling cell-cell junctions in polarized epithelium. The initial Ad5 infection in T84 cell culture was inefficient. However, progressive distortion of cell-cell junction in association with fiber release was evident during progression of Ad5 infection. Incubation of T84 cell cultures with virion-free supernatant from Ad5 infected culture resulted in distortion of cell-cell junctions and decreased infectivity of Ad5-GFP vector. We used gel filtration chromatography to fractionate fiber containing virion¢free supernatant from Ad5 infected culture supernatant. Fiber containing fractions were further characterized for their capacity to inhibit the infection of Ad5-GFP vector, their composition in adenovirus structural proteins using western blot and LC-MS/MS and their capacity in remolding cell-cell junctions. Fiber molecules in complexes containing penton base and hexon, or mainly hexon were identified. Only the fiber complexes with relatively high content of penton base, but not the fiber-hexon complexes with low penton base, were able to penetrate into T84 cells and cause distortion of cell-cell junctions. Our findings suggest that these two types of fiber complexes may play different roles in adenoviral infection. PMID:25723153
Genogeography and Immune Epitope Characteristics of Hepatitis B Virus Genotype C Reveals Two Distinct Types: Asian and Papua-Pacific.
Thedja, Meta Dewi; Muljono, David Handojo; Ie, Susan Irawati; Sidarta, Erick; Turyadi; Verhoef, Jan; Marzuki, Sangkot
Distribution of hepatitis B virus (HBV) genotypes/subgenotypes is geographically and ethnologically specific. In the Indonesian archipelago, HBV genotype C (HBV/C) is prevalent with high genome variability, reflected by the presence of 13 of currently existing 16 subgenotypes. We investigated the association between HBV/C molecular characteristics with host ethnicity and geographical distribution by examining various subgenotypes of HBV/C isolates from the Asia and Pacific region, with further analysis on the immune epitope characteristics of the core and surface proteins. Phylogenetic tree was constructed based on complete HBV/C genome sequences from Asia and Pacific region, and genetic distance between isolates was also examined. HBV/C surface and core immune epitopes were analyzed and grouped by comparing the amino acid residue characteristics and geographical origins. Based on phylogenetic tree and geographical origins of isolates, two major groups of HBV/C isolates-East-Southeast Asia and Papua-Pacific-were identified. Analysis of core and surface immune epitopes supported these findings with several amino acid substitutions distinguishing the East-Southeast Asia isolates from the Papua-Pacific isolates. A west-to-east gradient of HBsAg subtype distribution was observed with adrq+ prominent in the East and Southeast Asia and adrq- in the Pacific, with several adrq-indeterminate subtypes observed in Papua and Papua New Guinea (PNG). This study indicates that HBV/C isolates can be classified into two types, the Asian and the Papua-Pacific, based on the virus genome diversity, immune epitope characteristics, and geographical distribution, with Papua and PNG as the molecular evolutionary admixture region in the switching from adrq+ to adrq-. PMID:26162099
HIV type 1 mother-to-child transmission facilitated by distinctive glycosylation sites in the gp120 envelope glycoprotein.
Baan, Elly; de Ronde, Anthony; Luchters, Stanley; Vyankandondera, Joseph; Lange, Joep M; Pollakis, Georgios; Paxton, William A
The human immunodeficiency virus type 1 (HIV-1) characteristics associated with mother-to-child transmission (MTCT) are still poorly understood. We studied a cohort of 30 mothers from Rwanda infected with HIV-1 subtype A or C viruses of whom seven infected their children either during gestation or soon after birth. CD4 counts and viral load did not significantly differ between nontransmitting mother (NTM) versus transmitting mother (TM) groups. In contrast to earlier studies we not only analyzed and compared the genotypic characteristics of the V1-V5 region of the gp120 envelope of viruses found in TM and their infected children, but also included data from the NTM. No differences were found with respect to length and number of potential N-glycosylation sites (PNGS) in the V1-V2 and the V1-V5 region. We identified that viruses with a PNGS on positions AA234 and AA339 were preferably transmitted and that viruses with PNGS-N295 showed a disadvantage in transmission. We also showed that the frequency of PNGS-N339 in the viruses of TM and infected children was significantly higher than the frequency in NTM in our cohort and in viruses undergoing sexual transmission while the frequency of PNGS-N295 in children was significantly lower than the frequency in TM and acute horizontal infections. Collectively, our results provide evidence that the presence of the PNGS-N339 site and absence of the PNGS-N295 site in the gp120 envelope confers an advantage to HIV-1 when considering MTCT. PMID:21916748
Multiple Structurally Distinct ER? mRNA Variants in Zebrafish are Differentially Expressed by Tissue Type, Stage of Development and Estrogen Exposure
Cotter, Kellie A.; Yershov, Anya; Novillo, Apolonia; Callard, Gloria V.
It is well established that estrogen-like environmental chemicals interact with the ligand-binding site of estrogen receptors (ER) to disrupt transcriptional control of estrogen responsive targets. Here we investigate the possibility that estrogens also impact splicing decisions on estrogen responsive genes, such as that encoding ER? itself. Targeted PCR cloning was applied to identify six ER? mRNA variants in zebrafish. Sequencing revealed alternate use of transcription and translation start sites, multiple exon deletions, intron retention and alternate polyadenylation. As determined by quantitative (q)PCR, N-terminal mRNA variants predicting long (ER?L) and short (ER?S) isoforms were differentially expressed by tissue-type, sex, stage of development and estrogen exposure. Whereas ER?L mRNA was diffusely distributed in liver, brain, heart, eye, and gonads, ER?S mRNA was preferentially expressed in liver (female > male) and ovary. Neither ER?L nor ER?S transcripts varied significantly during development, but 17?-estradiol selectively increased accumulation of ER?S mRNA (~170-fold by 120 hpf), an effect mimicked by bisphenol-A and diethylstilbestrol. Significantly, a C-truncated variant (ER?S-Cx) lacking most of the ligand binding and AF-2 domains was transcribed exclusively from the short isoform promoter and was similar to ER?S in its tissue-, stage- and estrogen inducible expression. These results support the idea that promoter choice and alternative splicing of the esr1 gene of zebrafish are part of the autoregulatory mechanism by which estrogen modulates subsequent ER? expression, and further suggest that environmental estrogens could exert some of their toxic effects by altering the relative abundance of structurally and functionally distinct ER? isoforms. PMID:24090614
A Machine Learning Approach for Identifying Novel Cell Type¢Specific Transcriptional Regulators of Myogenesis
Kim, Yongsok; Tansey, Terese; Bloom, Molly J.; Ovcharenko, Ivan; Michelson, Alan M.
Transcriptional enhancers integrate the contributions of multiple classes of transcription factors (TFs) to orchestrate the myriad spatio-temporal gene expression programs that occur during development. A molecular understanding of enhancers with similar activities requires the identification of both their unique and their shared sequence features. To address this problem, we combined phylogenetic profiling with a DNA¢based enhancer sequence classifier that analyzes the TF binding sites (TFBSs) governing the transcription of a co-expressed gene set. We first assembled a small number of enhancers that are active in Drosophila melanogaster muscle founder cells (FCs) and other mesodermal cell types. Using phylogenetic profiling, we increased the number of enhancers by incorporating orthologous but divergent sequences from other Drosophila species. Functional assays revealed that the diverged enhancer orthologs were active in largely similar patterns as their D. melanogaster counterparts, although there was extensive evolutionary shuffling of known TFBSs. We then built and trained a classifier using this enhancer set and identified additional related enhancers based on the presence or absence of known and putative TFBSs. Predicted FC enhancers were over-represented in proximity to known FC genes; and many of the TFBSs learned by the classifier were found to be critical for enhancer activity, including POU homeodomain, Myb, Ets, Forkhead, and T-box motifs. Empirical testing also revealed that the T-box TF encoded by org-1 is a previously uncharacterized regulator of muscle cell identity. Finally, we found extensive diversity in the composition of TFBSs within known FC enhancers, suggesting that motif combinatorics plays an essential role in the cellular specificity exhibited by such enhancers. In summary, machine learning combined with evolutionary sequence analysis is useful for recognizing novel TFBSs and for facilitating the identification of cognate TFs that coordinate cell type¢specific developmental gene expression patterns. PMID:22412381
Further scale refinement for emotional labor : Exploring distinctions between types of surface versus deep acting using a difficult client referent
Gary Blau; Jason Fertig; Donna Surges Tatum; Stacey Connaughton; Dong Soo Park; Catherine Marshall
Purpose ¢ Within the emotional labor (EL) literature, the paper's aim is to test for additional scale distinctions in surface acting and deep acting, using a ōdifficult clientö referent. Design\\/methodology\\/approach ¢ Working with existing definitions and operationalizations across prior EL studies, an on-line sample of 1,975 massage therapists and bodywork practitioners (M&Bs) was used to test the hypotheses. Hinkin's recommended
Transcriptional Induction of the Pseudomonas aeruginosa Type III Secretion System by Low Ca2+ and Host Cell Contact Proceeds through Two Distinct Signaling Pathways
Nandini Dasgupta; Alix Ashare; Gary W. Hunninghake; Timothy L. Yahr
The opportunistic pathogen Pseudomonas aeruginosa utilizes a type III secretion system (T3SS) to intoxicate eukaryotic host cells. Transcription of the T3SS is induced under calcium-limited growth conditions or following intimate contact of P. aeruginosa with host cells. In the present study, we demonstrate that expression of the T3SS is controlled by two distinct regulatory mechanisms and that these mechanisms are
The first Fe-based Na(+)-ion cathode with two distinct types of polyanions: Fe3P5SiO19.
Kan, W H; Huq, A; Manthiram, A
Herein, we report the synthesis, structure, and electrochemistry of the first Na(+)-ion cathode with two distinct types of polyanions: Fe3P5SiO19. The Fe-based cathode has a reversible capacity of ca. 70 mA h g(-1); ca. 1.7 Na(+) ions per formula can be inserted/extracted at an average voltage of 2.5 V versus Na(+)/Na. PMID:26027701
Preferences for Pink and Blue: The Development of Color Preferences as a Distinct Gender-Typed Behavior in Toddlers.
Wong, Wang I; Hines, Melissa
Many gender differences are thought to result from interactions between inborn factors and sociocognitive processes that occur after birth. There is controversy, however, over the causes of gender-typed preferences for the colors pink and blue, with some viewing these preferences as arising solely from sociocognitive processes of gender development. We evaluated preferences for gender-typed colors, and compared them to gender-typed toy and activity preferences in 126 toddlers on two occasions separated by 6-8Āmonths (at Time 1, MĀ=Ā29Āmonths; range 20-40). Color preferences were assessed using color cards and neutral toys in gender-typed colors. Gender-typed toy and activity preferences were assessed using a parent-report questionnaire, the Preschool Activities Inventory. Color preferences were also assessed for the toddlers' parents using color cards. A gender difference in color preferences was present between 2 and 3Āyears of age and strengthened near the third birthday, at which time it was large (dĀ>Ā1). In contrast to their parents, toddlers' gender-typed color preferences were stronger and unstable. Gender-typed color preferences also appeared to establish later and were less stable than gender-typed toy and activity preferences. Gender-typed color preferences were largely uncorrelated with gender-typed toy and activity preferences. These results suggest that the factors influencing gender-typed color preferences and gender-typed toy and activity preferences differ in some respects. Our findings suggest that sociocognitive influences and play with gender-typed toys that happen to be made in gender-typed colors contribute to toddlers' gender-typed color preferences. PMID:25680819
A widespread bacterial type VI secretion effector superfamily identified using a heuristic approach
Russell, Alistair B.; Singh, Pragya; Brittnacher, Mitchell; Bui, Nhat Khai; Hood, Rachel D.; Carl, Mike A.; Agnello, Danielle M.; Schwarz, Sandra; Goodlett, David R.; Vollmer, Waldemar; Mougous, Joseph D.
Summary Sophisticated mechanisms are employed to facilitate information exchange between interfacing bacteria. A type VI secretion system (T6SS) of Pseudomonas aeruginosa was shown to deliver cell wall-targeting effectors to neighboring cells. However, the generality of bacteriolytic effectors, and moreover, of antibacterial T6S, remained unknown. Using parameters derived from experimentally validated bacterial T6SS effectors and informatics, we identified a phylogenetically disperse superfamily of T6SS-associated peptidoglycan-degrading effectors. The effectors separate into four families composed of peptidoglycan amidase enzymes of differing specificities. Effectors strictly co-occur with cognate immunity proteins, indicating that self-intoxication is a general property of antibacterial T6SSs and effector delivery by the system exerts a strong selective pressure in nature. The presence of antibacterial effectors in a plethora of organisms, including many that inhabit or infect polymicrobial niches in the human body, suggests that the system could mediate interbacterial interactions of both environmental and clinical significance. PMID:22607806
Probing cell type-specific functions of Gi in vivo identifies GPCR regulators of insulin secretion.
Regard, Jean B; Kataoka, Hiroshi; Cano, David A; Camerer, Eric; Yin, Liya; Zheng, Yao-Wu; Scanlan, Thomas S; Hebrok, Matthias; Coughlin, Shaun R
The in vivo roles of the hundreds of mammalian G protein-coupled receptors (GPCRs) are incompletely understood. To explore these roles, we generated mice expressing the S1 subunit of pertussis toxin, a known inhibitor of G(i/o) signaling, under the control of the ROSA26 locus in a Cre recombinase-dependent manner (ROSA26(PTX)). Crossing ROSA26(PTX) mice to mice expressing Cre in pancreatic beta cells produced offspring with constitutive hyperinsulinemia, increased insulin secretion in response to glucose, and resistance to diet-induced hyperglycemia. This phenotype underscored the known importance of G(i/o) and hence of GPCRs for regulating insulin secretion. Accordingly, we quantified mRNA for each of the approximately 373 nonodorant GPCRs in mouse to identify receptors highly expressed in islets and examined the role of several. We report that 3-iodothyronamine, a thyroid hormone metabolite, could negatively and positively regulate insulin secretion via the G(i)-coupled alpha(2A)-adrenergic receptor and the G(s)-coupled receptor Taar1, respectively, and protease-activated receptor-2 could negatively regulate insulin secretion and may contribute to physiological regulation of glucose metabolism. The ROSA26(PTX) system used in this study represents a new genetic tool to achieve tissue-specific signaling pathway modulation in vivo that can be applied to investigate the role of G(i/o)-coupled GPCRs in multiple cell types and processes. PMID:17992256
Probing cell type¢specific functions of Gi in vivo identifies GPCR regulators of insulin secretion
Regard, Jean B.; Kataoka, Hiroshi; Cano, David A.; Camerer, Eric; Yin, Liya; Zheng, Yao-Wu; Scanlan, Thomas S.; Hebrok, Matthias; Coughlin, Shaun R.
The in vivo roles of the hundreds of mammalian G protein¢coupled receptors (GPCRs) are incompletely understood. To explore these roles, we generated mice expressing the S1 subunit of pertussis toxin, a known inhibitor of Gi/o signaling, under the control of the ROSA26 locus in a Cre recombinase¢dependent manner (ROSA26PTX). Crossing ROSA26PTX mice to mice expressing Cre in pancreatic ? cells produced offspring with constitutive hyperinsulinemia, increased insulin secretion in response to glucose, and resistance to diet-induced hyperglycemia. This phenotype underscored the known importance of Gi/o and hence of GPCRs for regulating insulin secretion. Accordingly, we quantified mRNA for each of the approximately 373 nonodorant GPCRs in mouse to identify receptors highly expressed in islets and examined the role of several. We report that 3-iodothyronamine, a thyroid hormone metabolite, could negatively and positively regulate insulin secretion via the Gi-coupled ?2A-adrenergic receptor and the Gs-coupled receptor Taar1, respectively, and protease-activated receptor¢2 could negatively regulate insulin secretion and may contribute to physiological regulation of glucose metabolism. The ROSA26PTX system used in this study represents a new genetic tool to achieve tissue-specific signaling pathway modulation in vivo that can be applied to investigate the role of Gi/o-coupled GPCRs in multiple cell types and processes. PMID:17992256
EDAM: an ontology of bioinformatics operations, types of data and identifiers, topics and formats
Ison, Jon; KalaÜ, Mat·Ü; Jonassen, Inge; Bolser, Dan; Uludag, Mahmut; McWilliam, Hamish; Malone, James; Lopez, Rodrigo; Pettifer, Steve; Rice, Peter
Motivation: Advancing the search, publication and integration of bioinformatics tools and resources demands consistent machine-understandable descriptions. A comprehensive ontology allowing such descriptions is therefore required. Results: EDAM is an ontology of bioinformatics operations (tool or workflow functions), types of data and identifiers, application domains and data formats. EDAM supports semantic annotation of diverse entities such as Web services, databases, programmatic libraries, standalone tools, interactive applications, data schemas, datasets and publications within bioinformatics. EDAM applies to organizing and finding suitable tools and data and to automating their integration into complex applications or workflows. It includes over 2200 defined concepts and has successfully been used for annotations and implementations. Availability: The latest stable version of EDAM is available in OWL format from http://edamontology.org/EDAM.owl and in OBO format from http://edamontology.org/EDAM.obo. It can be viewed online at the NCBO BioPortal and the EBI Ontology Lookup Service. For documentation and license please refer to http://edamontology.org. This article describes version 1.2 available at http://edamontology.org/EDAM_1.2.owl. Contact: firstname.lastname@example.com PMID:23479348
Distinct clinical and laboratory characteristics of latent autoimmune diabetes in adults in relation to type 1 and type 2 diabetes mellitus
Pipi, Elena; Marketou, Marietta; Tsirogianni, Alexandra
Ever since its first appearance among the multiple forms of diabetes, latent autoimmune diabetes in adults (LADA), has been the focus of endless discussions concerning mainly its existence as a special type of diabetes. In this mini-review, through browsing important peer-reviewed publications, (original articles and reviews), we will attempt to refresh our knowledge regarding LADA hoping to enhance our understanding of this controversial diabetes entity. A unique combination of immunological, clinical and metabolic characteristics has been identified in this group of patients, namely persistent islet cell antibodies, high frequency of thyroid and gastric autoimmunity, DR3 and DR4 human leukocyte antigen haplotypes, progressive loss of beta cells, adult disease onset, normal weight, defective glycaemic control, and without tendency to ketoacidosis. Although anthropomorphic measurements are useful as a first line screening, the detection of C-peptide levels and the presence of glutamic acid decarboxylase (GAD) autoantibodies is undoubtedly the sine qua non condition for a confirmatory LADA diagnosis. In point of fact, GAD autoantibodies are far from being solely a biomarker and the specific role of these autoantibodies in disease pathogenesis is still to be thoroughly studied. Nevertheless, the lack of diagnostic criteria and guidelines still puzzle the physicians, who struggle between early diagnosis and correct timing for insulin treatment. PMID:25126396
The 'blue-on' opponent pathway in primate retina originates from a distinct bistratified ganglion cell type
Dennis M. Dacey; Barry B. Lee
COLOUR vision in humans and Old World monkeys begins with the differential activation of three types of cone photoreceptor which are maximally sensitive to short (S), medium (M) and long (L) wavelengths. Signals from the three cone types are relayed to the retinal ganglion cells via cone-specific bipolar cell types1-4. Colour-coding ganglion cells fall into two major physiological classes: the
Identifying the special needs of children with Type?1 diabetes in the school setting. An overview of parents? perceptions
B. Amillategui; J. R. Calle; M. A. Alvarez; M. A. Cardiel; R. Barrio
Aims The aims of this observational study were to identify the special needs of children with Type 1 diabetes in schools from the parents' point of view and the difficulties experienced with full integration, and to define a series of interventions which may improve the situation. Methods Parents of children aged 3-18 years with Type 1 diabetes were eligible. Those
Multilocus Sequence Typing Supports the Hypothesis that Cow and Human-Associated Salmonella Isolates Represent Distinct and Overlapping Populations
S. D. Alcaine; Y. Soyer; L. D. Warnick; W.-L. Su; S. Sukhnanand; J. Richards; E. D. Fortes; P. McDonough; T. P. Root; N. B. Dumas; Y. Grohn; M. Wiedmann
A collection of 179 human and 156 bovine clinical Salmonella isolates obtained from across New York state over the course of 1 year was characterized using serotyping and a multilocus sequence typing (MLST) scheme based on the sequencing of three genes (fimA, manB, and mdh). The 335 isolates were differentiated into 52 serotypes and 72 sequence types (STs). Analyses of
Exome sequencing identifies a REEP1 mutation involved in distal hereditary motor neuropathy type V.
Beetz, Christian; Pieber, Thomas R; Hertel, Nicole; Schabh³ttl, Maria; Fischer, Carina; Trajanoski, Slave; Graf, Elisabeth; Keiner, Silke; Kurth, Ingo; Wieland, Thomas; Varga, Rita-Eva; Timmerman, Vincent; Reilly, Mary M; Strom, Tim M; Auer-Grumbach, Michaela
The distal hereditary motor neuropathies (dHMNs) are a heterogeneous group of neurodegenerative disorders affecting the lower motoneuron. In a family with both autosomal-dominant dHMN and dHMN type V (dHMN/dHMN-V) present in three generations, we excluded mutations in all genes known to be associated with a dHMN phenotype through Sanger sequencing and defined three potential loci through linkage analysis. Whole-exome sequencing of two affected individuals revealed a single candidate variant within the linking regions, i.e., a splice-site alteration in REEP1 (c.304-2A>G). A minigene assay confirmed complete loss of splice-acceptor functionality and skipping of the in-frame exon 5. The resulting mRNA is predicted to be expressed at normal levels and to encode an internally shortened protein (p.102_139del). Loss-of-function REEP1 mutations have previously been identified in dominant hereditary spastic paraplegia (HSP), a disease associated with upper-motoneuron pathology. Consistent with our clinical-genetic data, we show that REEP1 is strongly expressed in the lower motoneurons as well. Upon exogeneous overexpression in cell lines we observe a subcellular localization defect for p.102_139del that differs from that observed for the known HSP-associated missense mutation c.59C>A (p.Ala20Glu). Moreover, we show that p.102_139del, but not p.Ala20Glu, recruits atlastin-1, i.e., one of the REEP1 binding partners, to the altered sites of localization. These data corroborate the loss-of-function nature of REEP1 mutations in HSP and suggest that a different mechanism applies in REEP1-associated dHMN. PMID:22703882
Expression Profiling of Human Immune Cell Subsets Identifies miRNA-mRNA Regulatory Relationships Correlated with Cell Type Specific Expression
Bergauer, Tobias; Ravindran, Palanikumar; Rossier, Michel F.; Ebeling, Martin; Badi, Laura; Reis, Bernhard; Bitter, Hans; D'Asaro, Matilde; Chiappe, Alberto; Sridhar, Sriram; Pacheco, Gonzalo Duran; Burczynski, Michael E.; Hochstrasser, Denis; Vonderscher, Jacky; Matthes, Thomas
Blood consists of different cell populations with distinct functions and correspondingly, distinct gene expression profiles. In this study, global miRNA expression profiling was performed across a panel of nine human immune cell subsets (neutrophils, eosinophils, monocytes, B cells, NK cells, CD4 T cells, CD8 T cells, mDCs and pDCs) to identify cell-type specific miRNAs. mRNA expression profiling was performed on the same samples to determine if miRNAs specific to certain cell types down-regulated expression levels of their target genes. Six cell-type specific miRNAs (miR-143; neutrophil specific, miR-125; T cells and neutrophil specific, miR-500; monocyte and pDC specific, miR-150; lymphoid cell specific, miR-652 and miR-223; both myeloid cell specific) were negatively correlated with expression of their predicted target genes. These results were further validated using an independent cohort where similar immune cell subsets were isolated and profiled for both miRNA and mRNA expression. miRNAs which negatively correlated with target gene expression in both cohorts were identified as candidates for miRNA/mRNA regulatory pairs and were used to construct a cell-type specific regulatory network. miRNA/mRNA pairs formed two distinct clusters in the network corresponding to myeloid (nine miRNAs) and lymphoid lineages (two miRNAs). Several myeloid specific miRNAs targeted common genes including ABL2, EIF4A2, EPC1 and INO80D; these common targets were enriched for genes involved in the regulation of gene expression (p<9.0E-7). Those miRNA might therefore have significant further effect on gene expression by repressing the expression of genes involved in transcriptional regulation. The miRNA and mRNA expression profiles reported in this study form a comprehensive transcriptome database of various human blood cells and serve as a valuable resource for elucidating the role of miRNA mediated regulation in the establishment of immune cell identity. PMID:22276136
Distinct sites of opiate reward and aversion within the midbrain identified using a herpes simplex virus vector expressing GluR1.
Carlezon, W A; Haile, C N; Coppersmith, R; Hayashi, Y; Malinow, R; Neve, R L; Nestler, E J
Repeated administration of morphine increases expression of GluR1 (an AMPA glutamate receptor subunit) in the ventral tegmental area (VTA) of the midbrain, an important neural substrate for the rewarding actions of morphine. Microinjections of a herpes simplex virus (HSV) vector that causes local overexpression of GluR1 (HSV-GluR1) into the VTA can enhance the ability of morphine to establish conditioned place preferences, suggesting that altered GluR1 expression in this region is directly associated with changes in the rewarding efficacy of morphine. We now report that in rats given HSV-GluR1 directly into the VTA, morphine is most rewarding when maximal transgene expression is in the rostral VTA, whereas morphine is aversive when maximal transgene expression is in the caudal VTA. Dual-labeling immunohistochemistry shows that this difference cannot be explained by a different fraction of dopaminergic neurons infected in the rostral versus caudal VTA. No such anatomical specificity is seen in rats given VTA microinjections of HSV-LacZ, a vector expressing a control protein (-galactosidase). These results suggest that distinct substrates within the VTA itself differentially contribute to the rewarding and aversive properties of opiates. PMID:10684909
Activation of three types of membrane currents by various divalent cations in identified molluscan pacemaker neurons
T. H. Muller; D. SWANDULLA; H. D. Lux
We investigated membrane currents activated by intracellular diva- lent cations in two types of molluscan pacemaker neurons. A fast and quantitative pressure injection technique was used to apply Ca ~+ and other divalent cations. Ca 2¦ was most effective in activating a nonspecific cation current and two types of K ¦ currents found in these cells. One type of outward
Crystal structure of a Xenopus laevis skin proto-type galectin, close to but distinct from galectin-1.
Nonaka, Yasuhiro; Ogawa, Takashi; Yoshida, Hiromi; Shoji, Hiroki; Nishi, Nozomu; Kamitori, Shigehiro; Nakamura, Takanori
Xenopus laevis (African clawed frog) has two types of proto-type galectins that are similar to mammalian galectin-1 in amino acid sequence. One type, comprising xgalectin-Ia and -Ib, is regarded as being equivalent to galectin-1, and the other type, comprising xgalectin-Va and -Vb, is expected to be a unique galectin subgroup. The latter is considerably abundant in frog skin; however, its biological function remains unclear. We determined the crystal structures of two proto-type galectins, xgalectin-Ib and -Va. The structures showed that both galectins formed a mammalian galectin-1-like homodimer, and furthermore, xgalectin-Va formed a homotetramer. This tetramer structure has not been reported for other galectins. Gel filtration and other experiments indicated that xgalectin-Va was in a dimer-tetramer equilibrium in solution, and lactose binding enhanced the tetramer formation. The residues involved in the dimer-dimer association were conserved in xgalectin-Va and -Vb, and one of the Xenopus (Silurana) tropicalis proto-type galectins, but not in xgalectin-Ia and -Ib, and other galectin-1-equivalent proteins. Xgalectin-Va preferred Gal?1-3GalNAc and not Gal?1-4GlcNAc, while xgalectin-Ib preferred Gal?1-4GlcNAc as well as human galectin-1. Xgalectin-Va/Vb would have diverged from the galectin-1 group with accompanying acquisition of the higher oligomer formation and altered ligand selectivity. PMID:25804418
Spatial Relationships between GABAergic and Glutamatergic Synapses on the Dendrites of Distinct Types of Mouse Retinal Ganglion Cells across Development
Bleckert, Adam; Parker, Edward D.; Kang, YunHee; Pancaroglu, Raika; Soto, Florentina; Lewis, Renate; Craig, Ann Marie; Wong, Rachel O. L.
Neuronal output requires a concerted balance between excitatory and inhibitory (I/E) input. Like other circuits, inhibitory synaptogenesis in the retina precedes excitatory synaptogenesis. How then do neurons attain their mature balance of I/E ratios despite temporal offset in synaptogenesis? To directly compare the development of glutamatergic and GABAergic synapses onto the same cell, we biolistically transfected retinal ganglion cells (RGCs) with PSD95CFP, a marker of glutamatergic postsynaptic sites, in transgenic Thy1ŁYFP?2 mice in which GABAA receptors are fluorescently tagged. We mapped YFP?2 and PSD95CFP puncta distributions on three RGC types at postnatal day P12, shortly before eye opening, and at P21 when robust light responses in RGCs are present. The mature IGABA/E ratios varied among ON-Sustained (S) A-type, OFF-S A-type, and bistratified direction selective (DS) RGCs. These ratios were attained at different rates, before eye-opening for ON-S and OFF-S A-type, and after eye-opening for DS RGCs. At both ages examined, the IGABA/E ratio was uniform across the arbors of the three RGC types. Furthermore, measurements of the distances between neighboring PSD95CFP and YFP?2 puncta on RGC dendrites indicate that their local relationship is established early in development, and cannot be predicted by random organization. These close spatial associations between glutamatergic and GABAergic postsynaptic sites appear to represent local synaptic arrangements revealed by correlative light and EM reconstructions of a single RGC's dendrites. Thus, although RGC types have different IGABA/E ratios and establish these ratios at separate rates, the local relationship between excitatory and inhibitory inputs appear similarly constrained across the RGC types studied. PMID:23922756
Characterization of the fetal blood transcriptome and proteome in maternal anti-fetal rejection: evidence of a distinct and novel type of human fetal systemic inflammatory response
Lee, JoonHo; Romero, Roberto; Chaiworapongsa, Tinnakorn; Dong, Zhong; Tarca, Adi L.; Xu, Yi; Chiang, Po Jen; Kusanovic, Juan Pedro; Hassan, Sonia S.; Yeo, Lami; Than, Nandor Gabor; Kim, Chong Jai
Background The human fetus is able to mount a systemic inflammatory response when exposed to microorganisms. This stereotypic response has been termed the ōfetal inflammatory response syndromeö (FIRS), defined as an elevation of fetal plasma interleukin-6 (IL-6). FIRS is frequently observed in patients who delivered preterm associated with intra-amniotic infection (IAI), acute inflammatory lesions in the placenta, and a high rate of neonatal morbidity. Recently, a novel form of fetal systemic inflammation, characterized by an elevation of fetal plasma CXCL10, has been identified in patients with placental lesions suggestive of ōmaternal anti-fetal rejectionö. These lesions include chronic chorioamnionitis, plasma cell deciduitis and villitis of unknown etiology (VUE). In addition, a seropositivity for HLA panel-reactive antibodies (PRA) in maternal sera can also be used as an index of suspicious for ōmaternal anti-fetal rejectionö. The purpose of this study was to determine: 1) the frequency of pathologic evidence of ōmaternal anti-fetal rejectionö in term and spontaneous preterm births; 2) the fetal serum concentration of CXCL10 in patients with and without evidence of maternal anti-fetal rejection; and 3) the fetal blood transcriptome and proteome in pregnancy with evidence of fetal inflammatory response associated with maternal anti-fetal rejection. Methods Maternal and fetal sera were obtained from normal term birth (N=150) and spontaneous preterm births (N=150). Fetal inflammatory response associated with maternal anti-fetal rejection was diagnosed when the patients met two or more of the following criteria: 1) presence of chronic placental inflammation; 2) ?80% of maternal HLA class I panel-reactive antibody (PRA) seropositivity; and 3) fetal serum CXCL10 concentration > 75th percentile of normal. Maternal HLA PRA was analyzed by flow cytometry. The concentration of fetal CXCL10 and IL-6 were determined by ELISA. Transcriptome analysis was undertaken after extraction of total RNA from white blood cells with a whole-genome DASL assay. Proteomic analysis of fetal serum was conducted by two-dimensional difference gel electrophoresis. Differential gene expression was considered significant when there was a p<0.01 and a fold-change >1.5. Results 1) The frequency of placental lesions consistent with maternal anti-fetal rejection was higher in patients with preterm delivery than in those with term delivery (56% vs. 32%; P<0.001); 2) patients with spontaneous preterm births had a higher rate of maternal HLA PRA class I positivity than those who delivered at term (50% vs. 32%; P=0.002); 3) fetuses who were born to mothers with positive maternal HLA PRA results had a higher median serum CXCL10 concentration than in those with negative HLA PRA results (P<0.001); 4) the median serum CXCL10 concentration (but not IL-6) was higher in fetuses with placental lesions associated with maternal anti-fetal rejection than in those without such lesions (P<0.001); 5) a whole-genome DASL assay of fetal blood RNA demonstrated differential expression of 128 genes between fetuses with and without fetal inflammatory response associated with maternal anti-fetal rejection; and 6) comparison of the fetal serum proteome demonstrated 20 proteins whose abundance differed between fetuses with and without fetal inflammatory response associated with maternal anti-fetal rejection. Conclusions We describe systemic inflammatory response in the fetus born to mothers with evidence of maternal anti-fetal rejection. Using high-dimensional biology techniques, the transcriptome and proteome of this novel type of fetal inflammatory response demonstrated the distinct profile from FIRS type I (which is associated with acute infection). This information is crucial to gain a mechanistic understanding of the syndrome as well as to identify biomarkers for this condition. PMID:23905683
Anomalous Type I Error Rates for Identifying One Type of Differential Item Functioning in the Presence of the Other
ERIC Educational Resources Information Center
Finch, W. Holmes; French, Brian F.
A number of statistical methods exist for the detection of differential item functioning (DIF). The performance of DIF methods has been widely studied and generally found to be effective in the detection of both uniform and nonuniform DIF. Anecdotal reports suggest that these techniques may too often incorrectly detect the presence of one type ofģ
R-subunit Isoform Specificity in Protein Kinase A: Distinct Features of Protein Interfaces in PKA Types I
Komives, Elizabeth A.
laser-desorption/ionization time-of-flight; PKA, protein kinase A; Mops, 3-(N used: H/2 H exchange, hydrogen/ deuterium exchange; MS, mass spectrometry; MALDI-TOF, matrix-assisted Types I and II by Amide H/2 H Exchange Mass Spectrometry Ganesh S. Anand1 , Matthew Hotchko2,3 , Simon H
PKscan: a program to identify H-type RNA pseudoknots in any RNA sequence with unlimited length
Huang, Xiaolan; Du, Zhihua; Cheng, Jie; Cheng, Qiang
A computer program written in C++ has been developed which can detect all potential H-type RNA pseudoknots within any given RNA sequence. There is no limit on the length of the input sequence. A validation run of the program using the full-length (8173 nt) genomic mRNA of simian retrovirus type-1 (SRV-1) identifies the established -1 frameshift stimulating pseudokont at the gagpro junction as the most stable pseudoknot within the genomic mRNA. PMID:23847396
Using genome-context data to identify specific types of functional associations in pathway\\/genome databases
Michelle L. Green; Peter D. Karp
Background: Hundreds of genes lacking homology to any protein of known function are sequenced every day. Genome-context methods have proved useful in providing clues about functional annotations for many proteins. However, genome-context methods detect many biological types of functional associations, and do not identify which type of functional association they have found. Results: We have developed two new genome-context-based algorithms.
Conditional IFNAR1 ablation reveals distinct requirements of Type I IFN signaling for NK cell maturation and tumor surveillance
Mizutani, Tatsuaki; Neugebauer, Nina; Putz, Eva M.; Moritz, Nadine; Simma, Olivia; Zebedin-Brandl, Eva; Gotthardt, Dagmar; Warsch, Wolfgang; Eckelhart, Eva; Kantner, Hans-Peter; Kalinke, Ulrich; Lienenklaus, Stefan; Weiss, Siegfried; Strobl, Birgit; M³ller, Mathias; Sexl, Veronika; Stoiber, Dagmar
Mice with an impaired Type I interferon (IFN) signaling (IFNAR1- and IFN?-deficient mice) display an increased susceptibility toward v-ABL-induced B-cell leukemia/lymphoma. The enhanced leukemogenesis in the absence of an intact Type I IFN signaling is caused by alterations within the tumor environment. Deletion of Ifnar1 in tumor cells (as obtained in Ifnar1f/f CD19-Cre mice) failed to impact on disease latency or type. In line with this observation, the initial transformation and proliferative capacity of tumor cells were unaltered irrespective of whether the cells expressed IFNAR1 or not. v-ABL-induced leukemogenesis is mainly subjected to natural killer (NK) cell-mediated tumor surveillance. Thus, we concentrated on NK cell functions in IFNAR1 deficient animals. Ifnar1-/- NK cells displayed maturation defects as well as an impaired cytolytic activity. When we deleted Ifnar1 selectively in mature NK cells (by crossing Ncr1-iCre mice to Ifnar1f/f animals), maturation was not altered. However, NK cells derived from Ifnar1f/f Ncr1-iCre mice showed a significant cytolytic defect in vitro against the hematopoietic cell lines YAC-1 and RMA-S, but not against the melanoma cell line B16F10. Interestingly, this defect was not related to an in vivo phenotype as v-ABL-induced leukemogenesis was unaltered in Ifnar1f/f Ncr1-iCre compared with Ifnar1f/f control mice. Moreover, the ability of Ifnar1f/f Ncr1-iCre NK cells to kill B16F10 melanoma cells was unaltered, both in vitro and in vivo. Our data reveal that despite the necessity for Type I IFN in NK cell maturation the expression of IFNAR1 on mature murine NK cells is not required for efficient tumor surveillance. PMID:23170251
The three human T-lymphotropic virus type I subtypes arose from three geographically distinct simian reservoirs
Hsin-Fu Liu; Patrick Goubau; Marianne Van Brussel; Kristel Van Laethem; Yao-Chang Chen; Jan Desmyter; Anne-Mieke Vandamme
To investigate the origin of human T-lymphotropic virus I (HTLV-I), strains of diverse geographical origin were analysed. We sequenced the LTR and env genes of HTLV-I strains from Brazil, Central African Republic, Taiwan and Zaire, and the simian T-lymphotropic virus type I (STLV-I) strain PHSul from a baboon from the Sukhumi primate centre. We performed phylogenetic analyses using neighbour-joining, parsimony
Radioligand-binding assay reveals distinct autoantibody preferences for type I interferons in APS I and myasthenia gravis subgroups.
Hapnes, Liv; Willcox, Nick; Oftedal, Bergithe E V; Owe, Jone F; Gilhus, Nils Erik; Meager, Anthony; Husebye, Eystein S; Wolff, Anette S B°e
Patients with autoimmune polyendocrine syndrome type I (APS I) or acquired thymoma-associated myasthenia gravis (MG) surprisingly share several common features, including defective expression of the transcription factor AIRE and autoantibodies against type I interferons. Here, we have adapted and validated the radioligand-binding assay we recently developed against (35)S-Met-interferon-?, for rapid and specific screening for autoantibodies against interferons-?2 and -?8. We then investigated their potential for diagnosis and for predicting clinical manifestations in patients with APS I and different subgroups of MG. Autoantibodies against interferons-?, -?2, and -?8 occurred more often in patients with APS I (100%) and MG with thymoma (73%) than in late-onset MG (39%) and early-onset MG (5%). These autoantibodies showed preferences for interferon-? in APS I and for the interferon-?s in MG, hinting at thymic aberrations in both groups. The exact profile of type I interferon antibodies may indicate MG subtype and may hint at thymoma recurrence. PMID:22127461
Definition of Genetic Events Directing the Development of Distinct Types of Brain Tumors from Postnatal Neural Stem/Progenitor Cells
Hertwig, Falk; Meyer, Katharina; Braun, Sebastian; Ek, Sara; Spang, Rainer; Pfenninger, Cosima V.; Artner, Isabella; Prost, Gaļlle; Chen, Xinbin; Biegel, Jaclyn A.; Judkins, Alexander R.; Englund, Elisabet; Nuber, Ulrike A.
Although brain tumors are classified and treated based upon their histology, the molecular factors involved in the development of various tumor types remain unknown. In this study, we show that the type and order of genetic events directs the development of gliomas, central nervous system primitive neuroectodermal tumors, and atypical teratoid/rhabdoid-like tumors from postnatal mouse neural stem/progenitor cells (NSC/NPC). We found that the overexpression of specific genes led to the development of these three different brain tumors from NSC/NPCs, and manipulation of the order of genetic events was able to convert one established tumor type into another. In addition, loss of the nuclear chromatin-remodeling factor SMARCB1 in rhabdoid tumors led to increased phosphorylation of eIF2?, a central cytoplasmic unfolded protein response (UPR) component, suggesting a role for the UPR in these tumors. Consistent with this, application of the proteasome inhibitor bortezomib led to an increase in apoptosis of human cells with reduced SMARCB1 levels. Taken together, our findings indicate that the order of genetic events determines the phenotypes of brain tumors derived from a common precursor cell pool, and suggest that the UPR may represent a therapeutic target in atypical teratoid/rhabdoid tumors. PMID:22719073
Disease fingerprinting with cDNA microarrays reveals distinct gene expression profiles in lethal type-1 and type-2 cytokine-mediated inflammatory reactions
Karl F. Hoffmann; Thomas C. McCarty; David H. Segal; Monica Chiaramonte; Matthias Hesse; Eric M. Davis; Allen W. Cheever; Paul S. Meltzer; Herbert C. Morse; Thomas A. Wynn
Development of polarized immune responses controls resistance and susceptibility to many microorganisms. However, studies of several inf ectious, allergic, and autoimmune diseases have shown that chronic type-1 and type-2 cytokine responses can also cause significant morbidity and mortality if left unchecked. We used mouse cDNA microarrays to molecularly phenotype the gene expression patterns that characterize two disparate but equally lethal
Distinct and Atypical Intrinsic and Extrinsic Cell Death Pathways between Photoreceptor Cell Types upon Specific Ablation of Ranbp2 in Cone Photoreceptors
Cho, Kyoung-in; Yu, Minzhong; Hao, Ying; Qiu, Sunny; Pillai, Indulekha C. L.; Peachey, Neal S.; Ferreira, Paulo A.
Non-autonomous cell-death is a cardinal feature of the disintegration of neural networks in neurodegenerative diseases, but the molecular bases of this process are poorly understood. The neural retina comprises a mosaic of rod and cone photoreceptors. Cone and rod photoreceptors degenerate upon rod-specific expression of heterogeneous mutations in functionally distinct genes, whereas cone-specific mutations are thought to cause only cone demise. Here we show that conditional ablation in cone photoreceptors of Ran-binding protein-2 (Ranbp2), a cell context-dependent pleiotropic protein linked to neuroprotection, familial necrotic encephalopathies, acute transverse myelitis and tumor-suppression, promotes early electrophysiological deficits, subcellular erosive destruction and non-apoptotic death of cones, whereas rod photoreceptors undergo cone-dependent non-autonomous apoptosis. Cone-specific Ranbp2 ablation causes the temporal activation of a cone-intrinsic molecular cascade highlighted by the early activation of metalloproteinase 11/stromelysin-3 and up-regulation of Crx and CoREST, followed by the down-modulation of cone-specific phototransduction genes, transient up-regulation of regulatory/survival genes and activation of caspase-7 without apoptosis. Conversely, PARP1+-apoptotic rods develop upon sequential activation of caspase-9 and caspase-3 and loss of membrane permeability. Rod photoreceptor demise ceases upon cone degeneration. These findings reveal novel roles of Ranbp2 in the modulation of intrinsic and extrinsic cell death mechanisms and pathways. They also unveil a novel spatiotemporal paradigm of progression of neurodegeneration upon cell-specific genetic damage whereby a cone to rod non-autonomous death pathway with intrinsically distinct cell-type death manifestations is triggered by cell-specific loss of Ranbp2. Finally, this study casts new light onto cell-death mechanisms that may be shared by human dystrophies with distinct retinal spatial signatures as well as with other etiologically distinct neurodegenerative disorders. PMID:23818861
Self-Selection Patterns of College Roommates as Identified by the Myers-Briggs Type Indicator.
ERIC Educational Resources Information Center
Anchors, W. Scott; Hale, John, Jr.
Investigated patterns and processes by which students (N=422) made unassisted roommate pairings within residence halls using the Myers-Briggs Type Indicator. Results indicated introverts, intuitives, feelers, and perceivers each tended to self-select. (BL)
MicroRNA transcriptomes of distinct human NK cell populations identify miR-362-5p as an essential regulator of NK cell function
Ni, Fang; Guo, Chuang; Sun, Rui; Fu, Binqing; Yang, Yue; Wu, Lele; Ren, Sitong; Tian, Zhigang; Wei, Haiming
Natural killer (NK) cells are critical effectors in the immune response against malignancy and infection, and microRNAs (miRNAs) play important roles in NK cell biology. Here we examined miRNA profiles of human NK cells from different cell compartments (peripheral blood, cord blood, and uterine deciduas) and of NKT and T cells from peripheral blood, and we identified a novel miRNA, miR-362-5p, that is highly expressed in human peripheral blood NK (pNK) cells. We also demonstrated that CYLD, a negative regulator of NF-?B signaling, was a target of miR-362-5p in NK cells. Furthermore, we showed that the over-expression of miR-362-5p enhanced the expression of IFN-?, perforin, granzyme-B, and CD107a in human primary NK cells, and we found that silencing CYLD with a small interfering RNA (siRNA) mirrored the effect of miR-362-5p over-expression. In contrast, the inhibition of miR-362-5p had the opposite effect in NK cells, which was abrogated by CYLD siRNA, suggesting that miR-362-5p promotes NK-cell function, at least in part, by the down-regulation of CYLD. These results provide a resource for studying the roles of miRNAs in human NK cell biology and contribute to a better understanding of the physiologic significance of miRNAs in the regulation of NK cell function. PMID:25909817
Functionally distinct subsets of human NK cells and monocyte/DC-like cells identified by coexpression of CD56, CD7, and CD4
Long, Brian R.; Snyder-Cappione, Jennifer E.; Cappione, Amedeo J.; York, Vanessa A.; Ndhlovu, Lishomwa C.; Lanier, Lewis L.; Michaļlsson, Jakob; Nixon, Douglas F.
The lack of natural killer (NK) cell¢specific markers, as well as the overlap among several common surface antigens and functional properties, has obscured the delineation between NK cells and dendritic cells. Here, novel subsets of peripheral blood CD3/14/19neg NK cells and monocyte/dendritic cell (DC)¢like cells were identified on the basis of CD7 and CD4 expression. Coexpression of CD7 and CD56 differentiates NK cells from CD56+ monocyte/DC-like cells, which lack CD7. In contrast to CD7+CD56+ NK cells, CD7negCD56+ cells lack expression of NK cell¢associated markers, but share commonalities in their expression of various monocyte/DC-associated markers. Using CD7, we observed approximately 60% of CD4+CD56+ cells were CD7neg cells, indicating the actual frequency of activated CD4+ NK cells is much lower in the blood than previously recognized. Functionally, only CD7+ NK cells secrete gamma interferon (IFN?) and degranulate after interleukin-12 (IL-12) plus IL-18 or K562 target cell stimulation. Furthermore, using CD7 to separate CD56+ NK cells and CD56+ myeloid cells, we demonstrate that unlike resting CD7+CD56+ NK cells, the CD7negCD56+ myeloid cells stimulate a potent allogeneic response. Our data indicate that CD7 and CD56 coexpression discriminates NK cells from CD7negCD56+ monocyte/DC-like cells, thereby improving our ability to study the intricacies of NK-cell subset phenotypes and functions in vivo. PMID:19805616
Differential Expression Profiling of Spleen MicroRNAs in Response to Two Distinct Type II Interferons in Tetraodon nigroviridis
Peng, Wan; Wang, Ting; Zhang, Yong; Lin, Haoran
MicroRNAs are endogenous, small non-coding RNAs approximately 18¢26 nucleotides in length that regulate target gene expression at the post-transcription level. Interferon-? (IFN-?) is a Th1 cytokine that is involved in both the innate and adaptive immune responses. We previously identified two IFN-? genes in green-spotted puffer fish (Tetraodon nigroviridis). To determine whether miRNAs participate in IFN-?-related immune responses, T. nigroviridis spleen cells were treated with recombinant IFN-? isoforms, and a Solexa high-throughput sequencing method was used to identify miRNAs. In total, 1,556, 1,538 and 1,573 miRNAs were found in the three samples, and differentially expressed miRNAs were determined. In total, 398 miRNAs were differentially expressed after rIFN-?1 treatment, and 438 miRNAs were differentially expressed after rIFN-?2 treatment; additionally, 403 miRNAs were differentially expressed between the treatment groups. Ten differentially expressed miRNAs were chosen for validation using qRT-PCR. Target genes for the differentially expressed miRNAs were predicted, and GO and KEGG analyses were performed. This study provides basic knowledge regarding fish IFN-?-induced miRNAs and offers clues for further studies into the mechanisms underlying fish IFN-?-mediated immune responses. PMID:24800866
Gene isolation and expression analysis of two distinct sweet orange [Citrus sinensis L. (Osbeck)] tau-type glutathione transferases.
Lo Piero, Angela Roberta; Mercurio, Valeria; Puglisi, Ivana; Petrone, Goffredo
Glutathione S-transferases (GSTs) represent a multifunctional family of enzymes grouped into four main classes (tau, phi, theta, and zeta) conjugating endobiotic and xenobiotic compounds to glutathione. In plants, this is considered to be a crucial step in the detoxification process as the S-glutathionylated metabolites are tagged for vacuolar sequestration. In this work, we have isolated two glutathione S-transferases belonging to the tau class GSTs from sweet orange leaves. The cDNA clones contained a complete open reading frame of 651 bp encoding two 216 amino acid proteins. Homology search and sequence alignment showed that the deduced amino acid sequences shared high identity with GSTs from other plant sources, including several strictly conservative motifs and distinctive amino acid residues specific of the tau class GSTs. The genomic clones of both isoforms were also isolated and the analysis of the gene organization confirmed the membership of both enzymes to the tau class GSTs. The encoded proteins differ only for three amino acids: the triplet R89, E117 and I172 found in the isoform named GSTU1 is replaced by the triplet P89, K117 and V172 in the GSTU2 isoform. The successful in vitro expression of the proteins led to the functional active form of both enzymes which showed different specific activity against CDNB as substrate, the GSTU1 showing values three fold lower than that observed for the GSTU2 enzyme. The analysis of the gene expressions suggested that the GST isoforms show either different distribution between leaf and flesh, the isoforms being decidedly expressed in the leaf, or cultivar related specificity, the U2 being highly expressed in the leaves of red orange whereas the U1 in the blond orange leaves. Furthermore, we also showed that the expression of U1 gene was remarkably induced in response to cadmium sulphate, CDNB and cyhalothrin treatments as well as to cold stress. On the contrary, the U2 isoform was constitutively expressed probably playing some sort of "default scavenging" activity in vivo. Taken together these results suggested that GSTU1 is a stress responsive gene and can be considered as potential target that is genetically modified so as create novel germoplasm with enhanced stress tolerance. PMID:19422890
Two distinct ferroelectric phases in the multiferroic Y -type hexaferrite Ba2Mg2Fe12O22
NASA Astrophysics Data System (ADS)
Sagayama, Hajime; Taniguchi, Kouji; Abe, Nobuyuki; Arima, Taka-Hisa; Nishikawa, Yusaku; Yano, Shin-Ichiro; Kousaka, Yusuke; Akimitsu, Jun; Matsuura, Masato; Hirota, Kazuma
The magnetic phase diagram of the Y -type hexaferrite Ba2Mg2Fe12O22 has been studied using single-crystal neutron diffraction. The result indicates successive phase transitions where the magnetic modulation wave number changed discontinuously when a magnetic field is applied and the temperature is varied. For the low-temperature spin-driven ferroelectric state, we have found a sixfold structure with q=(001/2) in weak magnetic fields and a twofold structure with q=(003/2) in strong magnetic fields between which a first-order transition intervenes accompanied by a hysteresis.
Two Distinct Ferroelectric Phases in Multiferroic Y-type Hexaferrite Ba2Mg2Fe12O22
NASA Astrophysics Data System (ADS)
Sagayama, Hajime; Taniguchi, Kouji; Abe, Nobuyuki; Taka-Hisa, Arima; Nishikawa, Yusaku; Yano, Shin-Ichiro; Kousaka, Yusuke; Akimitsu, Jun; Matsuura, Masato; Hirota, Kazuma
The magnetic phase diagram of the Y-type hexaferrite Ba2Mg2Fe12O22 has been studied using single-crystal neutron diffraction. The result indicates successive phase transitions where the magnetic modulation wave number changed discontinuously, when a magnetic field is applied and the temperature is varied. For the low-temperature spin-driven ferroelectric state, we have found a 6-fold structure with q=(0 0 1/2) in weak magnetic fields and a 2-fold structure with q=(0 0 3/2) in strong magnetic fields, between which a first-order transition intervenes accompanied by a hysteresis.
Characterizing the successful student in general chemistry and physical science classes in terms of Jung's personality types as identified by the Myers-Briggs Type Indicator
NASA Astrophysics Data System (ADS)
Riley, Wayne David
A student's success in a science class can depend upon previous experiences, motivation, and the level of interest in the subject. Since psychological type is intrinsic to a person's whole being, it can be influential upon the student's motivation and interests. Thus, a study of student psychological types versus the level of success in a class, as measured by a percentage, has potential to uncover certain personality characteristics which may be helpful to or which may hinder a student's learning environment. This study was initiated, using the Myers-Briggs Type Indicator, to evaluate any correlation between a student's personality type and his/her performance in a science class. A total of 1041 students from three classes: Chemistry 121/122, Chemistry 112, Physical Science 100, volunteered for the study. An analysis of variance (ANOVA) was used to determine the levels of significance among sixteen personality types' averages. The results reveal that for the Chemistry 1121/122 course, the average score of the INTJ personality type was 5.1 to 12.6 points higher than every other personality type. The ANOVA identifies 3 personality types with averages significantly below the INTJ at the p < 0.05 significance level. The ANOVA analysis for the Chemistry 112 course identified significances between student scores at p = 0.08. The significance level for the differences among scores for the Physical Science 100 course was determined at a level of p = 0.02. Significance levels for p < 0.05 and <0.01 were identified between several groups in this course. The data suggest, that although personality type may not predict a particular student's success in a science class, students with certain personality traits may be favored in a chemistry class due the structure of the instruction and the presentation of the subject matter.
Apoptolidins A and C activate AMPK in metabolically sensitive cell types and are mechanistically distinct from oligomycin A.
Serrill, Jeffrey D; Tan, Michelle; Fotso, Serge; Sikorska, Justyna; Kasanah, Noer; Hau, Andrew M; McPhail, Kerry L; Santosa, Dwi Andreas; Zabriskie, T Mark; Mahmud, Taifo; Viollet, Benoit; Proteau, Philip J; Ishmael, Jane E
Apoptolidin A was first isolated as a secondary metabolite of a Nocardiopsis sp. and is the founding member of a family of potential selective cancer cell toxins. We now report the isolation, production and pharmacological characterization of apoptolidins A and C from an alternate actinomycete producer, an Amycolatopsis sp. from soil samples collected in Indonesia. We investigated the action of apoptolidins A and C in representative human glioblastoma cells, lung cancer cells and mouse embryonic fibroblasts (MEFs) to better understand the mechanism of action of the known apoptolidins. Shifts in cellular metabolism in intact cells and the status of the AMP-activated protein kinase (AMPK) stress pathway in response to apoptolidin A were entirely consistent with the actions of an ATP synthase inhibitor. We find the metabolic phenotype of the cell to be a critical determinant of apoptolidin sensitivity and the likely basis for cancer cell selectivity. The apoptolidins induce indirect activation of AMPK and trigger autophagy in sensitive cell types without significant inhibition of mTORC1. Human U87-MG glioblastoma cells and wild type MEFs showed increased phosphorylation of AMPK (Thr172), ACC (Ser79) and ULK1 (Ser555), whereas AMPK?-null MEFs and more glycolytic SF-295 glioblastoma cells lacked this response. Although both are reported to be selective inhibitors of mitochondrial ATP synthase, differences between apoptolidin- and oligomycin A-induced responses in cells indicate that the action of these macrolides is not identical. PMID:25511868
Laminin and Type IV Collagen Isoform Substitutions Occur in Temporally and Spatially Distinct Patterns in Developing Kidney Glomerular Basement Membranes
St. John, Patricia L.; Stroganova, Larysa; Zelenchuk, Adrian; Steenhard, Brooke M.
Kidney glomerular basement membranes (GBMs) undergo laminin and type IV collagen isoform substitutions during glomerular development, which are believed to be required for maturation of the filtration barrier. Specifically, GBMs of earliest glomeruli contain laminin ?1?1?1 and collagen ?1?2?1(IV), whereas mature glomeruli contain laminin ?5?2?1 and collagen ?3?4?5(IV). Here, we used confocal microscopy to simultaneously evaluate expression of different laminin and collagen IV isoforms in newborn mouse GBMs. Our results show loss of laminin ?1 from GBMs in early capillary loop stages and continuous linear deposition of laminin bearing the ?5 chain thereafter. In contrast, collagen ?1?2?1(IV) persisted in linear patterns into late capillary loop stages, when collagen ?3?4?5(IV) first appeared in discontinuous, non-linear patterns. This patchy pattern for collagen ?3?4?5(IV) continued into maturing glomeruli where there were lengths of linear, laminin ?5-positive GBM entirely lacking either isoform of collagen IV. Relative abundance of laminin and collagen IV mRNAs in newborn and 5-week-old mouse kidneys also differed, with those encoding laminin ?1, ?5, ?1, ?2, and ?1, and collagen ?1(IV) and ?2(IV) chains all significantly declining at 5 weeks, but ?3(IV) and ?4(IV) were significantly upregulated. We conclude that different biosynthetic mechanisms control laminin and type IV collagen expression in developing glomeruli. PMID:23896970
The genome sequence of the most widely cultivated cacao type and its use to identify candidate genes regulating pod color
Technology Transfer Automated Retrieval System (TEKTRAN)
Background: Theobroma cacao L. cultivar Matina 1-6 belongs to the most cultivated cacao type. The availability of its genome sequence and methods for identifying genes responsible for important cacao traits will aid cacao researchers and breeders. Results: We describe the sequencing and assembly of...
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Ginzel, Matthew
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Different polysialic acid-neural cell adhesion molecule expression patterns in distinct types of mossy fiber boutons in the adult hippocampus.
Seki, T; Arai, Y
Dentate granule cells continue to be generated in the adult hippocampus, and the newly generated granule cells express the highly polysialylated neural cell adhesion molecule (PSA-NCAM), which has been shown to be important in neural development and plasticity. In the present study, the PSA-NCAM expression pattern in morphologically distinct types of mossy fiber boutons in adult rats was examined by immunoelectron and confocal laser scanning microscopy. Although many unmyelinated axons within the mossy fiber bundles expressed PSA-NCAM, most of the mature type of mossy fiber boutons were negative for polysialic acid (PSA) but positive for NCAM peptides, suggesting that NCAM is less polysialylated in the mature mossy fiber boutons. On the other hand, PSA was expressed by small round varicosities, irregularly shaped boutons, and the presumptive immature type of mossy fiber boutons. The PSA-positive small boutons were found to make synaptic contacts with CA3 pyramidal cells and nonpyramidal cells. The PSA-expressing presumptive immature boutons contained fewer clear synaptic vesicles and mitochondria, and, in some instances, they were invaginated by the PSA-positive, finger-like dendritic outgrowths arising from the dendritic shafts of the pyramidal cells, which are known to develop into a mossy fiber bouton-thorny excrescence complex. These findings indicate that distinct types of the mossy fiber boutons possess different PSA expression patterns in the adult hippocampus, and they also imply that PSA expression allows the mossy fibers to have the ability to regulate the bouton formation and remodeling that accompany synapse formation at the contact sites with pyramidal cells and nonpyramidal cells. PMID:10397399
Description of the georeferenced digital database produced by the U.S. EPA/MED along with the U.S. FWS for a R-EMAP project funded by EPA/ORD for Region 5 that produced an inventory of the coastal wetlands of the Great Lakes was described. The process used to identify and classif...
An instrumental method to identify electric charge types with a simple device
NASA Astrophysics Data System (ADS)
Isik, Hakan
In this study, an easy and enjoyable activity to determine the type of electric charge is presented, using a readymade electronic test screw. A four-way usage of the tester is explained with an electroscope. In the activity, ebonite and glass rods are negatively and positively charged by rubbing with paper sheets, respectively.
Joint annotation of chromatin state and chromatin conformation reveals relationships among domain types and identifies domains of cell-type-specific expression.
Libbrecht, Maxwell W; Ay, Ferhat; Hoffman, Michael M; Gilbert, David M; Bilmes, Jeffrey A; Noble, William Stafford
The genomic neighborhood of a gene influences its activity, a behavior that is attributable in part to domain-scale regulation. Previous genomic studies have identified many types of regulatory domains. However, due to the difficulty of integrating genomics data sets, the relationships among these domain types are poorly understood. Semi-automated genome annotation (SAGA) algorithms facilitate human interpretation of heterogeneous collections of genomics data by simultaneously partitioning the human genome and assigning labels to the resulting genomic segments. However, existing SAGA methods cannot integrate inherently pairwise chromatin conformation data. We developed a new computational method, called graph-based regularization (GBR), for expressing a pairwise prior that encourages certain pairs of genomic loci to receive the same label in a genome annotation. We used GBR to exploit chromatin conformation information during genome annotation by encouraging positions that are close in 3D to occupy the same type of domain. Using this approach, we produced a model of chromatin domains in eight human cell types, thereby revealing the relationships among known domain types. Through this model, we identified clusters of tightly regulated genes expressed in only a small number of cell types, which we term "specific expression domains." We found that domain boundaries marked by promoters and CTCF motifs are consistent between cell types even when domain activity changes. Finally, we showed that GBR can be used to transfer information from well-studied cell types to less well-characterized cell types during genome annotation, making it possible to produce high-quality annotations of the hundreds of cell types with limited available data. PMID:25677182
Functional and Structural Analysis of Five Mutations Identified in Methylmalonic Aciduria cbIB Type
Jorge-Finnigan, Ana; Aguado, Cristina; Sßnchez-Alcudia, Rocio; Abia, David; Richard, Eva; Merinero, Bego±a; Gßmez, Alejandra; Banerjee, Ruma; Desviat, Lourdes R.; Ugarte, Magdalena; Pķrez, Belen
ATP cob(I)alamin adenosyltransferase (ATR, E.C.22.214.171.124) converts reduced cob(I)alamin to the adenosylcobalamin cofactor. Mutations in the MMAB gene encoding ATR are responsible for the cblB type methylmalonic aciduria. Here we report the functional analysis of five cblB mutations to determine the underlying molecular basis of the dysfunction. The transcriptional profile along with minigenes analysis revealed that c.584G>A, c.349-1G>C and c.290G>A affect the splicing process. Wild-type ATR and the p.I96T (c.287T>C) and p.R191W (c.571C>T) mutant proteins were expressed in a prokaryote and a eukaryotic expression systems. The p.I96T protein was enzymatically active with a KM for ATP and KD for cob(I)alamin similar to wild-type enzyme, but exhibited a 40% reduction in specific activity. Both p.I96T and p.R191W mutant proteins are less stable than the wild-type protein, with increased stability when expressed under permissive folding conditions. Analysis of the oligomeric state of both mutants showed a structural defect for p.I96T and also a significant impact on the amount of recovered mutant protein that was more pronounced for p.R191W that, along with the structural analysis, suggest they might be misfolded. These results could serve as a basis for the implementation of pharmacological therapies aimed at increasing the residual activity of this type of mutations. PMID:20556797
Molecular typing of Cryptosporidium parvum associated with a diarrhoea outbreak identifies two sources of exposure
MATTSSON, J.ĀG.; INSULANDER, M.; LEBBAD, M.; BJųRKMAN, C.; SVENUNGSSON, B.
SUMMARY An outbreak of cryptosporidiosis associated with exposure to outdoor swimming-pool water affected an estimated 800¢1000 individuals. PCR products were obtained from faecal specimens from 30 individuals who tested positive for Cryptosporidium oocysts. RFLP and sequencing analyses showed that all individuals were infected with Cryptosporidium parvum. Among the infected individuals, five had just swum in an adjacent indoor pool during the same period, and had no identified contact with individuals linked to the outdoor pool. With the use of subgenotyping based on analysis of three mini- and microsatellite loci, MS1, TP14, and GP15, we could identify two sources of exposure. One subtype was associated with the outdoor pool and another with the indoor pool. These data demonstrate that the use of mini- and microsatellite loci as markers for molecular fingerprinting of C. parvum isolates are valuable in the epidemiological investigation of outbreaks. PMID:17961283
Psoriasis is associated with pleiotropic susceptibility loci identified in type II diabetes and Crohn disease
N Wolf; M Quaranta; N J Prescott; M Allen; R Smith; A D Burden; J Worthington; C E M Griffiths; C G Mathew; J N Barker; F Capon; R C Trembath
Background:Psoriasis is an immune-mediated skin disorder that is inherited as a multifactorial trait. Linkage analyses have clearly mapped a primary disease susceptibility locus to the major histocompatibility complex (MHC) region on chromosome 6p21. More recently, whole-genome association studies have identified two non-MHC disease genes (IL12B and IL23R), both of which also confer susceptibility to Crohn disease (CD).Objective and methods:To ascertain
Distinct pattern of antibody reactivity with oligomeric or polymeric forms of the capsular polysaccharide of Haemophilus influenzae type b.
Pillai, S; Ciciriello, S; Koster, M; Eby, R
The chain length of oligosaccharides required for antibody binding has been studied by using the capsular polysaccharide from Haemophilus influenzae type b or oligosaccharides derived from it. The concentration of competing antigens required to achieve a 50% inhibition of antibody binding by human polyclonal antisera in an in vitro competition enzyme-linked immunosorbent assay decreased progressively from greater than 10(-3) to 5 x 10(-7) M as the inhibiting saccharide chain length increased from 1 to 262 repeat units. Even small oligosaccharides (one or two repeat units) are potentially capable of competing to a significant level if a high enough concentration of saccharides is used. A similar pattern of reactivity was seen with a monoclonal anti-polyribosyl ribitol phosphate antibody, suggesting that the differences in the avidity of the antibody subpopulations in the polyclonal antisera do not contribute to the binding patterns observed. The binding reaction was specific as evaluated with pneumococcal saccharides. Furthermore, an oligosaccharide-protein conjugate binds antibody better than the free oligosaccharides do. Such a difference in binding was not observed between the polysaccharide and a polysaccharide-protein conjugate. Overall, the data suggest that identical epitopes are expressed by oligomeric and polymeric forms of the antigen and that a particularly more stable conformation in polysaccharides is preferred by antibodies. Covalent coupling of oligomers to protein increases the expression of stable conformation of epitopes. The data further suggest that this kind of antigenic analysis may be important for the design and synthesis of glycoconjugate vaccines. PMID:1718875
Identifying the types of waves: A value adding study on the ocean observing data buoy system
NASA Astrophysics Data System (ADS)
Ramakrishnan, B.; Sannasiraj, S.; Sundar, V.
Understanding of the wave climate in a particular place of interest is one of the primary aspects of any ocean observing system. Engineers and scientists working in the area of coastal or offshore engineering require to have knowledge on the types of waves that predominantly prevailing not only for the design of the ocean structures but also to understand the physical behavior of ocean surface. For example, identification of breaking waves is given prime importance as it has potential to answer for many of the water-air interaction or turbulence mixing problems. On the other hand, group of waves in which successive wave heights exceed the significant value could exert tremendous forces on the ocean structures and may lead catastrophic damage to it. Apart from deriving the conventional information such as the significant wave periods, heights and the predominant direction of prevailing, knowledge on the existence of type of waves would certainly help the designers, engineers and researchers. In an attempt to classify the types of waves from the buoy measurements, a detailed experimental program was conducted in the Department of Ocean Engineering, Indian Institute of Technology Madras. The buoy model was subjected to variety of waves such as group and breaking waves. The challenging task of the study is to simulate the group and breaking waves in the controlled laboratory environment. For which, initially, these waves are simulated theoretically, which intern converted into first order wave paddle signals to simulate the waves in the flume. The buoy heave, surge and pitch motions were measured by using potentiometers and the non-contact motion capturing cameras. The experimentally obtained wave elevation and the buoy motions time histories were analyzed by statistical, continuous wavelet transformation and phase-time methods to find the traces of wave types. A careful step by step analysis of the buoy motions yields presence of wave groupiness and breaking events. The details of the model, instrumentation, testing conditions and the analysis are presented and discussed in this paper.
A genome-wide association study identifies novel risk loci for type 2 diabetes
Robert Sladek; Ghislain Rocheleau; Johan Rung; Christian Dina; Lishuang Shen; David Serre; Philippe Boutin; Daniel Vincent; Alexandre Belisle; Samy Hadjadj; Beverley Balkau; Barbara Heude; Guillaume Charpentier; Thomas J. Hudson; Alexandre Montpetit; Alexey V. Pshezhetsky; Marc Prentki; Barry I. Posner; David J. Balding; David Meyre; Constantin Polychronakos; Philippe Froguel
Type 2 diabetes mellitus results from the interaction of environmental factors with a combination of genetic variants, most of which were hitherto unknown. A systematic search for these variants was recently made possible by the development of high-density arrays that permit the genotyping of hundreds of thousands of polymorphisms. We tested 392,935 single-nucleotide polymorphisms in a French case-control cohort. Markers
No increase in bleeding identified in type 1 VWD subjects with D1472H sequence variation.
Flood, Veronica H; Friedman, Kenneth D; Gill, Joan Cox; Haberichter, Sandra L; Christopherson, Pamela A; Branchford, Brian R; Hoffmann, Raymond G; Abshire, Thomas C; Dunn, Amy L; Di Paola, Jorge A; Hoots, W Keith; Brown, Deborah L; Leissinger, Cindy; Lusher, Jeanne M; Ragni, Margaret V; Shapiro, Amy D; Montgomery, Robert R
The diagnosis of von Willebrand disease (VWD) is complicated by issues with current laboratory testing, particularly the ristocetin cofactor activity assay (VWF:RCo). We have recently reported a sequence variation in the von Willebrand factor (VWF) A1 domain, p.D1472H (D1472H), associated with a decrease in the VWF:RCo/VWF antigen (VWF:Ag) ratio but not associated with bleeding in healthy control subjects. This report expands the previous study to include subjects with symptoms leading to the diagnosis of type 1 VWD. Type 1 VWD subjects with D1472H had a significant decrease in the VWF:RCo/VWF:Ag ratio compared with those without D1472H, similar to the findings in the healthy control population. No increase in bleeding score was observed, however, for VWD subjects with D1472H compared with those without D1472H. These results suggest that the presence of the D1472H sequence variation is not associated with a significant increase in bleeding symptoms, even in type 1 VWD subjects. PMID:23520336
Two mechanistically distinct effects of dihydropyridine nifedipine on CaV1.2 L-type Ca▓? channels revealed by Timothy syndrome mutation.
Sheng, Xiaona; Nakada, Tsutomu; Kobayashi, Motohiro; Kashihara, Toshihide; Shibazaki, Toshihide; Horiuchi-Hirose, Miwa; Gomi, Simmon; Hirose, Masamichi; Aoyama, Toshifumi; Yamada, Mitsuhiko
Dihydropyridine Ca(2+) channel antagonists (DHPs) block Ca(V)1.2 L-type Ca(2+) channels (LTCCs) by stabilizing their voltage-dependent inactivation (VDI); however, it is still not clear how DHPs allosterically interact with the kinetically distinct (fast and slow) VDI. Thus, we analyzed the effect of a prototypical DHP, nifedipine on LTCCs with or without the Timothy syndrome mutation that resides in the I-II linker (L(I)-(II)) of Ca(V)1.2 subunits and impairs VDI. Whole-cell Ba(2+) currents mediated by rabbit Ca(V)1.2 with or without the Timothy mutation (G436R) (analogous to the human G406R mutation) were analyzed in the presence and absence of nifedipine. In the absence of nifedipine, the mutation significantly impaired fast closed- and open-state VDI (CSI and OSI) at -40 and 0 mV, respectively, but did not affect channels' kinetics at -100 mV. Nifedipine equipotently blocked these channels at -80 mV. In wild-type LTCCs, nifedipine promoted fast CSI and OSI at -40 and 0 mV and promoted or stabilized slow CSI at -40 and -100 mV, respectively. In LTCCs with the mutation, nifedipine resumed the impaired fast CSI and OSI at -40 and 0 mV, respectively, and had the same effect on slow CSI as in wild-type LTCCs. Therefore, nifedipine has two mechanistically distinct effects on LTCCs: the promotion of fast CSI/OSI caused by L(I-II) at potentials positive to the sub-threshold potential and the promotion or stabilization of slow CSI caused by different mechanisms at potentials negative to the sub-threshold potential. PMID:22554770
Distinct subunit contributions to the activation of M-type potassium channels by PI(4,5)P2
Telezhkin, Vsevolod; Brown, David A.
Low-threshold voltage-gated M-type potassium channels (M channels) are tetraheteromers, commonly of two Kv7.2 and two Kv7.3 subunits. Though gated by voltage, the channels have an absolute requirement for binding of the membrane phospholipid phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) to open. We have investigated the quantitative relation between the concentration of a water-soluble PI(4,5)P2 analog, dioctanoyl-PI(4,5)P2 (DiC8-PI(4,5)P2), and channel open probability (Popen) by fast application of increasing concentrations of DiC8-PI(4,5)P2 to the inside face of membrane patches excised from Chinese hamster ovary cells expressing M channels as heteromeric Kv7.2/7.3 subunits. The rationale for the experiments is that this will mimic the effect of changes in membrane PI(4,5)P2 concentration. Single-channel conductances from channel current¢voltage relations in cell-attached mode were 9.2 ▒ 0.1 pS with a 2.5-mM pipette [K+]. Plots of Popen against DiC8-PI(4,5)P2 concentration were best fitted using a two-component concentration¢Popen relationship with high and low affinity, half-maximal effective concentration (EC50) values of 1.3 ▒ 0.14 and 75.5 ▒ 2.5 ĄM, respectively, and Hill slopes of 1.4 ▒ 0.06. In contrast, homomeric channels from cells expressing only Kv7.2 or Kv7.3 constructs yielded single-component curves with EC50 values of 76.2 ▒ 19.9 or 3.6 ▒ 1.0 ĄM, respectively. When wild-type (WT) Kv7.2 was coexpressed with a mutated Kv7.3 subunit with >100-fold reduced sensitivity to PI(4,5)P2, the high-affinity component of the activation curve was lost. Fitting the data for WT and mutant channels to an activation mechanism with independent PI(4,5)P2 binding to two Kv7.2 and two Kv7.3 subunits suggests that the two components of the M-channel activation curve correspond to the interaction of PI(4,5)P2 with the Kv7.3 and Kv7.2 subunits, respectively, that channels can open when only the two Kv7.3 subunits have bound DiC8-PI(4,5)P2, and that maximum channel opening requires binding to all four subunits. PMID:22689829
Morphologically distinct types of amyloid plaques point the way to a better understanding of Alzheimer's disease pathogenesis.
D'Andrea, M R; Nagele, R G
The details of the sequence of pathological events leading to neuron death in Alzheimer's disease (AD) are not known. Even the formation of amyloid plaques, one of the major histopathological hallmarks of AD, is not clearly understood; both the origin of the amyloid and the means of its deposition remain unclear. It is still widely considered, however, that amyloid plaques undergo gradual growth in the interstitial space of the brain via continual extracellular deposition of amyloid beta peptides at "seeding sites," and that these growing plaques encroach progressively on neurons and their axons and dendritic processes, eventually leading to neuronal death. Actually, histopathological evidence to support this mechanism is sparse and of uncertain validity. The fact that the amyloid deposits in AD brains that are collectively referred to as plaques are of multiple types and that each seems to have a different origin often is overlooked. We have shown experimentally that many of the so-called "diffuse amyloid plaques," which lack associated inflammatory cells, are either the result of leaks of amyloid from blood vessels at focal sites of blood-brain barrier breaches or are artifacts resulting from grazing sections through the margins of dense core plaques. In addition, we have provided experimental evidence that neuronal death via necrosis leaves a residue that takes the form of a spheroid "cloud" of amyloid, released by cell lysis, surrounding a dense core that often contains neuronal nuclear material. Support for a neuronal origin for these "dense core amyloid plaques" includes their ability to attract inflammatory cells (microglia and immigrant macrophages) and that they contain nuclear and cytoplasmic components that are somewhat resistant to proteolysis by lysosomes released during neuronal cell lysis. We discuss here the clinical and therapeutic importance of recognizing that amyloid deposition occurs both within neurons (intracellular) and in the interstitial (extracellular) space of the brain. For dense core plaques, we propose that the latter location largely follows from the former. This scenario suggests that blocking intraneuronal amyloid deposition should be a primary therapeutic target. This strategy also would be effective for blocking the gradual compromise of neuronal function resulting from this intraneuronal deposition, and the eventual death and lysis of these amyloid-burdened neurons that leads to amyloid release and the appearance of dense core amyloid plaques in the interstitium of AD brains. PMID:20121465
Catalytic- and ecto-domains of membrane type 1-matrix metalloproteinase have similar inhibition profiles but distinct endopeptidase activities.
Hurst, Douglas R; Schwartz, Martin A; Ghaffari, Mohammad A; Jin, Yonghao; Tschesche, Harald; Fields, Gregg B; Sang, Qing-Xiang Amy
Membrane type 1-matrix metalloproteinase (MT1-MMP/MMP-14) is a major collagenolytic enzyme that plays a vital role in development and morphogenesis. To elucidate further the structure-function relationship between the human MT1-MMP active site and the influence of the haemopexin domain on catalysis, substrate specificity and inhibition kinetics of the cdMT1-MMP (catalytic domain of MT1-MMP) and the ecto domain DeltaTM-MT1-MMP (transmembrane-domain-deleted MT1-MMP) were compared. For substrate 1 [Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH(2), where Mca stands for (7-methoxycoumarin-4-yl)acetyl- and Dpa for N -3-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl], the activation energy E (a) was determined to be 11.2 and 12.2 kcal/mol (1 cal=4.184 J) for cdMT1-MMP and DeltaTM-MT1-MMP respectively, which is consistent with k (cat)/ K (M) values of 7.37 and 1.46x10(4) M(-1).s(-1). The k (cat)/ K (M) values for a series of similar single-stranded peptide substrates were determined and found to correlate with a slope of 0.17 for the two enzyme forms. A triple-helical peptide substrate was predicted to have a k (cat)/ K (M) of 0.87x10(4) M(-1).s(-1) for DeltaTM-MT1-MMP based on the value for cdMT1-MMP of 5.12x10(4) M(-1).s(-1); however, the actual value was determined to be 2.5-fold higher, i.e. 2.18x10(4) M(-1).s(-1). These results suggest that cdMT1-MMP is catalytically more efficient towards small peptide substrates than DeltaTM-MT1-MMP and the haemopexin domain of MT1-MMP facilitates the hydrolysis of triple-helical substrates. Diastereomeric inhibitor pairs were utilized to probe further binding similarities at the active site. Ratios of K (i) values for the inhibitor pairs were found to correlate between the enzyme forms with a slope of 1.03, suggesting that the haemopexin domain does not significantly modify the enzyme active-site structure. PMID:14533979
Automated computation of arbor densities: a step toward identifying neuronal cell types
S³mb³l, Uygar; Zlateski, Aleksandar; Vishwanathan, Ashwin; Masland, Richard H.; Seung, H. Sebastian
The shape and position of a neuron convey information regarding its molecular and functional identity. The identification of cell types from structure, a classic method, relies on the time-consuming step of arbor tracing. However, as genetic tools and imaging methods make data-driven approaches to neuronal circuit analysis feasible, the need for automated processing increases. Here, we first establish that mouse retinal ganglion cell types can be as precise about distributing their arbor volumes across the inner plexiform layer as they are about distributing the skeletons of the arbors. Then, we describe an automated approach to computing the spatial distribution of the dendritic arbors, or arbor density, with respect to a global depth coordinate based on this observation. Our method involves three-dimensional reconstruction of neuronal arbors by a supervised machine learning algorithm, post-processing of the enhanced stacks to remove somata and isolate the neuron of interest, and registration of neurons to each other using automatically detected arbors of the starburst amacrine interneurons as fiducial markers. In principle, this method could be generalizable to other structures of the CNS, provided that they allow sparse labeling of the cells and contain a reliable axis of spatial reference. PMID:25505389
Automated computation of arbor densities: a step toward identifying neuronal cell types.
S³mb³l, Uygar; Zlateski, Aleksandar; Vishwanathan, Ashwin; Masland, Richard H; Seung, H Sebastian
The shape and position of a neuron convey information regarding its molecular and functional identity. The identification of cell types from structure, a classic method, relies on the time-consuming step of arbor tracing. However, as genetic tools and imaging methods make data-driven approaches to neuronal circuit analysis feasible, the need for automated processing increases. Here, we first establish that mouse retinal ganglion cell types can be as precise about distributing their arbor volumes across the inner plexiform layer as they are about distributing the skeletons of the arbors. Then, we describe an automated approach to computing the spatial distribution of the dendritic arbors, or arbor density, with respect to a global depth coordinate based on this observation. Our method involves three-dimensional reconstruction of neuronal arbors by a supervised machine learning algorithm, post-processing of the enhanced stacks to remove somata and isolate the neuron of interest, and registration of neurons to each other using automatically detected arbors of the starburst amacrine interneurons as fiducial markers. In principle, this method could be generalizable to other structures of the CNS, provided that they allow sparse labeling of the cells and contain a reliable axis of spatial reference. PMID:25505389
Picosecond-resolved FRET on non-amplified DNA for identifying individuals genetically susceptible to type-1 diabetes
NASA Astrophysics Data System (ADS)
Nardo, Luca; Tosi, Giovanna; Bondani, Maria; Accolla, Roberto; Andreoni, Alessandra
By tens-of-picosecond resolved fluorescence detection we study F÷rster resonance energy transfer between a donor and a black-hole-quencher bound at the 5'- and 3'-positions of an oligonucleotide probe matching the highly polymorphic region between codons 51 and 58 of the human leukocyte antigen DQB1 0201 allele, conferring susceptibility to type-1 diabetes. The probe is annealed with non-amplified genomic DNAs carrying either the 0201 sequence or other DQB1 allelic variants. We detect the longest-lived donor fluorescence in the case of hybridization with the 0201 allele and definitely faster and distinct decays for the other allelic variants, some of which are single-nucleotide polymorphic.
Environmental Trigger(s) of Type 1 Diabetes: Why So Difficult to Identify?
Type 1 diabetes (T1D) is one of the most common chronic diseases with childhood onset, and the disease has increased two- to fivefold over the past half century by as yet unknown means. T1D occurs when the body's immune system turns against itself so that, in a very specific and targeted way, it destroys the pancreatic ?-cells. T1D results from poorly defined interactions between susceptibility genes and environmental determinants. In contrast to the rapid progress in finding T1D genes, identification and confirmation of environmental determinants remain a formidable challenge. This review article will focus on factors which have to be evaluated and decision to take before starting a new prospective cohort study. Considering all the large ongoing prospective studies, new and more conclusive data than that obtained so far should instead come from international collaboration on the ongoing cohort studies. PMID:25883954
Integrated Genetic and Epigenetic Analysis Identifies Haplotype-Specific Methylation in the FTO Type 2 Diabetes and Obesity Susceptibility Locus
Christopher G. Bell; Sarah Finer; Cecilia M. Lindgren; Gareth A. Wilson; Vardhman K. Rakyan; Andrew E. Teschendorff; Pelin Akan; Elia Stupka; Thomas A. Down; Inga Prokopenko; Ian M. Morison; Jonathan Mill; Ruth Pidsley; Panos Deloukas; Timothy M. Frayling; Andrew T. Hattersley; Mark I. McCarthy; Stephan Beck; Graham A. Hitman; Thorkild I. A. Sorensen
Recent multi-dimensional approaches to the study of complex disease have revealed powerful insights into how genetic and epigenetic factors may underlie their aetiopathogenesis. We examined genotype-epigenotype interactions in the context of Type 2 Diabetes (T2D), focussing on known regions of genomic susceptibility. We assayed DNA methylation in 60 females, stratified according to disease susceptibility haplotype using previously identified association loci.
Random Mutagenesis Identifies a C-Terminal Region of YopD Important for Yersinia Type III Secretion Function
Solomon, Rebecca; Zhang, Weibing; McCrann, Grace; Bliska, James B.; Viboud, Gloria I.
A common virulence mechanism among bacterial pathogens is the use of specialized secretion systems that deliver virulence proteins through a translocation channel inserted in the host cell membrane. During Yersinia infection, the host recognizes the type III secretion system mounting a pro-inflammatory response. However, soon after they are translocated, the effectors efficiently counteract that response. In this study we sought to identify YopD residues responsible for type III secretion system function. Through random mutagenesis, we identified eight Y. pseudotuberculosis yopD mutants with single amino acid changes affecting various type III secretion functions. Three severely defective mutants had substitutions in residues encompassing a 35 amino acid region (residues 168¢203) located between the transmembrane domain and the C-terminal putative coiled-coil region of YopD. These mutations did not affect regulation of the low calcium response or YopB-YopD interaction but markedly inhibited MAPK and NF?B activation. When some of these mutations were introduced into the native yopD gene, defects in effector translocation and pore formation were also observed. We conclude that this newly identified region is important for YopD translocon function. The role of this domain in vivo remains elusive, as amino acid substitutions in that region did not significantly affect virulence of Y. pseudotuberculosis in orogastrically-infected mice. PMID:25807250
Drug-repurposing identified the combination of Trolox C and Cytisine for the treatment of type 2 diabetes
Background Drug-induced gene expression dataset (for example Connectivity Map, CMap) represent a valuable resource for drug-repurposing, a class of methods for identifying novel indications for approved drugs. Recently, CMap-based methods have successfully applied to identifying drugs for a number of diseases. However, currently few gene expression based methods are available for the repurposing of combined drugs. Increasing evidence has shown that the combination of drugs may valid for novel indications. Method Here, for this purpose, we presented a simple CMap-based scoring system to predict novel indications for the combination of two drugs. We then confirmed the effectiveness of the predicted drug combination in an animal model of type 2 diabetes. Results We applied the presented scoring system to type 2 diabetes and identified a candidate combination of two drugs, Trolox C and Cytisine. Finally, we confirmed that the predicted combined drugs are effective for the treatment of type 2 diabetes. Conclusion The presented scoring system represents one novel method for drug repurposing, which would provide helps for greatly extended the space of drugs. PMID:24885253
Human Immunodeficiency Virus Type 1 (HIV1) Genomic Sequences and Distinct Changes in CD8? Lymphocytes Precede Detectable Levels of HIV1 Antibodies in High-Risk Homosexuals
Mary Jane Yagi; Michael E. Joesten; Joyce Wallace; Julia P. Roboz; J. George Bekesi
Polymerase chain reaction (PCR) identified regions of the gag, LTR, and env genes of human immunodeficiency virus type 1 (HIV-1) in 5 (13%) of 38 high-risk homosexual men who were negative for HIV-1 antibodies by Western blot (WB). Significant increases in CD8? cells, particularly those bearing activation CD8?CD38? and CD8?Ia? antigens, and marked reductions in CD4? cells were detected in
The Potential Use of DNA Methylation Biomarkers to Identify Risk and Progression of Type 2 Diabetes
Gillberg, Linn; Ling, Charlotte
Type 2 diabetes mellitus (T2D) is a slowly progressive disease that can be postponed or even avoided through lifestyle changes. Recent data demonstrate highly significant correlations between DNA methylation and the most important risk factors of T2D, including age and body mass index, in blood and human tissues relevant to insulin resistance and T2D. Also, T2D patients and individuals with increased risk of the disease display differential DNA methylation profiles and plasticity compared to controls. Accordingly, the novel clues to DNA methylation fingerprints in blood and tissues with deteriorated metabolic capacity indicate that blood-borne epigenetic biomarkers of T2D progression might become a reality. This Review will address the most recent associations between DNA methylation and diabetes-related traits in human tissues and blood. The overall focus is on the potential of future epigenome-wide studies, carried out across tissues and populations with correlations to pre-diabetes and T2D risk factors, to build up a library of epigenetic markers of risk and early progression of T2D. These markers may, tentatively in combination with other predictors of T2D development, increase the possibility of individual-based lifestyle prevention of T2D and associated metabolic diseases. PMID:25870586
Identifying and meeting the challenges of insulin therapy in type 2 diabetes
Sorli, Christopher; Heile, Michael K
Type 2 diabetes mellitus (T2DM) is a chronic illness that requires clinical recognition and treatment of the dual pathophysiologic entities of altered glycemic control and insulin resistance to reduce the risk of long-term micro- and macrovascular complications. Although insulin is one of the most effective and widely used therapeutic options in the management of diabetes, it is used by less than one-half of patients for whom it is recommended. Clinician-, patient-, and health care system-related challenges present numerous obstacles to insulin use in T2DM. Clinicians must remain informed about new insulin products, emerging technologies, and treatment options that have the potential to improve adherence to insulin therapy while optimizing glycemic control and mitigating the risks of therapy. Patient-related challenges may be overcome by actively listening to the patientÆs fears and concerns regarding insulin therapy and by educating patients about the importance, rationale, and evolving role of insulin in individualized self-treatment regimens. Enlisting the services of Certified Diabetes Educators and office personnel can help in addressing patient-related challenges. Self-management of diabetes requires improved patient awareness regarding the importance of lifestyle modifications, self-monitoring, and/or continuous glucose monitoring, improved methods of insulin delivery (eg, insulin pens), and the enhanced convenience and safety provided by insulin analogs. Health care system-related challenges may be improved through control of the rising cost of insulin therapy while making it available to patients. To increase the success rate of treatment of T2DM, the 2012 position statement from the American Diabetes Association and the European Association for the Study of Diabetes focused on individualized patient care and provided clinicians with general treatment goals, implementation strategies, and tools to evaluate the quality of care. PMID:25061317
Frequent Intratype Neutralization by Plasma Immunoglobulin A Identified in HIV Type 2 Infection
MÕnsson, Fredrik; Palm, Angelica A.; Vincic, Elzbieta; da Silva, Zacarias; Medstrand, Patrik; Norrgren, Hans; Feny÷, Eva Maria; Jansson, Marianne
Abstract Human immunodeficiency virus type 2 (HIV-2) is less transmissible and less pathogenic compared to HIV-1 and, when matched for CD4+ T cell count, the plasma viral load in HIV-2-infected individuals is approximately one log lower than in HIV-1-infected individuals. The explanation for these observations is elusive, but differences in virus controlling immunity generated in the two infections may be contributing factors. In the present study, we investigated neutralization by immunoglobulin A (IgA), in parallel with IgG, purified from plasma of HIV-1, HIV-2, and HIV-1/HIV-2 dually (HIV-D) infected individuals. Neutralization was analyzed against HIV-1 and HIV-2 isolates using a plaque reduction assay. In HIV-2 infection, intratype-specific neutralization by IgA was frequently detected, although at a lesser magnitude then the corresponding IgG neutralizing titers. In contrast, neutralization by IgA could rarely be demonstrated in HIV-1 infection despite similar plasma IgA levels in both infections. In addition, IgA and IgG of HIV-D plasma neutralized the HIV-2 isolate more potently than the HIV-1 isolate, suggesting that the difference between neutralizing activity of plasma IgA and IgG depends on the virus itself. Taken together, these findings suggest that both IgA and IgG add to the potent intratype neutralizing activity detected in HIV-2 plasma, which may contribute to virus control in HIV-2 infection. PMID:23088167
A Rule-Based Prognostic Model for Type 1 Diabetes by Identifying and Synthesizing Baseline Profile Patterns
Lin, Ying; Qian, Xiaoning; Krischer, Jeffrey; Vehik, Kendra; Lee, Hye-Seung; Huang, Shuai
Objective To identify the risk-predictive baseline profile patterns of demographic, genetic, immunologic, and metabolic markers and synthesize these patterns for risk prediction. Research Design and Methods RuleFit is used to identify the risk-predictive baseline profile patterns of demographic, immunologic, and metabolic markers, using 356 subjects who were randomized into the control arm of the prospective Diabetes Prevention Trial-Type 1 (DPT-1) study. A novel latent trait model is developed to synthesize these baseline profile patterns for disease risk prediction. The primary outcome was Type 1 Diabetes (T1D) onset. Results We identified ten baseline profile patterns that were significantly predictive to the disease onset. Using these ten baseline profile patterns, a risk prediction model was built based on the latent trait model, which produced superior prediction performance over existing risk score models for T1D. Conclusion Our results demonstrated that the underlying disease progression process of T1D can be detected through some risk-predictive patterns of demographic, immunologic, and metabolic markers. A synthesis of these patterns provided accurate prediction of disease onset, leading to more cost-effective design of prevention trials of T1D in the future. PMID:24926781
Types of inter-atomic interactions at the MHC-peptide interface: Identifying commonality from accumulated data
Adrian, Png Eak Hock; Rajaseger, Ganapathy; Mathura, Venkatarajan Subramanian; Sakharkar, Meena Kishore; Kangueane, Pandjassarame
Background Quantitative information on the types of inter-atomic interactions at the MHC-peptide interface will provide insights to backbone/sidechain atom preference during binding. Qualitative descriptions of such interactions in each complex have been documented by protein crystallographers. However, no comprehensive report is available to account for the common types of inter-atomic interactions in a set of MHC-peptide complexes characterized by variation in MHC allele and peptide sequence. The available x-ray crystallography data for these complexes in the Protein Databank (PDB) provides an opportunity to identify the prevalent types of such interactions at the binding interface. Results We calculated the percentage distributions of four types of interactions at varying inter-atomic distances. The mean percentage distribution for these interactions and their standard deviation about the mean distribution is presented. The prevalence of SS and SB interactions at the MHC-peptide interface is shown in this study. SB is clearly dominant at an inter-atomic distance of 3┼. Conclusion The prevalently dominant SB interactions at the interface suggest the importance of peptide backbone conformation during MHC-peptide binding. Currently, available algorithms are developed for protein sidechain prediction upon fixed backbone template. This study shows the preference of backbone atoms in MHC-peptide binding and hence emphasizes the need for accurate peptide backbone prediction in quantitative MHC-peptide binding calculations. PMID:12010576
Genome-wide association study for type 2 diabetes in Indians identifies a new susceptibility locus at 2q21.
Tabassum, Rubina; Chauhan, Ganesh; Dwivedi, Om Prakash; Mahajan, Anubha; Jaiswal, Alok; Kaur, Ismeet; Bandesh, Khushdeep; Singh, Tejbir; Mathai, Benan John; Pandey, Yogesh; Chidambaram, Manickam; Sharma, Amitabh; Chavali, Sreenivas; Sengupta, Shantanu; Ramakrishnan, Lakshmi; Venkatesh, Pradeep; Aggarwal, Sanjay K; Ghosh, Saurabh; Prabhakaran, Dorairaj; Srinath, Reddy K; Saxena, Madhukar; Banerjee, Monisha; Mathur, Sandeep; Bhansali, Anil; Shah, Viral N; Madhu, Sri Venkata; Marwaha, Raman K; Basu, Analabha; Scaria, Vinod; McCarthy, Mark I; Venkatesan, Radha; Mohan, Viswanathan; Tandon, Nikhil; Bharadwaj, Dwaipayan
Indians undergoing socioeconomic and lifestyle transitions will be maximally affected by epidemic of type 2 diabetes (T2D). We conducted a two-stage genome-wide association study of T2D in 12,535 Indians, a less explored but high-risk group. We identified a new type 2 diabetes-associated locus at 2q21, with the lead signal being rs6723108 (odds ratio 1.31; P = 3.32 ū 10??). Imputation analysis refined the signal to rs998451 (odds ratio 1.56; P = 6.3 ū 10?╣▓) within TMEM163 that encodes a probable vesicular transporter in nerve terminals. TMEM163 variants also showed association with decreased fasting plasma insulin and homeostatic model assessment of insulin resistance, indicating a plausible effect through impaired insulin secretion. The 2q21 region also harbors RAB3GAP1 and ACMSD; those are involved in neurologic disorders. Forty-nine of 56 previously reported signals showed consistency in direction with similar effect sizes in Indians and previous studies, and 25 of them were also associated (P < 0.05). Known loci and the newly identified 2q21 locus altogether explained 7.65% variance in the risk of T2D in Indians. Our study suggests that common susceptibility variants for T2D are largely the same across populations, but also reveals a population-specific locus and provides further insights into genetic architecture and etiology of T2D. PMID:23209189
Genome-Wide Association Study for Type 2 Diabetes in Indians Identifies a New Susceptibility Locus at 2q21
Tabassum, Rubina; Chauhan, Ganesh; Dwivedi, Om Prakash; Mahajan, Anubha; Jaiswal, Alok; Kaur, Ismeet; Bandesh, Khushdeep; Singh, Tejbir; Mathai, Benan John; Pandey, Yogesh; Chidambaram, Manickam; Sharma, Amitabh; Chavali, Sreenivas; Sengupta, Shantanu; Ramakrishnan, Lakshmi; Venkatesh, Pradeep; Aggarwal, Sanjay K.; Ghosh, Saurabh; Prabhakaran, Dorairaj; Srinath, Reddy K.; Saxena, Madhukar; Banerjee, Monisha; Mathur, Sandeep; Bhansali, Anil; Shah, Viral N.; Madhu, Sri Venkata; Marwaha, Raman K.; Basu, Analabha; Scaria, Vinod; McCarthy, Mark I.; Venkatesan, Radha; Mohan, Viswanathan; Tandon, Nikhil; Bharadwaj, Dwaipayan
Indians undergoing socioeconomic and lifestyle transitions will be maximally affected by epidemic of type 2 diabetes (T2D). We conducted a two-stage genome-wide association study of T2D in 12,535 Indians, a less explored but high-risk group. We identified a new type 2 diabetes¢associated locus at 2q21, with the lead signal being rs6723108 (odds ratio 1.31; P = 3.32 ū 10?9). Imputation analysis refined the signal to rs998451 (odds ratio 1.56; P = 6.3 ū 10?12) within TMEM163 that encodes a probable vesicular transporter in nerve terminals. TMEM163 variants also showed association with decreased fasting plasma insulin and homeostatic model assessment of insulin resistance, indicating a plausible effect through impaired insulin secretion. The 2q21 region also harbors RAB3GAP1 and ACMSD; those are involved in neurologic disorders. Forty-nine of 56 previously reported signals showed consistency in direction with similar effect sizes in Indians and previous studies, and 25 of them were also associated (P < 0.05). Known loci and the newly identified 2q21 locus altogether explained 7.65% variance in the risk of T2D in Indians. Our study suggests that common susceptibility variants for T2D are largely the same across populations, but also reveals a population-specific locus and provides further insights into genetic architecture and etiology of T2D. PMID:23209189
Spectroscopic distinctions between two types of Ce(3+) ions in X2-Y2SiO5: a theoretical investigation.
Wen, Jun; Duan, Chang-Kui; Ning, Lixin; Huang, Yucheng; Zhan, Shengbao; Zhang, Jie; Yin, Min
The Ce(3+) ions occupying the two crystallographically distinct Y(3+) sites both with C1 point group symmetry in the X2-Y2SiO5 (X2-YSO) crystal are discriminated by their spectroscopic properties calculated with ab initio approaches and phenomenological model analyses. Density functional theory (DFT) calculations with the supercell approach are performed to obtain the local structures of Ce(3+), based on which the wave function-based embedded cluster calculations at the CASSCF/CASPT2 level are carried out to derive the 4f ? 5d transition energies. From the ab initio calculated energy levels and wave functions, the crystal-field parameters (CFPs) and the anisotropic g-factor tensors of Ce(3+) are extracted. The theoretical results agree well with available experimental data. The structural and spectroscopic properties for the two types of Ce(3+) ions in X2-YSO are thus distinguished in terms of the calculated local atomic structures, 4f ? 5d transition energies, and spectral parameters. PMID:24953347
Redox regulation of T-cell turnover by the p13 protein of human T-cell leukemia virus type 1: distinct effects in primary versus transformed cells.
Silic-Benussi, Micol; Cavallari, Ilaria; Vajente, Nicola; Vidali, Silvia; Chieco-Bianchi, Luigi; Di Lisa, Fabio; Saggioro, Daniela; D'Agostino, Donna M; Ciminale, Vincenzo
The present study investigated the function of p13, a mitochondrial protein of human T-cell leukemia virus type 1 (HTLV-1). Although necessary for viral propagation in vivo, the mechanism of function of p13 is incompletely understood. Drawing from studies in isolated mitochondria, we analyzed the effects of p13 on mitochondrial reactive oxygen species (ROS) in transformed and primary T cells. In transformed cells (Jurkat, HeLa), p13 did not affect ROS unless the cells were subjected to glucose deprivation, which led to a p13-dependent increase in ROS and cell death. Using RNA interference we confirmed that expression of p13 also influences glucose starvation-induced cell death in the context of HTLV-1-infected cells. ROS measurements showed an increasing gradient from resting to mitogen-activated primary T cells to transformed T cells (Jurkat). Expression of p13 in primary T cells resulted in their activation, an effect that was abrogated by ROS scavengers. These findings suggest that p13 may have a distinct impact on cell turnover depending on the inherent ROS levels; in the context of the HTLV-1 propagation strategy, p13 could increase the pool of "normal" infected cells while culling cells acquiring a transformed phenotype, thus favoring lifelong persistence of the virus in the host. PMID:20395415
Urinary Fetuin-A Is a Novel Marker for Diabetic Nephropathy in Type 2 Diabetes Identified by Lectin Microarray
Inoue, Kentaro; Wada, Jun; Eguchi, Jun; Nakatsuka, Atsuko; Teshigawara, Sanae; Murakami, Kazutoshi; Ogawa, Daisuke; Terami, Takahiro; Katayama, Akihiro; Tone, Atsuhito; Iseda, Izumi; Hida, Kazuyuki; Yamada, Masao; Ogawa, Tomohisa; Makino, Hirofumi
We analyzed the urine samples of patients with type 2 diabetes at various stages of diabetic nephropathy by lectin microarray to identify a biomarker to predict the progression of diabetic nephropathy. Japanese patients with type 2 diabetes at various stages of nephropathy were enrolled and we performed lectin microarray analyses (n?=?17) and measured urinary excretion of fetuin-A (n?=?85). The increased signals of urine samples were observed in Sia?2-6Gal/GalNAc-binding lectins (SNA, SSA, TJA-I) during the progression of diabetic nephropathy. We next isolated sialylated glycoproteins by using SSA-lectin affinity chromatography and identified fetuin-A by liquid chromatography¢tandem mass spectrometer. Urinary excretion of fetuin-A significantly increased during the progression of albuminuria (A1, 0.40▒0.43; A2, 0.60▒0.53; A3 1.57▒1.13 ng/gCr; p?=?7.29ū10?8) and of GFR stages (G1, 0.39▒0.39; G2, 0.49▒0.45; G3, 1.25▒1.18; G4, 1.34▒0.80 ng/gCr; p?=?3.89ū10?4). Multivariate logistic regression analysis was employed to assess fetuin-A as a risk for diabetic nephropathy with microalbuminuria or GFR<60 mL/min. Fetuin-A is demonstrated as a risk factor for both microalbuminuria and reduction of GFR in diabetic nephropathy with the odds ratio of 4.721 (1.881¢11.844) and 3.739 (1.785¢7.841), respectively. Collectively, the glycan profiling analysis is useful method to identify the urine biomarkers and fetuin-A is a candidate to predict the progression of diabetic nephropathy. PMID:24143207
Discrete typing units of Trypanosoma cruzi identified in rural dogs and cats in the humid Argentinean Chaco.
Enriquez, G F; Cardinal, M V; Orozco, M M; Lanati, L; Schijman, A G; G³rtler, R E
The discrete typing units (DTUs) of Trypanosoma cruzi that infect domestic dogs and cats have rarely been studied. With this purpose we conducted a cross-sectional xenodiagnostic survey of dog and cat populations residing in 2 infested rural villages in Pampa del Indio, in the humid Argentine Chaco. Parasites were isolated by culture from 44 dogs and 12 cats with a positive xenodiagnosis. DTUs were identified from parasite culture samples using a strategy based on multiple polymerase-chain reactions. TcVI was identified in 37 of 44 dogs and in 10 of 12 cats, whereas TcV was identified in 5 dogs and in 2 cats -a new finding for cats. No mixed infections were detected. The occurrence of 2 dogs infected with TcIII -classically found in armadillos- suggests a probable link with the local sylvatic transmission cycle involving Dasypus novemcinctus armadillos and a potential risk of human infection with TcIII. Our study reinforces the importance of dogs and cats as domestic reservoir hosts and sources of various DTUs infecting humans, and suggests a link between dogs and the sylvatic transmission cycle of TcIII. PMID:23058180
Discrete typing units of Trypanosoma cruzi identified in rural dogs and cats in the humid Argentinean Chaco
SUMMARY The discrete typing units (DTUs) of Trypanosoma cruzi that infect domestic dogs and cats have rarely been studied. With this purpose we conducted a cross-sectional xenodiagnostic survey of dog and cat populations residing in two infested rural villages in Pampa del Indio, in the humid Argentine Chaco. Parasites were isolated by culture from 44 dogs and 12 cats with a positive xenodiagnosis. DTUs were identified from parasite culture samples using a strategy based on multiple polymerase-chain reactions. TcVI was identified in 37 of 44 dogs and in 10 of 12 cats, whereas TcV was identified in five dogs and in two cats ¢a new finding for cats. No mixed infections were detected. The occurrence of two dogs infected with TcIII ¢classically found in armadillos¢ suggests a probable link with the local sylvatic transmission cycle involving Dasypus novemcinctus armadillos and a potential risk of human infection with TcIII. Our study reinforces the importance of dogs and cats as domestic reservoir hosts and sources of various DTUs infecting humans, and suggests a link between dogs and the sylvatic transmission cycle of TcIII. PMID:23058180
Eliminating Unwanted Far-Field Excitation in Objective-Type TIRF. Part I. Identifying Sources of Nonevanescent Excitation Light
Brunstein, Maia; Teremetz, Maxime; Hķrault, Karine; Tourain, Christophe; Oheim, Martin
Total internal reflection fluorescence microscopy (TIRFM) achieves subdiffraction axial sectioning by confining fluorophore excitation to a thin layer close to the cell/substrate boundary. However, it is often unknown how thin this light sheet actually is. Particularly in objective-type TIRFM, large deviations from the exponential intensity decay expected for pure evanescence have been reported. Nonevanescent excitation light diminishes the optical sectioning effect, reduces contrast, and renders TIRFM-image quantification uncertain. To identify the sources of this unwanted fluorescence excitation in deeper sample layers, we here combine azimuthal and polar beam scanning (spinning TIRF), atomic force microscopy, and wavefront analysis of beams passing through the objective periphery. Using a variety of intracellular fluorescent labels as well as negative staining experiments to measure cell-induced scattering, we find that azimuthal beam spinning produces TIRFM images that more accurately portray the real fluorophore distribution, but these images are still hampered by far-field excitation. Furthermore, although clearly measureable, cell-induced scattering is not the dominant source of far-field excitation light in objective-type TIRF, at least for most types of weakly scattering cells. It is the microscope illumination optical path that produces a large cell- and beam-angle invariant stray excitation that is insensitive to beam scanning. This instrument-induced glare is produced far from the sample plane, inside the microscope illumination optical path. We identify stray reflections and high-numerical aperture aberrations of the TIRF objective as one important source. This work is accompanied by a companion paper (Pt.2/2). PMID:24606927
Eliminating unwanted far-field excitation in objective-type TIRF. Part I. identifying sources of nonevanescent excitation light.
Brunstein, Maia; Teremetz, Maxime; Hķrault, Karine; Tourain, Christophe; Oheim, Martin
Total internal reflection fluorescence microscopy (TIRFM) achieves subdiffraction axial sectioning by confining fluorophore excitation to a thin layer close to the cell/substrate boundary. However, it is often unknown how thin this light sheet actually is. Particularly in objective-type TIRFM, large deviations from the exponential intensity decay expected for pure evanescence have been reported. Nonevanescent excitation light diminishes the optical sectioning effect, reduces contrast, and renders TIRFM-image quantification uncertain. To identify the sources of this unwanted fluorescence excitation in deeper sample layers, we here combine azimuthal and polar beam scanning (spinning TIRF), atomic force microscopy, and wavefront analysis of beams passing through the objective periphery. Using a variety of intracellular fluorescent labels as well as negative staining experiments to measure cell-induced scattering, we find that azimuthal beam spinning produces TIRFM images that more accurately portray the real fluorophore distribution, but these images are still hampered by far-field excitation. Furthermore, although clearly measureable, cell-induced scattering is not the dominant source of far-field excitation light in objective-type TIRF, at least for most types of weakly scattering cells. It is the microscope illumination optical path that produces a large cell- and beam-angle invariant stray excitation that is insensitive to beam scanning. This instrument-induced glare is produced far from the sample plane, inside the microscope illumination optical path. We identify stray reflections and high-numerical aperture aberrations of the TIRF objective as one important source. This work is accompanied by a companion paper (Pt.2/2). PMID:24606927
Prospective study of low-dose ristocetin-induced platelet aggregation to identify type 2B von Willebrand disease (VWD) and platelet-type VWD in children.
Frontroth, Juan Pablo; Hepner, Mirta; Sciuccati, Gabriela; Feli· Torres, Aurora; Pieroni, Graciela; Bonduel, Mariana
Type 2B von Willebrand disease (VWD2B) and platelet-type von Willebrand disease (PT-VWD) are rare bleeding disorders characterised by an increased ristocetin-induced platelet aggregation (RIPA) at low dose of ristocetin. It was the objective of this study to detect children with VWD2B and PT-VWD using RIPA at low dose of ristocetin (0.5 mg/ml) in the screening evaluation of bleeding disorders, and to analyse the phenotypic data along with the molecular findings. Over a 14-year period, 641 children with personal and family bleeding symptoms or bleeding from birth with previously uncharacterised haemostatic disorders were prospectively studied. Six unrelated patients (0.93%) showed RIPA at low dose of ristocetin. RIPA-based mixing studies identified that the plasma of the six probands and at least one parent from five unrelated families induced aggregation of normal platelets with the addition of low-dose ristocetin. None of the probands' platelets showed aggregation with cryoprecipitate. Low ristocetin cofactor activity/VWF antigen ratio with absent collagen binding activity or thrombocytopenia were detected respectively in only two patients. Molecular analysis of exon 28 of the VWF gene identified mutations in only three patients. No mutation in the GP1BA gene was found. In this large prospective paediatric study, the screening approach including RIPA at low dose of ristocetin permitted the detection of patients with VWD2B that would otherwise have been missed. No patient with phenotype or genotype of PT-VWD was identified. Heterogeneity of bleeding symptoms and phenotypic parameters were found among members of the same family. PMID:20941465
Distinct mechanisms of axonal globule formation in mice expressing human wild type ?-synuclein or dementia with Lewy bodies-linked P123H ▀-synuclein
Background Axonopathy is critical in the early pathogenesis of neurodegenerative diseases, including ParkinsonÆs disease (PD) and dementia with Lewy bodies (DLB). Axonal swellings such as globules and spheroids are a distinct feature of axonopathy and our recent study showed that transgenic (tg) mice expressing DLB-linked P123H ?-synuclein (P123H ?S) were characterized by P123H ?S-immunoreactive axonal swellings (P123H ?S-globules). Therefore, the objectives of this study were to evaluate ?-synuclein (?S)-immunoreactive axonal swellings (?S-globules) in the brains of tg mice expressing human wild-type ?S and to compare them with the globules in P123H ?S tg mice. Results In ?S tg mice, ?S-globules were formed in an age-dependent manner in various brain regions, including the thalamus and basal ganglia. These globules were composed of autophagosome-like membranous structures and were reminiscent of P123H ?S-globules in P123H ?S tg mice. In the ?S-globules, frequent clustering and deformation of mitochondria were observed. These changes were associated with oxidative stress, based on staining of nitrated ?S and 4-hydroxy-2-nonenal (4-HNE). In accord with the absence of mitochondria in the P123H ?S-globules, staining of nitrated ?S and 4-HNE in these globules was weaker than that for ?S-globules. Leucine-rich repeat kinase 2 (LRRK2), the PARK8 of familial PD, was detected exclusively in ?S-globules, suggesting a specific role of this molecule in these globules. Conclusions Lysosomal pathology was similarly observed for both ?S- and P123H ?S-globules, while oxidative stress was associated with the ?S-globules, and to a lesser extent with the P123H ?S-globules. Other pathologies, such as mitochondrial alteration and LRRK2 accumulation, were exclusively detected for ?S-globules. Collectively, both ?S- and P123H ?S-globules were formed through similar but distinct pathogenic mechanisms. Our findings suggest that synuclein family members might contribute to diverse axonal pathologies. PMID:23013868
Dorothy Hodgkin Lecture 2014. Understanding genes identified by genome-wide association studies for type 2 diabetes.
Rutter, G A
Whilst the heritable nature of Type 2 diabetes has been recognized for many years, only in the past two decades have linkage analyses in families and genome-wide association studies in large populations begun to reveal the genetic landscape of the disease in detail. Whilst the former have provided a powerful means of identifying the genes responsible for monogenic forms of the disease, the latter highlight relatively large genomic regions. These often harbour multiple genes, whose relative contribution to exaggerated disease risk is uncertain. In the present study, the approaches that have been used to dissect the role of just a few (TCF7L2, SLC30A8, ADCY5, MTNR1B and CDKAL1) of the ~Ā500 genes identified at dozens of implicated loci are described. These are usually selected based on the strength of their effect on disease risk, and predictions as to their likely biological role. Direct determination of the effects of identified polymorphisms on gene expression in disease-relevant tissues, notably the pancreatic islet, are then performed to identify genes whose expression is affected by a particular polymorphism. Subsequent functional analyses then involve perturbing gene expression in vitro in ?-cell lines or isolated islets and in vivo in animal models. Although the majority of polymorphisms affect insulin production rather than action, and mainly affect the ? cell, effects via other tissues may also contribute, requiring careful consideration in the design and interpretation of experiments in model systems. These considerations illustrate the scale of the task needed to exploit genome-wide association study data for the development of new therapeutic strategies. PMID:25186316
SLoWPoKES-II: Identifying Ultra-wide Binaries to the Late-M and L Spectral Types
NASA Astrophysics Data System (ADS)
Dhital, Saurav; West, A. A.; Stassun, K.; Schluns, K.; Massey, A. P.
The Sloan Low-mass Wide Pairs of Kinematically Equivalent Stars (SLoWPoKES) catalog identified over 1300 bona fide, common proper motion binary systems. While SLoWPoKES was the largest ever sample of wide low-mass binaries, some of the most interesting and valuable systemsŚthose with very low-mass components and therefore the most fragile systemsŚdo not have proper motion data available. To find these interesting systems, we have extended our techniques: we present the SLoWPoKES-II catalog of low-mass visual binaries identified from the Sloan Digital Sky Survey by matching photometric distances and without the need for proper motion information. We vetted the candidate pairs by comparing their Galactic positions to Monte Carlo realizations of a simulated Milky Way. Over 41,000 visual binaries (including over 400 very low-mass pairs) with angular separations of 0.?4-10?, were identified, each with a probability of chance alignment of ? 5%. The catalog contains a diversity of systemsŚin mass, mass ratios, metallicity, and evolutionary statesŚthat should facilitate follow-up studies to characterize the properties of low-mass stars and brown dwarfs. The identified SLoWPoKES-II systems are at distance up to 250 pc, which allows us to study the (wide) binary properties as a function of their position in the Galaxy. For example, the wide binary fraction shows a decline as a function of Galactic height (a proxy for age), suggesting dynamical processing of wide pairs with age. The trend is evident across the mid-K to mid-M spectral types and is accentuated at larger separations. The mass ratio, as estimated from their colors, distribution is significantly skewed towards unity. The data are publicly available on our data visualization portal at http://slowpokes.vanderbilt.edu.
'Snake River (SR)-type' volcanism at the Yellowstone hotspot track: Distinctive products from unusual, high-temperature silicic super-eruptions
Branney, M.J.; Bonnichsen, B.; Andrews, G.D.M.; Ellis, B.; Barry, T.L.; McCurry, M.
A new category of large-scale volcanism, here termed Snake River (SR)-type volcanism, is defined with reference to a distinctive volcanic facies association displayed by Miocene rocks in the central Snake River Plain area of southern Idaho and northern Nevada, USA. The facies association contrasts with those typical of silicic volcanism elsewhere and records unusual, voluminous and particularly environmentally devastating styles of eruption that remain poorly understood. It includes: (1) large-volume, lithic-poor rhyolitic ignimbrites with scarce pumice lapilli; (2) extensive, parallel-laminated, medium to coarse-grained ashfall deposits with large cuspate shards, crystals and a paucity of pumice lapilli; many are fused to black vitrophyre; (3) unusually extensive, large-volume rhyolite lavas; (4) unusually intense welding, rheomorphism, and widespread development of lava-like facies in the ignimbrites; (5) extensive, fines-rich ash deposits with abundant ash aggregates (pellets and accretionary lapilli); (6) the ashfall layers and ignimbrites contain abundant clasts of dense obsidian and vitrophyre; (7) a bimodal association between the rhyolitic rocks and numerous, coalescing low-profile basalt lava shields; and (8) widespread evidence of emplacement in lacustrine-alluvial environments, as revealed by intercalated lake sediments, ignimbrite peperites, rhyolitic and basaltic hyaloclastites, basalt pillow-lava deltas, rhyolitic and basaltic phreatomagmatic tuffs, alluvial sands and palaeosols. Many rhyolitic eruptions were high mass-flux, large volume and explosive (VEI 6-8), and involved H2O-poor, low-??18O, metaluminous rhyolite magmas with unusually low viscosities, partly due to high magmatic temperatures (900-1,050??C). SR-type volcanism contrasts with silicic volcanism at many other volcanic fields, where the fall deposits are typically Plinian with pumice lapilli, the ignimbrites are low to medium grade (non-welded to eutaxitic) with abundant pumice lapilli or fiamme, and the rhyolite extrusions are small volume silicic domes and coule??es. SR-type volcanism seems to have occurred at numerous times in Earth history, because elements of the facies association occur within some other volcanic fields, including Trans-Pecos Texas, Etendeka-Paran, Lebombo, the English Lake District, the Proterozoic Keewanawan volcanics of Minnesota and the Yardea Dacite of Australia. ?? Springer-Verlag 2007.
Mathematical modeling and experimental validation of the spatial distribution of boron in the root of Arabidopsis thaliana identify high boron accumulation in the tip and predict a distinct root tip uptake function.
Shimotohno, Akie; Sotta, Naoyuki; Sato, Takafumi; De Ruvo, Micol; Marķe, Athanasius F M; Grieneisen, Ver¶nica A; Fujiwara, Toru
Boron, an essential micronutrient, is transported in roots of Arabidopsis thaliana mainly by two different types of transporters, BORs and NIPs (nodulin26-like intrinsic proteins). Both are plasma membrane localized, but have distinct transport properties and patterns of cell type-specific accumulation with different polar localizations, which are likely to affect boron distribution. Here, we used mathematical modeling and an experimental determination to address boron distributions in the root. A computational model of the root is created at the cellular level, describing the boron transporters as observed experimentally. Boron is allowed to diffuse into roots, in cells and cell walls, and to be transported over plasma membranes, reflecting the properties of the different transporters. The model predicts that a region around the quiescent center has a higher concentration of soluble boron than other portions. To evaluate this prediction experimentally, we determined the boron distribution in roots using laser ablation-inductivity coupled plasma-mass spectrometry. The analysis indicated that the boron concentration is highest near the tip and is lower in the more proximal region of the meristem zone, similar to the pattern of soluble boron distribution predicted by the model. Our model also predicts that upward boron flux does not continuously increase from the root tip toward the mature region, indicating that boron taken up in the root tip is not efficiently transported to shoots. This suggests that root tip-absorbed boron is probably used for local root growth, and that instead it is the more mature root regions which have a greater role in transporting boron toward the shoots. PMID:25670713
Mathematical Modeling and Experimental Validation of the Spatial Distribution of Boron in the Root of Arabidopsis thaliana Identify High Boron Accumulation in the Tip and Predict a Distinct Root Tip Uptake Function
Shimotohno, Akie; Sotta, Naoyuki; Sato, Takafumi; De Ruvo, Micol; Marķe, Athanasius F.M.; Grieneisen, Ver¶nica A.; Fujiwara, Toru
Boron, an essential micronutrient, is transported in roots of Arabidopsis thaliana mainly by two different types of transporters, BORs and NIPs (nodulin26-like intrinsic proteins). Both are plasma membrane localized, but have distinct transport properties and patterns of cell type-specific accumulation with different polar localizations, which are likely to affect boron distribution. Here, we used mathematical modeling and an experimental determination to address boron distributions in the root. A computational model of the root is created at the cellular level, describing the boron transporters as observed experimentally. Boron is allowed to diffuse into roots, in cells and cell walls, and to be transported over plasma membranes, reflecting the properties of the different transporters. The model predicts that a region around the quiescent center has a higher concentration of soluble boron than other portions. To evaluate this prediction experimentally, we determined the boron distribution in roots using laser ablation-inductivity coupled plasma-mass spectrometry. The analysis indicated that the boron concentration is highest near the tip and is lower in the more proximal region of the meristem zone, similar to the pattern of soluble boron distribution predicted by the model. Our model also predicts that upward boron flux does not continuously increase from the root tip toward the mature region, indicating that boron taken up in the root tip is not efficiently transported to shoots. This suggests that root tip-absorbed boron is probably used for local root growth, and that instead it is the more mature root regions which have a greater role in transporting boron toward the shoots. PMID:25670713
A quantitative affinity-profiling system that reveals distinct CD4/CCR5 usage patterns among human immunodeficiency virus type 1 and simian immunodeficiency virus strains.
Johnston, Samantha H; Lobritz, Michael A; Nguyen, Sandra; Lassen, Kara; Delair, Shirley; Posta, Filippo; Bryson, Yvonne J; Arts, Eric J; Chou, Tom; Lee, Benhur
The affinity of human immunodeficiency virus (HIV) envelope for CD4 and CCR5 appears to be associated with aspects of R5 virus (virus using the CCR5 coreceptor) pathogenicity. However, entry efficiency results from complex interactions between the viral envelope glycoprotein and both CD4 and CCR5, which limits attempts to correlate viral pathogenicity with surrogate measures of envelope CD4 and CCR5 affinities. Here, we present a system that provides a quantitative and comprehensive characterization of viral entry efficiency as a direct interdependent function of both CD4 and CCR5 levels. This receptor affinity profiling system also revealed heretofore unappreciated complexities underlying CD4/CCR5 usage. We first developed a dually inducible cell line in which CD4 and CCR5 could be simultaneously and independently regulated within a physiologic range of surface expression. Infection by multiple HIV type 1 (HIV-1) and simian immunodeficiency virus isolates could be examined simultaneously for up to 48 different combinations of CD4/CCR5 expression levels, resulting in a distinct usage pattern for each virus. Thus, each virus generated a unique three-dimensional surface plot in which viral infectivity varied as a function of both CD4 and CCR5 expression. From this functional form, we obtained a sensitivity vector along with corresponding metrics that quantified an isolate's overall efficiency of CD4/CCR5 usage. When applied to viral isolates with well-characterized sensitivities to entry/fusion inhibitors, the vector metrics were able to encapsulate their known biological phenotypes. The application of the vector metrics also indicated that envelopes derived from elite suppressors had overall-reduced entry efficiencies compared to those of envelopes derived from chronically infected viremic progressors. Our affinity-profiling system may help to refine studies of R5 virus tropism and pathogenesis. PMID:19692480
Neurite outgrowth: this process, first discovered by Santiago Ramon y Cajal, is sustained by the exocytosis of two distinct types of vesicles.
Meldolesi, Jacopo
Neurite outgrowth is a fundamental process in the differentiation of neurons. The first, seminal study documenting the generation of "appendages" (now known as filopodia and lamellipodia) on the "cones d'accroissement," the specialized growth cones at the tips of neurites, was reported by Cajal still in the XIXth century, investigating chicken neurons embryos stained by the Golgi's reazione nera. Since then, studies have continued using, in addition to brain tissues, powerful in vitro models, i.e. primary cultures of pyramidal neurons from the hippocampus and neurosecretory cell lines, in particular PC12 cells. These studies have documented that neuronal neurites, upon sprouting from the cell body, give rise to both axons and dendrites. The specificity of these differentiated neurites depends on the diffusion barrier established at the initial segment of the axon and on the specialized domains, spines and presynaptic boutons, assembled around complexes of scaffold proteins. The two main, coordinate mechanisms that support neurite outgrowth are (a) the rearrangement of the cytoskeleton and (b) the expansion of the plasma membrane due to the exo/endocytosis of specific vesicles, distinct from those filled with neurotransmitters (clear and dense-core vesicles). The latter process is the main task of this review. In axons the surface-expanding exocytoses are concentrated at the growth cones; in dendrites they may be more distributed along the shaft. At least two types of exocytic vesicles appear to be involved, the enlargeosomes, positive for VAMP4, during early phases of development, and Ti-VAMP-positive vesicles later on. Outgrowth studies, that are now intensely pursued, have already yielded results of great importance in brain cell biology and function, and are playing an increasing role in pathology and medicine. PMID:20600308
Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians.
Cho, Yoon Shin; Chen, Chien-Hsiun; Hu, Cheng; Long, Jirong; Ong, Rick Twee Hee; Sim, Xueling; Takeuchi, Fumihiko; Wu, Ying; Go, Min Jin; Yamauchi, Toshimasa; Chang, Yi-Cheng; Kwak, Soo Heon; Ma, Ronald C W; Yamamoto, Ken; Adair, Linda S; Aung, Tin; Cai, Qiuyin; Chang, Li-Ching; Chen, Yuan-Tsong; Gao, Yutang; Hu, Frank B; Kim, Hyung-Lae; Kim, Sangsoo; Kim, Young Jin; Lee, Jeannette Jen-Mai; Lee, Nanette R; Li, Yun; Liu, Jian Jun; Lu, Wei; Nakamura, Jiro; Nakashima, Eitaro; Ng, Daniel Peng-Keat; Tay, Wan Ting; Tsai, Fuu-Jen; Wong, Tien Yin; Yokota, Mitsuhiro; Zheng, Wei; Zhang, Rong; Wang, Congrong; So, Wing Yee; Ohnaka, Keizo; Ikegami, Hiroshi; Hara, Kazuo; Cho, Young Min; Cho, Nam H; Chang, Tien-Jyun; Bao, Yuqian; Hedman, ┼sa K; Morris, Andrew P; McCarthy, Mark I; Takayanagi, Ryoichi; Park, Kyong Soo; Jia, Weiping; Chuang, Lee-Ming; Chan, Juliana C N; Maeda, Shiro; Kadowaki, Takashi; Lee, Jong-Young; Wu, Jer-Yuarn; Teo, Yik Ying; Tai, E Shyong; Shu, Xiao Ou; Mohlke, Karen L; Kato, Norihiro; Han, Bok-Ghee; Seielstad, Mark
We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, which is involved in pancreatic beta cell development and insulin gene expression, is known for its association with fasting glucose levels. The evidence of an association with T2D for PEPD and HNF4A has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings, derived from an east Asian population, provide new perspectives on the etiology of T2D. PMID:22158537
Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I.
Guelly, Christian; Zhu, Peng-Peng; Leonardis, Lea; Papi?, Lea; Zidar, Janez; Schabh³ttl, Maria; Strohmaier, Heimo; Weis, Joachim; Strom, Tim M; Baets, Jonathan; Willems, Jan; De Jonghe, Peter; Reilly, Mary M; Fr÷hlich, Eleonore; Hatz, Martina; Trajanoski, Slave; Pieber, Thomas R; Janecke, Andreas R; Blackstone, Craig; Auer-Grumbach, Michaela
Hereditary sensory neuropathy type I (HSN I) is an axonal form of autosomal-dominant hereditary motor and sensory neuropathy distinguished by prominent sensory loss that leads to painless injuries. Unrecognized, these can result in delayed wound healing and osteomyelitis, necessitating distal amputations. To elucidate the genetic basis of an HSN I subtype in a family in which mutations in the few known HSN I genes had been excluded, we employed massive parallel exon sequencing of the 14.3 Mb disease interval on chromosome 14q. We detected a missense mutation (c.1065C>A, p.Asn355Lys) in atlastin-1 (ATL1), a gene that is known to be mutated in early-onset hereditary spastic paraplegia SPG3A and that encodes the large dynamin-related GTPase atlastin-1. The mutant protein exhibited reduced GTPase activity and prominently disrupted ER network morphology when expressed in COS7 cells, strongly supporting pathogenicity. An expanded screen in 115 additional HSN I patients identified two further dominant ATL1 mutations (c.196G>C [p.Glu66Gln] and c.976 delG [p.Val326TrpfsX8]). This study highlights an unexpected major role for atlastin-1 in the function of sensory neurons and identifies HSN I and SPG3A as allelic disorders. PMID:21194679
Meta-analysis of genome-wide association studies identifies 8 new loci for type 2 diabetes in East Asians
Cho, Yoon Shin; Chen, Chien-Hsiun; Hu, Cheng; Long, Jirong; Ong, Rick Twee Hee; Sim, Xueling; Takeuchi, Fumihiko; Wu, Ying; Go, Min Jin; Yamauchi, Toshimasa; Chang, Yi-Cheng; Kwak, Soo Heon; Ma, Ronald C.W.; Yamamoto, Ken; Adair, Linda S.; Aung, Tin; Cai, Qiuyin; Chang, Li-Ching; Chen, Yuan-Tsong; Gao, Yutang; Hu, Frank B.; Kim, Hyung-Lae; Kim, Sangsoo; Kim, Young Jin; Lee, Jeannette Jen-Mai; Lee, Nanette R.; Li, Yun; Liu, Jian Jun; Lu, Wei; Nakamura, Jiro; Nakashima, Eitaro; Ng, Daniel Peng-Keat; Tay, Wan Ting; Tsai, Fuu-Jen; Wong, Tien Yin; Yokota, Mitsuhiro; Zheng, Wei; Zhang, Rong; Wang, Congrong; So, Wing Yee; Ohnaka, Keizo; Ikegami, Hiroshi; Hara, Kazuo; Cho, Young Min; Cho, Nam H; Chang, Tien-Jyun; Bao, Yuqian; Hedman, ┼sa K.; Morris, Andrew P.; McCarthy, Mark I.; Takayanagi, Ryoichi; Park, Kyong Soo; Jia, Weiping; Chuang, Lee-Ming; Chan, Juliana C.N.; Maeda, Shiro; Kadowaki, Takashi; Lee, Jong-Young; Wu, Jer-Yuarn; Teo, Yik Ying; Tai, E Shyong; Shu, Xiao Ou; Mohlke, Karen L.; Kato, Norihiro; Han, Bok-Ghee; Seielstad, Mark
We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in East Asian populations. The first stage meta-analysis of eight T2D genome-wide association studies (6,952 cases and 11,865 controls) was followed by a second stage in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which were mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, involved in pancreatic beta cell development and insulin gene expression1,2, is known for its association with fasting glucose levels3,4. The evidence of T2D association for PEPD5 and HNF4A6,7 has been detected in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings derived from East Asians provide new perspectives on the etiology of T2D. PMID:22158537
A chemical biology approach identified PI3K as a potential therapeutic target for neurofibromatosis type 2
Petrilli, Alejandra M; Fuse, Marisa A; Donnan, Mathew S; Bott, Marga; Sparrow, Nicklaus A; Tondera, Daniel; Huffziger, Julia; Frenzel, Corina; Malany, C Siobhan; Echeverri, Christophe J; Smith, Layton; Fernßndez-Valle, Cristina
Mutations in the merlin tumor suppressor gene cause Neurofibromatosis type 2 (NF2), which is a disease characterized by development of multiple benign tumors in the nervous system. The current standard of care for NF2 calls for surgical resection of the characteristic tumors, often with devastating neurological consequences. There are currently no approved non-surgical therapies for NF2. In an attempt to identify much needed targets and therapeutically active compounds for NF2 treatment, we employed a chemical biology approach using ultra-high-throughput screening. To support this goal, we created a merlin-null mouse Schwann cell (MSC) line to screen for compounds that selectively decrease their viability and proliferation. We optimized conditions for 384-well plate assays and executed a proof-of-concept screen of the Library of Pharmacologically Active Compounds. Further confirmatory and selectivity assays identified phosphatidylinositol 3-kinase (PI3K) as a potential NF2 drug target. Notably, loss of merlin function is associated with activation of the PI3K/Akt pathway in human schwannomas. We report that AS605240, a PI3K inhibitor, decreased merlin-null MSC viability in a dose-dependent manner without significantly decreasing viability of control Schwann cells. AS605240 exerted its action on merlin-null MSCs by promoting caspase-dependent apoptosis and inducing autophagy. Additional PI3K inhibitors tested also decreased viability of merlin-null MSCs in a dose-dependent manner. In summary, our chemical genomic screen and subsequent hit validation studies have identified PI3K as potential target for NF2 therapy. PMID:25360213
The genome sequence of the most widely cultivated cacao type and its use to identify candidate genes regulating pod color
Background Theobroma cacao L. cultivar Matina 1-6 belongs to the most cultivated cacao type. The availability of its genome sequence and methods for identifying genes responsible for important cacao traits will aid cacao researchers and breeders. Results We describe the sequencing and assembly of the genome of Theobroma cacao L. cultivar Matina 1-6. The genome of the Matina 1-6 cultivar is 445 Mbp, which is significantly larger than a sequenced Criollo cultivar, and more typical of other cultivars. The chromosome-scale assembly, version 1.1, contains 711 scaffolds covering 346.0 Mbp, with a contig N50 of 84.4 kbp, a scaffold N50 of 34.4 Mbp, and an evidence-based gene set of 29,408 loci. Version 1.1 has 10x the scaffold N50 and 4x the contig N50 as Criollo, and includes 111 Mb more anchored sequence. The version 1.1 assembly has 4.4% gap sequence, while Criollo has 10.9%. Through a combination of haplotype, association mapping and gene expression analyses, we leverage this robust reference genome to identify a promising candidate gene responsible for pod color variation. We demonstrate that green/red pod color in cacao is likely regulated by the R2R3 MYB transcription factor TcMYB113, homologs of which determine pigmentation in Rosaceae, Solanaceae, and Brassicaceae. One SNP within the target site for a highly conserved trans-acting siRNA in dicots, found within TcMYB113, seems to affect transcript levels of this gene and therefore pod color variation. Conclusions We report a high-quality sequence and annotation of Theobroma cacao L. and demonstrate its utility in identifying candidate genes regulating traits. PMID:23731509
Integrated Genetic and Epigenetic Analysis Identifies Haplotype-Specific Methylation in the FTO Type 2 Diabetes and Obesity Susceptibility Locus
Wilson, Gareth A.; Rakyan, Vardhman K.; Teschendorff, Andrew E.; Akan, Pelin; Stupka, Elia; Down, Thomas A.; Prokopenko, Inga; Morison, Ian M.; Mill, Jonathan; Pidsley, Ruth; Deloukas, Panos; Frayling, Timothy M.; Hattersley, Andrew T.; McCarthy, Mark I.; Beck, Stephan; Hitman, Graham A.
Recent multi-dimensional approaches to the study of complex disease have revealed powerful insights into how genetic and epigenetic factors may underlie their aetiopathogenesis. We examined genotype-epigenotype interactions in the context of Type 2 Diabetes (T2D), focussing on known regions of genomic susceptibility. We assayed DNA methylation in 60 females, stratified according to disease susceptibility haplotype using previously identified association loci. CpG methylation was assessed using methylated DNA immunoprecipitation on a targeted array (MeDIP-chip) and absolute methylation values were estimated using a Bayesian algorithm (BATMAN). Absolute methylation levels were quantified across LD blocks, and we identified increased DNA methylation on the FTO obesity susceptibility haplotype, tagged by the rs8050136 risk allele A (p?=?9.40ū10?4, permutation p?=?1.0ū10?3). Further analysis across the 46 kb LD block using sliding windows localised the most significant difference to be within a 7.7 kb region (p?=?1.13ū10?7). Sequence level analysis, followed by pyrosequencing validation, revealed that the methylation difference was driven by the co-ordinated phase of CpG-creating SNPs across the risk haplotype. This 7.7 kb region of haplotype-specific methylation (HSM), encapsulates a Highly Conserved Non-Coding Element (HCNE) that has previously been validated as a long-range enhancer, supported by the histone H3K4me1 enhancer signature. This study demonstrates that integration of Genome-Wide Association (GWA) SNP and epigenomic DNA methylation data can identify potential novel genotype-epigenotype interactions within disease-associated loci, thus providing a novel route to aid unravelling common complex diseases. PMID:21124985
Multiple-locus sequence typing analysis of Bacillus cereus and Bacillus thuringiensis reveals separate clustering and a distinct population structure of psychrotrophic strains.
Sorokin, Alexei; Candelon, Benjamin; Guilloux, Kķvin; Galleron, Nathalie; Wackerow-Kouzova, Natalia; Ehrlich, S Dusko; Bourguet, Denis; Sanchis, Vincent
We used multilocus sequence typing (MLST) to characterize phylogenetic relationships for a collection of Bacillus cereus group strains isolated from forest soil in the Paris area during a mild winter. This collection contains multiple strains isolated from the same soil sample and strains isolated from samples from different sites. We characterized 115 strains of this collection and 19 other strains based on the sequences of the clpC, dinB, gdpD, panC, purF, and yhfL loci. The number of alleles ranged from 36 to 53, and a total of 93 allelic profiles or sequence types were distinguished. We identified three major strain clusters-C, T, and W-based on the comparison of individual gene sequences or concatenated sequences. Some less representative clusters and subclusters were also distinguished. Analysis of the MLST data using the concept of clonal complexes led to the identification of two, five, and three such groups in clusters C, T, and W, respectively. Some of the forest isolates were closely related to independently isolated psychrotrophic strains. Systematic testing of the strains of this collection showed that almost all the strains that were able to grow at a low temperature (6 degrees C) belonged to cluster W. Most of these strains, including three independently isolated strains, belong to two clonal complexes and are therefore very closely related genetically. These clonal complexes represent strains corresponding to the previously identified species Bacillus weihenstephanensis. Most of the other strains of our collection, including some from the W cluster, are not psychrotrophic. B. weihenstephanensis (cluster W) strains appear to comprise an effectively sexual population, whereas Bacillus thuringiensis (cluster T) and B. cereus (cluster C) have clonal population structures. PMID:16461712
Global biochemical profiling identifies ?-hydroxypyruvate as a potential mediator of type 2 diabetes in mice and humans.
Zhang, Sheng; Wang, Songyan; Puhl, Matthew D; Jiang, Xuntian; Hyrc, Krzysztof L; Laciny, Erin; Wallendorf, Michael J; Pappan, Kirk L; Coyle, Joseph T; Wice, Burton M
Glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 are incretins secreted by respective K and L enteroendocrine cells after eating and amplify glucose-stimulated insulin secretion (GSIS). This amplification has been termed the "incretin response." To determine the role(s) of K cells for the incretin response and type 2 diabetes mellitus (T2DM), diphtheria toxin-expressing (DT) mice that specifically lack GIP-producing cells were backcrossed five to eight times onto the diabetogenic NONcNZO10/Ltj background. As in humans with T2DM, DT mice lacked an incretin response, although GLP-1 release was maintained. With high-fat (HF) feeding, DT mice remained lean but developed T2DM, whereas wild-type mice developed obesity but not diabetes. Metabolomics identified biochemicals reflecting impaired glucose handling, insulin resistance, and diabetes complications in prediabetic DT/HF mice. ?-Hydroxypyruvate and benzoate levels were increased and decreased, respectively, suggesting ?-hydroxypyruvate production from d-serine. In vitro, ?-hydroxypyruvate altered excitatory properties of myenteric neurons and reduced islet insulin content but not GSIS. ?-Hydroxypyruvate-to-d-serine ratios were lower in humans with impaired glucose tolerance compared with normal glucose tolerance and T2DM. Earlier human studies unmasked a neural relay that amplifies GIP-mediated insulin secretion in a pattern reciprocal to ?-hydroxypyruvate-to-d-serine ratios in all groups. Thus, K cells may maintain long-term function of neurons and ?-cells by regulating ?-hydroxypyruvate levels. PMID:25368100
Identification of the LWYIK motif located in the human immunodeficiency virus type 1 transmembrane gp41 protein as a distinct determinant for viral infection.
Chen, Steve S-L; Yang, Polung; Ke, Po-Yuan; Li, Hsiao-Fen; Chan, Woan-Eng; Chang, Ding-Kwo; Chuang, Chin-Kai; Tsai, Yu; Huang, Shu-Chen
The highly conserved LWYIK motif located immediately proximal to the membrane-spanning domain of the gp41 transmembrane protein of human immunodeficiency virus type 1 has been proposed as being important for the surface envelope (Env) glycoprotein's association with lipid rafts and gp41-mediated membrane fusion. Here we employed substitution and deletion mutagenesis to understand the role of this motif in the virus life cycle. None of the mutants examined affected the synthesis, precursor processing, CD4 binding, oligomerization, or cell surface expression of the Env, nor did they alter Env incorporation into the virus. All of the mutants, particularly the DeltaYI, DeltaIK, and DeltaLWYIK mutants, in which the indicated residues were deleted, exhibited greatly reduced one-cycle viral replication and the Env trans-complementation ability. All of these deletion mutant proteins were still localized in the lipid rafts. With the exception of the Trp-to-Ala (WA) mutant, which exhibited reduced viral infectivity albeit with normal membrane fusion, all mutants displayed loss of some or almost all of the membrane fusion ability. Although these deletion mutants partially inhibited in trans wild-type (WT) Env-mediated fusion, they were more effective in dominantly interfering with WT Env-mediated viral entry when coexpressed with the WT Env, implying a role of this motif in postfusion events as well. Both T20 and L43L peptides derived from the two gp41 extracellular C- and N-terminal alpha-helical heptad repeats, respectively, inhibited WT and DeltaLWYIK Env-mediated viral entry with comparable efficacies. Biotin-tagged T20 effectively captured both the fusion-active, prehairpin intermediates of WT and mutant gp41 upon CD4 activation. Env without the deletion of the LWYIK motif still effectively mediated lipid mixing but inhibited content mixing. Our study demonstrates that the immediate membrane-proximal LWYIK motif acts as a unique and distinct determinant located in the gp41 C-terminal ectodomain by promoting enlargement of fusion pores and postfusion activities. PMID:18987155
Large-Scale Gene-Centric Meta-Analysis across 39 Studies Identifies Type 2 Diabetes Loci
Saxena, Richa; Elbers, ClaraĀC.; Guo, Yiran; Peter, Inga; Gaunt, TomĀR.; Mega, JessicaĀL.; Lanktree, MatthewĀB.; Tare, Archana; Castillo, BertaĀAlmoguera; Li, YunĀR.; Johnson, Toby; Bruinenberg, Marcel; Gilbert-Diamond, Diane; Rajagopalan, Ramakrishnan; Voight, BenjaminĀF.; Balasubramanyam, Ashok; Barnard, John; Bauer, Florianne; Baumert, Jens; Bhangale, Tushar; B÷hm, BernhardĀO.; Braund, PeterĀS.; Burton, PaulĀR.; Chandrupatla, HareeshĀR.; Clarke, Robert; Cooper-DeHoff, RhondaĀM.; Crook, ErrolĀD.; Davey-Smith, George; Day, IanĀN.; deĀBoer, Anthonius; deĀGroot, MarkĀC.H.; Drenos, Fotios; Ferguson, Jane; Fox, CarolineĀS.; Furlong, ClementĀE.; Gibson, Quince; Gieger, Christian; Gilhuijs-Pederson, LisaĀA.; Glessner, JosephĀT.; Goel, Anuj; Gong, Yan; Grant, StruanĀF.A.; Grobbee, DiederickĀE.; Hastie, Claire; Humphries, SteveĀE.; Kim, CeciliaĀE.; Kivimaki, Mika; Kleber, Marcus; Meisinger, Christa; Kumari, Meena; Langaee, TaimourĀY.; Lawlor, DebbieĀA.; Li, Mingyao; Lobmeyer, MaximilianĀT.; Maitland-vanĀderĀZee, Anke-Hilse; Meijs, MatthijsĀF.L.; Molony, ClionaĀM.; Morrow, DavidĀA.; Murugesan, Gurunathan; Musani, SolomonĀK.; Nelson, ChristopherĀP.; Newhouse, StephenĀJ.; O'Connell, JefferyĀR.; Padmanabhan, Sandosh; Palmen, Jutta; Patel, SanjeyĀR.; Pepine, CarlĀJ.; Pettinger, Mary; Price, ThomasĀS.; Rafelt, Suzanne; Ranchalis, Jane; Rasheed, Asif; Rosenthal, Elisabeth; Ruczinski, Ingo; Shah, Sonia; Shen, Haiqing; Silbernagel, G³nther; Smith, ErinĀN.; Spijkerman, AnnemiekeĀW.M.; Stanton, Alice; Steffes, MichaelĀW.; Thorand, Barbara; Trip, Mieke; vanĀderĀHarst, Pim; vanĀderĀA, DaphneĀL.; vanĀIperen, ErikĀP.A.; vanĀSetten, Jessica; vanĀVliet-Ostaptchouk, JanaĀV.; Verweij, Niek; Wolffenbuttel, BruceĀH.R.; Young, Taylor; Zafarmand, M.ĀHadi; Zmuda, JosephĀM.; Boehnke, Michael; Altshuler, David; McCarthy, Mark; Kao, W.H.ĀLinda; Pankow, JamesĀS.; Cappola, ThomasĀP.; Sever, Peter; Poulter, Neil; Caulfield, Mark; Dominiczak, Anna; Shields, DenisĀC.; Bhatt, Deepak L.; Zhang, Li; Curtis, SeanĀP.; Danesh, John; Casas, JuanĀP.; vanĀderĀSchouw, YvonneĀT.; Onland-Moret, N.ĀCharlotte; Doevendans, PieterĀA.; Dorn, GeraldĀW.; Farrall, Martin; FitzGerald, GarretĀA.; Hamsten, Anders; Hegele, Robert; Hingorani, AroonĀD.; Hofker, MartenĀH.; Huggins, GordonĀS.; Illig, Thomas; Jarvik, GailĀP.; Johnson, JulieĀA.; Klungel, OlafĀH.; Knowler, WilliamĀC.; Koenig, Wolfgang; Mõrz, Winfried; Meigs, JamesĀB.; Melander, Olle; Munroe, PatriciaĀB.; Mitchell, BraxtonĀD.; Bielinski, SusanĀJ.; Rader, DanielĀJ.; Reilly, MuredachĀP.; Rich, StephenĀS.; Rotter, JeromeĀI.; Saleheen, Danish; Samani, NileshĀJ.; Schadt, EricĀE.; Shuldiner, AlanĀR.; Silverstein, Roy; Kottke-Marchant, Kandice; Talmud, PhilippaĀJ.; Watkins, Hugh; Asselbergs, Folkert W.; deĀBakker, PaulĀI.W.; McCaffery, Jeanne; Wijmenga, Cisca; Sabatine, MarcĀS.; Wilson, JamesĀG.; Reiner, Alex; Bowden, DonaldĀW.; Hakonarson, Hakon; Siscovick, DavidĀS.; Keating, BrendanĀJ.
To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ?50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ?2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7Āū 10?9) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4Āū 10?6). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4Āū 10?7) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1Āū 10?15). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1Āū 10?8). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups. PMID:22325160
Genetic Modifiers of Neurofibromatosis Type 1-Associated Cafķ-au-Lait Macule Count Identified Using Multi-platform Analysis
Pemov, Alexander; Sung, Heejong; Hyland, Paula L.; Sloan, Jennifer L.; Ruppert, Sarah L.; Baldwin, Andrea M.; Boland, Joseph F.; Bass, Sara E.; Lee, Hyo Jung; Jones, Kristine M.; Zhang, Xijun; Mullikin, James C.; Widemann, Brigitte C.; Wilson, Alexander F.; Stewart, Douglas R.
Neurofibromatosis type 1 (NF1) is an autosomal dominant, monogenic disorder of dysregulated neurocutaneous tissue growth. Pleiotropy, variable expressivity and few NF1 genotype-phenotype correlates limit clinical prognostication in NF1. Phenotype complexity in NF1 is hypothesized to derive in part from genetic modifiers unlinked to the NF1 locus. In this study, we hypothesized that normal variation in germline gene expression confers risk for certain phenotypes in NF1. In a set of 79 individuals with NF1, we examined the association between gene expression in lymphoblastoid cell lines with NF1-associated phenotypes and sequenced select genes with significant phenotype/expression correlations. In a discovery cohort of 89 self-reported European-Americans with NF1 we examined the association between germline sequence variants of these genes with cafķ-au-lait macule (CALM) count, a tractable, tumor-like phenotype in NF1. Two correlated, common SNPs (rs4660761 and rs7161) between DPH2 and ATP6V0B were significantly associated with the CALM count. Analysis with tiled regression also identified SNP rs4660761 as significantly associated with CALM count. SNP rs1800934 and 12 rare variants in the mismatch repair gene MSH6 were also associated with CALM count. Both SNPs rs7161 and rs4660761 (DPH2 and ATP6V0B) were highly significant in a mega-analysis in a combined cohort of 180 self-reported European-Americans; SNP rs1800934 (MSH6) was near-significant in a meta-analysis assuming dominant effect of the minor allele. SNP rs4660761 is predicted to regulate ATP6V0B, a gene associated with melanosome biology. Individuals with homozygous mutations in MSH6 can develop an NF1-like phenotype, including multiple CALMs. Through a multi-platform approach, we identified variants that influence NF1 CALM count. PMID:25329635
Canine parvovirus type 2c identified from an outbreak of severe gastroenteritis in a litter in Sweden.
Sutton, David; Vinberg, Carina; Gustafsson, Agneta; Pearce, Jacqueline; Greenwood, Neil
A litter of recently-vaccinated puppies in Sweden experienced signs of severe haemorrhagic gastroenteritis. Canine parvovirus (CPV) was suspected as the cause of this outbreak on the basis of the clinical signs and the presence of parvoviral antigen in the faeces from one of the affected pups - confirmed using a commercial in-clinic faecal antigen ELISA test kit. A concern was raised about whether the vaccine (which contained a live, attenuated strain of CPV) could have caused the disease and so further faecal samples from the affected pups were submitted for laboratory virus isolation and identification.On cell culture, two out of four faecal samples were found to be virus-positive. This was confirmed as being canine parvovirus by immuno-staining with CPV specific monoclonal antibody. The virus was then tested using a series of PCR probes designed to confirm the identity of CPV and to distinguish the unique vaccine strain from field virus. This confirmed that the virus was indeed CPV but that it was not vaccine strain. The virus was then typed by sequencing the 426 amino acid region of the capsid gene which revealed this to be a type 2c virus.Since its emergence in the late 1970s, canine parvovirus 2 (CPV2) has spread worldwide and is recognised as an important canine pathogen in all countries. The original CPV2 rapidly evolved into two antigenic variants, CPV2a and CPV2b, which progressively replaced the original CPV2. More recently a new antigenic variant, CPV2c, has appeared. To date this variant has been identified in many countries worldwide but there have been no reports yet of its presence in any Scandinavian countries. This case report therefore represents the first published evidence of the involvement of CPV2c in a severe outbreak of typical haemorrhagic gastroenteritis in a susceptible litter of pups in Scandinavia. PMID:24016358
Canine parvovirus type 2c identified from an outbreak of severe gastroenteritis in a litter in Sweden
A litter of recently-vaccinated puppies in Sweden experienced signs of severe haemorrhagic gastroenteritis. Canine parvovirus (CPV) was suspected as the cause of this outbreak on the basis of the clinical signs and the presence of parvoviral antigen in the faeces from one of the affected pups - confirmed using a commercial in-clinic faecal antigen ELISA test kit. A concern was raised about whether the vaccine (which contained a live, attenuated strain of CPV) could have caused the disease and so further faecal samples from the affected pups were submitted for laboratory virus isolation and identification. On cell culture, two out of four faecal samples were found to be virus-positive. This was confirmed as being canine parvovirus by immuno-staining with CPV specific monoclonal antibody. The virus was then tested using a series of PCR probes designed to confirm the identity of CPV and to distinguish the unique vaccine strain from field virus. This confirmed that the virus was indeed CPV but that it was not vaccine strain. The virus was then typed by sequencing the 426 amino acid region of the capsid gene which revealed this to be a type 2c virus. Since its emergence in the late 1970s, canine parvovirus 2 (CPV2) has spread worldwide and is recognised as an important canine pathogen in all countries. The original CPV2 rapidly evolved into two antigenic variants, CPV2a and CPV2b, which progressively replaced the original CPV2. More recently a new antigenic variant, CPV2c, has appeared. To date this variant has been identified in many countries worldwide but there have been no reports yet of its presence in any Scandinavian countries. This case report therefore represents the first published evidence of the involvement of CPV2c in a severe outbreak of typical haemorrhagic gastroenteritis in a susceptible litter of pups in Scandinavia. PMID:24016358
Modified Needle-Tip PcrV Proteins Reveal Distinct Phenotypes Relevant to the Control of Type III Secretion and Intoxication by Pseudomonas aeruginosa
Sato, Hiromi; Hunt, Meredith L.; Weiner, Joshua J.; Hansen, Andrew T.; Frank, Dara W.
The type III secretion system (T3SS) is employed to deliver effector proteins to the cytosol of eukaryotic hosts by multiple species of Gram-negative bacteria, including Pseudomonas aeruginosa. Translocation of effectors is dependent on the proteins encoded by the pcrGVHpopBD operon. These proteins form a T3S translocator complex, composed of a needle-tip complex (PcrV), translocons (PopB and PopD), and chaperones (PcrG and PcrH). PcrV mediates the folding and insertion of PopB/PopD in host plasmic membranes, where assembled translocons form a translocation channel. Assembly of this complex and delivery of effectors through this machinery is tightly controlled by PcrV, yet the multifunctional aspects of this molecule have not been defined. In addition, PcrV is a protective antigen for P. aeruginosa infection as is the ortholog, LcrV, for Yersinia. We constructed PcrV derivatives containing in-frame linker insertions and site-specific mutations. The expression of these derivatives was regulated by a T3S-specific promoter in a pcrV-null mutant of PA103. Nine derivatives disrupted the regulation of effector secretion and constitutively released an effector protein into growth medium. Three of these regulatory mutants, in which the linker was inserted in the N-terminal globular domain, were competent for the translocation of a cytotoxin, ExoU, into eukaryotic host cells. We also isolated strains expressing a delayed-toxicity phenotype, which secrete translocators slowly despite the normal level of effector secretion. Most of the cytotoxic translocation-competent strains retained the protective epitope of PcrV derivatives, and Mab166 was able to protect erythrocytes during infection with these strains. The use of defined PcrV derivatives possessing distinct phenotypes may lead to a better understanding of the functional aspects of T3 needle-tip proteins and the development of therapeutic agents or vaccines targeting T3SS-mediated intoxication. PMID:21479247
Oxazolomycin Biosynthesis in Streptomyces albus JA3453 Featuring an ōAcyltransferase-lessö Type I Polyketide Synthase That Incorporates Two Distinct Extender Units*
Zhao, Chunhua; Coughlin, Jane M.; Ju, Jianhua; Zhu, Dongqing; Wendt-Pienkowski, Evelyn; Zhou, Xiufen; Wang, Zhijun; Shen, Ben; Deng, Zixin
The oxazolomycins (OZMs) are a growing family of antibiotics produced by several Streptomyces species that show diverse and important antibacterial, antitumor, and anti-human immunodeficiency virus activity. Oxazolomycin A is a peptide-polyketide hybrid compound containing a unique spiro-linked ?-lactone/?-lactam, a 5-substituted oxazole ring. The oxazolomycin biosynthetic gene cluster (ozm) was identified from Streptomyces albus JA3453 and localized to 79.5-kb DNA, consisting of 20 open reading frames that encode non-ribosomal peptide synthases, polyketide synthases (PKSs), hybrid non-ribosomal peptide synthase-PKS, trans-acyltransferases (trans-ATs), enzymes for methoxymalonyl-acyl carrier protein (ACP) synthesis, putative resistance genes, and hypothetical regulation genes. In contrast to classical type I polyketide or fatty acid biosynthases, all 10 PKS modules in the gene cluster lack cognate ATs. Instead, discrete ATs OzmM (with tandem domains OzmM-AT1 and OzmM-AT2) and OzmC were equipped to carry out all of the loading functions of both malonyl-CoA and methoxymalonyl-ACP extender units. Strikingly, only OzmM-AT2 is required for OzmM activity for OZM biosynthesis, whereas OzmM-AT1 seemed to be a cryptic AT domain. The above findings, together with previous results using isotope-labeled precursor feeding assays, are assembled for the OZM biosynthesis model to be proposed. The incorporation of both malonyl-CoA (by OzmM-AT2) and methoxymalonyl-ACP (by OzmC) extender units seemed to be unprecedented for this class of trans-AT type I PKSs, which might be fruitfully manipulated to create structurally diverse novel compounds. PMID:20406823
Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal type
Huang, Yenlin; de ReyniĶs, Aurķlien; de Leval, Laurence; Ghazi, Bouchra; Martin-Garcia, Nadine; Travert, Marion; Bosq, Jacques; BriĶre, Josette; Petit, Barbara; Thomas, Emilie; Coppo, Paul; Marafioti, Teresa; Emile, Jean-Franńois; Delfau-Larue, Marie-HķlĶne; Schmitt, Christian
Biopsies and cell lines of natural killer/T-cell lymphoma, nasal type (NKTCL) were subject to combined gene expression profiling and array-based comparative genomic hybridization analyses. Compared with peripheral T-cell lymphoma, not otherwise specified, NKTCL had greater transcript levels for NK-cell and cytotoxic molecules, especially granzyme H. Compared with normal NKcells, tumors were closer to activated than resting cells and overexpressed several genes related to vascular biology, Epstein-Barr Virus¢induced genes, and PDGFRA. Notably, platelet-derived growth factor receptor ? and its phosphorylated form were confirmed at the protein level, and in vitro the MEC04 NKTCL cell line was sensitive to imatinib. Deregulation of the AKT, Janus kinase¢signal transducers and activators of transcription, and nuclear factor-?B pathways was corroborated by nuclear expression of phosphorylated AKT, signal transducers and activators of transcription 3, and RelA in NKTCL, and several deregulated genes in these pathways mapped to regions of recurrent copy number aberrations (AKT3 [1q44], IL6R [1q21.3], CCL2 [17q12], TNFRSF21 [6p12.3]). Several features of NKTCL uncovered by this analysis suggest perturbation of angiogenic pathways. Integrative analysis also evidenced deregulation of the tumor suppressor HACE1 in the frequently deleted 6q21 region. This study highlights emerging oncogenic pathways in NKTCL and identifies novel diagnostic and therapeutic targets. PMID:19965620
System and method employing a self-organizing map load feature database to identify electric load types of different electric loads
Lu, Bin; Harley, Ronald G.; Du, Liang; Yang, Yi; Sharma, Santosh K.; Zambare, Prachi; Madane, Mayura A.
A method identifies electric load types of a plurality of different electric loads. The method includes providing a self-organizing map load feature database of a plurality of different electric load types and a plurality of neurons, each of the load types corresponding to a number of the neurons; employing a weight vector for each of the neurons; sensing a voltage signal and a current signal for each of the loads; determining a load feature vector including at least four different load features from the sensed voltage signal and the sensed current signal for a corresponding one of the loads; and identifying by a processor one of the load types by relating the load feature vector to the neurons of the database by identifying the weight vector of one of the neurons corresponding to the one of the load types that is a minimal distance to the load feature vector.
inv(16)/t(16;16) acute myeloid leukemia with non-type A CBFB-MYH11 fusions associate with distinct clinical and genetic features and lack KIT mutations.
Schwind, Sebastian; Edwards, Colin G; Nicolet, Deedra; Mr¾zek, Krzysztof; Maharry, Kati; Wu, Yue-Zhong; Paschka, Peter; Eisfeld, Ann-Kathrin; Hoellerbauer, Pia; Becker, Heiko; Metzeler, Klaus H; Curfman, John; Kohlschmidt, Jessica; Prior, Thomas W; Kolitz, Jonathan E; Blum, William; Pettenati, Mark J; Dal Cin, Paola; Carroll, Andrew J; Caligiuri, Michael A; Larson, Richard A; Volinia, Stefano; Marcucci, Guido; Bloomfield, Clara D
The inv(16)(p13q22)/t(16;16)(p13;q22) in acute myeloid leukemia results in multiple CBFB-MYH11 fusion transcripts, with type A being most frequent. The biologic and prognostic implications of different fusions are unclear. We analyzed CBFB-MYH11 fusion types in 208 inv(16)/t(16;16) patients with de novo disease, and compared clinical and cytogenetic features and the KIT mutation status between type A (n = 182; 87%) and non-type A (n = 26; 13%) patients. At diagnosis, non-type A patients had lower white blood counts (P = .007), and more often trisomies of chromosomes 8 (P = .01) and 21 (P < .001) and less often trisomy 22 (P = .02). No patient with non-type A fusion carried a KIT mutation, whereas 27% of type A patients did (P = .002). Among the latter, KIT mutations conferred adverse prognosis; clinical outcomes of non-type A and type A patients with wild-type KIT were similar. We also derived a fusion-type-associated global gene-expression profile. Gene Ontology analysis of the differentially expressed genes revealed-among others-an enrichment of up-regulated genes involved in activation of caspase activity, cell differentiation and cell cycle control in non-type A patients. We conclude that non-type A fusions associate with distinct clinical and genetic features, including lack of KIT mutations, and a unique gene-expression profile. PMID:23160462
Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal-type
Paris-Sud XI, Universitķ de
1 Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK in the frequently deleted 6q21 region. This study highlights emerging oncogenic pathways in NKTCL and identifies
Distribution of presynaptic inhibition on type-identified motoneurones in the extensor carpi radialis pool in man.
Aimonetti, J M; Vedel, J P; Schmied, A; Pagni, S
The question was addressed as to whether the magnitude of Ia presynaptic inhibition might depend on the type of motor unit activated during voluntary contraction in the wrist extensor muscles. For this purpose, we investigated the effects of applying electrical stimulation to the median nerve on the responses of 25 identified motor units to radial nerve stimulation delivered 20 ms after a conditioning stimulation. The reflex responses of the motor units yielded peaks in the post-stimulus time histograms with latencies compatible with monosynaptic activation. Although median nerve stimulation did not affect the motoneurone net excitatory drive assessed from the mean duration of the inter-spike interval, it led to a decrease in the contents of the first two 0.25 ms bins of the peak. This decrease may be consistent with the Ia presynaptic inhibition known to occur under these stimulation conditions. In the trials in which the median nerve was being stimulated, the finding that the response probability of the motor units, even in their monosynaptic components, tended to increase as their force threshold and their macro-potential area increased and as their twitch contraction time decreased suggests that the median nerve stimulation may have altered the efficiency with which the Ia inputs recruited the motoneurones in the pool. These effects were consistently observed in seven pairs of motor units each consisting of one slow and one fast contracting motor unit which were simultaneously tested, which suggests that the magnitude of the Ia presynaptic inhibition may depend on the type of motor unit tested rather than on the motoneurone pool excitatory drive. The present data suggest for the first time that in humans, the Ia presynaptic inhibition may show an upward gradient working from fast to slow contracting motor units which is able to compensate for the downward gradient in monosynaptic reflex excitation from 'slow' to 'fast' motor units. From a functional point of view, a weaker Ia presynaptic inhibition acting on the fast contracting motor units may contribute to improving the proprioceptive assistance to the wrist myotatic unit when the contraction force has to be increased. PMID:10618157
Distribution of presynaptic inhibition on type-identified motoneurones in the extensor carpi radialis pool in man
Aimonetti, Jean-Marc; Vedel, Jean-Pierre; Schmied, Annie; Pagni, Simone
The question was addressed as to whether the magnitude of Ia presynaptic inhibition might depend on the type of motor unit activated during voluntary contraction in the wrist extensor muscles. For this purpose, we investigated the effects of applying electrical stimulation to the median nerve on the responses of 25 identified motor units to radial nerve stimulation delivered 20 ms after a conditioning stimulation.The reflex responses of the motor units yielded peaks in the post-stimulus time histograms with latencies compatible with monosynaptic activation. Although median nerve stimulation did not affect the motoneurone net excitatory drive assessed from the mean duration of the inter-spike interval, it led to a decrease in the contents of the first two 0.25 ms bins of the peak. This decrease may be consistent with the Ia presynaptic inhibition known to occur under these stimulation conditions.In the trials in which the median nerve was being stimulated, the finding that the response probability of the motor units, even in their monosynaptic components, tended to increase as their force threshold and their macro-potential area increased and as their twitch contraction time decreased suggests that the median nerve stimulation may have altered the efficiency with which the Ia inputs recruited the motoneurones in the pool.These effects were consistently observed in seven pairs of motor units each consisting of one slow and one fast contracting motor unit which were simultaneously tested, which suggests that the magnitude of the Ia presynaptic inhibition may depend on the type of motor unit tested rather than on the motoneurone pool excitatory drive.The present data suggest for the first time that in humans, the Ia presynaptic inhibition may show an upward gradient working from fast to slow contracting motor units which is able to compensate for the downward gradient in monosynaptic reflex excitation from æslowÆ to æfastÆ motor units. From a functional point of view, a weaker Ia presynaptic inhibition acting on the fast contracting motor units may contribute to improving the proprioceptive assistance to the wrist myotatic unit when the contraction force has to be increased. PMID:10618157
A genome-wide association study identifies GRK5 and RASGRP1 as type 2 diabetes loci in Chinese Hans.
Li, Huaixing; Gan, Wei; Lu, Ling; Dong, Xiao; Han, Xueyao; Hu, Cheng; Yang, Zhen; Sun, Liang; Bao, Wei; Li, Pengtao; He, Meian; Sun, Liangdan; Wang, Yiqin; Zhu, Jingwen; Ning, Qianqian; Tang, Yong; Zhang, Rong; Wen, Jie; Wang, Di; Zhu, Xilin; Guo, Kunquan; Zuo, Xianbo; Guo, Xiaohui; Yang, Handong; Zhou, Xianghai; Zhang, Xuejun; Qi, Lu; Loos, Ruth J F; Hu, Frank B; Wu, Tangchun; Liu, Ying; Liu, Liegang; Yang, Ze; Hu, Renming; Jia, Weiping; Ji, Linong; Li, Yixue; Lin, Xu
Substantial progress has been made in identification of type 2 diabetes (T2D) risk loci in the past few years, but our understanding of the genetic basis of T2D in ethnically diverse populations remains limited. We performed a genome-wide association study and a replication study in Chinese Hans comprising 8,569 T2D case subjects and 8,923 control subjects in total, from which 10 single nucleotide polymorphisms were selected for further follow-up in a de novo replication sample of 3,410 T2D case and 3,412 control subjects and an in silico replication sample of 6,952 T2D case and 11,865 control subjects. Besides confirming seven established T2D loci (CDKAL1, CDKN2A/B, KCNQ1, CDC123, GLIS3, HNF1B, and DUSP9) at genome-wide significance, we identified two novel T2D loci, including G-protein-coupled receptor kinase 5 (GRK5) (rs10886471: P = 7.1 ū 10(-9)) and RASGRP1 (rs7403531: P = 3.9 ū 10(-9)), of which the association signal at GRK5 seems to be specific to East Asians. In nondiabetic individuals, the T2D risk-increasing allele of RASGRP1-rs7403531 was also associated with higher HbA(1c) and lower homeostasis model assessment of ?-cell function (P = 0.03 and 0.0209, respectively), whereas the T2D risk-increasing allele of GRK5-rs10886471 was also associated with higher fasting insulin (P = 0.0169) but not with fasting glucose. Our findings not only provide new insights into the pathophysiology of T2D, but may also shed light on the ethnic differences in T2D susceptibility. PMID:22961080
Genomes of Ashbya Fungi Isolated from Insects Reveal Four Mating-Type Loci, Numerous Translocations, Lack of Transposons, and Distinct Gene Duplications
Dietrich, Fred S.; Voegeli, Sylvia; Kuo, Sidney; Philippsen, Peter
The filamentous fungus Ashbya gossypii is a cotton pathogen transmitted by insects. It is readily grown and manipulated in the laboratory and is commercially exploited as a natural overproducer of vitamin B2. Our previous genome analysis of A. gossypii isolate ATCC10895, collected in Trinidad nearly 100 years ago, revealed extensive synteny with the Saccharomyces cerevisiae genome, leading us to use it as a model organism to understand the evolution of filamentous growth. To further develop Ashbya as a model system, we have investigated the ecological niche of A. gossypii and isolated additional strains and a sibling species, both useful in comparative analysis. We isolated fungi morphologically similar to A. gossypii from different plant-feeding insects of the suborder Heteroptera, generated a phylogenetic tree based on rDNA-ITS sequences, and performed high coverage short read sequencing with one A. gossypii isolate from Florida, a new species, Ashbya aceri, isolated in North Carolina, and a genetically marked derivative of ATCC10895 intensively used for functional studies. In contrast to S. cerevisiae, all strains carry four not three mating type loci, adding a new puzzle in the evolution of Ashbya species. Another surprise was the genome identity of 99.9% between the Florida strain and ATCC10895, isolated in Trinidad. The A. aceri and A. gossypii genomes show conserved gene orders rearranged by eight translocations, 90% overall sequence identity, and fewer tandem duplications in the A. aceri genome. Both species lack transposable elements. Finally, our work identifies plant-feeding insects of the suborder Heteroptera as the most likely natural reservoir of Ashbya, and that infection of cotton and other plants may be incidental to the growth of the fungus in its insect host. PMID:23749448
Endocytotic routes of cobra cardiotoxins depend on spatial distribution of positively charged and hydrophobic domains to target distinct types of sulfated glycoconjugates on cell surface.
Lee, Shao-Chen; Lin, Chien-Chu; Wang, Chia-Hui; Wu, Po-Long; Huang, Hsuan-Wei; Chang, Chung-I; Wu, Wen-guey
Cobra cardiotoxins (CTX) are a family of three-fingered basic polypeptides known to interact with diverse targets such as heparan sulfates, sulfatides, and integrins on cell surfaces. After CTX bind to the membrane surface, they are internalized to intracellular space and exert their cytotoxicity via an unknown mechanism. By the combined in vitro kinetic binding, three-dimensional x-ray structure determination, and cell biology studies on the naturally abundant CTX homologues from the Taiwanese cobra, we showed that slight variations on the spatial distribution of positively charged or hydrophobic domains among CTX A2, A3, and A4 could lead to significant changes in their endocytotic pathways and action mechanisms via distinct sulfated glycoconjugate-mediated processes. The intracellular locations of these structurally similar CTX after internalization are shown to vary between the mitochondria and lysosomes via either dynamin2-dependent or -independent processes with distinct membrane cholesterol sensitivity. Evidence is presented to suggest that the shifting between the sulfated glycoconjugates as distinct targets of CTX A2, A3, and A4 might play roles in the co-evolutionary arms race between venomous snake toxins to cope with different membrane repair mechanisms at the cellular levels. The sensitivity of endocytotic routes to the spatial distribution of positively charged or hydrophobic domains may provide an explanation for the diverse endocytosis pathways of other cell-penetrating basic polypeptides. PMID:24898246
System and method employing a minimum distance and a load feature database to identify electric load types of different electric loads
Lu, Bin; Yang, Yi; Sharma, Santosh K; Zambare, Prachi; Madane, Mayura A
A method identifies electric load types of a plurality of different electric loads. The method includes providing a load feature database of a plurality of different electric load types, each of the different electric load types including a first load feature vector having at least four different load features; sensing a voltage signal and a current signal for each of the different electric loads; determining a second load feature vector comprising at least four different load features from the sensed voltage signal and the sensed current signal for a corresponding one of the different electric loads; and identifying by a processor one of the different electric load types by determining a minimum distance of the second load feature vector to the first load feature vector of the different electric load types of the load feature database.
Early Progenitor Cell Marker Expression Distinguishes Type II From Type I Focal Cortical Dysplasias
Ksenia A. Orlova; Victoria Tsai; Marianna Baybis; Gregory G. Heuer; Sanjay Sisodiya; Maria Thom; Kevin Strauss; Eleonora Aronica; Phillip B. Storm; Peter B. Crino
Type I and type II focal cortical dysplasias (FCDs) exhibit distinct histopathologic features that suggest different pathogenic mechanisms. Type I FCDs are characterized by mild laminar disorganization and hypertrophic neurons, whereas type II FCDs exhibit dramatic laminar disorganization and cytomegalic cells (balloon cells). Both FCD types are associated with intractable epilepsy; therefore, identifying cellular or molecular differences between these lesion
Distinct genotypes of human and canine isolates of Campylobacter upsaliensis determined by 16S rRNA gene typing and plasmid profiling.
Stanley, J; Jones, C; Burnens, A; Owen, R J
The utility of combined 16S rRNA (rrs) gene restriction fragment length polymorphism and plasmid profiles to differentiate between and within Campylobacter upsaliensis of human and canine origin was examined. Fourteen distinct rrs gene restriction fragment length polymorphs consisting of bands sized between 1.9 and 4.8 kb were observed. The copy number of the 16S rRNA gene was three in most strains of C. upsaliensis. Plasmids were found in almost 60% of the strains; ranging in size from 1.5 to 100 kb, they gave 15 distinct plasmid profiles. All isolates from humans contained one or more plasmids, as did strains isolated from dogs with sporadic diarrhea. The two commonest 16S ribotypes were divided into eight and nine subgroups by plasmid profiling. The genotyping of canine isolates from three veterinary surveys detected both multiple infections and reinfection of dogs. Except for one, each of the isolates from humans constituted a single and unique 16S ribotype, and these more frequently carried plasmids than did canine strains. Ribotypes of human strains were not found among canine isolates. These results suggest that host-specific genotypic differences may exist among strains of C. upsaliensis, for example, intraspecific clones or clone complexes pathogenic for humans. Images PMID:7523440
Genomic analyses across six cancer types identify basal-like breast cancer as a unique molecular entity.
Prat, Aleix; Adamo, Barbara; Fan, Cheng; Peg, Vicente; Vidal, Maria; Galvßn, Patricia; Vivancos, Ana; Nuciforo, Paolo; Palmer, Hķctor G; Dawood, Shaheenah; Rod¾n, Jordi; Ramon y Cajal, Santiago; Ramony Cajal, Santiago; Del Campo, Josep Maria; Felip, Enriqueta; Tabernero, Josep; Cortķs, Javier
To improve our understanding of the biological relationships among different types of cancer, we have characterized variation in gene expression patterns in a set of 1,707 samples representing 6 human cancer types (breast, ovarian, brain, colorectal, lung adenocarcinoma and squamous cell lung cancer). In the unified dataset, breast tumors of the Basal-like subtype were found to represent a unique molecular entity as any other cancer type, including the rest of breast tumors, while showing striking similarities with squamous cell lung cancers. Moreover, gene signatures tracking various cancer- and stromal-related biological processes such as proliferation, hypoxia and immune activation were found expressed similarly in different proportions of tumors across the various cancer types. These data suggest that clinical trials focusing on tumors with common profiles and/or biomarker expression rather than their tissue of origin are warranted with a special focus on Basal-like breast cancer and squamous cell lung carcinoma. PMID:24384914
Types of inter-atomic interactions at the MHC-peptide interface: Identifying commonality from accumulated data
Png Eak Hock Adrian; Ganapathy Rajaseger; Venkatarajan Subramanian Mathura; Meena Kishore Sakharkar; Pandjassarame Kangueane
BACKGROUND: Quantitative information on the types of inter-atomic interactions at the MHC-peptide interface will provide insights to backbone\\/sidechain atom preference during binding. Qualitative descriptions of such interactions in each complex have been documented by protein crystallographers. However, no comprehensive report is available to account for the common types of inter-atomic interactions in a set of MHC-peptide complexes characterized by variation
Epitope predictions indicate the presence of two distinct types of epitope-antibody-reactivities determined by epitope profiling of intravenous immunoglobulins.
LuÜtrek, Mitja; Lorenz, Peter; Kreutzer, Michael; Qian, Zilliang; Steinbeck, Felix; Wu, Di; Born, Nadine; Ziems, Bjoern; Hecker, Michael; Blank, Miri; Shoenfeld, Yehuda; Cao, Zhiwei; Glocker, Michael O; Li, Yixue; Fuellen, Georg; Thiesen, Hans-J³rgen
Epitope-antibody-reactivities (EAR) of intravenous immunoglobulins (IVIGs) determined for 75,534 peptides by microarray analysis demonstrate that roughly 9% of peptides derived from 870 different human protein sequences react with antibodies present in IVIG. Computational prediction of linear B cell epitopes was conducted using machine learning with an ensemble of classifiers in combination with position weight matrix (PWM) analysis. Machine learning slightly outperformed PWM with area under the curve (AUC) of 0.884 vs. 0.849. Two different types of epitope-antibody recognition-modes (Type I EAR and Type II EAR) were found. Peptides of Type I EAR are high in tyrosine, tryptophan and phenylalanine, and low in asparagine, glutamine and glutamic acid residues, whereas for peptides of Type II EAR it is the other way around. Representative crystal structures present in the Protein Data Bank (PDB) of Type I EAR are PDB 1TZI and PDB 2DD8, while PDB 2FD6 and 2J4W are typical for Type II EAR. Type I EAR peptides share predicted propensities for being presented by MHC class I and class II complexes. The latter interaction possibly favors T cell-dependent antibody responses including IgG class switching. Peptides of Type II EAR are predicted not to be preferentially presented by MHC complexes, thus implying the involvement of T cell-independent IgG class switch mechanisms. The high extent of IgG immunoglobulin reactivity with human peptides implies that circulating IgG molecules are prone to bind to human protein/peptide structures under non-pathological, non-inflammatory conditions. A webserver for predicting EAR of peptide sequences is available at www.sysmed-immun.eu/EAR. PMID:24244326
Epitope Predictions Indicate the Presence of Two Distinct Types of Epitope-Antibody-Reactivities Determined by Epitope Profiling of Intravenous Immunoglobulins
LuÜtrek, Mitja; Lorenz, Peter; Kreutzer, Michael; Qian, Zilliang; Steinbeck, Felix; Wu, Di; Born, Nadine; Ziems, Bjoern; Hecker, Michael; Blank, Miri; Shoenfeld, Yehuda; Cao, Zhiwei; Glocker, Michael O.; Li, Yixue; Fuellen, Georg; Thiesen, Hans-J³rgen
Epitope-antibody-reactivities (EAR) of intravenous immunoglobulins (IVIGs) determined for 75,534 peptides by microarray analysis demonstrate that roughly 9% of peptides derived from 870 different human protein sequences react with antibodies present in IVIG. Computational prediction of linear B cell epitopes was conducted using machine learning with an ensemble of classifiers in combination with position weight matrix (PWM) analysis. Machine learning slightly outperformed PWM with area under the curve (AUC) of 0.884 vs. 0.849. Two different types of epitope-antibody recognition-modes (Type I EAR and Type II EAR) were found. Peptides of Type I EAR are high in tyrosine, tryptophan and phenylalanine, and low in asparagine, glutamine and glutamic acid residues, whereas for peptides of Type II EAR it is the other way around. Representative crystal structures present in the Protein Data Bank (PDB) of Type I EAR are PDB 1TZI and PDB 2DD8, while PDB 2FD6 and 2J4W are typical for Type II EAR. Type I EAR peptides share predicted propensities for being presented by MHC class I and class II complexes. The latter interaction possibly favors T cell-dependent antibody responses including IgG class switching. Peptides of Type II EAR are predicted not to be preferentially presented by MHC complexes, thus implying the involvement of T cell-independent IgG class switch mechanisms. The high extent of IgG immunoglobulin reactivity with human peptides implies that circulating IgG molecules are prone to bind to human protein/peptide structures under non-pathological, non-inflammatory conditions. A webserver for predicting EAR of peptide sequences is available at www.sysmed-immun.eu/EAR. PMID:24244326
Coronary arterioles in type 2 diabetic (db\\/db) mice undergo a distinct pattern of remodeling associated with decreased vessel stiffness
Paige S. Katz; Aaron J. Trask; Flavia M. Souza-Smith; Kirk R. Hutchinson; Maarten L. Galantowicz; Kevin C. Lord; James A. Stewart; Mary J. Cismowski; Kurt J. Varner; Pamela A. Lucchesi
Little is known about the impact of type 2 diabetes mellitus (DM) on coronary arteriole remodeling. The aim of this study\\u000a was to determine the mechanisms that underlie coronary arteriole structural remodeling in type 2 diabetic (db\\/db) mice. Passive\\u000a structural properties of septal coronary arterioles isolated from 12- to 16-week-old diabetic db\\/db and control mice were\\u000a assessed by pressure myography.
Flanking proline residues identify the L-type Ca2+ channel binding site of calciseptine and FS2.
Kini, R M; Caldwell, R A; Wu, Q Y; Baumgarten, C M; Feher, J J; Evans, H J
Calciseptine and FS2 are 60-amino acid polypeptides, isolated from venom of the black mamba (Dendroaspis polylepis polylepis), that block voltage-dependent L-type Ca2+ channels. We predicted that these polypeptides contain an identical functional site between residues 43 and 46 by searching for proline residues that mark the flanks of protein-protein interaction sites [Kini, R. M., and Evans, H. J. (1966) FEBS Lett. 385, 81-86]. The predicted Ca2+ channel binding site also occurs in closely related toxins, C10S2C2 and S4C8. Therefore, it is likely that these toxins also will block L-type Ca2+ channels. To test the proposed binding site on calciseptine and FS2, an eight-residue peptide, named L-calchin (L-type calcium channel inhibitor), was synthesized and examined for biological activity. As expected for an L-type Ca2+ channel blocker, L-calchin reduced peak systolic and developed pressure in isolated rat heart Langendorff preparations without affecting diastolic pressure or heart rate. Furthermore, L-calchin caused a voltage-independent block of L-type Ca2+ channel currents in whole-cell patch-clamped rabbit ventricular myocytes. Thus the synthetic peptide exhibits the L-type Ca2+ channel blocking properties of the parent molecules, calciseptine and FS2, but with a lower potency. These results strongly support the identification of a site in calciseptine and FS2 that is important for binding to L-type Ca2+ channels and reinforce the importance of proline brackets flanking protein-protein interaction sites. PMID:9636051
Predictive Validity of Personality Types versus Personality Dimensions from Early Childhood to Adulthood: Implications for the Distinction between Core and Surface Traits
ERIC Educational Resources Information Center
Asendorpf, Jens B.; Denissen, Jaap J. A.
This study compared the long-term predictive validity of person-centered personality types and variable-centered personality dimensions assessed between ages 4-6 years in a population sample of 154 children. Results indicated that the predictive power of both approaches was remarkably robust between age 17 and 22, and even increased in the case ofģ
FUNCTIONAL EVIDENCE FOR THE EXISTENCE OF A THIRD CELL TYPE IN THE RENAL GLOMERULUS: Phagocytosis of Filtration Residues by a Distinctive \\
Two types of cclls can bc recognized on the luminal side of the glomcrular base- ment membrane: the superficial endothelial cells which directly line the lumen and are comparable to endothclia lining the capillarics of other tissues, and thc deep cells, ordi- narily not in contact with the lumen, which arc distinguishcd by their long cytoplasmic arms cxtending for some
Distinct p300Responsive Mechanisms Promote Caspase-Dependent Apoptosis by Human T-Cell Lymphotropic Virus Type 1 Tax Protein
The dysregulation of cellular apoptosis pathways has emerged as a critical early event associated with the development of many types of human cancers. Numerous viral and cellular oncogenes, aside from their inherent transforming properties, are known to induce programmed cell death, consistent with the hypothesis that genetic defects are required to support tumor survival. Here, we report that nuclear expression
A mutation unique in serine protease inhibitors (serpins) identified in a family with type II hereditary angioneurotic edema.
Ocejo-Vinyals, J. G.; Leyva-Cobi├Īn, F.; Fern├Īndez-Luna, J. L.
BACKGROUND: Hereditary angioneurotic edema (HANE) is an autosomal dominant disease due to genetic alterations at the C1 inhibitor gene. Mutations within the C1 inhibitor gene are responsible for the molecular defect in type II HANE. Most of the dysfunctional proteins result from mutations involving the Arg-444 (the P-1 site of the reactive center) or amino acids NH2-terminal to the reactive center. MATERIALS AND METHODS: We have studied a Spanish family with type II HANE by using polymerase chain reaction (PCR) to amplify the exon eight of the C1 inhibitor gene. The purified 338-bp PCR product was subcloned and transformed into competent cells. After overnight cultures, we extracted the cloning vector from the positive colonies and sequenced both strands of the PCR product from each patient and healthy members of the family. RESULTS: We show that affected individuals in this family have a missense mutation, changing an adenine to cytosine in the codon 445. This substitution changes threonine at the P-1' site of the reactive center to a proline. This mutation generates a new restriction site, recognized by Bsi YI. CONCLUSIONS: To our knowledge, this is the first molecular defect characterized in a Spanish family with type II HANE, and to date, this is the first reported mutation at the P-1' site of the reactive center in individuals with type II HANE. This new mutation located at the reactive center emphasizes once more time the enormous heterogeneity of this gene. Images FIG. 1 FIG. 2 FIG. 3 PMID:8529136
A founder AGL mutation causing glycogen storage disease type IIIa in Inuit identified through whole-exome sequencing: a case series
Rousseau-Nepton, Isabelle; Okubo, Minoru; Grabs, Rosemarie; Mitchell, John; Polychronakos, Constantin; Rodd, Celia
Background: Glycogen storage disease type III is caused by mutations in both alleles of the AGL gene, which leads to reduced activity of glycogen-debranching enzyme. The clinical picture encompasses hypoglycemia, with glycogen accumulation leading to hepatomegaly and muscle involvement (skeletal and cardiac). We sought to identify the genetic cause of this disease within the Inuit community of Nunavik, in whom previous DNA sequencing had not identified such mutations. Methods: Five Inuit children with a clinical and biochemical diagnosis of glycogen storage disease type IIIa were recruited to undergo genetic testing: 2 underwent whole-exome sequencing and all 5 underwent Sanger sequencing to confirm the identified mutation. Selected DNA regions near the AGL gene were also sequenced to identify a potential founder effect in the community. In addition, control samples from 4 adults of European descent and 7 family members of the affected children were analyzed for the specific mutation by Sanger sequencing. Results: We identified a homozygous frame-shift deletion, c.4456delT, in exon 33 of the AGL gene in 2 children by whole-exome sequencing. Confirmation by Sanger sequencing showed the same mutation in all 5 patients, and 5 family members were found to be carriers. With the identification of this mutation in 5 probands, the estimated prevalence of genetically confirmed glycogen storage disease type IIIa in this region is among the highest worldwide (1:2500). Despite identical mutations, we saw variations in clinical features of the disease. Interpretation: Our detection of a homozygous frameshift mutation in 5 Inuit children determines the cause of glycogen storage disease type IIIa and confirms a founder effect. PMID:25602008
Aggressive Emerging Pathovars of Xanthomonas arboricola Represent Widespread Epidemic Clones Distinct from Poorly Pathogenic Strains, as Revealed by Multilocus Sequence Typing.
Fischer-Le Saux, Marion; Bonneau, Sophie; Essakhi, Salwa; Manceau, Charles; Jacques, Marie-AgnĶs
Deep and comprehensive knowledge of the genetic structure of pathogenic species is the cornerstone on which the design of precise molecular diagnostic tools is built. Xanthomonas arboricola is divided into pathovars, some of which are classified as quarantine organisms in many countries and are responsible for diseases on nut and stone fruit trees that have emerged worldwide. Recent taxonomic studies of the genus Xanthomonas showed that strains isolated from other hosts should be classified in X. arboricola, extending the host range of the species. To investigate the genetic structure of X. arboricola and the genetic relationships between highly pathogenic strains and strains apparently not relevant to plant health, we conducted multilocus sequence analyses on a collection of strains representative of the known diversity of the species. Most of the pathovars were clustered in separate monophyletic groups. The pathovars pruni, corylina, and juglandis, responsible for pandemics in specific hosts, were highly phylogenetically related and clustered in three distinct clonal complexes. In contrast, strains with no or uncertain pathogenicity were represented by numerous unrelated singletons scattered in the phylogenic tree. Depending on the pathovar, intra- and interspecies recombination played contrasting roles in generating nucleotide polymorphism. This work provides a population genetics framework for molecular epidemiological surveys of emerging plant pathogens within X. arboricola. Based on our results, we propose to reclassify three former pathovars of Xanthomonas campestris as X. arboricola pv. arracaciae comb. nov., X. arboricola pv. guizotiae comb. nov., and X. arboricola pv. zantedeschiae comb. nov. An emended description of X. arboricola Vauterin et al. 1995 is provided. PMID:25934623
Genetic analysis of wild-type Dobrava hantavirus in Slovenia: co-existence of two distinct genetic lineages within the same natural focus
Tatjana Avsic-Zupanc; Kirill Nemirov; Miro Petrovec; Tomi Trilar; Mario Poljak; Antti Vaheri; Alexander Plyusnin
Genetic analysis was performed of wild-type (wt) Dobrava hantavirus (DOB) strains from Slovenia, the country where the virus was first discovered and where it was found to cause haemorrhagic fever with renal syndrome (HFRS), with a fatality rate of 12%. Two hundred and sixty mice of the genus Apodemus, trapped in five natural foci of DOB-associated HFRS during 1990-1996, were
Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci
Deborah J Smyth; Adam M Smiles; Vincent Plagnol; Neil M Walker; James E Allen; Kate Downes; Jeffrey C Barrett; Barry C Healy; Josyf C Mychaleckyj; James H Warram; John A Todd; Jason D Cooper
We carried out a meta-analysis of data from three genome-wide association (GWA) studies of type 1 diabetes (T1D), testing 305,090 SNPs in 3,561 T1D cases and 4,646 controls of European ancestry. We obtained further support for 4q27 (IL2-IL21, P = 1.9 ū 10?8) and, after genotyping an additional 6,225 cases, 6,946 controls and 2,828 families, convincing evidence for four previously
Two types of C/EBP? mutations play distinct but collaborative roles in leukemogenesis: lessons from clinical data and BMT models.
Kato, Naoko; Kitaura, Jiro; Doki, Noriko; Komeno, Yukiko; Watanabe-Okochi, Naoko; Togami, Katsuhiro; Nakahara, Fumio; Oki, Toshihiko; Enomoto, Yutaka; Fukuchi, Yumi; Nakajima, Hideaki; Harada, Yuka; Harada, Hironori; Kitamura, Toshio
Two types of mutations of a transcription factor CCAAT-enhancer binding protein ? (C/EBP?) are found in leukemic cells of 5%-14% of acute myeloid leukemia (AML) patients: N-terminal mutations expressing dominant negative p30 and C-terminal mutations in the basic leucine zipper domain. Our results showed that a mutation of C/EBP? in one allele was observed in AML after myelodysplastic syndrome, while the 2 alleles are mutated in de novo AML. Unlike an N-terminal frame-shift mutant (C/EBP?-N(m))-transduced cells, a C-terminal mutant (C/EBP?-C(m))-transduced cells alone induced AML with leukopenia in mice 4-12 months after bone marrow transplantation. Coexpression of both mutants induced AML with marked leukocytosis with shorter latencies. Interestingly, C/EBP?-C(m) collaborated with an Flt3-activating mutant Flt3-ITD in inducing AML. Moreover, C/EBP?-C(m) strongly blocked myeloid differentiation of 32Dcl3 cells, suggesting its class II mutation-like role in leukemogenesis. Although C/EBP?-C(m) failed to inhibit transcriptional activity of wild-type C/EBP?, it suppressed the synergistic effect between C/EBP? and PU.1. On the other hand, C/EBP?-N(m) inhibited C/EBP? activation in the absence of PU.1, despite low expression levels of p30 protein generated by C/EBP?-N(m). Thus, 2 types of C/EBP? mutations are implicated in leukemo-genesis, involving different and cooperating molecular mechanisms. PMID:20884804
Identifying Aerosol Type from Space: Absorption Angstrom Exponent as a Foundation for Multidimensional Supervised Clustering and Mahalanobis Classification
NASA Astrophysics Data System (ADS)
Russell, P. B.; Hamill, P.; Livingston, J. M.; Shinozuka, Y.; Strawa, A. W.; Redemann, J.; Omar, A. H.; Clarke, A. D.; Bergstrom, R. W.; Holben, B.; Ferrare, R. A.; Burton, S. P.
Determining either aerosol composition or multiwavelength absorption from space is difficult at best, but recent research on many fronts has improved prospects for success. Results from diverse air, ground, and laboratory studies using both radiometric and in situ techniques show that the fractions of black carbon, organic matter, and mineral dust in atmospheric aerosols determine the wavelength dependence of absorption (often expressed as Absorption Angstrom Exponent, or AAE). Recent results include analyses of the Dubovik et al. (2002) set of Aerosol Robotic Network (AERONET) retrievals from Sun-sky measurements describing full aerosol vertical columns. AAE values in this set are strongly correlated with aerosol composition or type. Specifically, AAE values are near 1 (the theoretical value for black carbon) for AERONET-measured aerosol columns dominated by urban-industrial aerosol, larger (though partially overlapping) for biomass burning aerosols, and largest for Sahara dust aerosols. These AERONET results are consistent with results from other, very different, techniques, including solar flux-aerosol optical depth (AOD) analyses and airborne in situ analyses examined in this presentation, as well as many other previous results. Although AAE is therefore a useful tool for helping to distinguish aerosol types, it cannot unambiguously distinguish urban-industrial from biomass burning aerosols, even when supplemented by measurements of Extinction Angstrom Exponent (EAE). Hence there is a need to add information from other remotely sensible properties to improve remote identification of aerosol type. Supervised clustering, combined with Mahalanobis classification, provides an objective way of using multiple dimensions of data for this purpose. We demonstrate the application of this technique (previously used with High Spectral Resolution Lidar data) to (1) the Dubovik (2002) AERONET data set, (2) an in situ data set, and (3) a larger Version 2 AERONET data set. Results show that combining AAE and EAE with variables such as real and/or imaginary refractive index (RRI, IRI) or single scattering albedo (SSA) can improve separation of urban-industrial from biomass burning aerosols. The soon-to-be-launched Glory Aerosol Polarimetry Sensor (APS) is expected to produce data sets amenable to this aerosol classification technique, especially when combined with OMI aerosol absorption measurements at shorter wavelengths and CALIPSO measurements of aerosol height, to reduce height-absorption aliasing.
Distinct docking and stabilization steps of the Pseudopilus conformational transition path suggest rotational assembly of type IV pilus-like fibers.
Nivaskumar, Mangayarkarasi; Bouvier, Guillaume; Campos, Manuel; Nadeau, Nathalie; Yu, Xiong; Egelman, Edward H; Nilges, Michael; Francetic, Olivera
The closely related bacterial type II secretion (T2S) and type IV pilus (T4P) systems are sophisticated machines that assemble dynamic fibers promoting protein transport, motility, or adhesion. Despite their essential role in virulence, the molecular mechanisms underlying helical fiber assembly remain unknown. Here, we use electron microscopy and flexible modeling to study conformational changes of PulG pili assembled by the Klebsiella oxytoca T2SS. Neural network analysis of 3,900 pilus models suggested a transition path toward low-energy conformations driven by progressive increase in fiber helical twist. Detailed predictions of interprotomer contacts along this path were tested by site-directed mutagenesis, pilus assembly, and protein secretion analyses. We demonstrate that electrostatic interactions between adjacent protomers (P-P+1) in the membrane drive pseudopilin docking, while P-P+3 and P-P+4 contacts determine downstream fiber stabilization steps. These results support a model of a spool-like assembly mechanism for fibers of the T2SS-T4P superfamily. PMID:24685147
Distinct docking and stabilization steps of the pseudopilus conformational transition path suggest rotational assembly of type IV pilus-like fibers
Nivaskumar, Mangayarkarasi; Bouvier, Guillaume; Campos, Manuel; Nadeau, Nathalie; Yu, Xiong; Egelman, Edward H.; Nilges, Michael; Francetic, Olivera
SUMMARY The closely related bacterial type II secretion (T2S) and type IV pilus (T4P) systems are sophisticated machines that assemble dynamic fibers promoting protein transport, motility or adhesion. Despite their essential role in virulence, the molecular mechanisms underlying helical fiber assembly remain unknown. Here we use electron microscopy and flexible modeling to study conformational changes of PulG pili assembled by the Klebsiella oxytoca T2SS. Neural network analysis of 3900 pilus models suggested a transition path towards low-energy conformations driven by progressive increase in fiber helical twist. Detailed predictions of inter-protomer contacts along this path were tested by site-directed mutagenesis, pilus assembly and protein secretion analyses. We demonstrate that electrostatic interactions between adjacent protomers (P-P+1) in the membrane drive pseudopilin docking, while P-P+3 and P-P+4 contacts determine downstream fiber stabilization steps. These results support a new model of a spool-like assembly mechanism for fibers of the T2SS-T4P superfamily. PMID:24685147
Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases
Perry, John R. B.; Voight, Benjamin F.; Yengo, Lo'c; Amin, Najaf; Dupuis, Josķe; Ganser, Martha; Grallert, Harald; Navarro, Pau; Li, Man; Qi, Lu; Steinthorsdottir, Valgerdur; Scott, Robert A.; Almgren, Peter; Arking, Dan E.; Aulchenko, Yurii; Balkau, Beverley; Benediktsson, Rafn; Bergman, Richard N.; Boerwinkle, Eric; Bonnycastle, Lori; Burtt, Noļl P.; Campbell, Harry; Charpentier, Guillaume; Collins, Francis S.; Gieger, Christian; Green, Todd; Hadjadj, Samy; Hattersley, Andrew T.; Herder, Christian; Hofman, Albert; Johnson, Andrew D.; Kottgen, Anna; Kraft, Peter; Labrune, Yann; Langenberg, Claudia; Manning, Alisa K.; Mohlke, Karen L.; Morris, Andrew P.; Oostra, Ben; Pankow, James; Petersen, Ann-Kristin; Pramstaller, Peter P.; Prokopenko, Inga; Rathmann, Wolfgang; Rayner, William; Roden, Michael; Rudan, Igor; Rybin, Denis; Scott, Laura J.; Sigurdsson, Gunnar; Sladek, Rob; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Tuomilehto, Jaakko; Uitterlinden, Andre G.; Vivequin, Sidonie; Weedon, Michael N.; Wright, Alan F.; Hu, Frank B.; Illig, Thomas; Kao, Linda; Meigs, James B.; Wilson, James F.; Stefansson, Kari; van Duijn, Cornelia; Altschuler, David; Morris, Andrew D.; Boehnke, Michael; McCarthy, Mark I.; Froguel, Philippe; Palmer, Colin N. A.; Wareham, Nicholas J.; Groop, Leif
Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m2) compared to obese cases (BMI?30 Kg/m2). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m2) or 4,123 obese cases (BMI?30 kg/m2), and 54,412 un-stratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified controls. To assess the effects of known signals, we tested the individual and combined effects of SNPs representing 36 type 2 diabetes loci. After combining data from discovery and replication datasets, we identified two signals not previously reported in Europeans. A variant (rs8090011) in the LAMA1 gene was associated with type 2 diabetes in lean cases (P?=?8.4ū10?9, OR?=?1.13 [95% CI 1.09¢1.18]), and this association was stronger than that in obese cases (P?=?0.04, OR?=?1.03 [95% CI 1.00¢1.06]). A variant in HMG20AŚpreviously identified in South Asians but not EuropeansŚwas associated with type 2 diabetes in obese cases (P?=?1.3ū10?8, OR?=?1.11 [95% CI 1.07¢1.15]), although this association was not significantly stronger than that in lean cases (P?=?0.02, OR?=?1.09 [95% CI 1.02¢1.17]). For 36 known type 2 diabetes loci, 29 had a larger odds ratio in the lean compared to obese (binomial P?=?0.0002). In the lean analysis, we observed a weighted per-risk allele OR?=?1.13 [95% CI 1.10¢1.17], P?=?3.2ū10?14. This was larger than the same model fitted in the obese analysis where the OR?=?1.06 [95% CI 1.05¢1.08], P?=?2.2ū10?16. This study provides evidence that stratification of type 2 diabetes cases by BMI may help identify additional risk variants and that lean cases may have a stronger genetic predisposition to type 2 diabetes. PMID:22693455
Human Immunodeficiency Virus (HIV) Antibody Avidity Testing To Identify Recent Infection in Newly Diagnosed HIV Type 1 (HIV1)Seropositive Persons Infected with Diverse HIV1 Subtypes
A. Chawla; G. Murphy; C. Donnelly; C. L. Booth; M. Johnson; J. V. Parry; A. Phillips; A. M. Geretti
A guanidine-based antibody avidity assay for the identification of recently acquired human immunodefi- ciency virus type 1 (HIV-1) infection was evaluated. The kinetics of maturation of antibody avidity were determined prospectively in 23 persons undergoing acute seroconversion followed for up to 1,075 days. Avidity indices (AI) of <0.75 and <0.80 reproducibly identified seroconversion within the previous 125 (95% confi- dence
Identifying open-volume defects in doped and undoped perovskite-type LaCoO3, PbTiO3, and BaTiO3
Vinita J. Ghosh; Bent Nielsen; Thomas Friessnegg
Dopants, vacancies, and impurity-vacancy clusters have a substantial impact on the properties of perovskite-type metal oxides (general formula ABO3). In order to determine synthesis and processing conditions that optimize the desirable properties of these materials a careful study of these defects is required. It is essential to identify the defects and to map the defect densities. Positron annihilation spectroscopy has
Oral benzo[a]pyrene-induced cancer: two distinct types in different target organs depend on the mouse Cyp1 genotype
Shi, Zhanquan; Dragin, Nadine; Miller, Marian L.; Stringer, Keith F.; Johansson, Elisabet; Chen, Jing; Uno, Shigeyuki; Gonzalez, Frank J.; Rubio, Carlos A.; Nebert, Daniel W.
Benzo[a]pyrene (BaP) is a prototypical polycyclic aromatic hydrocarbon (PAH) found in combustion processes. Cytochrome P450 1A1 and 1B1 enzymes (CYP1A1, CYP1B1) can both detoxify PAHs and activate them to cancer-causing reactive intermediates. Following high dosage of oral BaP (125 mg/kg/day), ablation of the mouse Cyp1a1 gene causes immunosuppression and death within ~28 days, whereas Cyp1(+/+) wild-type mice remain healthy for >12 months on this regimen. In the present study, male Cyp1(+/+) wild-type, Cyp1a1(?/?) and Cyp1b1(?/?) single-knockout, and Cyp1a1/1b1(?/?) double-knockout mice received a lower dose (12.5 mg/kg/day) of oral BaP. Tissues from 16 different organs¢¢including proximal small intestine (PSI), liver, preputial gland duct (PGD)¢¢were evaluated; microarray cDNA expression and >30 mRNA levels were measured. Cyp1a1(?/?) mice revealed markedly increased CYP1B1 mRNA levels in the PSI, and between 8 and 12 weeks developed unique PSI adenomas and adenocarcinomas. Cyp1a1/1b1(?/?) mice showed no PSI tumors but instead developed squamous cell carcinoma of the PGD. Cyp1(+/+) and Cyp1b1(?/?) mice remained healthy with no remarkable abnormalities in any tissue examined. PSI adenocarcinomas exhibited striking up-regulation of the Xist gene, suggesting epigenetic silencing of specific genes on the Y-chromosome; the Rab30 oncogene was up-regulated; the Nr0b2 tumor suppressor gene was down-regulated; paradoxical over-expression of numerous immunoglobulin kappa and heavy chain variable genes was found¢¢although the adenocarcinoma showed no immunohistochemical evidence of being lymphatic in origin. This oral BaP mouse paradigm represents an example of ōgene-environment interactionsö in which the same exposure of carcinogen results in altered target organ and tumor type, as a function of just one or two globally absent genes. PMID:20127859
Is mammary not otherwise specified-type sarcoma with CD10 expression a distinct entity? A rare case report with immunohistochemical and ultrastructural study
Abstract Mammary sarcoma is extremely rare and the diagnosis is established only after metaplastic carcinomas and malignant phyllodes tumours are excluded. A rare case of not otherwise specified-type sarcoma with CD10 expression in the left breast in a 45-year-old female was presented. It was a high-grade tumour composed of spindle cells histologically. The immunohistochemical results showed that CD10, vimentin and EGFR were positive diffusely and SMA presented focally, whereas epithelial markers and other myoepithelial or myogenic markers were all negative. The electron microscope investigation demonstrated fibroblast-like features. The exact entity of the tumour remains to be studied because it resembles undifferentiated sarcoma or sarcomatoid metaplastic carcinoma to some degree, as well as high-grade malignant phyllodes tumour in particular. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9019879588725702 PMID:23356903
Genome-wide methylation analyses of primary human leukocyte subsets identifies functionally important cell-type¢specific hypomethylated regions
Zilbauer, Matthias; Rayner, Tim F.; Clark, Christine; Coffey, Alison J.; Joyce, Chris J.; Palta, Priit; Palotie, Aarno; Smith, Kenneth G. C.
DNA methylation is an important mechanism by which gene transcription and hence cellular function are regulated. Here, we provide detailed functional genome-wide methylome maps of 5 primary peripheral blood leukocyte subsets including T cells, B cells, monocytes/macrophages, and neutrophils obtained from healthy individuals. A comparison of these methylomes revealed highly specific cell-lineage and cell-subset methylation profiles. DNA hypomethylation is known to be permissive for gene expression and we identified cell-subset¢specific hypomethylated regions (HMRs) that strongly correlate with gene transcription levels suggesting these HMRs may regulate corresponding cell functions. Single-nucleotide polymorphisms associated with immune-mediated disease in genome-wide association studies preferentially localized to these cell-specific regulatory HMRs, offering insight into pathogenesis by highlighting cell subsets in which specific epigenetic changes may drive disease. Our data provide a valuable reference tool for researchers aiming to investigate the role of DNA methylation in regulating primary leukocyte function in health and immune-mediated disease. PMID:24159175
TLR9 and TLR7 agonists mediate distinct type I IFN responses in humans and nonhuman primates in vitro and in vivo.
Puig, Montserrat; Tosh, Kevin W; Schramm, Lynnsie M; Grajkowska, Lucja T; Kirschman, Kevin D; Tami, Cecilia; Beren, Joel; Rabin, Ronald L; Verthelyi, Daniela
Human I-IFNs include IFN-? and 13 independently regulated subtypes of IFN-? (I-IFNs). TLR7 and -9 induce I-IFNs, but it is unknown whether their subtype repertoire is similar. This study used new PCR arrays that selectively amplify individual I-IFN subtype genes of human and nonhuman primates to characterize the TLR7- and -9-mediated IFN response in vitro and in vivo. We show that in human PBMCs, TLR7 agonists induce a rapid burst of I-IFN transcripts, consisting primarily of IFN-?1/13, -?2, and -?14. In contrast, TLR9 agonists, regardless of the type used (CpG C-, B-, or D-ODN), prompted slower but sustained expression of IFN-?1/13, -?2, -?7, -?8, -?10, -?14, -?16, and -?21. These qualitative differences were translated downstream as differences in the pattern of IFN-inducible genes. In macaque PBMCs, imiquimod produced a short burst of IFN mRNA, dominated by IFN-?8, whereas C- or D-ODN induced a greater than tenfold increase in transcripts for all I-IFN subtypes by 12 h of culture. Differences were more evident in vivo, where TLR7 and -9 agonists induced significantly different levels of I-IFN transcripts in skin. Although the rates of gene transcription differed significantly for individual TLR9 agonists, their IFN-? subtype signature was almost identical, indicating that the type of receptor dictates the quality of the I-IFN response in vitro and in vivo. These results may underlie the differential therapeutic effects of TLR7 and -9 agonists and should inform future clinical studies. PMID:22058422
Multilocus Sequence Typing Confirms the Close Genetic Interrelatedness of Three Distinct Flavescence Doree Phytoplasma Strain Clusters and Group 16SrV Phytoplasmas Infecting Grapevine and Alder in Europe
Guillaume Arnaud; Sylvie Malembic-Maher; Pascal Salar; Patrick Bonnet; Michael Maixner; Carmine Marcone; Elisabeth Boudon-Padieu; Xavier Foissac
Vineyards of southern France and northern Italy are affected by the flavescence doree (FD) phytoplasma, a quarantine pathogen transmitted by the leafhopper of Nearctic origin Scaphoideus titanus. To better trace propagation of FD strains and identify possible passage between the vineyard and wild plant compartments, molecular typing of phytoplasma strains was applied. The sequences of the two genetic loci map
Two progressive substrates of the M-intermediate can be identified in glucose-embedded, wild-type bacteriorhodopsin.
Vonck, J; Han, B G; Burkard, F; Perkins, G A; Glaeser, R M
Glucose-embedded bacteriorhodopsin shows M-intermediates with different Amide I infrared bands when samples are illuminated at 240 or 260 K, in contrast with fully hydrated samples where a single M-intermediate is formed at all temperatures. In hydrated, but not in glucose-embedded specimens, the N intermediate is formed together with M at 260 K. Both Fourier transform infrared and electron diffraction data from glucose-embedded bacteriorhodopsin suggest that at 260 K a mixture is formed of the M-state that is trapped at 240 K, and a different M-intermediate (MN) that is also formed by mutant forms of bacteriorhodopsin that lack a carboxyl group at the 96 position, necessary for the M to N transition. The fact that an MN species is trapped in glucose-embedded, wild-type bacteriorhodopsin suggests that the glucose samples lack functionally important water molecules that are needed for the proton transfer aspartate 96 to the Schiff base (and, thus, to form the N-intermediate); thus, aspartate 96 is rendered ineffective as a proton donor. PMID:7811930
Molecular cloning of the common acute lymphoblastic leukemia antigen (CALLA) identifies a type II integral membrane protein.
Shipp, M A; Richardson, N E; Sayre, P H; Brown, N R; Masteller, E L; Clayton, L K; Ritz, J; Reinherz, E L
Common acute lymphoblastic leukemia antigen (CALLA) is a 100-kDa cell-surface glycoprotein expressed on most acute lymphoblastic leukemias and certain other immature lymphoid malignancies and on normal lymphoid progenitors. The latter are either uncommitted to B- or T-cell lineage or committed to only the earliest stages of B- or T-lymphocyte maturation. To elucidate to homogeneity, obtained the NH2-terminal sequence from both the intact protein and derived tryptic and V8 protease peptides and isolated CALLA cDNAs from a Nalm-6 cell line lambda gt10 library using redundant oligonucleotide probes. The CALLA cDNA sequence predicts a 750-amino acid integral membrane protein with a single 24-amino acid hydrophobic segment that could function as both a transmembrane region and a signal peptide. The COOH-terminal 700 amino acids, including six potential N-linked glycosylation sites compose the extracellular protein segment, whereas the 25 NH2-terminal amino acids remaining after cleavage of the initiation methionine form the cytoplasmic tail. CALLA+ cells contain CALLA transcripts of 2.7 to 5.7 kilobases with the major 5.7- and 3.7-kilobase mRNAs being preferentially expressed in specific cell types. Images PMID:2968607
Multiscale Complexity Analysis of the Cardiac Control Identifies Asymptomatic and Symptomatic Patients in Long QT Syndrome Type 1
Bari, Vlasta; Valencia, Josķ F.; Vallverd·, Montserrat; Girardengo, Giulia; Marchi, Andrea; Bassani, Tito; Caminal, Pere; Cerutti, Sergio; George, Alfred L.; Brink, Paul A.; Crotti, Lia; Schwartz, Peter J.; Porta, Alberto
The study assesses complexity of the cardiac control directed to the sinus node and to ventricles in long QT syndrome type 1 (LQT1) patients with KCNQ1-A341V mutation. Complexity was assessed via refined multiscale entropy (RMSE) computed over the beat-to-beat variability series of heart period (HP) and QT interval. HP and QT interval were approximated respectively as the temporal distance between two consecutive R-wave peaks and between the R-wave apex and T-wave end. Both measures were automatically taken from 24-hour electrocardiographic Holter traces recorded during daily activities in non mutation carriers (NMCs, n?=?14) and mutation carriers (MCs, n?=?34) belonging to a South African LQT1 founder population. The MC group was divided into asymptomatic (ASYMP, n?=?11) and symptomatic (SYMP, n?=?23) patients according to the symptom severity. Analyses were carried out during daytime (DAY, from 2PM to 6PM) and nighttime (NIGHT, from 12PM to 4AM) off and on beta-adrenergic blockade (BBoff and BBon). We found that the complexity of the HP variability at short time scale was under vagal control, being significantly increased during NIGHT and BBon both in ASYMP and SYMP groups, while the complexity of both HP and QT variability at long time scales was under sympathetic control, being smaller during NIGHT and BBon in SYMP subjects. Complexity indexes at long time scales in ASYMP individuals were smaller than those in SYMP ones regardless of therapy (i.e. BBoff or BBon), thus suggesting that a reduced complexity of the sympathetic regulation is protective in ASYMP individuals. RMSE analysis of HP and QT interval variability derived from routine 24-hour electrocardiographic Holter recordings might provide additional insights into the physiology of the cardiac control and might be fruitfully exploited to improve risk stratification in LQT1 population. PMID:24705789
Distinct Modes of Ubiquitination of Peroxisome-targeting Signal Type 1 (PTS1) Receptor Pex5p Regulate PTS1 Protein Import*
Okumoto, Kanji; Noda, Hiromi; Fujiki, Yukio
Peroxisome targeting signal type-1 (PTS1) receptor, Pex5p, is a key player in peroxisomal matrix protein import. Pex5p recognizes PTS1 cargoes in the cytosol, targets peroxisomes, translocates across the membrane, unloads the cargoes, and shuttles back to the cytosol. Ubiquitination of Pex5p at a conserved cysteine is required for the exit from peroxisomes. However, any potential ubiquitin ligase (E3) remains unidentified in mammals. Here, we establish an in vitro ubiquitination assay system and demonstrate that RING finger Pex10p functions as an E3 with an E2, UbcH5C. The E3 activity of Pex10p is essential for its peroxisome-restoring activity, being enhanced by another RING peroxin, Pex12p. The Pex10pĘPex12p complex catalyzes monoubiquitination of Pex5p at one of multiple lysine residues in vitro, following the dissociation of Pex5p from Pex14p and the PTS1 cargo. Several lines of evidence with lysine-to-arginine mutants of Pex5p demonstrate that Pex10p RING E3-mediated ubiquitination of Pex5p is required for its efficient export from peroxisomes to the cytosol and peroxisomal matrix protein import. RING peroxins are required for both modes of Pex5p ubiquitination, thus playing a pivotal role in Pex5p shuttling. PMID:24662292
Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases
Basarab, Gregory S.; Kern, Gunther H.; McNulty, John; Mueller, John P.; Lawrence, Kenneth; Vishwanathan, Karthick; Alm, Richard A.; Barvian, Kevin; Doig, Peter; Galullo, Vincent; Gardner, Humphrey; Gowravaram, Madhusudhan; Huband, Michael; Kimzey, Amy; Morningstar, Marshall; Kutschke, Amy; Lahiri, Sushmita D.; Perros, Manos; Singh, Renu; Schuck, Virna J. A.; Tommasi, Ruben; Walkup, Grant; Newman, Joseph V.
With the diminishing effectiveness of current antibacterial therapies, it is critically important to discover agents that operate by a mechanism that circumvents existing resistance. ETX0914, the first of a new class of antibacterial agent targeted for the treatment of gonorrhea, operates by a novel mode-of-inhibition against bacterial type II topoisomerases. Incorporating an oxazolidinone on the scaffold mitigated toxicological issues often seen with topoisomerase inhibitors. Organisms resistant to other topoisomerase inhibitors were not cross-resistant with ETX0914 nor were spontaneous resistant mutants to ETX0914 cross-resistant with other topoisomerase inhibitor classes, including the widely used fluoroquinolone class. Preclinical evaluation of ETX0914 pharmacokinetics and pharmacodynamics showed distribution into vascular tissues and efficacy in a murine Staphylococcus aureus infection model that served as a surrogate for predicting efficacious exposures for the treatment of Neisseria gonorrhoeae infections. A wide safety margin to the efficacious exposure in toxicological evaluations supported progression to Phase 1. Dosing ETX0914 in human volunteers showed sufficient exposure and minimal adverse effects to expect a highly efficacious anti-gonorrhea therapy. PMID:26168713
Evidence for distinct proportions of subducted oceanic crust and lithosphere in HIMU-type mantle beneath El Hierro and La Palma, Canary Islands
NASA Astrophysics Data System (ADS)
Day, James M. D.; Pearson, D. Graham; Macpherson, Colin G.; Lowry, David; Carracedo, Juan Carlos
Shield-stage high-MgO alkalic lavas from La Palma and El Hierro (Canary Islands) have been characterized for their O-Sr-Nd-Os-Pb isotope compositions and major-, trace-, and highly siderophile-element (HSE: Os, Ir, Ru, Pt, Pd, Re) abundances. New data are also reported for associated evolved rocks, and entrained xenoliths. Clear differences in Pd/Ir and isotopic ratios for high Os (>50 ppt) lavas from El Hierro (? 18O olivine = 5.17 ▒ 0.08ē; 87Sr/ 86Sr = 0.7029 to 0.7031; ? Nd = +5.7 to +7.1; 187Os/ 188Os = 0.1481 to 0.1750; 206Pb/ 204Pb = 19.1 to 19.7; Pd/Ir = 6 ▒ 3) versus those from La Palma (? 18O olivine = 4.87 ▒ 0.18ē; 87Sr/ 86Sr = 0.7031 to 0.7032; ? Nd = +5.0 to +6.4; 187Os/ 188Os = 0.1421 to 0.1460; 206Pb/ 204Pb = 19.5 to 20.2; Pd/Ir = 11 ▒ 4) are revealed from the dataset. Crustal or lithospheric assimilation during magma transport cannot explain variations in isotopic ratios or element abundances of the lavas. Shallow-level crystal-liquid fractionation of olivine, clinopyroxene and associated early-crystallizing minerals (e.g., spinel and HSE-rich phases) controlled compatible element and HSE abundances; there is also evidence for sub-aerial degassing of rhenium. High-MgO lavas are enriched in light rare earth elements, Nb, Ta, U, Th, and depleted in K and Pb, relative to primitive mantle abundance estimates, typical of HIMU-type oceanic island basalts. Trace element abundances and ratios are consistent with low degrees (2-6%) of partial melting of an enriched mantle source, commencing in the garnet stability field (?110 km). Western Canary Island lavas were sulphur undersaturated with estimated parental melt HSE abundances (in ppb) of 0.07 ▒ 0.05 Os, 0.17 ▒ 0.16 Ir, 0.34 ▒ 0.32 Ru, 2.6 ▒ 2.5 Pt, 1.4 ▒ 1.2 Pd, 0.39 ▒ 0.30 Re. These estimates indicate that Canary Island alkali basalts have lower Os, Ir and Ru, but similar Pt, Pd and Re contents to Hawai'ian tholeiites. The HIMU affinities of the lavas, in conjunction with the low ? 18O olivine and high 206Pb/ 204Pb for La Palma, and elevated 187Os/ 188Os for El Hierro implies melting of different proportions of recycled oceanic crust and lithosphere. Our preferred model to explain isotopic differences between the islands is generation from peridotitic mantle metasomatised by <10% pyroxenite/eclogite made from variable portions of similar aged recycled oceanic crust and lithosphere. The correspondence of radiogenic 206Pb/ 204Pb, 187Os/ 188Os, elevated Re/Os and Pt/Os, and low-? 18O in western Canary Island lavas provides powerful support for recycled oceanic crust and lithosphere to generate the spectrum of HIMU-type ocean island basalt signatures. Persistence of geochemical heterogeneities throughout the stratigraphies of El Hierro and La Palma demonstrate long-term preservation of these recycled components in their mantle sources over relatively short-length scales (ś50 km).
Intense Raman scattering on hybrid Au/Ag nanoplatforms for the distinction of MMP-9-digested collagen type-I fiber detection.
Sivashanmugan, Kundan; Liao, Jiunn-Der; Shao, Pei-Lin; Haochih Liu, Bernard; Tseng, Te-Yu; Chang, Chih-Yu
Well-ordered Au-nanorod arrays were fabricated using the focused ion beam method (denoted as fibAu_NR). Au or Ag nanoclusters (NCs) of various sizes and dimensions were then deposited on the fibAu_NR arrays using electron beam deposition to improve the surface-enhanced Raman scattering (SERS) effect, which was verified using a low concentration of crystal violet (10(-)(5)M) as the probe molecule. An enhancement factor of 6.92ū10(8) was obtained for NCsfibAu_NR, which is attributed to the combination of intra-NC and NR localized surface plasmon resonance. When 4-aminobenzenethiol (4-ABT)-coated Au or Ag nanoparticles (NPs) were attached to NCsfibAu_NR, the small gaps between 4-ABT-coated NPs and intra-NCs allowed detection at the single-molecule level. Hotspots formed at the interfaces of NCs/NRs and NPs/NCs at a high density, producing a strong local electromagnetic effect. Raman spectra from as-prepared type I collagen (Col-I) and Ag-NP-coated Col-I fibers on NCsfibAu_NR were compared to determine the quantity of amino acids in their triple helix structure. Various concentrations of matrix-metalloproteinase-9-digested Col-I fibers on NCsfibAu_NR were qualitatively examined at a Raman laser wavelength of 785nm to determine the changes of amino acids in the Col-I fiber structure. The results can be used to monitor the growth of healing Col-I fibers in a micro-environment. PMID:25957832
Mutations in the human Na-K-2Cl cotransporter (NKCC2) identified in Bartter syndrome type I consistently result in nonfunctional transporters.
Starremans, Patrick G J F; Kersten, Ferry F J; Knoers, Nine V A M; van den Heuvel, Lambertus P W J; Bindels, Renķ J M
Bartter syndrome (BS) is a heterogeneous renal tubular disorder affecting Na-K-Cl reabsorption in the thick ascending limb of Henle's loop. BS type I patients typically present with profound hypokalemia and metabolic alkalosis. The main goal of the present study was to elucidate the functional implications of six homozygous mutations (G193R, A267S, G319R, A508T, del526N, and Y998X) in the bumetanide-sensitive Na-K-2Cl cotransporter (hNKCC2) identified in patients diagnosed with BS type I. To this end, capped RNA (cRNA) of FLAG-tagged hNKCC2 and the corresponding mutants was injected in Xenopus laevis oocytes and transporter activity was measured after 72 h by means of a bumetanide-sensitive (22)Na(+) uptake assay at 30 degrees C. Injection of 25 ng of hNKCC2 cRNA resulted in bumetanide-sensitive (22)Na(+) uptake of 2.5 +/- 0.5 nmol/oocyte per 30 min. Injection of 25 ng of mutant cRNA yielded no significant bumetanide-sensitive (22)Na(+) uptake. Expression of wild-type and mutant transporters was confirmed by immunoblotting, showing significantly less mutant protein compared with wild-type at the same cRNA injection levels. However, when the wild-type cRNA injection level was reduced to obtain a protein expression level equal to that of the mutants, the wild-type still exhibited a significant bumetanide-sensitive (22)Na(+) uptake. Immunocytochemical analysis showed immunopositive staining of hNKCC2 at the plasma membrane for wild-type and all studied mutants. In conclusion, mutations in hNKCC2 identified in type I BS patients, when expressed in Xenopus oocytes, result in a low expression of normally routed but functionally impaired transporters. These results are in line with the hypothesis that the mutations in hNKCC2 are the underlying cause of the clinical abnormalities seen in patients with type I BS. PMID:12761241
Distinct Increased Metabotropic Glutamate Receptor Type 5 (mGluR5) in Temporal Lobe Epilepsy With and Without Hippocampal Sclerosis
Kandratavicius, Ludmyla; Rosa-Neto, Pedro; Monteiro, Mariana Raquel; Guiot, Marie-Christine; Assirati, Joao Alberto; Carlotti, Carlos Gilberto; Kobayashi, Eliane; Leite, Joao Pereira
Metabotropic glutamate receptor type 5 (mGluR5) upregulation in temporal lobe epilepsy (TLE) and the correlation of its expression with features of hippocampal sclerosis (HS) remains unclear. Here we characterized mGluR5 immunoreactivity in hippocampus, entorhinal cortex (EC), and subiculum of TLE specimens with confirmed HS, with neocortical TLE (non-HS) and necropsy controls. We correlated mGluR5 immunoreactivity with neuronal density, mossy fiber sprouting, astrogliosis (GFAP), and dendritic alterations (MAP2). TLE specimens showed increased mGluR5 expression, which was most pronounced in the EC, subiculum, CA2, and dentate gyrus outer molecular layer. Increased mGluR5 expression was seen in hippocampal head and body segments and was independent of neuronal density, astrogliosis, or dendritic alterations. Positive correlation between mGluR5 expression with mossy fiber sprouting and with MAP2 in CA3 and CA1 was found only in HS specimens. Negative correlation between mGluR5 expression with seizure frequency and epilepsy duration was found only in non-HS cases. Specimens from HS patients without previous history of febrile seizure (FS) showed higher mGluR5 and MAP2 expression in CA2. Our study suggests that mGluR5 upregulation is part of a repertoire of post-synaptic adaptations that might control overexcitation and excessive glutamate release rather than a dysfunction that leads to seizure facilitation. That would explain why non-HS cases, on which seizures are likely to originate outside the hippocampal formation, also exhibit upregulated mGluR5. On the other hand, lower mGluR5 expression was related to increased seizure frequency. In addition to its role in hyperexcitability, mGluR5 upregulation could play a role in counterbalance mechanisms along the hyperexcitable circuitry uniquely altered in sclerotic hippocampal formation. Inefficient post-synaptic compensatory morphological (dendritic branching) and glutamatergic (mGluR5 expression) mechanisms in CA2 subfield could potentially underlie the association of FS with HS and TLE. ® 2013 Wiley Periodicals, Inc. PMID:23804486
Identifying the distinct features of geometric structures for hole trapping to generate radicals on rutile TiO?(110) in photooxidation using density functional theory calculations with hybrid functional.
Wang, Dong; Wang, Haifeng; Hu, P
Using density functional theory calculations with HSE 06 functional, we obtained the structures of spin-polarized radicals on rutile TiO2(110), which is crucial to understand the photooxidation at the atomic level, and further calculate the thermodynamic stabilities of these radicals. By analyzing the results, we identify the structural features for hole trapping in the system, and reveal the mutual effects among the geometric structures, the energy levels of trapped hole states and their hole trapping capacities. Furthermore, the results from HSE 06 functional are compared to those from DFT + U and the stability trend of radicals against the number of slabs is tested. The effect of trapped holes on two important steps of the oxygen evolution reaction, i.e. water dissociation and the oxygen removal, is investigated and discussed. PMID:25407436
Two Distinct Channels Mediated by m2mAChR and ?9nAChR Co-Exist in Type II Vestibular Hair Cells of Guinea Pig.
Zhou, Tao; Wang, Yi; Guo, Chang-Kai; Zhang, Wen-Juan; Yu, Hong; Zhang, Kun; Kong, Wei-Jia
Acetylcholine (ACh) is the principal vestibular efferent neurotransmitter among mammalians. Pharmacologic studies prove that ACh activates a small conductance Ca2+-activated K+ channels (KCa) current (SK2), mediated by ?9-containing nicotinic ACh receptor (?9nAChR) in mammalian type II vestibular hair cells (VHCs II). However, our studies demonstrate that the m2 muscarinic ACh receptor (m2mAChR) mediates a big conductance KCa current (BK) in VHCs II. To better elucidate the correlation between these two distinct channels in VHCs II of guinea pig, this study was designed to verify whether these two channels and their corresponding AChR subtypes co-exist in the same VHCs II by whole-cell patch clamp recordings. We found that m2mAChR sensitive BK currents were activated in VHCs II isolated by collagenase IA, while ?9nAChR sensitive SK2 currents were activated in VHCs II isolated by trypsin. Interestingly, after exposing the patched cells isolated by trypsin to collagenase IA for 3 min, the ?9nAChR sensitive SK2 current was abolished, while m2mAChR-sensitive BK current was activated. Therefore, our findings provide evidence that the two distinct channels and their corresponding AChR subtypes may co-exist in the same VHCs II, and the alternative presence of these two ACh receptors-sensitive currents depended on isolating preparation with different enzymes. PMID:23615472
Independent optical excitation of distinct neural populations
Klapoetke, Nathan Cao
Optogenetic tools enable examination of how specific cell types contribute to brain circuit functions. A long-standing question is whether it is possible to independently activate two distinct neural populations in mammalian ...
Complementation cloning identifies CDG-IIc, a new type of congenital disorders of glycosylation, as a GDP-fucose transporter deficiency.
L³bke, T; Marquardt, T; Etzioni, A; Hartmann, E; von Figura, K; K÷rner, C
Congenital disorders of glycosylation (CDG) comprise a rapidly growing group of inherited disorders in which glycosylation of glycoproteins is defective due to mutations in genes required for the assembly of lipid-linked oligosaccharides, their transfer to nascent glycoproteins (CDG-I) or the processing of protein-bound glycans (CDG-II). Previously' a defect in the GDP-fucose import into the lumen of the Golgi was identified in a person with CDG (A.C.) with a general deficiency of fucosyl residues in glycoproteins. This patient presents the clinical features of leukocyte adhesion deficiency type II (LAD II) including mental retardation, short stature, facial stigmata, and recurrent bacterial peripheral infections with persistently elevated peripheral leukocytes. Using a fucose-specific, lectin-staining procedure for detection of fucosylated glycoproteins and a retroviral cDNA library, we isolated a cDNA complementing the fucosylation defect in the patient's fibroblasts. The cDNA encodes a highly hydrophobic protein of 364 amino acids with multiple putative transmembrane domains. Restoration of GDP-fucose import activity in Golgi-enriched vesicles from the patient's fibroblasts verified the GDP-fucose transporter activity of this protein. We identified two missense mutations in the GDP-fucose transporter cDNA of patient A.C. and of two other people with LAD II. Thus complementation cloning allowed us to identify the human GDP-fucose transporter cDNA and GDP-fucose transporter deficiency as a cause for a new type of CDG. Following the recent recommendations for the nomenclature for CDG, this new type is classified as CDG-IIc (formerly LAD II). PMID:11326280
Use of Whole-Genome Phylogeny and Comparisons for Development of a Multiplex PCR Assay To Identify Sequence Type 36 Vibrio parahaemolyticus.
Whistler, Cheryl A; Hall, Jeffrey A; Xu, Feng; Ilyas, Saba; Siwakoti, Puskar; Cooper, Vaughn S; Jones, Stephen H
Vibrio parahaemolyticus sequence type 36 (ST36) strains that are native to the Pacific Ocean have recently caused multistate outbreaks of gastroenteritis linked to shellfish harvested from the Atlantic Ocean. Whole-genome comparisons of 295 genomes of V. parahaemolyticus, including several traced to northeastern U.S. sources, were used to identify diagnostic loci, one putatively encoding an endonuclease (prp), and two others potentially conferring O-antigenic properties (cps and flp). The combination of all three loci was present in only one clade of closely related strains of ST36, ST59, and one additional unknown sequence type. However, each locus was also identified outside this clade, with prp and flp occurring in only two nonclade isolates and cps in four. Based on the distribution of these loci in sequenced genomes, prp identified clade strains with >99% accuracy, but the addition of one more locus increased accuracy to 100%. Oligonucleotide primers targeting prp and cps were combined in a multiplex PCR method that defines species using the tlh locus and determines the presence of both the tdh and trh hemolysin-encoding genes, which are also present in ST36. Application of the method in vitro to a collection of 94 clinical isolates collected over a 4-year period in three northeastern U.S. states and 87 environmental isolates revealed that the prp and cps amplicons were detected only in clinical isolates identified as belonging to the ST36 clade and in no environmental isolates from the region. The assay should improve detection and surveillance, thereby reducing infections. PMID:25832299
Combinatorial expression of Prospero, Seven-up, and Elav identifies progenitor cell types during sense-organ differentiation in the Drosophila antenna.
Sen, Anindya; Reddy, G Venugopala; Rodrigues, Veronica
The Drosophila antenna has a diversity of chemosensory organs within a single epidermal field. We have some idea from recent studies of how the three broad categories of sense-organs are specified at the level of progenitor choice. However, little is known about how cell fates within single sense-organs are specified. Selection of individual primary olfactory progenitors is followed by organization of groups of secondary progenitors, which divide in a specific order to form a differentiated sensillum. The combinatorial expression of Prospero Elav, and Seven-up allows us to distinguish three secondary progenitor fates. The lineages of these cells have been established by clonal analysis and marker distribution following mitosis. High Notch signaling and the exclusion of these markers identifies PIIa; this cell gives rise to the shaft and socket. The sheath/neuron lineage progenitor PIIb, expresses all three markers; upon division, Prospero asymmetrically segregates to the sheath cell. In the coeloconica, PIIb undergoes an additional division to produce glia. PIIc is present in multiinnervated sense-organs and divides to form neurons. An understanding of the lineage and development of olfactory sense-organs provides a handle for the analysis of how olfactory neurons acquire distinct terminal fates. PMID:12606283
Characterization of the biological and biochemical activities of F 11782 and the bisdioxopiperazines, ICRF-187 and ICRF-193, two types of topoisomerase II catalytic inhibitors with distinctive mechanisms of action.
van Hille, B; Etiķvant, C; Barret, J M; Kruczynski, A; Hill, B T
F 11782 is a newly identified catalytic inhibitor of topoisomerases I and II, without any detectable interaction with DNA. This study aimed to establish whether its catalytic inhibition of topoisomerase II was mediated by mechanisms similar to those identified for the bisdioxopiperazines. In vitro combinations of F 11782 with etoposide resulted in greater than additive cytotoxicity in L1210 cells, contrasting with marked antagonism for combinations of etoposide with either ICRF-187 or ICRF-193. All three compounds caused a G2/M blockade of P388 cells after an 18-h incubation, but by 40 h polyploidization was evident only with the bisdioxopiperazines. Gel retardation data revealed that only F 11782, and not the bisdioxopiperazines, was capable of completely inhibiting the DNA-binding activity of topoisomerase II, confirming its novel mechanism of action. Furthermore, unlike ICRF-187 and ICRF-193, the cytotoxicity of F 11782 appeared mediated, at least partially, by DNA damage induction in cultured GCT27 human teratoma cells, as judged by a fluorescence-enhancement assay and monitoring p53 activation. Finally, the major in vivo antitumor activity of F 11782 against the murine P388 leukemia (i.v. implanted) and the B16 melanoma (s.c. grafted) contrasted with the bisdioxopiperazines' general lack of activity. Overall, F 11782 and the bisdioxopiperazines appear to function as quite distinctive catalytic topoisomerase II inhibitors. PMID:11142691
Replication Study for the Association Between Four Loci Identified by a Genome-Wide Association Study on European American Subjects With Type 1 Diabetes and Susceptibility to Diabetic Nephropathy in Japanese Subjects With Type 2 Diabetes
Maeda, Shiro; Araki, Shin-ichi; Babazono, Tetsuya; Toyoda, Masao; Umezono, Tomoya; Kawai, Koichi; Imanishi, Masahito; Uzu, Takashi; Watada, Hirotaka; Suzuki, Daisuke; Kashiwagi, Atsunori; Iwamoto, Yasuhiko; Kaku, Kohei; Kawamori, Ryuzo; Nakamura, Yusuke
OBJECTIVE Genetic factors are believed to contribute to the development and progression of diabetic nephropathy. Recently, a genome-wide association study for diabetic nephropathy revealed four novel candidate loci in European American subjects with type 1 diabetes. In this study, we determined the association of the four loci with diabetic nephropathy in Japanese subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS We genotyped 11 singlenucleotide polymorphisms (SNPs) in four distinct loci (rs39059 and rs39075 in the CPVL/CHN2, rs1888747 and rs10868025 in FRMD3, rs739401 and rs451041 in CARS, and rs1041466, rs1411766, rs6492208, rs7989848, and rs9521445 in a chromosome 13q locus) in four independent Japanese populations. RESULTS Six SNPs were nominally associated with diabetic nephropathy in one of the four Japanese populations (P < 0.05; rs451041 in study 1; rs39059 and rs1888747 in study 3; rs1411766 in studies 1 and 4; and rs7989848 and rs9521445 in study 4); however, no significant association was observed for any SNP after correction for multiple testing errors in the individual populations. Nevertheless, a meta-analysis performed for the data obtained from all four populations revealed that one SNP (rs1411766) in chromosome 13q was significantly associated with diabetic nephropathy in the Japanese populations (nominal P = 0.004, corrected P = 0.04, odds ratio 1.26 [95% CI = 1.07¢1.47]). CONCLUSIONS Our results suggest that the rs1411766 locus may be commonly involved in conferring susceptibility to diabetic nephropathy among subjects with type 1 or type 2 diabetes across different ethnic groups. PMID:20460425
Optimal Distinctiveness Theory
Geoffrey J. Leonardelli; Cynthia L. Pickett; Marilynn B. Brewer
Optimal distinctiveness theory [Brewer, M. B. (1991). The social self: on being the same and different at the same time. Personality & Social Psychology Bulletin, 17(5), 475¢482] proposes that individuals have two fundamental and competing human needsŚthe need for inclusion and the need for differentiationŚthat can be met by membership in moderately inclusive (optimally distinct) groups. In this chapter, the
Proinflammatory secreted phospholipase A2 type IIA (sPLA-IIA) induces integrin activation through direct binding to a newly identified binding site (site 2) in integrins ?v?3, ?4?1, and ?5?1.
Fujita, Masaaki; Zhu, Kan; Fujita, Chitose K; Zhao, Min; Lam, Kit S; Kurth, Mark J; Takada, Yoko K; Takada, Yoshikazu
Integrins are activated by signaling from inside the cell (inside-out signaling) through global conformational changes of integrins. We recently discovered that fractalkine activates integrins in the absence of CX3CR1 through the direct binding of fractalkine to a ligand-binding site in the integrin headpiece (site 2) that is distinct from the classical RGD-binding site (site 1). We propose that fractalkine binding to the newly identified site 2 induces activation of site 1 though conformational changes (in an allosteric mechanism). We reasoned that site 2-mediated activation of integrins is not limited to fractalkine. Human secreted phospholipase A2 type IIA (sPLA2-IIA), a proinflammatory protein, binds to integrins ?v?3 and ?4?1 (site 1), and this interaction initiates a signaling pathway that leads to cell proliferation and inflammation. Human sPLA2-IIA does not bind to M-type receptor very well. Here we describe that sPLA2-IIA directly activated purified soluble integrin ?v?3 and transmembrane ?v?3 on the cell surface. This activation did not require catalytic activity or M-type receptor. Docking simulation predicted that sPLA2-IIA binds to site 2 in the closed-headpiece of ?v?3. A peptide from site 2 of integrin ?1 specifically bound to sPLA2-IIA and suppressed sPLA2-IIA-induced integrin activation. This suggests that sPLA2-IIA activates ?v?3 through binding to site 2. sPLA2-IIA also activated integrins ?4?1 and ?5?1 in a site 2-mediated manner. We recently identified small compounds that bind to sPLA2-IIA and suppress integrin-sPLA2-IIA interaction (e.g. compound 21 (Cmpd21)). Cmpd21 effectively suppressed sPLA2-IIA-induced integrin activation. These results define a novel mechanism of proinflammatory action of sPLA2-IIA through integrin activation. PMID:25398877
Clinical characteristics, and time course of pancreatic beta-cell function and glutamic acid decarboxylase antibodies in Thai patients with adult-onset Type 1 diabetes: distinction between patients of rapid- and slow-onset.
Rattarasarn, C; Diosdado, M A
In order to study the clinical characteristics, time course of beta cell function and glutamic acid decarboxylase antibodies (GAD65Ab) in Thai patients with adult-onset Type 1 diabetes and to examine the distinctive features between patients with rapid-and slow-onset, 61 Thai patients with Type 1 diabetes who had age of disease onset at or after 20 years were studied. All patients were treated with insulin at the time of study and had fasting C-peptide levels +/-0.33 nmol/l. Twenty-six (42.6%) were in rapid-onset and 35 (57.4%) were in slow-onset groups. Fourty-four of 61 (70.5%) were male. About three-fourths had body mass index (BMI) < 19 kg/m2 at the time of insulin therapy. Only 7 of 61 (11.5%) patients had ketoacidosis at first presentation. Five patients had associated autoimmune thyroid disease and 10 (16.7%) patients had family history of diabetes in first-degree relatives. GAD65Ab was positive in 31 patients (50.8%); 10 (38.5%) were in rapid-onset and 21 (60.0%) were in slow-onset groups. GAD65Ab particularly of high levels were persistently elevated during 3-4 years follow-up period. The persistence of GAD65Ab were not associated with changes in fasting C-peptide levels. At the time of insulin dependency, there were no distinctive clinical features between rapid- and slow-onset patients except higher fasting C-peptide (0.08+/-0.08 vs. 0.14+/-0.10 nmol/l; p = 0.023) and GAD65Ab levels (19.6+/-17.4 vs. 46.1+/-49.7 U/ml; p = 0.036) in slow-onset patients. Fasting C-peptide levels of patients in the latter group were also demonstrated to be higher after 3-4 years of follow-up. In conclusion, most Thai patients with adult-onset Type 1 diabetes in this study were male and had significant degree of weight loss and lean BMI prior to insulin therapy. The presence of GAD65Ab did not predict clinical features or rate of beta cell loss. Patients in rapid-onset group had lower fasting C-peptide and GAD65Ab levels than those of slow-onset group which confirms the slower process of beta cell failure in the latter. PMID:10422726
Analysis of the Crystal Structure of the ExsC.ExsE Complex Reveals Distinctive Binding Interactions of the Pseudomonas aeruginosa Type III Secretion Chaperone ExsC with ExsE and ExsD
Vogelaar, N.J.; Robinson, H.; Jing, X.; Schubot, F. D.
Pseudomonas aeruginosa, like many Gram-negative bacterial pathogens, requires its type III secretion system (T3SS) to facilitate acute infections. In P. aeruginosa, the expression of all T3SS-related genes is regulated by the transcriptional activator ExsA. A signaling cascade involving ExsA and three additional proteins, ExsC, ExsD, and ExsE, directly ties the upregulation of ExsA-mediated transcription to the activation of the type III secretion apparatus. In order to characterize the events underlying the signaling process, the crystal structure of the T3SS chaperone ExsC in complex with its cognate effector ExsE has been determined. The structure reveals critical contacts that mediate the interactions between these two proteins. Particularly striking is the presence of two Arg-X-Val-X-Arg motifs in ExsE that form identical interactions along opposite sides of an ExsC dimer. The structure also provides insights into the interactions of ExsC with the antiactivator protein ExsD. It was shown that the amino-terminal 46 residues of ExsD are sufficient for ExsC binding. On the basis of these findings, a new model for the ExsC {center_dot} ExsD complex is proposed to explain its distinctive 2:2 stoichiometry and why ExsC displays a weaker affinity for ExsD than for ExsE.
Use of whole-genus genome sequence data to develop a multilocus sequence typing tool that accurately identifies Yersinia isolates to the species and subspecies levels.
Hall, Miquette; Chattaway, Marie A; Reuter, Sandra; Savin, Cyril; Strauch, Eckhard; Carniel, Elisabeth; Connor, Thomas; Van Damme, Inge; Rajakaruna, Lakshani; Rajendram, Dunstan; Jenkins, Claire; Thomson, Nicholas R; McNally, Alan
The genus Yersinia is a large and diverse bacterial genus consisting of human-pathogenic species, a fish-pathogenic species, and a large number of environmental species. Recently, the phylogenetic and population structure of the entire genus was elucidated through the genome sequence data of 241 strains encompassing every known species in the genus. Here we report the mining of this enormous data set to create a multilocus sequence typing-based scheme that can identify Yersinia strains to the species level to a level of resolution equal to that for whole-genome sequencing. Our assay is designed to be able to accurately subtype the important human-pathogenic species Yersinia enterocolitica to whole-genome resolution levels. We also report the validation of the scheme on 386 strains from reference laboratory collections across Europe. We propose that the scheme is an important molecular typing system to allow accurate and reproducible identification of Yersinia isolates to the species level, a process often inconsistent in nonspecialist laboratories. Additionally, our assay is the most phylogenetically informative typing scheme available for Y. enterocolitica. PMID:25339391
High-throughput typing method to identify a non-outbreak-involved Legionella pneumophila strain colonizing the entire water supply system in the town of Rennes, France.
Sobral, D; Le Cann, P; Gerard, A; Jarraud, S; Lebeau, B; Loisy-Hamon, F; Vergnaud, G; Pourcel, C
Two legionellosis outbreaks occurred in the city of Rennes, France, during the past decade, requiring in-depth monitoring of Legionella pneumophila in the water network and the cooling towers in the city. In order to characterize the resulting large collection of isolates, an automated low-cost typing method was developed. The multiplex capillary-based variable-number tandem repeat (VNTR) (multiple-locus VNTR analysis [MLVA]) assay requiring only one PCR amplification per isolate ensures a high level of discrimination and reduces hands-on and time requirements. In less than 2 days and using one 4-capillary apparatus, 217 environmental isolates collected between 2000 and 2009 and 5 clinical isolates obtained during outbreaks in 2000 and 2006 in Rennes were analyzed, and 15 different genotypes were identified. A large cluster of isolates with closely related genotypes and representing 77% of the population was composed exclusively of environmental isolates extracted from hot water supply systems. It was not responsible for the known Rennes epidemic cases, although strains showing a similar MLVA profile have regularly been involved in European outbreaks. The clinical isolates in Rennes had the same genotype as isolates contaminating a mall's cooling tower. This study further demonstrates that unknown environmental or genetic factors contribute to the pathogenicity of some strains. This work illustrates the potential of the high-throughput MLVA typing method to investigate the origin of legionellosis cases by allowing the systematic typing of any new isolate and inclusion of data in shared databases. PMID:21821761
Use of Whole-Genus Genome Sequence Data To Develop a Multilocus Sequence Typing Tool That Accurately Identifies Yersinia Isolates to the Species and Subspecies Levels
Hall, Miquette; Chattaway, Marie A.; Reuter, Sandra; Savin, Cyril; Strauch, Eckhard; Carniel, Elisabeth; Connor, Thomas; Van Damme, Inge; Rajakaruna, Lakshani; Rajendram, Dunstan; Jenkins, Claire; Thomson, Nicholas R.
The genus Yersinia is a large and diverse bacterial genus consisting of human-pathogenic species, a fish-pathogenic species, and a large number of environmental species. Recently, the phylogenetic and population structure of the entire genus was elucidated through the genome sequence data of 241 strains encompassing every known species in the genus. Here we report the mining of this enormous data set to create a multilocus sequence typing-based scheme that can identify Yersinia strains to the species level to a level of resolution equal to that for whole-genome sequencing. Our assay is designed to be able to accurately subtype the important human-pathogenic species Yersinia enterocolitica to whole-genome resolution levels. We also report the validation of the scheme on 386 strains from reference laboratory collections across Europe. We propose that the scheme is an important molecular typing system to allow accurate and reproducible identification of Yersinia isolates to the species level, a process often inconsistent in nonspecialist laboratories. Additionally, our assay is the most phylogenetically informative typing scheme available for Y. enterocolitica. PMID:25339391
High-Throughput Typing Method To Identify a Non-Outbreak-Involved Legionella pneumophila Strain Colonizing the Entire Water Supply System in the Town of Rennes, France ? å
Sobral, D.; Le Cann, P.; Gerard, A.; Jarraud, S.; Lebeau, B.; Loisy-Hamon, F.; Vergnaud, G.; Pourcel, C.
Two legionellosis outbreaks occurred in the city of Rennes, France, during the past decade, requiring in-depth monitoring of Legionella pneumophila in the water network and the cooling towers in the city. In order to characterize the resulting large collection of isolates, an automated low-cost typing method was developed. The multiplex capillary-based variable-number tandem repeat (VNTR) (multiple-locus VNTR analysis [MLVA]) assay requiring only one PCR amplification per isolate ensures a high level of discrimination and reduces hands-on and time requirements. In less than 2 days and using one 4-capillary apparatus, 217 environmental isolates collected between 2000 and 2009 and 5 clinical isolates obtained during outbreaks in 2000 and 2006 in Rennes were analyzed, and 15 different genotypes were identified. A large cluster of isolates with closely related genotypes and representing 77% of the population was composed exclusively of environmental isolates extracted from hot water supply systems. It was not responsible for the known Rennes epidemic cases, although strains showing a similar MLVA profile have regularly been involved in European outbreaks. The clinical isolates in Rennes had the same genotype as isolates contaminating a mall's cooling tower. This study further demonstrates that unknown environmental or genetic factors contribute to the pathogenicity of some strains. This work illustrates the potential of the high-throughput MLVA typing method to investigate the origin of legionellosis cases by allowing the systematic typing of any new isolate and inclusion of data in shared databases. PMID:21821761
Identification and separation of two distinct contributions to the training effect in polycrystalline exchange biased Co\\/FeMn bilayers
M. K. Chan; J. S. Parker; P. A. Crowell; C. Leighton
We show that polycrystalline Co\\/FeMn bilayers display two distinct forms of training and qualitatively explain their FeMn thickness (tFeMn) dependence. The two types of training can be identified and separated via their distinctive field cycle and tFeMn dependences, and the degree of asymmetry between the ascending and descending branches of the hysteresis loops. Samples were prepared via UHV dc magnetron
Quantitative Localization of Cav2.1 (P/Q-Type) Voltage-Dependent Calcium Channels in Purkinje Cells: Somatodendritic Gradient and Distinct Somatic Coclustering with Calcium-Activated Potassium Channels
Indriati, Dwi Wahyu; Kamasawa, Naomi; Matsui, Ko; Meredith, Andrea L.; Watanabe, Masahiko; Shigemoto, Ryuichi
P/Q-type voltage-dependent calcium channels play key roles in transmitter release, integration of dendritic signals, generation of dendritic spikes, and gene expression. High intracellular calcium concentration transient produced by these channels is restricted to tens to hundreds of nanometers from the channels. Therefore, precise localization of these channels along the plasma membrane was long sought to decipher how each neuronal cell function is controlled. Here, we analyzed the distribution of Cav2.1 subunit of the P/Q-type channel using highly sensitive SDS-digested freeze-fracture replica labeling in the rat cerebellar Purkinje cells. The labeling efficiency was such that the number of immunogold particles in each parallel fiber active zone was comparable to that of functional channels calculated from previous reports. Two distinct patterns of Cav2.1 distribution, scattered and clustered, were found in Purkinje cells. The scattered Cav2.1 had a somatodendritic gradient with the density of immunogold particles increasing 2.5-fold from soma to distal dendrites. The other population with 74-fold higher density than the scattered particles was found within clusters of intramembrane particles on the P-face of soma and primary dendrites. Both populations of Cav2.1 were found as early as P3 and increased in the second postnatal week to a mature level. Using double immunogold labeling, we found that virtually all of the Cav2.1 clusters were colocalized with two types of calcium-activated potassium channels, BK and SK2, with the nearest neighbor distance of ~40 nm. Calcium nanodomain created by the opening of Cav2.1 channels likely activates the two channels that limit the extent of depolarization. PMID:23426693
Quantitative localization of Cav2.1 (P/Q-type) voltage-dependent calcium channels in Purkinje cells: somatodendritic gradient and distinct somatic coclustering with calcium-activated potassium channels.
Indriati, Dwi Wahyu; Kamasawa, Naomi; Matsui, Ko; Meredith, Andrea L; Watanabe, Masahiko; Shigemoto, Ryuichi
P/Q-type voltage-dependent calcium channels play key roles in transmitter release, integration of dendritic signals, generation of dendritic spikes, and gene expression. High intracellular calcium concentration transient produced by these channels is restricted to tens to hundreds of nanometers from the channels. Therefore, precise localization of these channels along the plasma membrane was long sought to decipher how each neuronal cell function is controlled. Here, we analyzed the distribution of Ca(v)2.1 subunit of the P/Q-type channel using highly sensitive SDS-digested freeze-fracture replica labeling in the rat cerebellar Purkinje cells. The labeling efficiency was such that the number of immunogold particles in each parallel fiber active zone was comparable to that of functional channels calculated from previous reports. Two distinct patterns of Ca(v)2.1 distribution, scattered and clustered, were found in Purkinje cells. The scattered Ca(v)2.1 had a somatodendritic gradient with the density of immunogold particles increasing 2.5-fold from soma to distal dendrites. The other population with 74-fold higher density than the scattered particles was found within clusters of intramembrane particles on the P-face of soma and primary dendrites. Both populations of Ca(v)2.1 were found as early as P3 and increased in the second postnatal week to a mature level. Using double immunogold labeling, we found that virtually all of the Ca(v)2.1 clusters were colocalized with two types of calcium-activated potassium channels, BK and SK2, with the nearest neighbor distance of ?40 nm. Calcium nanodomain created by the opening of Ca(v)2.1 channels likely activates the two channels that limit the extent of depolarization. PMID:23426693
A distinct picornavirus group identified by sequence analysis.
Hyypiõ, T; Horsnell, C; Maaronen, M; Khan, M; Kalkkinen, N; Auvinen, P; Kinnunen, L; Stanway, G
Although echovirus 22 is presently classified as a member of the enterovirus group in the family of picornaviruses, it has been reported to have exceptional biological properties when compared with other representatives of the group. We have determined the complete nucleotide sequence of the echovirus 22 (Harris strain) genome, which appears to be significantly different from all the other studied picornaviruses. However, the organization of the genome [7339 nucleotides, excluding the poly(A) tract] is similar to that of previously sequenced picornaviruses. This genome includes a 5' untranslated region, relatively well-conserved when compared with aphtho- and cardioviruses, followed by an open reading frame coding for a 2180-amino acid-long polyprotein. The amino termini of capsid polypeptides VP1 and VP3 were determined by direct sequencing, and the other proteolytic cleavage sites in the polyprotein were predicted by comparison with other picornavirus proteins. The amino acid identities of echovirus 22 polypeptides with the corresponding proteins of other picornaviruses are in the 14-35% range, similar to those percentages seen when representatives of the five picornavirus groups (entero-, rhino-, cardio-, aphtho-, and hepatoviruses) are compared. Our results suggest that echovirus 22 belongs to an independent group of picornaviruses. Images PMID:1528901
[MRSA clones identified in outpatient dermatology clinics].
Hosoya, Shino; Ito, Teruyo; Misawa, Shigeki; Yoshiike, Takashi; Oguri, Toyoko; Hiramatsu, Keiichi
To know the characteristics of methicillin-resistant Staphylococcus aureus (MRSA) strains disseminating through the Japanese community, we have determined types of Staphylococcal cassette chromosome mec (SCCmec) elements, Multi-Locus Sequence Typing (MLST), and carriages of four exotoxin genes (toxic-shock syndrome toxin, Panton-Valentine Leukocidine, and exfoliative toxins a and b) using 54 MRSA strains isolated from outpatients attending dermatology clinics at the four university hospitals of Juntendo University. Ten clonal complexes and 12 SCCmec types have been identified. As a result, more than 15 MRSA clones that were defined by the combination of genotype and SCCmec type, were identified. Among them, Clonal Complex (CC) 5-type IIa SCCmec strains were the most major (16 strains). In contrast to the fact that CC5- type IIa SCCmec strains known as a hospital-associated MRSA clone in Japan carried toxic-shock syndrome toxin gene (tst), only 2 of 16 strains have been shown to carry tst. Thirty-eight (70.4%) of isolates belonged to the clones distinct from the CC5-type IIa SCCmec strains. Among them, CC8 strains were major (12 strains), which contained 9 tst-positive CC8-type IVl SCCmec clones and a CC8-type IVa SCCmec strain carrying the Panton Valentine Leukocidin gene (lukS, F-PV). Clones related to impetigo were also identified: 7 exfoliative toxin b (etb) -positive clones, CC89-type IIa SCCmec and CC89-type V SCCmec strains; and 2 exfoliative toxin a (eta) -positive CC121-type V SCCmec strains. Other clones were as follows: CC1-type IVa SCCmec, CC8-type I SCCmec, CC81-type IVg SCCmec, CC97-type IVc SCCmec, CC91-type IVa SCCmec, CC59-type IVg SCCmec, CC45-type IIn SCCmec, CC89-SCCmec nontypeable, and CC8-type IVm, novel subtype of type IV SCCmec were identified in this study. Our data showed that many novel MRSA clones have emerged in the community. PMID:25764806
Definition of a fluorescence in-situ hybridization score identifies high- and low-level FGFR1 amplification types in squamous cell lung cancer.
Schildhaus, Hans-Ulrich; Heukamp, Lukas C; Merkelbach-Bruse, Sabine; Riesner, Katharina; Schmitz, Katja; Binot, Elke; Paggen, Ellen; Albus, Kerstin; Schulte, Wolfgang; Ko, Yon-Dschun; Schlesinger, Andreas; Ansķn, Sascha; Engel-Riedel, Walburga; Brockmann, Michael; Serke, Monika; Gerigk, Ulrich; Huss, Sebastian; G÷ke, Friederike; Perner, Sven; Hekmat, Khosro; Frank, Konrad F; Reiser, Marcel; Schnell, Roland; Bos, Marc; Mattonet, Christian; Sos, Martin; Stoelben, Erich; Wolf, J³rgen; Zander, Thomas; Buettner, Reinhard
We recently reported fibroblast growth factor receptor-type 1 (FGFR1) amplification to be associated with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. This makes FGFR1 a novel target for directed therapy in these tumors. To reproducibly identify patients for clinical studies, we developed a standardized reading and evaluation strategy for FGFR1 fluorescence in-situ hybridization (FISH) and propose evaluation criteria, describe different patterns of low- and high-level amplifications and report on the prevalence of FGFR1 amplifications in pulmonary carcinomas. A total of 420 lung cancer patients including 307 squamous carcinomas, 100 adenocarcinomas of the lung and 13 carcinomas of other types were analyzed for FGFR1 amplification using a dual color FISH. We found heterogeneous and different patterns of gene copy numbers. FGFR1 amplifications were observed in 20% of pulmonary squamous carcinomas but not in adenocarcinomas. High-level amplification (as defined by an FGFR1/centromer 8 (CEN8) ratio ?2.0, or average number of FGFR1 signals per tumor cell nucleus ?6, or the percentage of tumor cells containing ?15 FGFR1 signals or large clusters ?10%) was detected at a frequency of 16% and low-level amplification (as defined by ?5 FGFR1 signals in ?50% of tumor cells) at a frequency of 4%. We conclude that FGFR1 amplification is one of the most frequent therapeutically tractable genetic lesions in pulmonary carcinomas. Standardized reporting of FGFR1 amplification in squamous carcinomas of the lung will become increasingly important to correlate therapeutic responses with FGFR1 inhibitors in clinical studies. Thus, our reading and evaluation strategy might serve as a basis for identifying patients for ongoing and upcoming clinical trials. PMID:22684217
Repressor- and activator-type ethylene response factors functioning in jasmonate signaling and disease resistance identified via a genome-wide screen of Arabidopsis transcription factor gene expression.
McGrath, Ken C; Dombrecht, Bruno; Manners, John M; Schenk, Peer M; Edgar, Cameron I; Maclean, Donald J; Scheible, Wolf-R³diger; Udvardi, Michael K; Kazan, Kemal
To identify transcription factors (TFs) involved in jasmonate (JA) signaling and plant defense, we screened 1,534 Arabidopsis (Arabidopsis thaliana) TFs by real-time quantitative reverse transcription-PCR for their altered transcript at 6 h following either methyl JA treatment or inoculation with the incompatible pathogen Alternaria brassicicola. We identified 134 TFs that showed a significant change in expression, including many APETALA2/ethylene response factor (AP2/ERF), MYB, WRKY, and NAC TF genes with unknown functions. Twenty TF genes were induced by both the pathogen and methyl JA and these included 10 members of the AP2/ERF TF family, primarily from the B1a and B3 subclusters. Functional analysis of the B1a TF AtERF4 revealed that AtERF4 acts as a novel negative regulator of JA-responsive defense gene expression and resistance to the necrotrophic fungal pathogen Fusarium oxysporum and antagonizes JA inhibition of root elongation. In contrast, functional analysis of the B3 TF AtERF2 showed that AtERF2 is a positive regulator of JA-responsive defense genes and resistance to F. oxysporum and enhances JA inhibition of root elongation. Our results suggest that plants coordinately express multiple repressor- and activator-type AP2/ERFs during pathogen challenge to modulate defense gene expression and disease resistance. PMID:16183832
Application of Multiple-Locus Variable Number Tandem Repeat Analysis to Identify Outbreak-Associated Neisseria meningitides Serogroup C Sequence Type 4821 in China
Shan, Xiaoying; Zhou, Haijian; Zhang, Ji; Zhu, Bingqing; Xu, Li; Hu, Guangchun; Bai, Aiying; Shao, Zhujun; Jiang, Baofa
Neisseria meningitidis (N. meningitidis) serogroup C sequence type (ST)-4821 caused an outbreak in 2010 in Shandong province of China. Twenty-one non-outbreak-associated strains were isolated, along with twenty-eight N. meningitides serogroup C ST-4821 isolates. Therefore, itÆs essential to identify and clarify characterization of the real outbreak-associated strains with a rapid method during an outbreak investigation. In this study, multiple-locus variable number tandem repeat analysis (MLVA) was applied to analyze 84 N. meningitidis strains, among which 58 were recovered from two outbreaks and 26 were sporadic isolates. Three MLVA schemes with different combination of VNTR loci were tested, and two of them were suitable for isolates from China: scheme 2 with six loci was found to separate ST into finer resolution, and scheme 3 with five loci can be used to identify outbreak-associated isolates from the same outbreak that caused by N. meningitidis serogroup C ST-4821. PMID:25603352
Cytometric profiling of CD133+ cells in human colon ?carcinoma cell lines identifies a common core phenotype ?and cell type-specific mosaics.
Gemei, Marica; Di Noto, Rosa; Mirabelli, Peppino; Del Vecchio, Luigi
In colorectal cancer, CD133+ cells from fresh biopsies proved to be more tumorigenic than their CD133- counterparts. Nevertheless, the function of CD133 protein in tumorigenic cells seems only marginal. Moreover, CD133 expression alone is insufficient to isolate true cancer stem cells, since only 1 out of 262 CD133+ cells actually displays stem-cell capacity. Thus, new markers for colorectal cancer stem cells are needed. Here, we show the extensive characterization of CD133+ cells in 5 different colon carcinoma continuous cell lines (HT29, HCT116, Caco2, GEO and LS174T), each representing a different maturation level of colorectal cancer cells. Markers associated with stemness, tumorigenesis and metastatic potential were selected. We identified 6 molecules consistently present on CD133+ cells: CD9, CD29, CD49b, CD59, CD151, and CD326. By contrast, CD24, CD26, CD54, CD66c, CD81, CD90, CD99, CD112, CD164, CD166, and CD200 showed a discontinuous behavior, which led us to identify cell type-specific surface antigen mosaics. Finally, some antigens, e.g. CD227, indicated the possibility of classifying the CD133+ cells into 2 subsets likely exhibiting specific features. This study reports, for the first time, an extended characterization of the CD133+ cells in colon carcinoma cell lines and provides a "dictionary" of antigens to be used in colorectal cancer research. PMID:23709346
Implicit parameters: dynamic scoping with static types
Jeffrey R. Lewis; John Launchbury; Erik Meijert; Mark B. Shields
This paper introduces a language feature, called implicit parameters, that provides dynamically scoped variables within a statically-typed Hindley-Milner framework. Implicit parameters are lexically distinct from regular identifiers, and are bound by a special with construct whose scope is dynamic, rather than static as with let. Implicit parameters are treated by the type system as parameters that are not explicitly declared,
Type 1A fibre Bragg grating photosensitivity and the development of optimum temperature invariant type I-type IA strain sensors
A. George Simpson; Kyriacos Kalli; Lin Zhang; Kaiming Zhou; Ian Bennion
Type 1A fibre Bragg gratings (FBG) form only after the erasure of a standard grating in hydrogenated germanosilicate fibre, under prolonged UV exposure. They are distinct from other grating types as they exhibit a uniquely large increase in the mean index of the core, readily identifiable by a large red shift in the Bragg wavelength. Type 1A gratings can surpass
Genetic Screen of a Library of Chimeric Poxviruses Identifies an Ankyrin Repeat Protein Involved in Resistance to the Avian Type I Interferon Response
Buttigieg, Karen; Laidlaw, Stephen M.; Ross, Craig; Davies, Marc; Goodbourn, Stephen
Viruses must be able to resist host innate responses, especially the type I interferon (IFN) response. They do so by preventing the induction or activity of IFN and/or by resisting the antiviral effectors that it induces. Poxviruses are no exception, with many mechanisms identified whereby mammalian poxviruses, notably, vaccinia virus (VACV), but also cowpox and myxoma viruses, are able to evade host IFN responses. Similar mechanisms have not been described for avian poxviruses (avipoxviruses). Restricted for permissive replication to avian hosts, they have received less attention; moreover, the avian host responses are less well characterized. We show that the prototypic avipoxvirus, fowlpox virus (FWPV), is highly resistant to the antiviral effects of avian IFN. A gain-of-function genetic screen identified fpv014 to contribute to increased resistance to exogenous recombinant chicken alpha IFN (ChIFN1). fpv014 is a member of the large family of poxvirus (especially avipoxvirus) genes that encode proteins containing N-terminal ankyrin repeats (ANKs) and C-terminal F-box-like motifs. By binding the Skp1/cullin-1 complex, the F box in such proteins appears to target ligands bound by the ANKs for ubiquitination. Mass spectrometry and immunoblotting demonstrated that tandem affinity-purified, tagged fpv014 was complexed with chicken cullin-1 and Skp1. Prior infection with an fpv014-knockout mutant of FWPV still blocked transfected poly(IĘC)-mediated induction of the beta IFN (ChIFN2) promoter as effectively as parental FWPV, but the mutant was more sensitive to exogenous ChIFN1. Therefore, unlike the related protein fpv012, fpv014 does not contribute to the FWPV block to induction of ChIFN2 but does confer resistance to an established antiviral state. PMID:23427151
Genome-Wide Association Study Identifies Two Novel Loci with Sex-Specific Effects for Type 2 Diabetes Mellitus and Glycemic Traits in a Korean Population
Go, Min Jin; Hwang, Joo-Yeon; Park, Tae-Joon; Kim, Young Jin; Oh, Ji Hee; Kim, Yeon-Jung; Han, Bok-Ghee
Background Until recently, genome-wide association study (GWAS)-based findings have provided a substantial genetic contribution to type 2 diabetes mellitus (T2DM) or related glycemic traits. However, identification of allelic heterogeneity and population-specific genetic variants under consideration of potential confounding factors will be very valuable for clinical applicability. To identify novel susceptibility loci for T2DM and glycemic traits, we performed a two-stage genetic association study in a Korean population. Methods We performed a logistic analysis for T2DM, and the first discovery GWAS was analyzed for 1,042 cases and 2,943 controls recruited from a population-based cohort (KARE, n=8,842). The second stage, de novo replication analysis, was performed in 1,216 cases and 1,352 controls selected from an independent population-based cohort (Health 2, n=8,500). A multiple linear regression analysis for glycemic traits was further performed in a total of 14,232 nondiabetic individuals consisting of 7,696 GWAS and 6,536 replication study participants. A meta-analysis was performed on the combined results using effect size and standard errors estimated for stage 1 and 2, respectively. Results A combined meta-analysis for T2DM identified two new (rs11065756 and rs2074356) loci reaching genome-wide significance in CCDC63 and C12orf51 on the 12q24 region. In addition, these variants were significantly associated with fasting plasma glucose and homeostasis model assessment of ?-cell function. Interestingly, two independent single nucleotide polymorphisms were associated with sex-specific stratification in this study. Conclusion Our study showed a strong association between T2DM and glycemic traits. We further observed that two novel loci with multiple diverse effects were highly specific to males. Taken together, these findings may provide additional insights into the clinical assessment or subclassification of disease risk in a Korean population. PMID:25349825
Genetic screen of a library of chimeric poxviruses identifies an ankyrin repeat protein involved in resistance to the avian type I interferon response.
Buttigieg, Karen; Laidlaw, Stephen M; Ross, Craig; Davies, Marc; Goodbourn, Stephen; Skinner, Michael A
Viruses must be able to resist host innate responses, especially the type I interferon (IFN) response. They do so by preventing the induction or activity of IFN and/or by resisting the antiviral effectors that it induces. Poxviruses are no exception, with many mechanisms identified whereby mammalian poxviruses, notably, vaccinia virus (VACV), but also cowpox and myxoma viruses, are able to evade host IFN responses. Similar mechanisms have not been described for avian poxviruses (avipoxviruses). Restricted for permissive replication to avian hosts, they have received less attention; moreover, the avian host responses are less well characterized. We show that the prototypic avipoxvirus, fowlpox virus (FWPV), is highly resistant to the antiviral effects of avian IFN. A gain-of-function genetic screen identified fpv014 to contribute to increased resistance to exogenous recombinant chicken alpha IFN (ChIFN1). fpv014 is a member of the large family of poxvirus (especially avipoxvirus) genes that encode proteins containing N-terminal ankyrin repeats (ANKs) and C-terminal F-box-like motifs. By binding the Skp1/cullin-1 complex, the F box in such proteins appears to target ligands bound by the ANKs for ubiquitination. Mass spectrometry and immunoblotting demonstrated that tandem affinity-purified, tagged fpv014 was complexed with chicken cullin-1 and Skp1. Prior infection with an fpv014-knockout mutant of FWPV still blocked transfected poly(IĘC)-mediated induction of the beta IFN (ChIFN2) promoter as effectively as parental FWPV, but the mutant was more sensitive to exogenous ChIFN1. Therefore, unlike the related protein fpv012, fpv014 does not contribute to the FWPV block to induction of ChIFN2 but does confer resistance to an established antiviral state. PMID:23427151
Targeted next-generation sequencing identifies novel compound heterozygous mutations of DYNC2H1 in a fetus with short rib-polydactyly syndrome, type III.
Mei, Libin; Huang, Yanru; Pan, Qian; Su, Wei; Quan, Yi; Liang, Desheng; Wu, Lingqian
A 26-year-old woman with a past history of fetal skeletal dysplasia was referred to our institution at 24weeks of gestation following a routine sonographic diagnosis of short limbs in the fetus. A fetal ultrasound showed short limbs, a narrow thorax, short ribs with marginal spurs, and polydactyly. Conventional cytogenetics analysis of cultured amniocytes demonstrated that the fetal karyotype was normal. Using targeted exome sequencing of 226 known genes implicated in inherited skeletal dysplasia, we identified compound heterozygous mutations in the DYNC2H1 gene in the fetus with short rib-polydactyly syndrome, type III (SRPS III), c.1151 C>T(p.Ala384Val) and c.4351 C>T (p.Gln1451*), which were inherited from paternally and maternally, respectively. These variants were further confirmed using Sanger sequencing and have not been previously reported. To our knowledge, this is the first report of DYNC2H1 mutations causing SRPS III, in the Chinese population. Our findings expand the number of reported cases of this rare disease, and indicate that targeted next-generation sequencing (NGS) is an accurate, rapid, and cost-effective method in the genetic diagnosis of fetal skeletal dysplasia. PMID:25982780
Allelic expression imbalance screening of genes in chromosome 1q21¢24 region to identify functional variants for Type 2 diabetes susceptibility
Mondal, Ashis K.; Sharma, Neeraj K.; Elbein, Steven C.
Type 2 diabetes (T2D)-associated SNPs are more likely to be expression quantitative trait loci (eQTLs). The allelic expression imbalance (AEI) analysis is the measure of relative expression between two allelic transcripts and is the most sensitive measurement to detect cis-regulatory effects. We performed AEI screening to detect cis-regulators for genes expressed in transformed lymphocytes of 190 Caucasian (CA) and African American (AA) subjects to identify functional variants for T2D susceptibility in the chromosome 1q21¢24 region of linkage. Among transcribed SNPs studied in 115 genes, significant AEI (P < 0.001) occurred in 28 and 30 genes in CA and AA subjects, respectively. Analysis of the effect of selected AEI-SNPs (?10% mean AEI) on total gene expression further established the cis-eQTLs in thioesterase superfamily member-4 (THEM4) (rs13320, P = 0.027), and IGSF8 (rs1131891, P = 0.02). Examination of published genome-wide association data identified significant associations (P < 0.01) of three AEI-SNPs with T2D in the DIAGRAM-v3 dataset. Six AEI single nucleotide polymorphisms, including rs13320 (P = 1.35E-04) in THEM4, were associated with glucose homeostasis traits in the MAGIC dataset. Evaluation of AEI-SNPs for association with glucose homeostasis traits in 611 nondiabetic subjects showed lower AIRG (P = 0.005) in those with TT/TC genotype for rs13320. THEM4 expression in adipose was higher (P = 0.005) in subjects carrying the T allele; in vitro analysis with luciferase construct confirmed the higher expression of the T allele. Resequencing of THEM4 exons in 192 CA subjects revealed four coding nonsynonymous variants, but did not explain transmission of T2D in 718 subjects from 67 Caucasian pedigrees. Our study indicates the role of a cis-regulatory SNP in THEM4 that may influence T2D predisposition by modulating glucose homeostasis. PMID:23673729
Comparative analysis of type 2 diabetes-associated SNP alleles identifies allele-specific DNA-binding proteins for the KCNQ1 locus.
Hiramoto, Masaki; Udagawa, Haruhide; Watanabe, Atsushi; Miyazawa, Keisuke; Ishibashi, Naoko; Kawaguchi, Miho; Uebanso, Takashi; Nishimura, Wataru; Nammo, Takao; Yasuda, Kazuki
Although recent genome-wide association studies (GWAS) have been extremely successful, it remains a big challenge to functionally annotate disease?associated single nucleotide polymorphismsĀ(SNPs), as the majority of these SNPs are located in non?coding regions of the genome. In this study, we described a novel strategy for identifying the proteins that bind to the SNP?containing locus in an allele?specific manner and successfully applied this method to SNPs in the typeĀ2 diabetes mellitus susceptibility gene, potassium voltage?gated channel, KQT?like subfamilyĀQ, memberĀ1Ā(KCNQ1). DNA fragments encompassing SNPs, and risk or non?risk alleles were immobilized onto the novel nanobeads and DNA?binding proteins were purified from the nuclear extracts of pancreatic ?Ācells using these DNA?immobilized nanobeads. Comparative analysis of the allele-specific DNA-binding proteins indicated that the affinities of several proteins for the examined SNPs differed between the alleles. Nuclear transcription factorĀYĀ(NF?Y) specifically bound the non?risk allele of the SNPĀrs2074196 region and stimulated the transcriptional activity of an artificial promoter containing SNPĀrs2074196 in an allele?specific manner. These results suggest that SNPĀrs2074196 modulates the affinity of the locus for NF?Y and possibly induces subsequent changes in gene expression. The findings of this study indicate that our comparative method using novel nanobeads is effective for the identification of allele?specific DNA?binding proteins, which may provide important clues for the functional impact of disease?associated non?coding SNPs. PMID:25955334
Genetic screen of a mutant poxvirus library identifies an ankyrin repeat protein involved in blocking induction of avian type I interferon.
Laidlaw, Stephen M; Robey, Rebecca; Davies, Marc; Giotis, Efstathios S; Ross, Craig; Buttigieg, Karen; Goodbourn, Stephen; Skinner, Michael A
Mammalian poxviruses, including vaccinia virus (VACV), have evolved multiple mechanisms to evade the host type I interferon (IFN) responses at different levels, with viral proteins targeting IFN induction, signaling, and antiviral effector functions. Avian poxviruses (avipoxviruses), which have been developed as recombinant vaccine vectors for permissive (i.e., poultry) and nonpermissive (i.e., mammals, including humans) species, encode no obvious equivalents of any of these proteins. We show that fowlpox virus (FWPV) fails to induce chicken beta IFN (ChIFN2) and is able to block its induction by transfected poly(IĘC), an analog of cytoplasmic double-stranded RNA (dsRNA). A broad-scale loss-of-function genetic screen was used to find FWPV-encoded modulators of poly(IĘC)-mediated ChIFN2 induction. It identified fpv012, a member of a family of poxvirus genes highly expanded in the avipoxviruses (31 in FWPV; 51 in canarypox virus [CNPV], representing 15% of the total gene complement), encoding proteins containing N-terminal ankyrin repeats (ANKs) and C-terminal F-box-like motifs. Under ectopic expression, the first ANK of fpv012 is dispensable for inhibitory activity and the CNPV ortholog is also able to inhibit induction of ChIFN2. FWPV defective in fpv012 replicates well in culture and barely induces ChIFN2 during infection, suggesting that other factors are involved in blocking IFN induction and resisting the antiviral effectors. Nevertheless, unlike parental and revertant viruses, the mutants induce moderate levels of expression of interferon-stimulated genes (ISGs), suggesting either that there is sufficient ChIFN2 expression to partially induce the ISGs or the involvement of alternative, IFN-independent pathways that are also normally blocked by fpv012. PMID:23427153
Association between Gene Polymorphisms of Seven Newly Identified Loci and Type 2 Diabetes and the Correlate Quantitative Traits in Chinese Dong Populations
LIU, Liya; CHEN, Lizhang; LI, Zhanzhan; LI, Liang; QU, Jian; XUE, Jing
Abstract Background There are much heterogeneity in the genetic variation of type 2 diabetes (T2D). The purpose of this study was to investigate the association of seven novel genetic loci identified in a recent genome-wide association studies (GWAS) with T2D in Chinese Dong populations. Methods A case-controlled study was performed in individuals of Chinese Dong nationality. The genotypes of PARD3B (rs849230), LOC729993 (rs149228), EPHA4 (rs16862811), HNT (rs3099797), PTPRD (rs17584499 and rs649891), TOMM7 (rs2240727) genes were determined using Multiplex PCR-SNaPshot. The independent association between each polymorphism and T2D was assessed using unconditional binary logistic regression analysis (BLR). Results A total of 136 cases of T2D and 136 control subjects were enrolled in the study. The polymorphism of rs2240727 in TOMM7 gene was associated with T2D (odds ratio (OR) = 1.65, per copy of the risk T allele, P = 0.004). In addition, CT and TT were risk genotypes for T2D (OR (95% CIs):2.64 (1.28-5.45) and 3.42 (1.58-7.41) respectively). After correcting for multiple testing, the above results remained significant (all P < 0.05). After adjusting for the confounders of age, gender, and BMI, the association between T2D and rs2240727 remained significant (P < 0.01). There were significantly statistical difference in levels of fasting plasm glucose(FPG) among genotypes of rs2240727 in controls and patients, the levels of FPG were significantly higher in CT and TT genotypes than in CC genotype in both groups (all P < 0.05). Conclusions The rs2240727 genetic variant in TOMM7 was associated with T2D of Chinese Dong individuals, and might enhance the risk of T2D by affecting the level of FPG.
Identifying the seasonal origins of human campylobacteriosis.
Strachan, N J C; Rotariu, O; Smith-Palmer, A; Cowden, J; Sheppard, S K; O'Brien, S J; Maiden, M C J; Macrae, M; Bessell, P R; Matthews, L; Reid, S W J; Innocent, G T; Ogden, I D; Forbes, K J
Human campylobacteriosis exhibits a distinctive seasonality in temperate regions. This paper aims to identify the origins of this seasonality. Clinical isolates [typed by multi-locus sequence typing (MLST)] and epidemiological data were collected from Scotland. Young rural children were found to have an increased burden of disease in the late spring due to strains of non-chicken origin (e.g. ruminant and wild bird strains from environmental sources). In contrast the adult population had an extended summer peak associated with chicken strains. Travel abroad and UK mainland travel were associated with up to 17% and 18% of cases, respectively. International strains were associated with chicken, had a higher diversity than indigenous strains and a different spectrum of MLST types representative of these countries. Integrating empirical epidemiology and molecular subtyping can successfully elucidate the seasonal components of human campylobacteriosis. The findings will enable public health officials to focus strategies to reduce the disease burden. PMID:22989449
J. Stepan
This paper describes an end office tributary identifier which sends to a toll center the calling subscriber's directory number. It is arranged to interface with the Bell System's centralized automatic message accounting (CAMA) centers. The electronic identifier operates on either a terminal per line, a terminal per station, or mixed basis. In operating, it feeds an ac signal on the
The expression of genes coding for distinct types of glycine-rich proteins varies according to the biology of three metastriate ticks, Rhipicephalus (Boophilus) microplus, Rhipicephalus sanguineus and Amblyomma cajennense
Background Ticks secrete a cement cone composed of many salivary proteins, some of which are rich in the amino acid glycine in order to attach to their hosts' skin. Glycine-rich proteins (GRPs) are a large family of heterogeneous proteins that have different functions and features; noteworthy are their adhesive and tensile characteristics. These properties may be essential for successful attachment of the metastriate ticks to the host and the prolonged feeding necessary for engorgement. In this work, we analyzed Expressed Sequence Tags (ESTs) similar to GRPs from cDNA libraries constructed from salivary glands of adult female ticks representing three hard, metastriate species in order to verify if their expression correlated with biological differences such as the numbers of hosts ticks feed on during their parasitic life cycle, whether one (monoxenous parasite) or two or more (heteroxenous parasite), and the anatomy of their mouthparts, whether short (Brevirostrata) or long (Longirostrata). These ticks were the monoxenous Brevirostrata tick, Rhipicephalus (Boophilus) microplus, a heteroxenous Brevirostrata tick, Rhipicephalus sanguineus, and a heteroxenous Longirostrata tick, Amblyomma cajennense. To further investigate this relationship, we conducted phylogenetic analyses using sequences of GRPs from these ticks as well as from other species of Brevirostrata and Longirostrata ticks. Results cDNA libraries from salivary glands of the monoxenous tick, R. microplus, contained more contigs of glycine-rich proteins than the two representatives of heteroxenous ticks, R. sanguineus and A. cajennense (33 versus, respectively, 16 and 11). Transcripts of ESTs encoding GRPs were significantly more numerous in the salivary glands of the two Brevirostrata species when compared to the number of transcripts in the Longirostrata tick. The salivary gland libraries from Brevirostrata ticks contained numerous contigs significantly similar to silks of true spiders (17 and 8 in, respectively, R. microplus and R. sanguineus), whereas the Longirostrata tick contained only 4 contigs. The phylogenetic analyses of GRPs from various species of ticks showed that distinct clades encoding proteins with different biochemical properties are represented among species according to their biology. Conclusions We found that different species of ticks rely on different types and amounts of GRPs in order to attach and feed on their hosts. Metastriate ticks with short mouthparts express more transcripts of GRPs than a tick with long mouthparts and the tick that feeds on a single host during its life cycle contain a greater variety of these proteins than ticks that feed on several hosts. PMID:20529354
Foundations of Distinctive Feature Theory.
ERIC Educational Resources Information Center
Baltaxe, Christiane A. M.
This treatise on the theoretical and historical foundations of distinctive feature theory traces the evolution of the distinctive features concept in the context of related notions current in linguistic theory, discusses the evolution of individual distinctive features, and criticizes certain acoustic and perceptual correlates attributed to theseģ
Genome-Wide Association Study Identifies a Novel Locus Contributing to Type 2 Diabetes Susceptibility in Sikhs of Punjabi Origin From India
Saxena, Richa; Saleheen, Danish; Been, Latonya F.; Garavito, Martha L.; Braun, Timothy; Bjonnes, Andrew; Young, Robin; Ho, Weang Kee; Rasheed, Asif; Frossard, Philippe; Sim, Xueling; Hassanali, Neelam; Radha, Venkatesan; Chidambaram, Manickam; Liju, Samuel; Rees, Simon D.; Ng, Daniel Peng-Keat; Wong, Tien-Yin; Yamauchi, Toshimasa; Hara, Kazuo; Tanaka, Yasushi; Hirose, Hiroshi; McCarthy, Mark I.; Morris, Andrew P.; Basit, Abdul; Barnett, Anthony H.; Katulanda, Prasad; Matthews, David; Mohan, Viswanathan; Wander, Gurpreet S.; Singh, Jai Rup; Mehra, Narinder K.; Ralhan, Sarju; Kamboh, M. Ilyas; Mulvihill, John J.; Maegawa, Hiroshi; Tobe, Kazuyuki; Maeda, Shiro; Cho, Yoon S.; Tai, E. Shyong; Kelly, M. Ann; Chambers, John C.; Kooner, Jaspal S.; Kadowaki, Takashi; Deloukas, Panos; Rader, Daniel J.; Danesh, John; Sanghera, Dharambir K.
We performed a genome-wide association study (GWAS) and a multistage meta-analysis of type 2 diabetes (T2D) in Punjabi Sikhs from India. Our discovery GWAS in 1,616 individuals (842 case subjects) was followed by in silico replication of the top 513 independent single nucleotide polymorphisms (SNPs) (P < 10?3) in Punjabi Sikhs (n = 2,819; 801 case subjects). We further replicated 66 SNPs (P < 10?4) through genotyping in a Punjabi Sikh sample (n = 2,894; 1,711 case subjects). On combined meta-analysis in Sikh populations (n = 7,329; 3,354 case subjects), we identified a novel locus in association with T2D at 13q12 represented by a directly genotyped intronic SNP (rs9552911, P = 1.82 ū 10?8) in the SGCG gene. Next, we undertook in silico replication (stage 2b) of the top 513 signals (P < 10?3) in 29,157 non-Sikh South Asians (10,971 case subjects) and de novo genotyping of up to 31 top signals (P < 10?4) in 10,817 South Asians (5,157 case subjects) (stage 3b). In combined South Asian meta-analysis, we observed six suggestive associations (P < 10?5 to < 10?7), including SNPs at HMG1L1/CTCFL, PLXNA4, SCAP, and chr5p11. Further evaluation of 31 top SNPs in 33,707 East Asians (16,746 case subjects) (stage 3c) and 47,117 Europeans (8,130 case subjects) (stage 3d), and joint meta-analysis of 128,127 individuals (44,358 case subjects) from 27 multiethnic studies, did not reveal any additional loci nor was there any evidence of replication for the new variant. Our findings provide new evidence on the presence of a population-specific signal in relation to T2D, which may provide additional insights into T2D pathogenesis. PMID:23300278
Types, numbers and distribution of synapses on the dendritic tree of an identified visual interneuron in the brain of the locust
F. Killmann; H. Gras; F.-W. Sch³rmann
The descending contralateral movement detector (DCMD), an identified descending interneuron in the brain of the locust Schistocerca gregaria has been investigated by using light and electron microscopy. We describe the fine structure, distribution and numbers of synapes that it receives from another identified brain neuron, the lobular giant movement detector (LGMD), and from unidentified neurons. The DCMD dendrites emerging from
Development of chemiluminescent probe hybridization, RT-PCR and nucleic acid cycle sequencing assays of Sabin type 3 isolates to identify base pair 472 Sabin type 3 mutants associated with vaccine associated paralytic poliomyelitis
Matthew O. Old; Linda H. Logan; Yvonne A. Maldonado
Sabin type 3 polio vaccine virus is the most common cause of poliovaccine associated paralytic poliomyelitis. Vaccine associated paralytic poliomyelitis cases have been associated with Sabin type 3 revertants containing a single U to C substitution at bp 472 of Sabin type 3. A rapid method of identification of Sabin type 3 bp 472 mutants is described. An enterovirus group-specific
Molecular typing of Mycobacterium tuberculosis by mycobacterial interspersed repetitive unit-variable-number tandem repeat analysis, a more accurate method for identifying epidemiological links between patients with tuberculosis
Henk van Deutekom; Ph. Supply; Haas de P. E. W; E. Willery; S. P. Hoijing; C. Locht; R. A. Coutinho; Soolingen van D
IS6110 fingerprinting of Mycobacterium tuberculosis is the standard identification method in studies on transmission of tuberculosis. However, intensive epidemiological investigation may fail to confirm transmis- sion links between patients clustered by IS6110-restriction fragment length polymorphism (RFLP) typing. We applied typing based on variable numbers of tandem repeats (VNTRs) of mycobacterial interspersed repetitive units (MIRUs) to isolates from 125 patients in
Repressor and Activator-Type Ethylene Response Factors Functioning in Jasmonate Signaling and Disease Resistance Identified via a Genome-Wide Screen of Arabidopsis Transcription Factor Gene Expression
Ken C. McGrath; Bruno Dombrecht; John M. Manners; Peer M. Schenk; Cameron I. Edgar; Donald J. Maclean; Wolf-Rudiger Scheible; Michael K. Udvardi; Kemal Kazan
To identify transcription factors (TFs) involved in jasmonate (JA) signaling and plant defense, we screened 1,534 Arabidopsis (Arabidopsis thaliana) TFs by real-time quantitative reverse transcription-PCR for their altered transcript at 6 h following either methyl JA treatment or inoculation with the incompatible pathogen Alternaria brassicicola. We identified 134 TFs that showed a significant change in expression,including many APETALA2\\/ethylene response factor
inv(16)/t(16;16) acute myeloid leukemia with non¢type A CBFB-MYH11 fusions associate with distinct clinical and genetic features and lack KIT mutations
Schwind, Sebastian; Edwards, Colin G.; Nicolet, Deedra; Mr¾zek, Krzysztof; Maharry, Kati; Wu, Yue-Zhong; Paschka, Peter; Eisfeld, Ann-Kathrin; Hoellerbauer, Pia; Becker, Heiko; Metzeler, Klaus H.; Curfman, John; Kohlschmidt, Jessica; Prior, Thomas W.; Kolitz, Jonathan E.; Blum, William; Pettenati, Mark J.; Dal Cin, Paola; Carroll, Andrew J.; Caligiuri, Michael A.; Larson, Richard A.; Volinia, Stefano
The inv(16)(p13q22)/t(16;16)(p13;q22) in acute myeloid leukemia results in multiple CBFB-MYH11 fusion transcripts, with type A being most frequent. The biologic and prognostic implications of different fusions are unclear. We analyzed CBFB-MYH11 fusion types in 208 inv(16)/t(16;16) patients with de novo disease, and compared clinical and cytogenetic features and the KIT mutation status between type A (n = 182; 87%) and non¢type A (n = 26; 13%) patients. At diagnosis, non¢type A patients had lower white blood counts (P = .007), and more often trisomies of chromosomes 8 (P = .01) and 21 (P < .001) and less often trisomy 22 (P = .02). No patient with non¢type A fusion carried a KIT mutation, whereas 27% of type A patients did (P = .002). Among the latter, KIT mutations conferred adverse prognosis; clinical outcomes of non¢type A and type A patients with wild-type KIT were similar. We also derived a fusion-type¢associated global gene-expression profile. Gene Ontology analysis of the differentially expressed genes revealedŚamong othersŚan enrichment of up-regulated genes involved in activation of caspase activity, cell differentiation and cell cycle control in non¢type A patients. We conclude that non¢type A fusions associate with distinctclinical and genetic features, including lack of KIT mutations, and a unique gene-expression profile. PMID:23160462
NSDL National Science Digital Library
In this activity, students describe the characteristics of different types of galaxies (spiral, elliptical, barred spiral, peculiar, or irregular) in their own words. They also classify galaxies seen in the Hubble Deep Field. This activity includes a student worksheet and background information for the teacher. This is activity two in "The Hidden Lives of Galaxies" information and activity booklet.
NSDL National Science Digital Library
In this environmental science activity (page 3 of the PDF), leaners will identify and explain the causes of erosion. They will observe the effects of erosion on the surrounding area and further explore examples of erosion online. An extension activity allows learners to make a hands-on model of soil erosion. Though this was created as a pre-visit activity for a workshop about water flow and erosion, it makes a great stand-alone activity as well!
NSDL National Science Digital Library
Mrs. Neubert
This unit will teach you how to identify symmetry in everyday objects and mathematical shapes in lines and rotational symmetry. What is line symmetry? Click on the link to find out: Line Symmetry Here is a line activity to see if you understand it: Line Symmetry Class Zone See if you understand the concepts by doing the following quiz: Line Symmetry Work Now for rotational symmetry: Rotational Symmetry See if you understand rotational symmetry by taking this quiz: Rotational Symmetry Work ...
Clonal Complexes of Campylobacter jejuni Identified by Multilocus Sequence Typing Are Reliably Predicted by Restriction Fragment Length Polymorphism Analyses of the flaA Gene?
Djordjevic, Steven P.; Unicomb, Leanne E.; Adamson, Penelope J.; Mickan, Lance; Rios, Rosa
Multilocus sequence typing (MLST) has provided important new insights into the population structure of Campylobacter jejuni and is rapidly becoming the gold standard for typing this species. However, the methodology is comparatively costly and slow to perform for the routine surveillance testing of large numbers of isolates required by public health laboratories. Restriction fragment length polymorphism analysis of the flaA gene (RFLP-flaA) and sequencing of the variable region in the fla locus (SVR-fla) were compared to MLST to determine if a low cost alternative could be found that reliably predicts clonal lineage (as determined by MLST). An isolate of C. jejuni from each of 153 patients from New South Wales, Australia, collected sequentially over a period of 30 months from 1999 to 2001 and comprising 40 sequence types (ST) from 15 clonal complexes (CC) was examined. Of 15 CC, 12 were represented by more than one isolate and a predominant RFLP-flaA type was found for 10 (83%). Of these, seven (70%) correctly predicted the predominant MLST CC with a probability of >0.8. Of 40 STs detected, 19 were reported for the first time, 9 of which were represented by more than one isolate. Eight of these were represented by a single RFLP-flaA type. Only two of eight major SVR-fla types were able to predict CC with a probability of >0.8, indicating that flaA-RFLP is a more reliable predictor of CC than SVR-fla and thus offers an alternative to MLST for use in routine surveillance. PMID:17093018
Identifying open-volume defects in doped and undoped perovskite-type LaCoO{sub 3}, PbTiO{sub 3}, and BaTiO{sub 3}
Ghosh, Vinita J. [Brookhaven National Laboratory, Upton, New York 11973 (United States)] [Brookhaven National Laboratory, Upton, New York 11973 (United States); Nielsen, Bent [Brookhaven National Laboratory, Upton, New York 11973 (United States)] [Brookhaven National Laboratory, Upton, New York 11973 (United States); Friessnegg, Thomas [University of Maryland, College Park, Maryland 20742 (United States)] [University of Maryland, College Park, Maryland 20742 (United States)
Dopants, vacancies, and impurity-vacancy clusters have a substantial impact on the properties of perovskite-type metal oxides (general formula ABO{sub 3}). In order to determine synthesis and processing conditions that optimize the desirable properties of these materials a careful study of these defects is required. It is essential to identify the defects and to map the defect densities. Positron annihilation spectroscopy has often been used to identify vacancy-type defects. Calculations of the positron lifetime and Doppler-broadened profiles of the positron-electron annihilation radiation in undoped and doped LaCoO{sub 3}, PbTiO{sub 3}, and BaTiO{sub 3} are reported, and compared with available experimental data. The results show that these positron techniques are excellent for studying open-volume defects, vacancy-impurity complexes, and for identifying the sublattice occupied by the dopants. (c) 2000 The American Physical Society.
Technology Transfer Automated Retrieval System (TEKTRAN)
Background: The incidence of human disease caused by E. coli O157:H7 is surprisingly low considering its ubiquitous distribution (and frequently, high prevalence) in the bovine reservoir and its low infectious dose for humans. The purpose of this study was to detect E. coli O157:H7 strain types in t...
Positive Selection Detection in 40,000 Human Immunodeficiency Virus (HIV) Type 1 Sequences Automatically Identifies Drug Resistance and Positive Fitness Mutations in HIV Protease and Reverse Transcriptase
Lamei Chen; Alla Perlina; Christopher J. Lee
Drug resistance is a major problem in the treatment of AIDS, due to the very high mutation rate of human immunodeficiency virus (HIV) and subsequent rapid development of resistance to new drugs. Identification of mutations associated with drug resistance is critical for both individualized treatment selection and new drug design. We have performed an automated mutation analysis of HIV Type
Emergence of a New Lineage of Dengue Virus Type 2 Identified in Travelers Entering Western Australia from Indonesia, 2010-2012
Ernst, Timo; McCarthy, Suzi; Chidlow, Glenys; Luang-Suarkia, Dagwin; Holmes, Edward C.; Smith, David W.; Imrie, Allison
Dengue virus (DENV) transmission is ubiquitous throughout the tropics. More than 70% of the current global dengue disease burden is borne by people who live in the Asia-Pacific region. We sequenced the E gene of DENV isolated from travellers entering Western Australia between 2010¢2012, most of whom visited Indonesia, and identified a diverse array of DENV1-4, including multiple co-circulating viral lineages. Most viruses were closely related to lineages known to have circulated in Indonesia for some time, indicating that this geographic region serves as a major hub for dengue genetic diversity. Most notably, we identified a new lineage of DENV-2 (Cosmopolitan genotype) that emerged in Bali in 2011¢2012. The spread of this lineage should clearly be monitored. Surveillance of symptomatic returned travellers provides important and timely information on circulating DENV serotypes and genotypes, and can reveal the herald wave of dengue and other emerging infectious diseases. PMID:25635775
Global optimal eBURST analysis of multilocus typing data using a graphic matroid approach
Alexandre P. Francisco; Miguel Bugalho; Mßrio Ramirez; JoŃo A. Carrińo
Background: Multilocus Sequence Typing (MLST) is a frequently used typing method for the analysis of the clonal relationships among strains of several clinically relevant microbial species. MLST is based on the sequence of housekeeping genes that result in each strain having a distinct numerical allelic profile, which is abbreviated to a unique identifier: the sequence type (ST). The relatedness between
Molecular Typing and Distribution of Staphylococcus aureus Isolates in Eastern Canadian Dairy Herds
P. M. Sabour; J. J. Gill; D. Lepp; J. C. Pacan; R. Ahmed; R. Dingwell; K. Leslie
Macrorestriction analysis of SmaI-digested chromosomal DNA, using pulsed field gel electrophoresis (PFGE) was performed to type and estimate genetic relationships among 288 Staphylococcus aureus isolates recovered from 58 Eastern Canadian dairy herds. In addition, a subset of the collection was phage typed and evaluated for sensitivity to 10 antimicrobial compounds. Of 288 isolates recovered, 29 distinct PFGE types were identified.
Mutational analysis of the Paracoccus denitrificans c-type cytochrome biosynthetic genes ccmABCDG : disruption of ccmC has distinct effects suggesting a role for CcmC independent of CcmAB
M. Dudley PageŃ; Stuart J. Ferguson
Each of the Paracoccus denitrificans genes in the c-type cytochrome biogenesis gene cluster ccmABCDG, plus the two flanking genes ORF117 and hisH, were individually disrupted by X insertion. Resultant phenotypes were restored to the wild-type by complementation from a set of plasmids. All of the ccm genes, but neither ORF117 nor hisH, were required for c-type cytochrome biogenesis; only ccmG
Development of Distinctive Feature Theory.
ERIC Educational Resources Information Center
Meyer, Peggy L.
Since the beginning of man's awareness of his language capabilities and language structure, he has assumed that speech is composed of discrete entities. The linguist attempts to establish a model of the workings of these distinctive sounds in a language. Utilizing an historical basis for discussion, this general survey of the distinctive featureģ
Counselor Identity: Conformity or Distinction?
ERIC Educational Resources Information Center
McLaughlin, Jerry E.; Boettcher, Kathryn
The authors explore 3 debates in other disciplines similar to counseling's identity debate in order to learn about common themes and outcomes. Conformity, distinction, and cohesion emerged as common themes. They conclude that counselors should retain their distinctive, humanistic approach rather than conforming to the dominant, medical approach.
Is Face Distinctiveness Gender Based?
ERIC Educational Resources Information Center
Baudouin, Jean-Yves; Gallay, Mathieu
Two experiments were carried out to study the role of gender category in evaluations of face distinctiveness. In Experiment 1, participants had to evaluate the distinctiveness and the femininity-masculinity of real or artificial composite faces. The composite faces were created by blending either faces of the same gender (sexed composite faces,ģ
A novel susceptibility locus for type 1 diabetes on Chr12q13 identified by a genome-wide association study
H. Hakonarson; H. Q. Qu; J. P. Bradfield; L. Marchand; C. E. Kim; J. T. Glessner; R. Grabs; T. Casalunovo; S. P. Taback; E. C. Frackelton; A. W. Eckert; K. Annaiah; M. L. Lawson; F. G. Otieno; E. Santa; J. L. Shaner; R. M. Smith; C. C. Onyiah; R. Skraban; R. M. Chiavacci; L. J. Robinson; C. A. Stanley; S. E. Kirsch; M. Devoto; D. S. Monos; S. F. Grant; C. Polychronakos
OBJECTIVE: In stage 1 of our genome-wide association (GWA) study for type 1 diabetes, one locus at 16p13 was detected (P = 1.03 x 10(-10)) and confirmed in two additional cohorts. Here we describe the results of testing, in these additional cohorts, 23 loci that were next in rank of statistical significance. RESEARCH DESIGN AND METHODS: Two independent cohorts were
Transcriptome Analysis of Arabidopsis Wild-Type and gl3-sst sim Trichomes Identifies Four Additional Genes Required for Trichome Development
M. David Marks; Jonathan P. Wenger; Edward Gilding; Ross Jilk; Richard A. Dixon
Transcriptome analyses have been performed on mature trichomes isolated from wild-type Arabidopsis leaves and on leaf trichomes isolated from the gl3-sst sim double mutant, which exhibit many attributes of immature trichomes. The mature trichome profile contained many highly expressed genes involved in cell wall synthesis, protein turnover, and abiotic stress response. The most highly expressed genes in the gl3-sst sim
NSDL National Science Digital Library
Michael DiSpezio
This two part activity will allow students to investigate biological diversity in the area of their school. They will first prepare a taxonomic key to distinguish between the four insects or spiders that they have selected. All of the keys are combined and students then perform a transect study of a neighborhood field or school playing ground. Finally as a class students will compile a list of the animals and plants that are found within a mile of their school. They may need to use field guides, local resources, taxonomic keys, and species lists to help identify these organisms. Once they have compiled their list they will organize the species into the taxonomic groups they have studied.
Latent Profiles of Problem Behavior within Learning, Peer, and Teacher Contexts: Identifying Subgroups of Children at Academic Risk across the Preschool Year
ERIC Educational Resources Information Center
Bulotsky-Shearer, Rebecca J.; Bell, Elizabeth R.; Dominguez, Ximena
Employing a developmental and ecological model, the study identified initial levels and rates of change in academic skills for subgroups of preschool children exhibiting problem behavior within routine classroom situations. Six distinct latent profile types of emotional and behavioral adjustment were identified for a cohort of low-income childrenģ
Parallel contributions of distinct human memory systems during probabilistic learning
Dickerson, Kathryn C.; Li, Jian; Delgado, Mauricio R.
Regions within the medial temporal lobe and basal ganglia are thought to subserve distinct memory systems underlying declarative and nondeclarative processes, respectively. One question of interest is how these multiple memory systems interact during learning to contribute to goal directed behavior. While some hypotheses suggest that regions such as the striatum and the hippocampus interact in a competitive manner, alternative views posit that these structures may operate in a parallel manner to facilitate learning. In the current experiment, we probed the functional connectivity between regions in the striatum and hippocampus in the human brain during an event related probabilistic learning task that varied with respect to type of difficulty (easy or hard cues) and type of learning (via feedback or observation). We hypothesized that the hippocampus and striatum would interact in a parallel manner during learning. We identified regions of interest (ROI) in the striatum and hippocampus that showed an effect of cue difficulty during learning and found that such ROIs displayed a similar pattern of blood oxygen level dependent (BOLD) responses, irrespective of learning type, and were functionally correlated as assessed by a Granger causality analysis. Given the connectivity of both structures with dopaminergic midbrain centers, we further applied a reinforcement learning algorithm often used to highlight the role of dopamine in human reward related learning paradigms. Activity in both the striatum and hippocampus positively correlated with a prediction error signal during feedback learning. These results suggest that distinct human memory systems operate in parallel during probabilistic learning, and may act synergistically particularly when a violation of expectation occurs, to jointly contribute to learning and decision making. PMID:21056678
Psychopathology as adaptive development along distinctive pathways.
Fischer, K W; Ayoub, C; Singh, I; Noam, G; Maraganore, A; Raya, P
Contrary to the standard assumption that psychopathology stems from developmental immaturity (retardation, fixation, regression), people diagnosed with psychopathology typically develop along distinctive pathways in which they build complex, advanced skills. These pathways are based on adaptation to trauma, such as maltreatment, or to problems in affective-cognitive regulation, such as those in autism. They do not fit normative developmental frameworks. Research has characterized several types of distinctive pathways, especially those arising from maltreatment; they are marked by normal developmental complexity but distinctive affective-cognitive organization. In one study sexually abused depressed adolescent girls admitted for treatment in a mental hospital described themselves-in-relationships with age-appropriate, complex developmental levels equal to those of both nonabused depressed girls and other adolescents. At the same time, they showed a powerful negativity bias contrasting with the positivity biases of other girls. Many of them produced dramatic switches in affective-cognitive organization across assessments contrasting with the similar organization showed by other girls. In another study toddlers from maltreating families showed a consistent negativity bias in play and representations of interactions. We show how to portray these distinctive developmental pathways through the example of Hidden Family Violence, in which people dissociate their private violent world from their public, good-citizen world. PMID:9449004
Exome Sequencing and Systems Biology Converge to Identify Novel Mutations in the L-Type Calcium Channel, CACNA1C, Linked to Autosomal Dominant Long QT Syndrome
Boczek, Nicole J.; Best, Jabe M.; Tester, David J.; Giudicessi, John R.; Middha, Sumit; Evans, Jared M.; Kamp, Timothy J.; Ackerman, Michael J.
Background Long QT syndrome (LQTS) is the most common cardiac channelopathy with 15 elucidated LQTS-susceptibility genes. Approximately 20% of LQTS cases remain genetically elusive. Methods and Results We combined whole exome sequencing (WES) and bioinformatic/systems biology to identify the pathogenic substrate responsible for non-syndromic, genotype-negative, autosomal dominant LQTS in a multigenerational pedigree and established the spectrum and prevalence of variants in the elucidated gene among a cohort of 102 unrelated patients with ōgenotype-negative/phenotype-positiveö LQTS. WES was utilized on three members within a genotype-negative/phenotype-positive family. Genomic triangulation combined with bioinformatic tools and ranking algorithms led to the identification of a CACNA1C mutation. This mutation, Pro857Arg-CACNA1C, co-segregated with the disease within the pedigree, was ranked by three disease-network algorithms as the most probable LQTS-susceptibility gene, and involves a conserved residue localizing to the PEST domain in the II¢III linker. Functional studies reveal that Pro857Arg-CACNA1C leads to a gain-of-function with increased ICa,L and increased surface membrane expression of the channel compared to wildtype. Subsequent mutational analysis identified 3 additional variants within CACNA1C in our cohort of 102 unrelated cases of genotype-negative/phenotype-positive LQTS. Two of these variants also involve conserved residues within Cav1.2Æs PEST domain. Conclusions This study provides evidence that coupling WES and bioinformatic/systems biology is an effective strategy for the identification of potential disease causing genes/mutations. The identification of a functional CACNA1C mutation co-segregating with disease in a single pedigree suggests that CACNA1C perturbations may underlie autosomal dominant LQTS in the absence of Timothy syndrome. PMID:23677916
Interaction of ┬╣┬▓ŌüĄI-labeled botulinum neurotoxins with nerve terminals. I. Ultrastructural autoradiographic localization and quantitation of distinct membrane acceptors for types A and B on motor nerves
Jennifer D. Black; J. OHver Dolly
The labeling patterns produced by radioiodinated botulinum neurotoxin (┬╣┬▓ŌüĄI-BoNT) types A and B at the vertebrate neuromuscular junction were investigated using electron microscopic autoradiography. The data obtained allow the following conclusions to be made. (a) ┬╣┬▓ŌüĄI-BoNT type A, applied in vivo or in vitro to mouse diaphragm or frog cutaneous pectoris muscle, interacts saturably with the motor nerve terminal only;
An NF-?B-Based High-Throughput Screen Identifies Piericidins as Inhibitors of the Yersinia pseudotuberculosis Type III Secretion System
Duncan, Miles C.; Wong, Weng Ruh; Dupzyk, Allison J.; Bray, Walter M.; Linington, Roger G.
The type III secretion system (T3SS) is a bacterial appendage used by dozens of Gram-negative pathogens to subvert host defenses and cause disease, making it an ideal target for pathogen-specific antimicrobials. Here, we report the discovery and initial characterization of two related natural products with T3SS-inhibitory activity that were derived from a marine actinobacterium. Bacterial extracts containing piericidin A1 and the piericidin derivative Mer-A 2026B inhibited Yersinia pseudotuberculosis from triggering T3SS-dependent activation of the host transcription factor NF-?B in HEK293T cells but were not toxic to mammalian cells. As the Yersinia T3SS must be functional in order to trigger NF-?B activation, these data indicate that piericidin A1 and Mer-A 2026B block T3SS function. Consistent with this, purified piericidin A1 and Mer-A 2026B dose-dependently inhibited translocation of the Y. pseudotuberculosis T3SS effector protein YopM inside CHO cells. In contrast, neither compound perturbed bacterial growth in vitro, indicating that piericidin A1 and Mer-A 2026B do not function as general antibiotics in Yersinia. In addition, when Yersinia was incubated under T3SS-inducing culture conditions in the absence of host cells, Mer-A 2026B and piericidin A1 inhibited secretion of T3SS cargo as effectively as or better than several previously described T3SS inhibitors, such as MBX-1641 and aurodox. This suggests that Mer-A 2026B and piericidin A1 do not block type III secretion by blocking the bacterium-host cell interaction, but rather inhibit an earlier stage, such as T3SS needle assembly. In summary, the marine-derived natural products Mer-A 2026B and piericidin A1 possess previously uncharacterized activity against the bacterial T3SS. PMID:24295981
Pathogenic and Antigenic Properties of Phylogenetically Distinct Reassortant H3N2 Swine Influenza Viruses Cocirculating in the United States
Jurgen A. Richt; Kelly M. Lager; Bruce H. Janke; Roger D. Woods; Robert G. Webster; Richard J. Webby
Swine influenza is an acute respiratory disease caused by type A influenza viruses. Before 1998, swine influenza virus isolates in the United States were mainly of the classical H1N1 lineage. Since then, phyloge- netically distinct reassortant H3N2 viruses have been identified as respiratory pathogens in pigs on U.S. farms. The H3N2 viruses presently circulating in the U.S. swine population are
Exome analysis identified a novel missense mutation in the CLPP gene in a consanguineous Saudi family expanding the clinical spectrum of Perrault Syndrome type-3.
Ahmed, Saleem; Jelani, Musharraf; Alrayes, Nuha; Mohamoud, Hussein Sheikh Ali; Almramhi, Mona Mohammad; Anshasi, Wasim; Ahmed, Naushad Ali Basheer; Wang, Jun; Nasir, Jamal; Al-Aama, Jumana Yousuf
Perrault syndrome (PRLTS) is a clinically and genetically heterogeneous disorder. Both male and female patients suffer from sensory neuronal hearing loss in early childhood, and female patients are characterized by premature ovarian failure and infertility after puberty. Clinical diagnosis may not be possible in early life, because key features of PRLTS, for example infertility and premature ovarian failure, do not appear before puberty. Limb spasticity, muscle weakness, and intellectual disability have also been observed in PRLTS patients. Mutations in five genes, HSD17B4, HARS2, CLPP, LARS2, and C10orf2, have been reported in five subtypes of PRLTS. We discovered a consanguineous Saudi family with the PRLTS3 phenotype showing an autosomal recessive mode of inheritance. The patients had developed profound hearing loss, brain atrophy, and lower limb spasticity in early childhood. For molecular diagnosis, we complimented genome-wide homozygosity mapping with whole exome sequencing analyses and identified a novel homozygous mutation in exon 6 of CLPP at chromosome 19p13.3. To our knowledge, early onset with regression is a unique feature of these PRLTS patients that has not been reported so far. This study broadens the clinical spectrum of PRLTS3. PMID:25956234
Genetic analysis of recently identified type 2 diabetes loci in 1,638 unselected patients with type 2 diabetes and 1,858 control participants from a Norwegian population-based cohort (the HUNT study)
J. K. Hertel; S. Johansson; H. Rµder; K. Midthjell; V. Lyssenko; L. Groop; A. Molven; P. R. Nj°lstad
Aims\\/hypothesisĀĀRecent genome-wide association studies performed in selected patients and control participants have provided strong support\\u000a for several new type 2 diabetes susceptibility loci. To get a better estimation of the true risk conferred by these novel\\u000a loci, we tested a completely unselected population of type 2 diabetes patients from a Norwegian health survey (the HUNT study).\\u000a \\u000a \\u000a \\u000a MethodsĀĀWe genotyped single nucleotide
Interdisciplinary orthodontic treatment for a patient with generalized aggressive periodontitis: Assessment of IgG antibodies to identify type of periodontitis and correct timing of treatment.
Ishihara, Yoshihito; Tomikawa, Kazuya; Deguchi, Toru; Honjo, Tadashi; Suzuki, Koji; Kono, Takayuki; Kuboki, Takuo; Kamioka, Hiroshi; Takashiba, Shogo; Yamashiro, Takashi
Aggressive periodontitis is a great challenge to clinicians when providing orthodontic treatment because of the potential for progression of periodontal disease. In this article, we report the successful comprehensive orthodontic treatment of bimaxillary protrusion and severe crowding in an adult with generalized aggressive periodontitis. A woman, aged 22Āyears 7Āmonths, with a chief complaint of incisal crowding was diagnosed with a skeletal Class I malocclusion associated with severe anterior crowding, possibly worsened by generalized aggressive periodontitis. In addition to a periodontal examination, a blood IgG antibody titer analysis and microbiologic examination for periodontal pathogens were used to diagnose the type of periodontal disease and determine the proper timing to initiate orthodontic treatment. The total active treatment period was 28Āmonths, followed by periodontal prostheses and regeneration therapy. Consequently, satisfactory facial profile, occlusion, and periodontal health were maintained for at least 36Āmonths. These results indicate that efficient screening is important for providing successful orthodontic treatment in patients with advanced periodontal disease. This report also demonstrates the diagnostic importance of blood IgG antibody titer assays and microbiologic examinations to detect periodontal pathogens. PMID:26038081
Identifying challenges in humanitarian logistics
Gy÷ngyi Kovßcs; Karen Spens
Purpose ¢ The purpose of this paper is to identify the challenges of humanitarian logisticians with respect to different types of disasters, phases of disaster relief and the type of humanitarian organization. A conceptual model is constructed that serves as a basis to identify these challenges. Design\\/methodology\\/approach ¢ The paper is based on a country as a case, namely Ghana.
Are Specific Language Impairment and Dyslexia Distinct Disorders?
ERIC Educational Resources Information Center
Catts, Hugh W.; Adlof, Suzanne M.; Hogan, Tiffany P.; Weismer, Susan Ellis
Purpose: The purpose of this study was to determine whether specific language impairment (SLI) and dyslexia are distinct developmental disorders. Method: Study 1 investigated the overlap between SLI identified in kindergarten and dyslexia identified in 2nd, 4th, or 8th grades in a representative sample of 527 children. Study 2 examinedģ
Circulating MiRNAs of æAsian Indian PhenotypeÆ Identified in Subjects with Impaired Glucose Tolerance and Patients with Type 2 Diabetes
Prabu, Paramasivam; Rome, Sophie; Sathishkumar, Chandrakumar; Aravind, Sankaramoorthy; Mahalingam, Balakumar; Shanthirani, Coimbatore Subramanian; Gastebois, Caroline; Villard, Audrey; Mohan, Viswanathan; Balasubramanyam, Muthuswamy
Several omics technologies are underway worldwide with an aim to unravel the pathophysiology of a complex phenotype such as type 2 diabetes mellitus (T2DM). While recent studies imply a clinically relevant and potential biomarker role of circulatory miRNAs in the etiology of T2DM, there is lack of data on this aspect in IndiansŚan ethnic population characterized to represent æAsian Indian phenotypeÆ known to be more prone to develop T2DM and cardiovascular disease than Europeans. We performed global serum miRNA profiling and the validation of candidate miRNAs by qRT-PCR in a cohort of subjects comprised of normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and patients with T2DM. Our study revealed 4 differentially expressed miRNAs (miR-128, miR-130b-3p, miR-374a-5p, miR-423-5p) in subjects with IGT and T2DM patients compared to control subjects. They were positively or negatively correlated to cholesterol levels, HbA1C, HOMA-IR and fasting insulin. Interestingly, circulating level of miR-128 and miR-130b-3p were also altered in serum of diet-induced diabetic mice compared to control animals. Among the altered circulating miRNAs, miR-128 had never been described in previous studies/populations and appeared to be a æNew LeadÆ in Indians. It was positively correlated with cholesterol both in prediabetic subjects and in diet-induced diabetic mice, suggesting that its increased level might be associated with the development of dyslipedemia associated with T2DM. Our findings imply directionality towards biomarker potential of miRNAs in the prevention/diagnosis/treatment outcomes of diabetes. PMID:26020947
HTS-Compatible Patient-Derived Cell-Based Assay to Identify Small Molecule Modulators of Aberrant Splicing in Myotonic Dystrophy Type 1
OÆLeary, Debra A.; Vargas, Leonardo; Sharif, Orzala; Garcia, Michael E.; Sigal, Yury J.; Chow, Siu-Kei; Schmedt, Christian; Caldwell, Jeremy S.; Brinker, Achim; Engels, Ingo H.
Myotonic dystrophy type 1 (DM1) is a genetic disorder characterized by muscle wasting, myotonia, cataracts, cardiac arrhythmia, hyperinsulinism and intellectual deficits, and is caused by expansion of a CTG repeat in the 3ÆUTR of the Dystrophia Myotonica-Protein Kinase (DMPK) gene. The DMPK transcripts containing expanded CUG repeats accumulate in nuclear foci and ultimately cause mis-splicing of secondary genes through the dysregulation of RNA-binding proteins including Muscleblind 1 (MBNL1) and CUG binding protein 1 (CUGBP1). Correction of mis-splicing of genes such as the Skeletal muscle-specific chloride channel 1 (CLCN1), Cardiac troponin T (TNNT2), Insulin receptor (INSR) and Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 1 (SERCA1) may alleviate some of the symptoms of DM1; hence identification of small molecule modulators is an important step towards a therapy for DM1 patients. Here we describe the generation of immortalized myoblast cell lines derived from healthy (DMPK CTG5) and DM1 patient (DMPK CTG1000) fibroblasts by constitutive overexpression of human telomerase reverse transcriptase (hTERT) and inducible overexpression of the Myoblast determination factor (MYOD). MBNL1-containing nuclear foci, mis-splicing events and defective myotube differentiation defects characteristic of DM1 were observed in these cells. A CLCN1 luciferase minigene construct (CLCN1-luc) was stably introduced to monitor intron 2 retention in the DM1 cellular context (a reported splicing defect in DM1). The assay was validated by performing a high-throughput screen (HTS) of ~13,000 low molecular weight compounds against the CLCN1-luc DM1 myoblast cell line, providing an ideal system for conducting HTS to better understand and treat DM1. PMID:20502647
Interaction of /sup 125/I-labeled botulinum neurotoxins with nerve terminals. I. Ultrastructural autoradiographic localization and quantitation of distinct membrane acceptors for types A and B on motor nerves
Black, J.D.; Dolly, J.O.
The labeling patterns produced by radioiodinated botulinum neurotoxin (/sup 125/I-BoNT) types A and B at the vertebrate neuromuscular junction were investigated using electron microscopic autoradiography. The data obtained allow the following conclusions to be made. (a) /sup 125/I-BoNT type A, applied in vivo or in vitro to mouse diaphragm or frog cutaneous pectoris muscle, interacts saturably with the motor nerve terminal only; silver grains occur on the plasma membrane, within the synaptic bouton, and in the axoplasm of the nerve trunk, suggesting internalization and retrograde intra-axonal transport of toxin or fragments thereof. (b) /sup 125/I-BoNT type B, applied in vitro to the murine neuromuscular junction, interacts likewise with the motor nerve terminal except that a lower proportion of internalized radioactivity is seen. This result is reconcilable with the similar, but not identical, pharmacological action of these toxin types. (c) The saturability of labeling in each case suggested the involvement of acceptors; on preventing the internalization step with metabolic inhibitors, their precise location became apparent. They were found on all unmyelinated areas of the nerve terminal membrane, including the preterminal axon and the synaptic bouton. (d) It is not proposed that these membrane acceptors target BoNT to the nerve terminal and mediate its delivery to an intracellular site, thus contributing to the toxin's selective inhibitory action on neurotransmitter release.
Brittle cornea syndrome: An heritable connective tissue disorder distinct from Ehlers-Danlos syndrome type VI and fragilitas oculi, with spontaneous perforations of the eye, blue sclerae, red hair, and normal collagen lysyl hydroxylation
P. M. Royce; B. Steinmann; A. Vogel; U. Steinhorst; A. Kohlschuetter
We report a patient with the characteristic features of the brittle cornea syndrome, a rare, autosomal recessively inherited disorder, namely brittle corneae, blue sclerae, and red hair. The patient also showed joint hyperextensibility, a soft skin, and dysplastic auricles with unusually soft cartilage. Phenotypically, the disorder bears a certain resemblance to fragilitas oculi and the type VI (ocular) form of
Islet Autoimmunity Identifies a Unique Pattern of Impaired Pancreatic Beta-Cell Function, Markedly Reduced Pancreatic Beta Cell Mass and Insulin Resistance in Clinically Diagnosed Type 2 Diabetes
Subauste, Angela; Gianani, Roberto; Chang, Annette M.; Plunkett, Cynthia; Pietropaolo, Susan L.; Zhang, Ying-Jian; Barinas-Mitchell, Emma; Kuller, Lewis H.; Galecki, Andrzej; Halter, Jeffrey B.; Pietropaolo, Massimo
There is a paucity of literature describing metabolic and histological data in adult-onset autoimmune diabetes. This subgroup of diabetes mellitus affects at least 5% of clinically diagnosed type 2 diabetic patients (T2DM) and it is termed Latent Autoimmune Diabetes in Adults (LADA). We evaluated indexes of insulin secretion, metabolic assessment, and pancreatic pathology in clinically diagnosed T2DM patients with and without the presence of humoral islet autoimmunity (Ab). A total of 18 patients with at least 5-year duration of clinically diagnosed T2DM were evaluated in this study. In those subjects we assessed acute insulin responses to arginine, a glucose clamp study, whole-body fat mass and fat-free mass. We have also analyzed the pancreatic pathology of 15 T2DM and 43 control cadaveric donors, using pancreatic tissue obtained from all the T2DM organ donors available from the nPOD network through December 31, 2013. The presence of islet Ab correlated with severely impaired ?-cell function as demonstrated by remarkably low acute insulin response to arginine (AIR) when compared to that of the Ab negative group. Glucose clamp studies indicated that both Ab positive and Ab negative patients exhibited peripheral insulin resistance in a similar fashion. Pathology data from T2DM donors with Ab or the autoimmune diabetes associated DR3/DR4 allelic class II combination showed reduction in beta cell mass as well as presence of autoimmune-associated pattern A pathology in subjects with either islet autoantibodies or the DR3/DR4 genotype. In conclusion, we provide compelling evidence indicating that islet Ab positive long-term T2DM patients exhibit profound impairment of insulin secretion as well as reduced beta cell mass seemingly determined by an immune-mediated injury of pancreatic ?-cells. Deciphering the mechanisms underlying beta cell destruction in this subset of diabetic patients may lead to the development of novel immunologic therapies aimed at halting the disease progression in its early stage. PMID:25226365
Distinct Ontogeny of Glucocorticoid and Mineralocorticoid Receptor and 11b-Hydroxysteroid Dehydrogenase Types I and II mRNAs in the Fetal Rat Brain Suggest a Complex Control of Glucocorticoid Actions
Rochellys Diaz; Roger W. Brown; Jonathan R. Seckl
Glucocorticoids (GCs) act via intracellular mineralocorticoid (MR) and glucocorticoid receptors (GR). However, it has re- cently been recognized that GC access to receptors is deter- mined by the presence of tissue-specific 11b-hydroxysteroid dehydrogenases (11b-HSDs) that catalyze the interconversion of active corticosterone and inert 11-dehydrocorticosterone. 11b-HSD type 1 (11b-HSD1) is a bidirectional enzyme in vitro that acts predominantly as a reductase
Evidence for distinct effects of exercise in different cardiac hypertrophic disorders.
Johnson, Emily J; Dieter, Brad P; Marsh, Susan A
Aerobic exercise training (AET) attenuates or reverses pathological cardiac remodeling after insults such as chronic hypertension and myocardial infarction. The phenotype of the pathologically hypertrophied heart depends on the insult; therefore, it is likely that distinct types of pathological hypertrophy require different exercise regimens. However, the mechanisms by which AET improves the structure and function of the pathologically hypertrophied heart are not well understood, and exercise research uses highly inconsistent exercise regimens in diverse patient populations. There is a clear need for systematic research to identify precise exercise prescriptions for different conditions of pathological hypertrophy. Therefore, this review synthesizes existing evidence for the distinct mechanisms by which AET benefits the heart in different pathological hypertrophy conditions, suggests strategic exercise prescriptions for these conditions, and highlights areas for future research. PMID:25632833
The operant-respondent distinction: Future directions
Pear, Joseph J.; Eldridge, Gloria D.
The operant-respondent distinction has provided a major organizing framework for the data generated through the experimental analysis of behavior. Problems have been encountered, however, in using it as an explanatory concept for such phenomena as avoidance and conditioned suppression. Data now exist that do not fit neatly into the framework. Moreover, the discovery of autoshaping has highlighted difficulties in isolating the two types of behavior and conditioning. Despite these problems, the operant-respondent framework remains the most successful paradigm currently available for organizing behavioral data. Research and theoretical efforts should therefore probably be directed to modifying the framework to account for disparate data. PMID:16812402
Human germline and pan-cancer variomes and their distinct functional profiles
Pan, Yang; Karagiannis, Konstantinos; Zhang, Haichen; Dingerdissen, Hayley; Shamsaddini, Amirhossein; Wan, Quan; Simonyan, Vahan; Mazumder, Raja
Identification of non-synonymous single nucleotide variations (nsSNVs) has exponentially increased due to advances in Next-Generation Sequencing technologies. The functional impacts of these variations have been difficult to ascertain because the corresponding knowledge about sequence functional sites is quite fragmented. It is clear that mapping of variations to sequence functional features can help us better understand the pathophysiological role of variations. In this study, we investigated the effect of nsSNVs on more than 17 common types of post-translational modification (PTM) sites, active sites and binding sites. Out of 1 705 285 distinct nsSNVs on 259 216 functional sites we identified 38 549 variations that significantly affect 10 major functional sites. Furthermore, we found distinct patterns of site disruptions due to germline and somatic nsSNVs. Pan-cancer analysis across 12 different cancer types led to the identification of 51 genes with 106 nsSNV affected functional sites found in 3 or more cancer types. 13 of the 51 genes overlap with previously identified Significantly Mutated Genes (Nature. 2013 Oct 17;502(7471)). 62 mutations in these 13 genes affecting functional sites such as DNA, ATP binding and various PTM sites occur across several cancers and can be prioritized for additional validation and investigations. PMID:25232094
Vaccine-Induced Linear Epitope-Specific Antibodies to Simian Immunodeficiency Virus SIVmac239 Envelope Are Distinct from Those Induced to the Human Immunodeficiency Virus Type 1 Envelope in Nonhuman Primates.
Shen, Xiaoying; Duffy, Ryan; Howington, Robert; Cope, Alethea; Sadagopal, Shanmugalakshmi; Park, Haesun; Pal, Ranajit; Kwa, Suefen; Ding, Song; Yang, Otto O; Fouda, Genevieve G; Le Grand, Roger; Bolton, Diane; Esteban, Mariano; Phogat, Sanjay; Roederer, Mario; Amara, Rama R; Picker, Louis J; Seder, Robert A; McElrath, M Juliana; Barnett, Susan; Permar, Sallie R; Shattock, Robin; DeVico, Anthony L; Felber, Barbara K; Pavlakis, George N; Pantaleo, Giuseppe; Korber, Bette T; Montefiori, David C; Tomaras, Georgia D
To evaluate antibody specificities induced by simian immunodeficiency virus (SIV) versus human immunodeficiency virus type 1 (HIV-1) envelope antigens in nonhuman primate (NHP), we profiled binding antibody responses to linear epitopes in NHP studies with HIV-1 or SIV immunogens. We found that, overall, HIV-1 Env IgG responses were dominated by V3, with the notable exception of the responses to the vaccine strain A244 Env that were dominated by V2, whereas the anti-SIVmac239 Env responses were dominated by V2 regardless of the vaccine regimen. PMID:26018159
Morphological Differences between Larvae of the Ciona intestinalis Species Complex: Hints for a Valid Taxonomic Definition of Distinct Species
Pennati, Roberta; Ficetola, Gentile Francesco; Brunetti, Riccardo; Caicci, Federico; Gasparini, Fabio; Griggio, Francesca; Sato, Atsuko; Stach, Thomas; Kaul-Strehlow, Sabrina; Gissi, Carmela; Manni, Lucia
The cosmopolitan ascidian Ciona intestinalis is the most common model species of Tunicata, the sister-group of Vertebrata, and widely used in developmental biology, genomics and evolutionary studies. Recently, molecular studies suggested the presence of cryptic species hidden within the C. intestinalis species, namely C. intestinalis type A and type B. So far, no substantial morphological differences have been identified between individuals belonging to the two types. Here we present morphometric, immunohistochemical, and histological analyses, as well as 3-D reconstructions, of late larvae obtained by cross-fertilization experiments of molecularly determined type A and type B adults, sampled in different seasons and in four different localities. Our data point to quantitative and qualitative differences in the trunk shape of larvae belonging to the two types. In particular, type B larvae exhibit a longer pre-oral lobe, longer and relatively narrower total body length, and a shorter ocellus-tail distance than type A larvae. All these differences were found to be statistically significant in a Discriminant Analysis. Depending on the number of analyzed parameters, the obtained discriminant function was able to correctly classify > 93% of the larvae, with the remaining misclassified larvae attributable to the existence of intra-type seasonal variability. No larval differences were observed at the level of histology and immunohistochemical localization of peripheral sensory neurons. We conclude that type A and type B are two distinct species that can be distinguished on the basis of larval morphology and molecular data. Since the identified larval differences appear to be valid diagnostic characters, we suggest to raise both types to the rank of species and to assign them distinct names. PMID:25955391
SPTAN1 encephalopathy: distinct phenotypes and genotypes.
Tohyama, Jun; Nakashima, Mitsuko; Nabatame, Shin; Gaik-Siew, Ch'ng; Miyata, Rie; Rener-Primec, Zvonka; Kato, Mitsuhiro; Matsumoto, Naomichi; Saitsu, Hirotomo
Recent progress in genetic analysis reveals that a significant proportion of cryptogenic epileptic encephalopathies are single-gene disorders. Mutations in numerous genes for early-onset epileptic encephalopathies have been rapidly identified, including in SPTAN1, which encodes ?-II spectrin. The aim of this review is to delineate SPTAN1 encephalopathy as a distinct clinical syndrome. To date, a total of seven epileptic patients with four different in-frame SPTAN1 mutations have been identified. The major clinical features of SPTAN1 mutations include epileptic encephalopathy with hypsarrhythmia, no visual attention, acquired microcephaly, spastic quadriplegia and severe intellectual disability. Brainstem and cerebellar atrophy and cerebral hypomyelination, as observed by magnetic resonance imaging, are specific hallmarks of this condition. A milder variant is characterized by generalized epilepsy with pontocerebellar atrophy. Only in-frame SPTAN1 mutations in the last two spectrin repeats in the C-terminal region lead to dominant negative effects and these specific phenotypes. The last two spectrin repeats are required for ?/? spectrin heterodimer associations and the mutations can alter heterodimer formation between the two spectrins. From these data we suggest that SPTAN1 encephalopathy is a distinct clinical syndrome owing to specific SPTAN1 mutations. It is important that this syndrome is recognized by pediatric neurologists to enable proper diagnostic work-up for patients. PMID:25631096
Common variable immunodeficiency disorders: division into distinct clinical phenotypes
Helen Chapel; Mary Lucas; Martin Lee; Janne Bjorkander; David Webster; Bodo Grimbacher; Claire Fieschi; Vojtech Thon; Mohammad R. Abedi; Lennart Hammarstrom
The European Common Variable Immuno- deficiency Disorders registry was started in 1996 to define distinct clinical pheno- types and determine overlap within indi- vidualpatients.Atotalof7centerscontrib- uted patient data, resulting in the largest cohort yet reported. Patients (334), vali- dated for the diagnosis, were followed for an average of 25.6 years (9461 patient- years). Data were used to define 5 distinct clinical
Shining Light on the Differences in Molecular Structural Chemical Makeup and the Cause of Distinct Degradation Behavior Between Malting- and Feed- Type Barley Using Synchrotorn FTIR Microspectroscopy: A Novel Approach
Yu,P.; Doiron, K.; Liu, D.
The objective of this study was to use advanced synchrotron-sourced FTIR microspectroscopy (SFTIRM) as a novel approach to identify the differences in protein and carbohydrate molecular structure (chemical makeup) between these two varieties of barley and illustrate the exact causes for their significantly different degradation kinetics. Items assessed included (1) molecular structural differences in protein amide I to amide II intensities and their ratio within cellular dimensions, (2) molecular structural differences in protein secondary structure profile and their ratios, and (3) molecular structural differences in carbohydrate component peak profile. Our hypothesis was that molecular structure (chemical makeup) affects barley quality, fermentation, and degradation behavior in both humans and animals. Using SFTIRM, the protein and carbohydrate molecular structural chemical makeup of barley was revealed and identified. The protein molecular structural chemical makeup differed significantly between the two varieties of barleys. No difference in carbohydrate molecular structural chemical makeup was detected. Harrington was lower than Valier in protein amide I, amide II, and protein amide I to amide II ratio, while Harrington was relatively higher in model-fitted protein a-helix and {beta}-sheet, but lower in the others ({beta}-turn and random coil). These results indicated that it is the molecular structure of protein (chemical makeup) that may play a major role in the different degradation kinetics between the two varieties of barleys (not the molecular structure of carbohydrate). It is believed that use of the advanced synchrotron technology will make a significant step and an important contribution to research in examining the molecular structure (chemical makeup) of plant, feed, and seeds.
Educational Psychology: The Distinctive Contribution
ERIC Educational Resources Information Center
Cameron, R. J.
This paper, written in the twenty-first anniversary year of the journal "Educational Psychology in Practice", attempts to uncover those distinctive aspects of the discipline and the practice of applied psychology in general and educational psychology in particular. After considering some of the reasons for attempting this task at this point inģ
Distinct Genetic Influences on Cortical
Matthew S. Panizzon; Christine Fennema-Notestine; Lisa T. Eyler; Terry L. Jernigan; Elizabeth Prom-Wormley; Michael Neale; Kristen Jacobson; Michael J. Lyons; Michael D. Grant; Carol E. Franz; Hong Xian; Ming Tsuang; Larry Seidman; Anders Dale
Neuroimaging studies examining the effects of aging and neuropsychiatric disorders on the cerebral cortex have largely been based on measures of cortical volume. Given that cortical volume is a product of thickness and surface area, it is plausible that measures of volume capture at least 2 distinct sets of genetic influences. The present study aims to examine the genetic relationships
Anticancer Properties of Distinct Antimalarial Drug Classes
Hooft van Huijsduijnen, Rob; Guy, R. Kiplin; Chibale, Kelly; Haynes, Richard K.; Peitz, Ingmar; Kelter, Gerhard; Phillips, Margaret A.; Vennerstrom, Jonathan L.; Yuthavong, Yongyuth; Wells, Timothy N. C.
We have tested five distinct classes of established and experimental antimalarial drugs for their anticancer potential, using a panel of 91 human cancer lines. Three classes of drugs: artemisinins, synthetic peroxides and DHFR (dihydrofolate reductase) inhibitors effected potent inhibition of proliferation with IC50s in the nM- low ĄM range, whereas a DHODH (dihydroorotate dehydrogenase) and a putative kinase inhibitor displayed no activity. Furthermore, significant synergies were identified with erlotinib, imatinib, cisplatin, dasatinib and vincristine. Cluster analysis of the antimalarials based on their differential inhibition of the various cancer lines clearly segregated the synthetic peroxides OZ277 and OZ439 from the artemisinin cluster that included artesunate, dihydroartemisinin and artemisone, and from the DHFR inhibitors pyrimethamine and P218 (a parasite DHFR inhibitor), emphasizing their shared mode of action. In order to further understand the basis of the selectivity of these compounds against different cancers, microarray-based gene expression data for 85 of the used cell lines were generated. For each compound, distinct sets of genes were identified whose expression significantly correlated with compound sensitivity. Several of the antimalarials tested in this study have well-established and excellent safety profiles with a plasma exposure, when conservatively used in malaria, that is well above the IC50s that we identified in this study. Given their unique mode of action and potential for unique synergies with established anticancer drugs, our results provide a strong basis to further explore the potential application of these compounds in cancer in pre-clinical or and clinical settings. PMID:24391728
A distinct dinosaur life history?
David J. Varricchio
Five factors, mobile terrestrial lifestyle, oviparity, parental care, multi-year maturation and juvenile sociality, contribute to a distinct life history for Mesozoic dinosaurs in comparison to extant archosaurs and mammals. Upright, para-sagittal gait reflects several synapomorphies of Dinosauria, and wide histological sampling suggests that multi-year maturation typified dinosaurs across a range of body sizes. Fossil support for juvenile sociality exceeds that
Observing, Describing, and Identifying Clouds
NSDL National Science Digital Library
The GLOBE Program, UCAR (University Corporation for Atmospheric Research)
In this activity students observe and sketch clouds, describing their forms. They initially generate descriptions of a personal nature and then move toward building a more scientific vocabulary. They then correlate their descriptions with the standard classifications using the ten cloud types identified for GLOBE. Each student develops a personal cloud booklet to be used in conjunction with the GLOBE Cloud Chart. . The intended outcome is that students will be able to identify cloud types using standard cloud classification names.
Distinctly Innovative www.hw.ac.uk
Greenaway, Alan
Distinctly Innovative www.hw.ac.uk Distinctly Ambitious www.hw.ac.uk Distinctly Innovative www.hw-Watt University 2Roslin Cellab, Scotland SUPA INSPIRE AGM 2012 1 #12;Distinctly Innovative www.hw.ac.uk2 Innovative www.hw.ac.uk3 Valve-based Cell Printing USB microscope Dispensing systems 3-axis CNC machine From
Alternative applications for distinct RNA sequencing strategies.
Han, Leng; Vickers, Kasey C; Samuels, David C; Guo, Yan
Recent advances in RNA library preparation methods, platform accessibility and cost efficiency have allowed high-throughput RNA sequencing (RNAseq) to replace conventional hybridization microarray platforms as the method of choice for mRNA profiling and transcriptome analyses. RNAseq is a powerful technique to profile both long and short RNA expression, and the depth of information gained from distinct RNAseq methods is striking and facilitates discovery. In addition to expression analysis, distinct RNAseq approaches also allow investigators the ability to assess transcriptional elongation, DNA variance and exogenous RNA content. Here we review the current state of the art in transcriptome sequencing and address epigenetic regulation, quantification of transcription activation, RNAseq output and a diverse set of applications for RNAseq data. We detail how RNAseq can be used to identify allele-specific expression, single-nucleotide polymorphisms and somatic mutations and discuss the benefits and limitations of using RNAseq to monitor DNA characteristics. Moreover, we highlight the power of combining RNA- and DNAseq methods for genomic analysis. In summary, RNAseq provides the opportunity to gain greater insight into transcriptional regulation and output than simply miRNA and mRNA profiling. PMID:25246237
Distinctive Feature Scoring of the California Consonant Test.
ERIC Educational Resources Information Center
Feeney, M. Patrick
The study evaluated a distinctive feature scoring technique for List 1 of the California Consonant Test for the purpose of improving test reliability in this test used to identify errors in speech recognition made by adult listeners (N=50) with high frequency sensorineural hearing loss. (DB)
Gender Distinction Using Short Segments of Speech Signal
Milan Sigmund
Summary This paper presents and discusses an approach to automatic gender distinction in a short segment of normally spoken continuous speech. In order to see which phonemes are effective for gender recognition, we analyzed individual vowels. Two different simple identifiers based on selected mel-frequency cepstral coefficients were evaluated. Using vowel phonemes, we achieved in short-time analysis (20 msec) a gender
Multiple hydroxyphenethyl glucosinolate isomers and their tandem mass spectrometric distinction in a geographically structured polymorphism in the crucifer Barbarea vulgaris.
Agerbirk, Niels; Olsen, Carl Erik; Heimes, Christine; Christensen, Stina; Bak, S°ren; Hauser, Thure P
Two distinct glucosinolate (GSL) chemotypes (P and G-types) of Barbarea vulgaris (Brassicaceae) were known from southern Scandinavia, but whether the types were consistent in a wider geographic area was not known. Populations (26) from Eastern and Central Europe were analyzed for GSLs in order to investigate whether the two types were consistent in this area. Most (21) could be attributed to one of the previously described GSL profile types, the P-type (13 populations) and the G-type (8 populations), based on differences in the stereochemistry of 2-hydroxylation, presence or absence of phenolic glucobarbarin derivatives, and qualitative differences in indole GSL decoration (tested for a subset of 8+6 populations only). The distinction agreed with previous molecular genetic analysis of the same individuals. Geographically, the P-type typically occurred in Eastern Europe while the G-type mainly occurred in Central Europe. Of the remaining five populations, minor deviations were observed in some individuals from two populations genetically assigned to the G-type, and a hybrid population from Finland contained an additional dihydroxyphenethyl GSL isomer attributed to a combinatorial effect of P-type and G-type genes. Major exceptions to the typical GSL profiles were observed in two populations: (1) A G-type population from Slovenia deviated by a high frequency of a known variant in glucobarbarin biosynthesis ('NAS form') co-occurring with usual G-type individuals. (2) A population from Caucasus exhibited a highly deviating GSL profile dominated by p-hydroxyphenethyl GSL that was insignificant in other accessions, as well as two GSLs investigated by NMR, m-hydroxyphenethylGSL and a partially identified m,p disubstituted hydroxy-methoxy derivative of phenethylGSL. Tandem HPLC-MS of seven NMR-identified desulfoGSLs was carried out and interpreted for increased certainty in peak identification and as a tool for partial structure elucidation. The distinct, geographically separated chemotypes and rare variants are discussed in relation to future taxonomic revision and the genetics and ecology of GSLs in B. vulgaris. PMID:25277803
Identifying Microlensing by Binaries
Rosanne Di Stefano; Rosalba Perna
The microlensing monitoring programs have studied large numbers of standard light curves which seem to be due to lensing by a dark point mass. Theory predicts that many microlensing events should display significant deviations from the standard form. Lens binarity in particular is expected to be common. So far, however, only a handful of light curves exhibit evidence that the lens is a binary; all of these display dramatic deviations from the standard light curve, exhibiting pronounced multiple peaks and/or caustic crossings. Binary-lens events in which the light curve is less dramatically perturbed should also exist in the data set. Why, then, have we not detected them? The answer may lie in the fact that the perturbations, though often significant, tend to be less distinctive than those associated with caustic crossings. We present a method to determine whether a light curve is due to lensing by a binary. The method works for both gently and dramatically perturbed binary-lens light curves. Our method identifies all degenerate solutions-- i.e., all possible lensing events that might have given rise to the observed light curve. It also enables us to eliminate from consideration large ranges of possible false positive identifications associated with light curves that might mimic microlensing by a binary. This method, or a generalization of it, can also be applied to the analysis of light curves that deviate from the standard point-mass lens form because of astronomical effects other than lens binarity.
Independent optical excitation of distinct neural populations.
Klapoetke, Nathan C; Murata, Yasunobu; Kim, Sung Soo; Pulver, Stefan R; Birdsey-Benson, Amanda; Cho, Yong Ku; Morimoto, Tania K; Chuong, Amy S; Carpenter, Eric J; Tian, Zhijian; Wang, Jun; Xie, Yinlong; Yan, Zhixiang; Zhang, Yong; Chow, Brian Y; Surek, Barbara; Melkonian, Michael; Jayaraman, Vivek; Constantine-Paton, Martha; Wong, Gane Ka-Shu; Boyden, Edward S
Optogenetic tools enable examination of how specific cell types contribute to brain circuit functions. A long-standing question is whether it is possible to independently activate two distinct neural populations in mammalian brain tissue. Such a capability would enable the study of how different synapses or pathways interact to encode information in the brain. Here we describe two channelrhodopsins, Chronos and Chrimson, discovered through sequencing and physiological characterization of opsins from over 100 species of alga. Chrimson's excitation spectrum is red shifted by 45 nm relative to previous channelrhodopsins and can enable experiments in which red light is preferred. We show minimal visual system-mediated behavioral interference when using Chrimson in neurobehavioral studies in Drosophila melanogaster. Chronos has faster kinetics than previous channelrhodopsins yet is effectively more light sensitive. Together these two reagents enable two-color activation of neural spiking and downstream synaptic transmission in independent neural populations without detectable cross-talk in mouse brain slice. PMID:24509633
Distinct cell shapes determine accurate chemotaxis
Tweedy, Luke; Meier, B÷rn; Stephan, J³rgen; Heinrich, Doris; Endres, Robert G.
The behaviour of an organism often reflects a strategy for coping with its environment. Such behaviour in higher organisms can often be reduced to a few stereotyped modes of movement due to physiological limitations, but finding such modes in amoeboid cells is more difficult as they lack these constraints. Here, we examine cell shape and movement in starved Dictyostelium amoebae during migration toward a chemoattractant in a microfluidic chamber. We show that the incredible variety in amoeboid shape across a population can be reduced to a few modes of variation. Interestingly, cells use distinct modes depending on the applied chemical gradient, with specific cell shapes associated with shallow, difficult-to-sense gradients. Modelling and drug treatment reveals that these behaviours are intrinsically linked with accurate sensing at the physical limit. Since similar behaviours are observed in a diverse range of cell types, we propose that cell shape and behaviour are conserved traits. PMID:24008441
Independent Optical Excitation of Distinct Neural Populations
Klapoetke, Nathan C; Murata, Yasunobu; Kim, Sung Soo; Pulver, Stefan R.; Birdsey-Benson, Amanda; Cho, Yong Ku; Morimoto, Tania K; Chuong, Amy S; Carpenter, Eric J; Tian, Zhijian; Wang, Jun; Xie, Yinlong; Yan, Zhixiang; Zhang, Yong; Chow, Brian Y; Surek, Barbara; Melkonian, Michael; Jayaraman, Vivek; Constantine-Paton, Martha; Wong, Gane Ka-Shu; Boyden, Edward S
Optogenetic tools enable the causal examination of how specific cell types contribute to brain circuit functions. A long-standing question is whether it is possible to independently activate two distinct neural populations in mammalian brain tissue. Such a capability would enable the examination of how different synapses or pathways interact to support computation. Here we report two new channelrhodopsins, Chronos and Chrimson, obtained through the de novo sequencing and physiological characterization of opsins from over 100 species of algae. Chrimson is 45 nm red-shifted relative to any previous channelrhodopsin, important for scenarios where red light would be preferred; we show minimal visual system mediated behavioral artifact in optogenetically stimulated Drosophila. Chronos has faster kinetics than any previous channelrhodopsin, yet is effectively more light-sensitive. Together, these two reagents enable crosstalk-free two-color activation of neural spiking and downstream synaptic transmission in independent neural populations in mouse brain slice. PMID:24509633
The rye Mutants Identify a Role for Ssn\\/Srb Proteins of the RNA Polymerase II Holoenzyme During Stationary Phase Entry in Saccharomyces cerevisiae
Ya-Wen Chang; Susie C. Howard; Yelena V. Budovskaya; Jasper Rine; Paul K. Herman
Saccharomyces cerevisiae cells enter into a distinct resting state, known as stationary phase, in response to specific types of nutrient deprivation. We have identified a collection of mutants that exhibited a defective transcriptional response to nutrient limitation and failed to enter into a normal stationary phase. These rye mutants were isolated on the basis of defects in the regulation of
Comparison of insect kinin analogs with cis-peptide bond, type VI-turn motifs identifies optimal stereochemistry for interaction with a recombinant arthropod kinin receptor from the southern cattle tick Boophilus microplus.
Taneja-Bageshwar, S; Strey, A; Kaczmarek, K; Zabrocki, J; Pietrantonio, P V; Nachman, R J
The multifunctional 'insect kinins' share the evolutionarily conserved C-terminal pentapeptide motif Phe-X1-X2-Trp-Gly-NH2, where X1=His, Asn, Ser, or Tyr and X2=Ser, Pro, or Ala; and are associated with the regulation of diuresis in a variety of species of insects. We previously reported the functional expression of a southern cattle tick (Boophilus microplus) G protein-coupled receptor that is activated by insect kinins. Four different stereochemical variants of each of the 4-aminopyroglutamic acid (APy) and tetrazole moieties, mimics of a cis-peptide bond, type VI beta-turn in insect kinins were now evaluated on the expressed tick receptor using a calcium bioluminescence plate assay. This study represents the first investigation of the interaction of restricted-conformation analogs incorporating components that mimic specific conformations and/or peptide bond orientations in an expressed arthropod neuropeptide receptor. Analog Ac-RF[APy]WGa (2R,4S) was at least 10-fold more active than the other analogs, thus identifying the optimal stereochemistry for tick receptor interaction. The optimal stereochemistry for the tetrazole insect kinin analogs in the tick receptor assay was identified as (D,L). The APy is superior to the tetrazole as a scaffold for the design of mimetic insect kinin analogs. These biostable analogs provide new tools for arthropod endocrinologists and potential leads in the development of selective, environmentally friendly arthropod pest control agents capable of disrupting insect kinin regulated processes. PMID:18192082
Rescue of an in vitro neuron phenotype identified in Niemann-Pick disease, type C1 induced pluripotent stem cell-derived neurons by modulating the WNT pathway and calcium signaling.
Efthymiou, Anastasia G; Steiner, Joe; Pavan, William J; Wincovitch, Stephen; Larson, Denise M; Porter, Forbes D; Rao, Mahendra S; Malik, Nasir
Niemann-Pick disease, type C1 (NPC1) is a familial disorder that has devastating consequences on postnatal development with multisystem effects, including neurodegeneration. There is no Food and Drug Administration-approved treatment option for NPC1; however, several potentially therapeutic compounds have been identified in assays using yeast, rodent models, and NPC1 human fibroblasts. Although these discoveries were made in fibroblasts from NPC1 subjects and were in some instances validated in animal models of the disease, testing these drugs on a cell type more relevant for NPC1 neurological disease would greatly facilitate both study of the disease and identification of more relevant therapeutic compounds. Toward this goal, we have generated an induced pluripotent stem cell line from a subject homozygous for the most frequent NPC1 mutation (p.I1061T) and subsequently created a stable line of neural stem cells (NSCs). These NSCs were then used to create neurons as an appropriate disease model. NPC1 neurons display a premature cell death phenotype, and gene expression analysis of these cells suggests dysfunction of important signaling pathways, including calcium and WNT. The clear readout from these cells makes them ideal candidates for high-throughput screening and will be a valuable tool to better understand the development of NPC1 in neural cells, as well as to develop better therapeutic options for NPC1. PMID:25637190
II. Comparisons among Three Distinct Types of Monoclonal Suppressor Factors
Recent advances in cell hybridization techniques have permitted the fusion of functional T cell subpopulations with tumor cells to yield stable T cell hybridomas (1-9). Such hybrids immortalize the biological activity of an individual cell and permit analysis of monoclonal T cell-derived helper (5) and suppression factors (2, 4, 6, 9, 10). The preparation of monoclonal T cell hybridomas and
Ferroan anorthosite - A widespread and distinctive lunar rock type
E. Dowty; M. Prinz; K. Keil
Eight of eleven Apollo 16 rake-sample anorthosites are very similar to each other, to hand-specimen Apollo 16 anorthosites, and to Apollo 15 anorthosites. They have feldspar An-96.6, both high- and low-Ca pyroxene with a restricted range of (low-magnesium) composition, minor olivine, traces of ilmenite and chromite, and originally coarse-grained, but now cataclastic texture. Such ferroan anorthosite is evidently a coherent,
Nevus anemicus: a distinctive cutaneous finding in neurofibromatosis type 1.
Hernßndez-MartĒn, Angela; GarcĒa-MartĒnez, Francisco Javier; Duat, Anna; L¾pez-MartĒn, Inmaculada; Noguera-Morel, Lucero; Torrelo, Antonio
Nevus anemicus (NA) is a cutaneous anomaly characterized by pale, well-defined patches with limited vascularization after rubbing. They are largely known to be associated with neurofibromatosis 1 (NF1) and have received little attention in the literature until recently. We sought to characterize the prevalence and clinical features of patients with NA and NF1. We conducted an observational prospective study of 99 children with NF1 at the Hospital Ni±o Jes·s, Madrid, Spain, from January 1, 2012, through July 31, 2013, and reviewed three other series of patients with NF1 and NA recently reported. The prevalence of NA in children with NF1 ranged from 8.8% to 51%, being much more prevalent at younger ages. Prospective studies yielded a higher prevalence than retrospective studies. NA was located most commonly on the trunk, particularly on the anterior chest wall, and was often multiple. Patients with segmental NF1 or isolated cafķ au lait spots rarely had NA, and NA was absent in other genodermatoses. The collection of data was not homogeneous in all studies. NA has a high prevalence in individuals with NF1 patients but seems to be absent in connection with other genodermatoses, therefore its presence can assist in the diagnosis of suspected cases of NF1. The subtle clinical appearance of NA makes its detection difficult, and physicians involved in the care of children with NF1 must be aware of its possible presence and significance. PMID:25690591
Distinctive voices enhance the visual recognition of unfamiliar faces.
B³lthoff, I; Newell, F N
Several studies have provided evidence in favour of a norm-based representation of faces in memory. However, such models have hitherto failed to take account of how other person-relevant information affects face recognition performance. Here we investigated whether distinctive or typical auditory stimuli affect the subsequent recognition of previously unfamiliar faces and whether the type of auditory stimulus matters. In this study participants learned to associate either unfamiliar distinctive and typical voices or unfamiliar distinctive and typical sounds to unfamiliar faces. The results indicated that recognition performance was better to faces previously paired with distinctive than with typical voices but we failed to find any benefit on face recognition when the faces were previously associated with distinctive sounds. These findings possibly point to an expertise effect, as faces are usually associated to voices. More importantly, it suggests that the memory for visual faces can be modified by the perceptual quality of related vocal information and more specifically that facial distinctiveness can be of a multi-sensory nature. These results have important implications for our understanding of the structure of memory for person identification. PMID:25584464
No Evidence of Persisting Unrepaired Nuclear DNA Single Strand Breaks in Distinct Types of Cells in the Brain, Kidney, and Liver of Adult Mice after Continuous Eight-Week 50 Hz Magnetic Field Exposure with Flux Density of 0.1 mT or 1.0 mT
Korr, Hubert; Angstman, Nicholas B.; Born, Tatjana B.; Bosse, Kerstin; Brauns, Birka; Demmler, Martin; Fueller, Katja; Kßntor, Orsolya; Kever, Barbara M.; Rahimyar, Navida; Salimi, Sepideh; Silny, Jiri; Schmitz, Christoph
Background It has been hypothesized in the literature that exposure to extremely low frequency electromagnetic fields (50 or 60 Hz) may lead to human health effects such as childhood leukemia or brain tumors. In a previous study investigating multiple types of cells from brain and kidney of the mouse (Acta Neuropathologica 2004; 107: 257¢264), we found increased unrepaired nuclear DNA single strand breaks (nDNA SSB) only in epithelial cells of the choroid plexus in the brain using autoradiographic methods after a continuous eight-week 50 Hz magnetic field (MF) exposure of adult mice with flux density of 1.5 mT. Methods In the present study we tested the hypothesis that MF exposure with lower flux densities (0.1 mT, i.e., the actual exposure limit for the population in most European countries, and 1.0 mT) shows similar results to those in the previous study. Experiments and data analysis were carried out in a similar way as in our previous study. Results Continuous eight-week 50 Hz MF exposure with 0.1 mT or 1.0 mT did not result in increased persisting unrepaired nDNA SSB in distinct types of cells in the brain, kidney, and liver of adult mice. MF exposure with 1.0 mT led to reduced unscheduled DNA synthesis (UDS) in epithelial cells in the choroid plexus of the fourth ventricle in the brain (EC-CP) and epithelial cells of the cortical collecting duct in the kidney, as well as to reduced mtDNA synthesis in neurons of the caudate nucleus in the brain and in EC-CP. Conclusion No evidence was found for increased persisting unrepaired nDNA SSB in distinct types of cells in the brain, kidney, and liver of adult mice after continuous eight-week 50 Hz magnetic field exposure with flux density of 0.1 mT or 1.0 mT. PMID:25302592
Political Science Departmental Distinction Certificate Program
Elsherbeni, Atef Z.
Political Science Departmental Distinction Certificate Program Purpose: The goal of the Departmental Distinction Certificate Program is to challenge and recognize excellent Political Science students both for their academic and academic- related work. Eligibility: Students majoring in Political Science
Local difference binary for ultrafast and distinctive feature description.
Yang, Xin; Cheng, Kwang-Ting Tim
The efficiency and quality of a feature descriptor are critical to the user experience of many computer vision applications. However, the existing descriptors are either too computationally expensive to achieve real-time performance, or not sufficiently distinctive to identify correct matches from a large database with various transformations. In this paper, we propose a highly efficient and distinctive binary descriptor, called local difference binary (LDB). LDB directly computes a binary string for an image patch using simple intensity and gradient difference tests on pairwise grid cells within the patch. A multiple-gridding strategy and a salient bit-selection method are applied to capture the distinct patterns of the patch at different spatial granularities. Experimental results demonstrate that compared to the existing state-of-the-art binary descriptors, primarily designed for speed, LDB has similar construction efficiency, while achieving a greater accuracy and faster speed for mobile object recognition and tracking tasks. PMID:24231876
Liquidity spillover in international stock markets through distinct time scales.
Righi, Marcelo Brutti; Vieira, Kelmara Mendes
This paper identifies liquidity spillovers through different time scales based on a wavelet multiscaling method. We decompose daily data from U.S., British, Brazilian and Hong Kong stock markets indices in order to calculate the scale correlation between their illiquidities. The sample is divided in order to consider non-crisis, sub-prime crisis and Eurozone crisis. We find that there are changes in correlations of distinct scales and different periods. Association in finest scales is smaller than in coarse scales. There is a rise on associations in periods of crisis. In frequencies, there is predominance for significant distinctions involving the coarsest scale, while for crises periods there is predominance for distinctions on the finest scale. PMID:24465918
Immunodominant mink cell focus-inducing murine leukemia virus (MuLV)-encoded CTL epitope, identified by its MHC class I-binding motif, explains MuLV-type specificity of MCF-directed cytotoxic T lymphocytes.
Sijts, A J; Ossendorp, F; Mengedķ, E A; van den Elsen, P J; Melief, C J
H-2b mice are immunologic responders to the tumorigenic MCF1233 murine leukemia virus (MuLV), an AKV-related virus derived from endogenous C57BL MuLV. We have identified an immunodominant CTL epitope that is expressed on MCF1233 MuLV-induced lymphomas of H-2b mice. C57BL/10 (B10) mice were immunized with an MCF1233-induced B10 B cell lymphoma, and tumor-specific CTL cultures were generated in vitro. These were tested for recognition of synthetic class I-binding MuLV peptides, selected for class I allele-specific motifs. One of 28 candidate peptides sensitized target cells for CTL recognition. This peptide seems to be an immuno-dominant epitope, because it was recognized by all independent CTL clones, isolated from the tumor-specific bulk culture. The epitope (KSPWFTTL) is derived from the MCF1233 MuLV envelope (env)-p15E region and is shared by all endogenous AKV types of MuLV. It has an optimal length of eight amino acids and is presented by the Kb H-2 class I molecule. Interestingly, Friend, Moloney, and Rauscher (FMR) types of MuLV are not recognized by MCF MuLV-directed CTL. The FMR env-p15E proteins have a single amino acid difference at the first position of the MCF1233 MuLV epitope (RSPWFTTL instead of KSPWFTTL). The corresponding FMR-encoded peptide bound class I H-2 Kb equally well as the MCF peptide, but it was poorly recognized by MCF1233 MuLV-specific CTL. Moreover, in the Rauscher MuLV-induced cell line RMA the FMr peptide seems not to be processed for recognition by CTL, which was illustrated by experiments with CTL elicited against this peptide. Altered TCR interaction as well as lack of processing thus may explain the type specificity of MCF1233 MuLV-directed CTL. PMID:8254184
Evolutionary analyses of the 12-kDa acidic ribosomal P-proteins reveal a distinct protein of higher plant ribosomes
Szick, Kathleen; Springer, Mark; Bailey-Serres, Julia
The P-protein complex of eukaryotic ribosomes forms a lateral stalk structure in the active site of the large ribosomal subunit and is thought to assist in the elongation phase of translation by stimulating GTPase activity of elongation factor-2 and removal of deacylated tRNA. The complex in animals, fungi, and protozoans is composed of the acidic phosphoproteins P0 (35 kDa), P1 (11¢12 kDa), and P2 (11¢12 kDa). Previously we demonstrated by protein purification and microsequencing that ribosomes of maize (Zea mays L.) contain P0, one type of P1, two types of P2, and a distinct P1/P2 type protein designated P3. Here we implemented distance matrices, maximum parsimony, and neighbor-joining analyses to assess the evolutionary relationships between the 12 kDa P-proteins of maize and representative eukaryotic species. The analyses identify P3, found to date only in mono- and dicotyledonous plants, as an evolutionarily distinct P-protein. Plants possess three distinct groups of 12 kDa P-proteins (P1, P2, and P3), whereas animals, fungi, and protozoans possess only two distinct groups (P1 and P2). These findings demonstrate that the P-protein complex has evolved into a highly divergent complex with respect to protein composition despite its critical position within the active site of the ribosome. PMID:9482893
TCEB1-mutated renal cell carcinoma: a distinct genomic and morphological subtype.
Hakimi, A Ari; Tickoo, Satish K; Jacobsen, Anders; Sarungbam, Judy; Sfakianos, John P; Sato, Yusuke; Morikawa, Teppei; Kume, Haruki; Fukayama, Masashi; Homma, Yukio; Chen, Ying-Bei; Sankin, Alexander I; Mano, Roy; Coleman, Jonathan A; Russo, Paul; Ogawa, Seishi; Sander, Chris; Hsieh, James J; Reuter, Victor E
Integrated sequencing analysis identified a group of tumors among clear cell renal cell carcinomas characterized by hotspot mutations in TCEB1 (a gene that contributes to the VHL complex to ubiquitinate hypoxia-inducible factor). We analyzed 11 tumors from two distinct cohorts with TCEB1 mutations along with an expanded cohort to assess whether these should be considered an entity distinct from clear cell renal cell carcinoma and clear cell papillary renal cell carcinoma. All tumors were characterized by hotspot mutations in TCEB1 Y79C/S/F/N or A100P. Morphological and immunohistochemical characteristics of the tumors were assessed by two experienced genitourinary pathologists. Clinical and pathological variables, copy number alterations, mutations, and expression signatures were compared with a cohort of TCEB1 wild-type tumors. All TCEB1-mutated tumors were VHL and PBRM1 wild type and contained distinct copy number profiles including loss of heterozygosity of chromosome 8, the location of TCEB1 (8q21.11). All tumors lacked the clear cell renal cell carcinoma signature 3p loss and contained distinct gene expression signatures. None of the clear cell papillary tumors harbored TCEB1 mutations. Pathologically, all TCEB1-mutated tumors shared characteristic features including thick fibromuscular bands transecting the tumor, pure clear cell cytology frequently with cells showing voluminous cytoplasm, and clear cell renal cell carcinoma-like acinar areas associated with infolding tubular and focally papillary architecture. The presence of voluminous cytoplasm, absence of luminal polarization of tumor nuclei, and lack of extensive cup-like distribution of carbonic anhydrase-IX expression distinguish it from clear cell papillary carcinoma. None of the patients developed metastases at last follow-up (median 48 months). In sum, TCEB1-mutated renal cell carcinoma is a distinct entity with recurrent hotspot mutations, specific copy number alterations, pathway activation, and characteristic morphological features. Further clinical follow-up is needed to determine whether these tumors are more indolent compared with the conventional clear cell renal cell carcinoma. PMID:25676555
Distinct Trajectories in the Transition to Adulthood: Are Children of Immigrants Advantaged?
ERIC Educational Resources Information Center
Hao, Lingxin; Woo, Han S.
Studies on children of immigrants have generally ignored distinct developmental trajectories during adolescence and their role in the transition to adulthood. This study identifies distinct trajectories in cognitive, sociobehavioral, and psychological domains and estimates their consequences for young adults. Drawing data from a nationallyģ
Magnaporthe oryzae populations adapted to finger millet and rice exhibit distinctive patterns of genetic diversity, sexuality and host interaction.
Takan, J P; Chipili, J; Muthumeenakshi, S; Talbot, N J; Manyasa, E O; Bandyopadhyay, R; Sere, Y; Nutsugah, S K; Talhinhas, P; Hossain, M; Brown, A E; Sreenivasaprasad, S
In this study, host-specific forms of the blast pathogen Magnaporthe oryzae in sub-Saharan Africa (SSA) were characterised from distinct cropping locations using a combination of molecular and biological assays. Finger millet blast populations in East Africa revealed a continuous genetic variation pattern and lack of clonal lineages, with a wide range of haplotypes. M. oryzae populations lacked the grasshopper (grh) element (96%) and appeared distinct to those in Asia. An overall near equal distribution (47-53%) of the mating types MAT1-1 and MAT1-2, high fertility status (84-89%) and the dominance of hermaphrodites (64%) suggest a strong sexual reproductive potential. Differences in pathogen aggressiveness and lack of cultivar incompatibility suggest the importance of quantitative resistance. Rice blast populations in West Africa showed a typical lineage-based structure. Among the nine lineages identified, three comprised ~90% of the isolates. Skewed distribution of the mating types MAT1-1 (29%) and MAT1-2 (71%) was accompanied by low fertility. Clear differences in cultivar compatibility within and between lineages suggest R gene-mediated interactions. Distinctive patterns of genetic diversity, sexual reproductive potential and pathogenicity suggest adaptive divergence of host-specific forms of M. oryzae populations linked to crop domestication and agricultural intensification. PMID:21701860
Identifying Biomarker Patterns and Predictors of Inflammation and Myocardial Stress
Masterson Creber, Ruth M.; Lee, Christopher S.; Margulies, Kenneth; Riegel, Barbara
Background Regular exercise is recommended to improve outcomes in patients with heart failure. Exercise is known to decrease inflammation and thought to decrease myocardial stress; however, studies of exercise in heart failure have had mixed results on levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity C-reactive protein (hsCRP). A multi-marker analysis may help identify distinct subgroups of patients who respond to exercise. The primary study objective was to identify common and distinct patterns of change in hsCRP and NT-proBNP and quantify the influence of exercise therapy on the observed patterns of change. Methods and Results NT-proBNP and hsCRP were assessed in a random sample of 320 participants from the biomarker sub-study of HF-ACTION, a randomized clinical trial of exercise training versus usual care in patients with stable and chronic heart failure. Growth mixture modeling was used to identify unique biomarker patterns over 12-months. Three statistically independent and clinically meaningful biomarker patterns of NTproBNP and hsCRP were identified. Two patterns were combined and compared to the ōlow/stableö pattern, which was characterized by the lowest levels of NT-proBNP and hsCRP over time. Participants who were taking a loop diuretic, had hypertension or ischemic etiology were about two times as likely to be in the ōelevated/worseningö biomarker pattern. Participants randomized to the exercise intervention were less likely to be in the elevated/worsening pattern of NT-proBNP and hsCRP (relative risk ratio: 0.56, CI: 0.32¢0.98, p=0.04). Conclusions Exercise therapy was protective for reducing the frequency of membership in the elevated/worsening biomarker pattern, indicating that exercise may be helpful in delaying the progression of heart failure. PMID:25727486
Similarity and rules: distinct? exhaustive? empirically distinguishable?
Ulrike Hahn; Nick Chater
The distinction between rule-based and similarity-based processes in cognition is of fundamental importance for cognitive science, and has been the focus of a large body of empirical research. However, intuitive uses of the distinction are subject to theoretical difficulties and their relation to empirical evidence is not clear. We propose a `core' distinction between rule- and similarity-based processes, in terms
Frequency and Spectrum of HPV Types Detected in Cutaneous Squamous-Cell Carcinomas Depend on the HPV Detection System: A Comparison of Four PCR Assays
Thomas Meyer; R³diger Arndt; Enno Christophers; Eggert Stockfleth; C. Piķrard-Franchimont; G. E. Piķrard; G. J. Kontochristopoulos; K. Krasagakis; S. Goerdt; R. Valsecchi; P. Leghissa; R. Cortinovis; L. Cologni; M. Shimosegawa; M. Worm
Background: The association of human papillomavirus (HPV) with cutaneous squamous-cell carcinomas (SCCs) has been described recently, but the frequency and spectrum of HPV types identified differed substantially in distinct studies. Objective: Comparison of different PCR assays with respect to sensitivity and range of HPV types detected. Method: Cutaneous SCC were analyzed for HPV DNA using both consensus PCR assays with
NSAID gastropathy and enteropathy: distinct pathogenesis likely necessitates distinct prevention strategies
Wallace, John L
The mechanisms underlying the ability of nonsteroidal anti-inflammatory drugs (NSAIDs) to cause ulceration in the stomach and proximal duodenum are well understood, and this injury can largely be prevented through suppression of gastric acid secretion (mainly with proton pump inhibitors). In contrast, the pathogenesis of small intestinal injury induced by NSAIDs is less well understood, involving more complex mechanisms than those in the stomach and proximal duodenum. There is clear evidence for important contributions to NSAID enteropathy of enteric bacteria, bile and enterohepatic recirculation of the NSAID. There is no evidence that suppression of gastric acid secretion will reduce the incidence or severity of NSAID enteropathy. Indeed, clinical data suggest little, if any, benefit. Animal studies suggest a significant exacerbation of NSAID enteropathy when proton pump inhibitors are co-administered with the NSAID. This worsening of damage appears to be linked to changes in the number and types of bacteria in the small intestine during proton pump inhibitor therapy. The distinct mechanisms of NSAID-induced injury in the stomach/proximal duodenum versus the more distal small intestine likely dictate distinct strategies for prevention. PMID:21627632
Invasion by Ligustrum lucidum(Oleaceae) in NW Argentina: early stage characteristics in different habitat types
Roxana Arag¾n; Martha Groom
Currently biological invasions are considered one of the world's most serious conservation problems. Ligustrum lucidum is the most abundant exotic tree in secondary forest patches of montane forests of NW Argentina. We studied the determinants of success of the early stages of its life cycle in distinct habitat types, with the hope of identifying vulnerabilities that could be exploited to
Theoretical and semantic distinctions of fuzzy, possibilistic, and mixed fuzzy\\/possibilistic optimization
Weldon A. Lodwick; K. David Jamison
Theoretical, semantic, and algorithmic distinctions among fuzzy, possibilistic and mixed fuzzy\\/possibilistic optimization are presented and illustrated. The theory underlying fuzzy, possibilistic, and mixed fuzzy\\/possibilistic optimization is developed and demonstrated and points to the appropriate use of distinct solution methods associated with each type of optimization dependant on the semantics of the problem. Semantics is key to both the input where
An Arabidopsis Transcriptional Regulatory Map Reveals Distinct Functional and Evolutionary Features of Novel Transcription Factors.
Jin, Jinpu; He, Kun; Tang, Xing; Li, Zhe; Lv, Le; Zhao, Yi; Luo, Jingchu; Gao, Ge
Transcription factors (TFs) play key roles in both development and stress responses. By integrating into and rewiring original systems, novel TFs contribute significantly to the evolution of transcriptional regulatory networks. Here, we report a high-confidence transcriptional regulatory map covering 388 TFs from 47 families in Arabidopsis. Systematic analysis of this map revealed the architectural heterogeneity of developmental and stress response subnetworks and identified three types of novel network motifs that are absent from unicellular organisms and essential for multicellular development. Moreover, TFs of novel families that emerged during plant landing present higher binding specificities and are preferentially wired into developmental processes and these novel network motifs. Further unveiled connection between the binding specificity and wiring preference of TFs explains the wiring preferences of novel-family TFs. These results reveal distinct functional and evolutionary features of novel TFs, suggesting a plausible mechanism for their contribution to the evolution of multicellular organisms. PMID:25750178
An Arabidopsis Transcriptional Regulatory Map Reveals Distinct Functional and Evolutionary Features of Novel Transcription Factors
Jin, Jinpu; He, Kun; Tang, Xing; Li, Zhe; Lv, Le; Zhao, Yi; Luo, Jingchu; Gao, Ge
Transcription factors (TFs) play key roles in both development and stress responses. By integrating into and rewiring original systems, novel TFs contribute significantly to the evolution of transcriptional regulatory networks. Here, we report a high-confidence transcriptional regulatory map covering 388 TFs from 47 families in Arabidopsis. Systematic analysis of this map revealed the architectural heterogeneity of developmental and stress response subnetworks and identified three types of novel network motifs that are absent from unicellular organisms and essential for multicellular development. Moreover, TFs of novel families that emerged during plant landing present higher binding specificities and are preferentially wired into developmental processes and these novel network motifs. Further unveiled connection between the binding specificity and wiring preference of TFs explains the wiring preferences of novel-family TFs. These results reveal distinct functional and evolutionary features of novel TFs, suggesting a plausible mechanism for their contribution to the evolution of multicellular organisms. PMID:25750178
Distinct Organizational States of Fully Developed Turbulent Pipe Flow
NASA Astrophysics Data System (ADS)
Dennis, David J. C.; Sogaro, Francesca M.
Organizational states of turbulence are identified through novel analysis of large scale pipe flow experiments at a Reynolds number of 35 000. The distinct states are revealed by an azimuthal decomposition of the two-point spatial correlation of the streamwise velocity fluctuation. States with dominant azimuthal wave numbers corresponding to k?=2 ,3,4,5,6 are discovered and their structure revealed as a series of alternately rotating quasistreamwise vortices. Such organizational states are highly reminiscent of the nonlinear traveling wave solutions previously identified at Reynolds numbers an order of magnitude lower.
Genome comparison of Candida orthopsilosis clinical strains reveals the existence of hybrids between two distinct subspecies.
Pryszcz, Leszek P; Nķmeth, Tibor; Gßcser, Attila; Gabald¾n, Toni
The Candida parapsilosis species complex comprises a group of emerging human pathogens of varying virulence. This complex was recently subdivided into three different species: C. parapsilosis sensu stricto, C. metapsilosis, and C. orthopsilosis. Within the latter, at least two clearly distinct subspecies seem to be present among clinical isolates (Type 1 and Type 2). To gain insight into the genomic differences between these subspecies, we undertook the sequencing of a clinical isolate classified as Type 1 and compared it with the available sequence of a Type 2 clinical strain. Unexpectedly, the analysis of the newly sequenced strain revealed a highly heterozygous genome, which we show to be the consequence of a hybridization event between both identified subspecies. This implicitly suggests that C. orthopsilosis is able to mate, a so-far unanswered question. The resulting hybrid shows a chimeric genome that maintains a similar gene dosage from both parental lineages and displays ongoing loss of heterozygosity. Several of the differences found between the gene content in both strains relate to virulent-related families, with the hybrid strain presenting a higher copy number of genes coding for efflux pumps or secreted lipases. Remarkably, two clinical strains isolated from distant geographical locations (Texas and Singapore) are descendants of the same hybrid line, raising the intriguing possibility of a relationship between the hybridization event and the global spread of a virulent clone. PMID:24747362
Identifying Differences in Cultural Behavior in Online Groups
Gregory, Michelle L.; Engel, David W.; Bell, Eric B.; Mcgrath, Liam R.
We have developed methods to identify online communities, or groups, using a combination of structural information variables and content information variables from weblog posts and their comments to build a characteristic footprint for groups. We have worked with both explicitly connected groups and 'abstract' groups, in which the connection between individuals is in interest (as determined by content based features) and behavior (metadata based features) as opposed to explicit links. We find that these variables do a good job at identifying groups, placing members within a group, and helping determine the appropriate granularity for group boundaries. The group footprint can then be used to identify differences between the online groups. In the work described here we are interested in determining how an individual's online behavior is influenced by their membership in more than one group. For example, individuals belong to a certain culture; they may belong as well to a demographic group, and other 'chosen' groups such as churches or clubs. There is a plethora of evidence surrounding the culturally sensitive adoption, use, and behavior on the Internet. In this work we begin to investigate how culturally defined internet behaviors may influence behaviors of subgroups. We do this through a series of experiments in which we analyze the interaction between culturally defined behaviors and the behaviors of the subgroups. Our goal is to (a) identify if our features can capture cultural distinctions in internet use, and (b) determine what kinds of interaction there are between levels and types of groups.
33 CFR 23.12 - Coast Guard identifying insignia.
Code of Federal Regulations, 2010 CFR
...2010-07-01 2010-07-01 false Coast Guard identifying insignia. 23.12...Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY GENERAL DISTINCTIVE MARKINGS FOR COAST GUARD VESSELS AND AIRCRAFT ¦...
The Interaction of Plasminogen Activator Inhibitor 1 With Plasminogen Activators (Tissue-Type and Urokinase-Type) and Fibrin: Localization of Interaction Sites and Physiologic Relevance
Jaap Keijer; Marijke Linders; Anton-Jan van Zonneveld; Hartmut J. Ehrlich; Jan-Paul de Boer; Hans Pannekoek
tory protein of the fibrinolytic system, harbors interaction sitesfor plasminogen activators (tissue-type (t-PA) and uroki- nase-type (u-PA)) and for fibrin. In this study, anti-PAl-1 monocional antibodies (MoAbs) were used to identify interac- tion sites of PAI-1 with these components. The binding sites of 18 different MoAbs were established and are located on five distinct \\
Engineering mesoscale structures with distinct dynamical implications
Engineering mesoscale structures with distinct dynamical implications Anne-Ly Do1 , Johannes H that there are certain mesoscale subgraphs that have precise and distinct consequences for the system-level dynamics. In particular, if mesoscale symmetries are present then eigenvectors of the Jacobian localise on the symmetric
Common and Distinct Patterns of Affective Response in Dimensions of Anxiety and Depression
Wisconsin at Madison, University of
Common and Distinct Patterns of Affective Response in Dimensions of Anxiety and Depression affective dimensions--anxious apprehension, anxious arousal, and anhedonic depression--using an emotion types of mood symptoms are discussed. Keywords: startle reflex, emotion, anxiety, depression, positive
Social conformity despite individual preferences for distinctiveness
Smaldino, Paul E.; Epstein, Joshua M.
We demonstrate that individual behaviours directed at the attainment of distinctiveness can in fact produce complete social conformity. We thus offer an unexpected generative mechanism for this central social phenomenon. Specifically, we establish that agents who have fixed needs to be distinct and adapt their positions to achieve distinctiveness goals, can nevertheless self-organize to a limiting state of absolute conformity. This seemingly paradoxical result is deduced formally from a small number of natural assumptions and is then explored at length computationally. Interesting departures from this conformity equilibrium are also possible, including divergence in positions. The effect of extremist minorities on these dynamics is discussed. A simple extension is then introduced, which allows the model to generate and maintain social diversity, including multimodal distinctiveness distributions. The paper contributes formal definitions, analytical deductions and counterintuitive findings to the literature on individual distinctiveness and social conformity.
NSDL National Science Digital Library
In this activity, students match unusual galaxies with their distinctive names and justify their reasoning. Students discover that often, galaxies acquire their names based upon how they appear to observers. This activity includes a student worksheet and background information for the teacher. This is activity four in "The Hidden Lives of Galaxies" information and activity booklet.
Ecological Dynamics of Two Distinct Viruses Infecting Marine Eukaryotic Decomposer Thraustochytrids (Labyrinthulomycetes, Stramenopiles)
Takao, Yoshitake; Tomaru, Yuji; Nagasaki, Keizo; Honda, Daiske
Thraustochytrids are cosmopolitan osmotrophic or heterotrophic microorganisms that are considered as important decomposers in coastal ecosystems. However, because of a lack of estimation method for each genus or systematic group of them, relatively little is known about their ecology in situ. Previously, we reported two distinct types of virus infecting thraustochytrids (AuRNAV: reported as SssRNAV, and SmDNAV) suggesting they have wide distributions in the host-virus systems of coastal environments. Here we conducted a field survey from 2004 through 2005 to show the fluctuation pattern of thraustochytrids and their viruses in Hiroshima Bay, Japan. During the field survey, we monitored the dynamics of the two types of thraustochytrid-infecting virus: small viruses causing lysis of Aurantiochytrium sp. NIBH N1-27 (identified as AuRNAV) and the large viruses of Sicyoidochytrium minutum NBRC 102975 (similar to SmDNAV in physiology and morphology). Fluctuation patterns of the two distinct types of virus were different from each other. This may reflect the difference in the preference of organic substrates; i.e., it may be likely the host of AuRNAV (Aurantiochytrium sp.) increases utilizing algal dead bodies or feeble cells as the virus shows a large increase in abundance following raphidophyte blooms; whereas, the trophic nutrient supply for S. minutum may primarily depend on other constantly-supplied organic compounds because it did not show any significant change in abundance throughout the survey. Further study concerning the population composition of thraustochytrids and their viruses may demonstrate the microbial ecology (especially concerning the detrital food web) of marine environments. PMID:26203654
Relationship between Distinct African Cholera Epidemics Revealed via MLVA Haplotyping of 337 Vibrio cholerae Isolates
Moore, Sandra; Miwanda, Berthe; Sadji, Adodo Yao; Thefenne, HķlĶne; Jeddi, Fakhri; Rebaudet, Stanislas; de Boeck, Hilde; Bidjada, Bawimodom; Depina, Jean-Jacques; Bompangue, Didier; Abedi, Aaron Aruna; Koivogui, Lamine; Keita, Sakoba; Garnotel, Eric; Plisnier, Pierre-Denis; Ruimy, Raymond; Thomson, Nicholas; Muyembe, Jean-Jacques; Piarroux, Renaud
Background Since cholera appeared in Africa during the 1970s, cases have been reported on the continent every year. In Sub-Saharan Africa, cholera outbreaks primarily cluster at certain hotspots including the African Great Lakes Region and West Africa. Methodology/Principal Findings In this study, we applied MLVA (Multi-Locus Variable Number Tandem Repeat Analysis) typing of 337 Vibrio cholerae isolates from recent cholera epidemics in the Democratic Republic of the Congo (DRC), Zambia, Guinea and Togo. We aimed to assess the relationship between outbreaks. Applying this method, we identified 89 unique MLVA haplotypes across our isolate collection. MLVA typing revealed the short-term divergence and microevolution of these Vibrio cholerae populations to provide insight into the dynamics of cholera outbreaks in each country. Our analyses also revealed strong geographical clustering. Isolates from the African Great Lakes Region (DRC and Zambia) formed a closely related group, while West African isolates (Togo and Guinea) constituted a separate cluster. At a country-level scale our analyses revealed several distinct MLVA groups, most notably DRC 2011/2012, DRC 2009, Zambia 2012 and Guinea 2012. We also found that certain MLVA types collected in the DRC persisted in the country for several years, occasionally giving rise to expansive epidemics. Finally, we found that the six environmental isolates in our panel were unrelated to the epidemic isolates. Conclusions/Significance To effectively combat the disease, it is critical to understand the mechanisms of cholera emergence and diffusion in a region-specific manner. Overall, these findings demonstrate the relationship between distinct epidemics in West Africa and the African Great Lakes Region. This study also highlights the importance of monitoring and analyzing Vibrio cholerae isolates. PMID:26110870
Demographic profiling for educational researchers: Using SPSS Optimal Scaling to identify distinct groups of participants
Bob Funnell; Fiona Bryer; Peter Grimbeek; Michael Davies
The French sociologist, Pierre Bourdieu, pioneered new methods for examining the way in which social actors occupy positions in a field, or social space. These methods also have application to educational research. Bourdieu's analysis of the French public's judgments about taste in art and wine, and their social class, yielded the useful insight that social actors make choices to differentiate
[Identifying distinct components in the cerebral treatment of visual sexual information through functional neuroimaging].
Mouras, Harold
For now several years, the growing developement of neuroimaging techniques such as Positron Emission Tomography (PET) or functional Magnetic Resonance Imaging (fMRI) allowed a better understanding of neural processes involved in human emotions and goal-directed behaviors. In particular, several studies are now available on the neural correlates of male sexual arousal. A neurobehavioral model of neural processes involved in sexual arousal has been proposed (Redoutķ et al., 2000) comprising: i) a cognitive component; ii) an emotional component; iii) a motivational component and iv) an autonomic component. Among other regions, several cerebral areas have been found to be linked to: 1) the cognitive component which comprises: i) the orbitofrontal cortex involved in attentional processes directed toward the target and the superior parietal lobules; ii) the inferior parietal lobules involved in motor imagery processes; 2) the motivational component which involves the caudal part of the anterior cingulate cortex, related to motor preparation processes; 3) the autonomic component: concurrent measures of cerebral activations by functional neuroimaging and of erectile response by penile plethysmography allow the demonstration of the involvement of the hypothalamus, the insula, and the rostral part of the anterior cingulate cortex in this component. PMID:15662942
Distinct Genomic Profiles in Hereditary Breast Tumors Identified by Array-Based Comparative Genomic Hybridization
Goran Jonsson; Johan Vallon-Christersson; Johan Staaf; Jia Huang; M. Renee Ward; Joel D. Greshock; Lena Luts; Ha¹kan Olsson; Nazneen Rahman; Michael Stratton; Markus Ringner; A¹ke Borg; Barbara L. Weber
Mutations in BRCA1 and BRCA2 account for a significant proportion of hereditary breast cancers. Earlier studies have shown that inherited and sporadic tumors progress along different somatic genetic pathways and that global gene expression profiles distinguish between these groups. To determine whether genomic profiles similarly discriminate among BRCA1, BRCA2, and sporadic tumors, we established DNA copy number profiles using comparative
p53 Status Identifies Two Subgroups of Triple-negative Breast Cancers with Distinct Biological Features
Aickelin, Uwe
University Foundation, Chieti Scalo and 8 Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale of Medical Statistics and Biometry `G.A. Maccacaro', University of Milan, Milan, 2 Unit of Medical Statistics, Liverpool John Moores University, Liverpool, 5 School of Molecular Medical Sciences, Nottingham University
Nucleotide Sequence Variation of the Envelope Protein Gene Identifies Two Distinct Genotypes of Yellow Fever Virus
The evolution of yellow fever virus over 67 years was investigated by comparing the nucleotide sequences of the envelope (E) protein genes of 20 viruses isolated in Africa, the Caribbean, and South America. Uniformly weighted parsimony algorithm analysis defined two major evolutionary yellow fever virus lineages designated E genotypes I and II. E genotype I contained viruses isolated from East
Atomic force microscopy identifies regions of distinct desmoglein 3 adhesive properties on living keratinocytes.
Vielmuth, Franziska; Hartlieb, Eva; Kugelmann, Daniela; Waschke, Jens; Spindler, Volker
Desmosomes provide strong cell-cell adhesion which is crucial for the integrity of tissues such as the epidermis. However, nothing is known about the distribution and binding properties of desmosomal adhesion molecules on keratinocytes. Here we used atomic force microscopy (AFM) to simultaneously visualize the topography of living human keratinocytes and the distribution and binding properties of the desmosomal adhesion molecule desmoglein 3 (Dsg3). Using recombinant Dsg3 as sensor, binding events were detectable diffusely and in clusters on the cell surface and at areas of cell-cell contact. This was blocked by removing Ca(2+) and by addition of Dsg3-specific antibodies indicating homophilic Dsg3 binding. Binding forces of Dsg3 molecules were lower on the cell surface compared to areas of cell-cell contact. Our data for the first time directly demonstrate the occurrence of Dsg3 molecules outside of desmosomes and show that Dsg3 adhesive properties differ depending on their localization. From the clinical editor: Using atomic force microscopy in the study of keratinocytes, this study directly demonstrates the occurrence of desmoglein 3 molecules outside of desmosomes and reveales that the adhesive properties of these molecules do differ depending on their localization. PMID:25510735
Gene-expression profiling identifies distinct subclasses of core binding factor acute myeloid leukemia
Lars Bullinger; Frank G. Rucker; Stephan Kurz; Juan Du; Claudia Scholl; Sandrine Sander; Andrea Corbacioglu; Claudio Lottaz; Jurgen Krauter; Stefan Frohling; Arnold Ganser; Richard F. Schlenk; Konstanze Dohner; Jonathan R. Pollack; Hartmut Dohner
Core binding factor (CBF) leukemias, characterized by either inv(16)\\/t(16;16) or t(8;21), constitute acute myeloid leuke- mia (AML) subgroups with favorable prog- nosis. However, there exists substantial biologic and clinical heterogeneity within these cytogenetic groups that is not fully reflected by the current classification sys- tem. To improve the molecular character- ization we profiled gene expression in a large series (n
Two distinct promoter elements in the human rRNA gene identified by linker scanning mutagenesis.
Haltiner, M M; Smale, S T; Tjian, R
A cell-free RNA polymerase I transcription system was used to evaluate the transcription efficiency of 21 linker scanning mutations that span the human rRNA gene promoter. Our analysis revealed the presence of two major control elements, designated the core and upstream elements, that affect the level of transcription initiation. The core element extends from -45 to +18 relative to the RNA start site, and transcription is severely affected (up to 100-fold) by linker scanning mutations in this region. Linker scanning and deletion mutations in the upstream element, located between nucleotides -156 and -107, cause a three- to fivefold reduction in transcription. Under certain reaction conditions, such as the presence of a high ratio of protein to template or supplementation of the reaction with partially purified protein fractions, sequences upstream of the core element can have an even greater effect (20- to 50-fold) on RNA polymerase I transcription. Primer extension analysis showed that RNA synthesized from all of these mutant templates is initiated at the correct in vivo start site. To examine the functional relationship between the core and the upstream region, mutant promoters were constructed that alter the orientation, distance, or multiplicity of these control elements relative to each other. The upstream control element appears to function in only one orientation, and its position relative to the core is constrained within a fairly narrow region. Moreover, multiple core elements in close proximity to each other have an inhibitory effect on transcription. Images PMID:3785147
Distinct Genetic Alterations in Colorectal Cancer
Ashktorab, Hassan; Schõffer, Alejandro A.; Daremipouran, Mohammad; Smoot, Duane T.; Lee, Edward; Brim, Hassan
Background Colon cancer (CRC) development often includes chromosomal instability (CIN) leading to amplifications and deletions of large DNA segments. Epidemiological, clinical, and cytogenetic studies showed that there are considerable differences between CRC tumors from African Americans (AAs) and Caucasian patients. In this study, we determined genomic copy number aberrations in sporadic CRC tumors from AAs, in order to investigate possible explanations for the observed disparities. Methodology/Principal Findings We applied genome-wide array comparative genome hybridization (aCGH) using a 105k chip to identify copy number aberrations in samples from 15 AAs. In addition, we did a population comparative analysis with aCGH data in Caucasians as well as with a widely publicized list of colon cancer genes (CAN genes). There was an average of 20 aberrations per patient with more amplifications than deletions. Analysis of DNA copy number of frequently altered chromosomes revealed that deletions occurred primarily in chromosomes 4, 8 and 18. Chromosomal duplications occurred in more than 50% of cases on chromosomes 7, 8, 13, 20 and X. The CIN profile showed some differences when compared to Caucasian alterations. Conclusions/Significance Chromosome X amplification in male patients and chromosomes 4, 8 and 18 deletions were prominent aberrations in AAs. Some CAN genes were altered at high frequencies in AAs with EXOC4, EPHB6, GNAS, MLL3 and TBX22 as the most frequently deleted genes and HAPLN1, ADAM29, SMAD2 and SMAD4 as the most frequently amplified genes. The observed CIN may play a distinctive role in CRC in AAs. PMID:20126641
Receptor tyrosine kinases modulate distinct transcriptional programs by differential usage of intracellular pathways.
Vasudevan, Harish N; Mazot, Pierre; He, Fenglei; Soriano, Philippe
Receptor tyrosine kinases (RTKs) signal through shared intracellular pathways yet mediate distinct outcomes across many cell types. To investigate the mechanisms underlying RTK specificity in craniofacial development, we performed RNA-seq to delineate the transcriptional response to platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) signaling in mouse embryonic palatal mesenchyme cells. While the early gene expression profile induced by both growth factors is qualitatively similar, the late response is divergent. Comparing the effect of MEK (Mitogen/Extracellular signal-regulated kinase) and PI3K (phosphoinositide-3-kinase) inhibition, we find the FGF response is MEK dependent, while the PDGF response is PI3K dependent. Furthermore, FGF promotes proliferation but PDGF favors differentiation. Finally, we demonstrate overlapping domains of PDGF-PI3K signaling and osteoblast differentiation in the palate and increased osteogenesis in FGF mutants, indicating this differentiation circuit is conserved in vivo. Our results identify distinct responses to PDGF and FGF and provide insight into the mechanisms encoding RTK specificity. PMID:25951516
Receptor tyrosine kinases modulate distinct transcriptional programs by differential usage of intracellular pathways
Vasudevan, Harish N; Mazot, Pierre; He, Fenglei; Soriano, Philippe
Receptor tyrosine kinases (RTKs) signal through shared intracellular pathways yet mediate distinct outcomes across many cell types. To investigate the mechanisms underlying RTK specificity in craniofacial development, we performed RNA-seq to delineate the transcriptional response to platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) signaling in mouse embryonic palatal mesenchyme cells. While the early gene expression profile induced by both growth factors is qualitatively similar, the late response is divergent. Comparing the effect of MEK (Mitogen/Extracellular signal-regulated kinase) and PI3K (phosphoinositide-3-kinase) inhibition, we find the FGF response is MEK dependent, while the PDGF response is PI3K dependent. Furthermore, FGF promotes proliferation but PDGF favors differentiation. Finally, we demonstrate overlapping domains of PDGF-PI3K signaling and osteoblast differentiation in the palate and increased osteogenesis in FGF mutants, indicating this differentiation circuit is conserved in vivo. Our results identify distinct responses to PDGF and FGF and provide insight into the mechanisms encoding RTK specificity. DOI: http://dx.doi.org/10.7554/eLife.07186.001 PMID:25951516
Mammalian CORVET is required for fusion and conversion of distinct early endosome subpopulations.
Perini, Enrico D; Schaefer, Ramona; St÷ter, Martin; Kalaidzidis, Yannis; Zerial, Marino
Early endosomes are organized in a network of vesicles shaped by cycles of fusion, fission, and conversion to late endosomes. In yeast, endosome fusion and conversion are regulated, among others, by CORVET, a hexameric protein complex. In the mammalian endocytic system, distinct subpopulations of early endosomes labelled by the Rab5 effectors APPL1 and EEA1 are present. Here, the function of mammalian CORVET with respect to these endosomal subpopulations was investigated. Tgfbrap1 as CORVET-specific subunit and functional ortholog of Vps3p was identified, demonstrating that it is differentially distributed between APPL1 and EEA1 endosomes. Surprisingly, depletion of CORVET-specific subunits caused fragmentation of APPL1-positive endosomes but not EEA1 endosomes in vivo. These and in vitro data suggest that CORVET plays a role in endosome fusion independently of EEA1. Depletion of CORVET subunits caused accumulation of large EEA1 endosomes indicative of another role in the conversion of EEA1 endosomes into late endosomes. In addition, depletion of CORVET-specific subunits caused alterations in transport depending on both the type of cargo and the specific endosomal subpopulation. These results demonstrate that CORVET plays distinct roles at multiple stages in the mammalian endocytic pathway. PMID:25266290
Distinction between epigenic and hypogenic maze caves
NASA Astrophysics Data System (ADS)
Palmer, Arthur N.
Certain caves formed by dissolution of bedrock have maze patterns composed of closed loops in which many intersecting fractures or pores have enlarged simultaneously. Their origin can be epigenic (by shallow circulation of meteoric groundwater) or hypogenic (by rising groundwater or production of deep-seated solutional aggressiveness). Epigenic mazes form by diffuse infiltration through a permeable insoluble caprock or by floodwater supplied by sinking streams. Most hypogenic caves involve deep sources of aggressiveness. Transverse hypogenic cave origin is a recently proposed concept in which groundwater of mainly meteoric origin rises across strata in the distal portions of large flow systems, to form mazes in soluble rock sandwiched between permeable but insoluble strata. The distinction between maze types is debated and is usually based on examination of diagnostic cave features and relation of caves to their regional setting. In this paper, the principles of mass transfer are applied to clarify the limits of each model, to show how cave origin is related to groundwater discharge, dissolution rate, and time. The results show that diffuse infiltration and floodwater can each form maze caves at geologically feasible rates (typically within 500 ka). Transverse hypogenic mazes in limestone, to enlarge significantly within 1 Ma, require an unusually high permeability of the non-carbonate beds (generally ? 10-4 cm/s), large discharge, and calcite saturation no greater than 90%, which is rare in deep diffuse flow in sedimentary rocks. Deep sources of aggressiveness are usually required. The origin of caves by transverse hypogenic flow is much more favorable in evaporite rocks than in carbonate rocks.
Two distinct neural mechanisms underlying indirect reciprocity
Watanabe, Takamitsu; Takezawa, Masanori; Nakawake, Yo; Kunimatsu, Akira; Yamasue, Hidenori; Nakamura, Mitsuhiro; Miyashita, Yasushi; Masuda, Naoki
Cooperation is a hallmark of human society. Humans often cooperate with strangers even if they will not meet each other again. This so-called indirect reciprocity enables large-scale cooperation among nonkin and can occur based on a reputation mechanism or as a succession of pay-it-forward behavior. Here, we provide the functional and anatomical neural evidence for two distinct mechanisms governing the two types of indirect reciprocity. Cooperation occurring as reputation-based reciprocity specifically recruited the precuneus, a region associated with self-centered cognition. During such cooperative behavior, the precuneus was functionally connected with the caudate, a region linking rewards to behavior. Furthermore, the precuneus of a cooperative subject had a strong resting-state functional connectivity (rsFC) with the caudate and a large gray matter volume. In contrast, pay-it-forward reciprocity recruited the anterior insula (AI), a brain region associated with affective empathy. The AI was functionally connected with the caudate during cooperation occurring as pay-it-forward reciprocity, and its gray matter volume and rsFC with the caudate predicted the tendency of such cooperation. The revealed difference is consistent with the existing results of evolutionary game theory: although reputation-based indirect reciprocity robustly evolves as a self-interested behavior in theory, pay-it-forward indirect reciprocity does not on its own. The present study provides neural mechanisms underlying indirect reciprocity and suggests that pay-it-forward reciprocity may not occur as myopic profit maximization but elicit emotional rewards. PMID:24591599
Biosynthesis of Dictyostelium discoideum differentiation-inducing factor by a hybrid type I fatty acid¢type III polyketide synthase
Michael B Austin; Tamao Saito; Marianne E Bowman; Stephen Haydock; Atsushi Kato; Bradley S Moore; Robert R Kay; Joseph P Noel
Differentiation-inducing factors (DIFs) are well known to modulate formation of distinct communal cell types from identical Dictyostelium discoideum amoebas, but DIF biosynthesis remains obscure. We report complimentary in vivo and in vitro experiments identifying one of two ?3,000-residue D. discoideum proteins, termed 'steely', as responsible for biosynthesis of the DIF acylphloroglucinol scaffold. Steely proteins possess six catalytic domains homologous to
Distinctive patterns of static and dynamic gamma motor activity during locomotion in the decerebrate cat
Taylor, A; Ellaway, P H; Durbaba, R; Rawlinson, S
Simultaneous recordings were made from gamma (?) motor axons and from muscle spindle afferents of the medial gastrocnemius (MG) muscle during locomotion in decerebrate cats. The ?-neurons were identified as static or dynamic (?s or ?d) by correlating their behaviour during midbrain stimulation with changes in muscle spindle afferent responses to muscle stretch. On the basis of their behaviour during locomotion, ?s neurons could be divided into two groups. One group (type-1) showed strongly and smoothly modulated discharge increasing in parallel with the active muscle shortening in ankle extension, but with phase advance. The other group (type-2) also showed a modulated pattern, but with increased firing centred on the flexion phase. The proportions of the two were 13 type-1 and 7 type-2. The type-1 firing pattern accurately predicted the difference in firing frequency for secondary afferents obtained by subtracting from the recordings made during active movements the response of the same units to the movements repeated passively in the absence of fusimotor activity. The type-2 pattern also became consistent with the difference signal, when operated on by a phase lag appropriate to the effects of bag2 intrafusal fibres. These results suggest that there may be some degree of separate control of chain and bag2 intrafusal fibres. T