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Venezuelan equine encephalitis replicon particles can induce rapid protection against foot-and-mouth disease virus.
Diaz-San Segundo, Fayna; Dias, Camila C A; Moraes, Mauro P; Weiss, Marcelo; Perez-Martin, Eva; Owens, Gary; Custer, Max; Kamrud, Kurt; de los Santos, Teresa; Grubman, Marvin J
We have previously shown that delivery of the porcine type I interferon gene (poIFN-?/?) with a replication-defective human adenovirus vector (adenovirus 5 [Ad5]) can sterilely protect swine challenged with foot-and-mouth disease virus (FMDV) 1 day later. However, the need of relatively high doses of Ad5 limits the applicability of such a control strategy in the livestock industry. Venezuelan equine encephalitis virus (VEE) empty replicon particles (VRPs) can induce rapid protection of mice against either homologous or, in some cases, heterologous virus challenge. As an alternative approach to induce rapid protection against FMDV, we have examined the ability of VRPs containing either the gene for green fluorescent protein (VRP-GFP) or poIFN-? (VRP-poIFN-?) to block FMDV replication in vitro and in vivo. Pretreatment of swine or bovine cell lines with either VRP significantly inhibited subsequent infection with FMDV as early as 6 h after treatment and for at least 120 h posttreatment. Furthermore, mice pretreated with either 10(7) or 10(8) infectious units of VRP-GFP and challenged with a lethal dose of FMDV 24 h later were protected from death. Protection was induced as early as 6 h after treatment and lasted for at least 48 h and correlated with induction of an antiviral response and production of IFN-?. By 6 h after treatment several genes were upregulated, and the number of genes and the level of induction increased at 24 h. Finally, we demonstrated that the chemokine IP-10, which is induced by IFN-? and VRP-GFP, is directly involved in protection against FMDV. PMID:23468490
Particles causing lung disease.
Kilburn, K H
The lung has a limited number of patterns of reaction to inhaled particles. The disease observed depends upon the location: conducting airways, terminal bronchioles and alveoli, and upon the nature of inflammation induced: acute, subacute or chronic. Many different agents cause narrowing of conducting airways (asthma) and some of these cause permanent distortion or obliteration of airways as well. Terminal bronchioles appear to be particularly susceptible to particles which cause goblet cell metaplasia, mucous plugging and ultimately peribronchiolar fibrosis. Cancer is the last outcome at the bronchial level and appears to depend upon continuous exposure to or retention of an agent in the airway and failure of the affected cells to be exfoliated which may be due to squamous metaplasia. Alveoli are populated by endothelial cells, Type I or pavement epithelial cells and metabolically active cuboidal Type II cells that produce the lungs specific surfactant, dipalmytol lecithin. Disturbances of surfactant lead to edema in distal lung while laryngeal edema due to anaphylaxis or fumes may produce asphyxia. Physical retention of indigestible particles or retention by immune memory responses may provoke hyaline membranes, stimulate alveolar lipoproteinosis and finally fibrosis. This later exuberant deposition of connective tissue has been best studied in the occupational pneumoconioses especially silicosis and asbestosis. In contrast emphysema a catabolic response, appears frequently to result from leakage or release of lysosomal proteases into the lung during processing of cigarette smoke particles. The insidious and probably most important human lung disease due to particles is bronchiolar obstruction and obliteration, producing progressive impairment of air flow. The responsible particle is the complex combination of poorly digestive lipids and complex carbohydrates with active chemicals which we call cigarette smoke. More research is needed to perfect, correct and quantify our preliminary picture of the pathogenesis of lung disease by particles, but a useful start has been made. Images FIGURE 1. PMID:6376114
Particles causing lung disease
Kilburn, K.H.
The lung has a limited number of patterns of reaction to inhaled particles. The disease observed depends upon the location: conducting airways, terminal bronchioles and alveoli, and upon the nature of inflammation induced: acute, subacute or chronic. Many different agents cause narrowing of conducting airways (asthma) and some of these cause permanent distortion or obliteration of airways as well. Terminal bronchioles appear to be particularly susceptible to particles which cause goblet cell metaplasia, mucous plugging and ultimately peribronchiolar fibrosis. Cancer is the last outcome at the bronchial level and appears to depend upon continuous exposure to or retention of an agent in the airway and failure of the affected cells to be exfoliated which may be due to squamous metaplasia. Alveoli are populated by endothelial cells, Type I or pavement epithelial cells and metabolically active cuboidal Type II cells that produce the lungs specific surfactant, dipalmytol lecithin. Disturbances of surfactant lead to edema in distal lung while laryngeal edema due to anaphylaxis or fumes may produce asphyxia. Physical retention of indigestible particles or retention by immune memory responses may provoke hyaline membranes, stimulate alveolar lipoproteinosis and finally fibrosis. This later exuberant deposition of connective tissue has been best studied in the occupational pneumoconioses especially silicosis and asbestosis. In contrast emphysema a catabolic response appears frequently to result from leakage or release of lysosomal proteases into the lung during processing of cigarette smoke particles. 164 references, 1 figure, 2 tables.
Toxicity of Mineral Dusts and a Proposed Mechanism for the Pathogenesis of Particle-Induced Lung Diseases
NASA Technical Reports Server (NTRS)
Lam, C.-W.; Zeidler-Erdely, P.; Scully, R.R.; Meyers, V.; Wallace, W.; Hunter, R.; Renne, R.; McCluskey, R.; Castranova, V.; Barger, M.; Meighan, T.; James, J.T.
Humans will set foot on the moon again. The lunar surface has been bombarded for 4 billion years by micrometeoroids and cosmic radiation, creating a layer of fine dust having a potentially reactive particle surface. To investigate the impact of surface reactivity (SR) on the toxicity of particles, and in particular, lunar dust (LD), we ground 2 Apollo 14 LD samples to increase their SR and compare their toxicity with those of unground LD, TiO2 and quartz. Intratracheally instilled at 0, 1, 2.5, or 7.5 mg/rat, all dusts caused dose-dependent increases in pulmonary lesions, and enhancement of biomarkers of toxicity assessed in bronchoalveolar lavage fluids (BALF). The toxicity of LD was greater than that of TiO2 but less than that of quartz. Three LDs differed 14-fold in SR but were equally toxic; quartz had the lowest SR but was most toxic. These results show no correlation between particle SR and toxicity. Often pulmonary toxicity of a dust can be attributed to oxidative stress (OS). We further observed dose-dependent and dustcytotoxicity- dependent increases in neutrophils. The oxidative content per BALF cell was also directly proportional to both the dose and cytotoxicity of the dusts. Because neutrophils are short-lived and release of oxidative contents after they die could initiate and promote a spectrum of lesions, we postulate a general mechanism for the pathogenesis of particle-induced diseases in the lung that involves chiefly neutrophils, the source of persistent endogenous OS. This mechanism explains why one dust (e.g., quartz or nanoparticles) is more toxic than another (e.g., micrometer-sized TiO2), why dust-induced lesions progress with time, and why lung cancer occurs in rats but not in mice and hamsters exposed to the same duration and concentration of dust.
Newcastle Disease Virus Vector Producing Human Norovirus-Like Particles Induces Serum, Cellular, and Mucosal Immune Responses in Mice
Kim, Shin-Hee; Chen, Shun; Jiang, Xi; Green, Kim Y.
ABSTRACT Human norovirus infection is the most common cause of viral gastroenteritis worldwide. Development of an effective vaccine is required for reducing norovirus outbreaks. The inability to grow human norovirus in cell culture has hindered the development of live-attenuated vaccines. To overcome this obstacle, we generated a recombinant Newcastle disease virus (rNDV)-vectored experimental norovirus vaccine by expressing the capsid protein (VP1) of norovirus strain VA387. We compared two different NDV vectors, a conventional rNDV vector and a modified rNDV vector, for their efficiencies in expressing VP1 protein. Our results showed that the modified vector replicated to higher titers and expressed higher levels of VP1 protein in DF1 cells and in allantoic fluid of embryonated chicken eggs than did the conventional vector. We further demonstrated that the VP1 protein produced by rNDVs was able to self-assemble into virus-like particles (VLPs) that are morphologically similar to baculovirus-expressed VLPs. Evaluation of their immunogenicity in mice showed that the modified rNDV vector induced a higher level of IgG response than those induced by the conventional vector and by the baculovirus-expressed VLPs. The rNDV vectors predominantly induced IgG2a subclass antibody for the Th1 response, and specifically, high levels of gamma interferon (IFN-?), tumor necrosis factor alpha (TNF-?), and interleukin-2 (IL-2) were detected in splenocytes. In addition, the modified rNDV vector induced a higher level of fecal IgA response in mice than did baculovirus-expressed VLPs. Our findings suggest that the rNDV vector is an efficient system to produce cost-effective VLPs in embryonated chicken eggs and has the potential to be used as a live-attenuated vaccine in humans. IMPORTANCE Noroviruses are the major cause of viral gastroenteritis worldwide. Currently, effective vaccines against norovirus infection are not available. In this study, we have evaluated Newcastle disease virus (NDV) as a vaccine vector for norovirus. Our results suggest that NDV can be used not only as a cost-effective method for large-scale production of norovirus-like particle vaccines but also as a live-attenuated vectored vaccine. PMID:24920815
Metal-sulfide mineral ores, Fenton chemistry and disease--particle induced inflammatory stress response in lung cells.
Harrington, Andrea D; Smirnov, Alexander; Tsirka, Stella E; Schoonen, Martin A A
The inhalation of mineral particulates and other earth materials, such as coal, can initiate or enhance disease in humans. Workers in occupations with high particulate exposure, such as mining, are particularly at risk. The ability of a material to generate an inflammatory stress response (ISR), a measure of particle toxicity, is a useful tool in evaluating said exposure risk. ISR is defined as the upregulation of cellular reactive oxygen species (ROS) normalized to cell viability. This study compares the ISR of A549 human lung epithelial cells after exposure to well-characterized common metal-sulfide ore mineral separates. The evaluation of the deleterious nature of ore minerals is based on a range of particle loadings (serial dilutions of 0.002m(2)/mL stock) and exposure periods (beginning at 30min and measured systematically for up to 24h). There is a wide range in ISR values generated by the ore minerals. The ISR values produced by the sphalerite samples are within the range of inert materials. Arsenopyrite generated a small ISR that was largely driven by cell death. Galena showed a similar, but more pronounced response. Copper-bearing ore minerals generated the greatest ISR, both by upregulating cellular ROS and generating substantial and sustained cell death. Chalcopyrite and bornite, both containing ferrous iron, generated the greatest ISR overall. Particles containing Fenton metals as major constituents produce the highest ISR, while other heavy metals mainly generate cell death. This study highlights the importance of evaluating the chemistry, oxidation states and structure of a material when assessing risk management. PMID:25107347
Venezuelan Equine Encephalitis Virus replicon particles can induce rapid protection against Foot-and-Mouth Disease Virus
Technology Transfer Automated Retrieval System (TEKTRAN)
We have previously shown that swine pretreated with a replication-defective human adenovirus vector (Ad5) containing the porcine type I interferon gene (poIFN-alpha/Beta) are sterilely protected when challenged one day later with Foot-and-Mouth Disease Virus (FMDV), but the dose required is relativ...
Drug Induced Interstitial Lung Disease
Schwaiblmair, Martin; Behr, Werner; Haeckel, Thomas; M�rkl, Bruno; Foerg, Wolfgang; Berghaus, Thomas
With an increasing number of therapeutic drugs, the list of drugs that is responsible for severe pulmonary disease also grows. Many drugs have been associated with pulmonary complications of various types, including interstitial inflammation and fibrosis, bronchospasm, pulmonary edema, and pleural effusions. Drug-induced interstitial lung disease (DILD) can be caused by chemotherapeutic agents, antibiotics, antiarrhythmic drugs, and immunosuppressive agents. There are no distinct physiologic, radiographic or pathologic patterns of DILD, and the diagnosis is usually made when a patient with interstitial lung disease (ILD) is exposed to a medication known to result in lung disease. Other causes of ILD must be excluded. Treatment is avoidance of further exposure and systemic corticosteroids in patients with progressive or disabling disease. PMID:22896776
Medici, T C; Fontana, A
Adverse drug reactions involving different organs, including the lung, are numerous; much more numerous, however, are the offending drugs. According to the results of the Boston Collaborative Drug Surveillance Program, adverse reactions occur in about 6% of all drug exposures and 28% of all patients. Drug-induced lung diseases may present as bronchial reactions (e.g. bronchial asthma), diseases of the parenchyma (e.g. pulmonary infiltrates with eosinophilia, diffuse fibrosing alveolitis), of the pulmonary vasculature (vasculitis) and of the pleura (e.g. pleurisy or pleural fibrosis). Pathogenetically the two most pertinent types of reaction are hypersensitivity or toxic reactions, and less often biologic reactions such as opportunistic infections after cytotoxic and immunosuppressive therapy. Many drug-induced respiratory diseases are reversible upon withdrawal of the offending agent; others may be irreversibly or even progress. PMID:13491
Cerebrospinal Fluid Particles in Alzheimer Disease and Parkinson Disease.
Yang, Yue; Keene, C Dirk; Peskind, Elaine R; Galasko, Douglas R; Hu, Shu-Ching; Cudaback, Eiron; Wilson, Angela M; Li, Ge; Yu, Chang-En; Montine, Kathleen S; Zhang, Jing; Baird, Geoffrey S; Hyman, Bradley T; Montine, Thomas J
Human cerebrospinal fluid (CSF) contains diverse lipid particles, including lipoproteins that are distinct from their plasma counterparts and contain apolipoprotein (apo) E isoforms, apoJ, and apoAI, and extracellular vesicles, which can be detected by annexin V binding. The aim of this study was to develop a method to quantify CSF particles and evaluate their relationship to aging and neurodegenerative diseases. We used a flow cytometric assay to detect annexin V-, apoE-, apoAI-, apoJ-, and amyloid (A) ?42-positive particles in CSF from 131 research volunteers who were neurologically normal or had mild cognitive impairment (MCI), Alzheimer disease (AD) dementia, or Parkinson disease. APOE ?4/?4 participants had CSF apoE-positive particles that were more frequently larger but at an 88% lower level versus those in APOE ?3/?3 or APOE ?3/?4 patients; this finding was reproduced in conditioned medium from mouse primary glial cell cultures with targeted replacement of apoE. Cerebrospinal fluid apoE-positive and ?-amyloid (A?42)-positive particle concentrations were persistently reduced one-third to one-half in middle and older age subjects; apoAI-positive particle concentration progressively increased approximately 2-fold with age. Both apoAI-positive and annexin V-positive CSF particle levels were reduced one-third to one-half in CSF of MCI and/or AD dementia patients versus age-matched controls. Our approach provides new methods to investigate CNS lipid biology in relation to neurodegeneration and perhaps develop new biomarkers for diagnosis or treatment monitoring. PMID:26083568
Metal-induced diffuse lung disease.
Fontenot, Andrew P; Amicosante, Massimo
The number of metals that are associated with the development of diffuse parenchymal lung disease continues to expand. In addition to lung fibrosis, inhalation of metal particulates can induce a wide range of lung pathology, including reactive airways disease and cancer. This article focuses on diffuse parenchymal diseases resulting from the inhalation of beryllium and cobalt. More is known regarding the immunopathogenesis of beryllium-induced disease than is known for disease induced by any other metal. Chronic beryllium disease (CBD) is a granulomatous lung disorder caused by beryllium exposure in the workplace and is characterized by the accumulation of beryllium-specific CD4 (+) T cells in the bronchoalveolar lavage. Genetic susceptibility markers associated with increased risk have been identified for both CBD and hard metal lung disease. The mechanism for the genetic susceptibility of CBD lies in the ability of certain human leukocyte antigen (HLA)-DP molecules to bind and present beryllium to pathogenic CD4 (+) T cells. Whether the same is true for hard metal lung disease is unknown. In contrast, no HLA allelic association has been identified in nickel allergic subjects. The study of metal-induced lung disease allows the investigation of the relationship between environmental exposure and genetic susceptibility. These studies will enhance our understanding of the immunopathogenesis of metal-induced disease and how exposure to these metals results in irreversible lung fibrosis. PMID:19221964
Oxidative stress and changed gene expression profiles in fiber-\\/particle-induced carcinogenesis
Kunal Bhattacharya; Gerrit Alink; Elke Dopp
KEYWORDS Fibers; metals; gene expression; oxidative stress; cancer ABSTRACT Exposure to ambient air pollution (particles, fibres) is associated with pulmonary diseases and cancer. The mechanisms of induced health effects are believed to involve inflammation and oxidative stress. Oxidative stress mediated by airborne particles and\\/or fibres may arise from direct generation of reactive oxygen species (ROS) from the surface of particles\\/fibres,
Insulin resistance, small LDL particles, and risk for atherosclerotic disease.
Toth, Peter P
There is a global epidemic of obesity, metabolic syndrome, and diabetes mellitus. Insulin resistance (IR) is etiologic for both metabolic syndrome and diabetes mellitus. IR induces a broad range of toxic systemic effects, including dyslipidemia, hypertension, hyperglycemia, increased production of advanced glycosylation end products, increased inflammatory tone, as well as a prothrombotic and pro-oxidative state. Patients with IR are highly vulnerable to the development of accelerated atherosclerosis as well its clinical sequelae, including coronary artery disease and myocardial infarction, carotid artery disease and ischemic stroke, peripheral arterial disease and claudication/lower extremity amputation, and coronary mortality. Among the most important risk factors patients afflicted with IR develop is the so-called atherogenic lipid triad: large numbers of small, dense low-density lipoprotein (sdLDL) particles, hypertriglyceridemia, and low serum concentrations of high-density lipoprotein cholesterol. Though controversial, much recent evidence suggests that the formation of sdLDL particles in the setting of IR is an important metabolic transition. Some studies suggest that these smaller particles are more atherogenic than their larger, more buoyant counterparts. At least part of the explanation for the apparent augmented atherogenicity of small LDL particles is their reduced systemic clearance by the LDL receptor, increased vulnerability to oxidation rendering them more apt for scavenging by macrophages, and possible increased flux into the subendothelial space of arterial walls. Numerous small studies suggest that sdLDL is highly correlated with cardiovascular events. Cardiovascular medicine is in need of a large prospective, randomized study that would more definitively investigate the impact of small, dense LDL (sdLDL) on risk for cardiovascular disease and whether therapeutic interventions designed to specifically reduce the burden of sdLDL are associated with reductions in cardiovascular events over and above that seen with LDL-C reduction per se. PMID:23627975
Particle Motion Induced by Bubble Cavitation
NASA Astrophysics Data System (ADS)
Poulain, St�phane; Guenoun, Gabriel; Gart, Sean; Crowe, William; Jung, Sunghwan
Cavitation bubbles induce impulsive forces on surrounding substrates, particles, or surfaces. Even though cavitation is a traditional topic in fluid mechanics, current understanding and studies do not capture the effect of cavitation on suspended objects in fluids. In the present work, the dynamics of a spherical particle due to a cavitation bubble is experimentally characterized and compared with an analytical model. Three phases are observed: the growth of the bubble where the particle is pushed away, its collapse where the particle approaches the bubble, and a longer time scale postcollapse where the particle continues to move toward the collapsed bubble. The particle motion in the longer time scale presumably results from the asymmetric cavitation evolution at an earlier time. Our theory considering the asymmetric bubble dynamics shows that the particle velocity strongly depends on the distance from the bubble as an inverse-fourth-power law, which is in good agreement with our experimentation. This study sheds light on how small free particles respond to cavitation bubbles in fluids.
Particle Motion Induced by Bubble Cavitation.
Poulain, St�phane; Guenoun, Gabriel; Gart, Sean; Crowe, William; Jung, Sunghwan
Cavitation bubbles induce impulsive forces on surrounding substrates, particles, or surfaces. Even though cavitation is a traditional topic in fluid mechanics, current understanding and studies do not capture the effect of cavitation on suspended objects in fluids. In the present work, the dynamics of a spherical particle due to a cavitation bubble is experimentally characterized and compared with an analytical model. Three phases are observed: the growth of the bubble where the particle is pushed away, its collapse where the particle approaches the bubble, and a longer time scale postcollapse where the particle continues to move toward the collapsed bubble. The particle motion in the longer time scale presumably results from the asymmetric cavitation evolution at an earlier time. Our theory considering the asymmetric bubble dynamics shows that the particle velocity strongly depends on the distance from the bubble as an inverse-fourth-power law, which is in good agreement with our experimentation. This study sheds light on how small free particles respond to cavitation bubbles in fluids. PMID:26066438
Oestrogen deficiency modulates particle-induced osteolysis
Introduction Postmenopausal osteoporosis may modulate bone response to wear debris. In this article, we evaluate the influence of oestrogen deficiency on experimental particle-induced osteolysis. Methods Polyethylene (PE) particles were implanted onto the calvaria of normal controls, sham-ovariectomized (OVX), OVX mice and OVX mice supplemented with oestrogen (OVX+E). After 14 days, seven skulls per group were analyzed using a high-resolution micro-computed tomography (micro-CT) and histomorphometry, and for tartrate-specific alkaline phosphatase. Five calvariae per group were cultured for the assay of IL-1?, IL-6, TNF-? and receptor activator of the nuclear factor ?B (RANKL) secretion using quantitative ELISA. Serum IL-6 concentrations were obtained. The expression of RANKL and osteoprotegerin (OPG) mRNA were evaluated using real-time PCR. Results As assessed by ?CT and by histomorphometry, PE particles induced extensive bone resorption and an intense inflammatory reaction in normal controls, sham-OVX and OVX+E mice, but not in the OVX mice group. In normal controls, sham-OVX and OVX+E mice, PE particles induced an increase in serum IL-6, in TNF-? and RANKL local concentrations, and resulted in a significant increase in RANKL/OPG messenger RNA (mRNA) ratio. Conversely, these parameters remained unchanged in OVX mice after PE implantation. Conclusions Oestrogen privation in the osteolysis murine model ultimately attenuated osteolytic response to PE particles, suggesting a protective effect. This paradoxical phenomenon was associated with a down-regulation of pro-resorptive cytokines. It is hypothesized that excessive inflammatory response was controlled, illustrated by the absence of increase of serum IL-6 in OVX mice after PE implantation. PMID:21696618
Light-induced forces on small particles
NASA Astrophysics Data System (ADS)
Ng, Tsz Fai Jack
Light-trapping is generally associated with the phenomenon that small particles are driven toward the intensity maxima of a carefully sculpted laser beam. There is another type of inter-particle optical force arising from the coherent multiple-scattering of light between the particles, previously observed in various experiments. This thesis is mainly devoted to the theoretical study of such optical binding force for a cluster of dielectric particles. In contrast to the intensity-driven light-trapping, the optical binding force is present even when a plane wave (with homogeneous intensity) is incident upon a collection of microparticles. Firstly, the theory of optical force for neutral dielectric Rayleigh particles is presented. We then show through rigorous calculations that the optical binding force (with the incident intensity �106 W/cm2) can dominate other interactions and bind dielectric microspheres in stable structures that behave like "molecules." Such photonic clusters can exhibit a multiplicity of static and drifting equilibrium configurations, with some having remarkable geometries such as a quasicrystal-like arrangement. The photonic clusters exhibit exotic dynamics, and the equilibrium configurations can correspond with either stable or a type of quasi-stable states in which the cluster maintains an average shape, with individual particles executing periodic motion in the presence of frictional dissipation. Photonic clusters consist of Rayleigh particles are also investigated. A stable one-dimensional lattice is found and analyzed, localized vibration modes are observed. Finally, we consider an interesting type of resonant inter-particle optical force. We shall see that tuning of the incident light's frequency to the morphology-dependent resonances of a cluster of transparent microspheres induces a strong, resonant optical force between the spheres. The resonant force can be enhanced by orders of magnitude so that it dominates other interactions (at a modest incident intensity of �104 W/cm2). We also proposed various ways to utilize the resonant force in the binding of a microsphere cluster.
Particle-Induced Pulmonary Acute Phase Response Correlates with Neutrophil Influx Linking Inhaled Particles and Cardiovascular Risk
Saber, Anne Thoustrup; Lamson, Jacob Stuart; Jacobsen, Nicklas Raun; Ravn-Haren, Gitte; Hougaard, Karin S�rig; Nyendi, Allen Njimeri; Wahlberg, Pia; Madsen, Anne Mette; Jackson, Petra; Wallin, H�kan; Vogel, Ulla
Background Particulate air pollution is associated with cardiovascular disease. Acute phase response is causally linked to cardiovascular disease. Here, we propose that particle-induced pulmonary acute phase response provides an underlying mechanism for particle-induced cardiovascular risk. Methods We analysed the mRNA expression of Serum Amyloid A (Saa3) in lung tissue from female C57BL/6J mice exposed to different particles including nanomaterials (carbon black and titanium dioxide nanoparticles, multi- and single walled carbon nanotubes), diesel exhaust particles and airborne dust collected at a biofuel plant. Mice were exposed to single or multiple doses of particles by inhalation or intratracheal instillation and pulmonary mRNA expression of Saa3 was determined at different time points of up to 4 weeks after exposure. Also hepatic mRNA expression of Saa3, SAA3 protein levels in broncheoalveolar lavage fluid and in plasma and high density lipoprotein levels in plasma were determined in mice exposed to multiwalled carbon nanotubes. Results Pulmonary exposure to particles strongly increased Saa3 mRNA levels in lung tissue and elevated SAA3 protein levels in broncheoalveolar lavage fluid and plasma, whereas hepatic Saa3 levels were much less affected. Pulmonary Saa3 expression correlated with the number of neutrophils in BAL across different dosing regimens, doses and time points. Conclusions Pulmonary acute phase response may constitute a direct link between particle inhalation and risk of cardiovascular disease. We propose that the particle-induced pulmonary acute phase response may predict risk for cardiovascular disease. PMID:23894396
Rasagiline induced hypersexuality in Parkinson's disease.
Reyes, Dennys; Kurako, Kateryna; Galvez-Jimenez, Nestor
Impulse control disorders (ICD) are increasingly recognized in patients with Parkinson's disease (PD), particularly when treated with commonly used dopamine agonists such as pramipexole and ropinirole. Less evident is the possible association between monoamine oxidase inhibitors type B (MAO-B) and the development of ICD. Rasagiline is a second generation MAO-B I inducing moderate symptomatic and possibly disease modifying benefits with apparently good tolerability and safety profile in PD patients. Rasagiline is effective and well tolerated in PD as a monotherapy or in combination with levodopa. Here, we report a patient with PD who developed ICD when treated de novo with MAO-B inhibitors. PMID:24055209
Apoptosis in animal models of virus-induced disease
Kenneth L. Tyler; Penny Clarke
Apoptosis is associated with virus-induced human diseases of the central nervous system, heart and liver, and causes substantial morbidity and mortality. Although virus-induced apoptosis is well characterized in individual cells in cell culture, virus-induced apoptosis in vivo and the role of apoptosis in virus-induced disease is not well established. This Review focuses on animal models of virus-induced diseases of the
Field induced reorientation in suspensions of anisotropic particles
Ohad Levy
The field induced reorientation of microellipsoids in suspension depends on particle parameters, e.g. intrinsic dielectric anisotropy, shape and size, as well as on the concentration of the particles. We study this process and the resulting orientational order parameter of suspensions in fields of arbitrary strength. The approach presented here provides an explicit link between particle properties and their orientation distribution,
Modelling induced resistance to plant diseases.
Abdul Latif, Nurul S; Wake, Graeme C; Reglinski, Tony; Elmer, Philip A G
Plant disease control has traditionally relied heavily on the use of agrochemicals despite their potentially negative impact on the environment. An alternative strategy is that of induced resistance (IR). However, while IR has proven effective in controlled environments, it has shown variable field efficacy, thus raising questions about its potential for disease management in a given crop. Mathematical modelling of IR assists researchers with understanding the dynamics of the phenomenon in a given plant cohort against a selected disease-causing pathogen. Here, a prototype mathematical model of IR promoted by a chemical elicitor is proposed and analysed. Standard epidemiological models describe that, under appropriate environmental conditions, Susceptible plants (S) may become Diseased (D) upon exposure to a compatible pathogen or are able to Resist the infection (R) via basal host defence mechanisms. The application of an elicitor enhances the basal defence response thereby affecting the relative proportion of plants in each of the S, R and D compartments. IR is a transient response and is modelled using reversible processes to describe the temporal evolution of the compartments. Over time, plants can move between these compartments. For example, a plant in the R-compartment can move into the S-compartment and can then become diseased. Once in the D-compartment, however, it is assumed that there is no recovery. The terms in the equations are identified using established principles governing disease transmission and this introduces parameters which are determined by matching data to the model using computer-based algorithms. These then give the best match of the model with experimental data. The model predicts the relative proportion of plants in each compartment and quantitatively estimates elicitor effectiveness. An illustrative case study will be given; however, the model is generic and will be applicable for a range of plant-pathogen-elicitor scenarios. PMID:24398025
Zhu, Hongxin; Rothermel, Beverly A.; Hill, Joseph A.
The heart is a highly plastic organ capable of remodeling in response to changes in physiological or pathological demand. When workload increases, the heart compensates through hypertrophic growth of individual cardiomyocytes to increase cardiac output. However, sustained stress, such as occurs with hypertension or following myocardial infarction, triggers changes in sarcomeric protein composition and energy metabolism, loss of cardiomyocytes, ventricular dilation, reduced pump function, and ultimately heart failure. It has been known for some time that autophagy is active in cardiomyocytes, occurring at increased levels in disease. Yet the potential contribution of cardiomyocyte autophagy to ventricular remodeling and disease pathogenesis has only recently been explored. This latter fact stems largely from the recent emergence of tools to probe molecular mechanisms governing cardiac plasticity and to define the role of autophagic flux in the context of heart disease. In this chapter, we briefly review prominent mouse models useful in the study of load-induced heart disease and standard techniques used to assess whether a molecular or cellular event is adaptive or maladaptive. We then outline methods available for monitoring autophagic activity in the heart, providing detailed protocols for several techniques unique to working with heart and other striated muscles. PMID:19216915
Asbestos-induced lung diseases: an update
Asbestos causes asbestosis (pulmonary fibrosis caused by asbestos inhalation) and malignancies (bronchogenic carcinoma and mesothelioma) by mechanisms that are not fully elucidated. Despite a dramatic reduction in asbestos use worldwide, asbestos-induced lung diseases remain a substantial health concern primarily because of the vast amounts of fibers that have been mined, processed, and used during the 20th century combined with the long latency period of up to 40 years between exposure and disease presentation. This review summarizes the important new epidemiologic and pathogenic information that has emerged over the past several years. Whereas the development of asbestosis is directly associated with the magnitude and duration of asbestos exposure, the development of a malignant clone of cells can occur in the setting of low-level asbestos exposure. Emphasis is placed on the recent epidemiologic investigations that explore the malignancy risk that occurs from nonoccupational, environmental asbestos exposure. Accumulating studies are shedding light on novel mechanistic pathways by which asbestos damages the lung. Attention is focused on the importance of alveolar epithelial cell (AEC) injury and repair, the role of iron-derived reactive oxygen species (ROS), and apoptosis by the p53- and mitochondria-regulated death pathways. Furthermore, recent evidence underscores crucial roles for specific cellular signaling pathways that regulate the production of cytokines and growth factors. An evolving role for epithelial-mesenchymal transition (EMT) is also reviewed. The translational significance of these studies is evident in providing the molecular basis for developing novel therapeutic strategies for asbestos-related lung diseases and, importantly, other pulmonary diseases, such as interstitial pulmonary fibrosis and lung cancer. PMID:19304273
Preventing diet induced disease: bioavailable nutrient-rich, low-
Paris-Sud XI, Universit� de
induced disease, including the use of food nanotechnology. nanotechnology promises to transform medicine intake and noting the importance of cofactors). Micro- and nanotechnologies are already engineering nano problems and challenges for society). Key words: nanotechnology, diet, disease, cardiovascular, heart
Neurobiology of Disease Subthalamic Stimulation-Induced Forelimb Dyskinesias Are
Paris-Sud XI, Universit� de
Neurobiology of Disease Subthalamic Stimulation-Induced Forelimb Dyskinesias Are Linked The neurobiological mechanisms by which high-frequency stimulation of the subthalamic nucleus (STN�HFS) alleviates
Biomarker detection of global infectious diseases based on magnetic particles.
Carinelli, Soledad; Mart�, Merc�; Alegret, Salvador; Pividori, Mar�a Isabel
Infectious diseases affect the daily lives of millions of people all around the world, and are responsible for hundreds of thousands of deaths, mostly in the developing world. Although most of these major infectious diseases are treatable, the early identification of individuals requiring treatment remains a major issue. The incidence of these diseases would be reduced if rapid diagnostic tests were widely available at the community and primary care level in low-resource settings. Strong research efforts are thus being focused on replacing standard clinical diagnostic methods, such as the invasive detection techniques (biopsy or endoscopy) or expensive diagnostic and monitoring methods, by affordable and sensitive tests based on novel biomarkers. The development of new methods that are needed includes solid-phase separation techniques. In this context, the integration of magnetic particles within bioassays and biosensing devices is very promising since they greatly improve the performance of a biological reaction. The diagnosis of clinical samples with magnetic particles can be easily achieved without pre-enrichment, purification or pretreatment steps often required for standard methods, simplifying the analytical procedures. The biomarkers can be specifically isolated and preconcentrated from complex biological matrixes by magnetic actuation, increasing specificity and the sensitivity of the assay. This review addresses these promising features of the magnetic particles for the detection of biomarkers in emerging technologies related with infectious diseases affecting global health, such as malaria, influenza, dengue, tuberculosis or HIV. PMID:25917978
Induced-Charge Electrophoresis of Metallodielectric Particles Sumit Gangwal,1
Bazant, Martin Z.
or conductance have been produced by thermal evaporation [18] or gold sputtering [19]. The mobility suspensions of anisotropic particles leads to unbalanced liquid flows and nonlinear, induced dielectric and one metal-coated hemisphere induced by uniform fields of frequency 100 Hz�10 kHz in Na
Inhaled particles in human disease and animal models: use of electron beam instrumentation
Brody, A.R.
The mineral pneumoconioses (lung disease caused by inhalation of inorganic dust) have been an important disease entity for centuries. In the last several decades, the electron microscope has been used to elucidate the distribution and identification of inhaled minerals, to aid in establishing etiologic factors, and less commonly, to determine the basic biologic mechanisms through which inhaled minerals cause lung disease. In this section, the author reviews instrumentation and tissue preparation currently used to address some modern problems in particle-induced lung disease. For example, human pneumoconioses of undetermined etiology can be clarified by electron microscopy and X-ray energy spectrometry. In addition, the initial deposition patterns of asbestos and silica are demonstrated in animal models, and the contributions of electron microscopy in establishing the initial lesions of asbestosis are described. 52 references, 14 figures.
Method for ion implantation induced embedded particle formation via reduction
Hampikian, Janet M (Decatur, GA); Hunt, Eden M (Atlanta, GA)
A method for ion implantation induced embedded particle formation via reduction with the steps of ion implantation with an ion/element that will chemically reduce the chosen substrate material, implantation of the ion/element to a sufficient concentration and at a sufficient energy for particle formation, and control of the temperature of the substrate during implantation. A preferred embodiment includes the formation of particles which are nano-dimensional (<100 m-n in size). The phase of the particles may be affected by control of the substrate temperature during and/or after the ion implantation process.
Drug-Induced Glomerular Disease: Attention Required!
Radhakrishnan, Jai; Perazella, Mark A
Drugs and toxins frequently are associated with the development of various types of acute kidney disease and CKD. Although medications are a widely known cause of tubulointerstitial damage, drug-related glomerular injury is not well appreciated but nonetheless, important. Glomerular damage that occurs after exposure to medications can be caused by direct cellular injury involving the mesangial, endothelial, or visceral epithelial cells (podocytes). Examples include nodular glomerulosclerosis associated with smoking and endothelial injury with thrombotic microangiopathy from a number of medications. Podocyte injury with the development of a minimal change or FSGS lesion has also been described with various medications. Glomerulopathies may also be associated with drug-induced immune-mediated processes. Through various pathways, drugs may promote the formation of a number of antibodies, which may, ultimately, affect the glomerulus. Examples include lupus-like renal lesions and ANCA-related pauci-immune vasculitis. It is critical to recognize these conditions early, because in many patients, there is improvement in renal parameters on stopping the offending medication. PMID:25876771
Aeolian Induced Erosion and Particle Entrainment
NASA Technical Reports Server (NTRS)
Saint, Brandon
The Granular Physics Department at The Kennedy Space Center is addressing the problem of erosion on the lunar surface. The early stages of research required an instrument that would produce erosion at a specific rate with a specific sample variation. This paper focuses on the development and experimental procedures to measure and record erosion rates. This was done with the construction of an open air wind tunnel, and examining the relationship between airflow and particle motion.
Low dose metal particles can induce monocyte/macrophage survival.
Lacey, Derek C; De Kok, Bernard; Clanchy, Felix I; Bailey, Mark J; Speed, Kathy; Haynes, David; Graves, Stephen E; Hamilton, John A
Aseptic loosening results in pain, loss of function, and ultimately prosthetic joint failure and revision surgery. The generation of wear particles from the prosthesis is a major factor in local osteolysis. We investigated the effects of such wear particles on the survival of monocytes and macrophages, populations implicated in wear particle-driven pathology. Particles from titanium aluminum vanadium (TiAlV) and cobalt chromium (CoCr) alloys were generated in-house and were equivalent in size (0.5-3 microm) to those seen in patients. Human CD14(+) monocytes and murine bone marrow-derived macrophages (BMM) were treated with TiAlV and CoCr particles in vitro, and cell survival was assayed. Both particles increased monocyte and macrophage survival in a dose-dependent manner, with an optimal concentration of around 10(7) particles/mL. Conditioned media from particle-treated BMM also increased macrophage survival. Studies with antibody blockade and gene-deficient mice suggest that particle-induced BMM survival is independent of endogenous CSF-1 (M-CSF), GM-CSF, and TNFalpha. These data indicate that wear particles can promote monocyte/macrophage survival in vitro possibly via an endogenous mediator. If this phenomenon occurs in vivo, it could mean that increased numbers of macrophages (and osteoclasts) would be found at a site of joint implant failure, which could contribute to the local inflammatory reaction and osteolysis. PMID:19459209
Infectious particles, stress, and induced prion amyloids
Transmissible encephalopathies (TSEs) are believed by many to arise by spontaneous conversion of host prion protein (PrP) into an infectious amyloid (PrP-res, PrPSc) without nucleic acid. Many TSE agents reside in the environment, with infection controlled by public health measures. These include the disappearance of kuru with the cessation of ritual cannibalism, the dramatic reduction of epidemic bovine encephalopathy (BSE) by removal of contaminated feed, and the lack of endemic scrapie in geographically isolated Australian sheep with susceptible PrP genotypes. While prion protein modeling has engendered an intense focus on common types of protein misfolding and amyloid formation in diverse organisms and diseases, the biological characteristics of infectious TSE agents, and their recognition by the host as foreign entities, raises several fundamental new directions for fruitful investigation such as: (1) unrecognized microbial agents in the environmental metagenome that may cause latent neurodegenerative disease, (2) the evolutionary social and protective functions of different amyloid proteins in diverse organisms from bacteria to mammals, and (3) amyloid formation as a beneficial innate immune response to stress (infectious and non-infectious). This innate process however, once initiated, can become unstoppable in accelerated neuronal aging. PMID:23633671
Field induced reorientation in suspensions of anisotropic particles
NASA Astrophysics Data System (ADS)
Levy, Ohad
The field induced reorientation of microellipsoids in suspension depends on particle parameters, e.g. intrinsic dielectric anisotropy, shape and size, as well as on the concentration of the particles. We study this process and the resulting orientational order parameter of suspensions in fields of arbitrary strength. The approach presented here provides an explicit link between particle properties and their orientation distribution, taking into account the electrostatic interaction at moderate concentrations. It reproduces published experimental observations in the steady state and should be useful for studying reorientation phenomena and electro-optical properties in these systems.
Cellular chemotaxis induced by wear particles from joint replacements
Stuart B. Goodman; Ting Ma
The destruction of bone around joint replacements (periprosthetic osteolysis) is an adverse biological response associated with the generation of excessive wear particles. Wear debris from the materials used for joint replacements stimulate a chronic inflammatory and foreign body reaction that leads to increased osteoclast differentiation and maturation, and decreased bone formation. Wear debris induces both local and systemic trafficking of
Abstract Submitted to the American Thoracic Society 98th International Conference, May 17 - 22, 2002, Atlanta, GA CARDIAC MOLECULAR EFFECTS INDUCED BY AIR POLLUTION PARTICLES K. Dreher1, R. Jaskot1, J. Richards1, and T. Knuckles2. 1U. S. Environmental Protection Agency,...
A compilation of charged-particle induced thermonuclear reaction rates
C. Angulo; M. Arnould; M. Rayet; P. Descouvemont; D. Baye; C. Leclercq-Willain; A. Coc; S. Barhoumi; P. Aguer; C. Rolfs; R. Kunz; J. W. Hammer; A. Mayer; T. Paradellis; S. Kossionides; C. Chronidou; K. Spyrou; S. Degl'Innocenti; G. Fiorentini; B. Ricci; S. Zavatarelli; C. Providencia; H. Wolters; J. Soares; C. Grama; J. Rahighi; A. Shotter; M. Lamehi Rachti
Low-energy cross section data for 86 charged-particle induced reactions involving light (1 ? Z ? 14), mostly stable, nuclei are compiled. The corresponding Maxwellian-averaged thermonuclear reaction rates of relevance in astrophysical plasmas at temperatures in the range from 106 K to 1010 K are calculated. These evaluations assume either that the target nuclei are in their ground state, or that
Mechanisms of particle-induced activation of alveolar macrophages.
Gercken, G; Berg, I; D�rger, M; Schl�ter, T
Bovine alveolar macrophages were exposed in vitro to quartz dusts, metal-containing dusts or silica particles coated with a single metal oxide. The release of reactive oxygen intermediates (ROI) was measured in short-term incubations (90 min). The secretion of both ROI was markedly enhanced by silica particles coated with vanadium oxide and lowered by copper oxide-coated particles. The particle-induced ROI release was significantly decreased by the inhibition of protein kinase C (PKC) as well as phospholipase A2, suggesting the involvement of both enzymes in the NADPH oxidase activation. Quartz dusts induced a transient increase of free cytosolic calcium ion concentration, slight intracellular acidification, and depolarization of the plasma membrane. In the presence of EGTA or verapamil the rise of [Ca2+]i was diminished, suggesting an influx of extracellular calcium ions. The PKC inhibitor GF 109203X did not inhibit the quartz-induced calcium rise, while both the cytosolic acidification and depolarization were prevented. BSA-coating of the quartz particles abolished the calcium influx as well as the decrease of pHi, and possibly hyperpolarized the plasma membrane. PMID:8920726
Induced-charge Electrophoresis of Metallo-dielectric Particles
Gangwal, Sumit; Bazant, Martin Z; Velev, Orlin D
The application of AC electric fields in aqueous suspensions of anisotropic particles leads to unbalanced liquid flows and nonlinear, induced-charge electrophoretic (ICEP) motion. We report experimental observations of the motion of "Janus" microparticles with one dielectric and one metal-coated hemisphere induced by uniform fields of frequency 100 Hz - 10 kHz in NaCl solutions. The motion is perpendicular to the field axis and persists after particles are attracted to a glass wall. The scalings with field strength and particle size agree with ICEP theory in dilute solutions (<= 0.1 mM), but we observe anomalous behavior at higher concentrations, including no motion above 10 mM. This phenomenon may find applications in microactuators, microsensors, and microfluidic devices.
Overview of Virus-induced Airway Disease
Sebastian L. Johnston
Acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD) are the major cause of morbidity, mortality, and health costs of both diseases. Currently available treatments are poorly effective in both acute treatment of and prevention of acute exacerbations. New treatments for intervention and prophylaxis are therefore required; to facilitate their development, we must understand the causes and mechanisms of
External front instabilities induced by a shocked particle ring
NASA Astrophysics Data System (ADS)
Rodriguez, V.; Saurel, R.; Jourdan, G.; Houas, L.
The dispersion of a cylindrical particle ring by a blast or shock wave induces the formation of coherent structures which take the form of particle jets. A blast wave, issuing from the discharge of a planar shock wave at the exit of a conventional shock tube, is generated in the center of a granular medium ring initially confined inside a Hele-Shaw cell. With the present experimental setup, under impulsive acceleration, a solid particle-jet formation is observed in a quasi-two-dimensional configuration. The aim of the present investigation is to observe in detail the formation of very thin perturbations created around the external surface of the dispersed particle layer. By means of fast flow visualization with an appropriate recording window, we focus solely on the first instants during which the external particle ring becomes unstable. We find that the critical area of the destabilization of the external ring surface is constant regardless of the acceleration of the initial layer. Moreover, we observe in detail the external front perturbation wavelength, rendered dimensionless by the initial ring perimeter, and follow its evolution with the initial particle layer acceleration. We report this quantity to be constant regardless of the evolution of the initial particle layer acceleration. Finally, we can reasonably assert that external front perturbations depend solely on the material of the particles.
External front instabilities induced by a shocked particle ring.
Rodriguez, V; Saurel, R; Jourdan, G; Houas, L
The dispersion of a cylindrical particle ring by a blast or shock wave induces the formation of coherent structures which take the form of particle jets. A blast wave, issuing from the discharge of a planar shock wave at the exit of a conventional shock tube, is generated in the center of a granular medium ring initially confined inside a Hele-Shaw cell. With the present experimental setup, under impulsive acceleration, a solid particle-jet formation is observed in a quasi-two-dimensional configuration. The aim of the present investigation is to observe in detail the formation of very thin perturbations created around the external surface of the dispersed particle layer. By means of fast flow visualization with an appropriate recording window, we focus solely on the first instants during which the external particle ring becomes unstable. We find that the critical area of the destabilization of the external ring surface is constant regardless of the acceleration of the initial layer. Moreover, we observe in detail the external front perturbation wavelength, rendered dimensionless by the initial ring perimeter, and follow its evolution with the initial particle layer acceleration. We report this quantity to be constant regardless of the evolution of the initial particle layer acceleration. Finally, we can reasonably assert that external front perturbations depend solely on the material of the particles. PMID:25375599
Alpha particles induce apoptosis through the sphingomyelin pathway.
Seideman, Jonathan H; Stancevic, Branka; Rotolo, Jimmy A; McDevitt, Michael R; Howell, Roger W; Kolesnick, Richard N; Scheinberg, David A
The sphingomyelin pathway involves the enzymatic cleavage of sphingomyelin to produce ceramide, a second messenger that serves as a key mediator in the rapid apoptotic response to various cell stressors. Low-linear energy transfer (LET) ? radiation can initiate this pathway, independent of DNA damage, via the cell membrane. Whether short-ranged, high-LET ? particles, which are of interest as potent environmental carcinogens, radiotherapies and potential components of dirty bombs, can act through this mechanism to signal apoptosis is unknown. Here we show that irradiation of Jurkat cells with ? particles emitted by the ��?Ac-DOTA-anti-CD3 IgG antibody construct results in dose-dependent apoptosis. This apoptosis was significantly reduced by pretreating cells with cholesterol-depleting nystatin, a reagent known to inhibit ceramide signaling by interfering with membrane raft coalescence and ceramide-rich platform generation. The effects of nystatin on ?-particle-induced apoptosis were related to disruption of the ceramide pathway and not to microdosimetry alterations, because similar results were obtained after external irradiation of the cells with a broad beam of collimated ? particles using a planar �?�Am source. External irradiation allowed for more precise control of the dosimetry and geometry of the irradiation, independent of antibody binding or cell internalization kinetics. Mechanistically consistent with these findings, Jurkat cells rapidly increased membrane concentrations of ceramide after external irradiation with an average of five ?-particle traversals per cell. These data indicate that ? particles can activate the sphingomyelin pathway to induce apoptosis. PMID:21631289
Phason-induced dynamics of colloidal particles on quasicrystalline substrates.
A Kromer, Justus; Schmiedeberg, Michael; Roth, Johannes; Stark, Holger
Phasons are special hydrodynamic modes that occur in quasicrystals. The trajectories of particles due to a phasonic drift were recently studied by Kromer et al. (Phys. Rev. Lett. 108, 218301 (2012)) for the case where the particles stay in the minima of a quasicrystalline potential. Here, we study the mean motion of colloidal particles in quasicrystalline laser fields when a phasonic drift or displacement is applied and also consider the cases where the colloids cannot follow the potential minima. While the mean square displacement is similar to the one of particles in a random potential with randomly changing potential wells, there also is a net drift of the colloids that reverses its direction when the phasonic drift velocity is increased. Furthermore, we explore the dynamics of the structural changes in a laser-induced quasicrystal during the rearrangement process that is caused by a steady phasonic drift or an instantaneous phasonic displacement. PMID:23512714
Anchanling reduces pathology in a lactacystin- induced Parkinson's disease model?
Li, Yinghong; Wu, Zhengzhi; Gao, Xiaowei; Zhu, Qingwei; Jin, Yu; Wu, Anmin; Huang, Andrew C. J.
A rat model of Parkinson's disease was induced by injecting lactacystin stereotaxically into the left mesencephalic ventral tegmental area and substantia nigra pars compacta. After rats were intragastrically perfused with Anchanling, a Chinese medicine, mainly composed of magnolol, for 5 weeks, when compared with Parkinson's disease model rats, tyrosine hydroxylase expression was increased, ?-synuclein and ubiquitin expression was decreased, substantia nigra cell apoptosis was reduced, and apomorphine-induced rotational behavior was improved. Results suggested that Anchanling can ameliorate Parkinson's disease pathology possibly by enhancing degradation activity of the ubiquitin-proteasome system. PMID:25767493
Drug-Induced Glomerular Disease: Immune-Mediated Injury.
Hogan, Jonathan J; Markowitz, Glen S; Radhakrishnan, Jai
Drug-induced autoimmune disease was initially described decades ago, with reports of vasculitis and a lupus-like syndrome in patients taking hydralazine, procainamide, and sulfadiazine. Over the years, multiple other agents have been linked to immune-mediated glomerular disease, often with associated autoantibody formation. Certain clinical and laboratory features may distinguish these entities from their idiopathic counterparts, and making this distinction is important in the diagnosis and management of these patients. Here, drug-induced, ANCA-associated vasculitis, drug-induced lupus, and drug-associated membranous nephropathy are reviewed. PMID:26092827
Decrease in particle-induced osteolysis in ovariectomized mice.
Nich, Christophe; Marchadier, Arnaud; Sedel, Laurent; Petite, Herv�; Vidal, Catherine; Hamadouche, Moussa
Postmenopausal osteoporosis is a common disorder that results from increased osteoclastic activity caused by estrogen deficiency. Whether postmenopausal bone remodeling can alter the response to particulate debris is unknown. The purpose of this study was to evaluate the bone response to polyethylene particles in an ovariectomized murine model. Polyethylene particles were implanted onto the calvaria of seven control mice and seven ovariectomized (OVX) mice, as compared with calvaria from sham-operated and OVX mice. Calvaria were harvested after 14 days. Skulls were analyzed with a high-resolution micro-CT and by histomorphometry after staining with Stevenel blue and picrofuschine, and for tartrate-specific alkaline phosphatase. As assessed by micro-CT, particle implantation induced a significant decrease in bone thickness in control mice, while bone thickness remained stable in OVX mice. In particle-implanted animals, the osteoclast number was 2.84 +/- 0.3 in control mice and 1.74 +/- 0.22 in OVX mice. Mean bone loss was -12% +/- 1.9% in control mice and -4.7% +/- 1.7% in OVX animals. The reduction of osteolytic response suggests that ovariectomy may have a protective role against particle-induced bone resorption. PMID:19725120
Electrokinetic motion of heterogeneous particles Electrophoresis, induced-charge electrophoresis, transverse electrophoresis.
Bazant, Martin Z.
Electrokinetic motion of heterogeneous particles Synonyms Electrophoresis, induced-charge electrophoresis, transverse electrophoresis. Definition The electrokinetic motion of heterogeneous particles due to the combined effects of electrophoresis, induced-charge electrophoresis, and dielectrophoresis
Chloroquine-induced lipidosis mimicking Fabry disease
Diana Albay; Sharon G Adler; Jaya Philipose; C C Calescibetta; Stephen G Romansky; Arthur H Cohen
Intracellular accumulation of phospholipids may be a consequence of inherited or acquired metabolic disorders. In Fabry disease, deficiency of ?-galactosidase A results in storage of globotriasylceramide in numerous cells including endothelium, striated muscle (skeletal, cardiac), smooth muscle, and renal epithelium among others; the ultrastructural appearance of the inclusions is of whorled layers of alternating dense and pale material (�zebra bodies�
Nuclear reactions induced by high-energy alpha particles
NASA Technical Reports Server (NTRS)
Shen, B. S. P.
Experimental and theoretical studies of nuclear reactions induced by high energy protons and heavier ions are included. Fundamental data needed in the shielding, dosimetry, and radiobiology of high energy particles produced by accelerators were generated, along with data on cosmic ray interaction with matter. The mechanism of high energy nucleon-nucleus reactions is also examined, especially for light target nuclei of mass number comparable to that of biological tissue.
Pollutant particles induce apoptosis and inflammation, but the relationship between these two biological processes is not entirely clear. In this study, we compared the proapoptotic and proinflammatory effects of four particles: residual oil fly ash (ROFA), St. Louis particles SR...
Alpha Particles Induce Apoptosis through the Sphingomyelin Pathway
Seideman, Jonathan H.; Stancevic, Branka; Rotolo, Jimmy A.; McDevitt, Michael R.; Howell, Roger W.; Kolesnick, Richard N.; Scheinberg, David A.
The sphingomyelin pathway involves the enzymatic cleavage of sphingomyelin to produce ceramide, a second messenger that serves as a key mediator in the rapid apoptotic response to various cell stressors. Low-linear energy transfer (LET) ? radiation can initiate this pathway, independent of DNA damage, via the cell membrane. Whether short-ranged, high-LET a particles, which are of interest as potent environmental carcinogens, radiotherapies and potential components of dirty bombs, can act through this mechanism to signal apoptosis is unknown. Here we show that irradiation of Jurkat cells with a particles emitted by the 225Ac-DOTA-anti-CD3 IgG antibody construct results in dose-dependent apoptosis. This apoptosis was significantly reduced by pretreating cells with cholesterol-depleting nystatin, a reagent known to inhibit ceramide signaling by interfering with membrane raft coalescence and ceramide-rich platform generation. The effects of nystatin on ?-particle-induced apoptosis were related to disruption of the ceramide pathway and not to microdosimetry alterations, because similar results were obtained after external irradiation of the cells with a broad beam of collimated a particles using a planar 241Am source. External irradiation allowed for more precise control of the dosimetry and geometry of the irradiation, independent of antibody binding or cell internalization kinetics. Mechanistically consistent with these findings, Jurkat cells rapidly increased membrane concentrations of ceramide after external irradiation with an average of five ?-particle traversals per cell. These data indicate that a particles can activate the sphingomyelin pathway to induce apoptosis. PMID:21631289
Drug-Induced Glomerular Disease: Direct Cellular Injury.
Markowitz, Glen S; Bomback, Andrew S; Perazella, Mark A
The potential of medications to cause kidney injury is well known. Although nephrotoxicity is most commonly associated with injury in the tubulointerstitial compartment as either acute tubular necrosis or acute interstitial nephritis, a growing body of literature has also highlighted the potential for drug-induced glomerular lesions. This review surveys the three primary patterns of drug-induced glomerular diseases stratified by the cell type at which the glomerular lesion is focused: visceral epithelial cell (or podoctye) injury, endothelial cell injury, and mesangial cell injury. A number of commonly prescribed medications, including IFNs, bisphosphonates, nonsteroidal anti-inflammatory drugs, antiplatelet agents, and antiangiogenesis drugs, that are both prescribed and available over the counter, have been implicated in these iatrogenic forms of glomerular disease. Recognition of these drug-induced etiologies of glomerular disease and rapid discontinuation of the offending agent are critical to maximizing the likelihood of renal function recovery. PMID:25862776
Human Induced Pluripotent Stem Cell Models of Inherited Cardiovascular Diseases.
Jiang, Wenjian; Lan, Feng; Zhang, Hongjia
Cardiovascular cells derived from patient specific induced Pluripotent Stem Cell (iPSC) harbor gene mutations associated with the pathogenesis of inherited cardiac diseases and congenital heart diseases (CHD). Numerous reports have demonstrated the utilization of human induced Pluripotent Stem Cell (hiPSC) to model cardiac diseases as a means of investigating their underlying mechanisms. So far, they have been shown to investigate the molecular mechanisms of many cardiac disorders, such as long-QT syndrome (LQT), catecholaminergic polymorphic ventricular tachycardia (CPVT), dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), LEOPARD syndrome (LS), arrhythmogenic cardiomyopathy (ACM), Friedreich ataxia (FRDA), Barth syndrome (BTHS), hypoplastic left heart syndrome (HLHS), Marfan syndrome (MFS) and other CHD. This article summarizes the growing body of research related to modeling various cardiac diseases using hiPSCs. Moreover, by reviewing the methods used in previous studies, we propose multiple novel applications of hiPSCs to investigate comprehensive cardiovascular disorders and facilitate drug discovery. PMID:25322695
Inhaled particles in human disease and animal models: use of electron beam instrumentation.
Brody, A R
The mineral pneumoconioses (lung disease caused by inhalation of inorganic dust) have been an important disease entity for centuries. In the last several decades, the electron microscope has been used to elucidate the distribution and identification of inhaled minerals, to aid in establishing etiologic factors, and less commonly, to determine the basic biologic mechanisms through which inhaled minerals cause lung disease. In this section, I review the instrumentation and tissue preparation currently used to address some modern problems in particle-induced lung disease. For example, human pneumoconioses of undetermined etiology can be clarified by electron microscopy and X-ray energy spectrometry. In addition, the initial deposition patterns of asbestos and silica are demonstrated in animal models, and the contributions of electron microscopy in establishing the initial lesions of asbestosis are described. Images FIGURE 1. FIGURE 2. FIGURE 3. FIGURE 4. FIGURE 5. FIGURE 6. FIGURE 7. FIGURE 8. FIGURE 9. FIGURE 9. FIGURE 10. FIGURE 11. FIGURE 12. FIGURE 13. FIGURE 14. PMID:6090114
The EPIC-MOS Particle-Induced Background Spectrum
NASA Technical Reports Server (NTRS)
Kuntz, K. D.; Snowden, S. L.
We have developed a method for constructing a spectrum of the particle-induced instrumental background of the XMM-Newton EPIC MOS detectors that can be used for observations of the diffuse background and extended sources that fill a significant fraction of the instrument field of view. The strength and spectrum of the particle-induced background, that is, the background due to the interaction of particles with the detector and the detector surroundings, is temporally variable as well as spatially variable over individual chips. Our method uses a combination of the filter-wheel-closed data and a database of unexposed-region data to construct a spectrum of the "quiescent" background. We show that, using this method of background subtraction, the differences between independent observations of the same region of "blank sky" are consistent with the statistical uncertainties except when there is clear evidence of solar wind charge exchange emission. We use the blank sky observations to show that contamination by SWCX emission is a strong function of the solar wind proton flux, and that observations through the flanks of the magnetosheath appear to be contaminated only at much higher solar wind fluxes. We have also developed a spectral model of the residual soft proton flares, which allows their effects to be removed to a substantial degree during spectral fitting.
Golli-induced paralysis: a study in anergy and disease.
Clark, L; Otvos, L; Stein, P L; Zhang, X M; Skorupa, A F; Lesh, G E; McMorris, F A; Heber-Katz, E
The Golli-MBP transcription unit contains three Golli-specific exons as well as the seven exons of the classical myelin basic protein (MBP) gene and encodes alternatively spliced proteins that share amino acid sequence with MBP. Unlike MBP, which is a late Ag expressed only in the nervous system, Golli exon-containing gene products are expressed both pre- and postnatally at many sites, including lymphoid tissue, as well as in the central nervous system. To investigate whether Golli-MBP peptides unique to Golli would result in neurological disease, we immunized rats and observed a novel neurological disease characterized by mild paralysis and the presence of groups of lymphocytes in the subarachnoid space but not in the parenchyma of the brain. Disease was induced by Th1-type T cells that displayed an unusual activation phenotype. Primary stimulation in vitro induced T cell proliferation with increased surface CD45RC that did not become down-regulated as it did in other Ag-stimulated cultures. Secondary stimulation of this CD45RChigh population with Ag, however, did not induce proliferation or IL-2 production, although an IFN-gamma-producing population resulted. Proliferation could be induced by secondary stimulation with IL-2 or PMA-ionomycin, suggesting an anergic T cell population. Cells could adoptively transfer disease after secondary stimulation with IL-2, but not with Ag alone. These responses are suggestive of a chronically stimulated, anergic population that can be transiently activated to cause disease, fall back into an anergic state, and reactivated to cause disease again. Such a scenario may be important in chronic human disease. PMID:10201962
Diesel exhaust particles induce the over expression of tumor necrosis factor-alpha (TNF-alpha) gene in alvelor machrophage and failed to induce apoptosis through activation of nuclear factor-kappaB (NF-kappaB)
Exposure to particulate matter (PM2.5-10), including diesel exhaust particles (DEP) has been reported to induce lung injury and exacerbation of asthma and chronic obstructive pulmonary disease. Alveolar macrophages play a major role in the lung's response to inhaled particles and...
Combination analgesic-induced kidney disease: The australian experience
Geoffrey G. Duggin
Analgesic nephropathy is a unique drug-induced kidney disease characterized pathologically by renal papillary necrosis and chronic interstitial nephritis, and is the result of excessive consumption of combination antipyretic analgesics. The clinical features of the disorder relate mainly to the papillary necrosis, renal colic, and obstructive uropathy and the development of chronic renal failure in a small percentage of patients. There
Drift-induced deceleration of Solar Energetic Particles
Dalla, S; Laitinen, T
We investigate the deceleration of Solar Energetic Particles (SEPs) during their propagation from the Sun through interplanetary space, in the presence of weak to strong scattering in a Parker spiral configuration, using relativistic full orbit test particle simulations. The calculations retain all three spatial variables describing particles' trajectories, allowing to model any transport across the magnetic field. Large energy change is shown to occur for protons, due to the combined effect of standard adiabatic deceleration and a significant contribution from particle drift in the direction opposite to that of the solar wind electric field. The latter drift-induced deceleration is found to have a stronger effect for SEP energies than for galactic cosmic rays. The kinetic energy of protons injected at 1 MeV is found to be reduced by between 35 and 90% after four days, and for protons injected at 100 MeV by between 20 and 55%. The overall degree of deceleration is a weak function of the scattering mean free p...
Investigation of the ?-particle induced nuclear reactions on natural molybdenum
NASA Astrophysics Data System (ADS)
Ditr�i, F.; Hermanne, A.; T�rk�nyi, F.; Tak�cs, S.; Ignatyuk, A. V.
Cross-sections of alpha particle induced nuclear reactions on natural molybdenum have been studied in the frame of a systematic investigation of charged particle induced nuclear reactions on metals for different applications. The excitation functions of 93mTc, 93gTc(m+), 94mTc, 94gTc, 95mTc, 95gTc, 96gTc(m+), 99mTc, 93mMo, 99Mo(cum), 90Nb(m+), 94Ru, 95Ru,97Ru, 103Ru and 88Zr were measured up to 40 MeV alpha energy by using a stacked foil technique and activation method. The main goals of this work were to get experimental data for accelerator technology, for monitoring of alpha beam, for thin layer activation technique and for testing nuclear reaction theories. The experimental data were compared with critically analyzed published data and with the results of model calculations, obtained by using the ALICE-IPPE, EMPIRE and TALYS codes (TENDL-2011).
Key Node Selection for Containing Infectious Disease Spread Using Particle Swarm Optimization
Wong, Limsoon
Key Node Selection for Containing Infectious Disease Spread Using Particle Swarm Optimization Xiuju infectious diseases have grown into global health threats due to high human mobility. It is important to have intervention plans for containing the spread of such infectious diseases. Among various intervention strategies
Fully biodegradable and cationic poly(amino oxalate) particles for the treatment of acetaminophen-induced acute liver failure.
Kim, Hyungmin; Kim, Yerang; Guk, Kyeonghye; Yoo, Donghyuck; Lim, Hyungsuk; Kang, Gilson; Lee, Dongwon
Acute inflammatory diseases are one of major causes of death in the world and there is great need for developing drug delivery systems that can target drugs to macrophages and enhance their therapeutic efficacy. Poly(amino oxalate) (PAOX) is a new family of fully biodegradable polymer that possesses tertiary amine groups in its backbone and has rapid hydrolytic degradation. In this study, we developed PAOX particles as drug delivery systems for treating acute liver failure (ALF) by taking the advantages of the natural propensity of particulate drug delivery systems to localize to the mononuclear phagocyte system, particularly to liver macrophages. PAOX particles showed a fast drug release kinetics and excellent biocompatibility in vitro and in vivo. A majority of PAOX particles were accumulated in liver, providing a rational strategy for effective treatment of ALF. A mouse model of acetaminophen (APAP)-induced ALF was used to evaluate the potential of PAOX particles using pentoxifylline (PTX) as a model drug. Treatment of PTX-loaded PAOX particles significantly reduced the activity of alanine transaminase (ALT) and inhibited hepatic cell damages in APAP-intoxicated mice. The high therapeutic efficacy of PTX-loaded PAOX particles for ALF treatment may be attributed to the unique properties of PAOX particles, which can target passively liver, stimulate cellular uptake and trigger a colloid osmotic disruption of the phagosome to release encapsulated PTX into the cytosol. Taken together, we believe that PAOX particles are a promising drug delivery candidate for the treatment of acute inflammatory diseases. PMID:22664461
Locoweed-induced neuronal storage disease characterized by meganeurite formation.
Walkley, S U; James, L F
Golgi staining was performed on cerebral cortex and thalamus of adult animals chronically intoxicated with an alpha-mannosidase inhibitor found in locoweed (Astragalus lentiginosus). The widespread occurrence of large, aspiny meganeurites was discovered on cortical pyramidal and thalamic principal neurons but aberrant spines and neurite growth were not observed. Ectopic neurite growth is known to be characteristic of alpha-mannosidosis of early onset in inherited and induced feline models. The absence of neuritogenesis in a storage disease known to be so characterized when induced in younger animals suggests that this unusual phenomenon is in some way linked to normal developmental processes associated with brain maturation. PMID:6518385
Geraniin suppresses RANKL-induced osteoclastogenesis in vitro and ameliorates wear particle-induced osteolysis in mouse model.
Xiao, Fei; Zhai, Zanjing; Jiang, Chuan; Liu, Xuqiang; Li, Haowei; Qu, Xinhua; Ouyang, Zhengxiao; Fan, Qiming; Tang, Tingting; Qin, An; Gu, Dongyun
Wear particle-induced osteolysis and subsequent aseptic loosening remains the most common complication that limits the longevity of prostheses. Wear particle-induced osteoclastogenesis is known to be responsible for extensive bone erosion that leads to prosthesis failure. Thus, inhibition of osteoclastic bone resorption may serve as a therapeutic strategy for the treatment of wear particle induced osteolysis. In this study, we demonstrated for the first time that geraniin, an active natural compound derived from Geranium thunbergii, ameliorated particle-induced osteolysis in a Ti particle-induced mouse calvaria model in vivo. We also investigated the mechanism by which geraniin exerts inhibitory effects on osteoclasts. Geraniin inhibited RANKL-induced osteoclastogenesis in a dose-dependent manner, evidenced by reduced osteoclast formation and suppressed osteoclast specific gene expression. Specially, geraniin inhibited actin ring formation and bone resorption in vitro. Further molecular investigation demonstrated geraniin impaired osteoclast differentiation via the inhibition of the RANKL-induced NF-?B and ERK signaling pathways, as well as suppressed the expression of key osteoclast transcriptional factors NFATc1 and c-Fos. Collectively, our data suggested that geraniin exerts inhibitory effects on osteoclast differentiation in vitro and suppresses Ti particle-induced osteolysis in vivo. Geraniin is therefore a potential natural compound for the treatment of wear particle induced osteolysis in prostheses failure. PMID:25016282
Interstitial Lung Disease Induced by Drugs and Radiation
Philippe Camus; Annlyse Fanton; Philippe Bonniaud; Clio Camus; Pascal Foucher
An ever-increasing number of drugs can reproduce variegated patterns of naturally occurring interstitial lung disease (ILD), including most forms of interstitial pneumonias, alveolar involvement and, rarely, vasculitis. Drugs in one therapeutic class may collectively produce the same pattern of involvement. A few drugs can produce more than one pattern of ILD. The diagnosis of drug-induced ILD (DI-ILD) essentially rests on
Moyamoya disease presenting with paroxysmal exercise-induced dyskinesia.
Lyoo, Chul Hyoung; Kim, Dong Joon; Chang, Hyuk; Lee, Myung Sik
We report a patient with moyamoya disease presenting with paroxysmal exercise-induced dyskinesia (PED). A 31-year-old lathe man developed recurrent attacks of paroxysmal hemichorea. The attacks always affected his left limbs and occurred either after several hours of working or while playing football. The duration of attacks ranged from 30 min to 4h. Attacks were not provoked by sudden movements, consumption of coffee or alcohol, hyperventilation, emotional stress, exposure to cold or passive movement. An MRI of the brain showed no parenchymal lesions. However, (99m)Tc-ethylcysteine dimer SPECT study showed hypoperfusion in the right striatum. Digital subtraction angiography showed stenosis of the right internal carotid and middle cerebral artery with prominent basal collaterals, which was compatible with moyamoya disease. Imaging studies of the cerebral arteries should be done in patients with clinical features of PED in order to detect possible cases of moyamoya disease. PMID:16952479
Some properties of the viroid inducing peach latent mosaic disease.
Flores, R; Hern�ndez, C; Desvignes, J C; Ll�cer, G
Analysis by polyacrylamide gel electrophoresis of nucleic acid extracts from different peach samples, healthy or infected with the peach latent mosaic (PLM) disease, demonstrated the association of this disease with an RNA exhibiting the electrophoretic properties typical of circular viroid molecules. This RNA was called peach latent mosaic viroid (PLMV), since a purified preparation of it, when inoculated into GF 305 peach seedlings induced characteristic symptoms of PLM disease. PLMV was estimated to have a molecular size in the range of 330-340 bases, by comparison of its electrophoretic mobility under denaturing conditions with those of several viroid RNA. Dot-blot analysis showed that PLMV had a sequence clearly different from other viroids, including citrus exocortis viroid, apple scar skin viroid (ASSV), hop stunt viroid (HSV) and avocado sunblotch viroid. The possible significance of the limited sequence homology shared by PLMV with HSV, and especially with ASSV, is discussed. PMID:2326551
Energy and particle densities from oxygen-induced nuclear reactions
Garpman, S.; Albrecht, R.; Awes, T.C.; Baktash, C.; Beckmann, P.; Berger, F.; Bock, R.; Claesson, G.; Dragon, L.; Ferguson, R.L.
Charged particle multiplicity and pseudo-rapidity distributions observed in /sup 16/O induced nuclear collisions at 60 and 200 A GeV are presented in conjunction with forward and transverse energy distributions. From the measurements estimates of the supreme energy density obtained in central /sup 16/O + /sup 197/Au collisions at 200 A GeV yield a value of about 3 GeV/fm/sup 3/ seemingly enough to fulfill the presumptions for chiral symmetry restoration. The target mass dependence on the pseudo-rapidity densities is examined using a power law parametrization. The data are also compared to simulations from the Lund model (Fritiof) for nucleus-nucleus collisions. 15 refs., 7 figs.
New molecular insights into inflammatory bowel disease-induced diarrhea
Tang, Yueming; Forsyth, Christopher B; Keshavarzian, Ali
Diarrhea is one of the common symptoms that significantly affects quality of life in patients with inflammatory bowel disease (IBD). The clinical manifestation of diarrhea is mainly dependant on the type of IBD and the location, extent and severity of intestinal inflammation. Understanding the pathophysiologic mechanisms of diarrhea in patients with IBD will be beneficial to developing effective treatments for IBD-associated diarrhea. In recent years, modern molecular techniques have been used intensively to dissect the role of the intestinal microbiota, epithelial barrier and the host immune system in the mechanisms of IBD-induced diarrhea. These studies have significantly advanced our knowledge of the mechanisms of IBD-induced diarrhea. In this article, we focus on the new and critical molecular insights into the contributions of the intestinal microbiota, epithelial tight junctions, proinflammatory cytokines and microRNA as potential mechanisms underlying to IBD-induced diarrhea. PMID:21910579
Hormetic effect induced by alpha-particle-induced stress communicated in vivo between zebrafish embryos.
Choi, V W Y; Cheung, A L Y; Cheng, S H; Yu, K N
We report data showing that embryos of the zebrafish, Danio rerio, at 1.5 h post fertilization (hpf) subjected to a low-dose alpha-particle irradiation can release a stress signal into the water, which can be communicated to unirradiated bystander zebrafish embryos sharing the same water medium to induce a hormetic effect in the bystander embryos. Hormetic responses are characterized as biphasic dose-response relationships exhibiting a low-dose stimulation and a high-dose inhibition. The effects on the whole embryos were studied through quantification of apoptotic signals at 24 hpf through staining with the vital dye acridine orange, followed by counting the stained cells under a microscope. The results show that, for low alpha-particle dose, the number of apoptotic signals decreases in the irradiated embryos and also in the unirradiated bystander embryos having partnered with the irradiated embryos. These suggested that alpha-particle-irradiated zebrafish embryos could release a stress signal into the water, which could be communicated to unirradiated bystander zebrafish embryos sharing the same water medium to induce a hormetic effect in the bystander embryos. PMID:23050846
Recombinant adeno-vaccine expressing enterovirus 71-like particles against hand, foot, and mouth disease.
Tsou, Yueh-Liang; Lin, Yi-Wen; Shao, Hsiao-Yun; Yu, Shu-Ling; Wu, Shang-Rung; Lin, Hsiao-Yu; Liu, Chia-Chyi; Huang, Chieh; Chong, Pele; Chow, Yen-Hung
Enterovirus 71 (EV71) and coxsackieviruses (CV) are the major causative agents of hand, foot and mouth disease (HFMD). There is not currently a vaccine available against HFMD, even though a newly developed formalin-inactivated EV71 (FI-EV71) vaccine has been tested in clinical trial and has shown efficacy against EV71. We have designed and genetically engineered a recombinant adenovirus Ad-EVVLP with the EV71 P1 and 3CD genes inserted into the E1/E3-deleted adenoviral genome. Ad-EVVLP were produced in HEK-293A cells. In addition to Ad-EVVLP particles, virus-like particles (VLPs) formed from the physical association of EV71 capsid proteins, VP0, VP1, and VP3 expressed from P1 gene products. They were digested by 3CD protease and confirmed to be produced by Ad-EVVLP-producing cells, as determined using transmission electron microscopy and western blotting. Mouse immunogenicity studies showed that Ad-EVVLP-immunized antisera neutralized the EV71 B4 and C2 genotypes. Activation of VLP-specific CD4+ and CD8+/IFN-? T cells associated with Th1/Th2-balanced IFN-?, IL-17, IL-4, and IL-13 was induced; in contrast, FI-EV71 induced only Th2-mediated neutralizing antibody against EV71 and low VLP-specific CD4+ and CD8+ T cell responses. The antiviral immunity against EV71 was clearly demonstrated in mice vaccinated with Ad-EVVLP in a hSCARB2 transgenic (hSCARB2-Tg) mouse challenge model. Ad-EVVLP-vaccinated mice were 100% protected and demonstrated reduced viral load in both the CNS and muscle tissues. Ad-EVVLP successfully induced anti-CVA16 immunities. Although antisera had no neutralizing activity against CVA16, the 3C-specific CD4+ and CD8+/IFN-? T cells were identified, which could mediate protection against CVA16 challenge. FI-EV71 did not induce 3C-mediated immunity and had no efficacy against the CVA16 challenge. These results suggest that Ad-EVVLP can enhance neutralizing antibody and protective cellular immune responses to prevent EV71 infection and cellular immune responses against CV infection. PMID:25855976
Virus-like particles associated with banana bunchy top disease contain small single-stranded DNA
Robert M. Harding; Thomas M. Burns; James L. Dale
Virus-like particles were purified from banana plants with banana bunchy top disease. These particles were isometric with a diameter of 18 to 20 nm and a density of 1.28 to 1-30 g\\/ml in caesium sulphate. Associated with these particles were an ssDNA of about 1 kb and one major protein of Mr 20100. DsDNA was synthe- sized from nucleic acid
Theory of mode-induced beam-particle loss in tokamaks
White, R.B.; Goldston, R.J.; McGuire, K.; Boozer, A.H.; Monticello, D.A.; Park, W.
Large-amplitude rotating magnetohydrodynamic modes have been observed to induce significant high-energy-beam particle loss during high-power perpendicular neutral-beam injection on PDX. A Hamiltonian formalism for drift-orbit trajectories in the presence of such modes is used to study induced particle loss analytically and numerically. Results are in good agreement with experiment.
Mineralogical and geochemical aspects of mineral-induced disease
Guthrie, G.; Raymond, R.; Saffiotti, U.; Aust, A. [Los Alamos National Lab., NM (United States); Mossman, B. [Univ. of Vermont, Burlington, VT (United States)
Many minerals are known to cause disease following inhalation, including asbestos, silica, zeolites, and clays. The mineralogical properties that determine toxicity are not known, hindering effective risk assessment. Consequently, many minerals that do not pose risks are controlled excessively and many minerals that do pose risk remain uncontrolled. The authors are integrating mineralogy and biology in an interdisciplinary scientific investigation of the mechanisms of mineral-induced disease. The biological endpoints include the formation of ferruginous bodies and chemical signaling (e.g., production of cytokines or active oxygen species) by cells; the mineralogical variables include structure, composition, and surface properties. The authors are also determining what information about the biological reaction is preserved in the mineral surface.
[The risk of cardiovascular diseases induced by radiotherapy].
Hudecov�, K; Urbanov�, D; Petr�sov�, H
At present the number of cancer survivors is still increasing. However, their long-term quality of life after anticancer treatment can be decreased. Radiotherapy may represent a risk for the future of some oncologic patients. The late cardiovascular effects of radiotherapy to the area of thorax, cranium and to the abdominal area are the actual multidisciplinary problem. The unique problem is mediastinal radiotherapy which may induce the development of the cardiomyopathy, constrictive pericarditis, coronary artery disease, myocardial infarction, valvular defects, arrhythmias and other complications. Exact knowledge of pathophysiological mechanisms of radiation induced cardiovascular damage after radiotherapy as well as using of new diagnostic cardiologic methods might be useful for the detection of subclinical abnormalities and their early treatment already in the asymptomatic patients. PMID:18672577
The effectiveness of polyethylene versus titanium particles in inducing osteolysis in vivo
Marius von Knoch; Donna E. Jewison; Jean D. Sibonga; Christoph Sprecher; Bernard F. Morrey; Franz Loer; Daniel J. Berry; Sean P. Scully
Bearing surface wear and periprosthetic osteolysis due to wear particles are among the most common reasons for joint replacement failure. A murine calvarial model of wear particle-induced osteolysis has been used to identify different biologic factors associated with this problem and to test nonsurgical methods of modulating the host response to particulate debris. This model has utilized titanium particles, however,
Particle-induced bit errors in high performance fiber optic data links for satellite data management
P. W. Marshall; Cheryl J. Dale; Martin A. Carts; K. A. LaBel
Experimental test methods and analysis tools are demonstrated to assess particle-induced bit errors on fiber optic link receivers for satellites. Susceptibility to direct ionization from low LET particles is quantified by analyzing proton and helium ion data as a function of particle LET. Existing single event analysis approaches are shown to apply, with appropriate modifications, to the regime of temporally
Hydrodynamic interactions in metal rod-like particle suspensions due to induced charge electroosmosis
K A Rose; B Hoffman; D Saintillan; E G Shaqfeh; J G Santiago
We present a theoretical and experimental study of the role of hydrodynamic interactions on the motion and dispersion of metal rod-like particles in the presence of an externally applied electric field. In these systems, the electric field polarizes the particles and induces an electroosmosis flow relative to the surface of each particle. The simulations include the effect of the gravitational
Hydrodynamic interactions in metal rodlike-particle suspensions due to induced charge electroosmosis
Klint A. Rose; Brendan Hoffman; David Saintillan; Eric S. G. Shaqfeh; Juan G. Santiago
We present a theoretical and experimental study of the role of hydrodynamic interactions on the motion and dispersion of metal rodlike particles in the presence of an externally applied electric field. In these systems, the electric field polarizes the particles and induces an electroosmotic flow relative to the surface of each particle. The simulations include the effect of the gravitational
Influence of Magnolol on the bystander effect induced by alpha-particle irradiation
Yu, K.N.
Influence of Magnolol on the bystander effect induced by alpha-particle irradiation T.P.W. Wong, Hong Kong a r t i c l e i n f o Keywords: Bystander effect Alpha-particle CHO cells Magnolol a b s t r a c t In this work, the influence of Magnolol on the bystander effect in alpha-particle irradiated
Thermally relativistic flows induced by gravitational-force-free particle motion in curved spacetime
Yano, Ryosuke; Suzuki, Kojiro; Kuroda, Hisayasu [Department of Advanced Energy, University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8561 (Japan); Department of Advanced Energy, University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8561 (Japan); Department of Information Technology, University of Ehime, 3 Bunkyo-cho, Matsuyama, Ehime 790-8577 (Japan)
Thermally relativistic flows in the early Universe can be characterized by the emergence of flows induced by gravitational-force-free particle motion in curved spacetime as well as induced by the gravitational force. In this paper, thermally relativistic flows induced by gravitational-force-free particle motion in curved spacetime are discussed on the basis of the general relativistic Boltzmann equation. As an object of analysis, we consider the flow from the static state inside the Schwarzschild radius of a thermally relativistic stuffed black hole induced by such motion. Analytical results obtained using the collisionless, nongravitational general relativistic Boltzmann equation reveal that the initial cluster is induced by gravitational-force-free particle motion. Numerical results obtained using the nongravitational general relativistic Anderson-Witting model confirm the presence of an initial cluster inside the thermally relativistic stuffed black hole, which is induced by gravitational-force-free particle motion.
High-density lipoprotein particles, coronary heart disease, and niacin
Technology Transfer Automated Retrieval System (TEKTRAN)
In clinical trials, the use of statins in patients with high risk for cardiovascular disease (CVD) has resulted in a 25% to 40% decrease in major clinical events. However, despite a marked reduction (up to 60%) in LDL-C, approximately 50% (or more) of patients continue to have CVD events. This high ...
Hepatic Differentiation of Murine Disease-Specific Induced Pluripotent Stem Cells Allows Disease Modelling In Vitro
Eggenschwiler, Reto; Loya, Komal; Sgodda, Malte; Andr�, Francoise; Cantz, Tobias
Direct reprogramming of somatic cells into pluripotent cells by retrovirus-mediated expression of OCT4, SOX2, KLF4, and C-MYC is a promising approach to derive disease-specific induced pluripotent stem cells (iPSCs). In this study, we focused on three murine models for metabolic liver disorders: the copper storage disorder Wilson's disease (toxic-milk mice), tyrosinemia type 1 (fumarylacetoacetate-hydrolase deficiency, FAH?/? mice), and alpha1-antitrypsin deficiency (PiZ mice). Colonies of iPSCs emerged 2-3 weeks after transduction of fibroblasts, prepared from each mouse strain, and were maintained as individual iPSC lines. RT-PCR and immunofluorescence analyses demonstrated the expression of endogenous pluripotency markers. Hepatic precursor cells could be derived from these disease-specific iPSCs applying an in vitro differentiation protocol and could be visualized after transduction of a lentiviral albumin-GFP reporter construct. Functional characterization of these cells allowed the recapitulation of the disease phenotype for further studies of underlying molecular mechanisms of the respective disease. PMID:21977043
Seamless Correction of the Sickle Cell Disease Mutation of the HBB Gene in Human Induced
Zhao, Huimin
ABSTRACT: Sickle cell disease (SCD) is the most common human genetic disease which is caused by a single; genome editing Human induced pluripotent stem cells (hiPSCs) are genetically reprogrammed from adultSeamless Correction of the Sickle Cell Disease Mutation of the HBB Gene in Human Induced
MOLECULAR CARCINOGENESIS 52:726738 (2013) Reduction of Inflammatory Bowel Disease-Induced
Hammock, Bruce D.
MOLECULAR CARCINOGENESIS 52:726�738 (2013) Reduction of Inflammatory Bowel Disease-Induced Tumor of sEH in inflammatory bowel disease (IBD) and its induced carcinogenesis. In the present study- ment for IBD. � 2012 Wiley Periodicals, Inc. Key words: inflammatory bowel disease; carcinogenesis
Placental Induced Growth Factor (PIGf) in Coronary Artery Disease
NASA Technical Reports Server (NTRS)
Sundaresan, Alamelu; Carabello, Blaise; Mehta, Satish; Schlegel, Todd; Pellis, Neal; Ott, Mark; Pierson, Duane
Our previous studies on normal human lymphocytes have shown a five-fold increase (p less than 0.001) in angiogenic inducers such as Placental Induced Growth Factor (PIGf) in physiologically stressful environments such as modeled microgravity, a space analog. This suggests de-regulation of cardiovascular signalling pathways indicated by upregulation of PIGf. In the current study, we measured PIGf in the plasma of 33 patients with and without coronary artery disease (CAD) to investigate whether such disease is associated with increased levels of PIGf. A control consisting of 31 sex matched apparently healthy subjects was also included in the study. We observed that the levels of PIGf in CAD patients were significantly increased compared to those in healthy control subjects (p less than 0.001) and usually increased beyond the clinical threshold level (greater than 27ng/L). The mechanisms leading to up-regulation of angiogenic factors and the adaptation of organisms to stressful environments such as isolation, high altitude, hypoxia, ischemia, microgravity, increased radiation, etc are presently unknown and require further investigation in spaceflight and these other physiologically stressed environments.
Different particle determinants induce apoptosis and cytokine release in primary alveolar macrophage cultures
Refsnes, Magne; Hetland, Ragna B; �vrevik, Johan; Sundf�r, Idunn; Schwarze, Per E; L�g, Marit
Background Particles are known to induce both cytokine release (MIP-2, TNF-?), a reduction in cell viability and an increased apoptosis in alveolar macrophages. To examine whether these responses are triggered by the same particle determinants, alveolar macrophages were exposed in vitro to mineral particles of different physical-chemical properties. Results The crystalline particles of the different stone types mylonite, gabbro, basalt, feldspar, quartz, hornfels and fine grain syenite porphyr (porphyr), with a relatively equal size distribution (? 10 ?m), but different chemical/mineral composition, all induced low and relatively similar levels of apoptosis. In contrast, mylonite and gabbro induced a marked MIP-2 response compared to the other particles. For particles of smaller size, quartz (? 2 ?m) seemed to induce a somewhat stronger apoptotic response than even smaller quartz (? 0.5 ?m) and larger quartz (? 10 ?m) in relation to surface area, and was more potent than hornfels and porphyr (? 2 ?m). The reduction in cell viability induced by quartz of the different sizes was roughly similar when adjusted to surface area. With respect to cytokines, the release was more marked after exposure to quartz ? 0.5 ?m than to quartz ? 2 ?m and ? 10 ?m. Furthermore, hornfels (? 2 ?m) was more potent than the corresponding hornfels (? 10 ?m) and quartz (? 2 ?m) to induce cytokine responses. Pre-treatment of hornfels and quartz particles ? 2 ?m with aluminium lactate, to diminish the surface reactivity, did significantly reduce the MIP-2 response to hornfels. In contrast, the apoptotic responses to the particles were not affected. Conclusion These results indicate that different determinants of mineral/stone particles are critical for inducing cytokine responses, reduction in cell viability and apoptosis in alveolar macrophages. The data suggest that the particle surface reactivity was critical for cytokine responses, but contributed less to cell death for the types of particles tested. The size-dependent variations, specially in cytokine release, seem not to be explained only by particle surface area. PMID:16774673
Anti-Newtonian dynamics and self-induced Bloch oscillations of correlated particles
Stefano Longhi
We predict that two correlated particles hopping on a one-dimensional Hubbard lattice can show transient self-acceleration and self-induced Bloch oscillations as a result of anti-Newtonian dynamics. Self-propulsion occurs for two particles with opposite effective mass on the lattice and requires long-range particle interaction. A photonic simulator of the two-particle Hubbard model with controllable long-range interaction, where self-propulsion can be observed, is discussed.
Pressure Induced Structural Transitions in Nanometer Size Particles of PbS
Syed B. Qadri; J. Yang; B. R. Ratna; Earl F. Skelton
The work reported in this paper was initiated to determine the effect of particle sizes in the nanometer range on the pressure induced phase transition in PbS. The particles were synthesized by a new technique. The three-dimensionally periodic and interconnected mesoporous structure of a bicontinuous cubic phase was used as a matrix to synthesize monodispersed nanosized PbS particles. The particle
Stochastic electrodynamics with particle structure Part I: Zero-point induced Brownian behavior
A. Rueda
If ordinary views on particle structure are introduced in a simple classical particle model in replacement of the point particles of standard use in stochastic electrodynamics, it can be shown that an internalZitterbewegung induced by the zero-point field background gives rise to a Brownian movement for the whole particle with a diffusion constant of the form D = ?\\/2mD ,
Magnetic-fluctuation-induced particle transport and density relaxation in a high-temperature plasma.
Ding, W X; Brower, D L; Fiksel, G; Den Hartog, D J; Prager, S C; Sarff, J S
The first direct measurement of magnetic-fluctuation-induced particle flux in the core of a high-temperature plasma is reported. Transport occurs due to magnetic field fluctuations associated with global tearing instabilities. The electron particle flux, resulting from the correlated product of electron density and radial magnetic fluctuations, accounts for density profile relaxation during a magnetic reconnection event. The measured particle transport is much larger than that expected for ambipolar particle diffusion in a stochastic magnetic field. PMID:19659214
Emission of light charged particles in photon induced fission
M. Verboven; E. Jacobs; D. de Frenne
The emission of light charged particles in the photofission of 230,232Th, 233,234,235,238U, 237Np, and 242Pu has been studied with bremsstrahlung with end-point energy of 12, 15, and 20 MeV. The light charged particles are measured using a setup consisting of eight DeltaE-E particle identification detector telescopes. The kinetic energy distributions and the emission probabilities of tritons and long-range alpha particles
Ultrafine carbon particles induce IL-8 expression in human airway epithelial cells through a post-transcritpional mechanism Epidemiological studies suggest that ultrafine particles contribute to particulate matter (PM) - induced adverse health effects. IL-8 is an i...
Alpha-particle-induced soft errors in dynamic memories
T. C. May; M. H. Woods
A new physical soft error mechanism in dynamic RAM's and CCD's is the upset of stored data by the passage of alpha particles through the memory array area. The alpha particles are emitted by the radioactive decay of uranium and thorium which are present in parts-per-million levels in packaging materials. When an alpha particle penetrates the die surface, it can
Environment as a Critical Factor for the Pathogenesis and Outcome of Gastrointestinal Disease: Experimental and Human Inflammatory Bowel Disease and Helicobacter-Induced Gastritis
A. Bleich; M. M�hler
Environmental factors play an important role in the manifestation, course, and prognosis of diseases of the gastrointestinal tract such as inflammatory bowel disease (IBD) and Helicobacter pylori-induced gastritis. These two disease complexes were chosen for a discussion of the contribution of environmental factors to the disease outcome in humans and animal models. Dissecting complex diseases like IBD and Helicobacter-induced gastritis
Drug-induced autoimmune liver disease: A diagnostic dilemma of an increasingly reported disease.
Castiella, Agustin; Zapata, Eva; Lucena, M Isabel; Andrade, Ra�l J
The aetiology of autoimmune hepatitis (AIH) is uncertain but the disease can be triggered in susceptible patients by external factors such as viruses or drugs. AIH usually develops in individuals with a genetic background mainly consisting of some risk alleles of the major histocompatibility complex (HLA). Many drugs have been linked to AIH phenotypes, which sometimes persist after drug discontinuation, suggesting that they awaken latent autoimmunity. At least three clinical scenarios have been proposed that refers to drug- induced autoimmune liver disease (DIAILD): AIH with drug-induced liver injury (DILI); drug induced-AIH (DI-AIH); and immune mediated DILI (IM-DILI). In addition, there are instances showing mixed features of DI-AIH and IM-DILI, as well as DILI cases with positive autoantibodies. Histologically distinguishing DILI from AIH remains a challenge. Even more challenging is the differentiation of AIH from DI-AIH mainly relying in histological features; however, a detailed standardised histologic evaluation of large cohorts of AIH and DI-AIH patients would probably render more subtle features that could be of help in the differential diagnosis between both entities. Growing information on the relationship of drugs and AIH is being available, being drugs like statins and biologic agents more frequently involved in cases of DIAILD. In addition, there is some evidence on the fact that patients diagnosed with DIAILD may have had a previous episode of hepatotoxicity. Further collaborative studies in DIAILD will strengthen the knowledge and understanding of this intriguing and complex disorder which might represent different phenotypes across the spectrum of disease. PMID:24799984
Drug-induced autoimmune liver disease: A diagnostic dilemma of an increasingly reported disease
Castiella, Agustin; Zapata, Eva; Lucena, M Isabel; Andrade, Ra�l J
The aetiology of autoimmune hepatitis (AIH) is uncertain but the disease can be triggered in susceptible patients by external factors such as viruses or drugs. AIH usually develops in individuals with a genetic background mainly consisting of some risk alleles of the major histocompatibility complex (HLA). Many drugs have been linked to AIH phenotypes, which sometimes persist after drug discontinuation, suggesting that they awaken latent autoimmunity. At least three clinical scenarios have been proposed that refers to drug- induced autoimmune liver disease (DIAILD): AIH with drug-induced liver injury (DILI); drug induced-AIH (DI-AIH); and immune mediated DILI (IM-DILI). In addition, there are instances showing mixed features of DI-AIH and IM-DILI, as well as DILI cases with positive autoantibodies. Histologically distinguishing DILI from AIH remains a challenge. Even more challenging is the differentiation of AIH from DI-AIH mainly relying in histological features; however, a detailed standardised histologic evaluation of large cohorts of AIH and DI-AIH patients would probably render more subtle features that could be of help in the differential diagnosis between both entities. Growing information on the relationship of drugs and AIH is being available, being drugs like statins and biologic agents more frequently involved in cases of DIAILD. In addition, there is some evidence on the fact that patients diagnosed with DIAILD may have had a previous episode of hepatotoxicity. Further collaborative studies in DIAILD will strengthen the knowledge and understanding of this intriguing and complex disorder which might represent different phenotypes across the spectrum of disease PMID:24799984
Newcastle disease virus-like particles: preparation, purification, quantification, and incorporation of foreign glycoproteins.
McGinnes, Lori W; Morrison, Trudy G
Virus-like particles (VLPs) are large particles, the size of viruses, composed of repeating structures that mimic those of infectious virus. Since their structures are similar to that of viruses, they have been used to study the mechanisms of virus assembly. They are also in development for delivery of molecules to cells and in studies of the immunogenicity of particle-associated antigens. However, they have been most widely used for development of vaccines and vaccine candidates. VLPs can form upon the expression of the structural proteins of many different viruses. This chapter describes the generation and purification of VLPs formed with the structural proteins, M, NP, F, and HN proteins, of Newcastle disease virus (NDV). Newcastle disease virus-like particles (ND VLPs) have also been developed as a platform for assembly into VLPs of glycoproteins from other viruses. This chapter describes the methods for this use of ND VLPs. PMID:24510891
Toxicogenomic analysis of the particle dose- and size-response relationship of silica particles-induced toxicity in mice
NASA Astrophysics Data System (ADS)
Lu, Xiaoyan; Jin, Tingting; Jin, Yachao; Wu, Leihong; Hu, Bin; Tian, Yu; Fan, Xiaohui
This study investigated the relationship between particle size and toxicity of silica particles (SP) with diameters of 30, 70, and 300 nm, which is essential to the safe design and application of SP. Data obtained from histopathological examinations suggested that SP of these sizes can all induce acute inflammation in the liver. In vivo imaging showed that intravenously administrated SP are mainly present in the liver, spleen and intestinal tract. Interestingly, in gene expression analysis, the cellular response pathways activated in the liver are predominantly conserved independently of particle dose when the same size SP are administered or are conserved independently of particle size, surface area and particle number when nano- or submicro-sized SP are administered at their toxic doses. Meanwhile, integrated analysis of transcriptomics, previous metabonomics and conventional toxicological results support the view that SP can result in inflammatory and oxidative stress, generate mitochondrial dysfunction, and eventually cause hepatocyte necrosis by neutrophil-mediated liver injury.
Passing particle toroidal precession induced by electric field in a tokamak
Andreev, V. V. [Peoples' Friendship University of Russia, Ordzhonikidze St. 3, Moscow 117198 (Russian Federation)] [Peoples' Friendship University of Russia, Ordzhonikidze St. 3, Moscow 117198 (Russian Federation); Ilgisonis, V. I.; Sorokina, E. A. [Peoples' Friendship University of Russia, Ordzhonikidze St. 3, Moscow 117198 (Russian Federation) [Peoples' Friendship University of Russia, Ordzhonikidze St. 3, Moscow 117198 (Russian Federation); NRC �Kurchatov Institute�, Kurchatov Sq. 1, Moscow 123182 (Russian Federation)
Characteristics of a rotation of passing particles in a tokamak with radial electric field are calculated. The expression for time-averaged toroidal velocity of the passing particle induced by the electric field is derived. The electric-field-induced additive to the toroidal velocity of the passing particle appears to be much smaller than the velocity of the electric drift calculated for the poloidal magnetic field typical for the trapped particle. This quantity can even have the different sign depending on the azimuthal position of the particle starting point. The unified approach for the calculation of the bounce period and of the time-averaged toroidal velocity of both trapped and passing particles in the whole volume of plasma column is presented. The results are obtained analytically and are confirmed by 3D numerical calculations of the trajectories of charged particles.
Development of Carbonaceous Particle Size Analyzer Using Laser-induced Incandescence Technology
NASA Astrophysics Data System (ADS)
Ikezawa, Satoshi; Wakamatsu, Muneaki; Zimin, Yury L'vovich; Pawlat, Joanna; Ueda, Toshitsugu
This paper presents a new sensing system for carbonaceous nanoparticle measurement using a laser-induced incandescence (LII) technique. Our research group has improved the laser-induced breakdown spectroscopy (LIBS) system used for quantitative analysis. Although the basic principles of LIBS quantitative measurements are well understood, several uncertainties remain concerning complete descriptions�especially for particle size measurement. The elemental composition and density of the particles are determined using LIBS, and particle size measurements are accomplished with the help of LII. In the case of the present system, with temporally resolved LII, measurement of soot primary particle sizes is feasible in a combustion process derived from the ratio of emission signals after a laser pulse because the cooling behaviour is characteristic of the particle size. The LII temporal analysis was performed by a streak camera, which was also used for LIBS analysis. The LII technique allows in situ measurement of the average primary particle size of nanoscale soot particles.
Experimental Radiation-Induced Heart Disease: Past, Present, and Future
Boerma, Marjan
Radiation-induced heart disease (RIHD) is a serious side effect of radiotherapy for intrathoracic and chest wall tumors. The threshold dose for development of clinically significant RIHD is believed to be lower than previously assumed. Therefore, research into mechanisms of RIHD has gained substantial momentum. RIHD becomes clinically apparent ten to fifteen years after radiation exposure. Chronic manifestations of RIHD include accelerated atherosclerosis, cardiomyopathy, and valve abnormalities. Reducing exposure of the heart during radiotherapy is the only known method of preventing RIHD, and there are no approaches to reverse RIHD once it occurs. We use a combination of pharmacological and genetic animal models to determine biological mechanisms of RIHD. Major technological advances in small animal research have made this type of study more valuable. The long-term goal of this work is to identify targets for intervention in RIHD, thereby enhancing the efficacy and safety of thoracic radiotherapy. PMID:22663150
Genetic predisposition to drug-induced liver disease.
Fontana, R J; Watkins, P B
Rarely do otherwise safe drugs administered at recommended doses produce liver damage that may progress to liver failure and death. Because we are generally unable to identify the patients most susceptible to this "idiosyncratic" form of toxicity, many potentially useful medications are not made available to patients. The most promising developments in identifying susceptible patients have stemmed from recent advances in characterization of bioactivation and detoxification enzyme systems, and the discovery of marked variation in the activities of these enzymes among patients. Tests capable of quantitating the activities of specific relevant enzymes have been recently developed and are now being applied in clinical trials to assess risk factors for drug-induced liver disease. These tests hold promise of identifying subsets of patients who may need close monitoring or who may be best served with an alternate treatment. PMID:8749900
Flow field induced particle accumulation inside droplets in rectangular channels.
Hein, Michael; Moskopp, Michael; Seemann, Ralf
Particle concentration is a basic operation needed to perform washing steps or to improve subsequent analysis in many (bio)-chemical assays. In this article we present field free, hydrodynamic accumulation of particles and cells in droplets flowing within rectangular micro-channels. Depending on droplet velocity, particles either accumulate at the rear of the droplet or are dispersed over the entire droplet cross-section. We show that the observed particle accumulation behavior can be understood by a coupling of particle sedimentation to the internal flow field of the droplet. The changing accumulation patterns are explained by a qualitative change of the internal flow field. The topological change of the internal flow field, however, is explained by the evolution of the droplet shape with increasing droplet velocity altering the friction with the channel walls. In addition, we demonstrate that accumulated particles can be concentrated, removing excess dispersed phase by splitting the droplet at a simple channel junction. PMID:26032835
Suppression of NF-?B signaling mitigates polyethylene wear particle-induced inflammatory response
Lin, Tzu-hua; Goodman, Stuart B.
In end-stage arthritis patients, total joint replacement is a very effective surgical procedure. Nevertheless, the high revision rate after surgery remains a major concern. The wear particles generated from biomaterial-induced tissue responses may lead to chronic inflammation and local bone destruction (periprosthetic osteolysis). Several important signaling pathways are involved in wear particles induced inflammatory reactions, including the transcription factor NF-?B. We recently reported that RAW264.7 macrophage cell exposure to ultra-high molecular weight polyethylene (UHMWPE) particles significantly increased the NF-?B activity in a generated NF-?B responsive luciferase reporter cell clone. The NF-?B activity induced by UHMWPE particles in a mouse RAW264.7 macrophage cell line, bone marrow derived macrophages, and human THP1 macrophage cell line, were suppressed by double strand decoy oligodeoxynucleotide (ODN) containing an NF-?B binding element. Macrophages exposure to UHMWPE particles with or without endotoxin induced pro-inflammatory cytokine and chemokine expression including TNF-?, MCP1, MIP1?, and others. Finally, the decoy ODN significantly suppressed the induced cytokine and chemokine expression in both murine and human macrophages, consequently reducing macrophage recruitment by cellular conditioned medium exposed to wear particles. These findings suggest that local suppression of inflammatory cytokine production via inhibition of NF-?B activity with decoy ODN in total joint replacement patients could potentially be an effective strategy to alleviate wear particle-induced chronic inflammation.
Disruption of the respiratory epithelium contributes to the progression of a variety of respiratory diseases that are aggravated by exposure to air pollutants, specifically traffic-based pollutants such as diesel exhaust particles (DEP). Recognizing that lung repair following inj...
Abundance of surfactant-like particles reflects mucosal integrity in patients with peptic ulcer disease
R Eliakim; D H Alpers; R Oren; A Fich; K DeSchryver-Kecskemeti
BACKGROUND: Surfactant-like particles, normal products of the human enterocyte, are released into the lumen and secreted into blood. AIMS: To assess their role as markers for mucosal functional integrity, this study examined their content in biopsy specimens and serum of patients with duodenal ulcer disease, compared with non-diseased control subjects. PATIENTS: Endoscopic biopsy specimens were taken 1-2 cm from areas
Abundance of surfactant-like particles reflects mucosal integrity in patients with peptic ulcer disease.
Eliakim, R; Alpers, D H; Oren, R; Fich, A; DeSchryver-Kecskemeti, K
BACKGROUND: Surfactant-like particles, normal products of the human enterocyte, are released into the lumen and secreted into blood. AIMS: To assess their role as markers for mucosal functional integrity, this study examined their content in biopsy specimens and serum of patients with duodenal ulcer disease, compared with non-diseased control subjects. PATIENTS: Endoscopic biopsy specimens were taken 1-2 cm from areas of active inflammation or ulcer (peptic ulcer patients) or just beyond the duodenal bulb (normals) in 35 consecutive subjects. METHODS: After staining for phospholipid, extracellular and intracellular particles were counted on transmission electron micrographs of coded specimens. Serum was obtained from 24 patients, and densitometry of the 59 kDa band detected on western blot by antiserum against human jejunal particle was measured. RESULTS: Normal duodenum (n = 15) contained more particles (44 (4.7)) particles/block, mean (SD) than active duodenal ulcer (n = 13, 17 (3.9)) or gastritis/duodenitis patients (n = 4, 9 (2.7)). Three patients examined after healing of duodenal ulcers showed abundant particles (n = 3, 67 (2.2)). Similarly, the 59 kDa band was decreased in serum of patients with active peptic ulcer disease (n = 11, 0.25 (0.04) absorbance units) compared with normal patients (n = 10, 0.40 (0.03)) or healed ulcers (n = 3, 0.62 (0.04)). There was good correlation between morphological mucosal particle abundance and particle protein content of serum assayed from the same patients (r = 0.831). These changes were independent of Helicobacter pylori status. CONCLUSION: The mucosal and serum content of surfactant-like particles may reflect general mucosal integrity of the enterocytes from which they are derived. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:8949636
Molecular Basis of Asbestos-Induced Lung Disease
Liu, Gang; Cheresh, Paul; Kamp, David W.
Asbestos causes asbestosis and malignancies by molecular mechanisms that are not fully understood. The modes of action underlying asbestosis, lung cancer, and mesothelioma appear to differ depending on the fiber type, lung clearance, and genetics. After reviewing the key pathologic changes following asbestos exposure, we examine recently identified pathogenic pathways, with a focus on oxidative stress. Alveolar epithelial cell apoptosis, which is an important early event in asbestosis, is mediated by mitochondria- and p53-regulated death pathways and may be modulated by the endoplasmic reticulum. We review mitochondrial DNA (mtDNA)-damage and -repair mechanisms, focusing on 8-oxoguanine DNA glycosylase, as well as cross talk between reactive oxygen species production, mtDNA damage, p53, OGG1, and mitochondrial aconitase. These new insights into the molecular basis of asbestos-induced lung diseases may foster the development of novel therapeutic targets for managing degenerative diseases (e.g., asbestosis and idiopathic pulmonary fibrosis), tumors, and aging, for which effective management is lacking. PMID:23347351
Combination analgesic-induced kidney disease: the Australian experience.
Duggin, G G
Analgesic nephropathy is a unique drug-induced kidney disease characterized pathologically by renal papillary necrosis and chronic interstitial nephritis, and is the result of excessive consumption of combination antipyretic analgesics. The clinical features of the disorder relate mainly to the papillary necrosis, renal colic, and obstructive uropathy and the development of chronic renal failure in a small percentage of patients. There are significant geographic variations in the clinical features that may be related to the differing combinations of analgesics. The pathogenesis of the disease is in part related to the kidneys' ability to concentrate drugs in the papillae. The following sequence of events presents a plausible explanation for the evolution of the disease. If a combination of phenacetin and aspirin is ingested, the following steps occur. Phenacetin is converted in the gut and liver to acetaminophen by first-pass metabolism. Acetaminophen is then taken up by the kidney and excreted. During its excretion, acetaminophen becomes concentrated in the papillae of the kidney during physiologic degrees of antidiuresis, the concentration being up to five times the intracellular concentration of other tissues. Acetaminophen undergoes oxidative metabolism by prostaglandin H synthase to a reactive quinoneimine that is conjugated to glutathione. If acetaminophen is present alone, there is sufficient glutathione generated in the papillae to detoxify the reactive intermediate. If the acetaminophen is ingested with aspirin, the aspirin is converted to salicylate and salicylate becomes highly concentrated in both the cortex and papillae of the kidney. Salicylate is a potent depletor of glutathione. The mechanism is not completely understood; however, the inhibition of the production of NADPH via the pentose shunt is a possible explanation. With the cellular glutathione depleted, the reactive metabolite of acetaminophen then produces lipid peroxides and arylation of tissue proteins, ultimately resulting in necrosis of the papillae. PMID:8669429
Serotonergic markers in Parkinson's disease and levodopa-induced dyskinesias.
Cheshire, Perdita; Ayton, Scott; Bertram, Kelly L; Ling, Helen; Li, Abi; McLean, Catriona; Halliday, Glenda M; O'Sullivan, Sean S; Revesz, Tamas; Finkelstein, David I; Storey, Elsdon; Williams, David R
Preclinical animal models implicate serotonin neurons in the pathophysiology of levodopa (l-dopa)-induced dyskinesias in Parkinson's disease (PD), but effective treatment remains elusive. We examined the relationship between serotonin and l-dopa-induced dyskinesias in a pathologically confirmed cohort of PD patients. We obtained brain tissue from 44 PD cases and 17 age-matched controls and assessed monoamine levels and the serotonin and dopamine transporters in the striatum, and the extent of dopaminergic and serotonergic cell preservation in the substantia nigra (SN) and the dorsal raphe nuclei (DRN), respectively. As expected, PD patients demonstrated a severe loss of all dopaminergic markers, including dopamine (P?0.0001) and the dopamine transporter (P?0.0001) in the striatum, and dopaminergic neurons (P?0.001) in the SN, compared with controls. Marked serotonin loss was observed in the caudate (but not putamen) in PD patients compared with controls (P?0.001), but no difference was found in the levels of the serotonin transporter in the striatum or density of serotonergic neurons in the DRN between these groups, suggesting a functional but not structural change in the serotonergic system in PD. No difference was seen in levels of serotonergic and dopaminergic markers in the striatum between PD patients with and without dyskinesias, or between cases separated according to the clinical severity of their dyskinesias. The absence of a correlation between striatal serotonin markers and the incidence and severity of l-dopa-induced dyskinesias suggests that an intact and functioning serotonergic system is not a risk factor for developing dyskinesias in PD. � 2015 International Parkinson and Movement Disorder Society. PMID:25649148
Characterization of nuclear physics targets using Rutherford backscattering and particle induced x-ray emission
Th. Rubehn; G. J. Wozniak; L. Phair; L. G. Moretto; Kin M. Yu
Rutherford backscattering and particle induced x-ray emission have been utilized to precisely characterize targets used in nuclear fission experiments. The method allows for a fast and non destructive determination of target thickness, homogeneity and element composition.
Simvastatin pretreatment prevents ambient particle-induced lung injury in mice.
Ferraro, Sebastian A; Yakisich, Juan S; Gallo, Francisco T; Tasat, Deborah R
Air particulate pollution negatively affects the health of the population exposed, being the lung the main target organ. Simvastatin (SV) is widely used for the prevention and risk reduction of coronary disease. Its pleiotropic effects may provide benefit for lung diseases. Here, we investigated the preventive effect of simvastatin pretreatment on acute intranasal exposure to ROFA (Residual Oil Fly Ash), and UAP (Urban Air Particle from Buenos Aires). Male BALB/c mice were randomized in two groups to receive either saline (control, C) solution or SV (1?mg/kg bw /day; ip) for 14 days. After SV treatment, ROFA or UAP (1?mg/kg bw) or saline were intranasally delivered for 24 hours generating 4 subgroups for the ROFA experiment (C, SV, ROFA and SV+ROFA) and 3 subgroups for the UAP experiment (C, SV, UAP and SV+UAP). Biomarkers of lung injury were examined in BAL cells evaluating total cell number (TCN), cell differential (CD) and superoxide anion generation (O2-), in lung homogenates assessing superoxide dismutase activity (SOD) and tumor necrosis factor ? (TNF?); and in blood samples determining interleukin 6 (IL-6) production. ROFA and UAP produced an acute pulmonary injury, characterized by an increase in BAL, TCN and neutrophilic inflammatory influx, a rise in O2- generation, and production of the proinflammatory TNF? cytokine. SV pretreatment had no significant effect per se on any of these biomarkers but prevented the pulmonary cytotoxicity and inflammation induced by ROFA and UAP. Our results encourage further studies to determine the preventive effects on lung injury induced by air pollutants. PMID:22122302
Aloe vera Induced Biomimetic Assemblage of Nucleobase into Nanosized Particles
Chauhan, Arun; Zubair, Swaleha; Sherwani, Asif; Owais, Mohammad
Aim Biomimetic nano-assembly formation offers a convenient and bio friendly approach to fabricate complex structures from simple components with sub-nanometer precision. Recently, biomimetic (employing microorganism/plants) synthesis of metal and inorganic materials nano-particles has emerged as a simple and viable strategy. In the present study, we have extended biological synthesis of nano-particles to organic molecules, namely the anticancer agent 5-fluorouracil (5-FU), using Aloe vera leaf extract. Methodology The 5-FU nano- particles synthesized by using Aloe vera leaf extract were characterized by UV, FT-IR and fluorescence spectroscopic techniques. The size and shape of the synthesized nanoparticles were determined by TEM, while crystalline nature of 5-FU particles was established by X-ray diffraction study. The cytotoxic effects of 5-FU nanoparticles were assessed against HT-29 and Caco-2 (human adenocarcinoma colorectal) cell lines. Results Transmission electron microscopy and atomic force microscopic techniques confirmed nano-size of the synthesized particles. Importantly, the nano-assembled 5-FU retained its anticancer action against various cancerous cell lines. Conclusion In the present study, we have explored the potential of biomimetic synthesis of nanoparticles employing organic molecules with the hope that such developments will be helpful to introduce novel nano-particle formulations that will not only be more effective but would also be devoid of nano-particle associated putative toxicity constraints. PMID:22403622
Description: Studies have shown that diesel exhaust particles (DEP) worsen respiratory diseases including allergic asthma. The adjuvant effects of DEP in the airways have been widely reported; however, the precise determinants and mechanisms of these effects are ill-defined. S...
Detection of charged particles emitted by electrolytically induced cold nuclear fusion
Ryoichi Taniguchi; Takao Yamamoto; Setsuko Irie
An attempt was made to obtain evidence for electrolytically induced cold nuclear fusion by detecting charged particles associated with the nuclear reaction. Charged particles were detected by a conventional silicon surface barrier detector attached close to the thin foil cathode which formed the bottom of an electrolysis cell. The efficiency and signal-to-noise ratio of this system are higher than those
Evaporation-Induced Particle Microseparations inside Droplets Floating on a Chip
Velev, Orlin D.
Evaporation-Induced Particle Microseparations inside Droplets Floating on a Chip Suk Tai Chang phenomena of colloidal particle transport and separation inside single microdroplets of water floating situated below the F-oil. The droplets floating on these electronically controlled dielectrophoreticliquid
Incipient motion of spherical particles induced by a vortex ring disturbance
Maria-Laura Beninati; Michael McErlean; Michael Krane; Arnold Fontaine
Experiments to characterize the ability of a vortical disturbance to induce incipent motion of a stationary particle resting on a horizontal planar surface are described. The ultimate goal of this study is to assess the role of turbulent boundary layer coherent structures in particle suspension. In this study, a vortex ring plays the role of a model flow disturbance because
Particle-induced damage and subsequent healing of materials: Erosion, corrosion and self-healing coatings
Akihiro Yabuki
This review summarizes research on particle-induced damage and the subsequent repair of metallic materials. Metallic materials are damaged by solid particle impact via two damage processes: repeated plastic deformation and cutting. At a certain low-impact velocity, the particle does not skid, resulting in only plastic deformation with no damage by cutting. The critical impact velocity has been theoretically derived. Self-healing
Thermal fatigue of particle reinforced metal�matrix composite induced by laser heating and mechanical load
S. G. Long; Y. C. Zhou
The thermal fatigue of particle reinforced metal�matrix composite induced by repetition-pulsed laser heating and mechanical load was experimentally and numerically studied. It is found that the fatigue damage is initial at the intersection region of laser irradiated brim region and the perpendicular direction of tensile load. The initial damage is induced by void nucleation, growth and subsequent coalescence in the
Toxicity of aged gasoline exhaust particles to normal and diseased airway epithelia
K�nzi, Lisa; Krapf, Manuel; Daher, Nancy; Dommen, Josef; Jeannet, Natalie; Schneider, Sarah; Platt, Stephen; Slowik, Jay G.; Baumlin, Nathalie; Salathe, Matthias; Pr�v�t, Andr� S. H.; Kalberer, Markus; Str�hl, Christof; D�mbgen, Lutz; Sioutas, Constantinos; Baltensperger, Urs; Geiser, Marianne
Particulate matter (PM) pollution is a leading cause of premature death, particularly in those with pre-existing lung disease. A causative link between particle properties and adverse health effects remains unestablished mainly due to complex and variable physico-chemical PM parameters. Controlled laboratory experiments are required. Generating atmospherically realistic aerosols and performing cell-exposure studies at relevant particle-doses are challenging. Here we examine gasoline-exhaust particle toxicity from a Euro-5 passenger car in a uniquely realistic exposure scenario, combining a smog chamber simulating atmospheric ageing, an aerosol enrichment system varying particle number concentration independent of particle chemistry, and an aerosol deposition chamber physiologically delivering particles on air-liquid interface (ALI) cultures reproducing normal and susceptible health status. Gasoline-exhaust is an important PM source with largely unknown health effects. We investigated acute responses of fully-differentiated normal, distressed (antibiotics-treated) normal, and cystic fibrosis human bronchial epithelia (HBE), and a proliferating, single-cell type bronchial epithelial cell-line (BEAS-2B). We show that a single, short-term exposure to realistic doses of atmospherically-aged gasoline-exhaust particles impairs epithelial key-defence mechanisms, rendering it more vulnerable to subsequent hazards. We establish dose-response curves at realistic particle-concentration levels. Significant differences between cell models suggest the use of fully-differentiated HBE is most appropriate in future toxicity studies. PMID:26119831
The preferential targeting of the diseased microvasculature by disk-like particles
Adriani, Giulia; de Tullio, Marco D.; Ferrari, Mauro; Hussain, Fazle; Pascazio, Giuseppe; Liu, Xuewu; Decuzzi, Paolo
Different classes of nanoparticles (NPs) have been developed for controlling and improving the systemic administration of therapeutic and contrast agents. Particle shape has been shown to be crucial in the vascular transport and adhesion of NPs. Here, we use mesoporous silicon non-spherical particles, of disk and rod shapes, ranging in size from 200 nm to 1800 nm. The fabrication process of the mesoporous particles is described in detail, and their transport and adhesion properties under flow are studied using a parallel plate flow chamber. Numerical simulations predict the hydrodynamic forces on the particles and help in interpreting their distinctive behaviors. Under microvascular flow conditions, for disk-like shape, 1000�400 nm particles show maximum adhesion, whereas smaller (600�200 nm) and larger (1800�600 nm) particles adhere less by a factor of about two. Larger rods (1800�400 nm) are observed to adhere at least 3 times more than smaller ones (1500�200 nm). For particles of equal volumes, disks adhere about 2 times more than rods. Maximum adhesion for intermediate sized disks reflects the balance between adhesive interfacial interactions and hydrodynamic dislodging forces. In view of the growing evidence on vascular molecular heterogeneity, the present data suggest that thin disk-like particles could more effectively target the diseased microvasculature as compared to spheres and slender rods. PMID:22579236
Toxicity of aged gasoline exhaust particles to normal and diseased airway epithelia.
K�nzi, Lisa; Krapf, Manuel; Daher, Nancy; Dommen, Josef; Jeannet, Natalie; Schneider, Sarah; Platt, Stephen; Slowik, Jay G; Baumlin, Nathalie; Salathe, Matthias; Pr�v�t, Andr� S H; Kalberer, Markus; Str�hl, Christof; D�mbgen, Lutz; Sioutas, Constantinos; Baltensperger, Urs; Geiser, Marianne
Particulate matter (PM) pollution is a leading cause of premature death, particularly in those with pre-existing lung disease. A causative link between particle properties and adverse health effects remains unestablished mainly due to complex and variable physico-chemical PM parameters. Controlled laboratory experiments are required. Generating atmospherically realistic aerosols and performing cell-exposure studies at relevant particle-doses are challenging. Here we examine gasoline-exhaust particle toxicity from a Euro-5 passenger car in a uniquely realistic exposure scenario, combining a smog chamber simulating atmospheric ageing, an aerosol enrichment system varying particle number concentration independent of particle chemistry, and an aerosol deposition chamber physiologically delivering particles on air-liquid interface (ALI) cultures reproducing normal and susceptible health status. Gasoline-exhaust is an important PM source with largely unknown health effects. We investigated acute responses of fully-differentiated normal, distressed (antibiotics-treated) normal, and cystic fibrosis human bronchial epithelia (HBE), and a proliferating, single-cell type bronchial epithelial cell-line (BEAS-2B). We show that a single, short-term exposure to realistic doses of atmospherically-aged gasoline-exhaust particles impairs epithelial key-defence mechanisms, rendering it more vulnerable to subsequent hazards. We establish dose-response curves at realistic particle-concentration levels. Significant differences between cell models suggest the use of fully-differentiated HBE is most appropriate in future toxicity studies. PMID:26119831
Marek's disease virus induced transient paralysis--a closer look
Technology Transfer Automated Retrieval System (TEKTRAN)
Marek�s Disease (MD) is a lymphoproliferative disease of domestic chickens caused by a highly cell-associated alpha herpesvirus, Marek�s disease virus (MDV). Clinical signs of MD include depression, crippling, weight loss, and transient paralysis (TP). TP is a disease of the central nervous system...
Needle-shaped polymeric particles induce transient disruption of cell membranes
Doshi, Nishit; Mitragotri, Samir
Nano- and microparticles of various shapes have recently been introduced for various drug-delivery applications. Shape of particles has been shown to have an impact on various processes including circulation, vascular adhesion and phagocytosis. Here, we assess the role of particle geometry and surface chemistry in their interactions with cell membranes. Using representative particles of different shape (spheres, elongated and flat particles), size (500 nm�1 �m) and surface chemistry (positively and negatively charged), we evaluated the response of endothelial cells to particles. While spherical and elliptical disc-shaped particles did not have an impact on cell spreading and motility, needle-shaped particles induced significant changes in the same. Further studies revealed that needle-shaped particles induced disruption of cell membranes as indicated by the release of lactate dehydrogenase and uptake of extracellular calcein. The effect of needle-shaped particles on cells was transient and was reversed over a time period of 1�48 h depending on particle parameters. PMID:20504803
Effect of induced electric field on migration of a charged porous particle.
Gopmandal, Partha P; Bhattacharyya, S; Barman, Bhanuman
The effect of ambient fluid flow on a charged porous spherical particle suspended in an aqueous medium is analyzed. The porous particle is ion permeable and fluid penetrable. The induced electric field due to the polarization of the particle's electric double layer and counterion condensation leads to a hindrance effect on particle migration by producing an electric force. The influence of this retardation force on the hydrodynamics of the particle is studied through the Nernst-Planck equations, which are coupled with the Stokes-Brinkman equation. The interactions of the double-layer polarization, shielding effect, electroosmosis of unbalanced ions and fluid convection are analyzed. The settling velocity and fluid collection efficiency of the charged aggregate is determined. We have studied the electrokinetics for a wide range of fixed charge density and permeability of the particle with no assumption made on the thickness of the double layer relative to the dimension of the particle. PMID:25374308
Enhanced homologous recombination is induced by alpha-particle radiation in somatic cells of Arabidopsis thaliana
NASA Astrophysics Data System (ADS)
Bian, Po; Liu, Ping; Wu, Yuejin
Almost 9 percent of cosmic rays which strike the earth's atmosphere are alpha particles. As one of the ionizing radiations (IR), its biological effects have been widely studied. However, the plant genomic instability induced by alpha-particle radiation was not largely known. In this research, the Arabidopsis thaliana transgenic for GUS recombination substrate was used to evaluate the genomic instability induced by alpha-particle radiation (3.3MeV). The pronounced effects of systemic exposure to alpha-particle radiation on the somatic homologous recombination frequency (HRF) were found at different doses. The 10Gy dose of radiation induced the maximal HRF which was 1.9-fold higher than the control. The local radiation of alpha-particle (10Gy) on root also resulted in a 2.5-fold increase of somatic HRF in non-radiated aerial plant, indicating that the signal(s) of genomic instability was transferred to non-radiated parts and initiated their genomic instability. Concurrent treatment of seedlings of Arabidopsis thaliana with alpha-particle and DMSO(ROS scavenger) both in systemic and local radiation signifi- cantly suppressed the somatic HR, indicating that the free radicals produced by alpha-particle radiation took part in the production of signal of genomic instability rather than the signal transfer. Key words: alpha-particle radiation, somatic homologous recombination, genomic instability
On the effect of induced electro-osmosis on a cylindrical particle next to a surface.
Zhao, Hui; Bau, Haim H
The effect of induced electro-osmosis on a cylindrical particle positioned next to a planar surface (wall) is studied theoretically both under the thin double layer approximation utilizing the Smoluchowski slip velocity approximation and under thick electric double layer conditions by solving the Poisson-Nernst-Planck (PNP) equations. The imposed, undisturbed electric field is parallel to the planar surface. The induced hydrodynamic and electrostatic forces are calculated as functions of the particle's and the medium's dielectric constants and the distance between the particle and the surface. The resultant force acting on the particle is directed normal to and away from the wall. The presence of such a repulsive force may adversely affect the interactions between macromolecules suspended in solution and wall-immobilized molecules and may be significant to near-wall particle imaging velocimetry (PIV) in electrokinetic flows. PMID:17311434
Apoptotic and inflammatory effects induced by different particles in human alveolar macrophages.
Huang, Yuh-Chin T; Li, Zhuowei; Harder, Shirley D; Soukup, Joleen M
Pollutant particles induce apoptosis and inflammation, but the relationship between these two biological processes is not entirely clear. In this study, we compared the proapoptotic and proinflammatory effects of four particles: residual oil fly ash (ROFA), St. Louis particles SRM 1648 (SL), Chapel Hill PM10 (CHP), and Mount St. Helens dust (MSH). Human alveolar macrophages (AM) were incubated with these particles at 100 microg/ml. Cell death was assessed by annexin V (AV) expression, histone release, nuclear morphology, caspase 3-like activity and release of caspase 1 for apoptosis, and propidium iodide (PI) for necrosis, and inflammation was measured by interleukin (IL)-1beta and IL-6. We found that particle effects on these cell death measurements varied, and ROFA affected most (four out of five) endpoints, including nuclear morphological changes. CHP and SL also caused necrosis. For cytokine release, the potency was CHP > SL > ROFA > MSH. The proapoptotic and proinflammatory effects induced by the whole particles were unaltered after the particles were washed with water. The water-soluble fraction was relatively inactive, as were individual soluble metals (V, Ni, Fe). ROFA-induced nuclear fragmentation was associated with upregulation and mitochondrial release of apoptosis-inducing factor (AIF), a caspase-independent chromatin condensation factor, and upregulation of DNase II, a lysosomal acid endonuclease. These results indicate that the potential for particles to induce apoptosis does not correlate with their proinflammatory properties, although active components for both processes reside in the water-insoluble core. Both apoptosis and inflammatory endpoints should be included when the toxicity of different pollutant particles is assessed. PMID:15764474
T cells reactive to an inducible heat shock protein induce disease in toxin-induced interstitial nephritis
T cells reactive against immunodominant regions of inducible heat shock proteins (HSPs) have been identified in the chronic inflammatory lesions of several experimental autoimmune diseases. Since HSPs are known to be induced by a number of renal tubular epithelial cell toxins associated with chronic interstitial nephritis, we investigated the relevance of HSP expression and T cell reactivity to HSP70 in a model of progressive inflammatory interstitial nephritis. Chronic administration of cadmium chloride (CdCl2) to SJL/J mice induces HSP70 expression in renal tubular cells 4-5 wk before the development of interstitial mononuclear cell infiltrates. CdCl2 also induces HSP70 expression in cultured tubular epithelial cells from SJL/J mice. CD4+, TCR-alpha/beta+ T cell lines specific for an immunodominant HSP peptide are cytotoxic to heat stressed or CdCl2-treated renal tubular cells. Such HSP-reactive T cells mediate an inflammatory interstitial nephritis after adoptive transfer to CdCl2-treated mice at a time when immunoreactive HSP70 is detectable in the kidneys, but before the development of interstitial mononuclear cell infiltrates. T cells isolated from the nephritic kidneys of mice treated with CdCl2 for 13 wk are also cytotoxic to heat shocked or cadmium-treated tubular cells. These kidney-derived T cells additionally induced interstitial nephritis after passive transfer, indicating their pathogenic significance. Our studies strongly support a role for HSP-reactive T cells in CdCl2-induced interstitial nephritis and suggest that the induction of HSPs in the kidney by a multitude of "non-immune" events may initiate or facilitate inflammatory damage by HSP-reactive lymphocytes. PMID:7964497
Synchronization of particle motion induced by mode coupling in a two-dimensional plasma crystal.
Cou�del, L; Zhdanov, S; Nosenko, V; Ivlev, A V; Thomas, H M; Morfill, G E
The kinematics of dust particles during the early stage of mode-coupling induced melting of a two-dimensional plasma crystal is explored. It is found that the formation of the hybrid mode causes the particle vibrations to partially synchronize at the hybrid frequency. Phase- and frequency-locked hybrid particle motion in both vertical and horizontal directions (hybrid mode) is observed. The system self-organizes in a rhythmic pattern of alternating in-phase and antiphase oscillating chains of particles. The spatial orientation of the synchronization pattern correlates well with the directions of the maximal increment of the shear-free hybrid mode. PMID:25353905
A self-consistent theory of collective alpha particle losses induced by Alfvenic turbulence
Biglari, H. [Princeton Univ., NJ (United States). Plasma Physics Lab.; Diamond, P.H. [California Univ., San Diego, La Jolla, CA (United States). Dept. of Physics
The nonlinear dynamics of kinetic Alfven waves, resonantly excited by energetic ions/alpha particles, is investigated. It is shown that {alpha}-particles govern both linear instability and nonlinear saturation dynamics, while the background MHD turbulence results only in a nonlinear real frequency shift. The most efficient saturation mechanism is found to be self-induced profile modification. Expressions for the fluctuation amplitudes and the {alpha}-particle radial flux are self-consistently derived. The work represents the first self-consistent, turbulent treatment of collective {alpha}-particle losses by Alfvenic fluctuations.
Manipulation of quantum particles in rapidly oscillating potentials by inducing phase hops
Armin Ridinger; Christoph Weiss
Analytical calculations show that the mean-motion of a quantum particle trapped by a rapidly oscillating potential can be significantly manipulated by inducing phase hops, i.e., by instantaneously changing the potential's phase. A phase hop can be visualized as being the result of a collision with an imaginary particle which can be controlled. Several phase hops can have accumulating effects on the particle's mean-motion, even if they transform the particle's Hamiltonian into its initial one. The theoretical predictions are verified by numerical simulations for the one-dimensional Paul-trap.
Stochastic electrodynamics with particle structure Part I: Zero-point induced Brownian behavior
NASA Astrophysics Data System (ADS)
Rueda, A.
If ordinary views on particle structure are introduced in a simple classical particle model in replacement of the point particles of standard use in stochastic electrodynamics, it can be shown that an internal Zitterbewegung induced by the zero-point field background gives rise to a Brownian movement for the whole particle with a diffusion constant of the form D = ?/2mD , where mD is a modeldependent mass. Since the days of Madeleung and Fuhr brownian behaviour has often been associated with quantization. We discuss this from the viewpoint of stochastic electrodynamics.
Pan, Liubin [Harvard-Smithsonian Center for Astrophysics, 60 Garden St., Cambridge, MA 02138 (United States); Padoan, Paolo, E-mail: email@example.com, E-mail: firstname.lastname@example.com [ICREA and ICC, University of Barcelona, Marti i Franqu�s 1, E-08028 Barcelona (Spain)
We study the relative velocity of inertial particles suspended in turbulent flows and discuss implications for dust particle collisions in protoplanetary disks. We simulate a weakly compressible turbulent flow, evolving 14 particle species with friction timescale, ?{sub p}, covering the entire range of scales in the flow. The particle Stokes numbers, St, measuring the ratio of ?{sub p} to the Kolmogorov timescale, are in the range 0.1 ?< St ?< 800. Using simulation results, we show that the model by Pan and Padoan gives satisfactory predictions for the rms relative velocity between identical particles. The probability distribution function (PDF) of the relative velocity is found to be highly non-Gaussian. The PDF tails are well described by a 4/3 stretched exponential function for particles with ?{sub p} ? 1-2 T{sub L}, where T{sub L} is the Lagrangian correlation timescale, consistent with a prediction based on PP10. The PDF approaches Gaussian only for very large particles with ?{sub p} ?> 54 T{sub L}. We split particle pairs at given distances into two types with low and high relative speeds, referred to as continuous and caustic types, respectively, and compute their contributions to the collision kernel. Although amplified by the effect of clustering, the continuous contribution vanishes in the limit of infinitesimal particle distance, where the caustic contribution dominates. The caustic kernel per unit cross section rises rapidly as St increases toward ? 1, reaches a maximum at ?{sub p} ? 2 T{sub L}, and decreases as ?{sub p}{sup -1/2} for ?{sub p} >> T{sub L}.
Radiation-induced damage in GaAs particle detectors
R. L. Bates; C. Da Via; A. Pickford; C. Raine; K. M. Smith
The motivation for investigating the use of GaAs as a material for detecting particles in experiments for high-energy physics (HEP) arose from its perceived resistance to radiation damage. This is a vital requirement for detector materials that are to be used in experiments at future accelerators where the radiation environments would exclude all but the most radiation resistant of detector
The potential role of strontium ranelate in treating particle-induced osteolysis.
Lu, Yung-Chang; Chang, Ting-Kuo; Yeh, Shu-Ting; Fang, Hsu-Wei; Lin, Chun-Yen; Hsu, Lin-I; Huang, Chun-Hsiung; Huang, Chang-Hung
Ultra high molecular weight polyethylene (UHMWPE) wear-particle-induced osteolysis is one of the major issues affecting the long-term survival of total joint prostheses. Currently, there are no effective therapeutic options to prevent osteolysis from occurring. The aim of this study was to evaluate the role of strontium ranelate (SR) in reducing the risk of particle-induced osteolysis. Forty-eight C57BL/6J ultra-high molecular weight polyethylene (UHMWPE) particle-induced murine calvarial osteolysis models were used. The mice were randomized into four groups as: sham (Group 1), UHMWPE particles (Group 2), and SR with UHMWPE particles (Group 3 and Group 4). Groups 1 to 3 were sacrificed at two weeks and group 4 was sacrificed at the fourth week. The skulls were then analyzed with a high-resolution micro-CT. Histological evaluation was then conducted and osteoclast numbers were analyzed for comparison. Based on the micro-CT, percentage bone volume and trabecular thickness were found to be significantly higher in Group 4 than in Group 2 (p<0.001). Osteoclast numbers in SR treated groups (Group 3 and Group 4) were reduced when compared to groups that did not receive SR treatment (Group 2). These results indicated that SR treatment helps to increase bone volume percentage and trabecular thickness and also suppresses osteoclast proliferation. It is suggested that oral SR treatment could serve as an alternative therapy for preventing particle-induced osteolysis. PMID:25841346
Foot and mouth disease (FMD) virus: Quantification of whole virus particles during the vaccine manufacturing process by size exclusion chromatography
Marcelo A. Spitteler; Ignacio Fern�ndez; Erika Schabes; Alejandro Krimer; Emmanuel G. R�gulier; Mariela Guinzburg; Eliana Smitsaart; M. Susana Levy
Foot and mouth disease (FMD) is a highly infectious viral disease that affects cattle, sheep, goats and swine causing severe economic losses worldwide. The efficacy of inactivated vaccines is critically dependent on the integrity of foot and mouth disease virus (FMDV) particles. The recommended method to quantify the active ingredient of vaccines is the 140S quantitative sucrose density gradient analysis.
Induced pluripotent stem cells � opportunities for disease modelling and drug discovery
Marica Grskovic; Ashkan Javaherian; Berta Strulovici; George Q. Daley
The ability to generate induced pluripotent stem cells (iPSCs) from patients, and an increasingly refined capacity to differentiate these iPSCs into disease-relevant cell types, promises a new paradigm in drug development � one that positions human disease pathophysiology at the core of preclinical drug discovery. Disease models derived from iPSCs that manifest cellular disease phenotypes have been established for several
Pollutant particles induce arginase II in human bronchial epithelial cells
Exposure to particulate matter (PM) is associated with adverse pulmonary effects, including induction and exacerbation of asthma. Recently arginase was shown to play an important role in the pathogenesis of asthma. In this study, we hypothesized that PM exposure would induce ar...
Experimental Investigation of Fluid and Particle Motion in Shear-Induced Scour
NASA Astrophysics Data System (ADS)
An, Zhongfeng; Krueger, Paul
A submerged particle bed subjected to fluid shear exhibits particle motion (scour) induced by drag and lift forces from the fluid at sufficiently high shear rates. To investigate this behavior, a particle bed was subjected to fluid shear in a narrow rectangular channel. The flow was driven by a pump for channel Reynolds numbers in the range 3500 - 6000. The particle bed consisted of monodisperse borosilicate glass spheres at several initial particle bed heights. The velocity field of the continuous phase was measured using digital particle image velocimetry (DPIV), while the velocities of the particles were obtained by image segmentation and processing of the dispersed phase from the DPIV images. To aide in visualizing the flow, the working fluid was an aqueous solution of sodium iodide with a refractive index matched to the particles. Comparing the velocity of the two phases, a particle velocity lag was observed at higher elevations, suggesting drag was the dominant fluid force on the particles, while observations of the particle motion indicated that collisions were important near the bed surface. Effects of different flow and initial conditions will be discussed. This material is based upon work supported by the National Science Foundation under Grant No. 1000908.
Energetic particle-induced enhancements of stratospheric nitric acid
NASA Technical Reports Server (NTRS)
Aikin, Arthur C.
Inclusion of complete ion chemistry in the calculation of minor species production during energetic particle deposition events leads to significant enhancement in the calculated nitric acid concentration during precipitation. An ionization rate of 1.2 x 10(exp 3)/cu cm/s imposed for 1 day increases HNO3 from 3 x 10(exp 5) to 6 x 10(exp 7)/cu cm at 50 km. With an ionization rate of 600 cu cm/s, the maximum HNO3 is 3 x 10(exp 7)/cu cm. Calculations which neglect negative ions predict the nitric acid will fall during precipitation events. The decay time for converting HNO3 into odd nitrogen and hydrogen is more than 1 day for equinoctial periods at 70 deg latitude. Examination of nitric acid data should yield important information on the magnitude and frequency of charged particle events.
Disorder-induced breakdown of soliton and polaron particles
Bishop, A.R.; Cai, D.; Gronbech-Jensen, N.; Salkola, M.I.
Using examples of the perturbed (1+1) dimensional sine-Gordon, the continuous and discrete nonlinear Schroedinger systems, and a three-site quantum polaron problem, the authors briefly review some phenomena related to the fascinating interplays between nonlinearity, disorder, noise, nonadiabaticity, and lattice discreteness. The concept of competing length-scales and time-scales is emphasized as they pertain to the common concept of solitons and polarons behaving as {open_quotes}particles.{close_quotes}
Rotavirus Virus-Like Particles Administered Mucosally Induce Protective Immunity
We have evaluated the immunogenicity and protective efficacy of rotavirus subunit vaccines administered by mucosal routes. Virus-like particles (VLPs) produced by self-assembly of individual rotavirus structural proteins coexpressed by baculovirus recombinants in insect cells were the subunit vaccine tested. We first compared the immunogenicities and protective efficacies of VLPs containing VP2 and VP6 (2\\/6-VLPs) and G3 2\\/6\\/7-VLPs mixed with cholera
Binding of (-)-epigallocatechin-3-gallate with thermally-induced bovine serum albumin/?-carrageenan particles.
Li, Jinbing; Wang, Xiaoyong
Novel thermally-induced BSA/?-carrageenan particles are used as a protective carrier for (-)-epigallocatechin-3-gallate (EGCG). The addition of EGCG to BSA/?-carrageenan particles can highly quench the intrinsic fluorescence of BSA, which is explained in terms of the binding of EGCG to the hydrophobic pockets of BSA mainly through the hydrophobic force. According to the double logarithm equation, the binding constant is determined as 1.1�10(8)M(-1) for the binding of EGCG with BSA/?-carrageenan particles. The high binding affinity is ascribed to both the molecular structure of EGCG and the partial unfolding state of BSA in BSA/?-carrageenan particles. The circular dichroism spectra and calculated ?-helix of BSA suggest that the bound EGCG leads to a more random secondary structure of BSA. Furthermore, BSA/?-carrageenan particles are found to be superior to native BSA and pure BSA particles for improving the stability and radical scavenging activity of EGCG. PMID:25172749
Accelerometric assessment of levodopa-induced dyskinesias in Parkinson's disease.
Hoff, J I; van den Plas, A A; Wagemans, E A; van Hilten, J J
Our objective was to develop parameters for objective ambulatory measurements of levodopa-induced dyskinesias (LID) in patients with Parkinson's disease (PD). Twenty-three PD patients with mild to severe LID were submitted to a standardized protocol of 1-minute recordings during rest, talking, stress, and four activities of daily life (ADL). Patients were simultaneously monitored with portable multi-channel accelerometry (four pairs of bi-axial sensors mounted onto the most affected arm, leg, and at the trunk) and recorded by video. LID severity was assessed with a modified Abnormal Involuntary Movement Scale (m-AIMS). The signals were analyzed, and every 1/8-second interval the amplitude was obtained of the dominant frequency within 1-4 Hz and 4-8 Hz frequency bands (Amp1-4 and Amp4-8). For both measures, convergent validity, reproducibility, and responsiveness were determined. In absence of voluntary movements, a significant relation was found between Amp1-4 and Amp4-8 and m-AIMS. Repeated measurements during rest showed a high reproducibility (intraclass correlation coefficient = 0.90 [Amp1-4] and 0.86 [Amp4-8]). The extent to which LID increased with talking and stress correlated significantly (p = 0.02) between the objective and clinical measures (intraclass correlation for differences = 0.67). During ADL, LID occurred in a similar frequency band as voluntary movements and only Amp1-4 and Amp4-8 of the trunk and leg sensor remained highly correlated with m-AIMS. Although objective measures of LID are reliable and responsive, they fail to distinguish LID from voluntary movements. These measures are of value only when obtained during rest (all sensor sites) or during ADL when derived from those body segments that are normally not involved in these ADL tasks (trunk and leg). PMID:11215593
PINK1-induced mitophagy promotes neuroprotection in Huntington's disease.
Khalil, B; El Fissi, N; Aouane, A; Cabirol-Pol, M-J; Rival, T; Li�vens, J-C
Huntington's disease (HD) is a fatal neurodegenerative disorder caused by aberrant expansion of CAG repeat in the huntingtin gene. Mutant Huntingtin (mHtt) alters multiple cellular processes, leading to neuronal dysfunction and death. Among those alterations, impaired mitochondrial metabolism seems to have a major role in HD pathogenesis. In this study, we used the Drosophila model system to further investigate the role of mitochondrial damages in HD. We first analyzed the impact of mHtt on mitochondrial morphology, and surprisingly, we revealed the formation of abnormal ring-shaped mitochondria in photoreceptor neurons. Because such mitochondrial spheroids were previously detected in cells where mitophagy is blocked, we analyzed the effect of PTEN-induced putative kinase 1 (PINK1), which controls Parkin-mediated mitophagy. Consistently, we found that PINK1 overexpression alleviated mitochondrial spheroid formation in HD flies. More importantly, PINK1 ameliorated ATP levels, neuronal integrity and adult fly survival, demonstrating that PINK1 counteracts the neurotoxicity of mHtt. This neuroprotection was Parkin-dependent and required mitochondrial outer membrane proteins, mitofusin and the voltage-dependent anion channel. Consistent with our observations in flies, we demonstrated that the removal of defective mitochondria was impaired in HD striatal cells derived from HdhQ111 knock-in mice, and that overexpressing PINK1 in these cells partially restored mitophagy. The presence of mHtt did not affect Parkin-mediated mitochondrial ubiquitination but decreased the targeting of mitochondria to autophagosomes. Altogether, our findings suggest that mitophagy is altered in the presence of mHtt and that increasing PINK1/Parkin mitochondrial quality control pathway may improve mitochondrial integrity and neuroprotection in HD. PMID:25611391
The Role of MAC1 in Diesel Exhaust Particle-induced Microglial Activation and Loss of Dopaminergic Neuron Function
Levesque, Shannon; Taetzsch, Thomas; Lull, Melinda E.; Johnson, Jo Anne; McGraw, Constance; Block, Michelle L.
Increasing reports support that air pollution causes neuroinflammation and is linked to central nervous system (CNS) disease/damage. Diesel exhaust particles (DEP) are a major component of urban air pollution, which has been linked to microglial activation and Parkinson�s disease-like pathology. To begin to address how DEP may exert CNS effects, microglia and neuron-glia cultures were treated with either nanometer-sized DEP (<0.22 �M; 50�g/mL), ultrafine carbon black (ufCB, 50�g/ml), or DEP extracts (eDEP; from 50 �g/ml DEP) and the effect of microglial activation and dopaminergic (DA) neuron function was assessed. All three treatments showed enhanced amoeboid microglia morphology, increased H2O2 production, and decreased DA uptake. Mechanistic inquiry revealed that the scavenger receptor inhibitor fucoidan blocked DEP internalization in microglia, but failed to alter DEP-induced H2O2 production in microglia. However, pretreatment with the MAC1/CD11b inhibitor antibody blocked microglial H2O2 production in response to DEP. MAC1?/? mesencephalic neuron-glia cultures were protected from DEP-induced loss of DA neuron function, as measured by DA uptake. These findings support that DEP may activate microglia through multiple mechanisms, where scavenger receptors regulate internalization of DEP and the MAC1 receptor is mandatory for both DEP-induced microglial H2O2 production and loss of DA neuron function. PMID:23470120
Avian adenovirus CELO recombinants expressing VP2 of infectious bursal disease virus induce protection against bursal disease in chickens
Achille Francois; Christophe Chevalier; Bernard Delmas; Nicolas Eterradossi; Didier Toquin; Ga�lle Rivallan; Patrick Langlois
To develop a CELO virus vector that can induce protection against infectious bursal disease, CELO viruses expressing the host-protective antigen VP2 of infectious bursal disease virus (IBDV) were constructed. In the engineered recombinants, the VP2 gene (the 441-first codons of the IBDA polyprotein) was placed under the control of the CMV promoter. Two positions in the CELO genome were chosen
MRI findings in Hirayama�s disease: flexion-induced cervical myelopathy or intrinsic motor neuron disease?
Rolf Schr�der; Ewald Keller; Sebastian Flacke; Stephan Schmidt; Christoph Pohl; Thomas Klockgether; Uwe Schlegel
Hirayama�s disease is a benign juvenile form of focal amyotrophy affecting the upper limbs. Previous studies have suggested\\u000a that the disorder is a neck flexion induced cervical myelopathy. We report clinical and magnetic resonance imaging findings\\u000a in nine patients with Hirayama�s disease. Cervical imaging of seven patients revealed spinal cord changes consisting of focal\\u000a atrophy and foci of signal alterations.
Flow-induced segregation in confined multicomponent suspensions: Effects of particle size and rigidity
NASA Astrophysics Data System (ADS)
Graham, Michael; Kumar, Amit
The effects of particle size and rigidity on segregation in confined flow of binary suspensions of fluid-filled capsules are investigated in a model system resembling whole blood. We study this problem using a boundary integral method as well as with a master equation model that incorporates wall-induced migration and hydrodynamic pair collisions. Boundary integral results indicate that, in a mixture of large and small particles, the small particles marginate, while the large particles antimarginate. Here margination refers to localization of particles near walls, while antimargination refers to the opposite. In a mixture of particles with equal size and unequal stiffness, the stiffer particles marginate while the flexible ones antimarginate. The master equation model traces the origins of these behaviors to the size and rigidity dependence of the wall-induced migration velocity and of the cross-stream particle displacements in various types of collisions. Finally, a set of coupled non-local drift-diffusion equations is derived, providing further insights in terms of the drift and diffusion of various species.
Induced phagocytic particle uptake into a giant unilamellar vesicle.
Meinel, Andreas; Tr�nkle, Benjamin; R�mer, Winfried; Rohrbach, Alexander
Phagocytosis, the uptake and ingestion of solid particles into living cells, is a central mechanism of our immune system. Due to the complexity of the uptake mechanism, the different forces involved in this process are only partly understood. Therefore the usage of a giant unilamellar vesicle (GUV) as the simplest biomimetic model for a cell allows one to investigate the influence of the lipid membrane on the energetics of the uptake process. Here, a photonic force microscope (PFM) is used to approach an optically trapped 1 ?m latex bead to an immobilized GUV to finally insert the particle into the GUV. By analysing the mean displacement and the position fluctuations of the trapped particle during the uptake process in 3D with nanometre precision, we are able to record force and energy profiles, as well as changes in the viscous drag and the stiffness. After observing a global followed by a local deformation of the GUV, we measured uptake energies of 2000 kT to 5500 kT and uptake forces of 4 pN to 16 pN for Egg-PC GUVs with sizes of 18-26 ?m and varying membrane tension. The measured energy profiles, which are compared to a Helfrich energy model for local and global deformation, show good coincidence with the theoretical results. Our proof-of-principle study opens the door to a large number of similar experiments with GUVs containing more biochemical components and complexity. This bottom-up strategy should allow for a better understanding of the physics of phagocytosis. PMID:24676395
Wave induced transport and mixing of buoyant particles
NASA Astrophysics Data System (ADS)
Drivdal, Magnus; Brostr�m, G�ran; Christensen, Kai H.
The modeling of wave-current and wave-turbulence interactions have received much attention during recent years. Both the breaking of surface waves and the inclusion of the Stokes shear production have been shown to increase the upper ocean turbulence. Furthermore the Coriolis force acting on the Stokes drift redistributes the momentum in the upper ocean, leading to a deflection of the currents. An important application affected by these processes that still needs to be studied is the mixing and drift of particles. Using an ocean column model, modified to take surface wave effects into account, we investigate how the increased mixing by wave breaking and Stokes shear production as well as the stronger veering by the Coriolis-Stokes force effects the drift of suspended particles. Here the suspended particles are buoyant tracers that can represent oil droplets or plankton, for example fish eggs and larvae. The energy and momentum fluxes as well as the Stokes drift depend on the directional wave spectrum that can be obtained from a wave model or from observations. Comparing with classical Ekman theory some physical effects on the system are studied, and as a realistic test case we use the model to study the oil drift after an offshore oil spill that took place outside the western coast of Norway in 2007. During this accident the average net drift of oil was observed to be approximately 0.1% of the wind speed at an angle of about 90-120 degrees to the right, far slower and more deflected away from the wind direction than predicted by both numerical and empirical models. With wind and wave forcing from ECMWF reanalysis data, it is shown that the wave effects are important for the resultant drift in this case, and has the potential to improve drift forecasting.
Collective two-particle resonances induced by photon entanglement
NASA Astrophysics Data System (ADS)
Richter, Marten; Mukamel, Shaul
An assembly of noninteracting atoms may become correlated upon interaction with entangled photons, and certain elements of their joint density matrix can then show collective resonances. We explore experimental signatures of these resonances in the nonlinear response of a pair of two-level atoms. We find that these resonances are canceled out in stimulated signals such as pump-probe and two-photon absorption due to the destructive interference of two-photon-absorption and emission pathways in the joint two-particle space. However, they may be observed in photon statistics (Hanbury-Brown-Twiss) measurements through the attenuation of two-time intensity correlations.
Coarsening of extracellularly biosynthesized cadmium crystal particles induced by thioacetamide in solution.
Chen, Gui-Qiu; Zou, Zheng-Jun; Zeng, Guang-Ming; Yan, Ming; Fan, Jia-Qi; Chen, An-Wei; Yang, Fan; Zhang, Wen-Juan; Wang, Liang
A novel coarsening route for extracellularly biosynthesized cadmium nanocrystals was investigated for the first time. In this process, the white rot fungus Coriolus versicolor was employed to take up cadmium ions and synthesize extracellular cadmium crystal particles. The coarsening of the particles was induced by thioacetamide under certain conditions. Scanning electron microscopy showed that the formed cadmium crystal particles were coarsened from about 100nm to 2-3?m. The corresponding energy-dispersive X-ray spectra confirmed the presence of proteins in the particles. The maximum removal efficiency of Cd(II) increased from 17% to 87%, and the corresponding sorption capacity of biomass increased from 4 to 24mgg(-1) with the completion of the coarsening process. The properties of the coarsened particles were also examined using X-ray diffraction (XRD) and transmission electron microscopy (TEM). XRD analysis of fungal mycelial pellets embedded with the coarsened particles confirmed the formation of cubic crystalline cadmium sulfide particles. The TEM results suggest that the coarsened particles were composed of clusters of several smaller particles. The changes in the functional groups on the biomass surface were studied through Fourier transform infrared spectroscopy. Based on the results above, a possible mechanism for the formation and coarsening of cadmium crystal particle is also discussed. PMID:21489598
Intracisternal Type A Particles Occurring in Foreign Body-induced Sarcomas1
Kenneth H. Johnson; Helmy K. G. Ghobrial; Lance C. Buoen; Inge Brand; K. Gerhard Brand
SUMMARY Eight sarcomas induced in mouse strains CBA\\/H, CBA\\/H- T6, and C57BL\\/10ScSn (or their hybrids) by s.c. implantation of smooth or roughened plastic films or glass pieces were examined electron microscopically. Type A virus particles were detected within dilated ergastoplasmic cisternae of the sarcoma cells from five mice. The doughnut-shaped particles measured 90 to 100 nm and were seen to
Ripple-induced energetic particle loss in tokamaks
White, R.B.; Goldston, R.J.; Redi, M.H.; Budny, R.V. [Plasma Physics Laboratory, Princeton University, P.O. Box 451, Princeton, New Jersey 08543 (United States)] [Plasma Physics Laboratory, Princeton University, P.O. Box 451, Princeton, New Jersey 08543 (United States)
The threshold for stochastic transport of high energy trapped particles in a tokamak due to toroidal field ripple is calculated by explicit construction of primary resonances, and a numerical examination of the route to chaos. Critical field ripple amplitude is determined for loss. The expression is given in magnetic coordinates and makes no assumptions regarding shape or up-down symmetry. An algorithm is developed including the effects of prompt axisymmetic orbit loss, ripple trapping, convective banana flow, and stochastic ripple loss, which gives accurate ripple loss predictions for representative Tokamak Fusion Test Reactor [R. Hawryluk, Plasma Phys. Controlled Fusion {bold 33}, 1509 (1991)] and International Thermonuclear Experimental Reactor [K. Tomabechi, {ital Proceedings} {ital of} {ital the} 12{ital th} {ital International} {ital Conference} {ital on} {ital Plasma} {ital Physics} {ital and} {ital Controlled} {ital Nuclear} {ital Fusion} {ital Research} (International Atomic Energy Agency, Vienna, 1989), Vol. 3, p. 214] equilibria. The algorithm is extended to include the effects of collisions and drag, allowing rapid estimation of alpha particle loss in tokamaks. {copyright} {ital 1996 American Institute of Physics.}
Epidemiological studies suggest that ultrafine particles contribute to particulate matter-induced adverse health effects. Interleukin (IL)-8 is an important proinflammatory cytokine in the human lung that is induced in respiratory cells exposed to a variety of environmental insul...
The Effect of Induced Electro-Osmosis on a Cylindrical Particle Next to a Surface
NASA Astrophysics Data System (ADS)
Zhao, Hui; Bau, Haim
The effect of induced electro-osmosis on a cylindrical particle positioned next to an insulated wall is studied theoretically. We calculate analytically the induced hydrodynamic (electro-osmotic) and electrostatic forces using a thin double layer approximation and numerically with a multi-ion model. The forces are calculated as functions of the particle and medium dielectric constants, the electrical double layer thickness, and the distance between the particle and wall. Not surprisingly, these forces decrease as the particle's dielectric constant decreases and the distance from the wall increases. The induced resultant and hydrodynamic forces are always directed normal to the direction of the imposed electric field and away from the wall. The electrostatic force that acts on the particle (excluding the adjacent electric double layer) is directed, respectively, away and towards the wall at low and high particle dielectric constants. At low and high electric field intensities, respectively, all the forces increase linearly and sublinearly with the square of the electric field intensity. Among other things, the work has important implications for PIV-based, near wall measurements in electro-osmotic flows.
Particle-induced spatial dark current fluctuations in focal plane arrays
Cheryl J. Dale; P. W. Marshall; E. A. Burke
An analytic calculation which describes the pixel-to-pixel variation in the particle-induced dark current distribution of a focal plane array is developed. The most important contributions to the dark current variance are shown to be the variations in the number of primary interactions, the energies of the primary recoils produced, and the charge emission from radiation-induced defects due to that electric
Non-targeted effects induced by high LET charged particles
NASA Astrophysics Data System (ADS)
Hei, Tom K.; Chai, Yunfei; Hamada, Nobuyuki; Kakinuma, Shizuko; Uchihori, Yukio
Radiation-induced non-targeted response represents a paradigm shift in our understanding of the radiobiological effects of ionizing radiation in that extranuclear and extracellular effects may also contribute to the final biological consequences of exposure to low doses of radiation. Using the gpt delta transgenic mouse model, there is evidence that irradiation of a small area (1 cm by 1 cm) of the lower abdominal area of animals with a 5 Gy dose of X-rays induced cyclooxygenase-2 as well as deletion mutations in the out-of-field lung tissues of the animals. The mutation correlated with an increase in prostaglandin levels in the bystander lung tissues and with an increase in the level of 8-hydroxydeoxyguanosine (8-OHdG), an oxidative DNA damage marker. An increase in COX-2 level was also detected in the out-of-field lung tissues of animals similarly exposed to high LET argon and carbon ions accelerated at the Heavy Ion Medical Accelerator in Chiba (HIMAC) at the National Institute of Radiological Sciences in Japan. These results provide the first evidence that the COX-2 -related pathway, which is essential in mediating cellular inflammatory response, is the critical signaling link for the non-targeted, bystander phenomenon. A better understanding of the cellular and molecular mechanisms of the non-targeted, out of field phenomenon together with evidence of their occurrence in vivo will allow us to formulate a more accurate assessment of radiation risk.
Preparation of polystyrene latex particles by ?-rays-induced emulsifier-free emulsion polymerization
NASA Astrophysics Data System (ADS)
Wang, Xinbo; Zhang, Zhicheng
Monodisperse polystyrene latex particles were prepared by 60Co- ?-ray radiation-induced emulsifier-free emulsion polymerization with the use of surfactant monomer at room temperature. The surfactant monomer 10(9)-hydroxyl-9(10)-allyl ether octadecanoic acid (HAEOA) was synthesized and characterized by FT-IR and 1H-NMR spectra. TEM was used to characterize the polystyrene latex particles. HAEOA acted as not only a comonomer but also a stabilizer to copolymerize with styrene and stabilize the polystyrene latex particles. Kinetics analysis shows that there is no constant rate stage which seems to indicate a droplet nucleation mechanism.
Particle-induced amorphization of complex ceramics. Final report
Ewing, R.C.; Wang, L.M.
The crystalline-to-amorphous (c-a) phase transition is of fundamental importance. Particle irradiations provide an important, highly controlled means of investigating this phase transformation and the structure of the amorphous state. The interaction of heavy-particles with ceramics is complex because these materials have a wide range of structure types, complex compositions, and because chemical bonding is variable. Radiation damage and annealing can produce diverse results, but most commonly, single crystals become aperiodic or break down into a polycrystalline aggregate. The authors continued the studies of the transition from the periodic-to-aperiodic state in natural materials that have been damaged by {alpha}-recoil nuclei in the uranium and thorium decay series and in synthetic, analogous structures. The transition from the periodic to aperiodic state was followed by detailed x-ray diffraction analysis, in-situ irradiation/transmission electron microscopy, high resolution transmission electron microscopy, extended x-ray absorption fine structure spectroscopy/x-ray absorption near edge spectroscopy and other spectroscopic techniques. These studies were completed in conjunction with bulk irradiations that can be completed at Los Alamos National Laboratory or Sandia National Laboratories. Principal questions addressed in this research program included: (1) What is the process at the atomic level by which a ceramic material is transformed into a disordered or aperiodic state? (2) What are the controlling effects of structural topology, bond-type, dose rate, and irradiation temperature on the final state of the irradiated material? (3) What is the structure of the damaged material? (4) What are the mechanisms and kinetics for the annealing of interstitial and aggregate defects in these irradiated ceramic materials? (5) What general criteria may be applied to the prediction of amorphization in complex ceramics?
The mechanism of particles transport induced by electrostatic perturbation in tokamak
Feng, Zhichen; Qiu, Zhiyong; Sheng, Zhengmao [Department of Physics, Institute for Fusion Theory and Simulation, Zhejiang University, Hangzhou 310027 (China)] [Department of Physics, Institute for Fusion Theory and Simulation, Zhejiang University, Hangzhou 310027 (China)
Particle transport in tokamak devices due to wave-particle resonance induced diffusion is studied. The diffusion coefficient is derived both analytically using quasilinear theory, and numerically using a test particle code, and the obtained diffusion coefficient agrees with each other in its validity regime. Dependence of the diffusion coefficient on turbulence intensity, turbulence radial mode structures, and particle energy is investigated. It is found that the diffusion coefficient is proportional to the turbulence intensity, and the diffusion is maximized for E{sub t}?T{sub i}, and k{sub r}?{sub 0}?1. Here, E{sub t} is the test particle energy, T{sub i} is the thermal ion temperature, ?{sub 0} is the distance between neighboring mode rational surfaces, and 1/k{sub r} is the half width of the fine radial mode structure on each rational surface.
Mesoporous silica shell alleviates cytotoxicity and inflammation induced by colloidal silica particles.
Wang, Jie; Shen, Yuqing; Bai, Ling; Lv, Dan; Zhang, Aifeng; Miao, Fengqin; Tang, Meng; Zhang, Jianqiong
Core-shell mesoporous silica (MPS) materials have been proven to perform multiple simultaneous functions in biological systems and they demonstrate a vast potential for applications in the medical arena. Exploring such extensive potential requires a meticulous evaluation of their interactions with cells. The aim of this study is to investigate the influence of MPS-shells on the viability and activation of human THP-1 macrophages by comparing core-shell MPS with colloidal silica particles. In the present study we find core-shell MPS particles with a solid colloidal silica core and a thin MPS-shell deliver significantly less cytotoxicity than their nonporous counterparts and induce lower expression and release of the pro-inflammatory cytokines in macrophages. Moreover, core-shell MPS particles show no effect on the activation of mitogen-activated protein kinases (MAPKs), while colloidal silica particles do activate MAPKs under identical conditions. The corona of core-shell MPS particles is composed of a greater amount and variety of proteins as compared with colloidal silica particles. The abundant protein composition of the corona may inhibit the cellular toxicity by masking surface silanol groups at the MPS-cellular interface. In conclusion, the MPS-shell significantly alleviates both cytotoxicity and immune responses induced by colloidal silica particles while greatly improving the biocompatibility of colloidal silica materials. PMID:24513963
Particle induced damage on heads and discs due to fine particles of different materials
Lihong Zhang; Ramesh Koka; Yewwah Yuen; Edwin Lam
Fine particles of aluminum, stainless steel, silicon, slider ceramic (Al2O3-TiC) and sputtered alumina were introduced at the head\\/disc interface of hard disc drives. Experiments were conducted with discs made from aluminum and glass substrates. Glass substrates were much harder than aluminum substrates. It was found that the type of damage introduced on the disc and slider was to some extent
Particle-induced indentation of the alveolar epithelium caused by surface tension forces
Kojic, M.; Tsuda, A.
Physical contact between an inhaled particle and alveolar epithelium at the moment of particle deposition must have substantial effects on subsequent cellular functions of neighboring cells, such as alveolar type-I, type-II pneumocytes, alveolar macrophage, as well as afferent sensory nerve cells, extending their dendrites toward the alveolar septal surface. The forces driving this physical insult are born at the surface of the alveolar air-liquid layer. The role of alveolar surfactant submerging a hydrophilic particle has been suggested by Gehr and Sch�rch's group (e.g., Respir Physiol 80: 17�32, 1990). In this paper, we extended their studies by developing a further comprehensive and mechanistic analysis. The analysis reveals that the mechanics operating in the particle-tissue interaction phenomena can be explained on the basis of a balance between surface tension force and tissue resistance force; the former tend to move a particle toward alveolar epithelial cell surface, the latter to resist the cell deformation. As a result, the submerged particle deforms the tissue and makes a noticeable indentation, which creates unphysiological stress and strain fields in tissue around the particle. This particle-induced microdeformation could likely trigger adverse mechanotransduction and mechanosensing pathways, as well as potentially enhancing particle uptake by the cells. PMID:20634359
Dieldrin-Induced Neurotoxicity: Relevance to Parkinson's Disease Pathogenesis
Anumantha G. Kanthasamy; Masashi Kitazawa; Arthi Kanthasamy; Vellareddy Anantharam
Parkinson's disease (PD) is increasingly recognized as a neurodegenerative disorder strongly associated with environmental chemical exposures. Recent epidemiological data demonstrate that environmental risk factors may play a dominant role as compared to genetic factors in the etiopathogenesis of idiopathic Parkinson's disease. Identification of key genetic defects such as alpha-synuclein and parkin mutations in PD also underscores the important role of
Maintenance of Medically Induced Remission of Crohn�s Disease
Jean-Jacques Gonvers; Pascal Juillerat; Christian Mottet; Val�rie Pittet; Christian Felley; John-Paul Vader; Pierre Michetti; Florian Froehlich
The natural history of Crohn�s disease is characterized by recurring flares alternating with periods of inactive disease and remission. This implies that most patients need to take medication for a large period of their life, mostly for maintenance of remission and, intermittently, additional therapy during a flare. Low-dose systemic corticosteroids are not effective in maintaining remission and should not be
Environmentally Induced Epigenetic Transgenerational Inheritance of Ovarian Disease
Eric Nilsson; Ginger Larsen; Mohan Manikkam; Carlos Guerrero-Bosagna; Marina I. Savenkova; Michael K. Skinner
The actions of environmental toxicants and relevant mixtures in promoting the epigenetic transgenerational inheritance of ovarian disease was investigated with the use of a fungicide, a pesticide mixture, a plastic mixture, dioxin and a hydrocarbon mixture. After transient exposure of an F0 gestating female rat during embryonic gonadal sex determination, the F1 and F3 generation progeny adult onset ovarian disease
Vibrational Raman studies of particle induced damage in oxide glasses
NASA Astrophysics Data System (ADS)
Exarhos, G. J.
Radiation effects in oxide glasses are manifested by color center formation, densification, and atom displacements. Localized vibrational modes are sensitive to such phenomena and exhibit both dose dependent frequency shifts and intensity variations in measured Raman spectra of irradiated glasses. Both bulk and glass fiber samples of NaPO 3, Y(PO 3) 3, and SiO 2 were subjected to external 5.5 MeV alpha irradiation in a nitrogen glove box from either 238Pu or 244Cm sources. Since damage is induced in a ca. 20 ?m surface layer, thin fiber samples were chosen to optimize surface effects. All glasses developed color centers upon irradiation observed in measured UV/VIS absorption spectra. Raman spectra of binary phosphate glasses reveal two strong bands assigned to symmetric stretching of network -P-O-P- groups and terminal -PO 2- groups which both exhibit dose dependent frequency shifts and intensity variations. Results indicate that the onset of radiation damage is manifested at nonbridging oxygen sites in the glass. The observation of nitrate stretching vibrations in alpha-irradiated NaPO 3, a glass known to contain significant surface absorbed water, suggests that moisture enhanced radiolysis of N 2 near the glass surface has occurred. This effect was not observed for the more durable yttrium containing glass. Raman spectra of alpha-irradiated fused silica show changes in accord with previously reported results for neutron compacted silica. Lines assigned to bonding defect modes in the glass intensify with increasing dose, while band intensities for network vibrational modes decrease exponentially. The implication of these results to induced microstructural changes in the glass following alpha irradiation will be discussed.
Solar particle induced upsets in the TDRS-1 attitude control system RAM during the October 1989 solar particle events
Croley, D.R. [SYSCON Corp., Montrose, CA (United States)] [SYSCON Corp., Montrose, CA (United States); Garrett, H.B.; Murphy, G.B. [Jet Propulsion Lab., Pasadena, CA (United States)] [Jet Propulsion Lab., Pasadena, CA (United States); Garrard, T.L. [California Inst. of Tech., Pasadena, CA (United States). George W. Downs Lab. of Physics] [California Inst. of Tech., Pasadena, CA (United States). George W. Downs Lab. of Physics
The three large solar particle events, beginning on October 19, 1989 and lasting approximately six days, were characterized by high fluences of solar protons and heavy ions at 1 AU. During these events, an abnormally large number of upsets (243) were observed in the random access memory of the attitude control system (ACS) control processing electronics (CPE) on-board the geosynchronous TDRS-1 (Telemetry and Data Relay Satellite). The RAM unit affected was composed of eight Fairchild 93L422 memory chips. The Galileo spacecraft, launched on October 18, 1989 (one day prior to the solar particle events) observed the fluxes of heavy ions experienced by TDRS-1. Two solid-state detector telescopes on-board Galileo, designed to measure heavy ion species and energy, were turned on during time periods within each of the three separate events. The heavy ion data have been modeled and the time history of the events reconstructed to estimate heavy ion fluences. These fluences were converted to effective LET spectra after transport through the estimated shielding distribution around the TDRS-1 ACS system. The number of single event upsets (SEU) expected was calculated by integrating the measured cross section for the Fairchild 93L422 memory chip with average effective LET spectrum. The expected number of heavy ion induced SEU`s calculated was 176. GOES-7 proton data, observed during the solar particle events, were used to estimate the number of proton-induced SEU`s by integrating the proton fluence spectrum incident on the memory chips, with the two-parameter Bendel cross section for proton SEU`s. The proton fluence spectrum at the device level was gotten by transporting the protons through the estimated shielding distribution. The number of calculated proton-induced SEU`s was 72, yielding a total of 248 predicted SEU`s, very close to the 243 observed SEU`s.
NF-?B, a pivotal transcription factor in silica-induced diseases
Fei Chen; Xianglin Shi
Inhalation of silica in a number of occupational settings can result in debilitating and costly lung disease. It is thought that the pathological replacement of functional lung tissue with fibrotic lesions in silica-induced lung disease is the result of chronic inflammation mediated by products of the silica-exposed alveolar macrophage. In particular, inflammatory cytokines, growth factors and reactive oxygen species have
Involvement of Caspase3 and GD3 Ganglioside in Ceramide-induced Apoptosis in Farber Disease
Felicia Farina; Francesco Cappello; Matilde Todaro; Fabio Bucchieri; Giovanni Peri; Giovanni Zummo; Giorgio Stassi
Farber's disease (FD) is a rare genetic disorder caused by ceramidase deficiency, which results in ceramide accumulation in lung, liver, colon, skeletal muscle, cartilage, and bone. Although this disease has been symptomatically characterized, little is known about its molecular pathogenetic process. Because recent studies reported that ceramide accumulation induces GD3 ganglioside formation and apoptosis, we investigated, in tissue obtained via
Induced pluripotent stem cells for retinal degenerative diseases: a new perspective on the challenges
Zi-Bing Jin; Satoshi Okamoto; Michiko Mandai; Masayo Takahashi
Retinal degenerative diseases, including age-related macular degeneration and retinitis pigmentosa, are the prodominant causes\\u000a of human blindness in the world; however, these diseases are difficult to treat. Currently, knowledge on the mechanisms of\\u000a these diseases is still very limited and no radical drugs are available. Induced pluripotent stem (iPS) cells are an innovative\\u000a technology that turns somatic cells into embryonic
Induced pluripotent stem cells (iPSCs) and neurological disease modeling: progress and promises
Marchetto, Maria C.; Brennand, Kristen J.; Boyer, Leah F.; Gage, Fred H.
The systematic generation of neurons from patients with neurological disorders can provide important insights into disease pathology, progression and mechanism. This review will discuss recent progress in modeling neurodegenerative and neurodevelopmental diseases using induced pluripotent stem cells (iPSCs) and highlight some of the current challenges in the field. Combined with other technologies previously used to study brain disease, iPSC modeling has the promise to influence modern medicine on several fronts: early diagnosis, drug development and effective treatment. PMID:21828073
Diesel and Carbon Particles Enhance House Dust Mite-Induced Pulmonary Hypersensitivity in Brown Norway Rats. P. Singh1, M.J. Daniels2, D. Winsett2, J. Richards2, K. Crissman2, M. Madden2 and M.I. Gilmour2. 1NCSU, Raleigh, NC and 2 USEPA, Research Triangle Park, NC. Ep...
Search for wave-induced particle precipitation from lightning and transmitter sources. Master's thesis
Wave-induced particle precipitation is introduced and examined for whistlers whose sources are within the plasmapause. The possible correlation between lightning strokes that carry positive charge to the ground and the observed Trimpi events is discussed, sudden phase and\\/or amplitude shifts of a received VLF signal with gradual return to predisturbed values. The thunderstorm charging mechanisms that lead to the observed
A search for wave induced particle precipitation from lightning and transmitter sources
Jon E. Lundberg
Wave induced particle precipitation is introduced and examined for whistlers whose sources are within the plasmapause. The possible correlation between lightning strokes that carry positive charge to the ground and the observed Trimpi events is discussed, sudden phase and\\/or amplitude shifts of a received VLF signal with gradual return to predisturbed values. The thunderstorm charging mechanisms that lead to the
Coagulation-induced particle-concentration fluctuations in homogeneous, isotropic turbulence
Coagulation-induced particle-concentration fluctuations in homogeneous, isotropic turbulence Donald Received 24 September 2001; accepted 26 March 2002; published 5 June 2002 The turbulent coagulation concentrations and coagulation rates in a set of fluid packets that are large compared with the Kolmogorov scale
Electrokinetic motion of polarizable particles Dielectrophoresis, induced-charge electrophoresis, electrophoresis of the second kind.
Bazant, Martin Z.
-charge electrophoresis, electrophoresis of the second kind. Definition The electrokinetic motion of polarizable particles results from electro-osmotic flow (induced- charge electrophoresis) of the first of second kind, in addition to electrostatic forces (dielectrophoresis). Overview The classical theory of electrophoresis
URBAN PARTICLE-INDUCED PULMONARY ARTERY CONSTRICTION IS MEDIATED BY SUPEROXIDE PRODUCTION.Jacqueline D. Carter, Zhuowei Li, Lisa A. Dailey, Yuh-Chin T. Huang. CEMALB, University of North Carolina, and ORD, US EPA, Chapel Hill, North Carolina. Exposure to particulate matter...
Purification, characterization and serological detection of virus-like particles associated with banana bunchy top disease in Australia
John E. Thomas; Ralf G. Dietzgen
Isometric virus-like particles, 18 nm in diameter, have been isolated from banana (Musa spp.) affected by bunchy top disease in Australia. Banana bunchy top disease-associated virus-like particles (BBTV) banded as a single component with buoyant density of 1-28 to 1.29 g\\/ml in Cs2SO4 and sedimented at about 46S in isokinetic sucrose density gradients. The A260\\/.42S 0 of purified preparations was
Light flash phenomena induced by HzE particles
NASA Technical Reports Server (NTRS)
Mcnulty, P. J.; Pease, V. P.
Astronauts and Apollo and Skylab missions have reported observing a variety of visual phenomena when their eyes are closed and adapted to darkness. These phenomena have been collectively labelled as light flashes. Visual phenomena which are similar in appearance to those observed in space have been demonstrated at the number of accelerator facilities by expressing the eyes of human subjects to beams of various types of radiation. In some laboratory experiments Cerenkov radiation was found to be the basis for the flashes observed while in other experiments Cerenkov radiation could apparently be ruled out. Experiments that differentiate between Cerenkov radiation and other possible mechanisms for inducing visual phenomena was then compared. The phenomena obtained in the presence and absence of Cerenkov radiation were designed and conducted. A new mechanism proposed to explain the visual phenomena observed by Skylab astronauts as they passed through the South Atlantic Anomaly, namely nuclear interactions in and near the sensitive layer of the retina, is covered. Also some studies to search for similar transient effects of space radiation on sensors and microcomputer memories are described.
Inhibitory effect of (-)-epigallocatechin gallate on titanium particle-induced TNF-? release and in vivo osteolysis
Jin, Shan; Park, Ju-Young; Hong, Jung-Min; Kim, Tae-Ho; Shin, Hong-In
Tumor necrosis factor-? (TNF-?) and inflammatory cytokines released from activated macrophages in response to particulate debris greatly impact periprosthetic bone loss and consequent implant failure. In the present study, we found that a major polyphenolic component of green tea, (-)-epigallocatechin gallate (EGCG), inhibited Ti particle-induced TNF-? release in macrophages in vitro and calvarial osteolysis in vivo. The Ti stimulation of macrophages released TNF-? in a dose- and time-dependent manner, and EGCG substantially suppressed Ti particle-induced TNF-? release. Analysis of signaling pathway showed that EGCG inhibited the Ti-induced c-Jun N-terminus kinase (JNK) activation and inhibitory ?B (I?B) degradation, and consequently the Ti-induced transcriptional activation of AP-1 and NF-?B. In a mouse calvarial osteolysis model, EGCG inhibited Ti particle-induced osteolysis in vivo by suppressing TNF-? expression and osteoclast formation. Therefore, EGCG may be a potential candidate compound for osteolysis prevention and treatment as well as aseptic loosening after total replacement arthroplasty. PMID:21633184
Maturation of the proteasome core particle induces an affinity switch that controls regulatory particle association.
Wani, Prashant S; Rowland, Michael A; Ondracek, Alex; Deeds, Eric J; Roelofs, Jeroen
Proteasome assembly is a complex process, requiring 66 subunits distributed over several subcomplexes to associate in a coordinated fashion. Ten proteasome-specific chaperones have been identified that assist in this process. For two of these, the Pba1-Pba2 dimer, it is well established that they only bind immature core particles (CPs) in vivo. In contrast, the regulatory particle (RP) utilizes the same binding surface but only interacts with the mature CP in vivo. It is unclear how these binding events are regulated. Here, we show that Pba1-Pba2 binds tightly to the immature CP, preventing RP binding. Changes in the CP that occur on maturation significantly reduce its affinity for Pba1-Pba2, enabling the RP to displace the chaperone. Mathematical modelling indicates that this 'affinity switch' mechanism has likely evolved to improve assembly efficiency by preventing the accumulation of stable, non-productive intermediates. Our work thus provides mechanistic insights into a crucial step in proteasome biogenesis. PMID:25812915
Human alkaloid biosynthesis : chemical inducers of Parkinson's disease?
Hatzios, Stavroula K. (Stavroula-Artemis K.)
The occurrence of certain alkaloids in the human brain appears to be associated with the onset of Parkinson's disease (PD). Recently, a human protein bearing homology to an alkaloid synthase in plants was identified. This ...
[Methodologic aspects of theories on trauma-induced disease].
Lytkin, M I; Petlenko, V P
The authors have summarized the materials on the theory of trauma disease from the standpoint of methodological principle of determinism. The appearance of a new type of association in functioning self-regulating systems is shown which are characterized by cyclic pattern in the form of interaction of processes of different direction. It was noted that different technical approaches to studying the trauma disease should not hide their methodological unity based upon principles and laws of dialectical materialism. PMID:3232292
High-energy particle-induced tumorigenesis throughout the gastrointestinal tract.
Trani, Daniela; Nelson, Scott A; Moon, Bo-Hyun; Swedlow, Jan J; Williams, Elizabeth M; Strawn, Steven J; Appleton, Paul L; Kallakury, Bhaskar; N�thke, Inke; Fornace, Albert J
Epidemiological data reveals the gastrointestinal (GI) tract as one of the main sites for low-LET radiation-induced cancers. Importantly, the use of particle therapy is increasing, but cancer risk by high-LET particles is still poorly understood. This gap in our knowledge also remains a major limiting factor in planning long-term space missions. Therefore, assessing risks and identifying predisposing factors for carcinogenesis induced by particle radiation is crucial for both astronauts and cancer survivors. We have previously shown that exposure to relatively high doses of high-energy (56)Fe ions induced higher intestinal tumor frequency and grade in the small intestine of Apc(Min/+) mice than ? rays. However, due to the high number of spontaneous lesions (?30) that develop in Apc(Min/+) animals, this Apc mutant model is not suitable to investigate effects of cumulative doses <1 Gy, which are relevant for risk assessment in astronauts and particle radiotherapy patients. However, Apc(1638N/+) mice develop a relatively small number of spontaneous lesions (?3 per animal) in both small intestine and colon, and thus we propose a better model for studies on radiation-induced carcinogenesis. Here, we investigated model particle radiation increases tumor frequency and grade in the entire gastrointestinal tract (stomach and more distal intestine) after high- and low-radiation doses whether in the Apc(1638N/+). We have previously reported that an increase in small intestinal tumor multiplicity after exposure to ? rays was dependent on gender in Apc(1638N/+) mice, and here we investigated responses to particle radiation in the same model. Phenotypical and histopathological observations were accompanied by late changes in number and position of mitotic cells in intestinal crypts from animals exposed to different radiation types. PMID:24512616
Icariin protects against titanium particle-induced osteolysis and inflammatory response in a mouse calvarial model.
Shao, Hongguo; Shen, Ji; Wang, Mingjun; Cui, Jingfu; Wang, Yijun; Zhu, Shijun; Zhang, Wen; Yang, Huilin; Xu, Yaozeng; Geng, Dechun
Periprosthetic osteolysis and subsequent aseptic loosening are common in implant failure, a complication with revision surgery being the only established treatment. Wear particle-induced inflammation and extensive osteoclastogenesis play critical roles in periprosthetic osteolysis. A recent approach in limiting osteolysis is therefore focused on inhibiting osteoclastic bone resorption. This study aimed to investigate the potential impact of icariin, the major ingredient of Epimedium, on titanium particle-induced osteolysis in a mouse calvarial model. Eighty-four male C57BL/J6 mice were divided randomly into four groups. Mice in the sham group underwent sham surgery only, whereas animals in the vehicle, low- and high-concentration icariin groups received titanium particles. Mice in the low- and high-concentration icariin groups were gavage-fed with icariin at 0.1 or 0.3�mg/g/day, respectively, until sacrifice. Mice in the sham and vehicle groups received phosphate-buffered saline daily. After 2 weeks, mouse calvariae were collected for micro-computed tomography, histomorphometry and molecular analysis. Icariin significantly reduced particle-induced bone resorption compared with the vehicle group. Icariin also prevented an increase in receptor activator of nuclear factor kappa B ligand/osteoprotegerin ratio and subsequently suppressed osteoclast formation in titanium particle-charged calvariae. In addition, immunohistochemical analysis and enzyme-linked immunosorbent assay showed icariin significantly reduced expression and secretion of tumor necrosis factor-?, interleukin-1? and interleukin-6 in the calvariae of titanium-stimulated mice. Collectively, these results suggest that icariin represents a potential treatment for titanium particle-induced osteolysis and could be developed as a new therapeutic candidate for the prevention and treatment of aseptic loosening. PMID:25985156
Mechanisms of Phosphate-induced Disease Resistance in Cucumber
Miroslav Orober; J�rgen Siegrist; Heinrich Buchenauer
Certain phosphate salts are known inducers of systemic acquired resistance (SAR). In the present study, a local spray application of dipotassium hydrogenphosphate (K2HPO4) was effective in inducing a high level of systemic protection in cucumber plants against anthracnose caused by Colletotrichum lagenarium. Resistance induction by K2HPO4 was associated with localized cell death in cucumber leaves treated with the phosphate salt.
Nimesulide Improves the Symptomatic and Disease Modifying Effects of Leflunomide in Collagen Induced Arthritis
Al-Abd, Ahmed M.; Al-Abbasi, Fahad A.; Nofal, Salwa M.; Khalifa, Amani E.; Williams, Richard O.; El-Eraky, Wafaa I.; Nagy, Ayman A.; Abdel-Naim, Ashraf B.
Nimesulide is a COX-2 inhibitor used for symptomatic relief of rheumatoid arthritis. Leflunomide is an anti-pyrimidine used to manage the progression of rheumatoid arthritis. Herein we studied the influence of nimesulide and leflunomide combination in terms of disease symptoms and progression using collagen-induced arthritis model in mice, as a model for rheumatoid arthritis. Collagen induced arthritis was induced by immunization with type II collagen. Assessment of joint stiffness and articular hyperalgesia were evaluated using a locomotor activity cage and the Hargreaves method, respectively. Disease progression was assessed via arthritic index scoring, X-ray imaging, myeloperoxidase enzyme activity and histopathologic examination. Nimesulide induced only transient symptomatic alleviation on the top of decreased leucocytic infiltration compared to arthritis group. However, nimesulide alone failed to induce any significant improvement in the radiological or pathological disease progression. Leflunomide alone moderately alleviates the symptoms of arthritis and moderately retarded the radiological and pathological disease progression. Combination of nimesulide and leflunomide significantly improved symptomatic (analgesia and joint stiffness) and arthritic disease progression (radiological, pathological and Myeloperoxidase enzyme activity) in collagen induced arthritis animal model. PMID:25375820
Neuroprotective effect of lycopene against MPTP induced experimental Parkinson's disease in mice.
Prema, Asokan; Janakiraman, Udaiyappan; Manivasagam, Thamilarasan; Arokiasamy, Justin Thenmozhi
Parkinson's disease (PD) is the second most common neurodegenerative disorder that mainly affects the movement of the aged populations. Lycopene is a carotenoid with unique pharmacological properties and its efficacy on experimental Hunginton's disease and brain ischemia has shown intense neuroprotective effects. The present study was aimed to explore the neuroprotective effect of lycopene against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced PD mice. Administration of lycopene (5, 10 and 20mg/kg/day orally) protected MPTP induced depletion of striatal dopamine (DA) and its metabolites in a dose dependent manner. It also attenuated MPTP-induced oxidative stress and motor abnormalities seen in PD mice. Our western blot studies showed that treatment with lycopene reversed MPTP induced apoptosis may be due to its antioxidant and antiapoptotic properties. As to conclude, lycopene reverses neurochemical deficts, oxidative stress, apoptosis and physiological abnormalities in PD mice and offer promise strategy in the treatment of this neurodegenerative disease. PMID:25980996
Respiratory disease and particulate air pollution in Santiago Chile: contribution of erosion particles from fine sediments.
Garcia-Chevesich, Pablo A; Alvarado, Sergio; Neary, Daniel G; Valdes, Rodrigo; Valdes, Juan; Aguirre, Juan Jos�; Mena, Marcelo; Pizarro, Roberto; Jofr�, Paola; Vera, Mauricio; Olivares, Claudio
Air pollution in Santiago is a serious problem every winter, causing thousands of cases of breathing problems within the population. With more than 6 million people and almost two million vehicles, this large city receives rainfall only during winters. Depending on the frequency of storms, statistics show that every time it rains, air quality improves for a couple of days, followed by extreme levels of air pollution. Current regulations focus mostly on PM10 and PM2.5, due to its strong influence on respiratory diseases. Though more than 50% of the ambient PM10s in Santiago is represented by soil particles, most of the efforts have been focused on the remaining 50%, i.e. particulate material originating from fossil and wood fuel combustion, among others. This document emphasizes the need for the creation of erosion/sediment control regulations in Chile, to decrease respiratory diseases on Chilean polluted cities. PMID:24485904
Preliminary investigation of the relationship between bovine congenital lathyrism induced by aminoacetonitrile and the lupine induced crooked calf disease.
Keeler, R F; Binns, W; James, L F; Shupe, J L
Maternal feeding of the lathyrogen aminoacetonitrile, the range plant Lupinus caudatus, and an extract of this plant - expected to contain lathyrogens if present in the plant - all produced clinically similar congenital defects in calves. The defects included excessive flexure, malpositioning, malalignment and rotation of the front limbs. The results suggest a possible relationship between lathyrism and lupine-induced crooked calf disease. PMID:4238569
Bubble dynamics induced by YAG laser focusing in liquid nitrogen and cryogenic laser processing for particles
NASA Astrophysics Data System (ADS)
Watanabe, Soju; Sirato, Takumi; Ota, Masanori; Maeno, Kazuo
The cryogenic liquid with vapor bubbles is regarded as phase-changing and unsteady field with heat and mass transfer phenomena. The cryogenic liquid has a characteristic feature of the small latent heat, surface tension, and viscosity, as compared with those of normal temperature water. As the cryogenic laser processing technology is still under development and research, there have been few reports on laser-matter interactions, for example, on micro/nano particle production. This paper firstly deals with behavior of a cavitation bubble induced by a pulsed YAG laser in liquid nitrogen. The interaction of the bubble with the solid wall has been studied by flow visualization, and, furthermore, the laser-particle processing in liquid nitrogen has been studied. As our research on cryogenic laser-submicron particle processing is in the first stage of experiment, the paper concentrates mainly on the microscopic observation of the laser-processed holes on Al surface and small particles.
Mechanism of production of light complex particles in nucleon-induced reactions
Dexian Wei; Ning Wang; Li Ou
The Improved Quantum Molecular Dynamics (ImQMD) model incorporated with the statistical decay model is successful in describing emission of nucleons in the intermediate energy spallation reactions, but not good enough in describing productions of light complex particles, i.e. $d$, $t$, $^3$He and $^4$He. To improve the description on emission of light complex particles, a phenomenological mechanism called surface coalescence and emission is introduced into ImQMD model: nucleon ready to escape from the compound nuclei can coalesce with the other nucleon(s) to form light complex particle and be emitted. With updated ImQMD model, the description on the experimental data of light complex particles produced in nucleon-induced reactions are great improved.
Frequency-dependent behaviors of individual microscopic particles in an optically induced dielectrophoresis device
Zhu, Xiaolu; Yi, Hong; Ni, Zhonghua
An optoelectronic microdevice is set up to drive single microparticles and a maximum synchronous velocity (MS-velocity) spectrum method is proposed for quantifying the frequency-dependent behaviors of individual neutral microparticles from 40 kHz to 10 MHz. Dielectrophoretic behaviors of three types of microparticles are investigated under the optically induced nonuniform electric field. Different MS-velocity spectra for the three different particles are experimentally found. Numerical calculations for the MS-velocity spectra of polystyrene microparticles are performed. The spectrum of the MS-velocities for a specific particle is mainly determined by the particle inherent property and the electric characteristics of the device. Moreover the experimental and the numerical MS-velocity spectra are compared to be accordant. Based on the dielectrophoretic (DEP) behaviors of the particles under a nonuniform electric field, microparticles can be finely characterized or distinguished according to their distinct MS-velocity spectra. PMID:20644665
Concentrated ambient air particles induce vasoconstriction of small pulmonary arteries in rats.
Batalha, Joao R F; Saldiva, Paulo H N; Clarke, Robert W; Coull, Brent A; Stearns, Rebecca C; Lawrence, Joy; Murthy, G G Krishna; Koutrakis, Petros; Godleski, John J
The objective of this study was to determine whether short-term exposures to concentrated ambient particles (CAPs) alter the morphology of small pulmonary arteries in normal rats and rats with chronic bronchitis (CB). Sprague-Dawley male rats were exposed to CAPs, using the Harvard Ambient Particle Concentrator, or to particle-free air (sham) under identical conditions during 3 consecutive days (5 hr/day) in six experimental sets. CB was induced by exposure to 276 +/- 9 ppm of sulfur dioxide (5 hr/day, 5 days/week, 6 weeks). Physicochemical characterization of CAPs included measurements of particle mass, size distribution, and composition. Rats were sacrificed 24 hr after the last CAPs exposure. Histologic slides were prepared from random sections of lung lobes and coded for blinded analysis. The lumen/wall area (L/W) ratio was determined morphometrically on transverse sections of small pulmonary arteries. When all animal data (normal and CB) were analyzed together, the L/W ratios decreased as concentrations of fine particle mass, silicon, lead, sulfate, elemental carbon, and organic carbon increased. In separate univariate analyses of animal data, the association for sulfate was significant only in normal rats, whereas silicon was significantly associated in both CB and normal rats. In multivariate analyses including all particle factors, the association with silicon remained significant. Our results indicate that short-term CAPs exposures (median, 182.75 micro g/m3; range, 73.50-733.00 micro g/m3) can induce vasoconstriction of small pulmonary arteries in normal and CB rats. This effect was correlated with specific particle components and suggests that the pulmonary vasculature might be an important target for ambient air particle toxicity. PMID:12460797
Labetalol-induced Peyronie's disease? A case report.
Kristensen, B O
Peyronie's disease (induratio penis plastica) has been observed in a 58-year-old man 8 months after initiation of treatment with the new combined alpha- and beta-blocking agent, labetalol. During the last 2 months before onset of symptoms he had received 2400 mg labetalol daily. He showed no other signs of abnormal fibrous tissue production and the ANF test was negative. Cessation of the drug revealed no improvement. Peyronie's disease has also been observed in relation to treatment with propranolol, practolol and metoprolol and might be due to an impaired balance between alpha- and beta-receptors in connective tissue, but there may also be an immunological basis for the fibrosis. A possible coincidence is stressed, as the ages of the reported cases are within the range where this disease most often develops. PMID:231377
Immunogenic and replicative properties of classical swine fever virus replicon particles modified to induce IFN-?/? and carry foreign genes.
Suter, Rolf; Summerfield, Artur; Thomann-Harwood, Lisa J; McCullough, Kenneth C; Tratschin, Jon-Duri; Ruggli, Nicolas
Virus replicon particles (VRP) are genetically engineered infectious virions incapable of generating progeny virus due to partial or complete deletion of at least one structural gene. VRP fulfil the criteria of a safe vaccine and gene delivery system. With VRP derived from classical swine fever virus (CSF-VRP), a single intradermal vaccination protects from disease. Spreading of the challenge virus in the host is however not completely abolished. Parameters that are critical for immunogenicity of CSF-VRP are not well characterized. Considering the importance of type I interferon (IFN-?/?) to immune defence development, we generated IFN-?/?-inducing VRP to determine how this would influence vaccine efficacy. We also evaluated the effect of co-expressing granulocyte macrophage colony-stimulating factor (GM-CSF) in the vaccine context. The VRP were capable of long-term replication in cell culture despite the presence of IFN-?/?. In vivo, RNA replication was essential for the induction of an immune response. IFN-?/?-inducing and GM-CSF-expressing CSF-VRP were similar to unmodified VRP in terms of antibody and peripheral T-cell responses, and in reducing the blood levels of challenge virus RNA. Importantly, the IFN-?/?-inducing VRP did show increased efficacy over the unmodified VRP in terms of B-cell and T-cell responses, when tested with secondary immune responses by in vitro restimulation assay. PMID:21184857
Fine oil combustion particle bioavailable constituents induce molecular profiles of oxidative stress, altered function, and cellular injury in cardiomyocytes.
Knuckles, Travis L; Dreher, Kevin L
Epidemiological studies have shown a positive association between exposure to air particulate matter (PM) pollution and adverse cardiovascular health effects in susceptible subpopulations such as those with pre-existing cardiovascular disease. The mechanism(s) through which pulmonary deposited PM, particularly fine PM2.5, PM with mass median aerodynamic diameter <2.5 microm, affects the cardiovascular system is currently not known and remains a major focus of investigation. In the present study, the transcriptosome and transcription factor proteome were examined in rat neonatal cardiomyocyte (RCM) cultures, following an acute exposure to bioavailable constituents of PM2.5 oil combustion particles designated residual oil fly ash leachate (ROFA-L). Out of 3924 genes examined, 38 genes were suppressed and 44 genes were induced following a 1-h exposure to 3.5 microg/ml of a particle-free leachate of ROFA (ROFA-L). Genomic alterations in pathways related to IGF-1, VEGF, IL-2, PI3/AKT, cardiovascular disease, and free radical scavenging, among others, were detected 1 h postexposure to ROFA-L. Global gene expression was altered in a manner consistent with cardiac myocyte electrophysiological remodeling, cellular oxidative stress, and apoptosis. ROFA-L altered the transcription factor proteome by suppressing activity of 24 and activating 40 transcription factors out of a total of 149. Genomic alterations were found to correlate with changes in transcription factor proteome. These acute changes indicate pathological molecular alterations, which may lead to possible chronic alterations to the cardiac myocyte. These data also potentially relate underlying cardiovascular effects from occupational exposure to ROFA and identify how particles from specific emission sources may mediate ambient PM cardiac effects. PMID:17934955
Dopamine-Induced Nonmotor Symptoms of Parkinson's Disease
Park, Ariane; Stacy, Mark
Nonmotor symptoms of Parkinson's disease (PD) may emerge secondary to the underlying pathogenesis of the disease, while others are recognized side effects of treatment. Inevitably, there is an overlap as the disease advances and patients require higher dosages and more complex medical regimens. The non-motor symptoms that emerge secondary to dopaminergic therapy encompass several domains, including neuropsychiatric, autonomic, and sleep. These are detailed in the paper. Neuropsychiatric complications include hallucinations and psychosis. In addition, compulsive behaviors, such as pathological gambling, hypersexuality, shopping, binge eating, and punding, have been shown to have a clear association with dopaminergic medications. Dopamine dysregulation syndrome (DDS) is a compulsive behavior that is typically viewed through the lens of addiction, with patients needing escalating dosages of dopamine replacement therapy. Treatment side effects on the autonomic system include nausea, orthostatic hypotension, and constipation. Sleep disturbances include fragmented sleep, nighttime sleep problems, daytime sleepiness, and sleep attacks. Recognizing the non-motor symptoms that can arise specifically from dopamine therapy is useful to help optimize treatment regimens for this complex disease. PMID:21603184
Epicuticular lipids induce aggregation in Chagas disease vectors
Alicia N Lorenzo Figueiras; Juan R Girotti; Sergio J Mijailovsky; M Patricia Ju�rez
BACKGROUND: The triatomine bugs are vectors of the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease. Aggregation behavior plays an important role in their survival by facilitating the location of refuges and cohesion of aggregates, helping to keep them safely assembled into shelters during daylight time, when they are vulnerable to predators. There are evidences that aggregation is
Ibuprofen-induced meningitis in mixed connective tissue disease
M. Hoffman; R. G. Gray
Summary��A young Black woman with mixed connective tissue disease (MCTD) developed an aseptic meningitis after receiving ibuprofen. The meningeal reaction, reported infrequently in systemic lupus erythematosus (SLE) and only once previously in MCTD, was characterized by a predominantly polymorphonu-clear cerebrospinal fluid (CSF) pleocytosis and depression of CSF glucose. Reversible renal insuffiency also occurred. Features suggestive of a hypersensitivity reaction included
Prediction of Lung Cells Oncogenic Transformation for Induced Radon Progeny Alpha Particles Using Sugarscape Cellular Automata
Baradaran, Samaneh; Maleknasr, Niaz; Setayeshi, Saeed; Akbari, Mohammad Esmaeil
Background Alpha particle irradiation from radon progeny is one of the major natural sources of effective dose in the public population. Oncogenic transformation is a biological effectiveness of radon progeny alpha particle hits. The biological effects which has caused by exposure to radon, were the main result of a complex series of physical, chemical, biological and physiological interactions. The cellular and molecular mechanisms for radon-induced carcinogenesis have not been clear yet. Methods Various biological models, including cultured cells and animals, have been found useful for studying the carcinogenesis effects of radon progeny alpha particles. In this paper, sugars cape cellular automata have been presented for computational study of complex biological effect of radon progeny alpha particles in lung bronchial airways. The model has included mechanism of DNA damage, which has been induced alpha particles hits, and then formation of transformation in the lung cells. Biomarkers were an objective measure or evaluation of normal or abnormal biological processes. In the model, the metabolism rate of infected cell has been induced alpha particles traversals, as a biomarker, has been followed to reach oncogenic transformation. Results The model results have successfully validated in comparison with �in vitro oncogenic transformation data� for C3H 10T1/2 cells. This model has provided an opportunity to study the cellular and molecular changes, at the various stages in radiation carcinogenesis, involving human cells. Conclusion It has become well known that simulation could be used to investigate complex biomedical systems, in situations where traditional methodologies were difficult or too costly to employ. PMID:25250147
Imbalance of Th1 and Th2 cells in cardiac injury induced by ambient fine particles.
Zhao, Jinzhuo; Xie, Yuquan; Qian, Chunyan; Li, Li; Jiang, Rongfang; Kan, Haidong; Chen, Ruizhen; Song, Weimin
The study was to explore the potential immunoregulatory mechanisms linking fine particles and cardiac injury. Wistar kyoto (WKY) rats were exposed by intratracheal instillation to fine particles with the doses of 0.0, 1.6, 8.0 and 40.0mg/kg b.w., respectively. The exposure was conducted once a day, for three consecutive days. Twenty-four hours after the last exposure, the rats were sacrificed. Th1- and Th2-related transcription factors and cytokines were assessed in left ventricle of rats. The mRNA expressions of Th1- and Th2-related transcription factors signal transducer and activator of transcriptionl 1 (STAT1), signal transducer and activator of transcriptional 6 (STAT6), GATA-3 and T-bet were assessed in left ventricle of rats using real-time PCR. Meanwhile, the levels of Th1- and Th2-related cytokines IL-4, IL-13 and interferon gamma (IFN-?) were determined by ELISA kits in cardiac homogenate supernatant of rats. Furthermore, the protein expression of IL-4 and IFN-? were detected in myocardium by Western blot. The results of cardiac histology demonstrated exacerbated cardiac lesions and histological characterization of inflammation and degeneration in rats after exposure to fine particles. Moreover, fine particles induced significant increase of IL-4 and IL-13 and decrease of IFN-? in myocardium of rats. The mRNA expression of STAT1, STAT6 and GATA-3 were up-regulated in left ventricle of rats in a dose-dependent manner, whereas T-bet was significantly down-regulated. The variations of these cytokines demonstrated the imbalance of Th1 and Th2 cytokines existed in cardiac injuries induced by fine particle. The imbalance of Th1/Th2 cytokines might be one of the mechanisms of immunotoxicity of cardiovascular system induced by ambient fine particles. PMID:22134058
Subclinical Celiac Disease and Crystal-Induced Kidney Disease Following Kidney Transplant
Capolongo, Giovanna; Abul-Ezz, Sameh; Moe, Orson W.; Sakhaee, Khashayar
Decreased kidney function from kidney deposition of calcium oxalate has been previously described in inflammatory bowel disease as well as following jejuno-ileal and Roux-en-Y gastric bypass surgeries. Although celiac disease is the most prevalent bowel abnormality associated with intestinal malabsorption, its relationship to high kidney oxalate burden and decreased kidney function has not been established. We report a case of subclinical celiac disease and hyperoxaluria that presented with loss of kidney function as a result of high oxalate load in the absence of overt diarrhea, documented intestinal fat malabsorption, and nephrolithiasis. Subclinical celiac disease is commonly overlooked and hyperoxaluria is not usually investigated in kidney patients. We propose that this entity should be suspected in patients with chronic kidney disease in which the etiology of kidney damage has not been clearly established. PMID:22739230
A Nonhuman Primate Model of Human Radiation-Induced Venocclusive Liver Disease and Hepatocyte Injury
Yannam, Govardhana Rao [Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska (United States); Han, Bing [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi (China); Setoyama, Kentaro [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Yamamoto, Toshiyuki [Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska (United States); Ito, Ryotaro; Brooks, Jenna M. [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Guzman-Lepe, Jorge [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Department of Pathology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); Galambos, Csaba [Department of Pathology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); Fong, Jason V. [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Deutsch, Melvin; Quader, Mubina A. [Department of Radiation Oncology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); Yamanouchi, Kosho [Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York (United States); Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York (United States); Kabarriti, Rafi; Mehta, Keyur [Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York (United States); Soto-Gutierrez, Alejandro [Department of Pathology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); and others
Background: Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease. Methods and Materials: We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. Results: At doses ?40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. Conclusions: The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury.
Gravitationally Induced Particle Production and its Impact on the WIMP Abundance
I. Baranov; J. A. S. Lima
A large set of independent astronomical observations have provided a strong evidence for nonbaryonic dark matter in the Universe. One of the most investigated candidates is an unknown long-lived Weakly Interacting Massive Particle (WIMP) which was in thermal equilibrium with the primeval plasma. Here we investigate the WIMP abundance based on the relativistic kinetic treatment for gravitationally induced particle production recently proposed in the literature (Lima \\& Baranov, Phys. Rev. D {\\bf 90}, 043515, 2014). The new evolution equation is deduced and solved both numerically and also through a semi-analytical approach. The predictions of the WIMP observables are discussed and compared with the ones obtained in the standard approach.
Gravitationally Induced Particle Production and its Impact on the WIMP Abundance
Baranov, I
A large set of independent astronomical observations have provided a strong evidence for nonbaryonic dark matter in the Universe. One of the most investigated candidates is an unknown long-lived Weakly Interacting Massive Particle (WIMP) which was in thermal equilibrium with the primeval plasma. Here we investigate the WIMP abundance based on the relativistic kinetic treatment for gravitationally induced particle production recently proposed in the literature (Lima \\& Baranov, Phys. Rev. D {\\bf 90}, 043515, 2014). The new evolution equation is deduced and solved both numerically and also through a semi-analytical approach. The predictions of the WIMP observables are discussed and compared with the ones obtained in the standard approach.
Role of mutagenicity in asbestos fiber-induced carcinogenicity and other diseases.
Huang, Sarah X L; Jaurand, Marie-Claude; Kamp, David W; Whysner, John; Hei, Tom K
The cellular and molecular mechanisms of how asbestos fibers induce cancers and other diseases are not well understood. Both serpentine and amphibole asbestos fibers have been shown to induce oxidative stress, inflammatory responses, cellular toxicity and tissue injuries, genetic changes, and epigenetic alterations in target cells in vitro and tissues in vivo. Most of these mechanisms are believe to be shared by both fiber-induced cancers and noncancerous diseases. This article summarizes the findings from existing literature with a focus on genetic changes, specifically, mutagenicity of asbestos fibers. Thus far, experimental evidence suggesting the involvement of mutagenesis in asbestos carcinogenicity is more convincing than asbestos-induced fibrotic diseases. The potential contributions of mutagenicity to asbestos-induced diseases, with an emphasis on carcinogenicity, are reviewed from five aspects: (1) whether there is a mutagenic mode of action (MOA) in fiber-induced carcinogenesis; (2) mutagenicity/carcinogenicity at low dose; (3) biological activities that contribute to mutagenicity and impact of target tissue/cell type; (4) health endpoints with or without mutagenicity as a key event; and finally, (5) determinant factors of toxicity in mutagenicity. At the end of this review, a consensus statement of what is known, what is believed to be factual but requires confirmation, and existing data gaps, as well as future research needs and directions, is provided. PMID:21534089
Role of Mutagenicity in Asbestos Fiber-Induced Carcinogenicity and Other Diseases
Huang, Sarah X. L.; Jaurand, Marie-Claude; Kamp, David W.; Whysner, John; Hei, Tom K.
The cellular and molecular mechanisms of how asbestos fibers induce cancers and other diseases are not well understood. Both serpentine and amphibole asbestos fibers have been shown to induce oxidative stress, inflammatory responses, cellular toxicity and tissue injuries, genetic changes, and epigenetic alterations in target cells in vitro and tissues in vivo. Most of these mechanisms are believe to be shared by both fiber-induced cancers and noncancerous diseases. This article summarizes the findings from existing literature with a focus on genetic changes, specifically, mutagenicity of asbestos fibers. Thus far, experimental evidence suggesting the involvement of mutagenesis in asbestos carcinogenicity is more convincing than asbestos-induced fibrotic diseases. The potential contributions of mutagenicity to asbestos-induced diseases, with an emphasis on carcinogenicity, are reviewed from five aspects: (1) whether there is a mutagenic mode of action (MOA) in fiber-induced carcinogenesis; (2) mutagenicity/carcinogenicity at low dose; (3) biological activities that contribute to mutagenicity and impact of target tissue/cell type; (4) health endpoints with or without mutagenicity as a key event; and finally, (5) determinant factors of toxicity in mutagenicity. At the end of this review, a consensus statement of what is known, what is believed to be factual but requires confirmation, and existing data gaps, as well as future research needs and directions, is provided. PMID:21534089
Extract of motorcycle exhaust particles induced macrophages apoptosis by calcium-dependent manner.
Lee, Chen-Chen; Kang, Jaw-Jou
Large survey and experiments have reported that environment pollutants from fossil fuel combustion would cause immune system deleterious by enhancement of allergic reaction and damage to respiratory tract. In this study, we reported that the extract of motorcycle exhaust particles (MEP) might affect the immune system by inducing cell apoptosis on macrophages. The motorcycle exhaust particles were collected from a two-stoke engine and their cytotoxic effect on macrophages was investigated. We found MEP is cytotoxic and induced apoptosis in RAW 264.7 cells, murine peritoneal macrophage, and rat alveolar macrophage. Pretreatment with mitochondria permeability transition inhibitor (cyclosporin A), intracellular (BAPTA-AM) and extracellular (EGTA) Ca(2+) chelator, and antioxidants (NAC, GSH, catalase, SOD) attenuated the MEP-induced cell apoptosis, and BAPTA-AM was the most effective one. Utilized Fura-2/AM loaded RAW 264.7 cells to directly detect the change of intracellular Ca(2+) concentration ([Ca(2+)](i)), we found that MEP could induce a sustained increase of [Ca(2+)](i). The raise of [Ca(2+)](i) induced by MEP could be completely blocked by the intracellular Ca(2+) chelator, BAPTA-AM, however, only partially inhibited by the extracellular Ca(2+) chelator, EGTA. These results suggested that both influx of extracellular Ca(2+) and release of Ca(2+) from the internal storage were involved. We also found that MEP caused a decrease of mitochondria membrane potential and an increase of oxidative stress in RAW 264.7 cells. In conclusion, we found that the particles, collected from the motorcycle exhaust, contain chemicals that will induce apoptosis of macrophage in calcium-dependent manner. PMID:12482235
Emerging Mechanistic Targets in Lung Injury Induced by Combustion-Generated Particles
Fariss, Marc W.; Gilmour, M. Ian; Reilly, Christopher A.; Liedtke, Wolfgang; Ghio, Andrew J.
The mechanism for biological effect following exposure to combustion-generated particles is incompletely defined. The identification of pathways regulating the acute toxicological effects of these particles provides specific targets for therapeutic manipulation in an attempt to impact disease following exposures. Transient receptor potential (TRP) cation channels were identified as �particle sensors� in that their activation was coupled with the initiation of protective responses limiting airway deposition and inflammatory responses, which promote degradation and clearance of the particles. TRPA1, V1, V4, and M8 have a capacity to mediate adverse effects after exposure to combustion-generated particulate matter (PM); relative contributions of each depend upon particle composition, dose, and deposition. Exposure of human bronchial epithelial cells to an organic extract of diesel exhaust particle was followed by TRPV4 mediating Ca++ influx, increased RAS expression, mitogen-activated protein kinase signaling, and matrix metalloproteinase-1 activation. These novel pathways of biological effect can be targeted by compounds that specifically inhibit critical signaling reactions. In addition to TRPs and calcium biochemistry, humic-like substances (HLS) and cell/tissue iron equilibrium were identified as potential mechanistic targets in lung injury after particle exposure. In respiratory epithelial cells, iron sequestration by HLS in wood smoke particle (WSP) was associated with oxidant generation, cell signaling, transcription factor activation, and release of inflammatory mediators. Similar to WSP, cytotoxic insoluble nanosized spherical particles composed of HLS were isolated from cigarette smoke condensate. Therapies that promote bioelimination of HLS and prevent the disruption of iron homeostasis could function to reduce the harmful effects of combustion-generated PM exposure. PMID:23322347
Emerging mechanistic targets in lung injury induced by combustion-generated particles.
Fariss, Marc W; Gilmour, M Ian; Reilly, Christopher A; Liedtke, Wolfgang; Ghio, Andrew J
The mechanism for biological effect following exposure to combustion-generated particles is incompletely defined. The identification of pathways regulating the acute toxicological effects of these particles provides specific targets for therapeutic manipulation in an attempt to impact disease following exposures. Transient receptor potential (TRP) cation channels were identified as "particle sensors" in that their activation was coupled with the initiation of protective responses limiting airway deposition and inflammatory responses, which promote degradation and clearance of the particles. TRPA1, V1, V4, and M8 have a capacity to mediate adverse effects after exposure to combustion-generated particulate matter (PM); relative contributions of each depend upon particle composition, dose, and deposition. Exposure of human bronchial epithelial cells to an organic extract of diesel exhaust particle was followed by TRPV4 mediating Ca(++) influx, increased RAS expression, mitogen-activated protein kinase signaling, and matrix metalloproteinase-1 activation. These novel pathways of biological effect can be targeted by compounds that specifically inhibit critical signaling reactions. In addition to TRPs and calcium biochemistry, humic-like substances (HLS) and cell/tissue iron equilibrium were identified as potential mechanistic targets in lung injury after particle exposure. In respiratory epithelial cells, iron sequestration by HLS in wood smoke particle (WSP) was associated with oxidant generation, cell signaling, transcription factor activation, and release of inflammatory mediators. Similar to WSP, cytotoxic insoluble nanosized spherical particles composed of HLS were isolated from cigarette smoke condensate. Therapies that promote bioelimination of HLS and prevent the disruption of iron homeostasis could function to reduce the harmful effects of combustion-generated PM exposure. PMID:23322347
Mutilocus genetic determinants of LDL particle size in coronary artery disease families
Rotter, J.I.; Bu, X.; Cantor, R.M. [and others
Recent interest in atherosclerosis has focused on the genetic determinants of low-density lipoprotein (LDL) particle size, because of (1) the association of small dense LDL particles with a three-fold increased risk for coronary artery disease (CAD) and (2) the recent report of linkage of the trait to the LDL receptor (chromosome 19). By utilizing nonparametric quantitative sib-pair and relative-pair-analysis methods in CAD families, we tested for linkage of a gene or genes controlling LDL particle sizes with the genetic loci for the major apolipoproteins and enzymes participating in lipoprotein metabolism. We confirmed evidence for linkage to the LDL receptor locus (P = .008). For six candidate gene loci, including apolipoprotein(apo)B, apoAII, apo(a), apoE-CI-CII, lipoprotein lipase, and high-density lipoprotein-binding protein, no evidence for linkage was observed by sib-pair linkage analyses (P values ranged from .24 to .81). However, in addition, we did find tentative evidence for linkage with the apoAI-CIII-AIV locus (chromosome 11) (P = .06) and significant evidence for linkage of the cholesteryl ester transfer protein locus (chromosome 16) (P = .01) and the manganese superoxide dismutase locus (chromosome 6) (P = .001), thus indicating multilocus determination of this atherogenic trait. 73 refs., 3 figs., 4 tabs.
Particle Motion under Shear-Induced Migration in Square-PDMS Microchannels
NASA Astrophysics Data System (ADS)
Kim, Young Won; Yoo, Jung Yul
An experimental study has been conducted to quantitatively characterize particle motion under shear-induced migration in square-PDMS microchannels by applying ?-PTV technique. It is shown that particles are accumulated at the equilibrium position of 0.67H, with H being a half width of the channel, which is analogous to what is observed in circular tube flow in macro scale. Since high shear rate can be induced due to the scale effect, particle migration occurs markedly even at low Reynolds number ranging from 4 to 57 while this phenomenon dose not typically occur at this range of the Reynolds number in macro scale. At Re = 57, it is found that particles are nearly absent around the center of the channel, which is coincident with previous numerical result obtained for a square duct at Re = 100. The outermost edge of particle cluster is in good agreement with previous study. It is rapidly converging to about y/H = 0.7 at L3 = 1, where L3 = (0.5dp/H)^3(l/2H)Re is the reduced tube length, dp is the diameter of the spherical particle and l is the measurement position from channel inlet. Since the thickness of particle-free layer is largest at L3 = 1, it is indicated that plasma selectivity and total amount of plasma separated can be maximized at this value of L3 when serum from the whole blood is separated into side channels in lab-on-a-chip systems, by minimizing the clogging of RBCs (Red Blood Cells). The present study is expected to give optimum factors for designing of microfluidic systems.
Inclusion body disease of cranes: comparison of pathologic findings in cranes with acquired vs. experimentally induced disease
Schuh, J.C.; Sileo, L.; Siegfried, L.M.; Yuill, Thomas M.
Inclusion body disease of cranes was the cause of death in 17 immature and mature cranes of 5 different species in Wisconsin. A herpesvirus of unknown origin was the apparent cause. An isolate of this herpesvirus was used to experimentally infect 3 species of cranes. Macroscopic and microscopic lesions associated with naturally acquired and experimentally induced disease were essentially identical. Multifocal hepatic and splenic necrosis was found in all cranes evaluated. Necrosis of the gastrointestinal tract, thymus, and bursa of Fabricius also was seen in some of the cranes. Eosinophilic intranuclear inclusion bodies often were commonly associated with hepatic lesions, sometimes with the splenic lesions, and rarely with the thymic or gastrointestinal tract lesions. The lesions of this inclusion body disease were similar to those reported for cranes in Austria from which a crane herpesvirus was isolated.
Pregnancy-induced hypertension and hyaline membrane disease
M. A. Carvalho; A. Fa�ndes; L. C. Santos
Objectives: (1) To determine whether the incidence of hyaline membrane disease (HMD) is different among premature babies of pre-eclamptic women and those of normotensive controls; (2) to determine the relative risk (RR) of HMD according to the severity of pre-eclampsia and gestational age. Methods: A retrospective and prospective cohort of 271 pre-eclamptic women and 271 normotensive controls, with gestational age
Soybean (Glycine max L. Merr.) Sprouts Germinated under Red Light Irradiation Induce Disease Resistance against Bacterial Rotting Disease
Dhakal, Radhika; Park, Euiho; Lee, Se-Weon; Baek, Kwang-Hyun
Specific wavelengths of light can exert various physiological changes in plants, including effects on responses to disease incidence. To determine whether specific light wavelength had effects on rotting disease caused by Pseudomonas putida 229, soybean sprouts were germinated under a narrow range of wavelengths from light emitting diodes (LEDs), including red (650�660), far red (720�730) and blue (440�450 nm) or broad range of wavelength from daylight fluorescence bulbs. The controls were composed of soybean sprouts germinated in darkness. After germination under different conditions for 5 days, the soybean sprouts were inoculated with P. putida 229 and the disease incidence was observed for 5 days. The sprouts exposed to red light showed increased resistance against P. putida 229 relative to those grown under other conditions. Soybean sprouts germinated under red light accumulated high levels of salicylic acid (SA) accompanied with up-regulation of the biosynthetic gene ICS and the pathogenesis- related (PR) gene PR-1, indicating that the resistance was induced by the action of SA via de novo synthesis of SA in the soybean sprouts by red light irradiation. Taken together, these data suggest that only the narrow range of red light can induce disease resistance in soybean sprouts, regulated by the SA-dependent pathway via the de novo synthesis of SA and up-regulation of PR genes. PMID:25679808
Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology
Gregg L. Semenza
Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding proteins that mediate adaptive responses to reduced oxygen availability. The HIF-1? subunit is constitutively expressed, whereas the HIF-1? subunit is subject to ubiquitination and proteasomal degradation, a process that is inhibited under hypoxic conditions. Recent data indicate that HIF-1 plays major roles in the prevention of myocardial and cerebral ischemia and
Enveloped virus-like particle expression of human cytomegalovirus glycoprotein B antigen induces antibodies with potent and broad neutralizing activity.
Kirchmeier, Marc; Fluckiger, Anne-Catherine; Soare, Catalina; Bozic, Jasminka; Ontsouka, Barthelemy; Ahmed, Tanvir; Diress, Abebaw; Pereira, Lenore; Sch�del, Florian; Plotkin, Stanley; Dalba, Charlotte; Klatzmann, David; Anderson, David E
A prophylactic vaccine to prevent the congenital transmission of human cytomegalovirus (HCMV) in newborns and to reduce life-threatening disease in immunosuppressed recipients of HCMV-infected solid organ transplants is highly desirable. Neutralizing antibodies against HCMV confer significant protection against infection, and glycoprotein B (gB) is a major target of such neutralizing antibodies. However, one shortcoming of past HCMV vaccines may have been their failure to induce high-titer persistent neutralizing antibody responses that prevent the infection of epithelial cells. We used enveloped virus-like particles (eVLPs), in which particles were produced in cells after the expression of murine leukemia virus (MLV) viral matrix protein Gag, to express either full-length CMV gB (gB eVLPs) or the full extracellular domain of CMV gB fused with the transmembrane and cytoplasmic domains from vesicular stomatitis virus (VSV)-G protein (gB-G eVLPs). gB-G-expressing eVLPs induced potent neutralizing antibodies in mice with a much greater propensity toward epithelial cell-neutralizing activity than that induced with soluble recombinant gB protein. An analysis of gB antibody binding titers and T-helper cell responses demonstrated that high neutralizing antibody titers were not simply due to enhanced immunogenicity of the gB-G eVLPs. The cells transiently transfected with gB-G but not gB plasmid formed syncytia, consistent with a prefusion gB conformation like those of infected cells and viral particles. Two of the five gB-G eVLP-induced monoclonal antibodies we examined in detail had neutralizing activities, one of which possessed particularly potent epithelial cell-neutralizing activity. These data differentiate gB-G eVLPs from gB antigens used in the past and support their use in a CMV vaccine candidate with improved neutralizing activity against epithelial cell infection. PMID:24334684
Enveloped Virus-Like Particle Expression of Human Cytomegalovirus Glycoprotein B Antigen Induces Antibodies with Potent and Broad Neutralizing Activity
Kirchmeier, Marc; Fluckiger, Anne-Catherine; Soare, Catalina; Bozic, Jasminka; Ontsouka, Barthelemy; Ahmed, Tanvir; Diress, Abebaw; Pereira, Lenore; Sch�del, Florian; Plotkin, Stanley; Dalba, Charlotte; Klatzmann, David
A prophylactic vaccine to prevent the congenital transmission of human cytomegalovirus (HCMV) in newborns and to reduce life-threatening disease in immunosuppressed recipients of HCMV-infected solid organ transplants is highly desirable. Neutralizing antibodies against HCMV confer significant protection against infection, and glycoprotein B (gB) is a major target of such neutralizing antibodies. However, one shortcoming of past HCMV vaccines may have been their failure to induce high-titer persistent neutralizing antibody responses that prevent the infection of epithelial cells. We used enveloped virus-like particles (eVLPs), in which particles were produced in cells after the expression of murine leukemia virus (MLV) viral matrix protein Gag, to express either full-length CMV gB (gB eVLPs) or the full extracellular domain of CMV gB fused with the transmembrane and cytoplasmic domains from vesicular stomatitis virus (VSV)-G protein (gB-G eVLPs). gB-G-expressing eVLPs induced potent neutralizing antibodies in mice with a much greater propensity toward epithelial cell-neutralizing activity than that induced with soluble recombinant gB protein. An analysis of gB antibody binding titers and T-helper cell responses demonstrated that high neutralizing antibody titers were not simply due to enhanced immunogenicity of the gB-G eVLPs. The cells transiently transfected with gB-G but not gB plasmid formed syncytia, consistent with a prefusion gB conformation like those of infected cells and viral particles. Two of the five gB-G eVLP-induced monoclonal antibodies we examined in detail had neutralizing activities, one of which possessed particularly potent epithelial cell-neutralizing activity. These data differentiate gB-G eVLPs from gB antigens used in the past and support their use in a CMV vaccine candidate with improved neutralizing activity against epithelial cell infection. PMID:24334684
The Effects of Disease-Induced Juvenile Mortality on the Transient and Asymptotic Population Dynamics of Chinook Salmon (Oncorhynchus tshawytscha)
Fujiwara, Masami; Mohr, Michael S.; Greenberg, Aaron
The effects of an increased disease mortality rate on the transient and asymptotic dynamics of Chinook salmon (Oncorhynchus tshawytscha) were investigated. Disease-induced mortality of juvenile salmon has become a serious concern in recent years...
The Effects of Disease-Induced Juvenile Mortality on the Transient and Asymptotic Population Dynamics of Chinook Salmon (Oncorhynchus tshawytscha)�
Fujiwara, Masami; Mohr, Michael S.; Greenberg, Aaron
The effects of an increased disease mortality rate on the transient and asymptotic dynamics of Chinook salmon (Oncorhynchus tshawytscha) were investigated. Disease-induced mortality of juvenile salmon has become a serious concern in recent years...
A Lagrangian particle model to predict the airborne spread of foot-and-mouth disease virus
NASA Astrophysics Data System (ADS)
Mayer, D.; Reiczigel, J.; Rubel, F.
Airborne spread of bioaerosols in the boundary layer over a complex terrain is simulated using a Lagrangian particle model, and applied to modelling the airborne spread of foot-and-mouth disease (FMD) virus. Two case studies are made with study domains located in a hilly region in the northwest of the Styrian capital Graz, the second largest town in Austria. Mountainous terrain as well as inhomogeneous and time varying meteorological conditions prevent from application of so far used Gaussian dispersion models, while the proposed model can handle these realistically. In the model, trajectories of several thousands of particles are computed and the distribution of virus concentration near the ground is calculated. This allows to assess risk of infection areas with respect to animal species of interest, such as cattle, swine or sheep. Meteorological input data like wind field and other variables necessary to compute turbulence were taken from the new pre-operational version of the non-hydrostatic numerical weather prediction model LMK ( Lokal-Modell-K�rzestfrist) running at the German weather service DWD ( Deutscher Wetterdienst). The LMK model provides meteorological parameters with a spatial resolution of about 2.8 km. To account for the spatial resolution of 400 m used by the Lagrangian particle model, the initial wind field is interpolated upon the finer grid by a mass consistent interpolation method. Case studies depict a significant influence of local wind systems on the spread of virus. Higher virus concentrations at the upwind side of the hills and marginal concentrations in the lee are well observable, as well as canalization effects by valleys. The study demonstrates that the Lagrangian particle model is an appropriate tool for risk assessment of airborne spread of virus by taking into account the realistic orographic and meteorological conditions.
A Lorentzian-Function Approximation developed in calculating the charged-particle-induced nonresonant reaction rate
NASA Astrophysics Data System (ADS)
He, J. J.
A Lorentzian-Function Approximation (LFA) has been developed in calculating the nonresonant reaction rate of charged-particle-induced reactions. The nonresonant reaction rate and the effective S -factor have been represented in terms of LFA. In the frame of LFA, the nonresonant reaction taken place within the Gamow window can be considered as a �resonance reaction� with a width of ? which is equal to that of 1/ e width (? in a well-known Gaussian-Function Approximation (GFA).
Influence of resistivity on energetic trapped particle-induced internal kink modes
Biglari, H.; Chen, L.
The influence of resistivity on energetic trapped particle-induced internal kink modes, dubbed ''fishbones'' in the literature, is explored. A general dispersion relation, which recovers the ideal theory in its appropriate limit, is derived and analyzed. An important implication of the theory for present generation fusion devices such as the Joint European Torus (Plasma Physics and Controlled Nuclear Fusion Research (IAEA, London, 1984), Vol I, p.11) is that they will be stable to fishbone activity.
Visible Light Induced Photocatalytic Degradation of Methyl Orange by Polythiophene\\/TiO 2 Composite Particles
Shoubin Xu; Yunfeng Zhu; Long Jiang; Yi Dan
The adsorption and photocatalytic degradation of methyl orange (MO) aqueous solution under visible light illumination by polythiophene\\/titanium\\u000a dioxide (PTh\\/TiO2) composite particles were studied. The experimental observations from UV�vis spectrophotometer indicate that MO molecules\\u000a were degraded in a different degree during the visible light-induced photocatalysis reaction. We propose a new degradation\\u000a mechanism of MO during the photocatalytic reaction, based on blue
Studies on fission phenomena induced by charged particles using the JAERI tandem accelerator
Y. Nagame; H. Ikezoe; N. Shikazono; T. Ohtsuki; H. Nakahara
Charged-particle-induced fission has been studied using the JAERI tandem accelerator. Characteristics of the symmetric mass division process at high angular momentum are investigated in the region of relatively light mass systems: 37Cl + 68Zn and 16O + 89Y. Observed widths of the mass and total kinetic energy distributions are broader than those expected from the liquid drop model. Pre-scission 4He
Transformation of an oblate-shaped vesicle induced by an adhering spherical particle.
Cao, Siqin; Wei, Guanghong; Chen, Jeff Z Y
We discuss vesicle-shaped transformations induced by an adhering spherical particle of different sizes using the classical Helfrich bending energy model. We focus on studying a model of an oblate vesicle with no spontaneous curvature in terms of fixed enclosing volume and surface area. Numerical solutions allow us to map out a complex phase diagram for such a simple, yet fundamental, physical system. PMID:22181362
Ebola Virus VP40Induced Particle Formation and Association with the Lipid Bilayer
Viral protein 40 (VP40) of Ebola virus appears equivalent to matrix proteins of other viruses, yet little is known about its role in the viral life cycle. To elucidate the functions of VP40, we investigated its ability to induce the formation of membrane-bound particles when it was expressed apart from other viral proteins. We found that VP40 is indeed able
Elemental analysis of agricultural soil samples by particle induced X-ray emission (PIXE) technique
Paulo E. Cruvinel; Robert G. Flocchini; Paulo Artaxo; Silvio Crestana; Paulo S. P. Herrmann Jr.
In agriculture, elements essential to vital processes are also called nutrients. A suitable and reliable particle induced X-ray emission (PIXE) methodology for content determination of essential nutrients in soil samples was developed and its effectiveness proved. The PIXE method is applied to intermediate thickness samples, whose mass per area unit are smaller than 1 ?g\\/cm2. Precision and accuracy of the
Compound Formula Rehmannia alleviates levodopa-induced dyskinesia in Parkinson's disease
Teng, Long; Hong, Fang; Zhang, Chenguang; He, Jiancheng; Wang, Haiying
Compound Formula Rehmannia has been shown to be clinically effective in treating Parkinson's disease and levodopa-induced dyskinesia; however, the mechanisms remain unclear. In this study, we established a model of Parkinson's disease dyskinesia in rats, and treated these animals with Compound Formula Rehmannia. Compound Formula Rehmannia inhibited the increase in mRNA expression of N-methyl-D-aspartate receptor subunits 1 and 2 and excitatory amino acid neurotransmitter genes, and it inhibited the reduction in expression of ?-aminobutyric acid receptor B1, an inhibitory amino acid neurotransmitter gene, in the corpus striatum. In addition, Compound Formula Rehmannia alleviated dyskinesia symptoms in the Parkinson's disease rats. These experimental findings indicate that Compound Formula Rehmannia alleviates levodopa-induced dyskinesia in Parkinson's disease by modulating neurotransmitter signaling in the corpus striatum. PMID:25206828
MicroRNAs and induced pluripotent stem cells for human disease mouse modeling.
Underbayev, Chingiz; Kasar, Siddha; Yuan, Yao; Raveche, Elizabeth
Human disease animal models are absolutely invaluable tools for our understanding of mechanisms involved in both physiological and pathological processes. By studying various genetic abnormalities in these organisms we can get a better insight into potential candidate genes responsible for human disease development. To this point a mouse represents one of the most used and convenient species for human disease modeling. Hundreds if not thousands of inbred, congenic, and transgenic mouse models have been created and are now extensively utilized in the research labs worldwide. Importantly, pluripotent stem cells play a significant role in developing new genetically engineered mice with the desired human disease-like phenotype. Induced pluripotent stem (iPS) cells which represent reprogramming of somatic cells into pluripotent stem cells represent a significant advancement in research armament. The novel application of microRNA manipulation both in the generation of iPS cells and subsequent lineage-directed differentiation is discussed. Potential applications of induced pluripotent stem cell--a relatively new type of pluripotent stem cells--for human disease modeling by employing human iPS cells derived from normal and diseased somatic cells and iPS cells derived from mouse models of human disease may lead to uncovering of disease mechanisms and novel therapies. PMID:22619497
Shear-induced particle rotation and its effect on electrorheological and dielectric properties in cellulose suspension
NASA Astrophysics Data System (ADS)
Misono, Y.; Negita, K.
Electrorheological (ER) and dielectric properties under high electric fields were measured simultaneously on hydroxypropylcellulose suspension. When measuring these properties as a function of frequency of the electric field, we found a positive peak in each spectrum of the ER effect and the first-order dielectric permittivity while a negative one in the spectrum of the third-order dielectric permittivity with these peak frequencies nearly equal to (shearrate)/4? . Referring to the well-known results for the particle rotation in the sheared suspension, it is suggested that the observed peaks are due to shear-induced particle rotation and the rotation occurs even under high electric field. On the basis of these results, effects of the particle rotation on the ER and the dielectric properties are discussed.
Factors associated with chloroquine-induced retinopathy in rheumatic diseases.
Araiza-Casillas, R; C�rdenas, F; Morales, Y; Cardiel, M H
Antimalarials are very useful drugs in the treatment of various rheumatic diseases. One of their main side effects is ocular toxicity, specifically retinopathy. Our objective was to identify risk factors associated with chloroquine retinopathy. A single, trained evaluator reviewed patient records with rheumatic diseases. They were taking chloroquine and identified by the ophthalmology department as having retinopathy during their routine eye evaluation. These cases were classified according to clinical evaluation, visual fields and fluorangiographic study. Up to four controls were selected for each case, matched by age, gender, diagnosis and similar time on chloroquine. In all, 34 variables were studied, among these: weight, age, disease duration, keratopathy, total cumulative dose (TCD), mean daily dose (MDD), lean body weight adjusted daily dose (LBWDD) and laboratory tests. Descriptive and inferential statistics comparing cases and controls in all patients and subgroup analysis were carried out. Significance was set at the 0.05 level. Odds ratio and 95% confidence intervals were calculated. Sixteen cases of chloroquine retinopathy were identified, eight patients with rheumatoid arthritis (RA), seven with systemic lupus erythematosus (SLE) and one with dermatomyositis. All were female. Mean age was 47.3 +/- 12.2 years; weight 59.5 +/- 10.7 kg; disease duration 12.8 +/- 6.0 years; time on chloroquine 54.1 +/- 27.8 (min-max: 30-197) months. There was a significant difference in the following variables in all patients: MDD 212.3 +/- 52.6 versus 170 +/- 51.3, p = 0.009; and LBWDD 5 +/- 1 versus 4.2 +/- 1.5, p = 0.03, for cases and controls, respectively. In subgroup analysis the MDD remained significantly different (235.5 +/- 45.8 versus 169.7 +/- 46.1, p = 0.004) only in RA, whereas LBWDD was different both in SLE and RA. Keratopathy increased the risk for retinopathy: OR, 95% CI: 5, 1.4-17.6, p = 0.01. In conclusion, in accordance with previous studies, the MDD, LBWDD and keratopathy were risk factors associated with chloroquine retinopathy. Periodic ophthalmologic evaluations are mandatory. PMID:14995005
Characterization of Arabidopsis enhanced disease susceptibility mutants that are affected in systemically induced resistance
Jurriaan Ton; Martin De Vos; Charlotte Robben; Anthony Buchala; Jean-Pierre M�traux; L. C. Van Loon; Corn� M. J. Pieterse
Summary In Arabidopsis, the rhizobacterial strain Pseudomonas fluorescens WCS417r triggers jasmonate (JA)- and ethylene (ET)-dependent induced systemic resistance (ISR) that is effective against different pathogens. Arabidopsis genotypes unable to express rhizobacteria-mediated ISR against the bacterial pathogen Pseudomonas syringae pv. tomato DC3000 (Pst DC3000) exhibit enhanced disease susceptibility towards this pathogen. To identify novel components controlling induced resistance, we tested 11
Human Metapneumovirus Virus-Like Particles Induce Protective B and T Cell Responses in a Mouse Model
Cox, Reagan G.; Erickson, John J.; Hastings, Andrew K.; Becker, Jennifer C.; Johnson, Monika; Craven, Ryan E.; Tollefson, Sharon J.; Boyd, Kelli L.
ABSTRACT Human metapneumovirus (HMPV) is a leading cause of respiratory disease in infants, children, and the elderly worldwide, yet no licensed vaccines exist. Live-attenuated vaccines present safety challenges, and protein subunit vaccines induce primarily antibody responses. Virus-like particles (VLPs) are an attractive alternative vaccine approach because of reduced safety concerns compared with live vaccines. We generated HMPV VLPs by expressing viral proteins in suspension-adapted human embryonic kidney epithelial (293-F) cells and found that the viral matrix (M) and fusion (F) proteins were sufficient to form VLPs. We previously reported that the VLPs resemble virus morphology and incorporate fusion-competent F protein (R. G. Cox, S. B. Livesay, M. Johnson, M. D. Ohi, and J. V. Williams, J. Virol. 86:12148�12160, 2012), which we hypothesized would elicit F-specific antibody and T cell responses. In this study, we tested whether VLP immunization could induce protective immunity to HMPV by using a mouse model. C57BL/6 mice were injected twice intraperitoneally with VLPs alone or with adjuvant and subsequently challenged with HMPV. Mice were euthanized 5 days postinfection, and virus titers, levels of neutralizing antibodies, and numbers of CD3+ T cells were quantified. Mice immunized with VLPs mounted an F-specific antibody response and generated CD8+ T cells recognizing an F protein-derived epitope. VLP immunization induced a neutralizing-antibody response that was enhanced by the addition of either TiterMax Gold or ?-galactosylceramide adjuvant, though adjuvant reduced cellular immune responses. Two doses of VLPs conferred complete protection from HMPV replication in the lungs of mice and were not associated with a Th2-skewed cytokine response. These results suggest that nonreplicating VLPs are a promising vaccine candidate for HMPV. IMPORTANCE Human metapneumovirus (HMPV) is a leading cause of acute respiratory infection in infants, children, and the elderly worldwide, yet no licensed vaccines exist. Live-attenuated vaccines present safety challenges, and protein subunit vaccines induce primarily antibody responses. Virus-like particles (VLPs) are an attractive alternative vaccine approach. We generated HMPV VLPs by expressing the viral matrix (M) and fusion (F) proteins in mammalian cells. We found that mice immunized with VLPs mounted an F-specific antibody response and generated CD8+ T cells recognizing an F protein-derived epitope. VLP immunization induced a neutralizing-antibody response that was enhanced by the addition of either TiterMax Gold or ?-galactosylceramide adjuvant. Two doses of VLPs conferred complete protection against HMPV replication in the lungs of mice and were not associated with a Th2-skewed cytokine response. These results suggest that nonreplicating VLPs are a promising vaccine candidate for HMPV. PMID:24672031
Oncogene-Induced Senescence as a New Mechanism of Disease: The Paradigm of Erdheim�Chester Disease
Cavalli, Giulio; Biavasco, Riccardo; Borgiani, Bruno; Dagna, Lorenzo
Erdheim�Chester disease (ECD) is a rare form of systemic histiocytosis characterized by the diffuse infiltration of tissues by lipid-laden macrophages. As the clinical course and prognosis are highly influenced by site of disease involvement, ECD course ranges from asymptomatic to life threatening, with a reported global 5-year mortality of 30�40%. Whether ECD is an inflammatory or clonal disease in its nature has long been debated. The disease is characterized by a network of pro-inflammatory cyto/chemokines responsible for the recruitment and activation of histiocytes into ECD lesions, similarly to what reported in Langerhans cell histiocytosis (LCH). Growing evidence supports a central role of the oncogenic BRAFV600E mutation in histiocytosis pathogenesis, and suggests oncogene-induced senescence (OIS), a major protective mechanism against oncogenic events characterized by cell-cycle arrest and the induction of pro-inflammatory molecules, as the possible link between the oncogenic mutation and the observed inflammation. Indeed, ECD recapitulates in vivo the molecular events associated with OIS, i.e., cell-cycle arrest and a potent local inflammatory response. Accordingly, the infiltration of different tissues by macrophages and the inflammatory local and systemic effects observed in ECD likely represent a drawback of OIS. Therefore, these findings delineate a new conception of OIS as a new pathogenic mechanism intrinsically responsible for disease development. PMID:24982657
Cellular and molecular analysis of mutagenesis induced by charged particles of defined linear energy transfer
NASA Technical Reports Server (NTRS)
Zhu, L. X.; Waldren, C. A.; Vannias, D.; Hei, T. K.; Chatterjee, A. (Principal Investigator)
Mutation induction by charged particles of defined linear energy transfer (LET) and gamma rays was scored using human-hamster hybrid AL cells. The LET values for charged particles accelerated at the Radiological Research Accelerator Facility ranged from 10 keV/microm protons to 150 keV/microm 4He ions. The induced mutant fractions at both the S1 and HGPRT loci were dependent on the dose and LET. In addition, for each dose examined, the mutant yield at the S1 locus was 30-60 fold higher than at the corresponding HGPRT locus. To determine whether the mutation spectrum was comparably dependent on dose and LET, independent S1- and HGPRT- mutants induced by 150 keV/microm 4He ions and gamma rays were isolated, and their DNA was analyzed by both Southern blotting and multiplex PCR methods. While the majority of radiation-induced mutants showed deletions of varying sizes, the relative percentage of large deletions was found to be related to both the dose and LET of the radiation examined. Using a mutation system that can detect multilocus changes, results of the present study show that radiation-induced chromosomal loss can be in the millions of base pairs.
Fine ambient particles induce oxidative stress and metal binding genes in human alveolar macrophages.
Huang, Yuh-Chin T; Li, Zhuowei; Carter, Jacqueline D; Soukup, Joleen M; Schwartz, David A; Yang, Ivana V
Exposure to pollutant particles increased respiratory morbidity and mortality. The alveolar macrophages (AMs) are one cell type in the lung directly exposed to particles. Upon contact with particles, AMs are activated and produce reactive oxygen species, but the scope of this oxidative stress response remains poorly defined. In this study, we determined the gene expression profile in human AMs exposed to particles, and sought to characterize the global response of pro- and antioxidant genes. We exposed AMs obtained by bronchoscopy from normal individuals to Chapel Hill particulate matter of 2.5-microm diameter or smaller (PM(2.5); 1 microg/ml) or vehicle for 4 hours (n = 6 independent samples). mRNAs were extracted, amplified, and hybridized to Agilent human 1A microarray. Significant genes were identified by significance analysis of microarrays (false discovery rate, 10%; P < or = 0.05) and mapped with Gene Ontology in the Database for Annotation, Visualization, and Integrated Discovery. We found 34 and 41 up- and down-regulated genes, respectively; 22 genes (approximately 30%) were involved in metal binding, and 11 were linked to oxidative stress, including up-regulation of five metallothionein (MT)-1 isoforms. Exogenous MT1 attenuated PM(2.5)-induced H2O2 release. PM(2.5) premixed with MT1 stimulated less H2O2 release. Knockdown of MT1F gene increased PM(2.5)-induced H2O2 release. PM(2.5) at 1 microg/ml did not increase H2O2 release. Mount St. Helens PM(2.5) and acid-extracted Chapel Hill PM(2.5), both poor in metals, did not induce MT1F or H2O2 release. Our results show that PM(2.5) induced a gene expression profile prevalent with genes related to metal binding and oxidative stress in human AMs, independent of oxidative stress. Metals associated with PM may play an important role in particle-induced gene changes. PMID:19251948
Fine Ambient Particles Induce Oxidative Stress and Metal Binding Genes in Human Alveolar Macrophages
Huang, Yuh-Chin T.; Li, Zhuowei; Carter, Jacqueline D.; Soukup, Joleen M.; Schwartz, David A.; Yang, Ivana V.
Exposure to pollutant particles increased respiratory morbidity and mortality. The alveolar macrophages (AMs) are one cell type in the lung directly exposed to particles. Upon contact with particles, AMs are activated and produce reactive oxygen species, but the scope of this oxidative stress response remains poorly defined. In this study, we determined the gene expression profile in human AMs exposed to particles, and sought to characterize the global response of pro- and antioxidant genes. We exposed AMs obtained by bronchoscopy from normal individuals to Chapel Hill particulate matter of 2.5-?m diameter or smaller (PM2.5; 1 ?g/ml) or vehicle for 4 hours (n = 6 independent samples). mRNAs were extracted, amplified, and hybridized to Agilent human 1A microarray. Significant genes were identified by significance analysis of microarrays (false discovery rate, 10%; P ? 0.05) and mapped with Gene Ontology in the Database for Annotation, Visualization, and Integrated Discovery. We found 34 and 41 up- and down-regulated genes, respectively; 22 genes (?30%) were involved in metal binding, and 11 were linked to oxidative stress, including up-regulation of five metallothionein (MT)-1 isoforms. Exogenous MT1 attenuated PM2.5-induced H2O2 release. PM2.5 premixed with MT1 stimulated less H2O2 release. Knockdown of MT1F gene increased PM2.5-induced H2O2 release. PM2.5 at 1 ?g/ml did not increase H2O2 release. Mount St. Helens PM2.5 and acid-extracted Chapel Hill PM2.5, both poor in metals, did not induce MT1F or H2O2 release. Our results show that PM2.5 induced a gene expression profile prevalent with genes related to metal binding and oxidative stress in human AMs, independent of oxidative stress. Metals associated with PM may play an important role in particle-induced gene changes. PMID:19251948
Therapeutic application of metallic nanoparticles combined with particle-induced x-ray emission effect
NASA Astrophysics Data System (ADS)
Kim, Jong-Ki; Seo, Seung-Jun; Kim, Ki-Hong; Kim, Tae-Jeong; Chung, Myung-Hwan; Kim, Kye-Ryung; Yang, Tae-Keun
Metallic nanoparticles (MNP) are able to release localized x-rays when activated with a high energy proton beam by the particle-induced x-ray emission (PIXE) effect. The exploitation of this phenomenon in the therapeutic irradiation of tumors has been investigated. PIXE-based x-ray emission directed at CT26 tumor cells in vitro, when administered with either gold (average diameter 2 and 13 nm) or iron (average diameter 14 nm) nanoparticles (GNP or SNP), increased with MNP solution concentration over the range of 0.1-2 mg ml - 1. With irradiation by a 45 MeV proton therapy (PT) beam, higher concentrations had a decreased cell survival fraction. An in vivo study in CT26 mouse tumor models with tumor regression assay demonstrated significant tumor dose enhancement, thought to be a result of the PIXE effect when compared to conventional PT without MNP (radiation-only group) using a 45 MeV proton beam (p < 0.02). Those receiving GNP or SNP injection doses of 300 mg kg - 1 body weight before proton beam therapy demonstrated 90% or 75% tumor volume reduction (TVR) in 20 days post-PT while the radiation-only group showed only 18% TVR and re-growth of tumor volume after 20 days. Higher complete tumor regression (CTR) was observed in 14-24 days after a single treatment of PT with an average rate of 33-65% for those receiving MNP compared with 25% for the radiation-only group. A lower bound of therapeutic effective MNP concentration range, in vivo, was estimated as 30-79 �g g - 1 tissue for both gold and iron nanoparticles. The tumor dose enhancement may compensate for an increase in entrance dose associated with conventional PT when treating large, solid tumors with a spread-out Bragg peak (SOBP) technique. The use of a combined high energy Bragg peak PT with PIXE generated by MNP, or PIXE alone, may result in new treatment options for infiltrative metastatic tumors and other diffuse inflammatory diseases.
Promising MS2 mediated virus-like particle vaccine against foot-and-mouth disease.
Dong, Yan-mei; Zhang, Guo-guang; Huang, Xiao-jun; Chen, Liang; Chen, Hao-tai
Foot-and-mouth disease (FMD) has caused severe economic losses to millions of farmers worldwide. In this work, the coding genes of 141-160 epitope peptide (EP141-160) of VP1 were inserted into the coat protein (CP) genes of MS2 in prokaryotic expression vector, and the recombinant protein self-assembled into virus-like particles (VLP). Results showed that the CP-EP141-160 VLP had a strong immunoreaction with the FMD virus (FMDV) antigen in vitro, and also had an effective immune response in mice. Further virus challenge tests were carried out on guinea pigs and swine, high-titer neutralizing antibodies were produced and the CP-EP141-160 VLP vaccine could protect most of the animals against FMDV. PMID:25676866
Fluid fragmentation shapes rain-induced foliar disease transmission.
Gilet, T; Bourouiba, L
Plant diseases represent a growing threat to the global food supply. The factors contributing to pathogen transmission from plant to plant remain poorly understood. Statistical correlations between rainfalls and plant disease outbreaks were reported; however, the detailed mechanisms linking the two were relegated to a black box. In this combined experimental and theoretical study, we focus on the impact dynamics of raindrops on infected leaves, one drop at a time. We find that the deposition range of most of the pathogen-bearing droplets is constrained by a hydrodynamical condition and we quantify the effect of leaf size and compliance on such constraint. Moreover, we identify and characterize two dominant fluid fragmentation scenarios as responsible for the dispersal of most pathogen-bearing droplets emitted from infected leaves: (i) the crescent-moon ejection is driven by the direct interaction between the impacting raindrop and the contaminated sessile drop and (ii) the inertial detachment is driven by the motion imparted to the leaf by the raindrop, leading to catapult-like droplet ejections. We find that at first, decreasing leaf size or increasing compliance reduces the range of pathogen-bearing droplets and the subsequent epidemic onset efficiency. However, this conclusion only applies for the crescent moon ejection. Above a certain compliance threshold a more effective mechanism of contaminated fluid ejection, the inertial detachment, emerges. This compliance threshold is determined by the ratio between the leaf velocity and the characteristic velocity of fluid fragmentation. The inertial detachment mechanism enhances the range of deposition of the larger contaminated droplets and suggests a change in epidemic onset pattern and a more efficient potential of infection of neighbouring plants. Dimensionless parameters and scaling laws are provided to rationalize our observations. Our results link for the first time the mechanical properties of foliage with the onset dynamics of foliar epidemics through the lens of fluid fragmentation. We discuss how the reported findings can inform the design of mitigation strategies acting at the early stage of a foliar disease outbreak. PMID:25652459
Preliminary Investigation of the Relationship Between Bovine Congenital Lathyrism Induced by Aminoacetonitrile and the Lupine Induced Crooked Calf Disease
Keeler, R. F.; Binns, W.; James, L. F.; Shupe, J. L.
Maternal feeding of the lathyrogen aminoacetonitrile, the range plant Lupinus caudatus, and an extract of this plant � expected to contain lathyrogens if present in the plant � all produced clinically similar congenital defects in calves. The defects included excessive flexure, malpositioning, malalignment and rotation of the front limbs. The results suggest a possible relationship between lathyrism and lupine-induced crooked calf disease. ImagesFig. 1.Fig. 2.Fig. 3.Fig. 4.Fig. 5.Fig. 6. PMID:4238569
Excess copper chelating therapy for Wilson disease induces anemia and liver dysfunction.
Harada, Masaru; Miyagawa, Koichiro; Honma, Yuichi; Hiura, Masaaki; Shibata, Michihiko; Matsuhashi, Toru; Abe, Shintaro; Harada, Riko; Tabaru, Akinari
A 37-year-old man was diagnosed with Wilson disease at the age of 14. His first manifestations were neurological. He was treated with trientine for more than 10 years and suffered from anemia and liver dysfunction. Wilson disease is a genetic disorder characterized by accumulation of copper in the body. Excess copper is toxic, but copper is an essential trace element. Copper-binding ceruloplasmin is important for iron metabolism. Excess copper chelating treatment-induced anemia and iron deposition in the liver was suspected. Proper monitoring of copper status is important for the management of Wilson disease. PMID:21757830
Is type 1 diabetes a food-induced disease?
Landin-Olsson, Mona; Hillman, Magnus; Erlanson-Albertsson, Charlotte
The incidence of type 1 diabetes among children has almost doubled during the last decades in Sweden. Type 1 diabetes is considered as an autoimmune disease with unknown aetiology. Here we propose that the immune reaction may be initiated by food-derived mechanisms. The incidence of diabetes parallels an increased consumption of pasta, white bread, meat, cheese, low-fat milk, exotic fruits, soda, and snacks. Simultaneously, the consumption of potatoes, butter, high-fat milk, and domestic fruit has decreased. Three categories of food related reaction mechanisms are discussed against the following items (1) proteins from wheat, meat, and milk, (2) fat from processed food, and (3) exotic fruits. The current food consumption is suggested to initiate a pro-inflammatory reaction in the intestine and thereby reduce the intestinal barrier function. This may influence tolerance development and thus pave the way for an autoimmune attack on pancreatic beta cells. PMID:23688738
A canine model of beryllium-induced granulomatous lung disease
Haley, P.J.; Finch, G.L.; Mewhinney, J.A.; Harmsen, A.G.; Hahn, F.F.; Hoover, M.D.; Muggenburg, B.A.; Bice, D.E. (Lovelace Biomedical and Environmental Research Institute, Albuquerque, NM (USA))
Groups of beagle dogs were exposed by inhalation to attain either low or high initial lung burdens (ILB) of BeO calcined at 500 degrees or 1000 degrees C. Dogs were killed at 8, 32, 64, 180, and 365 days after exposure for evaluation of beryllium tissue burdens and histopathologic examination. Histologic lesions were characterized by perivascular and peribronchiolar infiltrates of lymphocytes and macrophages 8 days after exposure. These lesions progressed to distinct microgranulomas accompanied by patchy granulomatous pneumonia. Lesions were more severe in dogs exposed to 500 degrees C BeO. Additional dogs were sampled by bronchoalveolar lavage at 3, 6, 7, 11, 15, 18, and 22 months after exposure for characterization of lung cytology and lung immune responses. Lymphocyte percentages and numbers were increased in lavage samples 3 months after exposure in dogs with both the high and low ILB of 500 degrees C. Values for both parameters decreased rapidly thereafter. Dogs with either low or high ILB of 1000 degrees C-treated BeO displayed negligible to low and variable changes in both lymphocyte percentages and numbers. In vitro lymphocyte stimulation by beryllium was increased 180 and 210 days after exposure in dogs with the high ILB 500 degrees C BeO only. A marked degree of individual variation in both histologic lesions and lymphocyte responses among dogs was noted. Less soluble 1000 degrees C-treated BeO was retained in the lung longer than the more soluble 500 degrees C-treated material that was cleared almost entirely by 1 year after exposure. Because these changes are similar to those reported in humans with chronic beryllium disease, these data suggest that the beagle represents a good model to study histologic and immunologic aspects of this disease syndrome.
Immunoprophylaxis of experimental Mycoplasma pneumoniae disease: effect of aerosol particle size and site of deposition of M. pneumoniae on the pattern of respiratory infection, disease, and immunity in hamsters.
Jemski, J V; Hetsko, C M; Helms, C M; Grizzard, M B; Walker, J S; Chanock, R M
The distribution of Mycoplasma pneumoniae infection in the respiratory tract and the extent of pulmonary pathology were determined by the site of deposition and the number of organisms administered to hamsters. Infection of the upper and lower areas of the respiratory tract occurred when organisms were introduced into both areas by small-particle aerosol (2.3 micrometer) or by intranasal (i.n.) instillation of a 200-microliter inoculum. In contrast, when organisms were delivered primarily to the upper respiratory tract by large-particle aerosol (8 micrometer) or by i.n. instillation of a small volume of inoculum (2 or 20 microliter), infection remained limited to this area in most or all instances. When the lungs became infected after i.n. administration of a 200-microliter inoculum, the most extensive pulmonary lesions were seen in the animals given the largest number of organisms. Each of the modes of administration of M. pneumoniae initiated an infection which conferred measurable resistance to a subsequent challenge capable of inducing extensive pulmonary disease. The most effective resistance was induced by the two modes of administration which produced an infection involving the entire respiratory tract, i.e., small-particle aerosol or i.n. instillation of a 200-microliter inoculum. PMID:873619
Toll-like receptors-2 and 4 are overexpressed in an experimental model of particle-induced osteolysis.
Valladares, Roberto D; Nich, Christophe; Zwingenberger, Stefan; Li, Chenguang; Swank, Katherine R; Gibon, Emmanuel; Rao, Allison J; Yao, Zhenyu; Goodman, Stuart B
Aseptic loosening secondary to particle-associated periprosthetic osteolysis remains a major cause of failure of total joint replacements (TJR) in the mid- and long term. As sentinels of the innate immune system, macrophages are central to the recognition and initiation of the inflammatory cascade, which results in the activation of bone resorbing osteoclasts. Toll-like receptors (TLRs) are involved in the recognition of pathogen-associated molecular patterns and danger-associated molecular patterns. Experimentally, polymethylmethacrylate and polyethylene (PE) particles have been shown to activate macrophages via the TLR pathway. The specific TLRs involved in PE particle-induced osteolysis remain largely unknown. We hypothesized that TLR-2, -4, and -9 mediated responses play a critical role in the development of PE wear particle-induced osteolysis in the murine calvarium model. To test this hypothesis, we first demonstrated that PE particles caused observable osteolysis, visible by microCT and bone histomorphometry when the particles were applied to the calvarium of C57BL/6 mice. The number of TRAP positive osteoclasts was significantly greater in the PE-treated group when compared to the control group without particles. Finally, using immunohistochemistry, TLR-2 and TLR-4 were highly expressed in PE particle-induced osteolytic lesions, whereas TLR-9 was downregulated. TLR-2 and -4 may represent novel therapeutic targets for prevention of wear particle-induced osteolysis and accompanying TJR failure. PMID:24115330
Detection of tire tread particles using laser-induced breakdown spectroscopy
NASA Astrophysics Data System (ADS)
Prochazka, David; Bil�k, Martin; Prochazkov�, Petra; Klus, Jakub; Po?�zka, Pavel; Novotn�, Jan; Novotn�, Karel; Ticov�, Barbora; Brad�?, Albert; Semela, Marek; Kaiser, Jozef
The objective of this paper is a study of the potential of laser induced breakdown spectroscopy (LIBS) for detection of tire tread particles. Tire tread particles may represent pollutants; simultaneously, it is potentially possible to exploit detection of tire tread particles for identification of optically imperceptible braking tracks at locations of road accidents. The paper describes the general composition of tire treads and selection of an element suitable for detection using the LIBS method. Subsequently, the applicable spectral line is selected considering interferences with lines of elements that might be present together with the detected particles, and optimization of measurement parameters such as incident laser energy, gate delay and gate width is performed. In order to eliminate the matrix effect, measurements were performed using 4 types of tires manufactured by 3 different producers. An adhesive tape was used as a sample carrier. The most suitable adhesive tape was selected from 5 commonly available tapes, on the basis of their respective LIBS spectra. Calibration standards, i.e. an adhesive tape with different area content of tire tread particles, were prepared for the selected tire. A calibration line was created on the basis of the aforementioned calibration standards. The linear section of this line was used for determination of the detection limit value applicable to the selected tire. Considering the insignificant influence of matrix of various types of tires, it is possible to make a simple recalculation of the detection limit value on the basis of zinc content in a specific tire.
Preventing diet induced disease: bioavailable nutrient-rich, low-energy-dense diets.
Robson, Anthony A
What the World needs is an integrated and sustainable food policy that makes the best and most appropriate use of the technologies at our disposal to promote health and help prevent disease. Diet induced diseases account for the largest burden of chronic illnesses and health problems Worldwide. Historically a lack of knowledge about human nutritional requirements (including for the brain) helped promote diet induced disease. The scientific knowledge currently exists to help prevent many of the current deficiencies and imbalances in human diet. Primary prevention of cardiovascular disease and mental ill health starts, crucially, with maternal nutrition before the inception of pregnancy and continues throughout life of the new born and includes consuming more DHA and EPA omega-3 fats (and their cofactors) and other bioavailable brain nutrients and less high-energy-dense (>2 kcal g(-1)) foods (e.g. land-based cereal, chocolate, alcohol and refined sugar, fat and oil), so tissues synthesize less inflammatory mediators and to lower transient short-lived meal-induced oxidative stress, inflammation, proliferation and impaired nitric oxide (e.g. approximately 0.35-3.5 g DHA/ EPA day(-1) dependant on energy intake and noting the importance of cofactors). Micro- and nanotechnologies are already engineering nano foods for human (and livestock) consumption that may eventually (without excessive consumption) prevent the current diet induced disease epidemic, especially in future generations, by preventing the causal mechanisms of disease. Greater knowledge about the causal mechanisms of disease awaits to be discovered, which could further enhance the human desire to increase longevity in optimum health (creating more problems and challenges for society). PMID:19835109
Altered particle size distribution of apolipoprotein A=l=containing lipoproteins in subjects with coronary artery disease
Marian C. Cheung; B. Greg Brown; Anitra C. Wolf; John J. Albers
Plasma high density lipoproteins (HDL) can be separated into two subpopulations of apolipoprotein A-I- containing particles: those that also contain apoA-I1 ( Lp(A1 w AH)) and those that do not (Lp(AI w\\/o AH)). These particles were isolated by immunoaffinity Chromatography from 17 men (9 normolipidemic (NL), 8 hyperlipidemic (HL)) with sympto- matic coronary artery disease (CAD), from 17 NL men
Mechanisms of action of inhaled fibers, particles and nanoparticles in lung and cardiovascular diseases
Mossman, Brooke T; Borm, Paul J; Castranova, Vincent; Costa, Daniel L; Donaldson, Kenneth; Kleeberger, Steven R
Background A symposium on the mechanisms of action of inhaled airborne particulate matter (PM), pathogenic particles and fibers such as silica and asbestos, and nanomaterials, defined as synthetic particles or fibers less than 100 nm in diameter, was held on October 27 and 28, 2005, at the Environmental Protection Agency (EPA) Conference Center in Research Triangle Park, North Carolina. The meeting was the eighth in a series of transatlantic conferences first held in Penarth, Wales, at the Medical Research Council Pneumoconiosis Unit (1979), that have fostered long-standing collaborations between researchers in the fields of mineralogy, cell and molecular biology, pathology, toxicology, and environmental/occupational health. Results The goal of this meeting, which was largely supported by a conference grant from the NHLBI, was to assemble a group of clinical and basic research scientists who presented and discussed new data on the mechanistic effects of inhaled particulates on the onset and development of morbidity and mortality in the lung and cardiovascular system. Another outcome of the meeting was the elucidation of a number of host susceptibility factors implicated in adverse health effects associated with inhaled pathogenic particulates. Conclusion New models and data presented supported the paradigm that both genetic and environmental (and occupational) factors affect disease outcomes from inhaled particulates as well as cardiopulmonary responses. These future studies are encouraged to allow the design of appropriate strategies for prevention and treatment of particulate-associated morbidity and mortality, especially in susceptible populations. PMID:17537262
Assembly and Biological and Immunological Properties of Newcastle Disease Virus-Like Particles?
McGinnes, Lori W.; Pantua, Homer; Laliberte, Jason P.; Gravel, Kathryn A.; Jain, Surbhi; Morrison, Trudy G.
Virus-like particles (VLPs) released from avian cells expressing the Newcastle disease virus (NDV) strain AV proteins NP, M, HN (hemagglutinin-neuraminidase), and F were characterized. The VLP-associated HN and F glycoproteins directed the attachment of VLPs to cell surfaces and fusion of VLP membranes with red blood cell membranes, indicating that they were assembled into VLPs in an authentic conformation. These particles were quantitatively prepared and used as an immunogen, without adjuvant, in BALB/c mice. The resulting immune responses, detected by enzyme-linked immunosorbent assay (ELISA), virus neutralization, and intracellular cytokine staining, were comparable to the responses to equivalent amounts of inactivated NDV vaccine virus. HN and F proteins from another strain of NDV, strain B1, could be incorporated into these VLPs. Foreign peptides were incorporated into these VLPs when fused to the NP or HN protein. The ectodomain of a foreign glycoprotein, the Nipah virus G protein, fused to the NDV HN protein cytoplasmic and transmembrane domains was incorporated into ND VLPs. Thus, ND VLPs are a potential NDV vaccine candidate. They may also serve as a platform to construct vaccines for other pathogens. PMID:20181713
Application of human induced pluripotent stem cells for modeling and treating neurodegenerative diseases.
Payne, Natalie L; Sylvain, Aude; O'Brien, Carmel; Herszfeld, Daniella; Sun, Guizhi; Bernard, Claude C A
The advent of human induced pluripotent stem cells (hiPSCs), reprogrammed in vitro from both healthy and disease-state human somatic cells, has triggered an enormous global research effort to realize personalized regenerative medicine for numerous degenerative conditions. hiPSCs have been generated from cells of many tissue types and can be differentiated in vitro to most somatic lineages, not only for the establishment of disease models that can be utilized as novel drug screening platforms and to study the molecular and cellular processes leading to degeneration, but also for the in vivo cell-based repair or modulation of a patient's disease profile. hiPSCs derived from patients with the neurodegenerative diseases amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease and multiple sclerosis have been successfully differentiated in vitro into disease-relevant cell types, including motor neurons, dopaminergic neurons and oligodendrocytes. However, the generation of functional iPSC-derived neural cells that are capable of engraftment in humans and the identification of robust disease phenotypes for modeling neurodegeneration still require several key challenges to be addressed. Here, we discuss these challenges and summarize recent progress toward the application of iPSC technology for these four common neurodegenerative diseases. PMID:24815224
LDL particle size and number compared with LDL cholesterol and risk categorization in end-stage renal disease patients
Bowden, Rodney G.; Wilson, Ronald L.; Beaujean, A. Alexander
Background Few studies have been conducted that make comparisons between traditional measures of cholesterol and cholesterol subfractions, and only one study has compared low-density lipoprotein cholesterol (LDL-C) particle number, LDL-C particle size and LDL-C among end-stage renal disease (ESRD) patients. The purpose of this study was to examine the relationships between cholesterol measures and differences in risk stratification when using ATP-III guidelines compared with cholesterol particle number and size in ESRD patients. Methods ESRD patients (n=1,092) from clinics associated with the Central Texas Nephrology Associates were recruited to participate in this study. Results LDL particle size categorized more patients at-risk when compared with LDL-C, non-HDL-C and triglycerides. Pearson correlation coefficients revealed a strong significant correlation between LDL-C and LDL particle number (r2=0.908, p=0.0001) and a significant correlation between LDL particle number and LDL particle size (r2=?0.290, p=0.0001). A significant but weak correlation existed between LDL-C and LDL particle size (r2=0.107, p=0.0001). A significant correlation existed between LDL particle number and triglycerides (r2=0.335, p=0.0001) and a significant inverse relationship between LDL particle size and triglycerides (r2=?0.500, p=0.0001). Conclusions Our study seems to suggest that using LDL particle size may help to identify those who would not be considered at-risk using LDL-C, non-HDL-C or triglycerides alone, and can be used as a further screening measure that may be more predictive of coronary heart disease outcomes. PMID:21360474
Avian oncogenesis induced by lymphoproliferative disease virus: a neglected or emerging retroviral pathogen?
Technology Transfer Automated Retrieval System (TEKTRAN)
Lymphoproliferative disease virus (LPDV) is an exogenous oncogenic retrovirus that induces lymphoid tumors in some galliform species of birds. Historically, outbreaks of LPDV have been reported from Europe and Israel. Although the virus has previously never been detected in North America, herein we ...
ETD-02-045 (GAVETT) GPRA # 10108 Neutrophils Play a Critical Role in the Development of LPS-Induced Airway Disease. Jordan D. Savov, Stephen H. Gavett*, David M. Brass, Daniel L. Costa*, and David A. Schwartz ABSTRACT We investigated the role of neutrophils...
Appraisal of experimental and commercial Marek's disease vaccines to induce bursal and thymic atrophy
Technology Transfer Automated Retrieval System (TEKTRAN)
Recently, several experimental Marek�s disease (MD) vaccines were developed that appear to protect equally or better than the best commercial vaccines. However, some of the experimental vaccines were reported to induce transient bursal and thymic atrophies. We will report on two promising experiment...
Effects of Systemic Neutrophil Depletion on LPS-induced Airway Disease Jordan D. Savov, Stephen H. Gavett*, David M. Brass, Daniel L. Costa*, David A. Schwartz Pulmonary and Critical Care Division, Dept of Medicine ? Duke University Medical Center * National Health and E...
Amiodarone-induced hepatic phospholipidosis: a morphological alteration independent of pseudoalcoholic liver disease
Bernard Guigui; Sylvain Perrot; Jean Pierre Berry; Jocelyne Fleury-Feith; Nadine Martin; J. M. Metreau; Daniel Dhumeaux; Elie Serge Zafrani
In order to study the relationship between amiodarone-induced hepatic phospholipidosis and liver disease, liver biopsies obtained from 13 patients treated with amiodarone for 4 months to 15 years were investigated by light and electron microscopy. Light microscopy showed pseudoalcoholic liver lesions that were probably related to amiodarone in four cases, various alterations (i.e. cirrhosis, three cases; steatosis and fibrosis, two
Walter M. Boyce; Leslie W. Woods; M. Kevin Keel; N. James MacLachlan; Charles O. Porter; Howard D. Lehmkuhl
Ten fawns and four adult black-tailed deer (Odocoileus hemionus) in a captive herd died as a result of adenovirus-induced hemorrhagic disease. Acute, systemic infections were characterized by hemorrhagic enteropathy, pulmonary edema, and occasional ulceration of the upper alimentary tract. Localized infections were limited to the upper alimentary tract and included stomatitis, pharyngitis, mandibular osteomyelitis, and rumenitis. In deer with acute,
Biologic susceptibility of hepatocellular carcinoma patients treated with radiotherapy to radiation-induced liver disease
Jason Chia-Hsien Cheng; Jian-Kuen Wu; Patricia Chiao-Tzu Lee; Hua-Shan Liu; James Jer-Min Jian; Yu-Mong Lin; Juei-Low Sung; Gwo-Jen Jan
Purpose:To identify the factors associated with radiation-induced liver disease (RILD) and to describe the difference in normal tissue complication probability (NTCP) between subgroups of hepatocellular carcinoma patients undergoing three-dimensional conformal radiotherapy (3D-CRT).
Influence of Mast Cells on Structural and Functional Manifestations of Radiation-Induced Heart Disease
Marjan Boerma; Junru Wang; Jan Wondergem; Jacob Joseph; Xiaohua Qiu; Richard H. Kennedy; Martin Hauer-Jensen
Radiation-induced heart disease (RIHD), characterized by accelerated atherosclerosis and adverse tissue remodeling, is a serious sequelae after radiotherapy of thoracic and chest wall tumors. Adverse cardiac remodeling in RIHD and other cardiac disorders is frequently accompanied by mast cell hyperplasia, suggesting that mast cells may affect the development of cardiac fibrosis. This study used a mast cell- deficient rat model
Genetic susceptibility to chronic trichuris muris induced experimental colitis: translation and relevance to human Crohn's disease
S E Levison; P Fisher; W Newman; J McLaughlin; R KGrencis; J L Pennock
IntroductionUnraveling the genetic architecture of complex traits presents a true challenge. The analysis of experimental models with strict phenotypic documentation and homology to human traits, alongside sensitive scientific methodologies, will facilitate future discoveries. Trichuris muris (T muris) induces chronic colitis in susceptible mouse strains, with previously described clinical, histological, and immunological commonalities to human Crohn's disease (CD). Conversely, resistant mouse
Sequential acetaldehyde production, lipid peroxidation, and fibrogenesis in micropig model of alcohol-induced liver disease
Onni Niemela; Seppo Parkkila; Seppo Yla-Herrruala; Jesus Villanueva; Boris Ruebner; Charles H. Halsted
The pathogenesis of alcohol-induced liver disease involves the adverse effects of ethanol metabolites and oxidative tissue injury. Previous studies indicated that covalent protein adducts with reactive aldehydes may be formed in alcohol consumers. To study the role of such protein adducts in the development of liver injury, we examined the sequential appearances of adducts of the ethanol metabolite acetaldehyde (AA)
Is delayed genomic instability specifically induced by high-LET particles?
NASA Astrophysics Data System (ADS)
Testard, Isabelle; Sabatier, Laure
Ionizing radiation can induce a large variety of damages in the DNA. The processing or repair of this damage occurs in the first minutes up to several hours after irradiation. Afterwhile the remaining lesions are fixed in an irreparable state. However, in recent years, data have accumulated to suggest that genomic instability can manifest in the progeny of irradiated cells leading to accumulation of damage through cell generations. Different biological endpoints were described: delayed cell death, delayed mutations, de novo chromosomal instability. The question regarding the ability of sparsely ionizing X-or ?-rays to induce such phenomenon is still unclear for normal cells. In most of the reports, high linear energy transfer (LET) particles are able to induce genomic instability but not low-LET particles. The mechanisms underlying this phenomenon are still unknown. In human fibroblasts irradiated by heavy ions in a large range of LETs, we showed that the chromosomal instability is characterized by telomeric associations (TAS) involving specific chromosomes. The same instability is observed during the senescence process and during the first passages after viral transfection. The specific chromosomal instability that we observed after irradiation would not be a direct consequence of irradiation but would be a natural phenomenon occurring after many cell divisions. The effect of the irradiation would lie on the bypass of the senescence process that would permit cells with end to end fusions to survive and be transmitted through cell generations, accumulating chromosome rearrangements and chromosome imbalances. Research on molecular mechanisms of chromosomal instability is focused on the role of telomeres in end to end fusions. Such observations could contribute to understand why chromosomal instability is not a dose dependant phenomenon. Why high-LET particles would be so potent in inducing delayed instability? The answer might lie in the study of primary effects of ionizing radiations (X-rays, ?-rays and heavy ions). Cell survival studies showed that K-shell ionizations could be the primary physical events responsible of cell death. The quality of the DNA damages and gene mutations high-LET induced could be the keyhole leading to the great efficiency of these particles.
Non-random distribution of DNA double-strand breaks induced by particle irradiation
NASA Technical Reports Server (NTRS)
Lobrich, M.; Cooper, P. K.; Rydberg, B.; Chatterjee, A. (Principal Investigator)
Induction of DNA double-strand breaks (dsbs) in mammalian cells is dependent on the spatial distribution of energy deposition from the ionizing radiation. For high LET particle radiations the primary ionization sites occur in a correlated manner along the track of the particles, while for X-rays these sites are much more randomly distributed throughout the volume of the cell. It can therefore be expected that the distribution of dsbs linearly along the DNA molecule also varies with the type of radiation and the ionization density. Using pulsed-field gel and conventional gel techniques, we measured the size distribution of DNA molecules from irradiated human fibroblasts in the total range of 0.1 kbp-10 Mbp for X-rays and high LET particles (N ions, 97 keV/microns and Fe ions, 150 keV/microns). On a mega base pair scale we applied conventional pulsed-field gel electrophoresis techniques such as measurement of the fraction of DNA released from the well (FAR) and measurement of breakage within a specific NotI restriction fragment (hybridization assay). The induction rate for widely spaced breaks was found to decrease with LET. However, when the entire distribution of radiation-induced fragments was analysed, we detected an excess of fragments with sizes below about 200 kbp for the particles compared with X-irradiation. X-rays are thus more effective than high LET radiations in producing large DNA fragments but less effective in the production of smaller fragments. We determined the total induction rate of dsbs for the three radiations based on a quantitative analysis of all the measured radiation-induced fragments and found that the high LET particles were more efficient than X-rays at inducing dsbs, indicating an increasing total efficiency with LET. Conventional assays that are based only on the measurement of large fragments are therefore misleading when determining total dsb induction rates of high LET particles. The possible biological significance of this non-randomness for dsb induction is discussed.
Pre-saddle neutron multiplicity for fission reactions induced by heavy ions and light particles
S. Soheyli; M. K. Khalili
Pre-saddle neutron multiplicity has been calculated for several fission reactions induced by heavy ions and light particles. Experimentally, it is impossible to determine the contribution of neutrons being emitted before the saddle point and those emitted between the saddle and the scission points. Determination of the pre-saddle neutron multiplicity in our research is based on the comparison between the experimental anisotropies and those predicted by the standard saddle-point statistical model. Analysis of the results shows that the pre-saddle neutron multiplicity depends on the fission barrier height and stability of the compound nucleus. In heavy ion induced fission, the number of pre-saddle neutrons decreases with increasing the excitation energy of the compound nucleus. A main cause of this behavior is due to a reduction in the ground state-to-saddle point transition time with increasing the excitation energy of the compound nucleus. Whereas in induced fission by light particles, the number of pre-saddle neutrons increases with increasing the excitation energy of the compound nucleus.
Charged particle density distributions in Au induced interactions with emulsion nuclei at 10.7 A GeV
M. I. Adamovich; M. M. Aggarwal; Y. A. Alexandrov; R. Amirikas; N. P. Andreeva; Z. V. Anzon; R. Arora; F. A. Avetyan; S. K. Badyal; A. M. Bakich; E. S. Basova; I. K. Bazarov; K. B. Bhalla; A. Bhasin; V. S. Bhatia; V. G. Bogdanov; V. Bradnova; V. I. Bubnov; T. H. Burnett; X. Cai; D. A. Carshiev; I. Y. Chasnikov; L. P. Chernova; M. M. Chernyavski; S. Dhamija; G. Z. Eligbaeva; L. E. Eremenko; A. S. Gaitinov; E. R. Ganssauge; S. Garpman; S. G. Gerassimov; C. Graf; J. Grote; K. G. Gulamov; S. K. Gupta; V. K. Gupta; B. Jakobsson; L. Just; S. Kachroo; G. S. Kalyachkina; E. K. Kanygina; M. Karabova; S. Kitroo; S. P. Kharlamov; A. D. Kovalenko; S. A. Krasnov; V. Kumar; V. G. Larionova; Y. D. Li; L. S. Liu; S. Lokanatan; J. J. Lord; N. S. Lukicheva; S. B. Luo; L. K. Mangotra; N. A. Marutyan; A. Y. Mashkov; N. V. Maslennikova; I. S. Mittra; S. Mokerjee; S. Z. Nasyrov; V. S. Navotny; J. Nystrand; M. Ochs; G. I. Orlova; I. Otterlund; L. S. Peak; N. G. Peresadko; N. V. Petrov; V. A. Plyushchev; V. V. Rusakova; W. Y. Qian; Y. M. Qin; R. Raniwala; N. K. Rao; M. Roeper; N. Saidkhanov; N. A. Salmanova; L. G. Sarkisova; V. R. Sarkisyan; G. S. Shabratova; A. M. Seitimbetov; C. I. Shakhova; S. N. Shpilev; D. Skelding; K. S�derstr�m; Z. I. Solovjeva; E. Stenlund; L. N. Svechnikova; T. Svensson; M. Tothova; M. I. Tretyakova; T. P. Trofimova; U. I. Tuleeva; B. P. Tursunov; S. Vokal; J. Vrlakova; H. Q. Wang; Z. Q. Weng; R. J. Wilkes; Y. L. Xia; C. B. Yang; D. H. Zhang; P. Y. Zheng; S. I. Zhokhova; D. C. Zhou
Charged particle pseudorapidity density distributions in Au induced reactions in nuclear emulsion at 10.7 A GeV have been measured. In peripheral events the shower particle distribution exhibits a two peak structure while in central collisions it has a Gaussian shape. The spectator protons appear in the second peak in the pseudorapidity spectra and exhibits a broader momentum distribution than expected
Studying effects of Magnolol on alpha-particle induced bystander effects using PADC-film based dishes
Yu, K.N.
Studying effects of Magnolol on alpha-particle induced bystander effects using PADC-film based May 2009 Accepted 17 October 2009 Keywords: Bystander effect Alpha-particle CHO cells Magnolol PADC irradiated directly by ionizing radiation. In the present paper, the effects of Magnolol, an extract from
Long-term changes in amphetamine-induced reinforcement and aversion in rats following exposure to 56Fe particle
NASA Technical Reports Server (NTRS)
Rabin, B. M.; Joseph, J. A.; Shukitt-Hale, B.
Exposing rats to heavy particles produces alterations in the functioning of dopaminergic neurons and in the behaviors that depend upon the integrity of the dopaminergic system. Two of these dopamine-dependent behaviors include amphetamine-induced reinforcement, measure using the conditioned place preference procedure, and amphetamine-induced reinforcement, measured using the conditioned place preference procedure, and amphetamine-induced aversion, measured using the conditioned taste aversion. Previous research has shown that exposing rats to 1.0 Gy of 1GeV/n 56Fe particles produced a disruption of an amphetamine-induced taste aversion 3 days following exposure, but produced an apparent enhancement of the aversion 112 days following exposure. The present experiments were designed to provide a further evaluation of these results by examining taste aversion learning 154 days following exposure to 1.0 Gy 56Fe particles and to establish the convergent validity of the taste aversion results by looking at the effects of exposure on the establishment of an amphetamine-induced conditioned place preference 3, 7, and 16 weeks following irradiation. The taste aversion results failed to confirm the apparent enhancement of the amphetamine-induced CTA observed in the prior experiment. However, exposure to 56Fe particles prevented the acquisition of amphetamine-induced place preference at all three-time intervals. The results are interpreted as indicating that exposure to heavy particles can produce long-term changes in behavioral functioning. c2002 COSPAR. Published by Elsevier Science Ltd. All rights reserved.
Small particle aerosol inoculation of cowpox Brighton Red in rhesus monkeys results in a severe respiratory disease.
Johnson, Reed F; Hammoud, Dima A; Lackemeyer, Matthew G; Yellayi, Srikanth; Solomon, Jeffrey; Bohannon, Jordan K; Janosko, Krisztina B; Jett, Catherine; Cooper, Kurt; Blaney, Joseph E; Jahrling, Peter B
Cowpox virus (CPXV) inoculation of nonhuman primates (NHPs) has been suggested as an alternate model for smallpox (Kramski et al., 2010, PLoS One, 5, e10412). Previously, we have demonstrated that intrabronchial inoculation of CPXV-Brighton Red (CPXV-BR) into cynomolgus monkeys resulted in a disease that shared many similarities to smallpox; however, severe respiratory tract disease was observed (Smith et al., 2011, J. Gen. Virol.). Here we describe the course of disease after small particle aerosol exposure of rhesus monkeys using computed tomography (CT) to monitor respiratory disease progression. Subjects developed a severe respiratory disease that was uniformly lethal at 5.7 log10 PFU of CPXV-BR. CT indicated changes in lung architecture that correlated with changes in peripheral blood monocytes and peripheral oxygen saturation. While the small particle aerosol inoculation route does not accurately mimic human smallpox, the data suggest that CT can be used as a tool to monitor real-time disease progression for evaluation of animal models for human diseases. PMID:25776759
Mammalian Orthoreovirus Particles Induce and Are Recruited into Stress Granules at Early Times Postinfection?
Qin, Qingsong; Hastings, Craig; Miller, Cathy L.
Infection with many mammalian orthoreovirus (MRV) strains results in shutoff of host, but not viral, protein synthesis via protein kinase R (PKR) activation and phosphorylation of translation initiation factor eIF2?. Following inhibition of protein synthesis, cellular mRNAs localize to discrete structures in the cytoplasm called stress granules (SGs), where they are held in a translationally inactive state. We examined MRV-infected cells to characterize SG formation in response to MRV infection. We found that SGs formed at early times following infection (2 to 6 h postinfection) in a manner dependent on phosphorylation of eIF2?. MRV induced SG formation in all four eIF2? kinase knockout cell lines, suggesting that at least two kinases are involved in induction of SGs. Inhibitors of MRV disassembly prevented MRV-induced SG formation, indicating that viral uncoating is a required step for SG formation. Neither inactivation of MRV virions by UV light nor treatment of MRV-infected cells with the translational inhibitor puromycin prevented SG formation, suggesting that viral transcription and translation are not required for SG formation. Viral cores were found to colocalize with SGs; however, cores from UV-inactivated virions did not associate with SGs, suggesting that viral core particles are recruited into SGs in a process that requires the synthesis of viral mRNA. These results demonstrate that MRV particles induce SGs in a step following viral disassembly but preceding viral mRNA transcription and that core particles are themselves recruited to SGs, suggesting that the cellular stress response may play a role in the MRV replication cycle. PMID:19710141
Methods to characterize spontaneous and startle-induced locomotion in a rotenone-induced Parkinson's disease model of Drosophila.
Liao, Jennifer; Morin, Laura W; Ahmad, S Tariq
Parkinson's disease is a neurodegenerative disorder that results from the degeneration of dopaminergic neurons in the central nervous system, primarily in the substantia nigra. The disease causes motor deficiencies, which present as rigidity, tremors and dementia in humans. Rotenone is an insecticide that causes oxidative damage by inhibiting the function of the electron transport chain in mitochondria. It is also used to model Parkinson's disease in the Drosophila. Flies have an inherent negative geotactic response, which compels them to climb upwards upon being startled. It has been established that rotenone causes early mortality and locomotion defects that disrupt the flies' ability to climb after they have been tapped downwards. However, the effect of rotenone on spontaneous movement is not well documented. This study outlines two sensitive, reproducible, and high throughput assays to characterize rotenone-induced deficiencies in short-term startle-induced locomotion and long-term spontaneous locomotion in Drosophila. These assays can be conveniently adapted to characterize other Drosophila models of locomotion defects and efficacy of therapeutic agents. PMID:25178101
Potential of human induced pluripotent stem cells in studies of liver disease.
Sampaziotis, Fotios; Segeritz, Charis-Patricia; Vallier, Ludovic
Liver disease is a leading cause of death in the Western world. However, our insight into the underlying disease mechanisms and the development of novel therapeutic agents has been hindered by limited availability of primary tissue, intraspecies variability associated with the use of animal models, and reduced long-term viability of isolated and diseased liver cells. The emergence of human induced pluripotent stem cells and differentiation protocols to generate hepatocyte-like cells has opened the possibility of addressing these issues. Here, we discuss the recent progress and potential in the production of various cell types constituting the liver and their applications to model liver diseases and test drug toxicity in vitro. (Hepatology 2015;62:303-311). PMID:25502113
Development of a Lorentzian-Function Approximation Utilizing in the - Particle-Induced Nonresonant Reaction Rate
NASA Astrophysics Data System (ADS)
He, J. J.; Li, L.; Hu, J.; Zhang, L. Y.; Xu, S. W.; Yu, X. Q.; Liu, M. L.
A development has been made for the charged-particle-induced nonresonant reaction-rate equations. The forms of reaction-rate equations for nonresonant and resonant reactions have been united in a frame of Lorentzian-Function Approximation (LFA) mathematically. In the frame of LFA, the nonresonant reaction taken place within the Gamow window can be considered, in form, as a "resonance" reaction with a full width at half maximum (FWHM, ?nr) equal to the 1/e width (?) in a well-known Gaussian-Function Approximation (GFA).
Peripheral nerve intramembranous particle density and distribution in chronic streptozotocin-induced diabetes in rats.
Gabriel, G; Thomas, P K; King, R H; Stolinski, C; Breathnach, A S
Freeze-fracture studies have been made on the sciatic nerve of rats with chronic streptozotocin-induced diabetes mellitus. The density of intramembranous particles was reduced in both P and E faces of the axolemma of myelinated and unmyelinated axons, in myelin and in the perineurial cells. This may reflect a general reduction in protein synthesis, or excessive protein degradation, related to the diabetic state. The perineurial cells also showed gap junctions which are not normally present in adult rat peripheral nerve. These may represent a reaction to changes in perineurial activity consequent to alterations in the endoneurial tissue fluid. PMID:2950714
A Metastable Alpha-Particle Irradiation Induced Defect in n-GaAs
NASA Astrophysics Data System (ADS)
Auret, F.; Erasmus, Rudolph; Goodman, Stewart
We report the introduction and characterization of a metastable alpha-particle irradiation induced defect, E?8, in n-GaAs by deep level transient spectroscopy (DLTS) using Schottky barrier diodes. The E?8 defect, with an energy level 0.18 eV below the conduction band, as determined by low-field DLTS measurements, could be reversibly transformed (removed and re-introduced) by employing zero and reverse bias anneals, respectively, in the 100 140 K temperature range. The transformation kinetics of E?8 displayed first order behaviour and was found to be charge state dependant.
Chronic liver disease in murine hereditary tyrosinemia type 1 induces resistance to cell death.
Vogel, Arndt; van Den Berg, Inge E T; Al-Dhalimy, Muhsen; Groopman, John; Ou, Ching-Nan; Ryabinina, Olga; Iordanov, Mihail S; Finegold, Milton; Grompe, Markus
The murine model of hereditary tyrosinemia type 1 (HT1) was used to analyze the relationship between chronic liver disease and programmed cell death in vivo. In healthy fumarylacetoacetate hydrolase deficient mice (Fah(-/-)), protected from liver injury by the drug 2-(2- nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), the tyrosine metabolite homogentisic acid (HGA) caused rapid hepatocyte death. In contrast, all mice survived the same otherwise lethal dose of HGA if they had preexisting liver damage induced by NTBC withdrawal. Similarly, Fah(-/-) animals with liver injury were also resistant to apoptosis induced by the Fas ligand Jo-2 and to necrosis-like cell death induced by acetaminophen (APAP). Molecular studies revealed a marked up-regulation of the antiapoptotic heat shock proteins (Hsp) 27, 32, and 70 and of c-Jun in hepatocytes of stressed mice. In addition, the p38 and Jun N-terminal kinase (JNK) stress-activated kinase pathways were markedly impaired in the cell-death resistant liver. In conclusion, these results provide evidence that chronic liver disease can paradoxically result in cell death resistance in vivo. Stress-induced failure of cell death programs may lead to an accumulation of damaged cells and therefore enhance the risk for cancer as observed in HT1 and other chronic liver diseases. PMID:14767996
Mathematical modelling of the pathogenesis of multiple myeloma-induced bone disease
Ji, Bing; Genever, Paul G; Patton, Ronald J; Fagan, Michael J
Multiple myeloma (MM) is the second most common haematological malignancy and results in destructive bone lesions. The interaction between MM cells and the bone microenvironment plays an important role in the development of the tumour cells and MM-induced bone disease and forms a �vicious cycle� of tumour development and bone destruction, intensified by suppression of osteoblast activity and promotion of osteoclast activity. In this paper, a mathematical model is proposed to simulate how the interaction between MM cells and the bone microenvironment facilitates the development of the tumour cells and the resultant bone destruction. It includes both the roles of inhibited osteoblast activity and stimulated osteoclast activity. The model is able to mimic the temporal variation of bone cell concentrations and resultant bone volume after the invasion and then removal of the tumour cells and explains why MM-induced bone lesions rarely heal even after the complete removal of MM cells. The behaviour of the model compares well with published experimental data. The model serves as a first step to understand the development of MM-induced bone disease and could be applied further to evaluate the current therapies against MM-induced bone disease and even suggests new potential therapeutic targets. � 2014 The Authors. International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons Ltd PMID:24817420
Ultrafine Carbon Black Particles Cause Early Airway Inflammation and Have Adjuvant Activity in a Mouse Allergic Airway Disease Model
Colin de Haar; Ine Hassing; Marianne Bol; Rob Bleumink; Raymond Pieters
To gain more insight into the mechanisms of particulate matter (PM)-induced adjuvant activity, we studied the kinetics of airway toxicity\\/inflammation and allergic sensitization to ovalbumin (OVA) in response to ultrafine carbon black particles (CBP). Mice were exposed intranasally to OVA alone or in combination with different concentrations of CBP. Airway toxicity and inflamma- tion were assessed at days 4 and
Protection of cisplatin-induced spermatotoxicity, DNA damage and chromatin abnormality by selenium nano-particles
Rezvanfar, Mohammad Amin; Rezvanfar, Mohammad Ali [Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences (TUMS), Tehran (Iran, Islamic Republic of)] [Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences (TUMS), Tehran (Iran, Islamic Republic of); Shahverdi, Ahmad Reza [Department of Pharmaceutical Biotechnology and Biotechnology Research Centre, Faculty of Pharmacy, TUMS, Tehran (Iran, Islamic Republic of)] [Department of Pharmaceutical Biotechnology and Biotechnology Research Centre, Faculty of Pharmacy, TUMS, Tehran (Iran, Islamic Republic of); Ahmadi, Abbas [Department of Histology and Embryology, Faculty of Veterinary Medicine, Urmia University, Urmia (Iran, Islamic Republic of)] [Department of Histology and Embryology, Faculty of Veterinary Medicine, Urmia University, Urmia (Iran, Islamic Republic of); Baeeri, Maryam; Mohammadirad, Azadeh [Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences (TUMS), Tehran (Iran, Islamic Republic of)] [Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences (TUMS), Tehran (Iran, Islamic Republic of); Abdollahi, Mohammad, E-mail: firstname.lastname@example.com [Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences (TUMS), Tehran (Iran, Islamic Republic of)] [Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences (TUMS), Tehran (Iran, Islamic Republic of)
Cisplatin (CIS), an anticancer alkylating agent, induces DNA adducts and effectively cross links the DNA strands and so affects spermatozoa as a male reproductive toxicant. The present study investigated the cellular/biochemical mechanisms underlying possible protective effect of selenium nano-particles (Nano-Se) as an established strong antioxidant with more bioavailability and less toxicity, on reproductive toxicity of CIS by assessment of sperm characteristics, sperm DNA integrity, chromatin quality and spermatogenic disorders. To determine the role of oxidative stress (OS) in the pathogenesis of CIS gonadotoxicity, the level of lipid peroxidation (LPO), antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) and peroxynitrite (ONOO) as a marker of nitrosative stress (NS) and testosterone (T) concentration as a biomarker of testicular function were measured in the blood and testes. Thirty-two male Wistar rats were equally divided into four groups. A single IP dose of CIS (7 mg/kg) and protective dose of Nano-Se (2 mg/kg/day) were administered alone or in combination. The CIS-exposed rats showed a significant increase in testicular and serum LPO and ONOO level, along with a significant decrease in enzymatic antioxidants levels, diminished serum T concentration and abnormal histologic findings with impaired sperm quality associated with increased DNA damage and decreased chromatin quality. Coadministration of Nano-Se significantly improved the serum T, sperm quality, and spermatogenesis and reduced CIS-induced free radical toxic stress and spermatic DNA damage. In conclusion, the current study demonstrated that Nano-Se may be useful to prevent CIS-induced gonadotoxicity through its antioxidant potential. Highlights: ? Cisplatin (CIS) affects spermatozoa as a male reproductive toxicant. ? Effect of Nano-Se on CIS-induced spermatotoxicity was investigated. ? CIS-exposure induces oxidative sperm DNA damage and impairs steroidogenesis. ? Nano-Se retained sperm quality against CIS-induced free radicals toxic stress.
Oxidative stress mediates air pollution particle-induced acute lung injury and molecular pathology.
Roberts, Elizabeth S; Richards, Judy H; Jaskot, Richard; Dreher, Kevin L
Insight into the mechanism(s) by which ambient air particulate matter (PM) mediates adverse health effects is needed to provide biological plausibility to epidemiological studies demonstrating associations between PM exposure and increased morbidity and mortality. Although in vitro PM studies provide an understanding of mechanisms by which PM affects pulmonary cells, it is difficult to extrapolate from in vitro to in vivo mechanisms of PM-induced lung injury. We examined in vivo mechanisms of lung injury generated by oil combustion particles. Rats were pretreated with dimethylthiourea (DMTU) before intratracheal instillation of residual oil fly ash (ROFA). Animals were examined by bronchoalveolar lavage for biomarkers of lung injury, and lung tissues were examined by immunohistochemical, biochemical, and molecular approaches to identify ROFA-induced alterations in intracellular signaling pathways and proinflammatory gene expression. Significant increases in pulmonary inflammation, cytotoxicity, activation of ERK mitogen-activated protein kinase (MAPK), and increases in mRNA levels encoding macrophage inflammatory protein (MIP)-2, interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, MCP-1 and matrilysin were observed. DMTU pretreatment inhibited ROFA-induced pulmonary inflammation, cytotoxicity, ERK MAPK activation, and cytokine gene expression. Our findings provide coherence with in vitro PM mechanistic information, allow direct in vitro to in vivo extrapolation, and demonstrate a critical role for oxidative stress in ROFA-induced lung injury and associated molecular pathology. PMID:14569496
Oxidative stress-induced signaling pathways implicated in the pathogenesis of Parkinson's disease.
Gaki, Georgia S; Papavassiliou, Athanasios G
Parkinson's disease is the second most common neurodegenerative movement disorder; however, its etiology remains elusive. Nevertheless, in vivo observations have concluded that oxidative stress is one of the most common causes in the pathogenesis of Parkinson's disease. It is known that mitochondria play a crucial role in reactive oxygen species-mediated pathways, and several gene products that associate with mitochondrial function are the subject of Parkinson's disease research. The PTEN-induced kinase 1 (PINK1) protects cells from mitochondrial dysfunction and is linked to the autosomal recessive familial form of the disease. PINK1 is a key player in many signaling pathways engaged in mitophagy, apoptosis, or microglial inflammatory response and is induced by oxidative stress. Several proteins participate in mitochondrial networks, and they are associated with PINK1. The E3 ubiquitin ligase Parkin, the protease presenilin-associated rhomboid-like serine protease, the tyrosine kinase c-Abl, the protein kinase MARK2, the protease HtrA2, and the tumor necrosis factor receptor-associated protein 1 (TRAP1) provide different steps of control in protection against oxidative stress. Furthermore, environmental toxins, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, have been identified as contributors to parkinsonism by increasing oxidative stress in dopaminergic neurons. The present review discusses the mechanisms and effects of oxidative stress, the emerging concept of the impact of environmental toxins, and a possible neuroprotective role of the antioxidant astaxanthin in various neurodegenerative disorders with particular emphasis in Parkinson's disease. PMID:24522549
Alpha particle induced DNA damage and repair in normal cultured thyrocytes of different proliferation status.
Lyckesv�rd, Madeleine Nord�n; Delle, Ulla; Kahu, Helena; Lindegren, Sture; Jensen, Holger; B�ck, Tom; Swanpalmer, John; Elmroth, Kecke
Childhood exposure to ionizing radiation increases the risk of developing thyroid cancer later in life and this is suggested to be due to higher proliferation of the young thyroid. The interest of using high-LET alpha particles from Astatine-211 ((211)At), concentrated in the thyroid by the same mechanism as (131)I [1], in cancer treatment has increased during recent years because of its high efficiency in inducing biological damage and beneficial dose distribution when compared to low-LET radiation. Most knowledge of the DNA damage response in thyroid is from studies using low-LET irradiation and much less is known of high-LET irradiation. In this paper we investigated the DNA damage response and biological consequences to photons from Cobolt-60 ((60)Co) and alpha particles from (211)At in normal primary thyrocytes of different cell cycle status. For both radiation qualities the intensity levels of ?H2AX decreased during the first 24h in both cycling and stationary cultures and complete repair was seen in all cultures but cycling cells exposed to (211)At. Compared to stationary cells alpha particles were more harmful for cycling cultures, an effect also seen at the pChk2 levels. Increasing ratios of micronuclei per cell nuclei were seen up to 1Gy (211)At. We found that primary thyrocytes were much more sensitive to alpha particle exposure compared with low-LET photons. Calculations of the relative biological effectiveness yielded higher RBE for cycling cells compared with stationary cultures at a modest level of damage, clearly demonstrating that cell cycle status influences the relative effectiveness of alpha particles. PMID:24769180
Epizootic Hemorrhagic Disease Virus Induces and Benefits from Cell Stress, Autophagy, and Apoptosis
Shai, Ben; Schmukler, Eran; Yaniv, Roy; Ziv, Naomi; Horn, Galit; Bumbarov, Velizar; Yadin, Hagai; Smorodinsky, Nechama I.; Bacharach, Eran; Pinkas-Kramarski, Ronit
The mode and timing of virally induced cell death hold the potential of regulating viral yield, viral transmission, and the severity of virally induced disease. Orbiviruses such as the epizootic hemorrhagic disease virus (EHDV) are nonenveloped and cytolytic. To date, the death of cells infected with EHDV, the signal transduction pathways involved in this process, and the consequence of their inhibition have yet to be characterized. Here, we report that the Ibaraki strain of EHDV2 (EHDV2-IBA) induces apoptosis, autophagy, a decrease in cellular protein synthesis, the activation of c-Jun N-terminal kinase (JNK), and the phosphorylation of the JNK substrate c-Jun. The production of infectious virions decreased upon inhibition of apoptosis with the pan-caspase inhibitor Q-VD-OPH (quinolyl-valyl-O-methylaspartyl-[-2,6-difluorophenoxy]-methyl ketone), upon inhibition of autophagy with 3-methyladenine or via the knockout of the autophagy regulator Atg5, or upon treatment of infected cells with the JNK inhibitor SP600125 or the cyclin-dependent kinase (CDK) inhibitor roscovitine, which also inhibited c-Jun phosphorylation. Moreover, Q-VD-OPH, SP600125, and roscovitine partially reduced EHDV2-IBA-induced cell death, and roscovitine diminished the induction of autophagy by EHDV2-IBA. Taken together, our results imply that EHDV induces and benefits from the activation of signaling pathways involved in cell stress and death. PMID:24089565
Impact of induced pluripotent stem cells on the study of central nervous system disease
Cundiff, Paige E.; Anderson, Stewart A.
The derivation of pluripotent stem cells from somatic tissues has provided researchers with a source of patient-specific stem cells. The potential applications of this technology are truly momentous, and include cellular modeling of disease processes, drug discovery, and cell-based therapy. Here, we review the use of induced pluripotent stem cells (iPSCs) to study CNS disease. Since the iPSC field is still in its infancy, we also discuss some of the challenges that will need to be overcome before the potential of this technology to study and to treat neurological and psychiatric disorders can be fully harnessed. PMID:21277194
Impact of induced pluripotent stem cells on the study of central nervous system disease.
Cundiff, Paige E; Anderson, Stewart A
The derivation of pluripotent stem cells from somatic tissues has provided researchers with a source of patient-specific stem cells. The potential applications of this technology are truly momentous, and include cellular modeling of disease processes, drug discovery, and cell-based therapy. Here, we review the use of induced pluripotent stem cells (iPSCs) to study CNS disease. Since the iPSC field is still in its infancy, we also discuss some of the challenges that will need to be overcome before the potential of this technology to study and to treat neurological and psychiatric disorders can be fully harnessed. PMID:21277194
Understanding the mechanisms of sickle cell disease by simulations with a discrete particle model
NASA Astrophysics Data System (ADS)
Hui, Katrina; Lin, Guang; Pan, Wenxiao
Sickle cell disease (SCD) is an inherited blood disorder characterized by rigid, sickle-shaped red blood cells (RBCs). Because of their rigidity and shape, sickle cells can get stuck in smaller blood vessels, causing blockages and depriving oxygen to tissues. This study develops and applies mathematical models to better understand the mechanism of SCD. Two-dimensional models of RBCs and blood vessels have been constructed by representing them as discrete particles interacting with different forces. The nonlinear, elastic property of healthy RBCs could be adequately reproduced using a cosine angle bending force and a worm-like chain spring force. With the ability to deform, RBCs can squeeze through narrow blood vessels. In modeling sickle cells as rigid bodies and applying repelling and friction forces from the blood vessel, this study shows that geometrical factors (dimensions of the sickle cell and blood vessels) as well as rigidity and adhesiveness of the sickle cell all play an important role in determining how, and if, sickle cells become trapped within narrow blood capillaries. With lack of data to validate the model, this study primarily provides a sensitivity analysis of factors influencing sickle cell occlusion and identified critical data to support future modeling.
"Ultramicroinjection" of macromolecules or small particles into animal cells. A new technique based on virus-induced cell fusion
A new method is described for the introduction of macromolecules and small particles into animal cells. The first step in this procedure is the trapping of particles in ghosts of human erythrocytes. This is achieved by the gradual hemolysis of erythrocytes in the presence of the particles to be trapped. The second step is the Sendai virus- induced fusion of the ghosts containing the particles with cells. By this method, ferritin and latex spheres (diameter 0.1 mum) have been "injected" into cells. PMID:167032
UHMWPE carrying estradiol to treat the particle-induced osteolysis-Processing and characterizing.
Liu, Aiqin; Qu, Shuxin; Chao, Mengmeng; Zhu, Minhao; Weng, Jie; Zhou, Zhongrong
The objective of this study was to explore the possibility of UHMWPE implant used as the drug carrier to treat particle-induced osteolysis. 17beta-estradiol (E2), which had the potential application on osteolysis treatment and the high melting point, was added into UHMWPE powder to produce UHMWPE-E2 composites through hot press processing. The hydrophobicity, crystallinity, mechanical properties, and wear performance of the UHMWPE-E2 were characterized compared with the control UHMWPE. The thermal analysis and Fourier Transform Infrared Spectroscopy results demonstrated that the hot press processing would not alter the functional groups of E2 in this study. There were no significant differences in the hydrophobicity and crystallinity between the UHMWPE-E2 and UHMWPE. The UHMWPE-E2 showed satisfying mechanical properties, including ultimate tensile strength (47.2 +/- 3.6 MPa), yield strength (25.0 +/- 0.6 MPa) and elongation at break (320 +/- 25.5 %), which were similar with the control UHMWPE. The friction coefficients and worn scars were similar between the UHMWPE-E2 and the control UHMWPE. The wear mechanism of the UHMWPE-E2 and UHMWPE both were abrasive wear under dry friction. The UHMWPE-E2 possesses the approving mechanical properties and wear performance compared with the control UHMWPE, which might be used as the potential implanted drug carrier to prevent the particle-induced osteolysis in joint replacements. PMID:18563828
Discrete particle detection and metal emissions monitoring using laser-induced breakdown spectroscopy
Hahn, D.W.; Flower, W.L.; Hencken, K.R. [Sandia National Laboratories, Livermore, California94551-0969 (United States)] [Sandia National Laboratories, Livermore, California94551-0969 (United States)
The unique conditions for the application of laser-induced breakdown spectroscopy (LIBS) as a metal emissions monitoring technology have been discussed. Because of the discrete, particulate nature of effluent metals, the utilization of LIBS is considered in part as a statistical sampling problem involving the finite laser-induced plasma volume, as well as the concentration and size distribution of the target metal species. Particle sampling rates are evaluated and Monte Carlo simulations are presented for relevant LIBS parameters and wastestream conditions. For low metal effluent levels and submicrometer-sized particles, a LIBS-based technique may become sample limited. An approach based on random LIBS sampling and the conditional analysis of the resulting data is proposed as a means to enhance the LIBS sensitivity in actual wastestreams. Monte Carlo simulations and experimental results from a pyrolytic waste processing facility are presented, which demonstrate that a significant enhancement of LIBS performance, greater than an order of magnitude, may be realized by taking advantage of the discrete particulate nature of metals. {copyright} {ital 1997} {ital Society for Applied Spectroscopy}
Asian Dust Particles Induce TGF-?1 via Reactive Oxygen Species in Bronchial Epithelial Cells
Kyung, Sun Young; Yoon, Jin Young; Kim, Yu Jin; Lee, Sang Pyo; Park, Jeong-Woong
Background Asian dust storms can be transported across eastern Asia. In vitro, Asian dust particle-induced inflammation and enhancement of the allergic reaction have been observed. However, the fibrotic effects of Asian dust particles are not clear. Production of transforming growth factor ?1 (TGF-?1) and fibronectin were investigated in the bronchial epithelial cells after exposure to Asian dust particulate matter (AD-PM10). Methods During Asian dust storm periods, air samples were collected. The bronchial epithelial cells were exposed to AD-PM10 with and without the antioxidant, N-acetyl-L-cysteine (NAC). Then TGF-?1 and fibronectin were detected by Western blotting. The reactive oxygen species (ROS) was detected by the measurement of dicholorodihydrofluorescin (DCF), using a FACScan, and visualized by a confocal microscopy. Results The expression of TGF-?1, fibronectin and ROS was high after being exposed to AD-PM10, compared to the control. NAC attenuated both TGF-?1 and fibronectin expression in the AD-PM10-exposed the bronchial epithelial cells. Conclusion AD-PM10 may have fibrotic potential in the bronchial epithelial cells and the possible mechanism is AD-PM10-induced intracellular ROS. PMID:23166540
Induced Matter and Particle Motion in Non-Compact Kaluza-Klein Gravity
Billyard, A P; Billyard, Andrew P.; Sajko, William N.
We examine generalizations of the five-dimensional canonical metric by including a dependence of the extra coordinate in the four-dimensional metric. We discuss a more appropriate way to interpret the four-dimensional energy-momentum tensor induced from the five-dimensional space-time and show it can lead to quite different physical situations depending on the interpretation chosen. Furthermore, we show that the assumption of five-dimensional null trajectories in Kaluza-Klein gravity can correspond to either four-dimensional massive or null trajectories when the path parameterization is chosen properly. Retaining the extra-coordinate dependence in the metric, we show the possibility of a cosmological variation in the rest masses of particles and a consequent departure from four-dimensional geodesic motion by a geometric force. In the examples given, we show that at late times it is possible for particles traveling along 5D null geodesics to be in a frame consistent with the induced matter scenario.
Induced Matter and Particle Motion in Non-Compact Kaluza-Klein Gravity
Andrew P. Billyard; William N. Sajko
We examine generalizations of the five-dimensional canonical metric by including a dependence of the extra coordinate in the four-dimensional metric. We discuss a more appropriate way to interpret the four-dimensional energy-momentum tensor induced from the five-dimensional space-time and show it can lead to quite different physical situations depending on the interpretation chosen. Furthermore, we show that the assumption of five-dimensional null trajectories in Kaluza-Klein gravity can correspond to either four-dimensional massive or null trajectories when the path parameterization is chosen properly. Retaining the extra-coordinate dependence in the metric, we show the possibility of a cosmological variation in the rest masses of particles and a consequent departure from four-dimensional geodesic motion by a geometric force. In the examples given, we show that at late times it is possible for particles traveling along 5D null geodesics to be in a frame consistent with the induced matter scenario.
Particle-induced cell migration assay (PICMA): A new in vitro assay for inflammatory particle effects based on permanent cell lines.
Westphal, G�tz A; Schremmer, Isabell; Rostek, Alexander; Loza, Kateryna; Rosenkranz, Nina; Br�ning, Thomas; Epple, Matthias; B�nger, J�rgen
Inflammation is a decisive pathophysiologic mechanism of particle toxicity and accumulation of neutrophils in the lung is believed to be a crucial step in this process. This study describes an in vitro model for investigations of the chemotactic attraction of neutrophils in response to particles using permanent cell lines. We challenged NR8383 rat macrophages with particles that were characterized concerning chemical nature, crystallinity, and size distribution in the dry state and in the culture medium. The cell supernatants were used to investigate migration of differentiated human leukemia cells (dHL-60 cells). The dose range for the tests was determined using an impedance-based Real-Time Cell Analyzer. The challenge of NR8383 cells with 32-96?gcm(-2) coarse and nanosized particles resulted in cell supernatants which induced strong and dose-dependent migration of dHL-60 cells. Quartz caused the strongest effects - exceeding the positive control "fetal calf serum" (FCS) several-fold, followed by silica, rutile, carbon black, and anatase. BaSO4 served as inert control and induced no cell migration. Particles caused NR8383 cells to secrete chemotactic compounds. The assay clearly distinguished between the particles of different inflammatory potential in a highly reproducible way. Specificity of the test is suggested by negative results with BaSO4. PMID:25896209
Epidemiological, clinical, and toxicological studies have demonstrated that exposure to ambient air particulate matter (PM) can alter cardiovascular function and may influence cardiovascular disease (CVD). It has been shown that exposure to concentrated ambient air particles (CA...
Structural properties of EGCG-induced, nontoxic Alzheimer's disease A? oligomers.
Lopez del Amo, Juan Miguel; Fink, Uwe; Dasari, Muralidhar; Grelle, Gerlinde; Wanker, Erich E; Bieschke, Jan; Reif, Bernd
The green tea compound epigallocatechin-3-gallate (EGCG) inhibits Alzheimer's disease ?-amyloid peptide (A?) neurotoxicity. Solution-state NMR allows probing initial EGCG-A? interactions. We show that EGCG-induced A? oligomers adopt a well-defined structure and are amenable for magic angle spinning solid-state NMR investigations. We find that EGCG interferes with the aromatic hydrophobic core of A?. The C-terminal part of the A? peptide (residues 22-39) adopts a ?-sheet conformation, whereas the N-terminus (residues 1-20) is unstructured. The characteristic salt bridge involving residues D23 and K28 is present in the structure of these oligomeric A? aggregates as well. The structural analysis of small-molecule-induced amyloid aggregates will open new perspectives for Alzheimer's disease drug development. PMID:22300765
Manganese-Induced Parkinsonism and Parkinson's Disease: Shared and Distinguishable Features.
Kwakye, Gunnar F; Paoliello, Monica M B; Mukhopadhyay, Somshuvra; Bowman, Aaron B; Aschner, Michael
Manganese (Mn) is an essential trace element necessary for physiological processes that support development, growth and neuronal function. Secondary to elevated exposure or decreased excretion, Mn accumulates in the basal ganglia region of the brain and may cause a parkinsonian-like syndrome, referred to as manganism. The present review discusses the advances made in understanding the essentiality and neurotoxicity of Mn. We review occupational Mn-induced parkinsonism and the dynamic modes of Mn transport in biological systems, as well as the detection and pharmacokinetic modeling of Mn trafficking. In addition, we review some of the shared similarities, pathologic and clinical distinctions between Mn-induced parkinsonism and Parkinson's disease. Where possible, we review the influence of Mn toxicity on dopamine, gamma aminobutyric acid (GABA), and glutamate neurotransmitter levels and function. We conclude with a survey of the preventive and treatment strategies for manganism and idiopathic Parkinson's disease (PD). PMID:26154659
Student Preferences Regarding Teaching Methods in a Drug-Induced Diseases and Clinical Toxicology Course
Gim, Suzanna
Objectives. To determine which teaching method in a drug-induced diseases and clinical toxicology course was preferred by students and whether their preference correlated with their learning of drug-induced diseases. Design. Three teaching methods incorporating active-learning exercises were implemented. A survey instrument was developed to analyze students� perceptions of the active-learning methods used and how they compared to the traditional teaching method (lecture). Examination performance was then correlated to students� perceptions of various teaching methods. Assessment. The majority of the 107 students who responded to the survey found traditional lecture significantly more helpful than active-learning methods (p=0.01 for all comparisons). None of the 3 active-learning methods were preferred over the others. No significant correlations were found between students� survey responses and examination performance. Conclusions. Students preferred traditional lecture to other instructional methods. Learning was not influenced by the teaching method or by preference for a teaching method. PMID:23966726
Disease modeling using human induced pluripotent stem cells: lessons from the liver.
Gieseck, Richard L; Colquhoun, Jennifer; Hannan, Nicholas R F
Human pluripotent stem cells (hPSCs) have the capacity to differentiate into any of the hundreds of distinct cell types that comprise the human body. This unique characteristic has resulted in considerable interest in the field of regenerative medicine, given the potential for these cells to be used to protect, repair, or replace diseased, injured, and aged cells within the human body. In addition to their potential in therapeutics, hPSCs can be used to study the earliest stages of human development and to provide a platform for both drug screening and disease modeling using human cells. Recently, the description of human induced pluripotent stem cells (hIPSCs) has allowed the field of disease modeling to become far more accessible and physiologically relevant, as pluripotent cells can be generated from patients of any genetic background. Disease models derived from hIPSCs that manifest cellular disease phenotypes have been established to study several monogenic diseases; furthermore, hIPSCs can be used for phenotype-based drug screens to investigate complex diseases for which the underlying genetic mechanism is unknown. As a result, the use of stem cells as research tools has seen an unprecedented growth within the last decade as researchers look for in vitro disease models which closely mimic in vivo responses in humans. Here, we discuss the beginnings of hPSCs, starting with isolation of human embryonic stem cells, moving into the development and optimization of hIPSC technology, and ending with the application of hIPSCs towards disease modeling and drug screening applications, with specific examples highlighting the modeling of inherited metabolic disorders of the liver. This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics. PMID:24943800
In situ pulmonary localization of air pollution particle-induced oxidative stress.
Roberts, Elizabeth S; Malstrom, Scott E; Dreher, Kevin L
Exposure to air particulate matter (PM) may be associated with increased morbidity and mortality. An improved understanding of the mechanism(s) by which PM induces adverse effects is needed. This preliminary study examined the ability to use unique bioluminescent technologies to identify acute localized areas of residual oil fly ash (ROFA)-induced, oxidative lung injury. Transgenic mice, in which luciferase (luc) expression was regulated by the heme oxygenase (HO)-1 promoter, were exposed by pharyngeal aspiration to either saline or 50 microg ROFA/mouse. HO-1-luc expression was determined at 2, 6, 12, and 24 h postexposure using luminescent quantification and Western blot analysis of lung protein extracts, as well as with a novel in situ pulmonary bioluminescence imaging approach. The different approaches for the detection of luciferase in lung protein extracts recovered from ROFA exposed HO-1-luc transgenic mice gave variable results. Pulmonary homogenate HO-1-luc levels were increased at 2 h and 24 h postexposure to ROFA when examined by chemilumescent and Western blot analyses, respectively. In situ bioluminescent imaging of pulmonary tissue sections detected ROFA-induced pulmonary luciferase expression by identifying highly localized increases in HO-1-luc expression at 12 h and 24 h postexposure. These results suggest that the variability observed in the methods of detection for luciferase may be due to a localization of cells expressing luciferase within tissue samples, demonstrating that the HO-1-luc transgenic mouse model is the preferred method to detect and pinpoint in vivo particle-induced, oxidative lung injury. The feasibility of using this in situ approach is a unique proof-of-concept application for the identification of localized sites of oxidative injury induced by environmental pollutants. PMID:17966064
Angular distribution in two-particle emission induced by neutrinos and electrons
NASA Astrophysics Data System (ADS)
Simo, I. Ruiz; Albertus, C.; Amaro, J. E.; Barbaro, M. B.; Caballero, J. A.; Donnelly, T. W.
The angular distribution of the phase space arising in two-particle emission reactions induced by electrons and neutrinos is computed in the laboratory (Lab) system by boosting the isotropic distribution in the center of mass (CM) system used in Monte Carlo generators. The Lab distribution has a singularity for some angular values, coming from the Jacobian of the angular transformation between CM and Lab systems. We recover the formula we obtained in a previous calculation for the Lab angular distribution. This is in accordance with the Monte Carlo method used to generate two-particle events for neutrino scattering [J. T. Sobczyk, Phys. Rev. C 86, 015504 (2012)]. Inversely, by performing the transformation to the CM system, it can be shown that the phase-space function, which is proportional to the two-particle-two-hole (2p-2h) hadronic tensor for a constant current operator, can be computed analytically in the frozen nucleon approximation, if Pauli blocking is absent. The results in the CM frame confirm our previous work done using an alternative approach in the Lab frame. The possibilities of using this method to compute the hadronic tensor by a boost to the CM system are analyzed.
Analysing the influence of different street vegetation on traffic-induced particle dispersion using microscale simulations.
Wania, Annett; Bruse, Michael; Blond, Nad�ge; Weber, Christiane
Urban vegetation can be viewed as compensation to the environmental drawbacks of urbanisation. However, its ecosystem function is not well-known and, for urban planning, vegetation is mainly considered as an element of urban design. This article argues that planning practice needs to re-examine the impact of vegetation cover in the urban fabric given our evaluation of vegetation's effects on air quality, including the dispersion of traffic-induced particles at street level. Using the three-dimensional microclimate model ENVI-met�, we evaluate these effects regarding the height-to-width ratio of streets flanked by buildings and the vertical and horizontal density of street vegetation. Our results reveal vegetation's effect on particle dispersion through its influence on street ventilation. In general, vegetation was found to reduce wind speed, causing inhibition of canyon ventilation and, consequently, an increase in particle concentrations. Vegetation was also found to reduce wind speed at crown-height and to disrupt the flow field in close vicinity to the canopy. With increasing height-to-width ratio of street canyons, wind speed reduction increases and the disturbance of the flow impacts across a canyon's entire width. We also found that the effect is more pronounced in configurations with poor ventilation, such as the low wind speed, perpendicular inflow direction, and in deep canyons cases. PMID:21924543
Study of fishbone instabilities induced by energetic particles in tokamak plasmas
NASA Astrophysics Data System (ADS)
He, H. D.; Dong, J. Q.; Fu, G. Y.; He, Z. X.; Jiang, H. B.; Wang, Z. T.; Zheng, G. Y.; Liu, F.; Long, Y. X.; Shen, Y.; Wang, L. F.
Fishbone instabilities, driven by trapped and barely passing energetic particles (EPs), including electrons and ions (EEs or EIs), are numerically studied with the spatial distribution of EPs taken into account. The dispersion relations of the modes are derived for slowing-down and Maxwellian models of EP energy distribution. It is found that the modes with frequency comparable to the toroidal precession frequency ?d of EPs are resonantly excited. Electron and ion fishbone modes share the same growth rates and real frequencies but rotate in opposite directions. The frequency of the modes is found to be higher in the case of near-axis heating than that of off-axis heating. The fishbone instabilities can only be excited by barely trapped or barely passing and deeply trapped particles in positive and negative spatial density gradient regions, respectively. In addition, the most interesting feature of the fishbone modes induced by barely passing particles is that there exists a second stable regime in the higher ?h (pressure of EPs/toroidal magnetic pressure) region, and the modes exist in the range of ?th1 < ?h < ?th2 (?th is threshold or critical beta of EPs) only. The results are well confirmed with Nyquist technology. The possible physical mechanism for the existence of the second stable regime is discussed.
Flow-induced translocation of polymers through a fluidic channel: a dissipative particle dynamics simulation study.
Guo, Jiayi; Li, Xuejin; Liu, Yuan; Liang, Haojun
The dynamics of flow-induced translocation of polymers through a fluidic channel has been studied by dissipative particle dynamics (DPD) approach. Unlike implicit solvent models, the many-body energetic and hydrodynamic interactions are preserved naturally by incorporating explicit solvent particles in this approach. The no-slip wall boundary and the adaptive boundary conditions have been implemented in the modified DPD approach to model the hydrodynamic flow within a specific wall structure of fluidic channel and control the particles' density fluctuations. The results show that the average translocation time versus polymer chain length satisfies a power-law scaling of ? ?N(1.152). The conformational changes and translocation dynamics of polymers through the fluidic channel have also been investigated in our simulations, and two different translocation processes, i.e., the single-file and double-folded translocation events, have been observed in detail. These findings may be helpful in understanding the conformational and dynamic behaviors of such polymer and/or DNA molecules during the translocation processes. PMID:21476773
Flow-induced translocation of polymers through a fluidic channel: A dissipative particle dynamics simulation study
NASA Astrophysics Data System (ADS)
Guo, Jiayi; Li, Xuejin; Liu, Yuan; Liang, Haojun
The dynamics of flow-induced translocation of polymers through a fluidic channel has been studied by dissipative particle dynamics (DPD) approach. Unlike implicit solvent models, the many-body energetic and hydrodynamic interactions are preserved naturally by incorporating explicit solvent particles in this approach. The no-slip wall boundary and the adaptive boundary conditions have been implemented in the modified DPD approach to model the hydrodynamic flow within a specific wall structure of fluidic channel and control the particles' density fluctuations. The results show that the average translocation time versus polymer chain length satisfies a power-law scaling of ? �N1.152. The conformational changes and translocation dynamics of polymers through the fluidic channel have also been investigated in our simulations, and two different translocation processes, i.e., the single-file and double-folded translocation events, have been observed in detail. These findings may be helpful in understanding the conformational and dynamic behaviors of such polymer and/or DNA molecules during the translocation processes.
The effect of flow geometry on shear-induced particle segregation and resuspension
NASA Astrophysics Data System (ADS)
Ramachandran, Arun
In this thesis, we investigate through theory and experiment the influence of the flow geometry on various shear-induced migration phenomena such as particle demixing, viscous resuspension and meniscus accumulation for a suspension of rigid, non-colloidal particles. The major focus of this thesis is the elucidation of a particle flux mechanism that has been ignored in the literature in the theoretical calculation of the concentration distribution in shear-induced migration phenomena. This mechanism is the convective flux due to the secondary currents arising from the non-Newtonian rheology of suspensions. Historically, suspensions have been modeled as Newtonian fluids with concentration dependent viscosities when calculating velocity distributions due to the tremendous simplification of the governing equations. The results presented in this thesis, however, demonstrate that it is critical to consider the complete rheology of a concentrated suspension when modeling flows in complex geometries. While the magnitude of the secondary currents is small, in many cases they are the dominant mechanism governing the resulting particle concentration distribution. In chapters 2 through 4, we investigate the impact of these secondary currents on the concentration profiles developed in suspension flow through conduits of arbitrary geometry, and in resuspension flow through a tube. In chapter 5, we examine the radial segregation of particles in the squeeze flow of concentrated suspensions. This flow is identical to that produced in loading suspensions on to a parallel plate viscometer and thus the concentration inhomogeneities generated during the loading phenomenon may play a role in the well known scatter of torque measurements in this system. We develop a criterion in terms of the experimental parameters in a parallel plate experiment for the onset of radial inhomogeneities. In the final investigation reported in this thesis, we develop a theoretical model for describing the droplet distribution in the Poiseuille flow of an emulsion through a tube. We show that the mathematical problem that results from this model is amenable to self-similar analysis via the trial function approach. The self-similar solution so obtained is used to evaluate oscillatory flows as a possible technique for separation of the dispersed phase from suspending fluid.
Mannan induces ROS-regulated, IL-17A�dependent psoriasis arthritis-like disease in mice
Khmaladze, Ia; Kelkka, Tiina; Guerard, Simon; Wing, Kajsa; Pizzolla, Angela; Saxena, Amit; Lundqvist, Katarina; Holmdahl, Meirav; Nandakumar, Kutty Selva; Holmdahl, Rikard
Psoriasis (Ps) and psoriasis arthritis (PsA) are poorly understood common diseases, induced by unknown environmental factors, affecting skin and articular joints. A single i.p. exposure to mannan from Saccharomyces cerevisiae induced an acute inflammation in inbred mouse strains resembling human Ps and PsA-like disease, whereas multiple injections induced a relapsing disease. Exacerbation of disease severity was observed in mice deficient for generation of reactive oxygen species (ROS). Interestingly, restoration of ROS production, specifically in macrophages, ameliorated both skin and joint disease. Neutralization of IL-17A, mainly produced by ?? T cells, completely blocked disease symptoms. Furthermore, mice depleted of granulocytes were resistant to disease development. In contrast, certain acute inflammatory mediators (C5, Fc? receptor III, mast cells, and histamine) and adaptive immune players (?? T and B cells) were redundant in disease induction. Hence, we propose that mannan-induced activation of macrophages leads to TNF-? secretion and stimulation of local ?? T cells secreting IL-17A. The combined action of activated macrophages and IL-17A produced in situ drives neutrophil infiltration in the epidermis and dermis of the skin, leading to disease manifestations. Thus, our finding suggests a new mechanism triggered by exposure to exogenous microbial components, such as mannan, that can induce and exacerbate Ps and PsA. PMID:25136095
Generation of Healthy Mice from Gene-Corrected Disease-Specific Induced Pluripotent Stem Cells
Guangming Wu; Na Liu; Ina Rittelmeyer; Amar Deep Sharma; Malte Sgodda; Holm Zaehres; Martina Bleidi�el; Boris Greber; Luca Gentile; Dong Wook Han; Cornelia Rudolph; Doris Steinemann; Axel Schambach; Michael Ott; Hans R. Sch�ler; Tobias Cantz
Using the murine model of tyrosinemia type 1 (fumarylacetoacetate hydrolase [FAH] deficiency; FAH?\\/? mice) as a paradigm for orphan disorders, such as hereditary metabolic liver diseases, we evaluated fibroblast-derived FAH?\\/?-induced pluripotent stem cells (iPS cells) as targets for gene correction in combination with the tetraploid embryo complementation method. First, after characterizing the FAH?\\/? iPS cell lines, we aggregated FAH?\\/?-iPS cells
Identification of antigenic proteins associated with trichloroethylene-induced autoimmune disease by serological proteome analysis
Liu Jianjun; Xing Xiumei; Huang Haiyan; Jiang Yingzhi; He Haowei; Xu Xinyun; Yuan Jianhui; Zhou Li; Yang Linqing [Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, No. 21, Rd 1st Tianbei, 518020 Shenzhen (China); Zhuang Zhixiong, E-mail: firstname.lastname@example.com [Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, No. 21, Rd 1st Tianbei, 518020 Shenzhen (China)
Although many studies indicated that trichloroethylene (TCE) could induce autoimmune diseases and some protein adducts were detected, the proteins were not identified and mechanisms remain unknown. To screen and identify autoantigens which might be involved in TCE-induced autoimmune diseases, three groups of sera were collected from healthy donors (I), patients suffering from TCE-induced exfoliative dermatitis (ED) (II), and the healed ones (III). Serological proteome analysis (SERPA) was performed with total proteins of TCE-treated L-02 liver cells as antigen sources and immunoglobins of the above sera as probes. Highly immunogenic spots (2-fold or above increase compared with group I) in group II and III were submitted to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and tandem mass spectrometry sequencing. Western blot analysis was followed using commercial antibodies and individual serum. Six proteins were identified. Among them, Enoyl Coenzyme A hydratase peroxisoma 1 and lactate dehydrogenase B only showed stronger immunogenicity for group II sera, while Purine nucleoside phosphorylase, ribosomal protein P0 and proteasome activator subunit1 isoform1 also showed stronger immunogenicity for group III sera. Noteworthy, NM23 reacted only with group II sera. Western blot analysis of NM23 expression indicated that all of the individual serum of group II showed immune activity, which confirmed the validity of SERPA result. These findings revealed that there exist autoantibodies in group II and III sera. Besides, autoantibodies of the two stages of disease course were different. These autoantigens might serve as biomarkers to elucidate mechanisms underlying TCE toxicity and are helpful for diagnosis, therapy and prognosis of TCE-induced autoimmune diseases.
Radiation-induced liver disease after radiotherapy for hepatocellular carcinoma: clinical manifestation and dosimetric description
Jason Chia-Hsien Cheng; Jian-Kuen Wu; Chao-Ming Huang; David Y. Huang; Skye H. Cheng; Yu-Mong Lin; James J. Jian; Po-Sheng Yang; Vincent P. Chuang; Andrew T. Huang
Twelve patients with hepatocellular carcinoma and chronic hepatitis developed radiation-induced liver disease (RILD) after three-dimensional conformal radiotherapy. Six patients died of RILD and six recovered. Mean prescribed dose was 50.6�4.3Gy, in a daily fraction of 1.8�2.0Gy. Commonly used dosimetric parameters, such as fraction volume of normal liver with radiation dose >30Gy, prediction score, and normal tissue complication probability, failed to
Levodopa-induced Dyskinesia in Parkinson�s disease: Epidemiology, etiology, and treatment
Theresa A. Zesiewicz; Kelly L. Sullivan; Robert A. Hauser
Although levodopa is the gold standard for treating motor symptoms of Parkinson�s disease (PD), long-term therapy leads to\\u000a levodopa-induced dyskinesia (LID). Dyskinesia refers to involuntary movements other than tremor and most commonly consists\\u000a of chorea that occurs when levodopa-derived dopamine is peaking in the brain (�peak-dose dyskinesia�). However, dyskinesia\\u000a can also consist of dystonia or myoclonus and occur during other
Macromolecular prodrug of dexamethasone prevents particle-induced peri-implant osteolysis with reduced systemic side effects
Ren, Ke; Dusad, Anand; Yuan, Fang; Yuan, Hongjiang; Purdue, P. Edward; Fehringer, Edward V.; Garvin, Kevin L.; Goldring, Steven R.; Wang, Dong
Aseptic implant loosening related to implant wear particle-induced inflammation is the most common cause of failure after joint replacement. Modulation of the inflammatory reaction to the wear products represents a rational approach for preventing aseptic implant failure. Long-term treatment using anti-inflammatory agents, however, can be associated with significant systemic side effects due to the drugs' lack of tissue specificity. To address this issue, N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-dexamethasone conjugate (P-Dex) was developed and evaluated for prevention of wear particle-induced osteolysis and the loss of fixation in a murine prosthesis failure model. Daily administration of free dexamethasone (Dex) was able to prevent wear particle-induced osteolysis, as assessed by micro-CT and histological analysis. Remarkably, monthly P-Dex administration (dose equivalent to free Dex treatment) was equally effective as free dexamethasone, but was not associated with systemic bone loss (a major adverse side effect of glucocorticoids). The reduced systemic toxicity of P-Dex is related to preferential targeting of the sites of wear particle-induced inflammation and its subcellular sequestration and retention by local inflammatory cell populations, resulting in sustained therapeutic action. These results demonstrate the feasibility of utilizing a macromolecular prodrug with reduced systemic toxicity to prevent wear particle-induced osteolysis. PMID:24326124
Macromolecular prodrug of dexamethasone prevents particle-induced peri-implant osteolysis with reduced systemic side effects.
Ren, Ke; Dusad, Anand; Yuan, Fang; Yuan, Hongjiang; Purdue, P Edward; Fehringer, Edward V; Garvin, Kevin L; Goldring, Steven R; Wang, Dong
Aseptic implant loosening related to implant wear particle-induced inflammation is the most common cause of failure after joint replacement. Modulation of the inflammatory reaction to the wear products represents a rational approach for preventing aseptic implant failure. Long-term treatment using anti-inflammatory agents, however, can be associated with significant systemic side effects due to the drugs' lack of tissue specificity. To address this issue, N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-dexamethasone conjugate (P-Dex) was developed and evaluated for prevention of wear particle-induced osteolysis and the loss of fixation in a murine prosthesis failure model. Daily administration of free dexamethasone (Dex) was able to prevent wear particle-induced osteolysis, as assessed by micro-CT and histological analysis. Remarkably, monthly P-Dex administration (dose equivalent to free Dex treatment) was equally effective as free dexamethasone, but was not associated with systemic bone loss (a major adverse side effect of glucocorticoids). The reduced systemic toxicity of P-Dex is related to preferential targeting of the sites of wear particle-induced inflammation and its subcellular sequestration and retention by local inflammatory cell populations, resulting in sustained therapeutic action. These results demonstrate the feasibility of utilizing a macromolecular prodrug with reduced systemic toxicity to prevent wear particle-induced osteolysis. PMID:24326124
Diet-Induced Dysbiosis of the Intestinal Microbiota and the Effects on Immunity and Disease
Brown, Kirsty; DeCoffe, Daniella; Molcan, Erin; Gibson, Deanna L.
The gastrointestinal (GI) microbiota is the collection of microbes which reside in the GI tract and represents the largest source of non-self antigens in the human body. The GI tract functions as a major immunological organ as it must maintain tolerance to commensal and dietary antigens while remaining responsive to pathogenic stimuli. If this balance is disrupted, inappropriate inflammatory processes can result, leading to host cell damage and/or autoimmunity. Evidence suggests that the composition of the intestinal microbiota can influence susceptibility to chronic disease of the intestinal tract including ulcerative colitis, Crohn�s disease, celiac disease and irritable bowel syndrome, as well as more systemic diseases such as obesity, type 1 diabetes and type 2 diabetes. Interestingly, a considerable shift in diet has coincided with increased incidence of many of these inflammatory diseases. It was originally believed that the composition of the intestinal microbiota was relatively stable from early childhood; however, recent evidence suggests that diet can cause dysbiosis, an alteration in the composition of the microbiota, which could lead to aberrant immune responses. The role of the microbiota and the potential for diet-induced dysbiosis in inflammatory conditions of the GI tract and systemic diseases will be discussed. PMID:23016134
Anacardic Acids from Cashew Nuts Ameliorate Lung Damage Induced by Exposure to Diesel Exhaust Particles in Mice
Carvalho, Ana Laura Nicoletti; Annoni, Raquel; Torres, Larissa Helena Lobo; Dur�o, Ana Carolina Cardoso Santos; Shimada, Ana Lucia Borges; Almeida, Francine Maria; Hebeda, Cristina Bichels; Lopes, Fernanda Degobbi Tenorio Quirino Santos; Dolhnikoff, Marisa; Martins, Milton Arruda; Silva, Luiz Fernando Ferraz; Farsky, Sandra Helena Poliselli; Saldiva, Paulo Hil�rio Nascimento; Ulrich, Cornelia M.; Owen, Robert W.; Marcourakis, Tania; Trevisan, Maria Teresa Salles; Mauad, Thais
Anacardic acids from cashew nut shell liquid, a Brazilian natural substance, have antimicrobial and antioxidant activities and modulate immune responses and angiogenesis. As inflammatory lung diseases have been correlated to environmental pollutants exposure and no reports addressing the effects of dietary supplementation with anacardic acids on lung inflammation in vivo have been evidenced, we investigated the effects of supplementation with anacardic acids in a model of diesel exhaust particle- (DEP-) induced lung inflammation. BALB/c mice received an intranasal instillation of 50??g of DEP for 20 days. Ten days prior to DEP instillation, animals were pretreated orally with 50, 150, or 250?mg/kg of anacardic acids or vehicle (100??L of cashew nut oil) for 30 days. The biomarkers of inflammatory and antioxidant responses in the alveolar parenchyma, bronchoalveolar lavage fluid (BALF), and pulmonary vessels were investigated. All doses of anacardic acids ameliorated antioxidant enzyme activities and decreased vascular adhesion molecule in vessels. Animals that received 50?mg/kg of anacardic acids showed decreased levels of neutrophils and tumor necrosis factor in the lungs and BALF, respectively. In summary, we demonstrated that AAs supplementation has a potential protective role on oxidative and inflammatory mechanisms in the lungs. PMID:23533495
Anacardic acids from cashew nuts ameliorate lung damage induced by exposure to diesel exhaust particles in mice.
Carvalho, Ana Laura Nicoletti; Annoni, Raquel; Torres, Larissa Helena Lobo; Dur�o, Ana Carolina Cardoso Santos; Shimada, Ana Lucia Borges; Almeida, Francine Maria; Hebeda, Cristina Bichels; Lopes, Fernanda Degobbi Tenorio Quirino Santos; Dolhnikoff, Marisa; Martins, Milton Arruda; Silva, Luiz Fernando Ferraz; Farsky, Sandra Helena Poliselli; Saldiva, Paulo Hil�rio Nascimento; Ulrich, Cornelia M; Owen, Robert W; Marcourakis, Tania; Trevisan, Maria Teresa Salles; Mauad, Thais
Anacardic acids from cashew nut shell liquid, a Brazilian natural substance, have antimicrobial and antioxidant activities and modulate immune responses and angiogenesis. As inflammatory lung diseases have been correlated to environmental pollutants exposure and no reports addressing the effects of dietary supplementation with anacardic acids on lung inflammation in vivo have been evidenced, we investigated the effects of supplementation with anacardic acids in a model of diesel exhaust particle- (DEP-) induced lung inflammation. BALB/c mice received an intranasal instillation of 50? ? g of DEP for 20 days. Ten days prior to DEP instillation, animals were pretreated orally with 50, 150, or 250?mg/kg of anacardic acids or vehicle (100? ? L of cashew nut oil) for 30 days. The biomarkers of inflammatory and antioxidant responses in the alveolar parenchyma, bronchoalveolar lavage fluid (BALF), and pulmonary vessels were investigated. All doses of anacardic acids ameliorated antioxidant enzyme activities and decreased vascular adhesion molecule in vessels. Animals that received 50?mg/kg of anacardic acids showed decreased levels of neutrophils and tumor necrosis factor in the lungs and BALF, respectively. In summary, we demonstrated that AAs supplementation has a potential protective role on oxidative and inflammatory mechanisms in the lungs. PMID:23533495
Acetaminophen-induced liver injury in obesity and nonalcoholic fatty liver disease.
Michaut, Ana�s; Moreau, Caroline; Robin, Marie-Anne; Fromenty, Bernard
Although acetaminophen (APAP) is usually considered as a safe drug, this painkiller can lead to acute liver failure after overdoses. Moreover, there is evidence that the maximum recommended dosage can induce hepatic cytolysis in some individuals. Several predisposing factors appear to enhance the risk and severity of APAP-induced liver injury including chronic alcoholic liver disease and nonalcoholic fatty liver disease (NAFLD), which refers to a large spectrum of hepatic lesions linked to obesity. In contrast, obesity by itself does not seem to be associated with a higher risk of APAP-induced liver injury. Since 1987, seven studies dealt with APAP-induced hepatotoxicity in rodent models of NAFLD and five of them found that this liver disease was associated with higher APAP toxicity. Unfortunately, these studies did not unequivocally established the mechanism(s) whereby NAFLD could favour APAP hepatotoxicity, although some investigations suggested that pre-existent induction of hepatic cytochrome P450 2E1 (CYP2E1) could play a significant role by increasing the generation of N-acetyl-p-benzoquinone imine (NAPQI), the toxic metabolite of APAP. Moreover, pre-existent mitochondrial dysfunction associated with NAFLD could also be involved. In contrast, some investigations suggested that factors that could reduce the risk and severity of APAP hepatotoxicity in obesity and NAFLD include higher hepatic APAP glucuronidation, reduced CYP3A4 activity and increased volume of body distribution. Thus, the occurrence and the outcome of APAP-induced liver injury in an obese individual with NAFLD might depend on a delicate balance between metabolic factors that can be protective and others that favour large hepatic levels of NAPQI. PMID:24575957
Butyrate enhances disease resistance of chickens by inducing antimicrobial host defense peptide gene expression.
Sunkara, Lakshmi T; Achanta, Mallika; Schreiber, Nicole B; Bommineni, Yugendar R; Dai, Gan; Jiang, Weiyu; Lamont, Susan; Lillehoj, Hyun S; Beker, Ali; Teeter, Robert G; Zhang, Guolong
Host defense peptides (HDPs) constitute a large group of natural broad-spectrum antimicrobials and an important first line of immunity in virtually all forms of life. Specific augmentation of synthesis of endogenous HDPs may represent a promising antibiotic-alternative approach to disease control. In this study, we tested the hypothesis that exogenous administration of butyrate, a major type of short-chain fatty acids derived from bacterial fermentation of undigested dietary fiber, is capable of inducing HDPs and enhancing disease resistance in chickens. We have found that butyrate is a potent inducer of several, but not all, chicken HDPs in HD11 macrophages as well as in primary monocytes, bone marrow cells, and jejuna and cecal explants. In addition, butyrate treatment enhanced the antibacterial activity of chicken monocytes against Salmonella enteritidis, with a minimum impact on inflammatory cytokine production, phagocytosis, and oxidative burst capacities of the cells. Furthermore, feed supplementation with 0.1% butyrate led to a significant increase in HDP gene expression in the intestinal tract of chickens. More importantly, such a feeding strategy resulted in a nearly 10-fold reduction in the bacterial titer in the cecum following experimental infections with S. enteritidis. Collectively, the results indicated that butyrate-induced synthesis of endogenous HDPs is a phylogenetically conserved mechanism of innate host defense shared by mammals and aves, and that dietary supplementation of butyrate has potential for further development as a convenient antibiotic-alternative strategy to enhance host innate immunity and disease resistance. PMID:22073293
Analysis of Clonostachys rosea-Induced Resistance to Tomato Gray Mold Disease in Tomato Leaves
Guan, Xin; Chen, Xiuling; Chen, Hongyu; Zhang, Jian; Zhang, Junfeng; Li, Jingfu; Yang, Yijun; Wang, Aoxue
Tomato gray mold disease, caused by Botrytis cinerea, is a serious disease in tomato. Clonostachys rosea is an antagonistic microorganism to B. cinerea. To investigate the induced resistance mechanism of C. rosea, we examined the effects of these microorganisms on tomato leaves, along with changes in the activities of three defense enzymes (PAL, PPO, GST), second messengers (NO, H2O2, O2?) and phytohormones (IAA, ABA, GA3, ZT, MeJA, SA and C2H4). Compared to the control, all treatments induced higher levels of PAL, PPO and GST activity in tomato leaves and increased NO, SA and GA3 levels. The expression of WRKY and MAPK, two important transcription factors in plant disease resistance, was upregulated in C. rosea- and C. rosea plus B. cinerea-treated samples. Two-dimensional gel electrophoresis analysis showed that two abundant proteins were present in the C. rosea plus B. cinerea-treated samples but not in the other samples. These proteins were determined (by mass spectrum analysis) to be LEXYL2 (?-xylosidase) and ATP synthase CF1 alpha subunit. Therefore, C. rosea plus B. cinerea treatment induces gray mold resistance in tomato. This study provides a basis for elucidating the mechanism of C. rosea as a biocontrol agent. PMID:25061981
Molecular mimicry as an inducing trigger for CNS autoimmune demyelinating disease.
Chastain, Emily M L; Miller, Stephen D
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that affects about 0.1% of the worldwide population. This deleterious disease is marked by infiltration of myelin-specific T cells that attack the protective myelin sheath that surrounds CNS nerve axons. Upon demyelination, saltatory nerve conduction is disrupted, and patients experience neurologic deficiencies. The exact cause for MS remains unknown, although most evidence supports the hypothesis that both genetic and environmental factors contribute to disease development. Epidemiologic evidence supports a role for environmental pathogens, such as viruses, as potentially key contributors to MS induction. Pathogens can induce autoimmunity via several well-studied mechanisms with the most postulated being molecular mimicry. Molecular mimicry occurs when T cells specific for peptide epitopes derived from pathogens cross-react with self-epitopes, leading to autoimmune tissue destruction. In this review, we discuss an in vivo virus-induced mouse model of MS developed in our laboratory, which has contributed greatly to our understanding of the mechanisms underlying molecular mimicry-induced CNS autoimmunity. PMID:22168423
As shown by epidemiologic studies, acute exposure to ambient particles is associated with exacerbation of pulmonary and cardiovascular diseases. Metals associated with particles are able to mediate lung injury via oxidant-catalyzed reactions. However, the underlying mechanism i...
Hydrogen peroxide induced adenosine diphosphate ribosyl transferase (ADPRT) response in patients with inflammatory bowel disease.
Markowitz, M M; Rozen, P; Pero, R W; Tobi, M; Miller, D G
The sample population in this initial case control study of the adenosine diphosphate ribosyl transferase (ADPRT) response of inflammatory bowel disease patients included: 23 patients with ulcerative colitis (UC)-active and inactive, 13 patients with Crohn's disease (CD)-active and inactive, 14 first degree relatives of UC and CD patients, and 19 age-matched controls. Adenosine diphosphate ribosyl transferase activity was determined after one hour incubation with 1% plasma (the constitutive value) or with 1% plasma and 100 microM H2O2 (the activated value) with the resulting difference designated as the induced value. Statistically significant decrease in ADPRT activity was found for the constitutive, activated and induced values in human mononuclear leucocytes of UC and CD patients, compared with controls. The values in the first degree relatives of UC and CD patients were not significantly different from either the control or disease populations, indicating an intermediate ADPRT response. These results may be related to the nature of the immunological response of IBD patients and comparable with similar findings in other diseases with known DNA repair deficiencies--for example, colon cancer. PMID:3146530
Impaired neural differentiation of induced pluripotent stem cells generated from a mouse model of Sandhoff disease.
Ogawa, Yasuhiro; Tanaka, Makoto; Tanabe, Miho; Suzuki, Toshihiro; Togawa, Tadayasu; Fukushige, Tomoko; Kanekura, Takuro; Sakuraba, Hitoshi; Oishi, Kazuhiko
Sandhoff disease (SD) is a glycosphingolipid storage disease that arises from mutations in the Hexb gene and the resultant deficiency in ?-hexosaminidase activity. This deficiency results in aberrant lysosomal accumulation of the ganglioside GM2 and related glycolipids, and progressive deterioration of the central nervous system. Dysfunctional glycolipid storage causes severe neurodegeneration through a poorly understood pathogenic mechanism. Induced pluripotent stem cell (iPSC) technology offers new opportunities for both elucidation of the pathogenesis of diseases and the development of stem cell-based therapies. Here, we report the generation of disease-specific iPSCs from a mouse model of SD. These mouse model-derived iPSCs (SD-iPSCs) exhibited pluripotent stem cell properties and significant accumulation of GM2 ganglioside. In lineage-directed differentiation studies using the stromal cell-derived inducing activity method, SD-iPSCs showed an impaired ability to differentiate into early stage neural precursors. Moreover, fewer neurons differentiated from neural precursors in SD-iPSCs than in the case of the wild type. Recovery of the Hexb gene in SD-iPSCs improved this impairment of neuronal differentiation. These results provide new insights as to understanding the complex pathogenic mechanisms of SD. PMID:23383290
Quinones and Aromatic Chemical Compounds in Particulate Matter Induce Mitochondrial Dysfunction: Implications for Ultrafine Particle Toxicity
Xia, Tian; Korge, Paavo; Weiss, James N.; Li, Ning; Venkatesen, M. Indira; Sioutas, Constantinos; Nel, Andre
Particulate pollutants cause adverse health effects through the generation of oxidative stress. A key question is whether these effects are mediated by the particles or their chemical compounds. In this article we show that aliphatic, aromatic, and polar organic compounds, fractionated from diesel exhaust particles (DEPs), exert differential toxic effects in RAW 264.7 cells. Cellular analyses showed that the quinone-enriched polar fraction was more potent than the polycyclic aromatic hydrocarbon (PAH)�enriched aromatic fraction in O2�? generation, decrease of membrane potential (??m), loss of mitochondrial membrane mass, and induction of apoptosis. A major effect of the polar fraction was to promote cyclosporin A (CsA)�sensitive permeability transition pore (PTP) opening in isolated liver mitochondria. This opening effect is dependent on a direct effect on the PTP at low doses as well as on an effect on ??m at high doses in calcium (Ca2+)-loaded mitochondria. The direct PTP effect was mimicked by redox-cycling DEP quinones. Although the aliphatic fraction failed to perturb mitochondrial function, the aromatic fraction increased the Ca2+ retention capacity at low doses and induced mitochondrial swelling and a decrease in ??m at high doses. This swelling effect was mostly CsA insensitive and could be reproduced by a mixture of PAHs present in DEPs. These chemical effects on isolated mitochondria could be reproduced by intact DEPs as well as ambient ultrafine particles (UFPs). In contrast, commercial polystyrene nanoparticles failed to exert mitochondrial effects. These results suggest that DEP and UFP effects on the PTP and ??m are mediated by adsorbed chemicals rather than the particles themselves. PMID:15471724
The role of calcitonin receptor signalling in polyethylene particle-induced osteolysis.
Neuerburg, Carl; Wedemeyer, Christian; Goedel, Jan; Schlepper, R�diger; Hilken, Gero; Schwindenhammer, Benjamin; Schilling, Arndt Friedrich; J�ger, Marcus; Kauther, Max Daniel
The detection of peptides from the calcitonin (CT) family in the periarticular tissue of loosened implants has raised hopes of opening new regenerative therapies in the process of aseptic loosening, which remains the major cause of early implant failure in endoprosthetic surgery. We have previously shown the roles of ?-calcitonin gene-related peptide (?-CGRP) and the CALCA gene which encodes ?-CGRP/CT in this process. To uncover the role of direct calcitonin receptor (CTR) mediated signalling, we studied particle-induced osteolysis (PIO) in a murine calvaria model with a global deletion of the CTR (CTR-KO) using ?CT analysis and histomorphometry. As expected, CTR-KO mice revealed reduced bone volume compared to wild-type (WT) controls (p<0.05). In CTR-KO mice we found significantly higher RANKL (receptor activator of NF-?B ligand) expression in the particle group than in the control group. The increase in osteoclast numbers by the particles was twice as high as the increase of osteoclasts in the WT mice (400 vs. 200%). Changes in the eroded surface and actual osteolysis due to ultrahigh-molecular-weight polyethylene particles were similar in WTs and CTR-KOs. Taken together, our findings strengthen the relevance of the OPG/RANK/RANKL system in the PIO process. CTR seems to have an effect on osteoclast differentiation in this context. As there were no obvious changes of the amount of PIO in CTR deficiency, regenerative strategies in aseptic loosening of endoprosthetic implants based on peptides arising from the CT family should rather focus on the impact of ?-CGRP. PMID:25486133
Avian adenovirus CELO recombinants expressing VP2 of infectious bursal disease virus induce protection against bursal disease in chickens.
Francois, Achille; Chevalier, Christophe; Delmas, Bernard; Eterradossi, Nicolas; Toquin, Didier; Rivallan, Ga�lle; Langlois, Patrick
To develop a CELO virus vector that can induce protection against infectious bursal disease, CELO viruses expressing the host-protective antigen VP2 of infectious bursal disease virus (IBDV) were constructed. In the engineered recombinants, the VP2 gene (the 441-first codons of the IBDA polyprotein) was placed under the control of the CMV promoter. Two positions in the CELO genome were chosen to insert the VP2 expression cassette. The recombinants were found apathogenic, when inoculated by different routes and even at high doses (up to 10(8) per animal). Chickens vaccinated oro-nasally with these different recombinants and challenged with very virulent IBDV were found to be poorly protected. In contrast, when inoculated with one or two (subcutaneous or intradermic) injections of CELOa-VP2, the chickens showed no clinical signs and no mortality after challenge. In the vaccinated chickens, the titers of neutralization antibody reached 7-9 values, showing that protection could be explained by the induction of a sufficient humoral response. After challenge, the weight ratio Bursa of Fabricius/body was about 2.5 per thousand, a value similar to that obtained with the commercial Bur706 vaccine. However, histological lesions in the Bursa of Fabricius were observed, showing that a complete protection was not totally achieved. Contact transmission was evidenced. Protection was also obtained when inoculation of CELOa-VP2 was carried out in ovo. Prime-boost strategies were also tested with the CELOa-VP2 vector used in association with the purified VP2 antigen, or DNA encoding VP2 or a CELO vector expressing chicken myeloid growth factor (cMGF). None of these regimens were shown to substantially increase the level of protection when compared to double CELOa-VP2 inoculations. These results indicate that CELO-based vectors are useful to safely induce a strong protective immunity against vvIBDV in chickens. PMID:15149796
Lipoxin A4 Attenuates Obesity-Induced Adipose Inflammation and Associated Liver and Kidney Disease.
B�rgeson, Emma; Johnson, Andrew M F; Lee, Yun Sok; Till, Andreas; Syed, Gulam Hussain; Ali-Shah, Syed Tasadaque; Guiry, Patrick J; Dalli, Jesmond; Colas, Romain A; Serhan, Charles N; Sharma, Kumar; Godson, Catherine
The role of inflammation in obesity-related pathologies is well established. We investigated the therapeutic potential of LipoxinA4 (LXA4:5(S),6(R),15(S)-trihydroxy-7E,9E,11Z,13E,-eicosatetraenoic acid) and a synthetic 15(R)-Benzo-LXA4-analog as interventions in a 3-month high-fat diet (HFD; 60% fat)-induced obesity model. Obesity caused distinct pathologies, including impaired glucose tolerance, adipose inflammation, fatty liver, and chronic kidney�disease (CKD). Lipoxins (LXs) attenuated obesity-induced CKD, reducing glomerular expansion, mesangial matrix, and urinary H2O2. Furthermore, LXA4 reduced liver weight, serum alanine-aminotransferase, and hepatic triglycerides. LXA4 decreased obesity-induced adipose inflammation, attenuating TNF-? and CD11c(+) M1-macrophages (M?s), while restoring CD206(+) M2-M?s and increasing Annexin-A1. LXs did not affect renal or hepatic M?s, suggesting protection occurred via attenuation of adipose inflammation. LXs restored adipose expression of autophagy markers LC3-II and p62. LX-mediated protection was demonstrable in adiponectin(-/-) mice, suggesting that the mechanism was adiponectin independent. In conclusion, LXs protect against obesity-induced systemic disease, and these data support a novel therapeutic paradigm for treating obesity and associated pathologies. PMID:26052006
Naive and memory T cells induce different types of graft-versus-host disease.
Dutt, Suparna; Tseng, Diane; Ermann, Joerg; George, Tracy I; Liu, Yin Ping; Davis, Corrine R; Fathman, C Garrison; Strober, Samuel
The goal of this study was to compare the ability of donor naive and alloantigen-primed effector memory T cells to induce graft-vs-host disease after bone marrow transplantation in MHC-mismatched irradiated host mice. Purified CD4(+) naive (CD62L(high)CD44(low)) T cells and CD4(+) effector memory (CD62L(low)CD44(high)) T cells obtained from unprimed donors and donors primed to host alloantigens, respectively, were injected into host mice, and the rapidity, severity, and pattern of tissue injury of graft-vs-host disease was assessed. Unexpectedly, the naive T cells induced a more acute and severe colitis than the primed memory cells. Whereas the naive T cells expressing CD62L and CCR7 lymph node homing receptors vigorously expanded in mesenteric lymph nodes and colon by day 6 after transplantation, the primed memory T cells without these receptors had 20- to 100-fold lower accumulation at this early time point. These differences were reflected in the significantly more rapid decline in survival and weight loss induced by naive T cells. The primed memory T cells had a greater capacity to induce chronic colitis and liver injury and secrete IL-2 and IFN-gamma in response to alloantigenic stimulation compared with memory T cells from unprimed donors. Nevertheless, the expected increase in potency as compared with naive T cells was not observed due to differences in the pattern and kinetics of tissue injury. PMID:17982043
Glutathione-S-transferase M1 regulation of diesel exhaust particle-induced pro-inflammatory mediator expression in normal human bronchial epithelial cells
Background Diesel exhaust particles (DEP) contribute substantially to ambient particulate matter (PM) air pollution in urban areas. Inhalation of PM has been associated with increased incidence of lung disease in susceptible populations. We have demonstrated that the glutathione S-transferase M1 (GSTM1) null genotype could aggravate DEP-induced airway inflammation in human subjects. Given the critical role airway epithelial cells play in the pathogenesis of airway inflammation, we established the GSTM1 deficiency condition in primary bronchial epithelial cells from human volunteers with GSTM1 sufficient genotype (GSTM1+) using GSTM1 shRNA to determine whether GSTM1 deficiency could exaggerate DEP-induced expression of interleukin-8 (IL-8) and IL-1? proteins. Furthermore, the mechanisms underlying GSTM1 regulation of DEP-induced IL-8 and IL-1? expression were also investigated. Methods IL-8 and IL-1? protein levels were measured using enzyme-linked immunosorbent assay. GSTM1 deficiency in primary human bronchial epithelial cells was achieved using lentiviral GSTM1 shRNA particles and verified using real-time polymerase chain reaction and immunoblotting. Intracellular reactive oxygen species (ROS) production was evaluated using flow cytometry. Phosphorylation of protein kinases was detected using immunoblotting. Results Exposure of primary human bronchial epithelial cells (GSTM1+) to 25-100??g/ml DEP for 24?h significantly increased IL-8 and IL-1? protein expression. Knockdown of GSTM1 in these cells further elevated DEP-induced IL-8 and IL-1? expression, implying that GSTM1 deficiency aggravated DEP-induced pro-inflammatory response. DEP stimulation induced the phosphorylation of extracellular signal-regulated kinase (ERK) and Akt, the downstream kinase of phosphoinositide 3-kinase (PI3K), in GSTM1+ bronchial epithelial cells. Pharmacological inhibition of ERK kinase and PI3K activity blocked DEP-induced IL-8 and IL-1? expression. DEP-induced ERK and Akt phosphorylation could be increased by GSTM1 knockdown. In addition, pretreatment of HBEC with the antioxidant N-acetyl cysteine significantly inhibited DEP-induced ERK and Akt phosphorylation, and subsequent IL-8 and IL-1? expression. Conclusion GSTM1 regulates DEP-induced IL-8 and IL-1? expression in primary human bronchial epithelial cells by modulation of ROS, ERK and Akt signaling. PMID:22867088
Evidence that ?-Secretase Mediates Oxidative Stress-Induced ?-Secretase Expression in Alzheimer's Disease
Jo, Dong-Gyu; Arumugam, Thiruma V.; Woo, Ha-Na; Park, Jong-Sung; Tang, Sung-Chun; Mughal, Mohamed; Hyun, Dong-Hoon; Park, Jun-Hyung; Choi, Yun-Hyung; Gwon, A-Ryeong; Camandola, Simonetta; Cheng, Aiwu; Cai, Huaibin; Song, Weihong; Markesbery, William R.; Mattson, Mark P.
?-secretase (BACE1), an enzyme responsible for the production of amyloid ?-peptide (A?), is increased by oxidative stress and is elevated in the brains of patients with sporadic Alzheimer's disease (AD). Here we show that oxidative stress fails to induce BACE1 expression in presenilin-1 (?-secretase)-deficient cells and in normal cells treated with ?-secretase inhibitors. Oxidative stress-induced ?-secretase activity and sAPP? levels were suppressed by ?-secretase inhibitors. Levels of ?- and ?-secretase activities were greater in brain tissue samples from AD patients compared to non-demented control subjects, and the elevated BACE1 level in the brains of 3xTgAD mice was reduced by treatment with a ?-secretase inhibitor. Our findings suggest that ?-secretase mediates oxidative stress-induced expression of BACE1 resulting in excessive A? production in AD. PMID:18687504
Characteristics of exhaled particle production in healthy volunteers: possible implications for infectious disease transmission
Wurie, Fatima
The size and concentration of exhaled particles may influence respiratory infection transmission risk. We assessed variation in exhaled particle production between individuals, factors associated with high production and stability over time. We measured exhaled particle production during tidal breathing in a sample of 79 healthy volunteers, using optical particle counter technology. Repeat measurements (several months after baseline) were obtained for 37 of the 79 participants. � Multilevel linear regression models of log transformed particle production measures were used to assess risk factors for high production. �Stability between measurements over time was assessed using Lin�s correlation coefficients. Ninety-nine percent of expired particles were <1?m in diameter. Considerable variation in exhaled particle production was observed between individuals and within individuals over time. Distribution of particle production was right skewed. �Approximately 90% of individuals produce <150 particles per litre in normal breathing. �A few individuals had measurements of over 1000 particles per litre (maximum 1456). Particle production increased with age (p<0.001) and was associated with high tree pollen counts. Particle production levels did not remain stable over time [rho 0.14 (95%CI -0.10, 0.38, p=0.238)]. Sub-micron particles conducive to airborne rather than droplet transmission form the great majority of exhaled particles in tidal breathing. There is a high level of variability between subjects but measurements are not stable over time. Production increases with age and may be influenced by airway inflammation caused by environmental irritants. Further research is needed to determine whether the observed variations in exhaled particle production affect transmission of respiratory infection. PMID:24555026
Continuum- and particle-based modeling of shapes and dynamics of red blood cells in health and disease
Li,, Xuejin; Vlahovska, Petia M.
We review recent advances in multiscale modeling of the mechanics of healthy and diseased red blood cells (RBCs), and blood flow in the microcirculation. We cover the traditional continuum-based methods but also particle-based methods used to model both the RBCs and the blood plasma. We highlight examples of successful simulations of blood flow including malaria and sickle cell anemia. PMID:23230450
Continuum- and particle-based modeling of shapes and dynamics of red blood cells in health and disease.
Li, Xuejin; Vlahovska, Petia M; Karniadakis, George Em
We review recent advances in multiscale modeling of the mechanics of healthy and diseased red blood cells (RBCs), and blood flow in the microcirculation. We cover the traditional continuum-based methods but also particle-based methods used to model both the RBCs and the blood plasma. We highlight examples of successful simulations of blood flow including malaria and sickle cell anemia. PMID:23230450
Neuroprotective effects of swimming training in a mouse model of Parkinson's disease induced by 6-hydroxydopamine.
Goes, A T R; Souza, L C; Filho, C B; Del Fabbro, L; De Gomes, M G; Boeira, S P; Jesse, C R
Parkinson's disease (PD) is characterized by progressive dopamine (DA) depletion in the striatum. Exercise has been shown to be a promising non-pharmacological approach to reduce the risk of neurodegeneration diseases. This study was designed to investigate the potential neuroprotective effect of swimming training (ST) in a mouse model of PD induced by 6-hydroxydopamine (6-OHDA) in mice. The present study demonstrated that a 4-week ST was effective in attenuating the following impairments resulting from 6-OHDA exposure: (i) depressive-like behavior in the tail suspension test; (ii) increase in the number of falls in the rotarod test; (iii) impairment on long-term memory in the object recognition test; (iv) increase of the reactive species and interleukin 1-beta (IL-1?) levels; (v) inhibition of the glutathione peroxidase (GPx) activity; (vi) rise of the glutathione reductase (GR) and glutathione S-transferase (GST) activities and vii) decrease of DA, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels. The mechanisms involved in this study are the modulation of GPx, GR and GST activities as well as IL-1? level in a PD model induced by 6-OHDA, protecting against the decrease of DA, DOPAC and HVA levels in the striatum of mice. These findings reinforce that one of the effects induced by exercise on neurodegenerative disease, such as PD, is due to antioxidant and anti-inflammatory properties. We suggest that exercise attenuates cognitive and motor declines, depression, oxidative stress, and neuroinflammation induced by 6-OHDA supporting the hypothesis that exercise can be used as a non-pharmacological tool to reduce the symptoms of PD. PMID:24090962
X-ray radiolysis induced formation of silver nano-particles: A SAXS and UV�visible absorption spectroscopy study
S. Remita; P. Fontaine; E. Lacaze; Y. Borensztein; H. Sellame; R. Farha; C. Rochas; M. Goldmann
We show that X-ray irradiation of metal salt aqueous solutions in the absence of any stabilizer leads to the synthesis of metal nano-particles, similarly to ?-ray irradiation. The chemical route is the reduction of silver metal ions induced by radiolysis of water. Moreover, X-rays used for the synthesis allow following in situ the formation of silver nano-particles by Small Angle
Contribution of ion-induced nucleation to new particle formation: Methodology and its application to atmospheric observations in Boulder, Colorado
Kenjiro Iida; Mark Stolzenburg; Peter McMurry; Matthew J. Dunn; James N. Smith; Fred Eisele; Pat Keady
This paper investigates the role of ion-induced nucleation (IIN) in new particle formation events observed near ground level at a sampling site located near Boulder, Colorado (14 March 2004 to 27 October 2005). Measurements of mobility distributions of small and intermediate ions (0.4�6.3 nm), size distributions of total particles (3 nm to 5 ?m), and charged fractions (2.5�25 nm) were
The effect of multi-component aerosol particles on quantitative laser-induced breakdown spectroscopy: Consideration of localized matrix effects
P. K. Diwakar; P. B. Jackson; D. W. Hahn
Spectral measurements were performed in a laser-induced plasma to assess the changes in sodium or magnesium analyte emission response from particle-derived sources with the addition of concomitant mass to the aerosol particles. Temporally resolved measurements revealed up to a 50% enhancement in analyte emission with the addition of the elements copper, zinc or tungsten at mass ratios from 1:9 to
Nuclear physics of cosmic ray interaction with semiconductor materials: Particle-induced soft errors from a physicist's perspective
Henry H. K. Tang
The key issues of cosmic-ray-induced soft-error rates, SER (also referred to as single-event upset, SEU, rates) in microelectronic devices are discussed from the viewpoint of fundamental atomic and nuclear interactions between high-energy particles and semiconductors. From sea level to moderate altitudes, the cosmic ray spectrum is dominated by three particle species: nucleons (protons and neutrons), pions, and muons. The characteristic
Successful EGFR-TKI rechallenge of leptomeningeal carcinomatosis after gefitinib-induced interstitial lung disease.
Nakamichi, Shinji; Kubota, Kaoru; Horinouchi, Hidehito; Kanda, Shintaro; Fujiwara, Yutaka; Nokihara, Hiroshi; Yamamoto, Noboru; Tamura, Tomohide
We report the case of a 49-year-old non-smoking Japanese woman with backache and difficulty in walking. She was diagnosed as having advanced lung adenocarcinoma, and an epithelial growth factor receptor mutation (in-frame deletions in exon 19) was found. After radiation therapy of bone metastases with spinal cord compression and brain metastases, gefitinib was administered. On day 2, she developed acute interstitial lung disease. Gefitinib therapy was discontinued and treatment with high-dose steroid therapy improved the interstitial lung disease. Cisplatin plus pemetrexed was initiated as second-line chemotherapy, but she was hospitalized again for leptomeningeal carcinomatosis. Considering the poor prognosis of leptomeningeal carcinomatosis, we decided that erlotinib was our only choice of treatment. As a third-line treatment, erlotinib was administered after informing the patient about the high risk of interstitial lung disease. Neurological symptoms were improved within a week and interstitial lung disease did not recur. The patient has received erlotinib successfully for 18 months without the recurrence of leptomeningeal carcinomatosis. Erlotinib rechallenge after gefitinib-induced interstitial lung disease must be carefully chosen based on the balance of a patient's risk and benefit. PMID:23410901
Anti-Tumor Necrosis Factor Ameliorates Joint Disease in Murine Collagen- Induced Arthritis
NASA Astrophysics Data System (ADS)
Williams, Richard O.; Feldmann, Marc; Maini, Ravinder N.
There is considerable evidence implicating tumor necrosis factor ? (TNF-?) in the pathogenesis of rheumatoid arthritis. This evidence is based not only on the universal presence of TNF-? in arthritic joints accompanied by the upregulation of TNF-? receptors but also on the effects of neutralizing TNF-? in joint cell cultures. Thus, neutralization of TNF-? in vitro results in inhibition of the production of interleukin 1, which like TNF-?, is believed to contribute to joint inflammation and erosion. To determine the validity of this concept in vivo, the effect of administering TNF-neutralizing antibodies to mice with collagen-induced arthritis has been studied. This disease model was chosen because of its many immunological and pathological similarities to human rheumatoid arthritis. TN3-19.12, a hamster IgG1 monoclonal antibody to murine TNF-?/?, was injected i.p. into mice either before the onset of arthritis or after the establishment of clinical disease. Anti-TNF administered prior to disease onset significantly reduced paw swelling and histological severity of arthritis without reducing the incidence of arthritis or the level of circulating anti-type II collagen IgG. More relevant to human disease was the capacity of the antibody to reduce the clinical score, paw swelling, and the histological severity of disease even when injected after the onset of clinical arthritis. These results have implications for possible modes of therapy of human arthritis.
Particle production in nucleon induced reactions above 14 MeV with an intranuclear cascade model
NASA Astrophysics Data System (ADS)
Duarte, H.
We present an intranuclear cascade (INC) model which includes the dynamics of the cascade particles and uses in-medium NN elastic cross sections. Our model is still based on the impulse approximation and does not have the complexity of other sophisticated nuclear models. Nevertheless, its results of angle-energy distributions of emitted nucleons in continuum are in good agreement with experimental data for nucleon induced reactions from low intermediate energy to high energy, between 14 MeV and 1.6 GeV, and for light to heavy target nuclei. Comparisons with results of Bertini's INC model and of a previous version of our INC model show the clear contribution of the combined effects of better dynamics and the in-medium NN cross sections. From our results, we conclude that our INC model effectively includes the preequilibrium emission.
Defect-induced performance degradation of 4H-SiC Schottky barrier diode particle detectors
NASA Astrophysics Data System (ADS)
Iwamoto, N.; Johnson, B. C.; Hoshino, N.; Ito, M.; Tsuchida, H.; Kojima, K.; Ohshima, T.
The formation and evolution of defects in 4H-SiC Schottky barrier diode high-energy particle detectors have been investigated and correlated with the detectors' properties. Low temperature annealing at 300 �C is found to significantly recover the charge collection efficiency as degraded by 1 MeV electron irradiation. At higher temperatures, an anneal-induced degradation in the detector's performance is observed. Current-voltage, capacitance-voltage, and deep level transient spectroscopy (DLTS) measurements are used to ascertain the effect of defects on the detector performance. The latter reveals that the DLTS defect levels, EH1 and EH3, are related to the initial recovery of the charge collection efficiency.
Changes in plasma chemistry after drug?induced liver disease or muscle necrosis in racing pigeons (Columba livia domestica)
J. T. Lumeij; M. Meidam; J. Wolfswinkel; M. H. Van der Hage; G. M. Dorrestein
Changes in plasma variables as a result of liver damage induced by ethylene glycol (group A) or D?galactosamine (group B) and of muscle damage induced by doxycycline were compared.Plasma bile acid concentration was both a specific and a sensitive indicator of liver disease. Another specific, but less sensitive indicator of liver disease was 7?GT. Plasma AS AT activity was the
Effect of hesperidin extraction on cell proliferation and apoptosis of Alzheimer's disease induced by A?25�35
Xiaoting Luo; Qin Huang; Shumei Li; Sisi Li; Liang Xiong; Minghua Dong
Objective: To study the effect of hesperidin extracted from the peel of Gannan kumquat on Alzheimer's disease and its possible mechanisms. Methods: Cellular model of Alzheimer's disease was established using PC 12 cell induced by serum starvation method and treated by ?-amyloid peptide 25-35 (A?25-35). Effect of hesperidin on proliferation of PC12 cell induced by AP25-35 was detected by the
Detection of immunoglobulins G and A to Aspergillus fumigatus by immunoblot analysis for monitoring Aspergillus-induced lung diseases
M. Th. M. van Rens; R. Vernooy-Jeras; M. Merton-de Ridder; H. van Velzen-Blad
aa Detection of immunoglobulins G and A to Aspergillus fumigatus by immunoblot analysis for monitoring Aspergillus-induced lung diseases. M.Th.M. van Rens, R. Vernooy-Jeras, M. Merton-de Ridder, H. van Velzen-Blad, J.M.M. van den Bosch. ?ERS Journals Ltd 1998. ABSTRACT: The aim of the study was to investigate whether patients with Aspergil- lus-induced lung disease can be monitored by immunoblot analysis to
Involvement of oxidative stress in motorcycle exhaust particle-induced DNA damage and inhibition of intercellular communication
Min-Liang Kuo; Shiou-Hwa Jee; Ming-Hong Chou; Tzuu-Huei Ueng
In this study, we investigated the involvement of reactive oxygen species (ROS) in the motorcycle exhaust particle (MEP)-induced genotoxic and non-genotoxic activity in mammalian cell systems. Initially, the capability of MEP to induce ROS was evaluated by using 2?,7?-dichlorofluorescin diacetate (DCFH-DA) to detect hydrogen peroxide (H2O2). A five-fold increase in H2O2 was observed in Chinese hamster lung V79 and human
Anti-oxidative and inflammatory responses induced by fly ash particles and carbon black in lung epithelial cells
Silvia Diabat�; Britta Bergfeldt; Diana Plaumann; Caroline �bel; Carsten Weiss
Combustion-derived nanoparticles as constituents of ambient particulate matter have been shown to induce adverse health effects\\u000a due to inhalation. However, the components inducing these effects as well as the biological mechanisms are still not fully\\u000a understood. The fine fraction of fly ash particles collected from the electrostatic precipitator of a municipal solid waste\\u000a incinerator was taken as an example for
Measurement of Beta Particles Induced Electron-Hole Pairs Recombination in Depletion Region of GaAs PN Junction
Hai-Yang Chen; Lan Jiang; Da-Rang Li
PN junctions and schottky diodes are widely employed as electron-hole pair collectors in electron beam induced current (EBIC) techniques and betavoltaic batteries, in which the recombination in depletion regions is ignored. We measured the beta particles induced electron-hole pairs recombination in the depletion region of a GaAs P+PN+ junction, based on comparisons between measured short currents and ideal values. The
Immune responses induced by lower airway mucosal immunisation with a human papillomavirus type 16 virus-like particle vaccine
Denise Nardelli-Haefliger; Floriana Lurati; Daniel Wirthner; Fran�ois Spertini; John T. Schiller; Douglas R. Lowy; Fran�oise Ponci; Pierre De Grandi
Cervical cancer results from cervical infection by human papillomaviruses (HPV), especially HPV16. Previous studies have shown that intramuscular vaccination of women with an HPV16 virus-like particle (VLP) vaccine induced a strong IgG response and protected against genital HPV16 infection. However, an alternative route of administration that avoids parenteral injection while inducing mucosal immunity might facilitate vaccine implementation in some settings,
Spatial learning and memory deficits induced by exposure to iron-56-particle radiation
NASA Technical Reports Server (NTRS)
Shukitt-Hale, B.; Casadesus, G.; McEwen, J. J.; Rabin, B. M.; Joseph, J. A.
It has previously been shown that exposing rats to particles of high energy and charge (HZE) disrupts the functioning of the dopaminergic system and behaviors mediated by this system, such as motor performance and an amphetamine-induced conditioned taste aversion; these adverse behavioral and neuronal effects are similar to those seen in aged animals. Because cognition declines with age, spatial learning and memory were assessed in the Morris water maze 1 month after whole-body irradiation with 1.5 Gy of 1 GeV/nucleon high-energy (56)Fe particles, to test the cognitive behavioral consequences of radiation exposure. Irradiated rats demonstrated cognitive impairment compared to the control group as seen in their increased latencies to find the hidden platform, particularly on the reversal day when the platform was moved to the opposite quadrant. Also, the irradiated group used nonspatial strategies during the probe trials (swim with no platform), i.e. less time spent in the platform quadrant, fewer crossings of and less time spent in the previous platform location, and longer latencies to the previous platform location. These findings are similar to those seen in aged rats, suggesting that an increased release of reactive oxygen species may be responsible for the induction of radiation- and age-related cognitive deficits. If these decrements in behavior also occur in humans, they may impair the ability of astronauts to perform critical tasks during long-term space travel beyond the magnetosphere.
Modeling particle-induced electron emission in a simplified plasma Test Cell
Giuliano, Paul N.; Boyd, Iain D. [Department of Aerospace Engineering, University of Michigan, Ann Arbor, Michigan 48109 (United States)
Particle-induced electron emission (PIE) is modeled in a simplified, well-characterized plasma Test Cell operated at UCLA. In order for PIE to be a useful model in this environment, its governing equations are first reduced to lower-order models which can be implemented in a direct simulation Monte Carlo and Particle-in-Cell framework. These reduced-order models are described in full and presented as semi-empirical models. The models are implemented to analyze the interaction of low- and high-energy ({approx}1-2 keV) xenon ions and atoms with the stainless steel electrodes of the Test Cell in order to gain insight into the emission and transport of secondary electrons. Furthermore, there is a lack of data for xenon-stainless steel atom- and ion-surface interactions for similar environments. Using experimental data as a reference, both total yields and emitted electron energy distribution functions can be deduced by observing sensitivities of current collection results to these numerical models and their parameters.
Mechanism of vibration-induced repulsion force on a particle in a viscous fluid cell.
Saadatmand, Mehrrad; Kawaji, Masahiro
Space platforms such as the Space Shuttle and International Space Station have been considered an ideal environment for production of protein and semiconductor crystals of superior quality due to the negligible gravity-induced convection. Although it was believed that under microgravity environment diffusive mass transport would dominate the growth of the crystals, some related experiments have not shown satisfactory results possibly due to the movement of the growing crystals in fluid cells caused by small vibrations present in the space platforms called g-jitter. In ground-based experiments, there have been clear observations of attraction and repulsion of a solid particle with respect to a nearby wall of the fluid cell due to small vibrations. The present work is a numerical investigation on the physical mechanisms responsible for the repulsion force, which has been predicted to increase with the cell vibration frequency and amplitude, as well as the fluid viscosity. Moreover, the simulations have revealed that the repulsion force occurs mostly due to the increased pressure in the narrow gap between the particle and the nearest wall. PMID:24032936
C - Reactive Protein Induced Rearrangement of Phosphatidylcholine on Nanoparticle Mimics of Lipoprotein Particles
Mackiewicz, Marilyn R.; Hodges, Heather L.
Lipid-coated metal nanoparticles are developed here as a mimic of low-density lipoprotein (LDL) particles and used to study C-reactive protein (CRP) binding to highly curved lipid membranes. A 12 nm shift in the localized surface plasmon resonance (LSPR) was observed when CRP was added to the lipid-coated gold nanoparticles. Transmission electron microscopy (TEM) revealed that CRP induced a structural change to the lipids, resulting in clusters of nanoparticles. This clustering provides a visualization of how CRP could cause the aggregation of LDL particles, which is a key step in atherosclerosis. The cluster formation and resultant LSPR shift requires the presence of both CRP and calcium. Fluorescence anisotropy, using a CRP-specific, fluorophore-labeled aptamer confirmed that CRP was bound to the lipid-coated nanoparticles. An increase in the fluorescence anisotropy (?r = +0.261 � 0.004) of the aptamer probe occurs in the presence of CRP, PC-coated nanoparticles, and calcium. Subsequent sequestration of calcium by EDTA leads to a decrease in the anisotropy (?r = -0.233 � 0.011), however, there is no change in the LSPR and no change to the cluster structure observed by TEM. This indicates that CRP binds to the PC membrane on the nanoparticle surface reversibly through a calcium bridging mechanism while changing the underlying membrane structure irreversibly as a result of binding. PMID:20364851
Disease modeling and lentiviral gene transfer in patient-specific induced pluripotent stem cells from late-onset Pompe disease patient
Sato, Yohei; Kobayashi, Hiroshi; Higuchi, Takashi; Shimada, Yohta; Era, Takumi; Kimura, Shigemi; Eto, Yoshikatsu; Ida, Hiroyuki; Ohashi, Toya
Pompe disease is an autosomal recessive inherited metabolic disease caused by deficiency of acid ?-glucosidase (GAA). Glycogen accumulation is seen in the affected organ such as skeletal muscle, heart, and liver. Hypertrophic cardiomyopathy is frequently seen in the infantile onset Pompe disease. On the other hand, cardiovascular complication of the late-onset Pompe disease is considered as less frequent and severe than that of infantile onset. There are few investigations which show cardiovascular complication of late onset Pompe disease due to the shortage of appropriate disease model. We have generated late-onset Pompe disease-specific induced pluripotent stem cell (iPSC) and differentiated them into cardiomyocytes. Differentiated cardiomyocyte shows glycogen accumulation and lysosomal enlargement. Lentiviral GAA rescue improves GAA enzyme activity and glycogen accumulation in iPSC. The efficacy of gene therapy is maintained following the cardiomyocyte differentiation. Lentiviral GAA transfer ameliorates the disease-specific change in cardiomyocyote. It is suggested that Pompe disease iPSC-derived cardiomyocyte is replicating disease-specific changes in the context of disease modeling, drug screening, and cell therapy. PMID:26199952
Salt-induced reentrant stability of polyion-decorated particles with tunable surface charge density
Simona Sennato; Laura Carlini; Domenico Truzzolillo; Federico Bordi
The electrostatic complexation between DOTAP-DOPC unilamellar liposomes and an oppositely charged polyelectrolyte (NaPA) has been investigated in a wide range of the liposome surface charge density. We systematically characterized the "reentrant condensation" and the charge inversion of polyelectrolyte-decorated liposomes by means of dynamic light scattering and electrophoresis. We explored the stability of this model polyelectrolyte/colloid system by fixing each time the charge of the bare liposomes and by changing two independent control parameters of the suspensions: the polyelectrolyte/colloid charge ratio and the ionic strength of the aqueous suspending medium. The progressive addition of neutral DOPC lipid within the liposome membrane gave rise to a new intriguing phenomenon: the stability diagram of the suspensions showed a novel reentrance due to the crossing of the desorption threshold of the polyelectrolyte. Indeed, at fixed charge density of the bare DOTAP/DOPC liposomes and for a wide range of polyion concentrations, we showed that the simple electrolyte addition first (low salt regime) destabilizes the suspensions because of the enhanced screening of the residual repulsion between the complexes, and then (high salt regime) determines the onset of a new stable phase, originated by the absence of polyelectrolyte adsorption on the particle surfaces. We show that the observed phenomenology can be rationalized within the Velegol-Thwar model for heterogeneously charged particles and that the polyelectrolyte desorption fits well the predictions of the adsorption theory of Winkler and Cherstvy. Our findings unambiguously support the picture of the reentrant condensation as driven by the correlated adsorption of the polyelectrolyte chains on the particle surface, providing interesting insights into possible mechanisms for tailoring complex colloids via salt-induced effects.
Energetic-particle-driven instabilities and induced fast-ion transport in a reversed field pincha)
NASA Astrophysics Data System (ADS)
Lin, L.; Anderson, J. K.; Brower, D. L.; Capecchi, W.; Ding, W. X.; Eilerman, S.; Forest, C. B.; Koliner, J. J.; Liu, D.; Nornberg, M. D.; Reusch, J.; Sarff, J. S.
Multiple bursty energetic-particle (EP) driven modes with fishbone-like structure are observed during 1 MW tangential neutral-beam injection in a reversed field pinch (RFP) device. The distinguishing features of the RFP, including large magnetic shear (tending to add stability) and weak toroidal magnetic field (leading to stronger drive), provide a complementary environment to tokamak and stellarator configurations for exploring basic understanding of EP instabilities. Detailed measurements of the EP mode characteristics and temporal-spatial dynamics reveal their influence on fast ion transport. Density fluctuations exhibit a dynamically evolving, inboard-outboard asymmetric spatial structure that peaks in the core where fast ions reside. The measured mode frequencies are close to the computed shear Alfv�n frequency, a feature consistent with continuum modes destabilized by strong drive. The frequency pattern of the dominant mode depends on the fast-ion species. Multiple frequencies occur with deuterium fast ions compared to single frequency for hydrogen fast ions. Furthermore, as the safety factor (q) decreases, the toroidal mode number of the dominant EP mode transits from n =5 to n =6 while retaining the same poloidal mode number m =1. The transition occurs when the m =1, n =5 wave-particle resonance condition cannot be satisfied as the fast-ion safety factor (qfi) decreases. The fast-ion temporal dynamics, measured by a neutral particle analyzer, resemble a classical predator-prey relaxation oscillation. It contains a slow-growth phase arising from the beam fueling followed by a rapid drop when the EP modes peak, indicating that the fluctuation-induced transport maintains a stiff fast-ion density profile. The inferred transport rate is strongly enhanced with the onset of multiple EP modes.
Antipsychotic-Induced Insulin Resistance and Postprandial Hormonal Dysregulation Independent of Weight Gain or Psychiatric Disease
Teff, Karen L.; Rickels, Michael R.; Grudziak, Joanna; Fuller, Carissa; Nguyen, Huong-Lan; Rickels, Karl
Atypical antipsychotic (AAP) medications that have revolutionized the treatment of mental illness have become stigmatized by metabolic side effects, including obesity and diabetes. It remains controversial whether the defects are treatment induced or disease related. Although the mechanisms underlying these metabolic defects are not understood, it is assumed that the initiating pathophysiology is weight gain, secondary to centrally mediated increases in appetite. To determine if the AAPs have detrimental metabolic effects independent of weight gain or psychiatric disease, we administered olanzapine, aripiprazole, or placebo for 9 days to healthy subjects (n = 10, each group) under controlled in-patient conditions while maintaining activity levels. Prior to and after the interventions, we conducted a meal challenge and a euglycemic-hyperinsulinemic clamp to evaluate insulin sensitivity and glucose disposal. We found that olanzapine, an AAP highly associated with weight gain, causes significant elevations in postprandial insulin, glucagon-like peptide 1 (GLP-1), and glucagon coincident with insulin resistance compared with placebo. Aripiprazole, an AAP considered metabolically sparing, induces insulin resistance but has no effect on postprandial hormones. Importantly, the metabolic changes occur in the absence of weight gain, increases in food intake and hunger, or psychiatric disease, suggesting that AAPs exert direct effects on tissues independent of mechanisms regulating eating behavior. PMID:23835329
Effect of Stem Cell Therapy on Amiodarone Induced Fibrosing Interstitial Lung Disease in Albino Rat
Zaglool, Somaya Saad; Zickri, Maha Baligh; Abd El Aziz, Dalia Hussein; Mabrouk, Doaa; Metwally, Hala Gabr
Background and Objectives: The fibrosing forms of interstitial lung disease (ILD) are associated with significant morbidity and mortality. ILD may be idiopathic, secondary to occupational, infection, complicate rheumatic diseases or drug induced. Efficacy of antifibrotic agents is as far as, limited and uncertain. No effective treatment was confirmed for pulmonary fibrosis except lung transplantation. The present study aimed at investigating the possible effect of human cord blood mesenchymal stem cell (MSC) therapy on fibrosing ILD. This was accomplished by using amiodarone as a model of induced lung damage in albino rat. Methods and Results: Seventeen adult male albino rats were divided into 3 groups. Rats of amiodarone group were given 30 mg/kg of amiodarone orally 6 days/ week for 6 weeks. Rats of stem cell therapy group were injected with stem cells in the tail vein following confirmation of lung damage and left for 4 weeks before sacrifice. Obstructed bronchioles, thickened interalveolar septa and thickened wall of pulmonary vessels were found and proved morphometrically. Reduced type I pneumocytes and increased area% of collagen fibers were recorded. All findings regressed on stem cell therapy. Conclusions: Cord blood MSC therapy proved definite amelioration of fibrosing interstitial lung disease provided therapy starts early in the development of the pathogenesis. PMID:24298346
Radiation-induced cardiovascular diseases: Is the epidemiologic evidence compatible with the radiobiologic data?
Schultz-Hector, Susanne [Helmholtz-Gemeinschaft, Berlin (Germany)]. E-mail: email@example.com; Trott, Klaus-Ruediger Prof. [Gray Cancer Institute, Northwood (United Kingdom)
The Life Span Study of Japanese atomic bomb survivors demonstrates that radiation exposure significantly increased the risk of developing ischemic heart disease, in particular myocardial infarction. Similarly, epidemiologic investigations in very large populations of patients who had received postoperative radiotherapy for breast cancer or for peptic ulcer demonstrate that radiation exposure of the heart with an average equivalent single dose of approximately 2 Gy significantly increased the risk of developing ischemic heart disease more than 10 years after irradiation. These epidemiologic findings are compatible with radiobiologic data on the pathogenesis of radiation-induced heart disease in experimental animals. The critical target structure appears to be the endothelial lining of blood vessels, in particular arteries, leading to early functional alterations such as pro-inflammatory responses and other changes, which are slowly progressive. Research should concentrate on the interaction of these radiation-induced endothelial changes with the early stages of age-related atherosclerosis to develop criteria for optimizing treatment plans in radiotherapy and also potential interventional strategies.
Insights from advances in research of chemically induced experimental models of human inflammatory bowel disease
Kawada, Mayumi; Arihiro, Atsuko; Mizoguchi, Emiko
Inflammatory bowel disease (IBD), the most important being Crohn's disease and ulcerative colitis, results from chronic dysregulation of the mucosal immune system in the gastrointestinal tract. Although the pathogenesis of IBD remains unclear, it is widely accepted that genetic, environmental, and immunological factors are involved. Recent studies suggest that intestinal epithelial defenses are important to prevent inflammation by protecting against microbial pathogens and oxidative stresses. To investigate the etiology of IBD, animal models of experimental colitis have been developed and are frequently used to evaluate new anti-inflammatory treatments for IBD. Several models of experimental colitis that demonstrate various pathophysiological aspects of the human disease have been described. In this manuscript, we review the characteristic features of IBD through a discussion of the various chemically induced experimental models of colitis (e.g., dextran sodium sulfate-, 2,4,6-trinitrobenzene sulfonic acid-, oxazolone-, acetic acid-, and indomethacin-induced models). We also summarize some regulatory and pathogenic factors demonstrated by these models that can, hopefully, be exploited to develop future therapeutic strategies against IBD. PMID:17948932
Interleukin-35 Induces Regulatory B Cells that Suppress CNS Autoimmune Disease
Wang, Ren-Xi; Yu, Cheng-Rong; Dambuza, Ivy M.; Mahdi, Rashid M.; Dolinska, Monika; Sergeey, Yuri V.; Wingfield, Paul T.; Kim, Sung-Hye; Egwuagu, Charles E.
Interleukin 10-producing regulatory B-cells (Breg-cells) suppress autoimmune diseases while aberrant elevation of Breg-cells prevents sterilizing immunity, promotes carcinogenesis and cancer metastasis by converting resting CD4+ T-cells to regulatory T-cells (Tregs). It is therefore of interest to discover factors that induce Breg-cells. Here we show that IL-35 induces Breg-cells in-vivo and promotes their conversion to a unique Breg subset that produces IL-35 (IL-35+Breg). Treatment of mice with IL-35 conferred protection from uveitis and mice lacking IL-35 or defective in IL-35-signaling produced less Breg-cells and developed severe uveitis. Ex-vivo generated Breg-cells also suppressed uveitis by inhibiting pathogenic Th17/Th1 while promoting Tregs expansion. We further show that IL-35 induced the conversion of human B-cells into Breg-cells and suppressed uveitis by activating STAT1/STAT3 through IL-35-Receptor comprising IL-12R?2/IL-27R? subunits. Discovery that IL-35 converts human B-cells into Breg-cells, allows ex-vivo production of autologous Breg-cells for immunotherapy and investigating Breg/IL-35+Breg cells roles in autoimmune diseases and cancer. PMID:24743305
Measurements on rotating ion cyclotron range of frequencies induced particle fluxes in axisymmetric mirror plasmas
Hatakeyama, R.; Hershkowitz, N.; Majeski, R.; Wen, Y.J.; Brouchous, D.B.; Proberts, P.; Breun, R.A.; Roberts, D.; Vukovic, M.; Tanaka, T. [Department of Nuclear Engineering and Engineering Physics, University of Wisconsin, Madison, Wisconsin 53706 (United States)] [Department of Nuclear Engineering and Engineering Physics, University of Wisconsin, Madison, Wisconsin 53706 (United States)
A comparison of phenomenological features of plasmas is made with a special emphasis on radio-frequency induced transport, which are maintained when a set of two closely spaced dual half-turn antennas in a central cell of the Phaedrus-B axisymmetric tandem mirror [J. J. Browning {ital et al.}, Phys. Fluids B {bold 1}, 1692 (1989)] is phased to excite electromagnetic fields in the ion cyclotron range of frequencies (ICRF) with m={minus}1 (rotating with ions) and m=+1 (rotating with electrons) azimuthal modes. Positive and negative electric currents are measured to flow axially to the end walls in the cases of m={minus}1 and m=+1 excitations, respectively. These parallel nonambipolar ion and electron fluxes are observed to be accompanied by azimuthal ion flows in the same directions as the antenna-excitation modes m. The phenomena are argued in terms of radial particle fluxes due to a nonambipolar transport mechanism [Hojo and Hatori, J. Phys. Soc. Jpn. {bold 60}, 2510 (1991); Hatakeyama {ital et al.}, J. Phys. Soc. Jpn. {bold 60}, 2815 (1991), and Phys. Rev. E {bold 52}, 6664 (1995)], which are induced when azimuthally traveling ICRF waves are absorbed in the magnetized plasma column. {copyright} {ital 1997 American Institute of Physics.}
Effect of particle-induced electron emission (PIEE) on the plasma sheath voltage
NASA Astrophysics Data System (ADS)
Schupfer, N.; Tskhakaya, D. D., Sr.; Khanal, R.; Kuhn, S.; Aumayr, F.; Figueira da Silva, S.; Winter, H. P.
This paper investigates the effect of ion- and electron-induced electron emission from a material wall on the voltage drop across the adjacent plasma sheath ('plasma sheath voltage' (PSV)). For this purpose, a new model involving a collisionless kinetic sheath consistently coupled to a fluid presheath is developed. The underlying analysis is valid for plasmas (both magnetized and unmagnetized) in which the Debye length is much smaller than the relevant characteristic presheath length ('asymptotic two-scale limit'). Material boundaries of particular interest are first walls and divertor target plates bounding magnetically confined fusion plasmas. Majority and impurity ions accelerated from the bulk plasma towards the material boundary release electrons flowing back into the plasma, thus giving rise to a lower PSV than without electron emission. In addition, sufficiently fast electrons from the plasma impinging on the bounding wall produce secondary electrons and are also partially reflected. The present work represents a first step in which the unmagnetized case is considered and electron reflection at the wall is still neglected. Considering typical boundary-plasma conditions and characteristic particle-induced electron emission (PIEE) data (i.e. electron yields and energy distributions), the PSV is self-consistently calculated by means of the new sheath model, showing appreciable effects of PIEE.
Understanding the synthesis of mesoporous silica particles by evaporation induced self assembly
NASA Astrophysics Data System (ADS)
Rathod, Shailendra B.
Evaporation-induced self-assembly (EISA) of amphiphilic molecules within aerosol droplets is an attractive method for synthesis of mesoporous silica particles. The aim of this research was to demonstrate synthetic methodologies to develop novel particle architectures using this technique, and to understand the influence of the competing dynamics within an evaporating droplet undergoing EISA on the particle morphology and mesostructure. Experiments were conducted to control particle characteristics. Particle size and distribution was varied by varying the size and distribution of starting droplets. The compressed gas atomizer, TSI 3076, gave a roughly micron-sized droplets with a polydisperse population, whereas the vibrating orifice aerosol generator (VOAG), TSI 3450, gave a highly monodisperse droplet population when orifices of diameters 10 mum and 20 mum were used. The mesopore size and mesostructure ordering were varied by employing amphiphiles of different geometry and by the use of 1,2,3-trimethylbenzene, a pore-swelling agent. The extent of ordering was influenced by factors that govern the rates of reactions of the silica precursors relative to the rates of amphiphile self-assembly. These factors included acid concentration, the alkyl group in the tetraalkoxysilane precursor, the time for which the sol was aged before droplet generation, and CTAB/Si ratio in the starting sol. Experiments and simulation studies were carried out for particles made using CTAB as the templating agent and TMB as a pore-swelling agent. Analysis of these experiments was used to get insight into the three main dynamic processes occurring inside these droplets: evaporation of the volatile species, amphiphile self-assembly and phase transformation, and hydrolysis and condensation reactions of the silica precursor species. Pore swelling was observed for particles made using the VOAG. Particles made using the 10 mum orifice retained their hexagonal mesostructure upon addition of TMB in the range 0 ? TMB/CTAB < 12.5. Particles made using the 20 mum orifice gave hexagonal mesostructure for the above-mentioned TMB/CTAB mole ratio range, except for 6.25, where a cubic mesostructure was obtained. On the contrary, particles made using the TSI 3076 showed no signs of pore swelling. Certain parameters were varied in droplets experiments as well as experiments in the bulk phase to understand the effect of TMB. It was found that addition of TMB increases the rate of condensation reactions of the silica precursor. For 0 ? TMB/CTAB ? 4.18, very little pore swelling was observed. For 4.18 ? TMB/CTAB ? 8.33, substantial pore swelling was observed, indicating significant TMB insertion into the hydrophobic regions of the self-assembled amphiphilic molecules. For 8.33 ? TMB/CTAB ? 12.5, very little change in mesopore diameter was observed, with evidence of an increase in microporosity. Presence of hysteresis in the nitrogen physisorption isotherms and a broadening of the BJH mesopore size was evident at higher TMB content (TMB/CTAB ? 6.25). The decreasing specific surface area and pore volume in the 0 ? TMB/CTAB ? 4.18 range implied that TMB addition leads to an increasing amount of a nonporous (or low porosity) silica phase. Simulation results show that there is ample time available once the solvent evaporation stops from micron-sized droplets till they reach the high temperature zone, where the rates of silicate reactions increase tremendously. This enabled the TMB molecules in the hydrophobic domains to diffuse out of the self-assembled structures and evaporate before the silicate reactions freezes the structure, and hence no pore swelling is observed in particles made from these droplets. However, in case of the larger droplets made from VOAG, a substantial fraction of TMB remains in the droplets that are still far from fully evaporated when they enter the high temperature region. Hence, pore swelling is observed in particles made from these droplets. Particles with hierarchical internal morphology were produced by addition of a h
Drug-induced liver disease (DILD) continues to cause significant morbidity and mortality and impair new drug development. Mounting evidence suggests that DILD is a complex, multifactorial disease in which no one factor is likely to be an absolute indicator of susceptibility. As a...
Immunogenic and replicative properties of classical swine fever virus replicon particles modified to induce IFN-?\\/? and carry foreign genes
Rolf Suter; Artur Summerfield; Lisa J. Thomann-Harwood; Kenneth C. McCullough; Jon-Duri Tratschin; Nicolas Ruggli
Virus replicon particles (VRP) are genetically engineered infectious virions incapable of generating progeny virus due to partial or complete deletion of at least one structural gene. VRP fulfil the criteria of a safe vaccine and gene delivery system. With VRP derived from classical swine fever virus (CSF-VRP), a single intradermal vaccination protects from disease. Spreading of the challenge virus in
Subcellular distribution of swine vesicular disease virus proteins and alterations induced in infected cells: A comparative study with foot-and-mouth disease virus and vesicular stomatitis virus
Miguel A. Mart�n-Acebes; M�nica Gonz�lez-Magaldi; Mar�a F. Rosas; Bel�n Borrego; Emiliana Brocchi; Rosario Armas-Portela; Francisco Sobrino
The intracellular distribution of swine vesicular disease virus (SVDV) proteins and the induced reorganization of endomembranes in IBRS-2 cells were analyzed. Fluorescence to new SVDV capsids appeared first upon infection, concentrated in perinuclear circular structures and colocalized to dsRNA. As in foot-and-mouth disease virus (FMDV)-infected cells, a vesicular pattern was predominantly found in later stages of SVDV capsid morphogenesis that
Modeling climate impact on an emerging disease, the Phytophthora alni-induced alder decline.
Aguayo, Jaime; Elegbede, Fabrice; Husson, Claude; Saintonge, Fran�ois-Xavier; Mar�ais, Beno�t
Alder decline caused by Phytophthora alni is one of the most important emerging diseases in natural ecosystems in Europe, where it has threatened riparian ecosystems for the past 20 years. Environmental factors, such as mean site temperature and soil characteristics, play an important role in the occurrence of the disease. The objective of the present work was to model and forecast the effect of environment on the severity of alder Phytophthora outbreaks, and to determine whether recent climate change might explain the disease emergence. Two alder sites networks in NE and SW France were surveyed to assess the crown health of trees; the oomycete soil inoculum was also monitored in the NE network. The main factors explaining the temporal annual variation in alder crown decline or crown recovery were the mean previous winter and previous summer temperatures. Both low winter temperatures and high summer temperatures were unfavorable to the disease. Cold winters promoted tree recovery because of poor survival of the pathogen, while hot summer temperature limited the incidence of tree decline. An SIS model explaining the dynamics of the P. alni-induced alder decline was developed using the data of the NE site network and validated using the SW site network. This model was then used to simulate the frequency of declining alder over time with historical climate data. The last 40 years' weather conditions have been generally favorable to the establishment of the disease, indicating that others factors may be implicated in its emergence. The model, however, showed that the climate of SW France was much more favorable for the disease than that of the Northeast, because it seldom limited the overwintering of the pathogen. Depending on the European area, climate change could either enhance or decrease the severity of the alder decline. PMID:24729529
Proteins induced by telomere dysfunction and DNA damage represent biomarkers of human aging and disease
Jiang, Hong; Schiffer, Eric; Song, Zhangfa; Wang, Jianwei; Z�rbig, Petra; Thedieck, Kathrin; Moes, Suzette; Bantel, Heike; Saal, Nadja; Jantos, Justyna; Brecht, Meiken; Jen�, Paul; Hall, Michael N.; Hager, Klaus; Manns, Michael P.; Hecker, Hartmut; Ganser, Arnold; D�hner, Konstanze; Bartke, Andrzej; Meissner, Christoph; Mischak, Harald; Ju, Zhenyu; Rudolph, K. Lenhard
Telomere dysfunction limits the proliferative capacity of human cells by activation of DNA damage responses, inducing senescence or apoptosis. In humans, telomere shortening occurs in the vast majority of tissues during aging, and telomere shortening is accelerated in chronic diseases that increase the rate of cell turnover. Yet, the functional role of telomere dysfunction and DNA damage in human aging and diseases remains under debate. Here, we identified marker proteins (i.e., CRAMP, stathmin, EF-1?, and chitinase) that are secreted from telomere-dysfunctional bone-marrow cells of late generation telomerase knockout mice (G4mTerc?/?). The expression levels of these proteins increase in blood and in various tissues of aging G4mTerc?/? mice but not in aging mice with long telomere reserves. Orthologs of these proteins are up-regulated in late-passage presenescent human fibroblasts and in early passage human cells in response to ?-irradiation. The study shows that the expression level of these marker proteins increases in the blood plasma of aging humans and shows a further increase in geriatric patients with aging-associated diseases. Moreover, there was a significant increase in the expression of the biomarkers in the blood plasma of patients with chronic diseases that are associated with increased rates of cell turnover and telomere shortening, such as cirrhosis and myelodysplastic syndromes (MDS). Analysis of blinded test samples validated the effectiveness of the biomarkers to discriminate between young and old, and between disease groups (MDS, cirrhosis) and healthy controls. These results support the concept that telomere dysfunction and DNA damage are interconnected pathways that are activated during human aging and disease. PMID:18695223
Proteins induced by telomere dysfunction and DNA damage represent biomarkers of human aging and disease.
Jiang, Hong; Schiffer, Eric; Song, Zhangfa; Wang, Jianwei; Z�rbig, Petra; Thedieck, Kathrin; Moes, Suzette; Bantel, Heike; Saal, Nadja; Jantos, Justyna; Brecht, Meiken; Jen�, Paul; Hall, Michael N; Hager, Klaus; Manns, Michael P; Hecker, Hartmut; Ganser, Arnold; D�hner, Konstanze; Bartke, Andrzej; Meissner, Christoph; Mischak, Harald; Ju, Zhenyu; Rudolph, K Lenhard
Telomere dysfunction limits the proliferative capacity of human cells by activation of DNA damage responses, inducing senescence or apoptosis. In humans, telomere shortening occurs in the vast majority of tissues during aging, and telomere shortening is accelerated in chronic diseases that increase the rate of cell turnover. Yet, the functional role of telomere dysfunction and DNA damage in human aging and diseases remains under debate. Here, we identified marker proteins (i.e., CRAMP, stathmin, EF-1alpha, and chitinase) that are secreted from telomere-dysfunctional bone-marrow cells of late generation telomerase knockout mice (G4mTerc(-/-)). The expression levels of these proteins increase in blood and in various tissues of aging G4mTerc(-/-) mice but not in aging mice with long telomere reserves. Orthologs of these proteins are up-regulated in late-passage presenescent human fibroblasts and in early passage human cells in response to gamma-irradiation. The study shows that the expression level of these marker proteins increases in the blood plasma of aging humans and shows a further increase in geriatric patients with aging-associated diseases. Moreover, there was a significant increase in the expression of the biomarkers in the blood plasma of patients with chronic diseases that are associated with increased rates of cell turnover and telomere shortening, such as cirrhosis and myelodysplastic syndromes (MDS). Analysis of blinded test samples validated the effectiveness of the biomarkers to discriminate between young and old, and between disease groups (MDS, cirrhosis) and healthy controls. These results support the concept that telomere dysfunction and DNA damage are interconnected pathways that are activated during human aging and disease. PMID:18695223
Mechanisms of action of inhaled fibers, particles and nanoparticles in lung and cardiovascular diseases
Brooke T Mossman; Paul J Borm; Vincent Castranova; Daniel L Costa; Kenneth Donaldson; Steven R Kleeberger
BACKGROUND: A symposium on the mechanisms of action of inhaled airborne particulate matter (PM), pathogenic particles and fibers such as silica and asbestos, and nanomaterials, defined as synthetic particles or fibers less than 100 nm in diameter, was held on October 27 and 28, 2005, at the Environmental Protection Agency (EPA) Conference Center in Research Triangle Park, North Carolina. The
ABSTRACT: A symposium on the mechanisms of action of inhaled airborne particulate matter (PM),pathogenic particles and fibers such as silica and asbestos, and nanomaterials, defined as synthetic particles or fibers less than 100 nm in diameter, was held on October 27 and 28, ...
Natural and Induced Regulatory T Cells: Targets for Immunotherapy of Autoimmune Disease and Allergy
Nicolson, K.S.; Wraith, D.C.
Recent advances in immunology have greatly increased our understanding of immunological tolerance. In particular, there has been a resurgence of interest in mechanisms of immune regulation. Immune regulation refers to the phenomenon, previously known as immune suppression, by which excessive responses to infectious agents and hypersensitivities to otherwise innocuous antigens such as self antigens and allergens are avoided. We now appreciate that various distinct cell types mediate immune suppression and that some of these may be induced by appropriate administration of antigens, synthetic peptides and drugs of various types. The induction of antigen specific immunotherapy for treatment of autoimmune and allergic diseases remains the �holy grail� for treatment of these diseases. This goal comes ever closer as understanding of the mechanisms of immune suppression and in particular antigen specific immunotherapy increases. Here we review evidence that immune suppression is mediated by various different subsets of CD4 T cells. PMID:16918477
Hypoxia-Inducible Factor (HIF) as a Pharmacological Target for Prevention and Treatment of Infectious Diseases.
Bhandari, Tamara; Nizet, Victor
In the present era of ever-increasing antibiotic resistance and increasingly complex and immunosuppressed patient populations, physicians and scientists are seeking novel approaches to battle difficult infectious disease conditions. Development of a serious infection implies a failure of innate immune capabilities in the patient, and one may consider whether pharmacological strategies exist to correct and enhance innate immune cell function. Hypoxia-inducible factor-1 (HIF-1), the central regulator of the cellular response to hypoxic stress, has recently been recognized to control the activation state and key microbicidal functions of immune cells. HIF-1 boosting drugs are in clinical development for anemia and other indications, and could be repositioned as infectious disease therapeutics. With equal attention to opportunities and complexities, we review our current understanding of HIF-1 regulation of microbial host-pathogen interactions with an eye toward future drug development. PMID:25134687
Intracellular influx of calcium induced by quartz particles in alveolar macrophages
Feng Tian [State Key Laboratory for Environmental Simulation and Pollution Control, College of Environmental Sciences and Engineering, Peking University, Beijing 100871 (China); Tong Zhu, E-mail: firstname.lastname@example.com [State Key Laboratory for Environmental Simulation and Pollution Control, College of Environmental Sciences and Engineering, Peking University, Beijing 100871 (China); Yu Shang [State Key Laboratory for Environmental Simulation and Pollution Control, College of Environmental Sciences and Engineering, Peking University, Beijing 100871 (China)
Historical studies report that cellular injury and silicosis are related to cytosolic free calcium (Ca{sup 2+}). Moreover, reactive oxygen species (ROS) have been linked to cellular injury. However, the detail mechanism of the increase in [Ca{sup 2+}]{sub i} and the relationship between [Ca{sup 2+}]{sub i} and ROS production remains unknown. Quartz particle has been found to increase [Ca{sup 2+}]{sub i} and activate the generation of ROS. Our hypothesis is that [Ca{sup 2+}]{sub i} increase induced by quartz particle is from extracellular Ca{sup 2+} through the Ca{sup 2+} channel, and [Ca{sup 2+}]{sub i} increase is believed to activate ROS production. In order to examine this hypothesis, we treated rat alveolar macrophages with quartz (SiO{sub 2}) particles and used laser scanning confocal microscopy to measure [Ca{sup 2+}]{sub i} and the fluorescence intensity of ROS. Time- and dose-dependent increases in [Ca{sup 2+}]{sub I} and ROS in macrophages as well as cell viability were observed. Through chelating extracellular Ca{sup 2+} with ethylene glycol tetraacetic acid and releasing intracellular Ca{sup 2+} with thapsigargin, we found that 72.7% of the [Ca{sup 2+}]{sub i} increase was due to the influx of Ca{sup 2+} from the extracellular environment, via Ca{sup 2+} channels in the plasma membrane. By adding mannitol to scavenge hydroxyl radicals (OH.), and removing surface iron from the quartz particles to reduce OH. generation, we observed a reduced level of ROS generation, whereas the increase in [Ca{sup 2+}]{sub i} was unaffected. When using EGTA to reduce [Ca{sup 2+}]{sub i}, we observed a decrease in ROS production. This study suggests that the [Ca{sup 2+}]{sub i} influx was independent of OH. production, and the [Ca{sup 2+}]{sub i} increase resulted in ROS production. These results further indicate that there is a strong relationship between cytosolic free Ca{sup 2+} content and cellular injury as well as silica exposure.
Familial Alzheimer�s disease modelling using induced pluripotent stem cell technology
Mohamet, Lisa; Miazga, Natalie J; Ward, Christopher M
Alzheimer�s disease (AD) is a progressive neurodegenerative disease in which patients exhibit gradual loss of memory that impairs their ability to learn or carry out daily tasks. Diagnosis of AD is difficult, particularly in early stages of the disease, and largely consists of cognitive assessments, with only one in four patients being correctly diagnosed. Development of novel therapeutics for the treatment of AD has proved to be a lengthy, costly and relatively unproductive process with attrition rates of > 90%. As a result, there are no cures for AD and few treatment options available for patients. Therefore, there is a pressing need for drug discovery platforms that can accurately and reproducibly mimic the AD phenotype and be amenable to high content screening applications. Here, we discuss the use of induced pluripotent stem cells (iPSCs), which can be derived from adult cells, as a method of recapitulation of AD phenotype in vitro. We assess their potential use in high content screening assays and the barriers that exist to realising their full potential in predictive efficacy, toxicology and disease modelling. At present, a number of limitations need to be addressed before the use of iPSC technology can be fully realised in AD therapeutic applications. However, whilst the use of AD-derived iPSCs in drug discovery remains a fledgling field, it is one with immense potential that is likely to reach fruition within the next few years. PMID:24772250
HIV-associated renal diseases and highly active antiretroviral therapy-induced nephropathy.
R�ling, J; Schmid, H; Fischereder, M; Draenert, R; Goebel, F D
Renal disease is becoming an increasingly prevalent entity in human immunodeficiency virus (HIV)-infected patients; it occurs in a variety of clinical settings and is associated with histopathological changes. HIV-related renal impairment can present as acute or chronic kidney disease; it can be caused directly or indirectly by HIV and/or by drug-related effects that are directly nephrotoxic or lead to changes in renal function by inducing metabolic vaculopathy and renal damage. Acute renal failure is frequently caused by the toxic effects of antiretroviral therapy or nephrotoxic antimicrobial substances used in the treatment of opportunistic infections. Chronic renal disease can be caused by multiple pathophysiological mechanisms, leading to HIV-associated nephropathy, a form of collapsing focal glomerulosclerosis, thrombotic microangiopathy, and various forms of immune complex glomerulonephritis. The increase in life expectancy and alteration of lipid metabolism due to receipt of highly active antiretroviral therapy are expected to result in an increased prevalence of diabetes and hypertension and, thus, to secondary diabetic and hypertensive renal damage. Antiretroviral agents, such as indinavir and tenofovir, have been associated with nephrotoxic drug effects that have been shown to be reversible in most cases. In this article, we review the current knowledge about acute and chronic HIV-associated renal disease, metabolic alterations and related nephropathies, and toxic drug effects of combination antiretroviral pharmacotherapy. PMID:16619164
Impact of Rhesus disease on the global problem of bilirubin-induced neurologic dysfunction.
Zipursky, Alvin; Bhutani, Vinod K
Clinical experience with Rhesus (Rh) disease and its post-icteric sequelae is limited among high-income countries because of nearly over four decades of effective prevention care. We hypothesized that Rh disease is prevalent in other regions of the world because it is likely that protection is limited or non-existent. Following a worldwide study, it has been concluded that Rh hemolytic disease is a significant public health problem resulting in stillbirths and neonatal deaths, and is a major cause of severe hyperbilirubinemia with its sequelae, kernicterus and bilirubin-induced neurologic dysfunction. Knowing that effective Rh-disease prophylaxis depends on maternal blood-type screening, healthcare afforded to the high-risk mothers needs to be free of bottlenecks and coupled with unfettered access to effective Rh-immunoglobulin. Future studies that match the universal identification of Rh-negative status of women and targeted use of immunoprophylaxis to prevent childhood bilirubin neurotoxicity are within reach, based on vast prior experiences. PMID:25582277
Concentrated ambient ultrafine particle exposure induces cardiac change in young healthy volunteers
Exposure to ambient ultrafine particles has been associated with cardiopulmonary toxicity and mortality. Adverse effects specifically linked to ultrafine particles include loss of sympathovagal balance and altered hemostasis. To characterize the effects of ultrafine particles in ...
Localized linear IgA disease induced by ampicillin/sulbactam.
Shimanovich, Iakov; Rose, Christian; Sitaru, Cassian; Br�cker, Eva-B; Zillikens, Detlef
We describe a patient who developed an exclusively perianal-intergluteal vesicular eruption after receiving a course of ampicillin/sulbactam. Direct immunofluorescence microscopy of perilesional skin demonstrated linear deposits of IgA along the dermal-epidermal junction. Circulating IgA autoantibodies against the 120-kd soluble ectodomain of bullous pemphigoid antigen 180 (LAD-1 autoantigen) were detected by immunoblotting. Discontinuation of the antibiotics resulted in a rapid resolution of the skin lesions. This is a most unusual case of localized drug-induced linear IgA disease. PMID:15243532
[Calcium polystyrene sulfonate induced colonic necrosis in patient with chronic kidney disease].
Lee, Sung Hoa; Kim, Sung Jung; Kim, Go Eun; Lee, Woo Jin; Hong, Won Ki; Baik, Gwang Ho; Choi, Young Hee; Kim, Dong Joon
A 63-year-old woman was admitted due to right upper quadrant abdominal pain. She was going through hemodialysis due to end stage renal disease and taking calcium polystyrene sulfonate orally and rectally due to hyperkalemia. Colonoscopy showed a circular ulcerative mass on the proximal ascending colon. Biopsy specimen from the mass showed inflammation and necrotic debris. It also revealed basophilic angulated crystals which were adherent to the ulcer bed and normal mucosa. These crystals were morphologically consistent with calcium polystyrene sulfonate. She was diagnosed with calcium polystyrene phosphate induced colonic necrosis and improved with conservative treatment. PMID:20389181
Systemic lupus erythematosus in Crohn�s disease: drug-induced or idiopathic?
Michalopoulos, George; Vrakas, Spyridon; Makris, Konstantinos; Tzathas, Charalampos
Coexistence of Crohn�s disease (CD) and idiopathic systemic lupus erythematosus (SLE) is very rare. On the other hand, drug-induced lupus erythematosus (DILE) due to anti-tumor necrosis factor (TNF) agents is a relatively more common entity. DILE due to anti-TNF agents and idiopathic SLE share common serologic and epidemiologic characteristics making the differentiation between those two entities difficult. We present a case of a 35-year-old woman with CD who developed SLE after treatment with adalimumab and denosumab and persisting symptoms eight months after discontinuation of those agents. PMID:26126856
Potential of human Induced Pluripotent Stem Cells in studies of liver disease
Sampaziotis, Fotios; Segeritz, Charis-Patricia; Vallier, Ludovic
Neurol. 2005;62:1057-62. 22 � 37. Leung A, Nah SK, Reid W, Ebata A, Koch CM, Monti S, et al. Induced 23 � pluripotent stem cell modeling of multisystemic, hereditary transthyretin 24 � amyloidosis. Stem Cell Reports. 2013. 31;1:451-63. 25 � 38... � � Pediatr. 2002;161:S20-S34. 1 � 39. Roberts EA, Schilsky ML; AASLD. Diagnosis and treatment of Wilson 2 � disease: an update. Hepatology. 2008;47:2089-111. 3 � 40. Zhang S, Chen S, Li W, Guo X, Zhao P, Xu J, et al. Rescue of ATP7B 4 � function...
A multiparameter approach to monitor disease activity in collagen-induced arthritis
Introduction Disease severity in collagen-induced arthritis (CIA) is commonly assessed by clinical scoring of paw swelling and histological examination of joints. Although this is an accurate approach, it is also labour-intensive and the application of less invasive and less time-consuming methods is of great interest. However, it is still unclear which of these methods represents the most discriminating measure of disease activity. Methods We undertook a comparative analysis in which different measurements of inflammation and tissue damage in CIA were studied on an individual mouse level. We compared the current gold standard methods - clinical scoring and histological examination - with alternative methods based on scoring of X-ray or micro-computed tomography (CT) images and investigated the significance of systemically expressed proteins, involved in CIA pathogenesis, that have potential as biomarkers. Results Linear regression analysis revealed a marked association of serum matrix metalloproteinase (MMP)-3 levels with all features of CIA including inflammation, cartilage destruction and bone erosions. This association was improved by combined detection of MMP-3 and anti-collagen IgG2a antibody concentrations. In addition, combined analysis of both X-ray and micro-CT images was found to be predictive for cartilage and bone damage. Most remarkably, validation analysis using an independent data set proved that variations in disease severity, induced by different therapies, could be accurately represented by predicted values based on the proposed parameters. Conclusions Our analyses revealed that clinical scoring, combined with serum MMP-3, anti-collagen IgG2a measurement and scoring of X-ray and micro-CT images, yields a comprehensive insight into the different aspects of disease activity in CIA. PMID:20731827
Pressure induced increase of particle size and resulting weakening of elastic stiffness of CeO2 nanocrystals
Downs, Robert T.
Pressure induced increase of particle size and resulting weakening of elastic stiffness of CeO2; accepted 14 May 2004) We demonstrate that the compressibility of cubic fluorite-structure CeO2 nanocrystals 10 nm increases at pressures above 20 GPa. At ambient pressure, CeO2 nanocrystals exhibit larger cell
Technology Transfer Automated Retrieval System (TEKTRAN)
Exposing rats to heavy particles produces alterations in the functioning of dopaminergic neurons and in the behaviors that depend upon the integrity of the dopaminergic system. Two of these dopamine-dependent behaviors include amphetamine-induced reinforcement, measured using the conditioned place ...
In situ observation of particle-induced desorption from a self-assembled monolayer by laser-ionization mass spectrometry
Zbigniew, Postawa
In situ observation of particle-induced desorption from a self-assembled monolayer by laser-stimulated desorption processes of highly ordered, self-assembled monolayers of biphenyl-based thiols covalently bound with a kinetic energy of 1 keV. The damage that accumulates in the self-assembled monolayer with increasing
Propagation distance of the alpha-particle-induced bystander effect: the role of nuclear traversal and gap junction communication.
Gaillard, Sylvain; Pusset, David; de Toledo, Sonia M; Fromm, Michel; Azzam, Edouard I
When cell populations are exposed to low-dose alpha-particle radiation, a significant fraction of the cells will not be traversed by a radiation track. However, stressful effects occur in both irradiated and bystander cells in the population. Characterizing these effects, and investigating their underlying mechanism(s), is critical to understanding human health risks associated with exposure to alpha particles. To this end, confluent normal human fibroblast cultures were grown on polyethylene terephthalate foil grafted to an ultrathin solid-state nuclear track detector and exposed under non-perturbing conditions to low-fluence alpha particles from a broadbeam irradiator. Irradiated and affected bystander cells were localized with micrometer precision. The stress-responsive protein p21(Waf1) (also known as CDKN1A) was induced in bystander cells within a 100-microm radius from an irradiated cell. The mean propagation distance ranged from 20 to 40 microm around the intranuclear alpha-particle impact point, which corresponds to a set of approximately 30 cells. Nuclear traversal, induced DNA damage, and gap junction communication were critical contributors to propagation of this stressful effect. The strategy described here may be ideal to investigate the size of radiation-affected target and the relative contribution of different cellular organelles to bystander effects induced by energetic particles, which is relevant to radioprotection and cancer radiotherapy. PMID:19580486
Propagation Distance of the ?-Particle-Induced Bystander Effect: The Role of Nuclear Traversal and Gap Junction Communication
Gaillard, Sylvain; Pusset, David; de Toledo, Sonia M.; Fromm, Michel; Azzam, Edouard I.
When cell populations are exposed to low-dose ?-particle radiation, a significant fraction of the cells will not be traversed by a radiation track. However, stressful effects occur in both irradiated and bystander cells in the population. Characterizing these effects, and investigating their underlying mechanism(s), is critical to understanding human health risks associated with exposure to ? particles. To this end, confluent normal human fibroblast cultures were grown on polyethylene terephthalate foil grafted to an ultrathin solid-state nuclear track detector and exposed under non-perturbing conditions to low-fluence ? particles from a broadbeam irradiator. Irradiated and affected bystander cells were localized with micrometer precision. The stress-responsive protein p21Waf1 (also known as CDKN1A) was induced in bystander cells within a 100-�m radius from an irradiated cell. The mean propagation distance ranged from 20 to 40 �m around the intranuclear ?-particle impact point, which corresponds to a set of ?30 cells. Nuclear traversal, induced DNA damage, and gap junction communication were critical contributors to propagation of this stressful effect The strategy described here may be ideal to investigate the size of radiation-affected target and the relative contribution of different cellular organelles to bystander effects induced by energetic particles, which is relevant to radioprotection and cancer radiotherapy. PMID:19580486
Carbon Nanotube-Induced Pulmonary Granulomatous Disease: Twist1 and Alveolar Macrophage M1 Activation
Barna, Barbara P.; Huizar, Isham; Malur, Anagha; McPeek, Matthew; Marshall, Irene; Jacob, Mark; Dobbs, Larry; Kavuru, Mani S.; Thomassen, Mary Jane
Sarcoidosis, a chronic granulomatous disease of unknown cause, has been linked to several environmental risk factors, among which are some that may favor carbon nanotube formation. Using gene array data, we initially observed that bronchoalveolar lavage (BAL) cells from sarcoidosis patients displayed elevated mRNA of the transcription factor, Twist1, among many M1-associated genes compared to healthy controls. Based on this observation we hypothesized that Twist1 mRNA and protein expression might become elevated in alveolar macrophages from animals bearing granulomas induced by carbon nanotube instillation. To address this hypothesis, wild-type and macrophage-specific peroxisome proliferator-activated receptor gamma (PPAR?) knock out mice were given oropharyngeal instillation of multiwall carbon nanotubes (MWCNT). BAL cells obtained 60 days later exhibited significantly elevated Twist1 mRNA expression in granuloma-bearing wild-type or PPAR? knock out alveolar macrophages compared to sham controls. Overall, Twist1 expression levels in PPAR? knock out mice were higher than those of wild-type. Concurrently, BAL cells obtained from sarcoidosis patients and healthy controls validated gene array data: qPCR and protein analysis showed significantly elevated Twist1 in sarcoidosis compared to healthy controls. In vitro studies of alveolar macrophages from healthy controls indicated that Twist1 was inducible by classical (M1) macrophage activation stimuli (LPS, TNF?) but not by IL-4, an inducer of alternative (M2) macrophage activation. Findings suggest that Twist1 represents a PPAR?-sensitive alveolar macrophage M1 biomarker which is induced by inflammatory granulomatous disease in the MWCNT model and in human sarcoidosis. PMID:24322444
Particle-Induced Cytokine Responses in Cardiac Cell Cultures--the Effect of Particles versus Soluble Mediators Released by Particle-Exposed Lung Cells
Annike I. Totlandsdal; Magne Refsnes; Tor Skomedal; Jan-Bj�rn Osnes; P. E. Schwarze; M. Lag
Increased levels of particulate matter have been associated with adverse effects in the respiratory as well as the cardiovascular system. The biological mechanisms behind these associations are still unresolved. Among potential mechanisms, particulate matter- associated cardiac effects may be initiated by inhaled small-sized particles, particle components and\\/or mediators related to in- flammation that translocate into the pulmonary circulation. In the
Determination of small soot particles in the presence of large ones from time-resolved laser-induced incandescence
NASA Astrophysics Data System (ADS)
Cenker, E.; Bruneaux, G.; Dreier, T.; Schulz, C.
A novel strategy for the analysis of time-resolved laser-induced incandescence (TiRe-LII), called two-exponential reverse fitting (TERF), is introduced. The method is based on combined monoexponential fits to the LII signal decay at various delay times and approximates the particle-size distribution as a weighted combination of one large and one small monodisperse equivalent mean particle size without requiring assumption on the particle-size distribution. The effects of particle size, heat-up temperature, aggregate size, and pressure on the uncertainty of this method are evaluated using numerical experiments for lognormal and bimodal size distributions. TERF is applied to TiRe-LII measured in an atmospheric pressure laminar non-premixed ethylene/air flame at various heights above burner. The results are compared to transmission electron microscopy (TEM) measurements of thermophoretically sampled soot. The particle size of the large particle-size class agreed well for both methods. The size of the small particle-size class and the relative contribution did not agree which is attributed to missing information in the TEM results for very small particles. These limitations of TEM measurements are discussed and the effect of the exposure time of the sampling grid is evaluated.
Swapping trajectories: a new wall-induced cross-streamline particle migration mechanism in a dilute suspension of spheres
M. Zurita-Gotor; J. Blawzdziewicz; E. Wajnryb
Binary encounters between spherical particles in shear flow are studied for a system bounded by a single planar wall or two parallel planar walls under creeping flow conditions. We show that wall proximity gives rise to a new class of binary trajectories resulting in cross-streamline migration of the particles. The spheres on these new trajectories do not pass each other (as they would in free space) but instead they swap their cross-streamline positions. To determine the significance of the wall-induced particle migration, we have evaluated the hydrodynamic self-diffusion coefficient associated with a sequence of uncorrelated particle displacements due to binary particle encounters. The results of our calculations quantitatively agree with the experimental value obtained by \\cite{Zarraga-Leighton:2002} for the self-diffusivity in a dilute suspension of spheres undergoing shear flow in a Couette device. We thus show that the wall-induced cross-streamline particle migration is the source of the anomalously large self-diffusivity revealed by their experiments.
A single amino acid in VP2 is critical for the attachment of infectious bursal disease subviral particles to immobilized metal ions and DF-1 cells.
Lai, Su-Yuan; Chang, Gary Ro-lin; Yang, Han-Jen; Lee, Cheng-Chung; Lee, Long-Huw; Vakharia, Vikram N; Wang, Min-Ying
VP2 protein is the primary host-protective immunogen of infectious bursal disease virus (IBDV). His249 and His253 are two surface histidine residues in IBDV subviral particles (SVP), which is formed by twenty VP2 trimers when the VP2 protein of a local isolate is expressed. Here, a systemic study was performed to investigate His249 or/and His253 on self-assembly, cell attachment and immunogenicity of SVP. Point-mutagenesis of either or both histidine residues to alanine did not affect self-assembly of the SVP, but the SVP lost its Ni-NTA binding affinity when the His253 was mutated. Indirect immunofluorescence assays and inhibitory experiments also showed that His253 is essential for SVP to attach onto the DF-1 cells and to inhibit IBDV infection of DF-1 cells. Finally, enzyme-linked immunosorbent assays and chicken protection assays demonstrated that SVP with a mutation of His253 to alanine induced comparable neutralizing antibody titers in chickens as the wild-type SVP did. It was concluded that VP2's His253, a site not significant for the overall immunogenicity induced by SVP, is crucial for the binding affinity of SVP to Ni-NTA and the attachment of an IBDV host cell line. This is the first paper to decipher the role of His253 played in receptor interaction and immunogenicity. PMID:24732578
Energetic-particle-driven instabilities and induced fast-ion transport in a reversed field pinch
NASA Astrophysics Data System (ADS)
Lin, Liang
Multiple bursty energetic-particle (EP) modes with fishbone-like structures are observed during 1 MW tangential neutral-beam injection into MST reversed field pinch (RFP) plasmas. The distinguishing features of the RFP, including large magnetic shear (tending to add stability) and weak toroidal magnetic field (leading to large fast ion beta and stronger drive), provide a complementary environment to tokamak and stellarator configurations for exploring basic understanding of these instabilities. Detailed measurements of the EP mode characteristics and temporal-spatial dynamics reveal their influence on fast ion transport and interaction with global tearing modes. Internal magnetic field fluctuations associated with the EP modes are directly observed for the first time by Faraday-effect polarimetry (frequency ~ 90 kHz and amplitude ~ 2 G). Simultaneously measured density fluctuations exhibit a dynamically evolving and asymmetric spatial structure that peaks near the core where fast ions reside and shifts outward as the instability evolves. Furthermore, the EP mode frequencies appear at ~k?VA , consistent with continuum modes destabilized by strong drive. The fast-ion temporal dynamics, measured by a neutral particle analyzer, resemble a classical predator-prey relaxation oscillation. It contains a slow-growing phase arising from the beam fueling followed by a rapid drop (~ 15 %) when the EP modes peak, indicating the fluctuation-induced transport maintains a stiff fast-ion density profile. The inferred transport rate is strongly enhanced (� 2) with the onset of multiple nonlinearly-interacting EP modes. The fast ions also impact global tearing modes, reducing their amplitudes by up to 65%. This mode reduction is lessened following the EP-bursts, further evidence for fast ion redistribution that weakens the suppression mechanism. Possible tearing mode suppression mechanisms will be discussed. Multiple bursty energetic-particle (EP) modes with fishbone-like structures are observed during 1 MW tangential neutral-beam injection into MST reversed field pinch (RFP) plasmas. The distinguishing features of the RFP, including large magnetic shear (tending to add stability) and weak toroidal magnetic field (leading to large fast ion beta and stronger drive), provide a complementary environment to tokamak and stellarator configurations for exploring basic understanding of these instabilities. Detailed measurements of the EP mode characteristics and temporal-spatial dynamics reveal their influence on fast ion transport and interaction with global tearing modes. Internal magnetic field fluctuations associated with the EP modes are directly observed for the first time by Faraday-effect polarimetry (frequency ~ 90 kHz and amplitude ~ 2 G). Simultaneously measured density fluctuations exhibit a dynamically evolving and asymmetric spatial structure that peaks near the core where fast ions reside and shifts outward as the instability evolves. Furthermore, the EP mode frequencies appear at ~k?VA , consistent with continuum modes destabilized by strong drive. The fast-ion temporal dynamics, measured by a neutral particle analyzer, resemble a classical predator-prey relaxation oscillation. It contains a slow-growing phase arising from the beam fueling followed by a rapid drop (~ 15 %) when the EP modes peak, indicating the fluctuation-induced transport maintains a stiff fast-ion density profile. The inferred transport rate is strongly enhanced (� 2) with the onset of multiple nonlinearly-interacting EP modes. The fast ions also impact global tearing modes, reducing their amplitudes by up to 65%. This mode reduction is lessened following the EP-bursts, further evidence for fast ion redistribution that weakens the suppression mechanism. Possible tearing mode suppression mechanisms will be discussed. Work supported by US DoE.
Role of serotonin in fatty acid-induced non-alcoholic fatty liver disease in mice
Background Saturated fatty acids are thought to be of relevance for the development of non-alcoholic fatty liver disease and obesity. However, the underlying mechanisms are poorly understood. In previous studies we found that food-derived carbohydrates such as fructose alter the intestinal serotonergic system while inducing fatty liver disease in mice. Here, we examined the effect of fatty acid quantity (11% versus 15%) and quality (saturated, monounsaturated, or polyunsaturated fatty acids) on hepatic fat accumulation, intestinal barrier and the intestinal serotonergic system. Methods C57BL/6 mice had free access to diets enriched with one of the three fatty acids or standard diet, for 8�weeks. In an additional experiment mice were fed diets enriched with saturated, monounsaturated fatty acids or standard diet supplemented with tryptophan (0.4�g/(kg.d), 8�weeks) or not. Hepatic fat accumulation, small intestinal barrier impairment and components of the serotonergic system were measured with RT-PCR, western blot or immunoassays. For statistical analysis t-test and one-way ANOVA with Tukey�s post hoc test and Bartlett�s test for equal variances was used. Results Hepatic triglycerides, liver weight and liver to body weight ratio were significantly changed depending on the fat quality but not fat quantity. In contrast, fat quantity but not quality decreased the expression of the tight junction proteins occludin and claudin-1 in the small intestine. These changes seemed to result in enhanced portal vein endotoxin concentrations and fatty liver disease after feeding diet enriched with saturated and monounsaturated fatty acids but not polyunsaturated fatty acids. Neither fatty acid quantity nor quality significantly influenced the intestinal serotonergic system. Similarly, tryptophan supplementation had no impact on small intestinal barrier or fatty liver disease. Conclusion In conclusion, diets rich in saturated or monounsaturated fatty acids promote the development of fatty liver disease in mice, likely by a dysfunction of the small intestinal mucosal barrier. PMID:24321090
Variability in the Generation of Induced Pluripotent Stem Cells: Importance for Disease Modeling
Matigian, Nicholas A.; Ravishankar, Sugandha; Bellette, Bernadette; Wood, Stephen A.; Wolvetang, Ernst J.
In the field of disease modeling, induced pluripotent stem cells (iPSCs) have become an appealing choice, especially for diseases that do not have an animal model. They can be generated from patients with known clinical features and compared with cells from healthy controls to identify the biological bases of disease. This study was undertaken to determine the variability in iPSC lines derived from different individuals, with the aim of determining criteria for selecting iPSC lines for disease models. We generated and characterized 18 iPSC lines from eight donors and considered variability at three levels: (a) variability in the criteria that define iPSC lines as pluripotent cells, (b) variability in cell lines from different donors, and (c) variability in cell lines from the same donor. We found that variability in transgene expression and pluripotency marker levels did not prevent iPSCs from fulfilling all other criteria for pluripotency, including teratoma formation. We found low interindividual and interclonal variability in iPSCs that fulfilled the most stringent criteria for pluripotency, with very high correlation in their gene expression profiles. Interestingly, some cell lines exhibited reprogramming instability, spontaneously regressing from a fully to a partially reprogrammed state. This was associated with a low percentage of cells expressing the pluripotency marker stage-specific embryonic antigen-4. Our study shows that it is possible to define a similar �ground state� for each cell line as the basis for making patient versus control comparisons, an essential step in order to identify disease-associated variability above individual and cell line variability. PMID:23197870
Parasite induced genetically driven autoimmune Chagas heart disease in the chicken model.
Teixeira, Antonio R L; Nitz, Nadjar; Bernal, Francisco M; Hecht, Mariana M
The Trypanosoma cruzi acute infections acquired in infancy and childhood seem asymptomatic, but approximately one third of the chronically infected cases show Chagas disease up to three decades or later. Autoimmunity and parasite persistence are competing theories to explain the pathogenesis of Chagas disease. To separate roles played by parasite persistence and autoimmunity in Chagas disease we inoculate the T. cruzi in the air chamber of fertilized eggs. The mature chicken immune system is a tight biological barrier against T. cruzi and the infection is eradicated upon development of its immune system by the end of the first week of growth. The chicks are parasite-free at hatching, but they retain integrated parasite mitochondrial kinetoplast DNA (kDNA) minicircle within their genome that are transferred to their progeny. Documentation of the kDNA minicircle integration in the chicken genome was obtained by a targeted prime TAIL-PCR, Southern hybridizations, cloning, and sequencing. The kDNA minicircle integrations rupture open reading frames for transcription and immune system factors, phosphatase (GTPase), adenylate cyclase and phosphorylases (PKC, NF-Kappa B activator, PI-3K) associated with cell physiology, growth, and differentiation, and other gene functions. Severe myocarditis due to rejection of target heart fibers by effectors cytotoxic lymphocytes is seen in the kDNA mutated chickens, showing an inflammatory cardiomyopathy similar to that seen in human Chagas disease. Notably, heart failure and skeletal muscle weakness are present in adult chickens with kDNA rupture of the dystrophin gene in chromosome 1. Similar genotipic alterations are associated with tissue destruction carried out by effectors CD45+, CD8??+, CD8? lymphocytes. Thus this protozoan infection can induce genetically driven autoimmune disease. PMID:22951533
Elevated Endothelial Hypoxia-Inducible Factor-1? Contributes to Glomerular Injury and Promotes Hypertensive Chronic Kidney Disease.
Luo, Renna; Zhang, Weiru; Zhao, Cheng; Zhang, Yujin; Wu, Hongyu; Jin, Jianping; Zhang, Wenzheng; Grenz, Almut; Eltzschig, Holger K; Tao, Lijian; Kellems, Rodney E; Xia, Yang
Hypertensive chronic kidney disease is one of the most prevalent medical conditions with high morbidity and mortality in the United States and worldwide. However, early events initiating the progression to hypertensive chronic kidney disease are poorly understood. We hypothesized that elevated endothelial hypoxia-inducible factor-1? (HIF-1?) is a common early insult triggering initial glomerular injury leading to hypertensive chronic kidney disease. To test our hypothesis, we used an angiotensin II infusion model of hypertensive chronic kidney disease to determine the specific cell type and mechanisms responsible for elevation of HIF-1? and its role in the progression of hypertensive chronic kidney disease. Genetic studies coupled with reverse transcription polymerase chain reaction profiling revealed that elevated endothelial HIF-1? is essential to initiate glomerular injury and progression to renal fibrosis by the transcriptional activation of genes encoding multiple vasoactive proteins. Mechanistically, we found that endothelial HIF-1? gene expression was induced by angiotensin II in a nuclear factor-?B-dependent manner. Finally, we discovered reciprocal positive transcriptional regulation of endothelial Hif-1? and Nf-?b genes is a key driving force for their persistent activation and disease progression. Overall, our findings revealed that the stimulation of HIF-1? gene expression in endothelial cells is detrimental to induce kidney injury, hypertension, and disease progression. Our findings highlight early diagnostic opportunities and therapeutic approaches for hypertensive chronic kidney disease. PMID:25987665
Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson's disease patients.
Politis, Marios; Wu, Kit; Loane, Clare; Brooks, David J; Kiferle, Lorenzo; Turkheimer, Federico E; Bain, Peter; Molloy, Sophie; Piccini, Paola
Levodopa-induced dyskinesias (LIDs) are the most common and disabling adverse motor effect of therapy in Parkinson's disease (PD) patients. In this study, we investigated serotonergic mechanisms in LIDs development in PD patients using 11C-DASB PET to evaluate serotonin terminal function and 11C-raclopride PET to evaluate dopamine release. PD patients with LIDs showed relative preservation of serotonergic terminals throughout their disease. Identical levodopa doses induced markedly higher striatal synaptic dopamine concentrations in PD patients with LIDs compared with PD patients with stable responses to levodopa. Oral administration of the serotonin receptor type 1A agonist buspirone prior to levodopa reduced levodopa-evoked striatal synaptic dopamine increases and attenuated LIDs. PD patients with LIDs that exhibited greater decreases in synaptic dopamine after buspirone pretreatment had higher levels of serotonergic terminal functional integrity. Buspirone-associated modulation of dopamine levels was greater in PD patients with mild LIDs compared with those with more severe LIDs. These findings indicate that striatal serotonergic terminals contribute to LIDs pathophysiology via aberrant processing of exogenous levodopa and release of dopamine as false neurotransmitter in the denervated striatum of PD patients with LIDs. Our results also support the development of selective serotonin receptor type 1A agonists for use as antidyskinetic agents in PD. PMID:24531549
Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson�s disease patients
Politis, Marios; Wu, Kit; Loane, Clare; Brooks, David J.; Kiferle, Lorenzo; Turkheimer, Federico E.; Bain, Peter; Molloy, Sophie; Piccini, Paola
Levodopa-induced dyskinesias (LIDs) are the most common and disabling adverse motor effect of therapy in Parkinson�s disease (PD) patients. In this study, we investigated serotonergic mechanisms in LIDs development in PD patients using 11C-DASB PET to evaluate serotonin terminal function and 11C-raclopride PET to evaluate dopamine release. PD patients with LIDs showed relative preservation of serotonergic terminals throughout their disease. Identical levodopa doses induced markedly higher striatal synaptic dopamine concentrations in PD patients with LIDs compared with PD patients with stable responses to levodopa. Oral administration of the serotonin receptor type 1A agonist buspirone prior to levodopa reduced levodopa-evoked striatal synaptic dopamine increases and attenuated LIDs. PD patients with LIDs that exhibited greater decreases in synaptic dopamine after buspirone pretreatment had higher levels of serotonergic terminal functional integrity. Buspirone-associated modulation of dopamine levels was greater in PD patients with mild LIDs compared with those with more severe LIDs. These findings indicate that striatal serotonergic terminals contribute to LIDs pathophysiology via aberrant processing of exogenous levodopa and release of dopamine as false neurotransmitter in the denervated striatum of PD patients with LIDs. Our results also support the development of selective serotonin receptor type 1A agonists for use as antidyskinetic agents in PD. PMID:24531549
Protective Effects of Curcumin Against Rotenone and Salsolinol Induced Toxicity: Implications for Parkinson�s Disease
Qualls, Zakiya; Brown, Dwayne; Ramlochansingh, Carlana; Hurley, Laura L.; Tizabi, Yousef
Parkinson�s disease (PD) is a debilitating neurodegenerative disorder that results from the loss of or damage to dopaminergic cells in the substantia nigra. Exposure to either the pesticide rotenone or the endogenous neurotoxin salsolinol has been shown to mimic this dopaminergic cell loss. In this study we first sought to determine whether combination of rotenone and salsolinol would result in an additive or synergistic toxicity. For this purpose we utilized SH-SY5Y cells, a human neuroblastoma cell line that is commonly used to model dopaminergic neurodegeneration. We then tested whether curcumin, a natural plant compound with known health benefits including potential neuroprotective properties, could also protect against rotenone and/or salsolinol induced toxicity. Moreover, since apoptotic mechanism has been implicated in toxicity of these compounds the anti-apoptotic effect of curcumin was also evaluated. Our results indicate a synergistic toxicity of low concentrations of rotenone (1 and 5 uM) and salsolinol (25 and 50 mM) that was associated with apoptosis as determined by cell flow cytometry. There was also an increase in caspase-3 levels. Pretreatment with curcumin (1-10 uM) dose-dependently attenuated rotenone and/or salsolinol induced toxicity and the associated apoptosis. These results suggest that exposure to a combination of rotenone and salsolinol may contribute to the pathology of PD, and that curcumin has a therapeutic potential in this disease. PMID:24122264
Reactivity against microsatellite instability-induced frameshift mutations in patients with inflammatory bowel disease
Kuehn, Florian; Klar, Ernst; Bliemeister, Anja; Linnebacher, Michael
AIM: To analyze the cellular immune response towards microsatellite-instability (MSI)-induced frameshift-peptides (FSPs) in patients suffering from inflammatory bowel disease (IBD) with and without thiopurine-based immunosuppressive treatment. METHODS: Frequencies of peripheral blood T cell responses of IBD patients (n = 75) against FSPs derived from 14 microsatellite-containing candidate genes were quantified by interferon-? enzyme-linked immunospot. T cells derived from 20 healthy individuals served as controls. RESULTS: Significant T cell reactivities against MSI-induced FSPs were observed in 59 of 75 IBD patients (78.7%). This was significantly more as we could observe in 20 healthy controls (P = 0.001). Overall, the reactivity was significantly influenced by thiopurine treatment (P = 0.032) and duration of disease (P = 0.002) but not by duration or cumulative amount of thiopurine therapy (P = 0.476). Unexpected, 15 of 24 (62.5%) IBD patients without prior thiopurine treatment also showed increased FSP-specific immune responses (P = 0.001). CONCLUSION: These findings propose FSPs as potential novel class of inflammation-associated antigens and this in turn may have implications for screening, diagnosis as well as clinical management of patients suffering from IBD and other inflammatory conditions. PMID:25574094
Chimeric GII.4 Norovirus Virus-Like-Particle-Based Vaccines Induce Broadly Blocking Immune Responses
Debbink, Kari; Lindesmith, Lisa C.; Donaldson, Eric F.; Swanstrom, Jesica
ABSTRACT There is currently no licensed vaccine for noroviruses, and development is hindered, in part, by an incomplete understanding of the host adaptive immune response to these highly heterogeneous viruses and rapid GII.4 norovirus molecular evolution. Emergence of a new predominant GII.4 norovirus strain occurs every 2 to 4 years. To address the problem of GII.4 antigenic variation, we tested the hypothesis that chimeric virus-like particle (VLP)-based vaccine platforms, which incorporate antigenic determinants from multiple strains into a single genetic background, will elicit a broader immune response against contemporary and emergent strains. Here, we compare the immune response generated by chimeric VLPs to that of parental strains and a multivalent VLP cocktail. Results demonstrate that chimeric VLPs induce a more broadly cross-blocking immune response than single parental VLPs and a similar response to a multivalent GII.4 VLP cocktail. Furthermore, we show that incorporating epitope site A alone from one strain into the background of another is sufficient to induce a blockade response against the strain donating epitope site A. This suggests a mechanism by which population-wide surveillance of mutations in a single epitope could be used to evaluate antigenic changes in order to identify potential emergent strains and quickly reformulate vaccines against future epidemic strains as they emerge in human populations. IMPORTANCE Noroviruses are gastrointestinal pathogens that infect an estimated 21 million people per year in the United States alone. GII.4 noroviruses account for >70% of all outbreaks, making them the most clinically important genotype. GII.4 noroviruses undergo a pattern of epochal evolution, resulting in the emergence of new strains with altered antigenicity over time, complicating vaccine design. This work is relevant to norovirus vaccine design as it demonstrates the potential for development of a chimeric VLP-based vaccine platform that may broaden the protective response against multiple GII.4 strains and proposes a potential reformulation strategy to control newly emergent strains in the human population. PMID:24741081
Neural correlates of STN DBS-induced cognitive variability in Parkinson disease
Campbell, M.C.; Karimi, M.; Weaver, P.M.; Wu, J.; Perantie, D.C.; Golchin, N.A.; Tabbal, S.D.; Perlmutter, J. S.; Hershey, T.
Background Although deep brain stimulation of the subthalamic nucleus (STN DBS) in Parkinson disease (PD) improves motor function, it has variable effects on working memory (WM) and response inhibition (RI) performance. The purpose of this study was to determine the neural correlates of STN DBS-induced variability in cognitive performance. Methods We measured bilateral STN DBS-induced blood flow changes (PET and [15O]-water on one day) in the supplementary motor area (SMA), dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), and right inferior frontal cortex (rIFC) as well as in exploratory ROIs defined by published meta-analyses. STN DBS-induced WM and RI changes (Spatial Delayed Response and Go-No-Go on the next day) were measured in 24 PD participants. On both days, participants withheld PD medications overnight and conditions (OFF v. ON) were administered in a counterbalanced, double-blind manner. Results As predicted, STN DBS-induced DLPFC blood flow change correlated with change in WM, but not RI performance. Furthermore, ACC blood flow change correlated with change in RI but not WM performance. For both relationships, increased blood flow related to decreased cognitive performance in response to STN DBS. Of the exploratory regions, only blood flow changes in DLPFC and ACC were correlated with performance. Conclusions These results demonstrate that variability in the effects of STN DBS on cognitive performance relates to STN DBS-induced cortical blood flow changes in DLPFC and ACC. This relationship highlights the need to further understand the factors that mediate the variability in neural and cognitive response to STN DBS. PMID:18682259
Hyperosmolar Stress Induces Neutrophil Extracellular Trap Formation: Implications for Dry Eye Disease
Tibrewal, Sapna; Ivanir, Yair; Sarkar, Joy; Nayeb-Hashemi, Neema; Bouchard, Charles S.; Kim, Eunjae; Jain, Sandeep
Purpose. To determine if hyperosmolar stress can stimulate human neutrophils to form neutrophil extracellular traps (NETs) and to investigate potential strategies to reduce formation of NETs (NETosis) in a hyperosmolar environment. Methods. Neutrophils were isolated from peripheral venous blood of healthy subjects and incubated in iso-osmolar (280 mOsM) or hyperosmolar (420 mOsM) media for 4 hours. Neutrophil extracellular traps were quantified using a PicoGreen dye assay to measure extracellular DNA. Two known inhibitors of NETosis, staurosporine and anti-?2 integrin blocking antibody, and two proresolution formyl peptide receptor 2 (FPR2) agonists, annexin/lipocortin-1 mimetic peptide and 15-epi-lipoxin A4, were evaluated as possible strategies to reduce hyperosmolarity-induced NETosis. Results. The amount of NETs induced by hyperosmolar medium (420 mOsM) increased linearly over time to 3.2 � 0.3 times that induced by iso-osmolar medium at 4 hours (P < 0.05). NETosis increased exponentially with increasing osmolarity and was independent of the stimulus used to increase osmolarity. Upon neutrophil exposure to hyperosmolar stress, restoration of iso-osmolar conditions decreased NET formation by 52.7% � 5% (P < 0.05) but did not completely abrogate it. Among the strategies tested to reduce NETosis in a hyperosmolar environment, annexin-1 peptide was the most efficacious. Conclusions. Hyperosmolarity induces formation of NETs by neutrophils. This NETosis mechanism may explain the presence of excessive NETs on the ocular surface of patients with dry eye disease. Because they reduce hyperosmolarity-induced NETosis, FPR2 agonists may have therapeutic potential in these patients. PMID:25406284
RANKL Inhibitors Induce Osteonecrosis of the Jaw in Mice With Periapical Disease
Aghaloo, Tara L; Cheong, Simon; Bezouglaia, Olga; Kostenuik, Paul; Atti, Elisa; Dry, Sarah M; Pirih, Flavia Q; Tetradis, Sotirios
Antiresorptive medications are essential in treating diseases of pathologic osteoclastic bone resorption, including bone cancer and osteoporosis. Bisphosphonates (BPs) are the most commonly used antiresorptives in clinical practice. Although inhibition of bone resorption is important in regulating unwanted malignant and metabolic osteolysis, BP treatment is associated with potential side effects, including osteonecrosis of the jaws (ONJ). Recently, non-BP antiresorptive medications targeting osteoclastic function and differentiation, such as denosumab, have entered the clinical arena. Denosumab treatment results in a similar rate of ONJ as BPs. Animal models of ONJ, using high-dose BP treatment in combination with tooth extraction or dental disease, provide valuable tools and insight in exploring ONJ pathophysiology. However, the ability of other antiresorptives to induce ONJ-like lesions in animal models has not been explored. Such studies would be beneficial in providing support for the role of osteoclast inhibition in ONJ pathogenesis versus a direct BP effect on oral tissues. Here, we tested the ability of the receptor activator of NF-kB ligand (RANKL) inhibitors RANK-Fc (composed of the extracellular domain of RANK fused to the fragment crystallizable [Fc] portion of immunoglobulin G [IgG]) and OPG-Fc (composed of the RANKL-binding domains of osteoprotegerin [OPG] linked to the Fc portion of IgG) to induce ONJ in mice in the presence of periapical disease, but in the absence of dental extractions. We demonstrate radiographic evidence of ONJ in RANK-Fc�treated and OPG-Fc�treated mice, including inhibition of bone loss, increased bone density, lamina dura thickening, and periosteal bone deposition. These findings closely resembled the radiographic appearance of an ONJ patient on denosumab treatment. Histologic examination revealed that RANK-Fc treatment and OPG-Fc treatment resulted in absence of osteoclasts, periosteal bone formation, empty osteocytic lacunae, osteonecrosis, and bone exposure. In conclusion, we have successfully induced ONJ in mice with periapical disease, using potent osteoclast inhibitors other than BPs. Our findings, coupled with ONJ animal models using high-dose BPs, suggest that osteoclast inhibition is pivotal to the pathogenesis of ONJ. PMID:24115073
A TNFSF15 disease-risk polymorphism increases pattern-recognition receptor-induced signaling through caspase-8�induced IL-1
Hedl, Matija; Abraham, Clara
Inflammatory diseases are characterized by dysregulated cytokine production. Altered functions for most risk loci, including the inflammatory bowel disease and leprosy-associated tumor necrosis factor ligand superfamily member 15 (TNFSF15) region, are unclear. Regulation of pattern-recognition-receptor (PRR)-induced signaling and cytokines is crucial for immune homeostasis; TNFSF15:death receptor 3 (DR3) contributions to PRR responses have not been described. We found that human macrophages expressed DR3 and that TNFSF15:DR3 interactions were critical for amplifying PRR-initiated MAPK/NF-?B/PI3K signaling and cytokine secretion in macrophages. Mechanisms mediating TNFSF15:DR3 contributions to PRR outcomes included TACE-induced TNFSF15 cleavage to soluble TNFSF15; soluble TNFSF15 then led to TRADD/FADD/MALT-1� and caspase-8�mediated autocrine IL-1 secretion. Notably, TNFSF15 treatment also induced cytokine secretion through a caspase-8�dependent pathway in intestinal myeloid cells. Importantly, rs6478108 A disease risk-carrier macrophages demonstrated increased TNFSF15 expression and PRR-induced signaling and cytokines. Taken together, TNFSF15:DR3 interactions amplify PRR-induced signaling and cytokines, and the rs6478108 TNFSF15 disease-risk polymorphism results in a gain of function. PMID:25197060
Induced pluripotent stem cell model recapitulates pathologic hallmarks of Gaucher disease
Panicker, Leelamma M.; Miller, Diana; Park, Tea Soon; Patel, Brijesh; Azevedo, Judi L.; Awad, Ola; Masood, M. Athar; Veenstra, Timothy D.; Goldin, Ehud; Stubblefield, Barbara K.; Tayebi, Nahid; Polumuri, Swamy K.; Vogel, Stefanie N.; Sidransky, Ellen; Zambidis, Elias T.; Feldman, Ricardo A.
Gaucher disease (GD) is an autosomal recessive disorder caused by mutations in the acid ?-glucocerebrosidase gene. To model GD, we generated human induced pluripotent stem cells (hiPSC), by reprogramming skin fibroblasts from patients with type 1 (N370S/N370S), type 2 (L444P/RecNciI), and type 3 (L444P/L444P) GD. Pluripotency was demonstrated by the ability of GD hiPSC to differentiate to all three germ layers and to form teratomas in vivo. GD hiPSC differentiated efficiently to the cell types most affected in GD, i.e., macrophages and neuronal cells. GD hiPSC-macrophages expressed macrophage-specific markers, were phagocytic, and were capable of releasing inflammatory mediators in response to LPS. Moreover, GD hiPSC-macrophages recapitulated the phenotypic hallmarks of the disease. They exhibited low glucocerebrosidase (GC) enzymatic activity and accumulated sphingolipids, and their lysosomal functions were severely compromised. GD hiPSC-macrophages had a defect in their ability to clear phagocytosed RBC, a phenotype of tissue-infiltrating GD macrophages. The kinetics of RBC clearance by types 1, 2, and 3 GD hiPSC-macrophages correlated with the severity of the mutations. Incubation with recombinant GC completely reversed the delay in RBC clearance from all three types of GD hiPSC-macrophages, indicating that their functional defects were indeed caused by GC deficiency. However, treatment of induced macrophages with the chaperone isofagomine restored phagocytosed RBC clearance only partially, regardless of genotype. These findings are consistent with the known clinical efficacies of recombinant GC and isofagomine. We conclude that cell types derived from GD hiPSC can effectively recapitulate pathologic hallmarks of the disease. PMID:23071332
Emission-particle-induced ventilatory abnormalities in a rat model of pulmonary hypertension.
Gardner, Sarah Y; McGee, John K; Kodavanti, Urmila P; Ledbetter, Allen; Everitt, Jeffrey I; Winsett, Darrell W; Doerfler, Donald L; Costa, Daniel L
Preexistent cardiopulmonary disease in humans appears to enhance susceptibility to the adverse effects of ambient particulate matter. Previous studies in this laboratory have demonstrated enhanced inflammation and mortality after intratracheal instillation (IT) and inhalation (INH) of residual oil fly ash (ROFA) in a rat model of pulmonary hypertension induced by monocrotaline (MCT). The present study was conducted to examine the effects of ROFA in this model on ventilatory function in unanesthetized, unrestrained animals. Sixty-day-old male CD rats were injected with MCT (60 mg/kg) or vehicle (VEH) intraperitoneally 10 days before IT of ROFA (8.3 mg/kg) or saline (SAL) (control) or nose-only INH of ROFA [15 mg/m3 for 6 hr on 3 consecutive days or air (control)]. At 24 and 72 hr after exposure, rats were studied individually in a simultaneous gas uptake/whole-body plethysmograph. Lungs were removed at 72 hr for histology. Pulmonary test results showed that tidal volume (VT) decreased 24 hr after IT of ROFA in MCT-treated rats. Breathing frequency, minute volume (VE), and the ventilatory equivalent for oxygen increased in MCT- and VEH-treated rats 24 hr after IT or INH of ROFA and remained elevated 72 hr post-IT. O2 uptake (VO2) decreased after IT of ROFA in MCT-treated rats. Carbon monoxide uptake decreased 24 hr after IT of ROFA, returning to control values in VEH-treated rats but remaining low in MCT-treated rats 72 hr post-IT. ROFA exposure induced histologic changes and abnormalities in several ventilatory parameters, many of which were enhanced by MCT treatment. PMID:15175175
Induced pluripotent stem cells: applications in regenerative medicine, disease modeling, and drug discovery.
Singh, Vimal K; Kalsan, Manisha; Kumar, Neeraj; Saini, Abhishek; Chandra, Ramesh
Recent progresses in the field of Induced Pluripotent Stem Cells (iPSCs) have opened up many gateways for the research in therapeutics. iPSCs are the cells which are reprogrammed from somatic cells using different transcription factors. iPSCs possess unique properties of self renewal and differentiation to many types of cell lineage. Hence could replace the use of embryonic stem cells (ESC), and may overcome the various ethical issues regarding the use of embryos in research and clinics. Overwhelming responses prompted worldwide by a large number of researchers about the use of iPSCs evoked a large number of peple to establish more authentic methods for iPSC generation. This would require understanding the underlying mechanism in a detailed manner. There have been a large number of reports showing potential role of different molecules as putative regulators of iPSC generating methods. The molecular mechanisms that play role in reprogramming to generate iPSCs from different types of somatic cell sources involves a plethora of molecules including miRNAs, DNA modifying agents (viz. DNA methyl transferases), NANOG, etc. While promising a number of important roles in various clinical/research studies, iPSCs could also be of great use in studying molecular mechanism of many diseases. There are various diseases that have been modeled by uing iPSCs for better understanding of their etiology which maybe further utilized for developing putative treatments for these diseases. In addition, iPSCs are used for the production of patient-specific cells which can be transplanted to the site of injury or the site of tissue degeneration due to various disease conditions. The use of iPSCs may eliminate the chances of immune rejection as patient specific cells may be used for transplantation in various engraftment processes. Moreover, iPSC technology has been employed in various diseases for disease modeling and gene therapy. The technique offers benefits over other similar techniques such as animal models. Many toxic compounds (different chemical compounds, pharmaceutical drugs, other hazardous chemicals, or environmental conditions) which are encountered by humans and newly designed drugs may be evaluated for toxicity and effects by using iPSCs. Thus, the applications of iPSCs in regenerative medicine, disease modeling, and drug discovery are enormous and should be explored in a more comprehensive manner. PMID:25699255
Statin-Induced Increase in HDL-C and Renal Function in Coronary Heart Disease Patients�
Athyros, Vasilios G; Kakafika, Anna I; Papageorgiou, Athanasios A; Pagourelias, Efstathios D; Savvatianos, Savvas D; Elisaf, Moses; Karagiannis, Asterios; Tziomalos, Konstantinos; Mikhailidis, Dimitri P
Background Little is known about the potential of statin-induced high-density lipoprotein cholesterol (HDL-C) increase to improve renal function in coronary heart disease (CHD) patients. Methods and Results In thispost hocanalysis of the GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) Study we investigated the effect of HDL-C increase after statin treatment on renal function. From a total of 1,600 patients, 880 were on various statins (mainly atorvastatin) and 720 were not. Other secondary prevention therapies were similar in the 2 groups. After a 3 year follow up, the lipid profile was unchanged in the statin untreated group and estimated glomerular filtration rate (eGFR) was reduced by 5.1% compared with baseline (P<0.0001). In contrast, in the statin treated group non-HDL-C was reduced by 43%, HDL-C was increased by 7% and there was a significant increase in eGFR compared with baseline by 9.8% (P<0.0001). In multiple regression analysis, the mean 7% increase in HDL-C in the treated arm during the entire study was associated with a 5.6% increase in eGFR recorded after the 6th week of treatment. The odds ratio of eGFR increase with every 5% statin-induced rise in HDL-C was 1.78 (95% confidence interval 1.19-3.34; P=0.001). Conclusions Statin treatment significantly improved renal function. Statin-induced HDL-C increase significantly and independently contributed to this improvement. This finding supports the concept that improving lipid variables other than low density lipoprotein cholesterol is also beneficial to preserving renal function. PMID:18949085
Components of Streptococcus pneumoniae suppress allergic airways disease and NKT cells by inducing regulatory T cells.
Thorburn, Alison N; Foster, Paul S; Gibson, Peter G; Hansbro, Philip M
Asthma is an allergic airways disease (AAD) caused by dysregulated immune responses and characterized by eosinophilic inflammation, mucus hypersecretion, and airway hyperresponsiveness (AHR). NKT cells have been shown to contribute to AHR in some mouse models. Conversely, regulatory T cells (Tregs) control aberrant immune responses and maintain homeostasis. Recent evidence suggests that Streptococcus pneumoniae induces Tregs that have potential to be harnessed therapeutically for asthma. In this study, mouse models of AAD were used to identify the S. pneumoniae components that have suppressive properties, and the mechanisms underlying suppression were investigated. We tested the suppressive capacity of type-3-polysaccharide (T3P), isolated cell walls, pneumolysoid (Ply) and CpG. When coadministered, T3P + Ply suppressed the development of: eosinophilic inflammation, Th2 cytokine release, mucus hypersecretion, and AHR. Importantly, T3P + Ply also attenuated features of AAD when administered during established disease. We show that NKT cells contributed to the development of AAD and also were suppressed by T3P + Ply treatment. Furthermore, adoptive transfer of NKT cells induced AHR, which also could be reversed by T3P + Ply. T3P + Ply-induced Tregs were essential for the suppression of NKT cells and AAD, which was demonstrated by Treg depletion. Collectively, our results show that the S. pneumoniae components T3P + Ply suppress AAD through the induction of Tregs that blocked the activity of NKT cells. These data suggest that S. pneumoniae components may have potential as a therapeutic strategy for the suppression of allergic asthma through the induction of Tregs and suppression of NKT cells. PMID:22461699
Results and perspectives of the investigation of traditional and thermal stress induced thermophoresis of particles in gas in microgravity
NASA Astrophysics Data System (ADS)
Vedernikov, Andrei; Balapanov, Daniyar; Beresnev, Sergey; Queeckers, Patrick
Thermophoretic motion of particles suspended in a gas has been a subject of extensive theoretical and experimental investigations for many years because of its wide spread in nature, significance for fundamental and applied aerosol physic. Negative thermophoresis, i.e. solid particle motion towards hotter region in a gas and not as usually from hotter region, was predicted more than 40 years ago and remains an unsolved problem for a choice between different models treating main driving mechanisms -- thermal slip and thermal stress induced gas motion. For a problem of negative thermophoresis, we present experimental evidences in favor of the latter mechanism based on direct observation of particle motion at microgravity; Knudsen particle number 2\\cdot 10(-3) (Kn being the ratio of the molecular mean free path to the particle size); particle-to-gas heat conductivity ratios 2\\cdot 10(4) for copper solid particles and 1.8 for glass bubbles. For both types of particles the experimental results fit well the gas kinetic model of Beresnev and Chernyak [1]. We present characteristics of a set-up and procedures that are able to provide sufficient accuracy and volume of experimental data for testing any model of particle thermophoresis. High quality microgravity is a necessity for such investigations. The short duration microgravity of drop towers suits well this requirement. The sign and value of the thermophoretic force strongly depends on the Knudsen number, particle-to-gas heat conductivity ratio and accommodation coefficients, all of which vary within several decimal orders of magnitude. In order to make crucial conclusions on the choice of the adequate model, there should be hundreds of short duration microgravity experiments. The European Space Agency scientific project Interaction in Cosmic and Atmospheric Particle Systems (ICAPS) [2] planned for the International Space Station, provides complementary opportunities for the investigation of thermophoresis at large and very large Knudsen numbers for single particles and large clusters of particles under wide range of experimental parameters, i.e. different particle sizes, shapes, materials; different properties of gases; several types of additional forces and their time-space variation. ESA PRODEX Program, Belgian Federal Science Policy Office and Bremen Drop Tower Operation and Service Company ZARM FABmbH (Germany) are greatly acknowledged for their support. [1] Beresnev S., Chernyak V. Thermophoresis of a spherical particle in a rarefied gas: Numerical analysis based on the model kinetic equations // Phys. Fluids. 1995. V.7. P.1743. [2] Blum, J. et al. "Dust in Space", Europhysicsnews, Vol. 39, pp. 27-29, 2008.
Induced pluripotent stem cell-derived cardiomyocytes for cardiovascular disease modeling and drug screening
Human induced pluripotent stem cells (hiPSCs) have emerged as a novel tool for drug discovery and therapy in cardiovascular medicine. hiPSCs are functionally similar to human embryonic stem cells (hESCs) and can be derived autologously without the ethical challenges associated with hESCs. Given the limited regenerative capacity of the human heart following myocardial injury, cardiomyocytes derived from hiPSCs (hiPSC-CMs) have garnered significant attention from basic and translational scientists as a promising cell source for replacement therapy. However, ongoing issues such as cell immaturity, scale of production, inter-line variability, and cell purity will need to be resolved before human clinical trials can begin. Meanwhile, the use of hiPSCs to explore cellular mechanisms of cardiovascular diseases in vitro has proven to be extremely valuable. For example, hiPSC-CMs have been shown to recapitulate disease phenotypes from patients with monogenic cardiovascular disorders. Furthermore, patient-derived hiPSC-CMs are now providing new insights regarding drug efficacy and toxicity. This review will highlight recent advances in utilizing hiPSC-CMs for cardiac disease modeling in vitro and as a platform for drug validation. The advantages and disadvantages of using hiPSC-CMs for drug screening purposes will be explored as well. PMID:24476344
Ameliorating Adriamycin-Induced Chronic Kidney Disease in Rats by Orally Administrated Cardiotoxin from Naja naja atra Venom
Ding, Zhi-Hui; Xu, Li-Min; Wang, Shu-Zhi; Kou, Jian-Qun; Xu, Yin-Li; Chen, Cao-Xin; Yu, Hong-Pei; Qin, Zheng-Hong; Xie, Yan
Previous studies reported the oral administration of Naja naja atra venom (NNAV) reduced adriamycin-induced chronic kidney damage. This study investigated the effects of intragastric administrated cardiotoxin from Naja naja atra venom on chronic kidney disease in rats. Wistar rats were injected with adriamycin (ADR; 6?mg/kg body weight) via the tail vein to induce chronic kidney disease. The cardiotoxin was administrated daily by intragastric injection at doses of 45, 90, and 180??g/kg body weight until the end of the protocol. The rats were placed in metabolic cages for 24 hours to collect urine, for determination of proteinuria, once a week. After 6 weeks, the rats were sacrificed to determine serum profiles relevant to chronic kidney disease, including albumin, total cholesterol, phosphorus, blood urea nitrogen, and serum creatinine. Kidney histology was examined with hematoxylin and eosin, periodic acid-Schiff, and Masson's trichrome staining. The levels of kidney podocin were analyzed by Western blot analysis and immunofluorescence. We found that cardiotoxin reduced proteinuria and can improve biological parameters in the adriamycin-induced kidney disease model. Cardiotoxin also reduced adriamycin-induced kidney pathology, suggesting that cardiotoxin is an active component of NNAV for ameliorating adriamycin-induced kidney damage and may have a potential therapeutic value on chronic kidney disease. PMID:24876873
Signal-sequence induced conformational changes in the signal recognition particle.
Hainzl, Tobias; Sauer-Eriksson, A Elisabeth
Co-translational protein targeting is an essential, evolutionarily conserved pathway for delivering nascent proteins to the proper cellular membrane. In this pathway, the signal recognition particle (SRP) first recognizes the N-terminal signal sequence of nascent proteins and subsequently interacts with the SRP receptor. For this, signal sequence binding in the SRP54 M domain must be effectively communicated to the SRP54 NG domain that interacts with the receptor. Here we present the 2.9?� crystal structure of unbound- and signal sequence bound SRP forms, both present in the asymmetric unit. The structures provide evidence for a coupled binding and folding mechanism in which signal sequence binding induces the concerted folding of the GM linker helix, the finger loop, and the C-terminal alpha helix ?M6. This mechanism allows for a high degree of structural adaptability of the binding site and suggests how signal sequence binding in the M domain is coupled to repositioning of the NG domain. PMID:26051119
Strain-induced transformation of amorphous spherical precipitates into platelets: Application to oxide particles in silicon
Voronkov, V. V.; Falster, R.
The spherical shape of an amorphous precipitate becomes unstable if the combination P{sup 2}R of precipitate radius R and pressure P exceeds some critical value. This critical value was found to be about 4.44 G{sigma}, where G is the matrix shear modulus and {sigma} is the specific energy of the precipitate/matrix interface. Once this instability criterion is fulfilled, the initially spherical particle will reduce the total free energy (the sum of strain energy and the surface energy) by becoming a thin oblate spheroid (effectively, a platelet). The actual pressure P in the course of oxygen precipitation in silicon is controlled by a high self-interstitial supersaturation caused by emission of self-interstitials by growing precipitates. The duration of annealing necessary to reach the stage of collapse of spheres into platelets is calculated as a function of temperature and the precipitate density. Calculated results are compatible with the experimentally observed annealing conditions for platelet formation. Another important example of sphere to platelet transformation is microdefect formation in vacancy-type silicon. In this case a large negative value of P is sufficient to induce collapse. {copyright} 2001 American Institute of Physics.
Particle-Induced X-Ray Emission (PIXE) Of Silicate Coatings On High Impact Resistance Polycarbonates
NASA Astrophysics Data System (ADS)
Xing, Qian; Hart, M. A.; Culbertson, R. J.; Bradley, J. D.; Herbots, N.; Wilkens, Barry J.; Sell, David A.; Watson, Clarizza Fiel
Particle-Induced X-ray Emission (PIXE) analysis was employed to characterize hydroxypropyl methylcellulose (HPMC) C32H60O19 polymer film via areal density measurement on silicon-based substrates utilizing the differential PIXE concept, and compared with Rutherford backscattering spectrometry (RBS) results. It is demonstrated in this paper that PIXE and RBS measurements both yield comparable results for areal densities ranging from 1018 atom/cm2 to several 1019 atom/cm2. A collection of techniques including PIXE, RBS, tapping mode atomic force microscopy (TMAFM), and contact angle analysis were used to compute surface free energy, analyze surface topography and roughness parameters, determine surface composition and areal density, and to predict the water affinity and condensation behaviors of silicates and other compounds used for high impact resistance vision ware coatings. The visor surface under study is slightly hydrophilic, with root mean square of surface roughness on the order of one nm, and surface wavelength between 200 nm and 300 nm. Water condensation can be controlled on such surfaces via polymers adsorption. HPMC polymer areal density measurement supports the analysis of the surface water affinity and topography and the subsequent control of condensation behavior. HPMC film between 1018 atom/cm2 and 1019 atom/cm2 was found to effectively alter the water condensation pattern and prevents fogging by forming a wetting layer during condensation.
Signal-sequence induced conformational changes in the signal recognition particle
Hainzl, Tobias; Sauer-Eriksson, A. Elisabeth
Co-translational protein targeting is an essential, evolutionarily conserved pathway for delivering nascent proteins to the proper cellular membrane. In this pathway, the signal recognition particle (SRP) first recognizes the N-terminal signal sequence of nascent proteins and subsequently interacts with the SRP receptor. For this, signal sequence binding in the SRP54 M domain must be effectively communicated to the SRP54 NG domain that interacts with the receptor. Here we present the 2.9?� crystal structure of unbound- and signal sequence bound SRP forms, both present in the asymmetric unit. The structures provide evidence for a coupled binding and folding mechanism in which signal sequence binding induces the concerted folding of the GM linker helix, the finger loop, and the C-terminal alpha helix ?M6. This mechanism allows for a high degree of structural adaptability of the binding site and suggests how signal sequence binding in the M domain is coupled to repositioning of the NG domain. PMID:26051119
Development of imatinibmesylate-induced interstitial lung disease 2?weeks after discontinuation of the treatment: a case report
Background Imatinibmesylate (imatinib) is a small molecule tyrosine kinase inhibitor administered to patients with chronic myelogenous leukemia and gastrointestinal stromal tumor. Although imatinib-associated interstitial lung disease is uncommon, a few cases have been reported so far. However, in all these cases interstitial lung disease developed during the use of imatinib. The present case is the first report of imatinib-induced interstitial lung disease developing after discontinuation of the drug. Case presentation A 51-year-old woman was administered oral imatinib for gastrointestinal stromal tumor. Ten weeks later, imatinib was discontinued because of facial edema. On this occasion, chest radiography showed no abnormal findings. However, 2?weeks after discontinuation of imatinib, she developed fever, dry cough, and dyspnea. Chest radiography and computed tomography showed diffuse interstitial infiltrates in both lungs. Examination of bronchoalveolar lavage fluid showed an increased proportion of lymphocytes. Imatinib-induced interstitial lung disease was suspected, because no other cause was evident. After administration of corticosteroids, her clinical condition and chest radiographic findings improved. Conclusion We report a unique case of imatinib-induced interstitial lung disease that developed 2?weeks after discontinuation of the drug. Physicians should consider occurrence of imatinib-induced interstitial lung disease even after discontinuation of the drug. PMID:23174134
Ameliorative effect of chrysin on adenine-induced chronic kidney disease in rats.
Ali, Badreldin H; Adham, Sirin A; Al Za'abi, Mohammed; Waly, Mostafa I; Yasin, Javed; Nemmar, Abderrahim; Schupp, Nicole
Chrysin (5, 7- dihydroxyflavone) is a flavonoid with several pharmacological properties that include antioxidant, anti-inflammatory and antiapoptotic activities. in this work, we investigated some effects of three graded oral doses of chrysin (10, 50 and 250 mg/kg) on kidney structure and function in rats with experimental chronic renal disease (CKD) induced by adenine (0.25% w/w in feed for 35 days), which is known to involve inflammation and oxidative stress. Using several indices in plasma, urine and kidney homogenates, adenine was found to impair kidney function as it lowered creatinine clearance and increased plasma concentrations of creatinine, urea, neutrophil gelatinase-associated lipocalin and N-Acetyl-beta-D-glucosaminidase activity. Furthermore, it raised plasma concentrations of the uremic toxin indoxyl sulfate, some inflammatory cytokines and urinary albumin concentration. Renal morphology was severely damaged and histopathological markers of inflammation and fibrosis were especially increased. In renal homogenates, antioxidant indices, including superoxide dismutase and catalase activities, total antioxidant capacity and reduced glutathione were all adversely affected. Most of these adenine - induced actions were moderately and dose -dependently mitigated by chrysin, especially at the highest dose. Chrysin did not cause any overt adverse effect on the treated rats. The results suggest that different doses of chrysin produce variable salutary effects against adenine-induced CKD in rats, and that, pending further pharmacological and toxicological studies, its usability as a possible ameliorative agent in human CKD should be considered. PMID:25909514
Generation and large-scale expansion of human inducible regulatory T cells that suppress graft-versus-host disease.
Hippen, K L; Merkel, S C; Schirm, D K; Nelson, C; Tennis, N C; Riley, J L; June, C H; Miller, J S; Wagner, J E; Blazar, B R
Adoptive transfer of thymus-derived natural regulatory T cells (nTregs) effectively suppresses disease in murine models of autoimmunity and graft-versus-host disease (GVHD). TGF� induces Foxp3 expression and suppressive function in stimulated murine CD4+25- T cells, and these induced Treg (iTregs), like nTreg, suppress auto- and allo-reactivity in vivo. However, while TGF� induces Foxp3 expression in stimulated human T cells, the expanded cells lack suppressor cell function. Here we show that Rapamycin (Rapa) enhances TGF�-dependent Foxp3 expression and induces a potent suppressor function in naive (CD4+ 25-45RA+) T cells. Rapa/TGF� iTregs are anergic, express CD25 at levels higher than expanded nTregs and few cells secrete IL-2, IFN? or IL-17 even after PMA and Ionomycin stimulation in vitro. Unlike other published methods of inducing Treg function, Rapa/TGF� induces suppressive function even in the presence of memory CD4+ T cells. A single apheresis unit of blood yields an average ~240 � 10? (range ~ 70-560 � 10?) iTregs from CD4+25- T cells in ? 2 weeks of culture. Most importantly, Rapa/TGF� iTregs suppress disease in a xenogeneic model of GVHD. This study opens the door for iTreg cellular therapy for human diseases. PMID:21564534
Generation and large-scale expansion of human inducible regulatory T cells that suppress graft-versus-host disease
Hippen, K.L.; Merkel, S.C.; Schirm, D.K.; Nelson, C.; Tennis, N.C.; Riley, J.L.; June, C.H.; Miller, J.S.; Wagner, J.E.; Blazar, B.R.
Adoptive transfer of thymus-derived natural regulatory T-cells (nTregs) effectively suppresses disease in murine models of autoimmunity and graft-versus-host disease (GVHD). TGF? induces Foxp3 expression and suppressive function in stimulated murine CD4+25- T cells, and these induced Treg (iTregs), like nTreg, suppress auto- and allo-reactivity in vivo. However, while TGF? induces Foxp3 expression in stimulated human T-cells, the expanded cells lack suppressor cell function. Here we show that Rapamycin (Rapa) enhances TGF?-dependent Foxp3 expression and induces a potent suppressor function in na�ve (CD4+25-45RA+) T cells. Rapa/TGF? iTregs are anergic, express CD25 at levels higher than expanded nTregs, and few cells secrete IL-2, IFN? or IL-17 even after PMA and Ionomycin stimulation in vitro. Unlike other published methods of inducing Treg function, Rapa/TGF? induces suppressive function even in the presence of memory CD4+ T-cells. A single apheresis unit of blood yields an average ~240�109 (range ~70�560�109) iTregs from CD4+25- T-cells in ? 2 weeks of culture. Most importantly, Rapa/TGF? iTregs suppress disease in a xenogeneic model of GVHD. This study opens the door for iTreg cellular therapy for human diseases. PMID:21564534
Influenza virus-like particles engineered by protein transfer with tumor-associated antigens induces protective antitumor immunity.
Patel, Jaina M; Vartabedian, Vincent F; Kim, Min-Chul; He, Sara; Kang, Sang-Moo; Selvaraj, Periasamy
Delivery of antigen in particulate form using either synthetic or natural particles induces stronger immunity than soluble forms of the antigen. Among naturally occurring particles, virus-like particles (VLPs) have been genetically engineered to express tumor-associated antigens (TAAs) and have shown to induce strong TAA-specific immune responses due to their nano-particulate size and ability to bind and activate antigen-presenting cells. In this report, we demonstrate that influenza VLPs can be modified by a protein transfer technology to express TAAs for induction of effective antitumor immune responses. We converted the breast cancer HER-2 antigen to a glycosylphosphatidylinositol (GPI)-anchored form and incorporated GPI-HER-2 onto VLPs by a rapid protein transfer process. Expression levels on VLPs depended on the GPI-HER-2 concentration added during protein transfer. Vaccination of mice with protein transferred GPI-HER-2-VLPs induced a strong Th1 and Th2-type anti-HER-2 antibody response and protected mice against a HER-2-expressing tumor challenge. The Soluble form of GPI-HER-2 induced only a weak Th2 response under similar conditions. These results suggest that influenza VLPs can be enriched with TAAs by protein transfer to develop effective VLP-based subunit vaccines against cancer without chemical or genetic modifications and thus preserve the immune stimulating properties of VLPs for easier production of antigen-specific therapeutic cancer vaccines. Biotechnol. Bioeng. 2015;112: 1102-1110. � 2015 Wiley Periodicals, Inc. PMID:25689082
Charged particle trajectories in a toroidal magnetic and rotation-induced electric field around a black hole
Sujan Sengupta
Trajectories of charged particle in combined poloidal, toroidal magnetic field and rotation-induced unipolar electric field superposed in Schwarzschild background geometry have been investigated extensively in the context of accreting black holes. The main purpose of the paper is to obtain a reasonably well insight on the effect of spacetime curvature to the electromagnetic field surrounding black holes. The coupled equations of motion have been solved numerically and the results have been compared with that for flat spacetime. It is found that the toroidal magnetic field dominates the induced electric field in determining the motion of charged particles in curved spacetime. The combined electromagnetic field repels a charged particle from the vicinity of a compact massive object and deconfines the particle from its orbit. In the absence of toroidal magnetic field the particle is trapped in a closed orbit. The major role of gravitation is to reduce the radius of gyration significantly while the electric field provides an additional force perpendicular to the circular orbit. Although the effect of inertial frame dragging and the effect of magnetospheric plasma have been neglected, the results provide a reasonably well qualitative picture of the important role played by gravitation in modifying the electromagnetic field near accreting black holes and hence the results have potentially important implications on the dynamics of the fluid and the radiation spectrum associated with accreting black holes.
Role of Exopolysaccharide in Aggregatibacter actinomycetemcomitans�Induced Bone Resorption in a Rat Model for Periodontal Disease
Shanmugam, Mayilvahanan; Gopal, Prerna; El Abbar, Faiha; Schreiner, Helen C.; Kaplan, Jeffrey B.; Fine, Daniel H.; Ramasubbu, Narayanan
Aggregatibacter actinomycetemcomitans a causative agent of periodontal disease in humans, forms biofilm on biotic and abiotic surfaces. A. actinomycetemcomitans biofilm is heterogeneous in nature and is composed of proteins, extracellular DNA and exopolysaccharide. To explore the role played by the exopolysaccharide in the colonization and disease progression, we employed genetic reduction approach using our rat model of A. actinomycetemcomitans-induced periodontitis. To this end, a genetically modified strain of A. actinomycetemcomitans lacking the pga operon was compared with the wild-type strain in the rat infection model. The parent and mutant strains were primarily evaluated for bone resorption and disease. Our study showed that colonization, bone resorption/disease and antibody response were all elevated in the wild-type fed rats. The bone resorption/disease caused by the pga mutant strain, lacking the exopolysaccharide, was significantly less (P < 0.05) than the bone resorption/disease caused by the wild-type strain. Further analysis of the expression levels of selected virulence genes through RT-PCR showed that the decrease in colonization, bone resorption and antibody titer in the absence of the exopolysaccharide might be due to attenuated levels of colonization genes, flp-1, apiA and aae in the mutant strain. This study demonstrates that the effect exerted by the exopolysaccharide in A. actinomycetemcomitans-induced bone resorption has hitherto not been recognized and underscores the role played by the exopolysaccharide in A. actinomycetemcomitans-induced disease. PMID:25706999
Commensal Bacteroides species induce colitis in host-genotype-specific fashion in a mouse model of inflammatory bowel disease
Bloom, Seth M.; Bijanki, Vinieth N.; Nava, Gerardo M.; Sun, Lulu; Malvin, Nicole P.; Donermeyer, David L.; Dunne, W. Michael; Allen, Paul M.; Stappenbeck, Thaddeus S.
SUMMARY The intestinal microbiota is important for induction of inflammatory bowel disease (IBD). IBD is associated with complex shifts in microbiota composition, but it is unclear whether specific bacterial subsets induce IBD and, if so, whether their proportions in the microbiota are altered during disease. Here we fulfilled Koch�s postulates in host-genotype-specific fashion using a mouse model of IBD with human-relevant disease-susceptibility mutations. From screening experiments we isolated common commensal Bacteroides species, introduced them into antibiotic-pretreated mice, and quantitatively re-isolated them in culture. The bacteria colonized IBD-susceptible and non-susceptible mice equivalently, but induced disease exclusively in susceptible animals. Conversely, commensal Enterobacteriaceae were >100-fold enriched during spontaneous disease but an Enterobacteriaceae isolate failed to induce disease in antibiotic-pretreated mice despite robust colonization. We thus demonstrate that IBD-associated microbiota alterations do not necessarily reflect underlying disease etiology. These findings establish important experimental criteria and a conceptual framework for understanding microbial contributions to IBD. PMID:21575910
Increasing both CoCrMo-alloy Particle Size and Surface Irregularity Induces Increased Macrophage Inflammasome Activation In vitro Potentially through Lysosomal Destabilization Mechanisms
Caicedo, Marco S; Samelko, Lauryn; McAllister, Kyron; Jacobs, Joshua J; Hallab, Nadim J
Recent investigations indicate that innate immune �danger-signaling� pathways mediate metal implant debris induced-inflammatory responses, e.g. NALP3 inflammasome. How the physical characteristics of particles, (size, shape and chemical composition) affect this inflammatory reactivity remains controversial. We examined the role of Cobalt-Chromium-Molybdenum (CoCrMo) alloy particle shape and size on human macrophage phagocytosis, lysosomal destabilization, and inflammasome activation. Round/smooth vs. irregularly shaped/rough CoCrMo-alloy particles of ~1�m and 6 to 7�m diameter were investigated for differential lysosomal damage and inflammasome activation in human monocytes/macrophages. While spherical/smooth 1�m CoCrMo-alloy particles did not measurably affect macrophage IL-1? production, irregular 1�m CoCrMo-alloy particles induced significant IL-1? increases over controls. Both round/smooth particles and irregular CoCrMo-alloy particles that were 6 to 7� min size induced >10-fold increases in IL-1? production compared to similarly shaped smaller particles (p<0.05). Larger irregular particles induced a greater degree of intracellular lysosomal damage and a >3-fold increase in IL-1? vs. similarly sized round/smooth particles (at an equal dose, particles/cell). CoCrMo-alloy particle-size-induced IL-1? production was dependent on the lysosomal protease Cathepsin B, further supporting lysosomal destabilization as causative in inflammation. Phagocytosable larger/irregular shaped particles (6�m) demonstrated the greatest lysosomal destabilization (observed immunofluorescently) and inflammatory reactivity when compared on an equal dose basis (particles/cell) to smaller/spherical 1�m particles in vitro. PMID:23794526
Neurostimulation of the Cholinergic Anti-Inflammatory Pathway Ameliorates Disease in Rat Collagen-Induced Arthritis
Levine, Yaakov A.; Koopman, Frieda A.; Faltys, Michael; Caravaca, April; Bendele, Alison; Zitnik, Ralph; Vervoordeldonk, Margriet J.; Tak, Paul Peter
Introduction The inflammatory reflex is a physiological mechanism through which the nervous system maintains immunologic homeostasis by modulating innate and adaptive immunity. We postulated that the reflex might be harnessed therapeutically to reduce pathological levels of inflammation in rheumatoid arthritis by activating its prototypical efferent arm, termed the cholinergic anti-inflammatory pathway. To explore this, we determined whether electrical neurostimulation of the cholinergic anti-inflammatory pathway reduced disease severity in the collagen-induced arthritis model. Methods Rats implanted with vagus nerve cuff electrodes had collagen-induced arthritis induced and were followed for 15 days. Animals underwent active or sham electrical stimulation once daily from day 9 through the conclusion of the study. Joint swelling, histology, and levels of cytokines and bone metabolism mediators were assessed. Results Compared with sham treatment, active neurostimulation of the cholinergic anti-inflammatory pathway resulted in a 52% reduction in ankle diameter (p?=?0.02), a 57% reduction in ankle diameter (area under curve; p?=?0.02) and 46% reduction overall histological arthritis score (p?=?0.01) with significant improvements in inflammation, pannus formation, cartilage destruction, and bone erosion (p?=?0.02), accompanied by numerical reductions in systemic cytokine levels, not reaching statistical significance. Bone erosion improvement was associated with a decrease in serum levels of receptor activator of NF-?B ligand (RANKL) from 132�13 to 6�2 pg/mL (mean�SEM, p?=?0.01). Conclusions The severity of collagen-induced arthritis is reduced by neurostimulation of the cholinergic anti-inflammatory pathway delivered using an implanted electrical vagus nerve stimulation cuff electrode, and supports the rationale for testing this approach in human inflammatory disorders. PMID:25110981
Immunoreactivity and trypsin sensitivity of recombinant virus-like particles of foot-and-mouth disease virus.
Basagoudanavar, S H; Hosamani, M; Tamil, R P; Sreenivasa, B P; Chandrasekhar, B K; Venkataramanan, R
Foot-and-mouth disease (FMD) is an important infection affecting the health and productivity of cloven-hoofed livestock. Development of improved vaccines and diagnostic reagents is being explored to facilitate the disease control. There is an emerging interest in virus-like particles (VLPs), as their constituent structural proteins are the major immunogens. The VLPs are similar to natural virus particles but lack viral nucleic acid. The objective of the present study was to express the VLPs of FMD virus (FMDV) serotype Asia-1 (IND 63/72), using baculovirus system and characterize them for antigenic structure. The VLPs expressed in insect cells showed immunoreactivity similar to inactivated cell culture FMDV. Further they possess similar sensitivity to trypsin as the inactivated cell culture FMDV, suggesting that trypsin-sensitive antigenic sites could be similarly arranged. Our findings suggest that the FMD VLPs have similar antigenic conformational feature like the wild type virus, thus supporting their utility in development of non-infectious FMD vaccines and/or diagnostic assays. PMID:25790055
Linear motion of dielectric particles and living cells in microfabricated structures induced by traveling electric fields
G. Fuhr; R. Hagedorn; T. Muller; B. Wagner; W. Benecke
Arrangements of microelectrodes as obtained by a microfabrication technique are found to be well suited for a linear transfer of microscopic particles such as biological cells and other objects of microscopic dimensions. The conditions for an effective manipulation of the particles are electrode geometries which correspond to the dimensions of the particle and adapted electrical excitation of the electrodes (traveling
Co�Cr�Mo alloy particles induce tumor necrosis factor alpha production in MLO-Y4 osteocytes: A role for osteocytes in particle-induced inflammation
Arihiko Kanaji; Marco S. Caicedo; Amarjit S. Virdi; D. Rick Sumner; Nadim J. Hallab; Kotaro Sena
Wear debris-induced osteolysis is purportedly the limiting problem affecting the long term results of joint arthroplasty. Pathogenic effects of wear debris in peri-implant cells such as macrophages, osteoblasts and osteoclasts have been well studied. In contrast, the effects of wear debris on osteocytes, which make up over 90% of all bone cells, remain unknown. We hypothesized that metal implant debris
Role of Advanced Glycation End Products and Its Receptors in the Pathogenesis of Cigarette Smoke-Induced Cardiovascular Disease.
Prasad, Kailash; Dhar, Indu; Caspar-Bell, Gudrun
The interaction of advanced glycation end products (AGEs) with its cell-bound receptor RAGE increases gene expression and release of proinflammatory cytokines and increase generation of reactive oxygen species (ROS). Circulating receptors, soluble RAGE (sRAGE), and endosecretory RAGE (esRAGE) by binding with RAGE ligands have protective effects against AGE-RAGE interaction. Cigarette smoking is a risk factor for coronary artery disease, stroke, and peripheral vascular disease. This article reviews; if the AGE-RAGE axis is involved in the cigarette smoke-induced cardiovascular diseases. There are various sources of AGEs in smokers including, gas/tar of cigarette, activation of macrophages and polymorphonuclear leukocytes, uncoupling of endothelial isoform of nitric oxide synthase (eNOS) and xanthine oxidase. The levels of AGEs are elevated in smokers. Serum levels of sRAGE have been reported to be reduced, elevated, or unchanged in smokers. Mostly the levels are reduced. There is one article which shows an elevation of levels of sRAGE in smokers. Serum levels of esRAGE are unaltered in smokers. Mechanism of AGE-RAGE-induced atherosclerosis has been discussed. Atherosclerosis leads to the cardiovascular diseases. It has been suggested that ratio of AGE/sRAGE or AGE/esRAGE is useful in determining the deleterious effects of AGE-RAGE interaction in smokers. sRAGE alone is not a good marker for smoke-induced cardiovascular disease. In conclusion cigarette smoke induces formation of AGEs and reduces sRAGE resulting in the development of atherosclerosis and related coronary heart disease, stroke, and peripheral vascular disease. Ratio of AGEs/sRAGE is a better marker for cardiovascular disease than AGEs or sRAGE alone in smokers. PMID:26060376
Large animal induced pluripotent stem cells as pre-clinical models for studying human disease
Plews, Jordan R; Gu, Mingxia; Longaker, Michael T; Wu, Joseph C
Abstract The derivation of human embryonic stem cells and subsequently human induced pluripotent stem cells (iPSCs) has energized regenerative medicine research and enabled seemingly limitless applications. Although small animal models, such as mouse models, have played an important role in the progression of the field, typically, they are poor representations of the human disease phenotype. As an alternative, large animal models should be explored as a potentially better approach for clinical translation of cellular therapies. However, only fragmented information regarding the derivation, characterization and clinical usefulness of pluripotent large animal cells is currently available. Here, we briefly review the latest advances regarding the derivation and use of large animal iPSCs. PMID:22212700
Validation of murine dextran sulfate sodium-induced colitis using four therapeutic agents for human inflammatory bowel disease
Silvia Melgar; Lisa Karlsson; Erika Rehnstr�m; Agneta Karlsson; Helena Utkovic; Liselotte Jansson; Erik Micha�lsson
Dextran sulfate sodium (DSS)-induced colitis is one of the most frequently used rodent models for inflammatory bowel disease (IBD). The aim of this study was to validate the murine DSS-induced colitis model using four therapeutic agents for IBD. C57BL\\/6 mice were exposed to 3% DSS for 5days followed by 7�9 days of water (acute inflammation) or 20�31 days of water
Tryptamine induces axonopathy and mitochondriopathy mimicking neurodegenerative diseases via tryptophanyl-tRNA deficiency.
Paley, Elena L; Perry, George; Sokolova, Olga
Neurodegeneration is induced by tryptamine, a human diet constituent, which easily crosses the blood/brain barrier. Tryptamine neurotoxicity, caused by tryptophanyl-tRNA synthetase (TrpRS) inhibition and downregulation leads to tryptophanyl-tRNA deficiency and synthesis of aberrant proteins. We identified axonal defects in hippocampus of tryptamine- treated mice similar to those observed in human brain of patients with Alzheimer's disease, multiple sclerosis and epilepsy using anti-TrpRS site-directed antibodies. The axonal defects are characterized by swellings that accumulate abnormal amounts of helical filaments and amyloid. Tryptamine produced a decreased density of somatic mitochondria concomitant with neuronal loss in mouse hippocampus. In addition, tryptamine evoked accumulation and clustering of small mitochondria in mouse hippocampus causing axonal swellings. Similarly, mitochondrial fission, fusion and clustering were revealed in human neuronal cells after tryptamine administration. Moreover the tryptamine-induced mitochondrial neuropathology includes electron-dense deposits comprising helical fibrils, cristae disruption, cristolysis, mitochondrial swelling and mitochondria-derived vesicles. TrpRS+ helical filamentous tangles formed in both neuronal and kidney cells following tryptamine treatment suggest a tryptamine broad cytotoxic repertoire in damaging vital organs. Tryptamine elicited vesicularization of inner and outer mitochondrial membranes, axonal and cell membranes. Ultrastructurally, fragmentation of swollen degenerated mitochondria, small mitochondria clustering and neurofibrillary tangles are associated with axonal membrane protrusions attributed as neuritic swellings at a lower magnification. TrpRS+ axonal swellings associated with neuropathology of patients and tryptamine-treated human cells suggest that under toxic concentrations, tryptamine is implicated as a causative agent in neurodegeneration resembling that defining a number of human diseases. PMID:24117115
Molecular Mechanisms of Neurodegenerative Diseases Induced by Human Retroviruses: A Review
Irish, Bryan P.; Khan, Zafar K.; Jain, Pooja; Nonnemacher, Michael R.; Pirrone, Vanessa; Rahman, Saifur; Rajagopalan, Nirmala; Suchitra, Joyce B.; Mostoller, Kate; Wigdahl, Brian
Problem statement Infection with retroviruses such as human immunodeficiency virus type 1 (HIV-1) and human T cell leukemia virus type 1 (HTLV-1) have been shown to lead to neurodegenerative diseases such as HIV-associated dementia (HAD) or neuroAIDS and HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP), respectively. Approach HIV-1-induced neurologic disease is associated with an influx of HIV-infected monocytic cells across the blood-brain barrier. Following neuroinvasion, HIV-1 and viral proteins, in addition to cellular mediators released from infected and uninfected cells participate in astrocytic and neuronal dysregulation, leading to mild to severe neurocognitive disorders. Results The molecular architecture of viral regulatory components including the Long Terminal Repeat (LTR), genes encoding the viral proteins Tat, Vpr and Nef as well as the envelope gene encoding gp120 and gp41 have been implicated in �indirect� mechanisms of neuronal injury, mechanisms which are likely responsible for the majority of CNS damage induced by HIV-1 infection. The neuropathogenesis of HAM/TSP is linked, in part, with both intra-and extracellular effectors functions of the viral transactivator protein Tax and likely other viral proteins. Tax is traditionally known to localize in the nucleus of infected cells serving as a regulator of both viral and cellular gene expression. Conclusion/Recommendations However, recent evidence has suggested that Tax may also accumulate in the cytoplasm and be released from the infected cell through regulated cellular secretion processes. Once in the extracellular environment, Tax may cause functional alterations in cells of the peripheral blood, lymphoid organs and the central nervous system. These extracellular biological activities of Tax are likely very relevant to the neuropathogenesis of HTLV-1 and represent attractive targets for therapeutic intervention. PMID:20352020
Characterization of inducible models of Tay-Sachs and related disease.
Sargeant, Timothy J; Drage, Deborah J; Wang, Susan; Apostolakis, Apostolos A; Cox, Timothy M; Cach�n-Gonz�lez, M Bego�a
Tay-Sachs and Sandhoff diseases are lethal inborn errors of acid ?-N-acetylhexosaminidase activity, characterized by lysosomal storage of GM2 ganglioside and related glycoconjugates in the nervous system. The molecular events that lead to irreversible neuronal injury accompanied by gliosis are unknown; but gene transfer, when undertaken before neurological signs are manifest, effectively rescues the acute neurodegenerative illness in Hexb-/- (Sandhoff) mice that lack ?-hexosaminidases A and B. To define determinants of therapeutic efficacy and establish a dynamic experimental platform to systematically investigate cellular pathogenesis of GM2 gangliosidosis, we generated two inducible experimental models. Reversible transgenic expression of ?-hexosaminidase directed by two promoters, mouse Hexb and human Synapsin 1 promoters, permitted progression of GM2 gangliosidosis in Sandhoff mice to be modified at pre-defined ages. A single auto-regulatory tetracycline-sensitive expression cassette controlled expression of transgenic Hexb in the brain of Hexb-/- mice and provided long-term rescue from the acute neuronopathic disorder, as well as the accompanying pathological storage of glycoconjugates and gliosis in most parts of the brain. Ultimately, late-onset brainstem and ventral spinal cord pathology occurred and was associated with increased tone in the limbs. Silencing transgenic Hexb expression in five-week-old mice induced stereotypic signs and progression of Sandhoff disease, including tremor, bradykinesia, and hind-limb paralysis. As in germline Hexb-/- mice, these neurodegenerative manifestations advanced rapidly, indicating that the pathogenesis and progression of GM2 gangliosidosis is not influenced by developmental events in the maturing nervous system. PMID:23028353
Light charged particle and intermediate mass fragment cross-sections in GeV proton-induced reactions
V. Bollini; A. Bubak; A. Budzanowski; J. Cugnon; D. Filges; F. Goldenbaum; A. Heczko; H. Hodde; L. Jarczyk; B. Kamys; M. Kistryn; A. Kowalczyk; P. Kulessa; H. Machner; A. Magiera; W. Migdal; K. N�nighoff; N. Paul; B. Piskor-Ignatowicz; K. Pysz; Z. Rudy; R. Siudak; M. Wojciechowski; E. Kozik
As an international collaboration PISA (Proton Induced SpAllation) has initiated measurements of total and double differential cross-sections for products of spallation reactions at the proton accelerator COSY in J�lich (Germany) in order to study secondary particle production created in structural, window, and target materials by proton beams up to 2.5GeV incident kinetic energy. In the framework of Spallation Neutron Sources
Search for neutrino-induced particle showers with IceCube-40
NASA Astrophysics Data System (ADS)
Aartsen, M. G.; Abbasi, R.; Ackermann, M.; Adams, J.; Aguilar, J. A.; Ahlers, M.; Altmann, D.; Arguelles, C.; Arlen, T. C.; Auffenberg, J.; Bai, X.; Baker, M.; Barwick, S. W.; Baum, V.; Bay, R.; Beatty, J. J.; Becker Tjus, J.; Becker, K.-H.; BenZvi, S.; Berghaus, P.; Berley, D.; Bernardini, E.; Bernhard, A.; Besson, D. Z.; Binder, G.; Bindig, D.; Bissok, M.; Blaufuss, E.; Blumenthal, J.; Boersma, D. J.; Bohm, C.; Bose, D.; B�ser, S.; Botner, O.; Brayeur, L.; Bretz, H.-P.; Brown, A. M.; Bruijn, R.; Casey, J.; Casier, M.; Chirkin, D.; Christov, A.; Christy, B.; Clark, K.; Classen, L.; Clevermann, F.; Coenders, S.; Cohen, S.; Cowen, D. F.; Cruz Silva, A. H.; Danninger, M.; Daughhetee, J.; Davis, J. C.; Day, M.; de Andr�, J. P. A. M.; De Clercq, C.; De Ridder, S.; Desiati, P.; de Vries, K. D.; de With, M.; DeYoung, T.; D�az-V�lez, J. C.; Dunkman, M.; Eagan, R.; Eberhardt, B.; Eichmann, B.; Eisch, J.; Euler, S.; Evenson, P. A.; Fadiran, O.; Fazely, A. R.; Fedynitch, A.; Feintzeig, J.; Feusels, T.; Filimonov, K.; Finley, C.; Fischer-Wasels, T.; Flis, S.; Franckowiak, A.; Frantzen, K.; Fuchs, T.; Gaisser, T. K.; Gallagher, J.; Gerhardt, L.; Gladstone, L.; Gl�senkamp, T.; Goldschmidt, A.; Golup, G.; Gonzalez, J. G.; Goodman, J. A.; G�ra, D.; Grandmont, D. T.; Grant, D.; Gretskov, P.; Groh, J. C.; Gro�, A.; Ha, C.; Haj Ismail, A.; Hallen, P.; Hallgren, A.; Halzen, F.; Hanson, K.; Hebecker, D.; Heereman, D.; Heinen, D.; Helbing, K.; Hellauer, R.; Hickford, S.; Hill, G. C.; Hoffman, K. D.; Hoffmann, R.; Homeier, A.; Hoshina, K.; Huang, F.; Huelsnitz, W.; Hulth, P. O.; Hultqvist, K.; Hussain, S.; Ishihara, A.; Jacobi, E.; Jacobsen, J.; Jagielski, K.; Japaridze, G. S.; Jero, K.; Jlelati, O.; Kaminsky, B.; Kappes, A.; Karg, T.; Karle, A.; Kauer, M.; Kelley, J. L.; Kiryluk, J.; Kl�s, J.; Klein, S. R.; K�hne, J.-H.; Kohnen, G.; Kolanoski, H.; K�pke, L.; Kopper, C.; Kopper, S.; Koskinen, D. J.; Kowalski, M.; Krasberg, M.; Kriesten, A.; Krings, K.; Kroll, G.; Kunnen, J.; Kurahashi, N.; Kuwabara, T.; Labare, M.; Landsman, H.; Larson, M. J.; Lesiak-Bzdak, M.; Leuermann, M.; Leute, J.; L�nemann, J.; Mac�as, O.; Madsen, J.; Maggi, G.; Maruyama, R.; Mase, K.; Matis, H. S.; McNally, F.; Meagher, K.; Merck, M.; Meures, T.; Miarecki, S.; Middell, E.; Milke, N.; Miller, J.; Mohrmann, L.; Montaruli, T.; Morse, R.; Nahnhauer, R.; Naumann, U.; Niederhausen, H.; Nowicki, S. C.; Nygren, D. R.; Obertacke, A.; Odrowski, S.; Olivas, A.; Omairat, A.; O'Murchadha, A.; Palczewski, T.; Paul, L.; Pepper, J. A.; P�rez de los Heros, C.; Pfendner, C.; Pieloth, D.; Pinat, E.; Posselt, J.; Price, P. B.; Przybylski, G. T.; Quinnan, M.; R�del, L.; Rameez, M.; Rawlins, K.; Redl, P.; Reimann, R.; Resconi, E.; Rhode, W.; Ribordy, M.; Richman, M.; Riedel, B.; Robertson, S.; Rodrigues, J. P.; Rott, C.; Ruhe, T.; Ruzybayev, B.; Ryckbosch, D.; Saba, S. M.; Sander, H.-G.; Santander, M.; Sarkar, S.; Schatto, K.; Scheriau, F.; Schmidt, T.; Schmitz, M.; Schoenen, S.; Sch�neberg, S.; Sch�nwald, A.; Schukraft, A.; Schulte, L.; Schulz, O.; Seckel, D.; Sestayo, Y.; Seunarine, S.; Shanidze, R.; Sheremata, C.; Smith, M. W. E.; Soldin, D.; Spiczak, G. M.; Spiering, C.; Stamatikos, M.; Stanev, T.; Stanisha, N. A.; Stasik, A.; Stezelberger, T.; Stokstad, R. G.; St��l, A.; Strahler, E. A.; Str�m, R.; Strotjohann, N. L.; Sullivan, G. W.; Taavola, H.; Taboada, I.; Tamburro, A.; Tepe, A.; Ter-Antonyan, S.; Te�i?, G.; Tilav, S.; Toale, P. A.; Tobin, M. N.; Toscano, S.; Tselengidou, M.; Unger, E.; Usner, M.; Vallecorsa, S.; van Eijndhoven, N.; Van Overloop, A.; van Santen, J.; Vehring, M.; Voge, M.; Vraeghe, M.; Walck, C.; Waldenmaier, T.; Wallraff, M.; Weaver, Ch.; Wellons, M.; Wendt, C.; Westerhoff, S.; Whelan, B.; Whitehorn, N.; Wiebe, K.; Wiebusch, C. H.; Williams, D. R.; Wissing, H.; Wolf, M.; Wood, T. R.; Woschnagg, K.; Xu, D. L.; Xu, X. W.; Yanez, J. P.; Yodh, G.; Yoshida, S.; Zarzhitsky, P.; Ziemann, J.; Zierke, S.; Zoll, M.; IceCube Collaboration
We report on the search for neutrino-induced particle showers, so-called cascades, in the IceCube-40 detector. The data for this search were collected between April 2008 and May 2009 when the first 40 IceCube strings were deployed and operational. Three complementary searches were performed, each optimized for different energy regimes. The analysis with the lowest energy threshold (2 TeV) targeted atmospheric neutrinos. A total of 67 events were found, consistent with the expectation of 41 atmospheric muons and 30 atmospheric neutrino events. The two other analyses targeted a harder, astrophysical neutrino flux. The analysis with an intermediate threshold of 25 TeV leads to the observation of 14 cascadelike events, again consistent with the prediction of 3.0 atmospheric neutrino and 7.7 atmospheric muon events. We hence set an upper limit of E2?lim?7.46�10-8 GeV sr-1 s-1 cm-2 (90% C.L.) on the diffuse flux from astrophysical neutrinos of all neutrino flavors, applicable to the energy range 25 TeV to 5 PeV, assuming an E?-2 spectrum and a neutrino flavor ratio of 1?1?1 at the Earth. The third analysis utilized a larger and optimized sample of atmospheric muon background simulation, leading to a higher energy threshold of 100 TeV. Three events were found over a background prediction of 0.04 atmospheric muon events and 0.21 events from the flux of conventional and prompt atmospheric neutrinos. Including systematic errors this corresponds to a 2.7? excess with respect to the background-only hypothesis. Our observation of neutrino event candidates above 100 TeV complements IceCube's recently observed evidence for high-energy astrophysical neutrinos.
Differential proinflammatory responses induced by diesel exhaust particles with contrasting PAH and metal content.
Totlandsdal, Annike I; L�g, Marit; Lilleaas, Edel; Cassee, Flemming; Schwarze, Per
Exposure to diesel engine exhaust particles (DEPs), representing a complex and variable mixture of components, has been linked with cellular production and release of several types of mediators related to pulmonary inflammation. A key challenge is to identify the specific components, which may be responsible for these effects. The aim of this study was to compare the proinflammatory potential of two DEP-samples with contrasting contents of polycyclic aromatic hydrocarbons (PAHs) and metals. The DEP-samples were compared with respect to their ability to induce cytotoxicity, expression and release of proinflammatory mediators (IL-6, IL-8), activation of mitogen-activated protein kinases (MAPKs) and expression of CYP1A1 and heme oxygenase-1 (HO-1) in human bronchial epithelial (BEAS-2B) cells. In addition, dithiothreitol and ascorbic acid assays were performed in order to examine the oxidative potential of the PM samples. The DEP-sample with the highest PAH and lowest metal content was more potent with respect to cytotoxicity and expression and release of proinflammatory mediators, CYP1A1 and HO-1 expression and MAPK activation, than the DEP-sample with lower PAH and higher metal content. The DEP-sample with the highest PAH and lowest metal content also possessed a greater oxidative potential. The present results indicate that the content of organic components may be determinant for the proinflammatory effects of DEP. The findings underscore the importance of considering the chemical composition of particulate matter-emissions, when evaluating the potential health impact and implementation of air pollution regulations. PMID:23900936
Energetic-particle-induced electromagnetic geodesic acoustic mode in tokamak plasmas
Wang, Lingfeng, E-mail: email@example.com; He, Zhixiong; He, Hongda; Shen, Y. [Southwestern Institute of Physics, Chengdu 610041 (China); Dong, J. Q. [Institute for Fusion Theory and Simulation, Zhejiang University, Hangzhou 310027 (China); Southwestern Institute of Physics, Chengdu 610041 (China)
Energetic-particle-induced kinetic electromagnetic geodesic acoustic modes (EKEGAMs) are numerically studied in low ? (=plasma pressure/magnetic pressure) tokamak plasmas. The parallel component of the perturbed vector potential is considered along with the electrostatic potential perturbation. The effects of finite Larmor radius and finite orbit width of the bulk and energetic ions as well as electron parallel dynamics are all taken into account in the dispersion relation. Systematic harmonic and ordering analysis are performed for frequency and growth rate spectra of the EKEGAMs, assuming (k?{sub i})?q{sup ?3}???1, where q, k, and ?{sub i} are the safety factor, radial component of the EKEGAMs wave vector, and the Larmor radius of the ions, respectively. It is found that there exist critical ?{sub h}/?{sub i} values, which depend, in particular, on pitch angle of energetic ions and safety factor, for the mode to be driven unstable. The EKEGAMs may also be unstable for pitch angle ?{sub 0}B<0.4 in certain parameter regions. Finite ? effect of the bulk ions is shown to have damping effect on the EKEGAMs. Modes with higher radial wave vectors have higher growth rates. The damping from electron dynamics is found decreasing with decrease of the temperature ratio T{sub e}/T{sub i}. The modes are easily to be driven unstable in low safety factor q region and high temperature ratio T{sub h}/T{sub i} region. The harmonic features of the EKEGAMs are discussed as well.
Low doses of alpha particles do not induce sister chromatid exchanges in bystander Chinese hamster cells defective in homologous recombination
Nagasawa, H; Wilson, P F; Chen, D J; Thompson, L H; Bedford, J S; Little, J B
We reported previously that the homologous recombinational repair (HRR)-deficient Chinese hamster mutant cell line irs3 (deficient in the Rad51 paralog Rad51C) showed only a 50% spontaneous frequency of sister chromatid exchange (SCE) as compared to parental wild-type V79 cells. Furthermore, when irradiated with very low doses of alpha particles, SCEs were not induced in irs3 cells, as compared to a prominent bystander effect observed in V79 cells (Nagasawa et al., Radiat. Res. 164, 141-147, 2005). In the present study, we examined additional Chinese hamster cell lines deficient in the Rad51 paralogs Rad51C, Rad51D, Xrcc2, and Xrcc3 as well as another essential HRR protein, Brca2. Spontaneous SCE frequencies in non-irradiated wild-type cell lines CHO, AA8 and V79 were 0.33 SCE/chromosome, whereas two Rad51C-deficient cell lines showed only 0.16 SCE/chromosome. Spontaneous SCE frequencies in cell lines defective in Rad51D, Xrcc2, Xrcc3, and Brca2 ranged from 0.23-0.33 SCE/chromosome, 0-30% lower than wild-type cells. SCEs were induced significantly 20-50% above spontaneous levels in wild-type cells exposed to a mean dose of 1.3 mGy of alpha particles (<1% of nuclei traversed by an alpha particle). However, induction of SCEs above spontaneous levels was minimal or absent after {alpha}-particle irradiation in all of the HRR-deficient cell lines. These data suggest that Brca2 and the Rad51 paralogs contribute to DNA damage repair processes induced in bystander cells (presumably oxidative damage repair in S-phase cells) following irradiation with very low doses of alpha particles.
Detection and Reduction of the Yield Impact of Particle Induced Structure Defects at Batch Ion Implanters
NASA Astrophysics Data System (ADS)
Schmeide, Matthias; Kokot, Michael; Franke, Dirk-Wito; Sauter, Bernd
This paper focuses on the introduction and qualification of the in situ particle monitor so called High Yield Technology (HYT) sensor on an Axcelis NV-GSD/E 200mm high current batch implanter to detect particles in real time during the implantation process. The particles on the wafer surface were measured with Surfscan and their composition was determined by means of Energy Dispersive X-ray (EDX) analysis. A good correlation between the HYT particle counts and surface particles on dummy wafers as well as defect densities measured on wafers structured with photo resist was found. Moreover, there is a well defined linear correlation of the HYT particle counts to the yield loss. To reduce the level of particle contamination, preventive maintenance procedures were optimized and the hardware in the beam line was modified. In order to minimize structural damage from high velocity particles, the disk drive was upgraded from a belt drive to a direct drive which offers the possibility to decrease the spin speed, thus to reduce the kinetic energy of the particles. Furthermore, measures to repair the already broken structures and to reduce the impact of particles on the products were taken. Depending on the values of the HYT in situ particle monitor, rework steps on various products were introduced. The results of these actions are discussed in combination with the costs.
Glycopolymers as Antiadhesives of E. coli Strains Inducing Inflammatory Bowel Diseases.
Yan, Xibo; Sivignon, Adeline; Yamakawa, Nao; Crepet, Agnes; Travelet, Christophe; Borsali, Redouane; Dumych, Tetiana; Li, Zhaoli; Bilyy, Rostyslav; Deniaud, David; Fleury, Etienne; Barnich, Nicolas; Darfeuille-Michaud, Arlette; Gouin, S�bastien G; Bouckaert, Julie; Bernard, Julien
n-Heptyl ?-d-mannose (HM) is a nanomolar antagonist of FimH, a virulence factor of E. coli. Herein we report on the construction of multivalent HM-based glycopolymers as potent antiadhesives of type 1 piliated E. coli. We investigate glycopolymer/FimH and glycopolymer/bacteria interactions and show that HM-based glycopolymers efficiently inhibit bacterial adhesion and disrupt established cell-bacteria interactions in vitro at very low concentration (0.1 ?M on a mannose unit basis). On a valency-corrected basis, HM-based glycopolymers are, respectively, 10(2) and 10(6) times more potent than HM and d-mannose for their capacity to disrupt the binding of adherent-invasive E. coli to T84 intestinal epithelial cells. Finally, we demonstrate that the antiadhesive capacities of HM-based glycopolymers are preserved ex vivo in the colonic loop of a transgenic mouse model of Crohn's disease. All together, these results underline the promising scope of HM-based macromolecular ligands for the antiadhesive treatment of E. coli induced inflammatory bowel diseases. PMID:25961760
Heme-induced neutrophil extracellular traps contribute to the pathogenesis of sickle cell disease
Chen, Grace; Zhang, Dachuan; Fuchs, Tobias A.; Manwani, Deepa; Wagner, Denisa D.
Sickle cell disease (SCD) is characterized by recurring episodes of vascular occlusion in which neutrophil activation plays a major role. The disease is associated with chronic hemolysis with elevated cell-free hemoglobin and heme. The ensuing depletion of heme scavenger proteins leads to nonspecific heme uptake and heme-catalyzed generation of reactive oxygen species. Here, we have identified a novel role for heme in the induction of neutrophil extracellular trap (NET) formation in SCD. NETs are decondensed chromatin decorated by granular enzymes and are released by activated neutrophils. In humanized SCD mice, we have detected NETs in the lungs and soluble NET components in plasma. The presence of NETs was associated with hypothermia and death of these mice, which could be prevented and delayed, respectively, by dismantling NETs with DNase I treatment. We have identified heme as the plasma factor that stimulates neutrophils to release NETs in vitro and in vivo. Increasing or decreasing plasma heme concentrations can induce or prevent, respectively, in vivo NET formation, indicating that heme plays a crucial role in stimulating NET release in SCD. Our results thus suggest that NETs significantly contribute to SCD pathogenesis and can serve as a therapeutic target for treating SCD. PMID:24620350
Amiodarone-induced hepatic phospholipidosis: a morphological alteration independent of pseudoalcoholic liver disease.
Guigui, B; Perrot, S; Berry, J P; Fleury-Feith, J; Martin, N; M�treau, J M; Dhumeaux, D; Zafrani, E S
In order to study the relationship between amiodarone-induced hepatic phospholipidosis and liver disease, liver biopsies obtained from 13 patients treated with amiodarone for 4 months to 15 years were investigated by light and electron microscopy. Light microscopy showed pseudoalcoholic liver lesions that were probably related to amiodarone in four cases, various alterations (i.e. cirrhosis, three cases; steatosis and fibrosis, two cases; chronic venous congestion, one case; acute hepatitis, one case) that could be explained by another cause than amiodarone in seven cases and normal liver in two cases. In all cases, electron microscopy showed intralysosomal myelin figures suggestive of phospholipidosis. These myelin figures were associated with intralysosomal electron-dense deposits. In the four cases in which analysis by electron microprobe was performed, it demonstrated large amounts of iodine in the electron-dense deposit-containing lysosomes, indicating the accumulation of amiodarone. These results show that hepatic phospholipidosis is constantly observed in amiodarone-treated patients, whether or not pseudoalcoholic liver lesions are present. This phospholipidosis, which could be only a morphological marker of intrahepatic accumulation of the drug, should not therefore be considered grounds for attributing liver disease to the drug. PMID:3417226
Telomere dynamics in induced pluripotent stem cells: Potentials for human disease modeling
Ly, Hinh
Recent advances in reprograming somatic cells from normal and diseased tissues into induced pluripotent stem cells (iPSCs) provide exciting possibilities for generating renewed tissues for disease modeling and therapy. However, questions remain on whether iPSCs still retain certain markers (e.g. aging) of the original somatic cells that could limit their replicative potential and utility. A reliable biological marker for measuring cellular aging is telomere length, which is maintained by a specialized form of cellular polymerase known as telomerase. Telomerase is composed of the cellular reverse transcriptase protein, its integral RNA component, and other cellular proteins (e.g. dyskerin). Mutations in any of these components of telomerase can lead to a severe form of marrow deficiency known as dyskeratosis congenita (DC). This review summarizes recent findings on the effect of cellular reprograming via iPS of normal or DC patient-derived tissues on telomerase function and consequently on telomere length maintenance and cellular aging. The potentials and challenges of using iPSCs in a clinical setting will also be discussed. PMID:22110834
Amiodarone-induced hepatic phospholipidosis: a morphological alteration independent of pseudoalcoholic liver disease
Guigui, B.; Perrot, S.; Berry, J.P.; Fleury-Feith, J.; Martin, N.; Metreau, J.M.; Dhumeaux, D.; Zafrani, E.S.
In order to study the relationship between amiodarone-induced hepatic phospholipidosis and liver disease, liver biopsies obtained from 13 patients treated with amiodarone for 4 months to 15 years were investigated by light and electron microscopy. Light microscopy showed pseudoalcoholic liver lesions that were probably related to amiodarone in four cases, various alterations (i.e. cirrhosis, three cases; steatosis and fibrosis, two cases; chronic venous congestion, one case; acute hepatitis, one case) that could be explained by another cause than amiodarone in seven cases and normal liver in two cases. In all cases, electron microscopy showed intralysosomal myelin figures suggestive of phospholipidosis. These myelin figures were associated with intralysosomal electron-dense deposits. In the four cases in which analysis by electron microprobe was performed, it demonstrated large amounts of iodine in the electron-dense deposit-containing lysosomes, indicating the accumulation of amiodarone. These results show that hepatic phospholipidosis is constantly observed in amiodarone-treated patients, whether or not pseudoalcoholic liver lesions are present. This phospholipidosis, which could be only a morphological marker of intrahepatic accumulation of the drug, should not therefore be considered grounds for attributing liver disease to the drug.
How do plant viruses induce disease? Interactions and interference with host components.
Pallas, Vicente; Garc�a, Juan Antonio
Plant viruses are biotrophic pathogens that need living tissue for their multiplication and thus, in the infection-defence equilibrium, they do not normally cause plant death. In some instances virus infection may have no apparent pathological effect or may even provide a selective advantage to the host, but in many cases it causes the symptomatic phenotypes of disease. These pathological phenotypes are the result of interference and/or competition for a substantial amount of host resources, which can disrupt host physiology to cause disease. This interference/competition affects a number of genes, which seems to be greater the more severe the symptoms that they cause. Induced or repressed genes belong to a broad range of cellular processes, such as hormonal regulation, cell cycle control and endogenous transport of macromolecules, among others. In addition, recent evidence indicates the existence of interplay between plant development and antiviral defence processes, and that interference among the common points of their signalling pathways can trigger pathological manifestations. This review provides an update on the latest advances in understanding how viruses affect substantial cellular processes, and how plant antiviral defences contribute to pathological phenotypes. PMID:21900418
Dysfunction of peroxisomes in twitcher mice brain: A possible mechanism of psychosine-induced disease
Haq, Ehtishamul [Department of Pediatrics and The Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425 (United States); Contreras, Miguel A. [Department of Pediatrics and The Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425 (United States); Giri, Shailendra [Department of Pediatrics and The Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425 (United States); Singh, Inderjit [Department of Pediatrics and The Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425 (United States); Singh, Avtar K. [Department of Pathology and Laboratory Medicine, Medical University of South Carolina and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29425 (United States)]. E-mail: firstname.lastname@example.com
Psychosine (galactosylsphingosine) accumulates in Brain of Krabbe disease (KD) patients as well as twitcher mice, a murine model of KD, resulting in loss of oligodendrocytes and myelin. This study documents progressive loss of peroxisomal proteins/functions and induction of expression of inflammatory cytokine TNF-{alpha} in twitcher brain. The observed decrease in peroxisomal proteins was accompanied by decreased level of peroxisome proliferator-activated receptor-alpha (PPAR-{alpha}), one of the transcription factors required for expression of peroxisomal protein genes. The role of psychosine in down-regulation of PPAR-{alpha} activity was further supported by decreased PPAR-{alpha} mediated PPRE transcriptional activity in cells transfected with PPAR-{alpha} and PPRE reporters. The psychosine-induced down-regulation of PPAR activity and cell death was attenuated by sPLA{sub 2} inhibitor. Therefore, this study provides First evidence of peroxisomal abnormality in a lysosomal disorder, suggesting that such dysfunction of peroxisomes may play a role in the pathogenesis of Krabbe disease.
HIV infection--induced posttranslational modification of T cell signaling molecules associated with disease progression.
Stefanov�, I; Saville, M W; Peters, C; Cleghorn, F R; Schwartz, D; Venzon, D J; Weinhold, K J; Jack, N; Bartholomew, C; Blattner, W A; Yarchoan, R; Bolen, J B; Horak, I D
In attempt to elucidate the mechanism of the HIV infection induced T cell unresponsiveness, we studied signal-transducing molecules proximal to the T cell receptor (TCR) in T lymphocytes of HIV-infected individuals. Total amounts of protein tyrosine kinases (PTKs) Lck, Fyn, and ZAP-70 and the zeta chain of the TCR were found significantly decreased in T cells of symptomatic/AIDS patients as well as in T cells of individuals in acute and early asymptomatic stages of HIV infection. Unexpectedly, the detection of Lck, Fyn, and ZAP-70 was reversed after the treatment of cell lysates with dithiothreitol. This suggests that PTKs Lck, Fyn, and ZAP-70 were modified by a mechanism altering the status of sulfhydryl groups. Moreover, this mechanism seems to affect selectively T cells of HIV infected patients since B cell PTKs Syk and Lyn were detected structurally and functionally intact. Interestingly, similar alterations of signaling molecules were not detected in T cells of HIV-infected long-term asymptomatic individuals. Modification of T cell PTKs may thus underlie the HIV-induced impairment of lymphocyte function and may potentially predict disease progression. PMID:8823293
The Batten disease gene CLN3 confers resistance to endoplasmic reticulum stress induced by tunicamycin.
Wu, Dan; Liu, Jing; Wu, Baiyan; Tu, Bo; Zhu, Weiguo; Luo, Jianyuan
Mutations in CLN3 gene cause juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease), an early-onset neurodegenerative disorder that is characterized by the accumulation of ceroid lipofuscin within lysosomes. The function of the CLN3 protein remains unclear and is presumed to be related to Endoplasmic reticulum (ER) stress. To investigate the function of CLN3 in the ER stress signaling pathway, we measured proliferation and apoptosis in cells transfected with normal and mutant CLN3 after treatment with the ER stress inducer tunicamycin (TM). We found that overexpression of CLN3 was sufficient in conferring increased resistance to ER stress. Wild-type CLN3 protected cells from TM-induced apoptosis and increased cell proliferation. Overexpression of wild-type CLN3 enhanced expression of the ER chaperone protein, glucose-regulated protein 78 (GRP78), and reduced expression of the proapoptotic protein CCAAT/-enhancer-binding protein homologous protein (CHOP). In contrast, overexpression of mutant CLN3 or siRNA knockdown of CLN3 produced the opposite effect. Together, our data suggest that the lack of CLN3 function in cells leads to a failure of management in the response to ER stress and this may be the key deficit in JNCL that causes neuronal degeneration. PMID:24699413
The Power and the Promise of Restimulation-Induced Cell Death in Human Immune Diseases
Snow, Andrew L.; Pandiyan, Pushpa; Zheng, Lixin; Krummey, Scott M.; Lenardo, Michael J.
Summary Controlled expansion and contraction of lymphocytes both during and after an adaptive immune response is imperative to sustaining a healthy immune system. Both extrinsic and intrinsic pathways of lymphocyte apoptosis are programmed to eliminate cells at the proper time to ensure immune homeostasis. Genetic disorders of apoptosis described in mice and humans have established Fas and Bim as critical pro-apoptotic molecules responsible for T-cell death in response to T-cell receptor restimulation and cytokine withdrawal, respectively. Emerging evidence prompts revision of this classic paradigm, especially for our understanding of restimulation-induced cell death (RICD) and its physiological purpose. Recent work indicates that RICD employs both Fas and Bim for T-cell deletion, dispelling the notion that these molecules are assigned to mutually exclusive apoptotic pathways. Furthermore, new mouse model data combined with our discovery of defective RICD in X-linked lymphoproliferative disease (XLP) patient T cells suggest RICD is essential for precluding excess T-cell accumulation and associated immunopathology during the course of certain infections. Here we review how these advances offer a refreshing new perspective on the phenomenon of T-cell apoptosis induced through antigen restimulation, including its relevance to immune homeostasis and potential for therapeutic interventions. PMID:20636809
Carvedilol-induced hyperkalemia in a patient with chronic kidney disease.
Hahn, Lindsay; Hahn, Martin
A 69-year-old male was admitted to the hospital with a chief complaint of abdominal pain, nausea, and vomiting. He had an extensive past medical history, including diabetes mellitus type 2 and chronic kidney disease stage III. Prior to admission, the patient was taking carvedilol 3.125 mg twice daily with no abnormality in his serum potassium. During hospitalization, his carvedilol was increased to 6.25 mg twice daily. The patient's serum potassium then rose from 4.8 to 6.7 mEq/L, with no improvement following administration of sodium polystyrene sulfonate. Nephrology concluded the carvedilol could be contributing to the hyperkalemia. The dose was decreased back to 3.125 mg twice daily, leading to the potassium normalizing to 4.4 mEq/L. The reported incidence of beta-blocker-induced hyperkalemia is less than 5%. A literature search revealed several cases of beta-blocker-induced hyperkalemia, but to the authors' knowledge, this is the first case describing carvedilol specifically. Utilization of the Naranjo probability scale indicated a possible probability that the carvediol was the cause. PMID:25715086
Kalivendi, Shasi V.; Yedlapudi, Deepthi; Hillard, Cecilia J.; Kalyanaraman, B.
?-Synuclein (?-syn) is a presynaptic protein that is widely implicated in the pathophysiology of Parkinson�s disease (PD). Emerging evidence indicates a strong correlation between ?-syn aggregation and proteasomal dysfunction as one of the major pathways responsible for destruction of the dopamine neurons. Using Parkinsonism mimetics (MPP+, rotenone) and related oxidants, we have identified an oxidant-induced alternative splicing of ?-syn mRNA, generating a shorter isoform of ?-syn with deleted exon-5 (112-syn). This spliced isoform has an altered localization and profoundly inhibits proteasomal function. The generation of 112-syn was suppressed by constitutively active MEK-1 and enhanced by inhibition of the Erk-MAP kinase pathway. Overexpression of 112-syn exacerbated cell death in a human dopaminergic cell line compared to full length protein. Expression of 112-syn and proteasomal dysfunction were also evident in the substantia nira and to a lesser extent in striatum, but not in the cortex of MPTP treated mice. We conclude that oxidant-induced alternative splicing of ?-syn plays a crucial role in the mechanism of dopamine neuron cell death and thus contributes to PD. PMID:19857570
Neuroprotective effect of cyclooxygenase inhibitors in ICV-STZ induced sporadic Alzheimer's disease in rats.
Dhull, Dinesh Kumar; Jindal, Ankur; Dhull, Rakesh K; Aggarwal, Saurabh; Bhateja, Deepak; Padi, Satyanarayana S V
Sporadic Alzheimer's disease is an age-related neurological and psychiatric disorder characterized by impaired energy metabolism. Oxidative stress and neuroinflammation have been implicated in pathophysiology of sporadic type of dementia. The central streptozotocin administration induces behavioral and biochemical alterations resembling those in sporadic type of Alzheimer's patients. The present study was designed to investigate the effects of chronic pretreatment with cyclooxygenase-1 or cyclooxygenase-2 or cyclooxygenase-3 selective inhibitors on cognitive dysfunction and oxidative stress markers in intracerebroventricular streptozotocin-treated rats. Chronic treatment with valeryl salicylate (5 and 10 mg/kg, i.p.) and etoricoxib (5 and 10 mg/kg, i.p.) on a daily basis for a period of 21 days, beginning 1 h prior to first intracerebroventricular streptozotocin injection, significantly improved streptozotocin-induced cognitive impairment. However, phenacetin (20 and 40 mg/kg, i.p.) failed to restore the cognitive performances of streptozotocin-treated rats. Besides, improving cognitive dysfunction, chronic administration of highly selective cyclooxygenase-1 and/or cyclooxygenase-2 inhibitors (valeryl salicylate and etoricoxib, respectively), but not cyclooxygenase-3 inhibitor (phenacetin), significantly reduced elevated malondialdehyde, nitrite levels, and restored reduced glutathione and superoxide dismutase levels. Furthermore, cyclooxygenase-1 and/or cyclooxygenase-2 inhibitors significantly increased the survival of pyramidal neurons. In summary, we demonstrate for the first time that both cyclooxygenase-1 and cyclooxygenase-2 isoforms, but not cyclooxygenase-3, are involved in the progression of neuronal damage in intracerebroventricular streptozotocin-treated rats. PMID:21701788
Unconventional Maturation of Dendritic Cells Induced by Particles from the Laminated Layer of Larval Echinococcus granulosus
Casaravilla, Cecilia; Pittini, �lvaro; R�ckerl, Dominik; Seoane, Paula I.; Jenkins, Stephen J.; MacDonald, Andrew S.; Ferreira, Ana M.; Allen, Judith E.
The larval stage of the cestode parasite Echinococcus granulosus causes hydatid disease in humans and livestock. This infection is characterized by the growth in internal organ parenchymae of fluid-filled structures (hydatids) that elicit surprisingly little inflammation in spite of their massive size and persistence. Hydatids are protected by a millimeter-thick layer of mucin-based extracellular matrix, termed the laminated layer (LL), which is thought to be a major factor determining the host response to the infection. Host cells can interact both with the LL surface and with materials that are shed from it to allow parasite growth. In this work, we analyzed the response of dendritic cells (DCs) to microscopic pieces of the native mucin-based gel of the LL (pLL). In vitro, this material induced an unusual activation state characterized by upregulation of CD86 without concomitant upregulation of CD40 or secretion of cytokines (interleukin 12 [IL-12], IL-10, tumor necrosis factor alpha [TNF-?], and IL-6). When added to Toll-like receptor (TLR) agonists, pLL-potentiated CD86 upregulation and IL-10 secretion while inhibiting CD40 upregulation and IL-12 secretion. In vivo, pLL also caused upregulation of CD86 and inhibited CD40 upregulation in DCs. Contrary to expectations, oxidation of the mucin glycans in pLL with periodate did not abrogate the effects on cells. Reduction of disulfide bonds, which are known to be important for LL structure, strongly diminished the impact of pLL on DCs without altering the particulate nature of the material. In summary, DCs respond to the LL mucin meshwork with a �semimature� activation phenotype, both in vitro and in vivo. PMID:24842926
COX-2 expression induced by diesel particles involves chromatin modification and degradation of HDAC1
Cyclooxygenase-2 (COX-2) plays an important role in the inflammatory response induced by physiologic and stress stimuli. Exposure to diesel exhaust particulate matter (DEP) has been shown to induce pulmonary inflammation and exacerbate asthma and chronic obstructive pulmonary dis...
Inorganic particles in human tissues and their association with neoplastic disease
Langer, Arthur M.
An increased gastrointestinal cancer risk is associated with occupational exposure to asbestos fiber. Examination of tissues obtained from extrapulmonary organs of exposed workmen demonstrates the presence of asbestos fibers and bodies. The amount of fiber present in these tissues is many magnitudes less than encountered in the lung tissues from the same individuals. Ingestion of asbestos fiber in some environmental instances may approach in magnitude the amount resulting from occupational exposure. Disease factors are discussed. PMID:4470940
Effect of dietary monosodium glutamate on trans fat-induced nonalcoholic fatty liver disease
Collison, Kate S.; Maqbool, Zakia; Saleh, Soad M.; Inglis, Angela; Makhoul, Nadine J.; Bakheet, Razan; Al-Johi, Mohammed; Al-Rabiah, Rana; Zaidi, Marya Z.; Al-Mohanna, Futwan A.
The effects of dietary monosodium glutamate (MSG) on trans-fatty acid (TFA)-induced nonalcoholic fatty liver disease (NAFLD) are addressed in an animal model. We used Affymetrix microarray analysis to investigate hepatic gene expression and the contribution of visceral white adipose tissue (WAT) to diet-induced NAFLD. Trans-fat feeding increased serum leptin, FFA, HDL-cholesterol (HDL-C), and total cholesterol (T-CHOL) levels, while robustly elevating the expression of genes involved in hepatic lipogenesis, including the transcription factor sterol-regulatory element binding protein 1c. Histological examination revealed hepatic macrosteatosis in TFA-fed animals. Conversely, dietary MSG at doses similar to human average daily intake caused hepatic microsteatosis and the expression of ?-oxidative genes. Serum triglyceride, FFA, and insulin levels were elevated in MSG-treated animals. The abdominal cavities of TFA- or MSG-treated animals had increased WAT deposition compared with controls. Microarray analysis of WAT gene expression revealed increased lipid biosynthetic gene expression, together with a 50% decrease in the key transcription factor Ppargc1a. A combination of TFA+MSG resulted in the highest levels of serum HDL-C, T-CHOL, and leptin. Microarray analysis of TFA+MSG-treated livers showed elevated expression of markers of hepatic inflammation, lipid storage, cell damage, and cell cycle impairment. TFA+MSG mice also had a high degree of WAT deposition and lipogenic gene expression. Levels of Ppargc1a were further reduced to 25% by TFA+MSG treatment. MSG exacerbates TFA-induced NAFLD. PMID:19001666
Particle-induced artifacts in the MTT and LDH viability assays
Holder, Amara L.; Goth-Goldstein, Regine; Lucas, Donald; Koshland, Catherine P.
In vitro testing is a common first step in assessing combustion generated and engineered nanoparticle related health hazards. Commercially available viability assays are frequently used to compare the toxicity of different particle types and to generate dose response data. Nanoparticles, well known for having large surface areas and chemically active surfaces, may interfere with viability assays, producing a false assessment of toxicity and making it difficult to compare toxicity data. The objective of this study is to measure the extent of particle interference in two common viability assays, the MTT reduction and the lactate dehydrogenase (LDH) release assays. Diesel particles, activated carbon, flame soot, oxidized flame soot, and titanium dioxide particles are assessed for interactions with the MTT and LDH assay under cell-free conditions. Diesel particles, at concentrations as low as 0.05 ?g/ml, reduce MTT. Other particle types reduce MTT only at a concentration of 50 ?g/ml and higher. The activated carbon, soot, and oxidized soot particles bind LDH to varying extents, reducing the concentration measured in the LDH assay. The interfering effects of the particles explain in part the different toxicities measured in human bronchial epithelial cells (16HBE14o). We conclude that valid particle toxicity assessments can only be assured after first performing controls to verify that the particles under investigation do not interfere with a specific assay at the expected concentrations. PMID:22799765
[Metabolic activation of azaheterocyclics induced dopaminergic toxicity: possible candidate neurotoxins underlying idiopathic Parkinson's disease].
Matsubara, K
In 1983, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a contaminant of "synthetic heroin", has been reported to induce parkinsonian symptoms in humans, who were responsive to L-DOPA therapy, as a result of the degeneration of nigrostriatal neurons. The "MPTP story" hypothesizes that Parkinson's disease may be initiated or percipitated by environmental and/or endogenous toxins by a mechanism similar to that of MPTP in genetically-predisposed individuals. Several classes of heterocyclic molecules structurally related to MPTP have been advanced as possible neurotoxicant precursors underlying the nigrostriatal degeneration in Parkinson's disease. Indoleamine-related beta-carbolines (beta Cs), a class of heterocyclics which are basically plant alkaloids, are proposed as the most promising natural MPTP-like toxicants or protoxicants. In this article, beta Cs and N-methylated beta C cations are reviewed with regards to their formation, bioactivation, toxicity and presence in the human central nervous system. The enzymes in mammalian brain particulate fractions methylate beta Cs, sequentially forming 2-mono-[N]-methylated (2-Me beta C+s) and neurotoxic 2,9-di-[N, N']-methylated (2,9-Me2 beta C+s) beta-carbolinium cations. These beta C+s are structural analogs of 1-methyl-4-phenylpyridinium ion (MPP+), an active metabolite of MPTP, with a nitrogen bridge. The beta C+s not only inhibit DA reuptake and tyrosine hydroxylase, but also function as NADH-linked respiratory inhibitors in isolated mitochondria. The quarternization of beta C strikingly increased the affinity for dopamine transporter with 2-10 times greater Km and 10 times smaller Vmax values than MPP+. Furthermore, we have found higher concentrations of beta C+s localized in the nigra than in the cortex, and observed the S-adenosyl-L-methionine-dependent methylation of 2[beta]- and 9[indole]-nitrogens of beta Cs in non-parkinsonian human brains. Moreover, the cerebrospinal fluid levels of these beta C+s are higher in parkinsonian than non-parkinsonian patients. Simple beta-carboline induced parkinsonian-like symptoms in mice via N-methylation. These results indicated that beta C is a selective dopaminergic toxin precursor, that is sequentially methylated to form 2,9-Me2 beta C+ that could be an underlying factor in idiopathic Parkinson's disease. PMID:10077975
The role of induced pluripotent stem cells in regenerative medicine: neurodegenerative diseases
Jun Peng; Xianmin Zeng
Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Friedreich's ataxia are\\u000a the most common human neurodegenerative diseases pathologically characterized by a progressive and specific loss of certain\\u000a neuronal populations. The exact mechanisms of neuronal cell death in these diseases are unclear, although some forms of the\\u000a diseases are inherited and genes causing these diseases have been identified. Currently
The impact of obesity and metabolic syndrome on chronic hepatitis B and drug-induced liver disease.
Pais, Raluca; Rusu, Elena; Ratziu, Vlad
Steatosis and insulin resistance (IR) are no more frequent in chronic hepatitis B (CHB) than in the general population. Although experimental studies suggest that the HBx protein induces liver fat, human studies have shown that steatosis and IR are related to coexistent metabolic risk factors, thus epidemiologically linked rather than virally induced. Diabetes and obesity are associated with advanced fibrosis and increased risk of hepatocellular carcinoma in CHB. Despite abundant experimental data showing that fatty liver is more susceptible to liver injury, drug-induced liver disease seems no more frequent in NAFLD patients, except, possibly, a higher incidence but not severity of acetaminophen hepatotoxicity. PMID:24274872
Motorcycle exhaust particles induce IL-8 production through NF-kappaB activation in human airway epithelial cells.
Lee, Chen-Chen; Cheng, Yu-Wen; Kang, Jaw-Jou
Motorcycle exhaust particles (MEP) are among the major air pollutants, especially in urban area of Taiwan. In our previous study, data showed that MEP induce proinflammatory and proallergic response profiles in BALB/c mice. Effects of MEP on interleukin (IL)-8 production in A549 human airway epithelial cells were further investigated in this study. It was found that MEP enhanced IL-8 protein and mRNA expression in human epithelial cells. Pretreatment with an NF-kappaB inhibitor (1 mM PDTC), extracellular signal-regulated kinase (ERK) inhibitor (50 microM PD98059), JNK inhibitor (25 microM SP600125), p38 inhibitor (2 microM SB203580), and three antioxidants (500 U/ml superoxide dismutase [SOD], 50 microM vitamin E, 10 mMN-acetylcysteine [NAC]) attenuated the MEP-induced increase in IL-8 production. Through further, direct detection of nuclear factor (NF)-kappaB activation in epithelial cells using immunoblotting of nuclear p65 and NF-kappaB reporter assay, data showed that MEP induced nuclear translocation of p65 and enhancement of NF-kappaB luciferase gene expression. MEP also induced activation of ERK, JNK, and p38 signaling pathways and produced an increase of oxidative stress in A549 cells. By using mitogen-activated protein kinase (MAPK) inhibitors and antioxidant, it was demonstrated that ERK inhibitor, JNK inhibitor, and antioxidants but not p38 inhibitor attenuated the MEP-induced increase in NF-kappaB reporter activity. In conclusion, evidence shows that filter-trapped particles emitted from unleaded gasoline-fueled, two-stroke motorcycle engines induce an increase in IL-8 production by activation of NF-kappaB in human airway epithelial cells. PMID:16076765
Consequences of developmental exposure to concentrated ambient ultrafine particle air pollution combined with the adult paraquat and maneb model of the Parkinson's disease phenotype in male mice.
Allen, Joshua L; Liu, Xiufang; Weston, Douglas; Conrad, Katherine; Oberd�rster, G�nter; Cory-Slechta, Deborah A
Current evidence suggests suceptibility of both the substantia nigra and striatum to exposure to components of air pollution. Further, air pollution has been associated with increased risk of PD diagnsosis in humans or PD-like pathology in animals. This study examined whether exposure of mice to concentrated ambient ultrafine particles (CAPS; <100nm diameter) during the first two weeks of life would alter susceptibility to induction of the Parkinson's disease phenyotype (PDP) in a pesticide-based paraquat and maneb (PQ+MB) model during adulthood utilizing i.p. injections of 10mg/kg PQ and 30mg/kg MB 2� per week for 6 weeks. Evidence of CAPS-induced enhancement of the PQ+MB PDP was limited primarily to delayed recovery of locomotor activity 24 post-injection of PQ+MB that could be related to alterations in striatal GABA inhibitory function. Absence of more extensive interactions might also reflect the finding that CAPS and PQ+MB appeared to differentially target the nigrostriatal dopamine and amino acid systems, with CAPS impacting striatum and PQ+MB impacting dopamine-glutamate function in midbrain; both CAPS and PQ+MB elevated glutamate levels in these specific regions, consistent with potential excitotoxicity. These findings demonstrate the ability of postnatal CAPS to produce locomotor dysfunction and dopaminergic and glutamateric changes, independent of PQ+MB, in brain regions involved in the PDP. PMID:24486957
Protective Effects of N-Acetyl Cysteine against Diesel Exhaust Particles-Induced Intracellular ROS Generates Pro-Inflammatory Cytokines to Mediate the Vascular Permeability of Capillary-Like Endothelial Tubes
Tseng, Chia-Yi; Chang, Jing-Fen; Wang, Jhih-Syuan; Chang, Yu-Jung; Gordon, Marion K.; Chao, Ming-Wei
Exposure to diesel exhaust particles (DEP) is associated with pulmonary and cardiovascular diseases. Previous studies using in vitro endothelial tubes as a simplified model of capillaries have found that DEP-induced ROS increase vascular permeability with rearrangement or internalization of adherens junctional VE-cadherin away from the plasma membrane. This allows DEPs to penetrate into the cell and capillary lumen. In addition, pro-inflammatory cytokines are up-regulated and mediate vascular permeability in response to DEP. However, the mechanisms through which these DEP-induced pro-inflammatory cytokines increase vascular permeability remain unknown. Hence, we examined the ability of DEP to induce permeability of human umbilical vein endothelial cell tube cells to investigate these mechanisms. Furthermore, supplementation with NAC reduces ROS production following exposure to DEP. HUVEC tube cells contributed to a pro-inflammatory response to DEP-induced intracellular ROS generation. Endothelial oxidative stress induced the release of TNF-? and IL-6 from tube cells, subsequently stimulating the secretion of VEGF-A independent of HO-1. Our data suggests that DEP-induced intracellular ROS and release of the pro-inflammatory cytokines TNF- ? and IL-6, which would contribute to VEGF-A secretion and disrupt cell-cell borders and increase vasculature permeability. Addition of NAC suppresses DEP-induced ROS efficiently and reduces subsequent damages by increasing endogenous glutathione. PMID:26148005
Lamina propria T cells in Crohn's disease and other gastrointestinal inflammation show defective CD2 pathway-induced apoptosis
Monica Boirivant; Marco Marini; Gabriella Di Felice; Anna Maria Pronio; Chiara Montesani; Roberto Tersigni; Warren Strober
Background & Aims: Normal human lamina propria lymphocytes manifest increased unstimulated apoptosis compared with peripheral lymphocytes, which are enhanced after stimulation via the CD2 activation pathway. This activation-induced apoptosis down-regulates cell expansion and cytokine production. In previous studies, it was shown that lamina propria T cells from patients with Crohn's disease and ulcerative colitis manifest abnormal proliferation and cytokine production.
Dopamine mediated iron release from ferritin is enhanced at higher temperatures: Possible implications for fever-induced Parkinson's disease
NASA Astrophysics Data System (ADS)
Babincov�, Mel�nia; Babinec, Peter
A new molecular mechanism is proposed to explain the pathogenesis of fever-induced Parkinson's disease. This proposal is based on dopamine and 6-hydroxydopamine-mediated free iron release from ferritin magnetic nanoparticles, which is enhanced at higher temperatures, and which may lead to substantial peroxidation and injury of lipid biomembranes of the substantia nigra in the brain.
Influence of particle size distribution on the analysis of pellets of plant materials by laser-induced breakdown spectroscopy
NASA Astrophysics Data System (ADS)
de Carvalho, Gabriel Gustinelli Arantes; Santos, D�rio, Jr.; da Silva Gomes, Marcos; Nunes, Lidiane Cristina; Guerra, Marcelo Braga Bueno; Krug, Francisco Jos�
Pellets of sieved plant materials (150, 106, 75, 53 and 20 ?m sieve apertures) were prepared and analyzed by laser-induced breakdown spectroscopy (LIBS), and the results for Ca, K, Mg, P, B and Mn were discussed as a function of particle size distribution. This parameter is of key importance for appropriate test sample presentation in the form of pressed pellets for quantitative analysis by LIBS. Experiments were carried out with a Q-switched Nd:YAG laser at 1064 nm, and a spectrometer with Echelle optics and an intensified charge-coupled device. Results indicated that smaller particles yielded up to 50% emission signal intensities' enhancement and attained better measurements' precision (site-to-site variation). Moreover, matrix effects were reduced by analyzing pellets prepared from < 75 ?m sieved fractions (mean particle size = 32 ?m; d95 = 102 ?m) and by using a 50 J cm- 2 laser fluence (220 mJ per pulse; 750 ?m laser spot size). The preparation of pellets from laboratory samples with monomodal particle size distributions, where most particles were smaller than 100 ?m, was decisive for improving analyte micro-homogeneity within the test samples and for attaining lower coefficients of variation of measurements, typically lower than 10% (n = 10 sites per pellet; 20 laser pulses per site).
Influence of 50-nm polystyrene particles in inducing cytotoxicity in mice co-injected with carbon tetrachloride, cisplatin, or paraquat.
Shimizu, Y; Isoda, K; Tezuka, E; Yufu, T; Nagai, Y; Ishida, I; Tezuka, M
The toxicity of nanomaterials has yet to be fully investigated. In particular, the interactions between nanomaterials and therapeutic drugs require further study. We investigated whether nano-sized polystyrene particles affect drug-induced toxicity. The particles, which are widely used industrially, had diameters of 50 (NPP50), 200 (NPP200) or 1000 (NPP1000) nm. The toxic chemicals tested were carbon tetrachloride, cisplatin (a popular anti-tumor agent), and a widely used herbicide, paraquat. Mice were treated intraperitoneally with either carbon tetrachloride (0.01 ml/kg), cisplatin (100 micromol/kg) or paraquat (50 mg/kg), with or without intravenous administration of polystyrene particles. All treatments in the absence of the nanoparticles were non-lethal and did not result in severe toxicity. However, when mice were injected with paraquat or cisplatin together with polystyrene particles, synergistic, enhanced toxicity was observed in mice injected with NPP50. These synergic effects were not observed in mice co-injected with NPP200 or NPP1000. These findings suggest that further evaluation of the interactions between polystyrene nano-particles and drugs is a critical prerequisite to the pharmaceutical application of nanotechnology. PMID:22957437
Expression of inflammatory cytokines and inducible nitric oxide synthase in brains of SIV-infected rhesus monkeys: applications to HIV-induced central nervous system disease.
Lane, T. E.; Buchmeier, M. J.; Watry, D. D.; Fox, H. S.
BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system (CNS) can lead to severe impairments in cognition, behavior, and motor skills. The mechanism(s) by which HIV-1 induces CNS disease are not well understood. Recent evidence suggests that expression of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) may contribute to HIV-1-induced neurologic disease. We sought to determine if these factors were present in the CNS of rhesus monkeys with simian immunodeficiency virus (SIV)-induced CNS disease. MATERIALS AND METHODS: Total NO production in cerebral spinal fluid (CSF) from infected monkeys was determined by measuring nitrite (NO2-) and nitrate (NO3-) (stable NO degradation products) utilizing Greiss reagents. In situ hybridization revealed iNOS, interferon-gamma (IFNgamma), and interleukin 1 beta (IL-1 beta) mRNA in the brains of SIV-infected monkeys. Microglia were isolated from animals infected with SIV. Following stimulation with LPS, induction of iNOS mRNA in isolated microglia was analyzed by reverse transcriptase-polymerase chain reaction. RESULTS: Serial CSF samples from an SIV-infected monkey reveal increased levels of NO2-/NO3-. In situ hybridization demonstrated iNOS, IFN gamma, and IL-1 beta mRNAs in post-mortem brain tissue of SIV-infected monkeys. Furthermore, stimulated microglia from an SIV-infected monkey could produce iNOS mRNA. CONCLUSIONS: The presence of iNOS in the brain and NO2-/NO3- in the CSF indicates that NO is produced in the CNS of SIV-infected monkeys. The data suggest that iNOS and NO may be contributing to SIV-induced CNS disease. Images FIG. 2 FIG. 3 PMID:8900532
Ameliorative effect of Sida cordifolia in rotenone induced oxidative stress model of Parkinson's disease.
Khurana, Navneet; Gajbhiye, Asmita
Present study focused on the evaluation of aqueous extract of Sida cordifolia (AESC), and its different fractions; hexane (HFSC), chloroform (CFSC) and aqueous (AFSC), against rotenone induced biochemical, neurochemical, histopathological and behavioral alterations in a rat model of Parkinson's disease (PD). An estimation of the level of thiobarbituric acid reactive substances (TBARS), glutathione (GSH) and catalase (CAT) along with superoxide anion generation (SAG) in different brain regions (cortex, midbrain and cerebellum) was carried out to assess biochemical changes. Behavioral evaluation tests (catalepsy, rearing behavior and posture instability) and neurochemical estimations (norepinephrine, dopamine and serotonin level) along with histopathological evaluations of different brain regions were also performed. The varying doses (50, 100, 250mg/kg; p.o.) of different test treatments (AESC, HFSC, CFSC and AFSC) were co-administered along with rotenone (2mg/kg; s.c.), for a period of 35 days to rats of various groups and compared with rotenone per se (negative control) and l-deprenyl (positive control; 10mg/kg; p.o.) treated groups for the above mentioned parameters. The increase in catalepsy and posture instability along with decrease in rearing behavior observed due to rotenone treatment was significantly attenuated by co-treatment with varying doses of AESC and AFSC. Results of the histopathological studies of different brain regions of rats showed eosinophilic lesions in the mid brain region due to rotenone treatment. The eosinophilic lesions were significantly attenuated in co-treated groups of AESC-100mg/kg and AFSC-100mg/kg. Rotenone induced oxidative damage, revealed by increased level of TBARS, SAG and decreased level of GSH and CAT in mid brain region of rats, was attenuated by the co-treatment of AESC and AFSC. The rotenone induced decrease of dopamine level in the midbrain region of rats was also attenuated by co-treatment of AESC-100mg/kg and AFSC-100mg/kg. The maximum effect in all the above activities was observed in AFSC (100mg/kg) treated group, which was comparable to l-deprenyl treated group. The HFSC and CFSC co-treatment failed to show significant attenuation of rotenone induced damage. These results indicate the possible therapeutic potential of most polar fraction of AESC i.e. AFSC in PD by virtue of its antioxidative actions. PMID:23994302
Impaired mitophagy leads to cigarette smoke stress-induced cellular senescence: implications for chronic obstructive pulmonary disease.
Ahmad, Tanveer; Sundar, Isaac K; Lerner, Chad A; Gerloff, Janice; Tormos, Ana M; Yao, Hongwei; Rahman, Irfan
Cigarette smoke (CS)-induced cellular senescence is involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). The molecular mechanism by which CS induces cellular senescence is unknown. Here, we show that CS stress (exposure of primary lung cells to CS extract 0.2-0.75% with a half-maximal inhibitory concentration of ?0.5%) led to impaired mitophagy and perinuclear accumulation of damaged mitochondria associated with cellular senescence in both human lung fibroblasts and small airway epithelial cells (SAECs). Impaired mitophagy was attributed to reduced Parkin translocation to damaged mitochondria, which was due to CS-induced cytoplasmic p53 accumulation and its interaction with Parkin. Impaired Parkin translocation to damaged mitochondria was also observed in mouse lungs with emphysema (6 months CS exposure, 100 mg TPM/m(3)) as well as in lungs of chronic smokers and patients with COPD. Primary SAECs from patients with COPD also exhibited impaired mitophagy and increased cellular senescence via suborganellar signaling. Mitochondria-targeted antioxidant (Mito-Tempo) restored impaired mitophagy, decreased mitochondrial mass accumulation, and delayed cellular senescence in Parkin-overexpressing cells. In conclusion, defective mitophagy leads to CS stress-induced lung cellular senescence, and restoring mitophagy delays cellular senescence, which provides a promising therapeutic intervention in chronic airway diseases.-Ahmad, T., Sundar, I. K., Lerner, C. A., Gerloff, J., Tormos, A. M., Yao, H., Rahman, I. Impaired mitophagy leads to cigarette smoke stress-induced cellular senescence: implications for chronic obstructive pulmonary disease. PMID:25792665
Evidence that disease-induced population decline changes genetic structure and alters dispersal patterns in the Tasmanian devil
Lachish, S; Miller, K J; Storfer, A; Goldizen, A W; Jones, M E
Infectious disease has been shown to be a major cause of population declines in wild animals. However, there remains little empirical evidence on the genetic consequences of disease-mediated population declines, or how such perturbations might affect demographic processes such as dispersal. Devil facial tumour disease (DFTD) has resulted in the rapid decline of the Tasmanian devil, Sarcophilus harrisii, and threatens to cause extinction. Using 10 microsatellite DNA markers, we compared genetic diversity and structure before and after DFTD outbreaks in three Tasmanian devil populations to assess the genetic consequences of disease-induced population decline. We also used both genetic and demographic data to investigate dispersal patterns in Tasmanian devils along the east coast of Tasmania. We observed a significant increase in inbreeding (FIS pre/post-disease ?0.030/0.012, P<0.05; relatedness pre/post-disease 0.011/0.038, P=0.06) in devil populations after just 2�3 generations of disease arrival, but no detectable change in genetic diversity. Furthermore, although there was no subdivision apparent among pre-disease populations (?=0.005, 95% confidence interval (CI) ?0.003 to 0.017), we found significant genetic differentiation among populations post-disease (?=0.020, 0.010�0.027), apparently driven by a combination of selection and altered dispersal patterns of females in disease-affected populations. We also show that dispersal is male-biased in devils and that dispersal distances follow a typical leptokurtic distribution. Our results show that disease can result in genetic and demographic changes in host populations over few generations and short time scales. Ongoing management of Tasmanian devils must now attempt to maintain genetic variability in this species through actions designed to reverse the detrimental effects of inbreeding and subdivision in disease-affected populations. PMID:20216571
Comparative Elongated Mineral Particle Toxicology & Erionite?s Apparent� High Potency for Inducing Mesothelioma
Recent NHEERL research under EPA's Libby Action Plan has determined that elongated particle relative potency for rat pleural mesothelioma is best predicted on the basis of total external surface area (TSA) of slightly acid leached test samples which simulate particle bio-durabili...
Optoacoustic effects accompanying laser-induced breakdowns on monodispersed solid aerosol particles
Sergei V. Shamanaev
Generation of acoustic radiation by local plasma formations initiated by solid aerosol particles is one of the nonlinear effects of interaction between high-power laser radiation and atmospheric aerosols. In the present report, time histories of acoustic pulses radiated by discrete plasma formations, initiated under the action of focused laser radiation on a single solid aerosol particle suspended in the laser
Adsorption-induced conformational changes of proteins onto ceramic particles: Differential scanning calorimetry and FTIR analysis
Natascha Brandes; Petra B. Welzel; Carsten Werner; Lothar W. Kroh
Three model proteins, bovine serum albumin, hen's egg lysozyme and bovine serum fibrinogen, were adsorbed from aqueous solution onto finely dispersed ceramic particles, namely different kinds of alumina and hydroxyapatite particles. The influence of adsorption on protein secondary structure was investigated. The FTIR spectroscopic findings were compared with the results of DSC measurements. In almost all cases it was found
We tested the hypothesis that exposure of healthy volunteers to concentrated ambient particles (CAPS) is associated with an influx of inflammatory cells into the lower respiratory tract. Thirty-eight volunteers were exposed to either filtered air or particles concentrated fro...
Charging-induced diffusion of aerosol particles moving under external electric fields in ionized gases
Y. S. Mayya; S. V. Malvankar
The stochastic motion of aerosol particles in an external electric field (E) is investigated in the continuum and free-molecular regimes, under the condition of bipolar charging with radiation sources. The charging process is shown to give rise to a random 'diffusive motion' of the particles along the field lines, in addition to their well-known drift motion (migration velocity). The 'coefficient
Hematologic and hemorheological determinants of resting and exercise-induced hemoglobin oxygen desaturation in children with sickle cell disease
Waltz, Xavier; Romana, Marc; Lalanne-Mistrih, Marie-Laure; Machado, Roberto F.; Lamarre, Yann; Tarer, Vanessa; Hardy-Dessources, Marie-Dominique; Tressi�res, Beno�t; Divialle-Doumdo, Lydia; Petras, Marie; Maillard, Frederic; Etienne-Julan, Maryse; Connes, Philippe
The aim of the study was to determine the factors associated with resting and exercise-induced hemoglobin oxygen desaturation. The well-established six-minute walk test was conducted in 107 sickle cell children (50 with sickle hemoglobin C disease and 57 with sickle cell anemia) at steady state. Hemoglobin oxygen saturation was measured before and immediately after the six-minute walk test. Blood samples were obtained on the same day to measure hematologic and hemorheological parameters. Exercise-induced hemoglobin oxygen desaturation was defined as a drop in hemoglobin oxygen saturation of 3% or more at the end of the six-minute walk test compared to resting levels. No children with sickle hemoglobin C disease, but approximately 50% of children with sickle cell anemia showed mild or moderate oxygen desaturation at rest, which was independently associated with the percentage of reticulocytes. Exercise-induced hemoglobin oxygen desaturation was observed in 18% of children with sickle hemoglobin C disease and 34% of children with sickle cell anemia, and was independently associated with the six-minute walk test, acute chest syndrome rate and the strength of red blood cell aggregates in children with sickle cell anemia. No association was found in children with sickle hemoglobin C disease between exercise-induced hemoglobin oxygen desaturation and the measured parameters. Hemoglobin oxygen desaturation at rest was common in children with sickle cell anemia but not in children with sickle hemoglobin C disease, and was mainly associated with greater hemolysis. Physiological strain during exercise and red blood cell aggregation properties may predict the occurrence of exercise-induced hemoglobin oxygen desaturation in children with sickle cell anemia. PMID:23539539
Probing nuclear dissipation with particle multiplicity in heavy-ion-induced light fissioning systems
NASA Astrophysics Data System (ADS)
Ye, W.; Wang, N.; Tian, J.
Based on the stochastic Langevin model, we study the effects of angular momentum (?) on the multiplicities of postsaddle neutrons, protons, and ? particles as a function of postsaddle friction strength (?) for 200Pb nucleus. It is shown that with increasing ? the sensitivity of these particles to ? is significantly enhanced. Moreover, we find that neutrons (charged particles) evaporated from light 200Pb having high ? and high excitation energy E* exhibit a similar (greater) sensitivity to ? as compared to the case of heavy 251Es having low ? and low E*. Our findings suggest that on the experimental side, to accurately probe information of postsaddle dissipation with particle multiplicity, in particular with the multiplicity of charged particles, it is optimal to populate light fissioning systems with large angular momentum and high excitation energy.
Noninfectious Virus-Like Particle Antigen for Detection of Swine Vesicular Disease Virus Antibodies in Pigs by Enzyme-Linked Immunosorbent Assay
Young-Joon Ko; Kang-Seuk Choi; Jin-Ju Nah; David J. Paton; Jae-Ku Oem; Ginette Wilsden; Shien-Young Kang; Nam-In Jo; Joo-Ho Lee; Jae-Hong Kim; Hee-Woo Lee; Jong-Myeong Park
An inactivated SVDV antigen is used in current enzyme-linked immunosorbent assays (ELISAs) for the detection of antibodies to swine vesicular disease virus (SVDV). To develop a noninfectious recombinant alternative, we produced SVDV-like particles (VLPs) morphologically and antigenically resembling authentic SVDV particles by using a dual baculovirus recombinant, which expresses simultaneously the P1 and 3CD protein genes of SVDV under different
Supplemental dietary whey protein concentrate reduces rotavirus-induced disease symptoms in suckling mice.
Wolber, Frances M; Broomfield, Anne M; Fray, Linley; Cross, Martin L; Dey, Debjit
Rotavirus-induced diarrhea is a common infection that results in the death of nearly 500,000 children annually. Currently, no large-scale preventative treatments or vaccines exist. Because some whey protein concentrates (WPC) were shown to contain bioactive ingredients that may activate immune cells and/or prevent infection, the current study was conducted to assess whether the proprietary WPC IMUCARE (WPC-IC) could protect against rotavirus. Suckling BALB/c mice were treated by gavage once daily with WPC-IC or with the control protein bovine serum albumin from the age of 9 to 17 d, and were infected with murine rotavirus at the age of 11 d. Disease symptoms were graded as mild, moderate, or severe, and viral shedding was measured in fecal samples during the postinfection period. Severe diarrhea occurred in 63% of control mice; this was significantly reduced to 36% in WPC-IC-fed mice. Severe diarrhea occurred for a 4-d period in the control group but only for a 2-d period in the WPC-IC group. Although the mean viral load per mouse did not differ between the groups, the proportion of mice shedding high levels of the virus in the feces postinfection was significantly lower in the WPC-IC group on d 13, 16, and 17, and significantly higher on d 14. Rotavirus-specific antibody levels in serum and gut fluid did not differ between groups. Thus, prophylactic treatment with WPC-IC may reduce rotaviral disease by decreasing the prevalence of severe diarrhea and by decreasing the time period during which severe symptoms and high viral shedding occur. PMID:15930454
The spontaneously hypertensive rat: an experimental model of sulfur dioxide-induced airways disease.
Kodavanti, Urmila P; Schladweiler, Mette C; Ledbetter, Allen D; Ortuno, Roselia Villalobos; Suffia, Marie; Evansky, Paul; Richards, Judy H; Jaskot, Richard H; Thomas, Ronald; Karoly, Edward; Huang, Yuh-Chin T; Costa, Daniel L; Gilmour, Peter S; Pinkerton, Kent E
Chronic obstructive pulmonary disease (COPD) is characterized by airway obstruction, inflammation, and mucus hypersecretion, features that are common in bronchitis, emphysema, and often asthma. However, current rodent models do not reflect this human disease. Because genetically predisposed spontaneously hypertensive (SH) rats display phenotypes such as systemic inflammation, hypercoagulation, oxidative stress, and suppressed immune function that are also apparent in COPD patients, we hypothesized that SH rat may offer a better model of experimental bronchitis. We, therefore, exposed SH and commonly used Sprague Dawley (SD) rats (male, 13- to 15-weeks old) to 0, 250, or 350 ppm sulfur dioxide (SO(2)), 5 h/day for 4 consecutive days to induce airway injury. SO(2) caused dose-dependent changes in breathing parameters in both strains with SH rats being slightly more affected than SD rats. Increases in bronchoalveolar lavage fluid (BALF) total cells and neutrophilic inflammation were dose dependent and significantly greater in SH than in SD rats. The recovery was incomplete at 4 days following SO(2) exposure in SH rats. Pulmonary protein leakage was modest in either strain, but lactate dehydrogenase and N-acetyl glucosaminidase activity were increased in BALF of SH rats. Airway pathology and morphometric evaluation of mucin demonstrated significantly greater impact of SO(2) in SH than in SD rats. Baseline differences in lung gene expression pattern suggested marked immune dysregulation, oxidative stress, impairment of cell signaling, and fatty acid metabolism in SH rats. SO(2) effects on these genes were more pronounced in SH than in SD rats. Thus, SO(2) exposure in SH rats may yield a relevant experimental model of bronchitis. PMID:16929007
Generation of Healthy Mice from Gene-Corrected Disease-Specific Induced Pluripotent Stem Cells
Rittelmeyer, Ina; Sharma, Amar Deep; Sgodda, Malte; Zaehres, Holm; Bleidi�el, Martina; Greber, Boris; Gentile, Luca; Han, Dong Wook; Rudolph, Cornelia; Steinemann, Doris; Schambach, Axel; Ott, Michael; Sch�ler, Hans R.; Cantz, Tobias
Using the murine model of tyrosinemia type 1 (fumarylacetoacetate hydrolase [FAH] deficiency; FAH?/? mice) as a paradigm for orphan disorders, such as hereditary metabolic liver diseases, we evaluated fibroblast-derived FAH?/?-induced pluripotent stem cells (iPS cells) as targets for gene correction in combination with the tetraploid embryo complementation method. First, after characterizing the FAH?/? iPS cell lines, we aggregated FAH?/?-iPS cells with tetraploid embryos and obtained entirely FAH?/?-iPS cell�derived mice that were viable and exhibited the phenotype of the founding FAH?/? mice. Then, we transduced FAH cDNA into the FAH?/?-iPS cells using a third-generation lentiviral vector to generate gene-corrected iPS cells. We could not detect any chromosomal alterations in these cells by high-resolution array CGH analysis, and after their aggregation with tetraploid embryos, we obtained fully iPS cell�derived healthy mice with an astonishing high efficiency for full-term development of up to 63.3%. The gene correction was validated functionally by the long-term survival and expansion of FAH-positive cells of these mice after withdrawal of the rescuing drug NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione). Furthermore, our results demonstrate that both a liver-specific promoter (transthyretin, TTR)-driven FAH transgene and a strong viral promoter (from spleen focus-forming virus, SFFV)-driven FAH transgene rescued the FAH-deficiency phenotypes in the mice derived from the respective gene-corrected iPS cells. In conclusion, our data demonstrate that a lentiviral gene repair strategy does not abrogate the full pluripotent potential of fibroblast-derived iPS cells, and genetic manipulation of iPS cells in combination with tetraploid embryo aggregation provides a practical and rapid approach to evaluate the efficacy of gene correction of human diseases in mouse models. PMID:21765802
Generation of healthy mice from gene-corrected disease-specific induced pluripotent stem cells.
Wu, Guangming; Liu, Na; Rittelmeyer, Ina; Sharma, Amar Deep; Sgodda, Malte; Zaehres, Holm; Bleidissel, Martina; Greber, Boris; Gentile, Luca; Han, Dong Wook; Rudolph, Cornelia; Steinemann, Doris; Schambach, Axel; Ott, Michael; Sch�ler, Hans R; Cantz, Tobias
Using the murine model of tyrosinemia type 1 (fumarylacetoacetate hydrolase [FAH] deficiency; FAH?/? mice) as a paradigm for orphan disorders, such as hereditary metabolic liver diseases, we evaluated fibroblast-derived FAH?/?-induced pluripotent stem cells (iPS cells) as targets for gene correction in combination with the tetraploid embryo complementation method. First, after characterizing the FAH?/? iPS cell lines, we aggregated FAH?/?-iPS cells with tetraploid embryos and obtained entirely FAH?/?-iPS cell-derived mice that were viable and exhibited the phenotype of the founding FAH?/? mice. Then, we transduced FAH cDNA into the FAH?/?-iPS cells using a third-generation lentiviral vector to generate gene-corrected iPS cells. We could not detect any chromosomal alterations in these cells by high-resolution array CGH analysis, and after their aggregation with tetraploid embryos, we obtained fully iPS cell-derived healthy mice with an astonishing high efficiency for full-term development of up to 63.3%. The gene correction was validated functionally by the long-term survival and expansion of FAH-positive cells of these mice after withdrawal of the rescuing drug NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione). Furthermore, our results demonstrate that both a liver-specific promoter (transthyretin, TTR)-driven FAH transgene and a strong viral promoter (from spleen focus-forming virus, SFFV)-driven FAH transgene rescued the FAH-deficiency phenotypes in the mice derived from the respective gene-corrected iPS cells. In conclusion, our data demonstrate that a lentiviral gene repair strategy does not abrogate the full pluripotent potential of fibroblast-derived iPS cells, and genetic manipulation of iPS cells in combination with tetraploid embryo aggregation provides a practical and rapid approach to evaluate the efficacy of gene correction of human diseases in mouse models. PMID:21765802
Could charcoal filtration of cigarette smoke reduce smoking-induced disease? A review of the literature.
Coggins, Christopher R E; Gaworski, Charles L
A review of the published work with charcoal-filtered cigarettes indicates that there are reductions in the concentrations for many gas-vapor phase constituents found in mainstream smoke. However, charcoal filters provided no apparent capacity for reduction of smoke particulate phase components. The reductions in gas-vapor phase smoke chemistry analytes generally correspond with findings of reduced toxicological activity, principally related to a reduction in the cytotoxic action of the volatile smoke constituents. Results of a short-term clinical study show small reductions in the biomarkers of the gas-vapor phase smoke constituents in subjects smoking charcoal-filtered cigarettes, compared to subjects smoking non-charcoal filtered cigarettes. The very limited epidemiology data (a single study) fail to demonstrate a conclusive beneficial effect of charcoal-filtered cigarette products compared to non-charcoal filtered cigarette products. Review of the scientific literature is hindered due to the lack of documentation regarding the activity of the charcoal used in the filter, and the inconsistency in product designs used between the various different disciplines (chemistry, pre-clinical, clinical and epidemiology) that have conducted studies with charcoal filtered cigarettes. There do not appear to be any published studies using a combination of data from the different disciplines based on a consistently designed charcoal cigarette filter. Although the literature presently available would suggest that smoke filtration provided by current charcoal filter techniques alone may not be substantial enough to reduce smoking-related disease, the data are limited. Therefore, for the reduction of smoking-induced disease, it is difficult to come to a definitive conclusion regarding the potential health benefits of using charcoal as a smoke filtration technology. PMID:18289753
C-MYC�induced Apoptosis in Polycystic Kidney Disease Is Bcl-2 and p53 Independent
Trudel, Marie; Lanoix, Jacqueline; Barisoni, Laura; Blouin, Marie-Jos�; Desforges, Marc; L'Italien, Catherine; D'Agati, Vivette
The SBM mouse is a unique transgenic model of polycystic kidney disease (PKD) induced by the dysregulated expression of c-myc in renal tissue. In situ hybridization analysis demonstrated intense signal for the c-myc transgene overlying tubular cystic epithelium in SBM mice. Renal proliferation index in SBM kidneys was 10-fold increased over nontransgenic controls correlating with the presence of epithelial hyperplasia. The specificity of c-myc for the proliferative potential of epithelial cells was demonstrated by substitution of c-myc with the proto-oncogene c-fos or the transforming growth factor (TGF)-? within the same construct. No renal abnormalities were detected in 13 transgenic lines established, indicating that the PKD phenotype is dependent on functions specific to c-myc. We also investigated another well characterized function of c-myc, the regulation of apoptosis through pathways involving p53 and members of the bcl-2 family, which induce and inhibit apoptosis, respectively. The SBM kidney tissues, which overexpress c-myc, displayed a markedly elevated (10�100-fold) apoptotic index. However, no significant difference in bcl-2, bax, or p53 expression was observed in SBM kidney compared with controls. Direct proof that the heightened renal cellular apoptosis in PKD is not occurring through p53 was obtained by successive matings between SBM and p53?/? mice. All SBM offspring, irrespective of their p53 genotype, developed PKD with increased renal epithelial apoptotic index. In addition, overexpression of both bcl-2 and c-myc in double transgenic mice (SBB+/SBM+) also produced a similar PKD phenotype with a high apoptotic rate, showing that c-myc can bypass bcl-2 in vivo. Thus, the in vivo c-myc apoptotic pathway in SBM mice occurs through a p53- and bcl-2�independent mechanism. We conclude that the pathogenesis of PKD is c-myc specific and involves a critical imbalance between the opposing processes of cell proliferation and apoptosis. PMID:9382886