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Estrogen offers important assignments in the initiation and advancement of benign prostatic hyperplasia (BPH). the proliferation of stromal cells 0.05). Our data demonstrated for the very first time that AZD5438 Ral may possess a job in the response from the rat prostate to selective ER modulators. check. Differences were regarded significant at 0.05. Outcomes Ral antagonized estrogen-stimulated proliferation in PrSCs E2 marketed the proliferation from the PrSC series WPMY-1 by 31% ( 0.05), whereas Ral, Tam and ICI had no the result. Nevertheless, Ral, Tam and Fin antagonized the proliferation of WPMY-1 cells when utilized as well as E2 by 17%, 16% and 25%, respectively ( 0.05, Figure 1A). Cell keeping track of supplied the same outcomes ( 0.05, Figure 1B). Open up in another window Amount 1 Raloxifene (Ral) antagonized estrogen-stimulated WPMY-1 cell proliferation. Prostate stromal WPMY-1 cells had been seeded right into a 24-well dish with 2 104 cells per AZD5438 well. After serum hunger for 24 h, cells had been treated with 0.1 mol L?1 17–oestradiol (E2), tamoxifen (Tam), Ral, finasteride (Fin), and ICI alone or as well as E2. After 48 h of incubation, proliferation was assessed by MTT assay (A) and cell keeping track of (B). a, control; b, 0.1 mol ITGA2B L?1 E2; c, 1 mol L?1 Ral; d, 1 mol L?1 Ral + 0.1 mol L?1 E2; e, 1 mol L?1 Tam; f, 1 mol L?1 Tam + 0.1 mol L?1 E2; g, 1 mol L?1 Fin; h, 1 mol L?1 Fin + 0.1 mol L?1 E2; i, 1 mol L?1 ICI; j, 1 mol L?1 ICI + 0.1 mol L?1 E2. * 0.05, weighed against control, 0.05, weighed against 0.1 mol L?1 E2. Ral antagonized estrogen-stimulated proliferation in harmless prostatic hyperplasia epithelial cells E2 marketed the proliferation from the BPH-1 by 23% ( 0.05), whereas Tam, Ral and ICI had no the result. However, when found in mixture with E2, Ral antagonized the estrogenic impact to advertise BPH-1 cell proliferation by 21% ( 0.05). Likewise, Tam decreased estrogen-stimulated proliferation by 19% ( 0.05). Fin by itself inhibited BPH-1 cell proliferation by 26%, whereas it decreased estrogen-stimulated BPH-1 cell proliferation by 39% ( 0.05, Figure 2A). Cell keeping track of supplied the same outcomes ( 0.05, Figure 2B). Open up in another window Amount 2 Ral antagonized estrogen-stimulated harmless prostatic hyperplasia-1 (BPH-1) cell proliferation. Prostatic epithelial BPH-1 cells had been seeded right into a 96-well dish with 4 103 cells per well. After serum hunger for 24 h, the cells had been treated with Tam, Ral, Fin or ICI by itself or as well as oestradiol (E2). After 48 h incubation, proliferation was dependant on MTT assay (A) and cell keeping track of (B). a, control; b, 0.1 mol L?1 E2; c, 1 mol L?1 Ral; d, 1 mol AZD5438 L?1 Ral + 0.1 mol L?1 E2; e, 1 mol L?1 Tam; f, 1 mol L?1 Tam + 0.1 mol L?1 E2; g, 1 mol L?1 Fin; h, 1 mol L?1 Fin + 0.1 mol L?1 E2; i, 1 mol L?1 ICI; j, 1 mol L?1 ICI + 0.1 mol L?1 E2. * 0.05, weighed against control; 0.05, weighed against 0.1 mol L?1 E2. Aftereffect of Ral on stopping prostatic stromal hyperplasia in E/T-induced BPH rats Quantitative evaluation of rat AZD5438 prostate histology H&E staining outcomes from the rat prostate indicated which the lumens of prostate acini had been regular in the sham-operated control AZD5438 group which the epithelial cells in the prostatic acini made an appearance cuboidal or columnar.
A1 Receptors
The actions of glucocorticoids in the feto-maternal interface aren't well understood.
The actions of glucocorticoids in the feto-maternal interface aren't well understood. to modulate regional angiogenesis, to recruit specialised uterine organic killer cells and macrophages, also to withstand environmental and oxidative tension (19, 20). Predicated on these observations, we speculated that induction of 11HSD1 would result in improved F bioavailability, which regulates the manifestation of PF299804 specific GR- and MR-dependent gene systems in decidualizing HESCs. Components and Methods Individual selection This research was authorized by the Hammersmith and Queen Charlotte's and Chelsea Study Ethics Committee (1997/5065). Written educated consent was from all taking part subjects before cells collection. Endometrial biopsies had been timed between 7 and 11 d following the preovulatory LH surge. Major cell tradition Endometrial samples had been from Rabbit Polyclonal to Catenin-alpha1 premenopausal ladies without uterine pathology, and HESCs had been isolated, cultured, and taken care of as referred to previously (16). Examples were gathered in Earle's buffered saline including 100 U/ml penicillin and 100 g/ml streptomycin. The cells were washed double inside a 1:1 combination of DMEM and Ham's F12 (DMEM/F12) (Sigma, Poole, UK), finely minced, and enzymatically digested with collagenase (134 U/ml) and deoxyribonuclease type I (156 U/ml) (Sigma) for 1 h at 37 C. After centrifugation at 400 for 4 min, the pellet was resuspended in maintenance moderate of DMEM/F12 including 10% dextran-coated charcoal-treated fetal bovine serum (DCC-FBS), 1% l-glutamine, and 1% antibiotic-antimycotic remedy. Proliferating HESCs had been cultured in maintenance moderate until confluence. In decidualization tests, confluent monolayers had been taken care of in DMEM/F12 right now including 2% DCC-FBS and treated with 0.5 mm 8-bromoadenosine cAMP (8-bromo-cAMP) (Sigma, St. Louis, MO) only or in conjunction with 1 m medroxyprogesterone acetate (MPA) (Sigma), 1 m P4 (Sigma), 0.1 m dexamethasone (DEX) (Sigma), 0.1 m E (Sigma), 1 m aldosterone (Sigma), 10 m RU26752 (Sigma), 0.1 m carbenoxolone disodium sodium (CBX) (Sigma), or 0.1 m PF 915275 (PF) (Tocris Bioscience, Abingdon, UK). Transient transfection Main HESCs, cultured in 12-well plates until confluency, had been transfected using the ProFection mammalian transfection package (Promega, Madison, WI), with 100 nm per well of the next little interfering RNA (siRNA) reagents (Dharmacon, Lafayette, CO): sinontargeting (NT) siRNA pool, GR siSMARTpool siRNA, or MR siSMARTpool siRNA. Traditional western blot evaluation Whole-cell protein components were acquired by immediate lysis in Laemmli buffer warmed to 100 C. Protein solved by SDS-PAGE had been used in a polyvinyl difluoride membrane (GE Health care, Uppsala, Sweden) and probed with antibodies elevated against GR, 1:1000 (E-20: SC-1003; Santa Cruz Biotechnology, Inc., Santa Cruz, CA); MR, 1:1000 (H-300: SC-11412; Santa Cruz Biotechnology, Inc.); 11HSD1, 1:1000 (ab83522; Abcam, Cambridge, UK); 11HSD2, 1:2000 (ab80317; Abcam); P4 receptor (PR), 1:1000 (NCL-L-PGR-312; Leica Biosystems, Newcastle, UK); histone 3 lysine 9 (H3K9) trimethylation (H3K9me3), 1:1000 (49-1008; Invitrogen Ltd., Paisley, UK); dehydrogenase/reductase PF299804 superfamily (DHRS)3, 1:1000 (15393-1-AP; Proteintech Group, Manchester, UK); and -actin, 1:100,000 (A1978; Sigma). After incubation with horseradish peroxidase-conjugated supplementary antibodies, 1:2500, (Roche Diagnostics, Mannheim, Germany), chemiluminescence was visualized using the ECL+ chemiluminescence recognition kit (Amersham, Small Chalfont, UK). Real-time quantitative (RTQ)-PCR Total RNA was extracted from main HESC ethnicities. After treatment with amplification PF299804 quality deoxyribonuclease I (Invitrogen Ltd.), cDNA was generated using the SuperScript First-Strand Synthesis Program for RT-PCR package (Invitrogen Ltd.). Design template quantification was performed with an ABI THE FIRST STEP Program (Applied Biosystems, Foster Town, CA) using Power SYBR Green PCR Grasp Blend (Applied Biosystems) as dye coating and the comparative standard curve computation method. RNA insight variances had been normalized against the degrees of the L19 housekeeping gene, which encodes a ribosomal proteins. All measurements had been performed in duplicate. Particular primer pairs had been designed using Primer3 software program (http://frodo.wi.mit.edu): L19 feeling, 5-GCG GAA GGG TAC AGC CAA T-3 and L19-R antisense, 5-GCA GCC GGC GCA AA-3; 11HSD1 feeling, 5-AGC AAG TTT GCT TTG GAT GG-3 and 11HSD1 antisense, 5-AGA GCT.
DNA is continually subjected to both endogenous and exogenous problems. on
DNA is continually subjected to both endogenous and exogenous problems. on their comparative amounts, the cell routine phase, the percentage between deoxy- and ribo-nucleotide swimming pools as well as the connection with particular auxiliary protein, the restoration reactions completed by these enzymes is definitely an important way to obtain genetic instability, due to restoration errors. This review summarizes the newest results within the ambivalent properties of the enzymes in restricting or promoting hereditary instability in mammalian cells, aswell as their potential make use of as focuses on for anticancer chemotherapy. and [114]. Nevertheless, this substance inhibited also Pol and HIV-1 RT. The organic substances from the course of tetralols, nodulisporol and nodulisporone, made by a fungi (sp.), had been found to particularly inhibit Pol in the micromolar level [115]. In 2014, Mizushina et al. found that components from germinated soybean (L.), made up primarily by glucosyls, particularly inhibited the experience of eukaryotic Pol and possessed anti-inflammatory properties [116]. Dihydrocapsaicin IC50 7.4. Pol Artificial Little Molecule Inhibitors Particular methoxy-derivatives of resveratrol, a known antioxidant substance, were discovered to selectively inhibit Pol , however, not the related Pol and TdT [117]. In silico testing greater than 9000 substances to discover molecular probes that selectively inhibit Pol yielded there book classes of Pol inhibitors: rhodanines, carbohydrazides as well as the substances with the two 2,4-pentadione component [118]. Of the, rhodanines led to being the strongest Pol inhibitors. Additional research within the rhodanine derivatives exposed ten substances that demonstrated to specifically focus on Pol [107] and synergistically potentiated the eliminating of colorectal tumor cells by DNA-damaging providers. 7.5. Dual Pols and Organic Inhibitors Some inhibitors determined before manifested dual activity on both Pol and Pol . A good example of such an all natural inhibitor is definitely solanapyrone A, that was found out in 2002 from the band of Mizushina et al. [119]. Kimura et al. determined two azaphilones, kasanosins A and B, as particular Pol and Pol inhibitors [120]. Additional classes of organic substances that inhibit particularly mammalian X family members Pols (, , TdT), using the most powerful inhibitory activity towards Pol , are displayed by diallyl sulfides isolated from [121]. Oddly enough, these substances didn't inhibit the actions of family members A, B and Y Pols, and also other DNA-metabolic enzymes, such as for example HIV-1 RT, T7 RNA polymerase and T4 polynucleotide kinase. 8. Conclusions and Perspectives Probably one of the most interesting observations from the last 10 years, continues to be the realization that while just four Pols (, , and ) are essential and adequate for the duplication of both nuclear and mitochondrial DNA, greater than a dozen extra Pols are needed in mammalian cells to guarantee the maintenance of the hereditary details. Biochemical, structural Dihydrocapsaicin IC50 and hereditary KIAA0562 antibody studies have uncovered that these specific Pols are endowed with particular properties, which will make them exclusively fit for a specific DNA fix event, it getting either a particular pathway or perhaps a particular DNA lesion. Nevertheless, a number of these enzymes possess potentially overlapping assignments, thus requiring cautious regulation, with regards to expression amounts, intracellular localization and timing of recruitment to a specific subcellular area. When such a good legislation fails, these enzymes could be detrimental, Dihydrocapsaicin IC50 instead of beneficial, towards the cell, leading to mutations and hereditary instability. This example is normally well exemplified with the case of Pol and . These enzymes play important roles in lots of different fix pathways. Pol may be the primary enzyme involved with BER, which is important Dihydrocapsaicin IC50 during development, specifically in the mind, as testified with the embryonic lethality of Pol knockout mice. Pol , alternatively, is not important, at least for mouse advancement, since Pol knockout mice are practical and fertile. Nevertheless, modifications of its amounts have been obviously linked to several types of DNA harm accumulation and hereditary instability. Both these enzymes are hence.
Myeloid cell leukemia 1 (MCL-1) is a prosurvival BCL-2 protein family
Myeloid cell leukemia 1 (MCL-1) is a prosurvival BCL-2 protein family member highly expressed in hematopoietic stem cells (HSCs) and regulated by growth factor signals that manifest antiapoptotic activity. a decreased ability to subsequently restart DNA synthesis, which is normally dependent upon HR-mediated resolution of collapsed forks. Therefore, the present data support a model whereby MCL-1 depletion increases 53BP1 and RIF1 colocalization at DSBs, which Rucaparib inhibits BRCA1 recruitment, and sensitizes cells to DSBs from IR or stalled replication forks that require HR for repair. into the cytoplasm activates caspases which are responsible for the majority of the macromolecular degradation observed during apoptosis (3). Suppression of BAK and BAX polymerization by MCL-1 is prevented either by MCL-1 degradation or by Rucaparib saturating and inhibiting the MCL-1 binding sites on BAK/BAX with BH3 proteins or mimetics. Under normal growth conditions, MCL-1 is important for mouse embryonic survival (4) and critical for the survival of neutrophils, lymphocytes, hematopoietic stem cells, and neurons (5). MCL-1 overexpression is the hallmark of several cancers, including hematological malignancies as well as solid tumors. Elevated cellular MCL-1 expression correlates with resistance to drug toxicity and ionizing radiation (IR), whereas its inhibition sensitizes cells to both. The BCL-2 family of proteins is characterized by the presence of BCL-2 homology (BH) domains (1, 2). The MCL-1 protein itself is unique among BCL-2 members in also containing multiple N-terminal PEST motifs in addition to BH1, BH2, BH3, and C-terminal transmembrane (TM) domains. PEST is a signature of short-lived proteins degraded by the ubiquitin pathway, which explains the shorter half-life of MCL-1 than for other BCL-2 proteins (3). MCL-1 also has a smaller isoform (MCL-1S) that has only a BH3 domain and lacks the BH1, BH2, and TM domains (6, 7). BCL-2 family members have been reported to affect DNA damage repair (8,C10), and MCL-1 depletion can decrease Chk1 phosphorylation and increase phosphorylated H2AX (-H2AX) in etoposide-treated cells (11). Moreover, MCL-1 has also Adamts4 been shown to interact with several DNA damage response (DDR) proteins, including -H2AX, NBS1, and Ku70 (10, 12, 13), but the molecular details as to how MCL-1 may regulate DNA double-strand break (DSB) repair have not been established. We report here that MCL-1 deficiency impairs DNA DSB repair by homologous recombination (HR) and inhibits the resolution Rucaparib of stalled replication forks. RESULTS Depletion of MCL-1 increases genomic instability and decreases cell survival postirradiation. Inhibition of MCL-1 sensitizes cancer cells to chemotherapeutic drugs and IR (12, 14,C16). Consistent with the current literature, we found that MCL-1 depletion (Fig. 1) increased caspase 3/7 activity in irradiated DAOY cells (Fig. 1C) (other cell data not shown) and IR-induced killing of DAOY (Fig. 1Da), U2OS (Fig. 1Dc), and H1299 (Fig. 1Db) cells, as assayed by clonogenic survival (17). However, the increase in caspase 3/7 activity was observed only when the cells were exposed to a higher IR (6-Gy) dose, and there was no change in caspase activity at lower doses (2 Gy and 4 Gy). Ectopic expression of MCL-1 (pTOPO-MCL-1) in DAOY cells after depletion of endogenous MCL-1 restored normal radioresistance in the cells (Fig. 1Dd). Expression of pcDNA3-MCL-1S in cells depleted of both MCL-1 and MCL-1S (Fig. 1De) did not restore normal radioresistance, confirming the protective role of MCL-1 but not MCL-1S in postirradiation cell survival. FIG 1 Ionizing radiation response in cells with and without MCL-1. (A) The left side shows Western blots representative of MCL-1 knockdown in three cell lines using MCL-1 siRNA, and the right side shows Western blot analysis of MCL-1 levels in control siRNA- … To determine whether the increased radiosensitivity of MCL-1-depleted cells Rucaparib was due to defective DNA damage repair, we measured chromosome aberrations in MCL-1-depleted and control cells before and after irradiation. Genomic integrity is partly dependent upon telomeres whose dysfunction can lead to telomere fusions that produce di- or multicentric chromosomes. We examined telomeres and centromeres by fluorescent ihybridization (FISH) analysis and found that MCL-1 depletion results in telomeric signal loss along with dicentric or multicentric chromosome formation and aneuploidy (Fig. 2A, ?,BiBi to iii, and ?andC).C). Similarly, treatment of MCL-1-depleted cells with IR increased the number of cells with aneuploidy and chromosome aberrations (Fig..
Investigations of the molecular mechanisms underlying major depressive disorder (MDD) have
Investigations of the molecular mechanisms underlying major depressive disorder (MDD) have been hampered by the complexity of brain tissue and sensitivity of gene expression profiling approaches. in a discrete region of MDD subjects and contribute to further elucidation of the molecular alterations of this complex mood disorder. Materials and Methods Human subjects Brain samples were collected at autopsy at the Cuyahoga County Coroners Office (Cleveland, OH). Informed written consent was obtained from the legal next-of-kin of all subjects. Next-of-kin for all subjects were interviewed using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders IV (SCID) (First et al., 2001), and retrospective psychiatric assessments were conducted in accordance with Institutional Review Board policies. The use of retrospective informant-based Axis I diagnoses was validated by Kelly and Mann (1996) and reviewed by Lewis (2002). Fifteen subjects met diagnostic criteria for MDD based on the Diagnostic and Statistical Manual of Mental Disorders IV (American Psychiatric Association, Mouse monoclonal to IgG2a Isotype Control.This can be used as a mouse IgG2a isotype control in flow cytometry and other applications 2000). All topics with MDD had been experiencing a despondent episode in the last month of lifestyle, and, therefore, the results ought to be interpreted as reflecting over the state as opposed to the characteristic of unhappiness when the topics had been asymptomatic. Fifteen psychiatrically regular control topics were matched up using the 15 frustrated topics according to age group, ethnicity, gender, and postmortem hold off (Desk 1). There is no proof a neurological disorder in virtually any of the topics. Among the 15 frustrated topics, nine had prescriptions for antidepressant medication and one for an antipsychotic medication over the last month of lifestyle also. An antidepressant medicine (sertraline, venlafaxine, or nortriptyline) was within the bloodstream of four despondent topics, and chlorpromazine and buy 1380672-07-0 amitriptyline were within a fifth subject matter. Ethanol was detected postmortem in the bloodstream of two urine and topics of 1 subject matter. None of the three despondent topics met requirements for an alcoholic beverages use disorder. Desk 1 Case demographics from the matched up handles and MDD topics Human brain tissues planning Blocks of tissues in the DLPFC filled with Brodmanns region 9 were iced at autopsy using isopentane cooled in dried out ice and kept at ?80C. Frozen areas were cut on the cryostat (50 = 15) and matched up handles (= 15) had been invert transcribed into cDNA and indirectly tagged using a delicate fluorescent labeling method (Genisphere, Hatfield, PA). A two-step hybridization and labeling process was utilized (Genisphere array 350 process). The Agilent Individual 1A Oligo chip (Agilent Technology) was hybridized right away to cDNA in Agilent buffer, cleaned to eliminate nonspecifically destined probe stringently, and poststained with fluorescent dendrimers using Genisphere 2 SDS phosphate buffer then. After posthybridization washes, slides had been scanned utilizing a GenePix scanning device (Molecular Gadgets, Sunnyvale, CA). Picture evaluation was performed using GenePix Pro 4.0 software program (Molecular Gadgets). Microarray data evaluation Filtering and lacking buy 1380672-07-0 data imputation The fresh dataset contains 15 Agilent Individual 1A array scans regarding comparative hybridizations of an individual tagged with cyanine-3 (Cy3) against a matched up control sample tagged with Cy5. A complete of 20,173 probes had been scanned. All probe pieces that didn't match a gene in GenBank had been fell, and probe pieces with an increase of than six no phone calls were buy 1380672-07-0 fell. This still left 11,351 probe pieces. The dataset was after that examined in R/Bioconductor using the bundle (Cui and Churchill, 2003). Strength data were changed using the linear-log change technique (Cui et al., 2003), and scatter plots had been examined just before and after change. This change method yielded outcomes that were more advanced than the other strategies examined (e.g., LOWESS). Array amount 15 was fell from additional evaluation due to an sick conditioned scatter story that cannot be sufficiently normalized. Missing data had been imputed in the dataset using the k-nearest neighbor technique using the function in the collection in R (Troyanskaya et al., 2001) using the nearest 20 neighbours method. Mixed-model evaluation Although samples had been matched up, matching had not been perfect, specifically regarding antidepressant use. Eight from the 14 despondent topics were recommended antidepressants. A statistical strategy that was with the capacity of evaluating the impact of the imperfect complementing was therefore needed. Toward this final end, we utilized a mixed-model strategy as applied in the bundle in R to permit all resources of variation to become rigorously assessed. Due to limited levels of freedom, every one of the covariates appealing could not end up being entered right into a one model. Instead, some models were examined using the array impact entered being a mixed impact, (package.
Understanding the relationship between genetic variation and gene expression is definitely
Understanding the relationship between genetic variation and gene expression is definitely a central query in genetics. usually correlate with its manifestation levels [24],[25]. To overcome these problems, we adopt a platform from network component analysis (NCA) [26] that considers a simple bipartite network model of transcription rules involving only transcription factors and their focuses on. With this model, the manifestation of a target gene is completely captured by two properties of the network, the concentrations and promoter affinities of transcription factors. In general, inferring these two quantities from your manifestation profiles of the prospective genes alone is definitely hard. But by leveraging protein-DNA binding data from ChIP-Chip experiments [27],[28], a partial topology of the network can be constructed and one can make the inference given particular constraints [26]. The NCA method as explained by liao et 5-Iodotubercidin IC50 al. has been successfully applied to several gene manifestation datasets to understand transcription rules inside a temporal setting [26] and in the context of gene knockouts [29]. In this study, we prolonged NCA to study transcription rules over a populace gradient by modeling three mechanisms by which genetic variations perturb the concentrations and promoter affinities of active transcription factors to induce differential manifestation. Figure 1 gives a simple example that illustrates the original NCA model and our extensions. Think about we have a small experiment where we collected the gene expressions of four genes, the genotypes of three markers over three individuals. Given the topology of the bipartite network between transcription factors and their focuses on (Number 1B), the NCA algorithm allows us to infer the active transcription element concentrations (C) and the respective promoter affinities (PA) from your given gene expressions (E) 5-Iodotubercidin IC50 inside a log-linear fashion (Number 1A, see Methods). With this example, SNP1 and SNP3 are linked to the expressions of G1 and G3 while SNP2 is definitely linked to the expressions of G2 and G4. We propose three possible mechanisms any one SNP can perturb the regulatory network and display an instance of each using the given example. Number 1 Graphical illustration of NCA and extension of NCA to include genetic perturbations. SNP perturbs the concentration of an active transcription factor. SNP1 is definitely linked to the concentration of TF1 and expressions of G1 and G3, both focuses on of TF1 (Number 1C). Biologically, SNP1 could be located in close or much proximity to TF1 to change the concentration of TF1 through transcriptional, translational or post translational rules causing differential manifestation of the prospective genes. SNP perturbs the promoter affinities of a transcription factor globally. SNP2 is definitely linked to the expressions of G2 and G4, both focuses on of TF2. Here, SNP2 is not linked 5-Iodotubercidin IC50 to the concentration of TF2 but can still mediate global differential manifestation by altering the promoter affinities of TF2 on its focuses on (Number 1D). Biologically, SNP2 could be located either in close or much proximity to TF2 and alters TF2's affinities to many promoter areas either through a rare Rabbit Polyclonal to MSK2 non-synonymous mutation or a change in binding affinity between transcription factors in a complex, causing the global differential manifestation of the prospective genes. SNP perturbs the promoter affinities of transcription factors on a gene locally. SNP3 is definitely linked to the manifestation levels of G1 and G3 but is only to G3. It perturbs the local promoter affinities of TF1 and TF2 on G3 causing differential manifestation of G3 (Number 1E). Biologically, SNP3 could be located in G3's promoter region altering the promoter affinities of a transcription element (i.e. TF1) or a complex of transcription factors (we.e. TF1 and TF2), causing local differential manifestation of the prospective gene between populations. This mechanism differs from SNPs perturbing promoter affinities globally in that differential manifestation for only one gene (local), versus many genes (global) is definitely 5-Iodotubercidin IC50 induced. Because the inclusion of genetic variation creates additional guidelines in each.
Age-related cerebrovascular dysfunction contributes to ischemic stroke, intracerebral hemorrhages, microbleeds, cerebral
Age-related cerebrovascular dysfunction contributes to ischemic stroke, intracerebral hemorrhages, microbleeds, cerebral amyloid angiopathy (CAA), and cognitive decline. need for new strategies that improve BBB function and limit the development of beta-amyloidosis in the cerebral vasculature. Keywords: Alzheimer disease, cerebral amyloid angiopathy, bloodstream brain hurdle, immunotherapy, hypertension Launch Nearly all elderly have human brain pathology, and the ones with multiple human brain pathologies have a larger threat of developing dementia [1, 2]. The normal co-occurrence of Alzheimers disease (Advertisement) and vascular pathology PHA-680632 claim that many vascular risk elements can also be risk elements for human brain atrophy and dementia [3, 4]. Furthermore, cerebral amyloid angiopathy (CAA) along with hypertension, will be the two most common factors behind intracerebral hemorrhage (ICH), and CAA continues to be correlated with microbleeds in older people also. Age-related modifications in transport over the BBB, and a decrease in the efficiency from the perivascular drainage pathway have already been proposed to improve deposition of parenchymal and cerebrovascular amyloid debris in older people [5C10]. Interestingly, modeling claim that vessel pulsations supply the powerful power to operate a vehicle perivascular drainage, and age-related stiffening of arteries has been hypothesized to reduce flow thereby enhancing A deposition in the perivascular space therefore further slowing the clearance of A from your CNS [8, 9]. There is at least some hope for CAA-induced neuropathology because inside a subset of individuals having a analysis of CAA where there were clinical manifestations of the CAA-related swelling PHA-680632 there was significant medical improvement following anti-inflammatory therapy. The medical symptoms were subacute cognitive decrease or seizure rather than hemorrhagic stroke. Of six inflammatory CAA individuals with available follow-up information, five shown medical and radiographic improvement after immunosuppressive treatment [11]. Additional studies have found associations between CAA, inflammation and dementia [12C14]. One conundrum of epidemiological studies linking anti-inflammatory medicines to favorable medical results [15] and studies of human diseases in animal models [16] is definitely that they often fail in subsequent clinical tests. A likely crucial factor in the achievement of anti-inflammatory medications in treating illnesses with associated irritation is normally when the treatment is actually implemented. For instance, in a recently available survey where induction of autoimmune tolerance removed relapses, but didn't halt disease development in a pet style of multiple sclerosis [17], recommending that supplementary disease processes had been in charge of the continued drop in behavioral methods. The remainder of the critique we will concentrate on the pathological implications of CAA under regular aging circumstances and in the current presence of anti-A immunotherapy in human beings and in transgenic pet models. We may also discuss potential therapies to reduce the deposition of CAA and decrease CAA-induced pathological problems. Cerebral amyloid angiopathy CAA is normally a collective name for the number of illnesses of different etiology writing similar pathology. These are seen as a congophilic deposition of amyloid produced by different peptides like a, cystatin C, Rabbit polyclonal to FAK.Focal adhesion kinase was initially identified as a major substrate for the intrinsic proteintyrosine kinase activity of Src encoded pp60. The deduced amino acid sequence of FAK p125 hasshown it to be a cytoplasmic protein tyrosine kinase whose sequence and structural organization areunique as compared to other proteins described to date. Localization of p125 byimmunofluorescence suggests that it is primarily found in cellular focal adhesions leading to itsdesignation as focal adhesion kinase (FAK). FAK is concentrated at the basal edge of only thosebasal keratinocytes that are actively migrating and rapidly proliferating in repairing burn woundsand is activated and localized to the focal adhesions of spreading keratinocytes in culture. Thus, ithas been postulated that FAK may have an important in vivo role in the reepithelialization of humanwounds. FAK protein tyrosine kinase activity has also been shown to increase in cells stimulated togrow by use of mitogenic neuropeptides or neurotransmitters acting through G protein coupledreceptors. gelsolin, prion proteins, PHA-680632 ABri and ADan inside the wall space of little and moderate size cerebral arteries and occasionally in the microvasculature [18C21]. Nevertheless, the most typical type of CAA is normally due to cerebrovascular accumulation of the in sporadic disorders in older people and exists in 80C100% of Advertisement sufferers, and 100% of people with Down Symptoms [19, 22C25]. The occurrence of CAA in older people population without Advertisement or various other neuropathological abnormalities is normally age reliant and boosts from 13.8% of individuals between PHA-680632 60 and 69 years to 44.8% of these 80 years and older [26]. CAA isn't restricted to human beings only and will be easily within aged mammals: canines and nonhuman primates [27C29]. In human beings hereditary CAA is normally frequently complemented by hemorrhages and heart stroke and initiated by vasculotropic autosomal prominent mutations within a series of Dutch, Iowa, Flemish, Arctic and Italian types [12, 30C33]. Various other familial mutations connected with increased threat of CAA also linked to extra copies of APP such as French households with APP duplication [34], trisomy 21 [23], or APP processing-related enzymes presenelin-1 or ?2 [35C39]. Cerebral amyloid angiopathy and hypertension CAA is normally, along with hypertension, the most frequent reason behind ICH in the.
Background: In lupus nephritis (LN), deposition of pathogenic autoantibodies in the
Background: In lupus nephritis (LN), deposition of pathogenic autoantibodies in the glomeruli is mediated via cross-reactivity with alpha-actinin. that serum AA reduces in LN and serum level 59.5 pg/ml is SLE and is predictive of nephritis Key Words: Systemic lupus erythematous, Nephritis, Anti-alpha-actinicn antibody, Diagnosis. Systemic lupus erythematous (SLE) is definitely associated with multiple organ involvement and high morbidity as well as mortality (1-4). Among the several manifestations of SLE, nephritis is definitely of particular concern ,because lupus nephritis (LN) is definitely associated with extra risk of death, malignancy and cardiovascular complications (3, 4). Rabbit polyclonal to ALOXE3. Alpha-actinin (-actinin) is definitely a ubiquitous cytoskeletal protein which belongs to the superfamily of filamentous actin (F-actin) crosslinking proteins. It is present in multiple subcellular regions of both muscle mass PF-04217903 and non-muscle cells, including cellCcell and cellCmatrix contact sites, cellular protrusions and stress dietary fiber dense areas. It seems to keep multiple important tasks in the cell by linking cytoskeleton to many different transmembrane proteins in a variety of junctions. Deposition of autoantibodies in the glomeruli seems to be important for development of LN (5). In SLE, anti C alpha-actinin (AA) is definitely a major cross-reactive focus on for anti-dsDNA antibodies (6) and pathogenicity of some anti-DNA antibodies is normally mediated via cross-reactivity with alpha-actinin (7-9). Previously research PF-04217903 show that renal pathogenicity of murine lupus antibodies are reliant on immediate binding of antibodies to AA (7-9). Dynamic LN weighed against SLE sufferers without nephritis shows better AA binding (6). It's been proven that pathogenic anti-ds DNA antibodies bind highly to AA and raised degrees of serum AA antibodies are connected with a 2.5 -fold upsurge in the prevalence of nephritis (6). In a single research, 10 out of PF-04217903 22 (45.1%) sufferers with AA antibody had LN, while just 14 away of 78 (17.9%) SLE sufferers without AA antibody acquired LN. This means that a substantial association between serum AA antibody and LN (6). Even so, SLE sufferers without nephritis as well as sufferers without SLE could also possess serum AA antibody (8-10). Croqueted et al. likened the prevalence of AA, between SLE and additional rheumatic illnesses versus healthy settings (9). The full total outcomes demonstrated higher prevalence of AA antibody in SLE weighed against rheumatoid joint disease, Siogren symptoms, and healthy settings (22.3%, 3.92%, 3%, and 0.6% respectively). In Renaudineau et al,s research (6), the prevalence price of AA antibody positivity was higher in anti-dsDNA positive versus anti-dsDNA adverse SLE (33.8% vs 2.8%). However, inside a longitudinal research of 16 individuals with new-onset-biopsy-proven LN, there is an optimistic association between actions of LN with anti-DNA and anti-nucleosome however, not with AA antibody (11). In a few research, the partnership between serum AA antibody and SLE disease activity index (SLDAI) or anti-ds DNA was evaluated and the outcomes revealed a poor relationship of AA with SLEDA and positive relationship with anti-dsDNA (6, 9, 10, 12). Obtainable data reveal that binding of pathogenic autoantibodies to AA antibody is crucial for the introduction of nephritis PF-04217903 in SLE, recommending a relationship between serum AA LN and antibody. Nevertheless, the full total outcomes of research with this framework are questionable (6, 10, 11, 12) which might be attributed to insufficient sample size, unacceptable research designs, individual selection or non-homogeneous distribution of predisposing elements of LN across different research. To conquer these shortcomings, today's case- control research was made to evaluate SLE individuals with and without nephritis concerning serum AA antibody amounts also to investigate the partnership between serum AA antibody and LN. The supplementary reason for this research was to determine a cutoff degree of AA antibody for the discrimination of SLE individuals with and without nephritis. Strategies Ninety individuals with lupus erythematous had been recruited consecutively relating PF-04217903 to inclusion requirements among those that shown to rheumatology treatment centers of Mashhad College or university of Medical Sciences, Mashhad, Iran, From Oct 2011 to Sept 2012 Individual selection was performed more than twelve months period. The analysis of SLE was verified from the American University of Rheumatology.
Background: Some types of gastric intestinal metaplasia (GIM) could be precancerous
Background: Some types of gastric intestinal metaplasia (GIM) could be precancerous however the cellular phenotype that predisposes to gastric carcinogenesis isn't good characterised. the phenotypes of GIM. The colonic phenotype of GIM, as discovered by mAb Das-1, is connected with gastric carcinoma strongly. divided GIM into comprehensive (little intestinal) and imperfect (colonic) types using enzyme methods.2 Another classification categorised GIM into three types: I (complete), and II and III (incomplete).3 That is based on the actual fact that little intestinal goblet cells make sialoglycoprotein that stains with periodic acid-Schiff (PAS) and alcian blue (AB), and colonic goblet cells make sulphomucin that's detected by AB/high iron diamine (HID) staining.1,4,5 Incomplete GIM seems to carry the best preneoplastic prospect of the intestinal selection of gastric carcinoma, which may be the most common kind of gastric carcinoma; despite the fact that some research have got connected finish GIM with gastric carcinoma also. 6 Using histochemical and histological mucin staining methods, it's been tough to accurately ASA404 define the phenotypic differentiation of GIM because of observer reliant variability in determining subtle colour distinctions.7 This example is often further challenging with the coexistence of various kinds of GIM and the current presence of mosaic cases, which were reported that occurs in 41% of sufferers. A biomarker(s) to reliably differentiate numerous kinds of GIM, and recognize sufferers who could be at an increased threat of developing gastric carcinoma, will be medically very ASA404 helpful. Using a colon epithelial protein, we developed a novel murine monoclonal antibody, mAb Das-1 (formerly known as 7E12H12, IgM isotype), that reacts with colonic epithelium.8 Using both immunoperoxidase and immunofluorescence assays, we while others have independently demonstrated that mAb Das-1 specifically reacts with colonic epithelium (both goblet and non-goblet absorptive cells) but not with small intestinal enterocytes (including goblet cells) from your jejunum or ileum, or normal epithelium from the rest of the gastrointestinal tract.8,9 Although mAb Das-1 does not react with normal gastric and oesophageal epithelium, it reacts sensitively (95%) and specifically (100%) with Barretts epithelium and adenocarcinoma of the oesophagus, indicating a strong association of its reactivity to this precancerous condition.10,11 In the present study, we explored if mAb Das-1 reactivity helps to identify the colonic phenotype of metaplasia in ASA404 the belly and its association with gastric carcinoma. We examined the immunoreactivity of the mAb against the cells with different histological spectra of chronic gastritis beginning at an early stage before the development of GIM, in the intermediate stage when GIM experienced developed but no malignancy was detectable, and finally in the point where GIM was associated with gastric carcinoma. As gastric carcinoma is definitely more common in Japan, we compared the reactivity in the cells specimens from ASA404 the USA Rabbit polyclonal to HAtag. (New Jersey, NJ) and Japan. MATERIALS AND METHODS Paraffin inlayed cells blocks were from 150 individuals from NJ and Japan. Group A (n=60) We used the computer database of the pathology departments to randomly select 60 cells blocks having a analysis of GIM associated with gastric carcinoma. Thirty five individuals from Japan (group A1) and 25 from NJ (group A2) were included. For each of these 60 individuals, paired samples of belly (medical specimens) included both malignancy areas and histologically proved GIM areas away from the malignancy segments. Group B (n=72) Biopsy cells specimens comprising GIM without gastric ASA404 carcinoma were acquired both from Japan (group B1, n=31) and NJ (group B2, n=41). Group C (n=18) Eighteen biopsy samples were from Japan with chronic gastritis, without evidence of GIM. The biopsy samples in organizations B and C were obtained during routine upper endoscopy methods for a variety of indications (usually dyspepsia and peptic ulcer disease) other than gastric carcinoma. Five serial 5 m sections were.
Low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and total
Low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and total cholesterol are heritable, modifiable, risk factors for coronary artery disease. lipids are heritable, modifiable, risk factors for coronary artery disease (CAD)1,2, a leading cause of death3. Human genetic studies of lipid levels can identify targets for new therapies for cholesterol management and prevention of heart disease, and can complement animal studies4,5. Studies of naturally Carfilzomib occurring genetic variation can proceed through large-scale association analyses focused on unrelated individuals or through investigation of Mendelian forms of dyslipidemia in families6. We previously identified 95 loci associated with blood lipids, accounting for ~10-12% of the total trait variance4 and showed that variants with small effects can point to pathways and restorative focuses on that enable clinically-important changes in blood lipids4,7. Here, we statement on studies of naturally happening variance in 188,578 European-ancestry individuals and 7,898 non-European ancestry individuals. Our analyses determine 157 loci associated with lipid levels at < 510?8, including 62 new loci. Thirty of the 62 loci do not include genes implicated in lipid biology by earlier literature. We tested lipid-associated SNPs for association with mRNA manifestation levels, carried out pathway analyses to uncover human relationships between loci, and compared the locations Carfilzomib of lipid-associated SNPs with those of genes and additional functional elements in the genome. These results provide direction for biological and restorative study into risk factors for CAD. Results Novel loci associated with blood lipid levels We examined subjects of Western ancestry, including 94,595 individuals from 23 studies genotyped with GWAS arrays4 and 93,982 individuals from 37 studies genotyped with the Metabochip array8 (Supplementary Table 1 and Supplementary Fig. 1). The Metabochip includes variants representing encouraging loci from our earlier GWAS (14,886 SNPs) and from GWAS of additional CAD risk factors and related qualities (50,459 SNPs), variants from your 1000 Genomes Project9 and focused resequencing10 attempts in 64 previously connected loci (28,923 SNPs), and fine-mapping variants in 181 loci associated with additional qualities (93,308 SNPs). In cases where Metabochip and GWAS array data were available for the same individuals, we used Metabochip data to ensure important variants were directly genotyped, rather than GIII-SPLA2 imputed. We excluded individuals known to be on lipid decreasing medications and evaluated the additive effects of each SNP on blood lipid levels after modifying for age and sex. Genomic control ideals11 for the initial meta-analyses were 1.10 Carfilzomib C 1.15, low for a sample of this size, indicating that human population stratification should have only a minor impact on our results (Supplementary Fig. 2). After genomic control correction, 157 loci associated with blood lipid levels were recognized (< 510?8), including 62 new loci (Furniture 1A-?-D,D, Number 1, Supplementary Furniture 2 and 3). Loci were >1 Mb apart and nearly self-employed (r2 < 0.10). Of the 62 novel loci, 24 shown the strongest evidence of association with HDL cholesterol, 15 with LDL cholesterol, 8 with triglyceride levels, and 15 with total cholesterol (Supplementary Fig. 3). Several of these loci were validated by a similar extension based on GLGC GWAS results 12. Number 1 Overlap between loci associated with different lipid qualities TABLE 1A Novel Loci Primarily Associated with HDL Cholesterol From Joint GWAS and Metabochip Meta-analysis TABLE 1D Novel Loci Primarily Associated with Triglycerides From Joint GWAS and Metabochip Meta-analysis The effects of newly recognized loci were generally smaller than in earlier GWAS (Supplementary Fig. 4). For the 62 newly recognized variants, trait variance explained in the Framingham offspring were 1.6% for HDL cholesterol, 2.1% for triglycerides, 2.4% for LDL cholesterol, and 2.6% for total cholesterol. Overlap of genetic discoveries and previous knowledge To investigate Carfilzomib contacts between our fresh loci and known lipid biology, we 1st catalogued genes within 100 kb of the peak connected SNPs and looked PubMed and OMIM for occurrences of.


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subset: commoncrawl


text:
|Repairable chip bonding/interconnect process
|Bernhardt et al.
|Method of fabrication of endcap chip with conductive, monolithic L-connect for multichip stack
|Bertin et al.
|Method of manufacturing edge connected semiconductor die
|Method for interconnecting a stack of integrated circuits at a very high density
|Eichelberger et al.
|Method and means for handling semiconductor and similar electronic devices
|Atlhouse et al.
temporarily holding a plurality of chips for processing,
forming a dielectric layer on the top surface and at least one sidewall of the chips,
opening vias in the dielectric layer on the top surface and the at least one sidewall of each chip,
forming patterned metal traces connected to the bond pads on the top surface and extending only onto the at least one sidewall of each chip using laser pantography, and
removing the thus processed chips from the temporary holding arrangement.
providing a plurality of chips having bond pads on a surface thereof, and
forming L-connects on the surface and one or more sidewalls of the chips which are in electrical contact with the bond pads,
forming of the L-connects by providing the chips with a dielectric film on the surface and one or more sidewalls, forming vias in the dielectric film, and directing laser energy onto the dielectric film forming patterned metal traces, and
stacking the chips one on top of another whereby the chips can be interconnected via the L-connects on the one or more sidewalls.
The present invention relates to stacking of integrated circuit chips, particularly to the formation on bond pads on the sidewalls of the chips which enable ready access for interconnecting stacked chips or chip packages, and more particularly to a low cost manufacturing process for producing chips with bond pads on the sidewalls thereof by forming electrical interconnects with bonding pads on the top surface of the chips.
The memory density of integrated circuit memory chips has been increasing at a rapid rate over the past decade, and this need for increased density will continue in the near future for applications such as super computer memories. In addition, there is a demand for increased chip packaging density to increase performance, reduce space, and provide higher functionality per unit volume needed for applications such as space-based electronic systems, miniaturized electronics for weaponry and surveillance, and hand-held electronics systems. One solution to the demand for increased density is to package the chips closer together, so that the effective density per unit volume increases. The densest packaging of chips is to stack them one on top of another into a single three dimensional (3D) unit or cube. In order to stack chips on top of each other, the bond pads, normally located on a top surface of the chip, must be extended to the edge surface or sidewall of the chip, and must be exposed so that attachment to another level of the stacked chips for packaging is readily accessible.
The extending of the bond pads to the edge of the chip has been carried out in a number of ways. One of the more elegant, simple, and straightforward methods involves the implementation of L-connects, which are metal traces patterned with laser pantography from the top of the chip, over the edge, and onto the sidewall before the chips are stacked. This method is described and claimed in U.S. application Ser. No. 08/733,854, filed Oct. 18, 1996, entitled "L-Connect Routing Of Die Surface Pad To The Die Edge For Stacking In A 3D Array," assigned to the same assignee. With the input/output (I/O) pads routed onto the sidewall of the chip, they are available for ready attachment to any point of use, particularly for stacking of chips and packaging of stacked chips.
The present invention provides a manufacturing process which implements the 3D chip stacking using interconnects, such as "L-connect" of the above-referenced copending application, for extending the chip bond pads to a sidewall or sidewalls of the chip. The invention involves an improved process for forming the "L-connect" (electrical interconnect) which holds the chips during processing, utilizes a dielectric passivation layer on the top surface and sidewalls of the chips, forming opening vias through the passivation layer in the top and sidewalls in a desired pattern, and forming electrically conductive traces on the patterned vias using robust laser pantography.
It is an object of the present invention to provide a manufacturing process for producing integrated circuit chips capable of three dimensional stacking.
A further object of the invention is to provide a low cost manufacturing process for forming interconnects extending from a bond pad on a top surface of a chip to one or more sidewalls of the chip.
Another object of the invention is to provide an improved process for forming an "L-connect" on integrated circuit chips for enabling stacking of chips.
Another object of the invention is to provide a process which implements the 3-D chip stacking approach using an "L-connect" (interconnect) arrangement, which involves holding individual chips for batch processing, formation of a dielectric layer thereon, forming a desired pattern of vias in the dielectric, and forming the interconnects using laser pantography.
Other objects and advantages of the present invention will become apparent from the following description and accompanying drawings. The invention is primarily directed to an implementation of the "L-connect" concept of the above-referenced application Ser. No. 08/733,854, wherein L-connects (electrical interconnections) are patterned from the top surface of an integrated circuit chip or die to the sidewall of the chip using laser pantography. Implementation of the L-connect approach includes a process which involves holding individual chips for batch processing, depositing a dielectric passivation layer on the top and sidewalls of the chip, opening patterned vias in the dielectric, forming the L-connects using laser pantography, and removing the chips from the holding package. The improved process of this invention provides low cost manufacture of the chip configured to enable stacking of the chips for increased performance, reduced space, and higher functionality per unit volume, for applications such as super computers, space-based and hand-held electronic systems, and miniaturized electronics for weaponry and surveillance.
The accompanying drawings, which are incorporated into and form a part of the disclosure illustrate an embodiment of the invention and, together with the description, serve to explain the principles of the invention.
FIG. 1 is a perspective view of a conventional integrated circuit chip or die.
FIG. 2 is a perspective view of the chip of FIG. 1 with L-connects formed thereon in accordance with the invention.
FIG. 3 is a perspective exploded view of stacked integrated circuit chips, each made in accordance with the invention.
The present invention is directed to a manufacturable process which implements 3-D chip stacking using interconnects, such as the L-connects of above-referenced copending application Ser. No. 08/733,854. L-connects are metal traces patterned with laser pantography from the top surface of a chip or die, over the edge of the chips, and onto a sidewall before the chips are stacked, thereby extending the bond pads normally located on the top surface of the chip to the sidewall of the chip. With the I/O pads routed onto the sidewall, they are readily available for attachment to a desired location. Implementation of the L-connect top surface to sidewall approach requires:
1. Placing the chips or die in a temporary handling arrangement for holding individual chips securely in an efficient, damage-free manner, during handling, processing, and patterning, and facilitate batch processing of chips after they have been cut from an original silicon wafer into individual chips.
2. Depositing a dielectric passivation layer on both the top surface and sidewalls of the chips.
3. Opening vias through the dielectric layer on the top and one or more sidewalls of the chip, in order to electrically connect to the bond pads on the top of the chip, which are to be routed over the dielectric layer to the sidewalls to form the L-connects.
4. By laser pantography, forming the metal traces from the top surface of the chip to the sidewalls.
5. Removing the chips from the temporary handling arrangement.
Methods for handling individual chips for processing are known in the art. Two such methods are described by way of example. The first of these methods uses a hold-and-release method developed by Victor Athouse, Gel-Pak, Inc., as described in U.S. Pat. Nos. 4,667,944 issued May 26, 1987; No. 4,711,014 issued Dec. 8, 1987, and 4,778,326 issued Oct. 18, 1988. In this method a silicone polymer sheet is stretched over a mesh or screen. Chips can be attached to the silicone because the silicone has sufficient tack to hold chips that are lightly pressed onto it. To remove the chips, a vacuum is pulled through the mesh, which is on the other side of the silicone from the chips, which causes the silicone to be drawn into the mesh, decreasing the surface area of silicone on the back of the chips. The chips can easily be removed with a vacuum wand or tweezers. The silicone has been shown to be compatible with subsequent processing. The second method for holding the chips involves the adhesion of the chips onto a temporary substrate using small amounts of adhesive to hold the chips in place. The adhesive must be capable of withstanding the subsequent processing required by laser pantography. A pick-and-place or a template can be used to position the chips accurately with respect to each other (the adhesive should be thermoplastic enough to soften at elevated temperatures to facilitate removal of the chips). Alternatively, the adhesive can be dissolved away to remove the chips. The first method has the advantage of fewer steps with less post process cleaning required.
Vapor deposition polymerization (VDP) of polyimide is an effective and efficient method for producing a dielectric passivation film on both the top and sidewalls of the chips. The polyimide is deposited in a vacuum chamber followed by a short curing step. This operation is described in greater detail hereinafter.
Other methods of forming the dielectric passivation film, such as PECVD of silicon oxide or silicon nitride or silicon oxy-nitride, polyamide and parlyene, or RIE etching, are available; but the VDP polyimide method has the fewest steps with the highest yield potential, which translates into a manufacturable process.
The vias can be opened in the VDP polyimide with a single step laser ablation using a pulsed or CW ultraviolet (UV) laser, as described hereinafter.
The metal traces or L-connects are then formed on the top and sidewall of the chip by laser pantography for patterning in three (3) dimensions the desired interconnects. This can be accomplished using the steps outlined in copending application Ser. No. 08/387,495, filed Feb. 13, 1995, entitled "3-D Laser Patterning Process," assigned to the same assignee, and described in greater detail hereinafter. Laser pantography may be carried out using a continuous wave (CW) laser, such as an argon-ion laser, or using a pulsed laser, such as an Nd:YAG, excimer, and nitrogen laser.
Referring now to the drawings, FIG. 1 illustrates a conventional integrated circuit chip 10 having a top surface 11 and sidewalls 12, with a plurality of bond pads 13 on the top surface 11.
FIG. 2 illustrates an embodiment of a chip 10 processed in accordance with the invention in which L-connects 14 extend from the bond pads 13 across the top surface 11, over the edges 15 and/or 16, to the sidewalls 12. Bond pads 17 are formed on the sidewalls 12 in contact with the L-connects 14, and may be formed integral with the L-connects 14 or separately, or the bond pads can be omitted. While FIG. 2 illustrates the L-connects 14 extending over edges 15 and 16 onto opposite sidewalls of the chip 10, as a current general practice the L-connects would extend onto one sidewall only; but in the future several chip sides may be patterned.
FIG. 3 illustrates an exploded stack of chips 10 having L-connects 14 extending from bond pads 13 to only one sidewall 12, with bond pads 17 formed thereon. It is readily seen that when the chips 10 of FIG. 3 are stacked one on top of another electrical interconnects between the sidewall bond pads 17, or the interconnect portions on the sidewalls if bond pads are omitted, of the various chips can be easily made. Also, with the chips stacked, packaging of the stacked chips with other chips or desired component can be readily accomplished due to the sidewall bond pads 17.
The following sets forth a specific operational sequence for forming the L-connects and sidewall bond pads on integrated circuit chips:
1. Holding for processing, a plurality of chips having bond pads on the top surfaces thereof, by:
Chips are adhered to a substrate (typically a 4" silicon wafer) with very small amounts of a 2-part 30 minute open time epoxy adhesive. The chips are placed in the slots of a template to insure adequate alignment.
Alternately, the chips are placed onto a Gel-Pak carrier, the case of which is made of aluminum in place of the normally-used plastic. A pick and place can be used to control the alignment.
Alignment is not a critical issue because the Laser Pantography apparatus can compensate. However, the better the alignment, the faster the process.
2. Forming a dielectric passivation film or layer on the top surface and sidewalls of the chip by:
The Si substrate with attached chips is mounted on a rotating planetary which is upside down in a vacuum evaporator system which has been modified to deposit co-polymers from monomer sources. The baseline pressure is in the 10(-6) range, while the operating pressure is in the low 10(-5) range. The "gun," or source, consists of two thermally separated chambers each of which contains one monomer. These chambers are individually heated, resulting in sublimation of the monomers. The rate of effusion from the chambers is monitored with Inficon crystals. The monomers escape from the chambers through a small opening in each which is directed up toward the planetary.
Pyromellitic dianhydride (PMDA) is co-deposited with 4,4"-oxydianiline (ODA) to produce a film (PMDA/ODA) which is chemically identical to Kapton. Other monomer combinations are also possible, such as 3,3', 4,4'-biphenyl tetracarboxylic dianhidride (BPDA) and p-phenylene diamine (PPD).
PMDA/ODA is deposited at a rate of 2-3 microns an hour. Typically, 1-2 microns are deposited. The individual monomers are heated to 100°-150° C. The substrate is not heated.
The deposited polymer film must be cured to form polyimide. The substrate is placed in an oven at 120° C. for 15 minutes. The temperature is then ramped to 260°-400° C. for one hour.
3. Opening vias in the dielectric film by:
An argon-ion CW laser operating in the multiline UV at 3-4 Watts power can be used to open the vias. A power of 300 milliwatts focused into a 40 micron by 5 micron beam is sufficient to remove a 1 micron thick polyimide film.
Alternately, a pulsed Nd:YAG laser quadrupled to produce the 254 nm line can be used to open almost any thickness of polyimide.
Alternately, an excimer laser could also be used. Any UV wavelength would be appropriate.
A short ashing step (oxygen plasma for 10 minutes at 150 Watts) is useful for cleaning any debris left in the vias.
4. Forming the L-connects or metal traces by:
A seed layer consisting of a titanium layer (500-1000Å thick) followed by a copper layer (2000-6000Å thick) is sputtered onto the part (i.e., substrate with dice attached). A positive electrodeposited photoresist (Shipley's PEPR 2400) is plated onto the part (5-10 microns). A CW argon-ion laser focused to a 40 micron by 5 micron beam is used to expose the pattern on the chip. To pattern the sidewalls, the beam is sent through an objective at an angle to the substrate. The resist is developed in 1% potassium carbonate. Copper (3-7 microns) is plated through the resist mask. The remaining resist is stripped with hot base. The copper seed is removed with ammonium persulfate, and the titanium adhesion layer is removed with SF6 in an RIE reactor.
5. Removing the processed chips from the holding arrangement by:
The chips are removed from the Si substrate by heating the substrate to 100°-200° C. for a few minutes on a hot plate, and gently pushing off the chips.
The chips are removed from the Gel-Pak by applying a vacuum to the package, which causes the silicone film to be drawn partially through the mesh, reducing the surface area of the silicone to chip interface, allowing the chips to be removed easily with a vacuum wand.
It has thus been shown that the present invention provides an implementation method by which chips having L-connects for stacking can be fabricated in a batch process. While the process has been described relative to the formation of L-connects (L-shaped electrical interconnects) the process can be utilized using any desired interconnect configuration or combination of interconnect configurations, whereby bond pads on a top surface of a chip are extended to an edge or sidewall of the chip. Also, by this process top surface bond pads can be extended to one or more of the chip sidewalls which enables stacking of the chips, interconnection of the chip to other components, and/or packaging of stacked chips to other stacked chips or components.
While particular embodiments, a specific operational sequence, materials, parameters, laser parameters, etc., have been described and/or illustrated to exemplify and set forth the principles of the invention, such are not intended to be limiting. Modifications and changes may become apparent to those skilled in the art, and it is intended that the invention by limited only by the scope of the appended claims.


text:
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« AnteriorContinuar »
Dear Sir,
A complete stranger to you, I came to your house; and you not only granted me the rites of hospitality, but at a moment when I was deprived of all the means of executing my purpose of preaching the tidings of salvation in the land of Bokhara and Affghanistaun, you offered me, without my soliciting it, your kind assistance."' After enjoying for several months your most instructive conversation, and wandering in spirit together through the opinions of the ancients, and communicating our ideas on higher points, regarding the eternal welfare of human beings, I set out for my perilous journey: with your help I was able to make out my way, and to rescue myself from difficulties; and during the time of my absence, you, your sister and Miss Jane Frere treated with the utmost kindness those that are dearest to me; so that even my boy of three years old seems to be sensible of it, and has learnt to look up to you with reverence and gratitude. To whom else, therefore, but to you should I dedicate these humble pages, containing the Acts of my Pilgrimage to Bokhara, Balkh, Cabool, Cashmeer, and
* Mr. Wolff repaid Mr. Frere every penny.
Hindoostaun? especially as I hope soon to undertake another pilgrimage; not knowing that which may befall me, nor whether I shall ever see you again. To none then, I repeat it, can I dedicate the results of my labours with more satisfaction to myself, than to you. But I feel that I am addressing one of whom I am incompetent to speak in terms commensurate with merit; indeed, to the inhabitants of this island it were superiluous to do so: all, from the highest to the lowest, allow, that to the native poor you are looked upon as a blessing; your hospitality is known to all. And I confidently add, that I do not know where I should look for an individual, combining, like yourself, so many of the best gifts of our nature with so much profound erudition; so much benevolence with so much nobleness of intellect. In venturing to write this my genuine sentiment, it is not flattery, but truth which prompts me, and I am convinced that in doing so I have the suflrages of all who know you. This book then, thus dedicated, may remain as a mark of the ardent gratitude of the writer, who, with prayers for you and your whole house, is ever, Dear Sir, Your most humble and affectionate Friend and servant, JOSEPH WOLFF, ' Missionary. Malta, 29th January, 1835. ,
The Reader must not expect to find in the pages of my journal descriptions of ancient monuments, or of natural or artificial curiosities. The object of my journey, as I have stated in it, was solely to proclaim the Gospel of the kingdom of Christ, among the Jews, and the tribes whom I have visited; and to seek for those tribes of Israel whom I conceive to be the Kings of the East, mentioned in the Revelation of Jesus Christ. I have however at the same time given the best account in my power of those sects which have been hitherto unknown, and of the character of those nations to whom the Gospel of Jesus Christ has not been revealed, their good qualities, and their vices; but chiefly the expectations, expressed by my own nation, the Jews, in distant countries. I have not entirely passed over in silence the adventures I met with in those countries, and the disappointments I experienced in my labours; nor the customs and manners of the nations I visited; which especially illustrate historical facts, manners, and modes of speaking, and which we frequently meet with in sacred writ. I have also pointed out such situations in which Missionary Societies may extend their operations; and I have spoken with impartiality of the success which Missionaries have met with in the East. So that I humbly trust, the Christian will here find sufficient motives to admire God's providence in preserving his servants; and Missionary Societies find matter for encouragement in the extending of their labours to those benighted countries. The individual Missionary may find matter for confirming his confidence; in the Lord; the Divine, matter for research. By my openly disputing with Mussulmans at Meshed, and throughout Khorossaun, which I am enabled to testify by letters from Mohammedans of those countries, and the passports of the Princes of Persia, and the King of Bokhara, which I haveannexed, it may be seen that one may travel with these objects without disguise. I have abstained from introducing subjects of controversy amongst real Christians; for my purpose in publishing this journal is, to edify all those who worship the name of our divine Lord and Saviour Jesus Christ, and to encourage them in uniting together in opposition to Jews, Mohammedans, Infidels, and Pagans. If the Reader should find that these objects have been attained, it will be a great satisfaction to the Author; and if they should feel themselves in some measure disappointed in their expectations, they will take into consideration, that these pages came from a humble individual, such as
REV. JOSEPH Wolff.
I Have already given to the public, in three separate volumes, the journals of my Missionary labours among my brethren of the Jewish nation in Palestine, Egypt, Mesopotamia, Persia, Krimea, Georgia, and the Turkish Empire, which I began in 1821 and accomplished in 1826. My labours among my brethren in England, Scotland, Ireland, Holland, and again in the Mediterranean, from the year 1826 to 1830, were published in the "Jewish Expositor." I now communicate to the Church my labours among my brethren
in TURKEY, PERSIA, TURKESTAUN, BOKHARA, AFFGHANISTAUN, CASH
Meer, Hindoostan, and the Red Sea, from the year 1831 to 1834, which I have accomplished through divine grace, with the motives also, which induced me to undertake this journey.
In the first place, it was my earnest desire to make known to my brethren of the Jewish nation, Jesus Christ, the Son of God and rightful heir to David's throne; whose kingdom shall extend itself from the rising of the sun, to the going down thereof; and, encouraged by the example of St. Paul, (Rom. xv. 20,) to preach the tidings of Salvation in those places, where the pure light of the Gospel does not yet shine.
Besides this, I often asked myself, how my brethren fare, whose ancestors were scattered, after the captivity of Babylon: those tribes of Israel, who, according to the sacred oracles, shall be united to the house of Judah; and whose present abode is a matter of speculation among many Christian Divines, and Jewish Rabbies. The latter assign to them a fabulous country, which they call "The land of darkness, beyond the Sabbathical river." Benjamin Tudela, and the Jews of Jerusalem boldly asserted, that they were residing at Halah and Habor, which they state to be the present Balkh and Bokhara. In the year 1829, being then at Jerusalem, I said to my wife, "Bokhara and Balkh are very much in my mind, for I think I shall there find the Ten Tribes." "Well," she replied, "I have no objection to your going there." In consequence of this, I took my wife to Alexandria, and then made an excursion to Salonica, to see the followers of Shabatay Zebi, a Jewish sect; B


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Adkins Historical & Museum Complex, Inc
Ten historical buildings and a privy are open for free tours.
Ten historical buildings and a privy are open for free tours.
Wicomico County's Nanticoke River watershed area's history, traditions, and cultural heritage, special focus on town's history as a mineral water spa attraction and more than 25 exhibits.
Built in 1842 by Presbyterian and used as a school; was restored as historical building in 1995.
A variety of sporting clays and shooting ranges offered.
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We offer vedic online Puja or Pooja, Hindu Rituals...
Online Puja of Sri Dhanvantri
Sri Dhanvantri Online Puja for good Health
Sri Dhanvantri Puja is done for good Health and getting rid of diseases.
Dhanvantri, the physician of gods, who appeared at the churning of the ocean is worshipped on this day, specially by the physician-community.
Dhanvantri is the father of Vedic science of medicine and Ayurveda is attributed to him. He is also called Sudha pani, because he appeared from the ocean, carrying nectar in his hands.
Sri Dhanvantri online puja is to be done when a person is suffering from ill health.and there is no option of getting well.
When this pooja is done once in a year,there is an atmosphere of positive energy everywhere,there by reducing ill effects on the health. Sri Dhanvantri Online Puja is very powerful.
Contact Us for Sri Dhanvantri Online Puja. Pooja is done by well renewed and learned priest.
© All the text and images of this web site is copyright of www.onlinepuja.org Coping, republishing matter of this web site is strongly prohibited.
Contact Us For online Puja | Back To Home


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Please select from the links below to download any of our patient forms:
What To Expect On Your First Visit
Please arrive 15 minutes before appointment time to complete paperwork. Make sure you bring your insurance card and co-pay. Bring a list of all the medications you have taken in the last year, and any relevant lab work done in the last 2 years. Please be prepared to be here for at least one hour in order to allow a thorough evaluation.
You will initially be seen by our trained allergy nurse who will obtain vital signs, record your medication list and perform pulmonary function testing if you have any respiratory or cough issues.
You will then spend extensive time with Dr. Cymerman. Much of that time will be discussing why you are here, what evaluation and treatment you have had in the past, and most importantly, what events led up to your current condition. A physical exam relevant to your allergy symptoms will be performed; a loose-fitting shirt is helpful.
Allergy testing via skin prick testing may or may not be performed the first visit, depending on what medications you are taking, what your respiratory status is and other factors. Skin testing can NOT be done if you have NOT eaten in more than an hour, if you are ill, if you have a reduced respiratory status or if you have taken antihistamines in the previous 72 hours. If Dr. Cymerman assesses allergy testing to be appropriate, skin testing will be performed. Please keep in mind skin testing is not appropriate for every patient for a number of possible reasons.
Please do not stop any asthma medications that you are taking under any circumstances.
Feel free to call and ask questions at any time.
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Way down to Kokomo
Jun 25, 2012
|Well actually up. We are in Kokomo Indiana (IN). The Beach Boys song says we'll get there fast and then we'll take it slow but, a 140 mile trip took nearly 300 miles because of construction and detours. Anyway, we are not in a hot parking lot anymore. We are in the trees and waiting to visit with my radio friend Curt. I haven't seen him since 1984 BUT he is one of 5 people who have made me gaffau in my lifetime. I mean really flat out belly laugh. It is a short list and some of you reading know who makes it. OK...... I'll break the suspense. My Father, Collins (my Daughter) Don Orilio, Mark Diamond (a Junior High School friend) and Curt. I hired him as a news man when I was Program Director of WBTF in Attica NY. Not only was he good but he went to Geneseo, definitely a plus. Going to catch up with Curt tomorrow, and laugh. Enjoy the pics.


text: Wine Press is on its way By thelazydog Admin on December 07, 2018 Our Friends in Germany have done us proud. A second hand press in excellent condition had been found. A new bladder has been fitted and she is due to arrive in time for Christmas. Time Line Share Share on Facebook Tweet Tweet on Twitter Pin it Pin on Pinterest


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Florala State Park in Alabama combines the beauty of Florida and Alabama, just as its name implies. This park resembles the lush green fields of the south, but incorporates the beautiful white sandy beaches, turquoise water and palm trees commonly seen in Florida. The park itself consumes 40 acres; it sits along the shore of 500-acre Lake Jackson.
Water sports and swimming is what most visitors come here to do. The white sandy beaches give the feeling of being in the ocean, minus the salty water and higher waves. Water in Lake Jackson is exceptionally clear and has a comfortable temperature. Swimmers should only swim in the marked areas. The lake does contain some places that are not safe for swimming. Also it is important not to swim past the safe areas into the deeper parts of the lake. Bass and catfish are the main types of fish caught in Lake Jackson. Fishing at night with spotlights for catfish is illegal and the park rangers do monitor the grounds for violators. A state fishing license or park permit and license is required to be able to fish. Boat fishing is also permitted. There is a launch site for boats along the shore. Water skiing, jet-skis and other small watercraft are also welcome on the lake. Park officials encourage everyone to wear life vests at all times. Deeper parts of the lake may have strong undercurrents in some areas, just as any other lake. Some people in the area have reported seeing a Florida Green water snake in the lake. Visitors may be alarmed at the sight of this creepy inhabitant, but they are non-venomous, so they are not harmful. They also do not attack humans; these snakes prefer secluded areas and will avoid people.
There is a bicycle and walking path that encompasses the entire length of the park, which is about one and one-quarter of a mile. At one end of the trail is the Old Depot, an interesting tourist site to see. The other end of the trail is the site of the City Wetlands Park. Florala State Park has a playground area that children are welcome to use. The park is also home to several picnic areas, shelters, tables and grills. Picnic areas are obtained by a first-come, first-serve basis. Picnic pavilions are also available for rent. Pavilions are covered and must be reserved well in advance. Because of the beautiful scenery and weather in this area, reservations fill up quickly for these locations. The rental fee for a pavilion is between $30 and $40 per day.
Camping is allowed in Florala State Park. The park has 28 campsites with power hookups, water and sewage. Each camp site has a grill and picnic table. Located near the camping area is a modern shower house and bathroom. A coin-operated laundry facility is also available for visitors to use. A common area for larger gatherings or parties is also offered to campers, but it is open on a first-come, first-serve basis. There is no fee to use it, unlike the pavilions in the main area of the park. Camping is not free; the more amenities a camp site has, the higher the price is. Sites that include all of the above-listed features are about $28 per night. A primitive camp site with no amenities is betwen $12 and $15, depending on the days of stay during the week. Camp sites with some amenities range between the highest and lowest-priced sites. Weekly and monthly discounted rates are also available for all types of camp sites.
This part of the state is very humid during most of the year. Summers are hot and when mixed with the humidity, the temperatures may be miserable for some visitors who are not accustomed to the climate. Fortunately, the lake provides a great way to cool off. The best time of year to visit is during the later fall months, such as September through November. By this time, the bugs have lowered in numbers and the temperatures are mild and enjoyable. For more information about camping rates or to reserve pavilion rentals, contact the main office at:
439 Victoria Lane
Florala, AL 36442


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(February 23, 2020 / JNS)
Naomi Linder Kahn is Director of the International Division of Regavim, an Israeli NGO dedicated to protecting Israel's land resources.
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Simit (Turkish Sesame Bread Rings)
2 made it | 0 reviews | 1 photos
"These small bread rings coated with sesame seeds, called simit, are a popular Turkish snack or street food."
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Ingredients1 h 40 m servings 405
Original recipe yields 8 servings (8 simit)
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- Toast sesame seeds in a dry frying pan over low heat until golden and fragrant, about 5 minutes. Keep a close eye as they change color very quickly.
- Combine flour, yeast, and salt in a large bowl. Make a well in the flour mixture and add water, milk, melted butter, and olive oil; stir well until dough pulls together. Turn dough out onto a lightly floured surface and knead until smooth and elastic, about 8 minutes.
- Place dough in a large, lightly-oiled bowl and turn to coat. Cover with a towel and let rise in a warm place until doubled in volume, 30 minutes to 1 hour.
- Line a baking sheet with parchment paper.
- Divide dough in to 8 parts and roll each part into a 6- to 8-inch long rope. Join ends together and seal to form a ring. Place rings on prepared baking sheet, cover with a clean kitchen towel and let rise for 15 minutes.
- Preheat oven to 350 degrees F (175 degrees C). Brush rings with beaten egg and sprinkle generously with toasted sesame seeds.
- Bake in the preheated oven until golden and crusty, about 20 minutes.
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- Cook's Notes:
- Use nigella or poppy seeds instead of sesame seeds, if desired.
- Using a bread machine:
- Place olive oil, melted butter, water, milk, and egg in the pan of the bread machine. Add flour, salt, and yeast and select the setting for Basic or White Bread. The dough should come out smooth and elastic.
Nutrition Facts
Per Serving: 405 calories; 18.4 50.6 9.5 36 346 Full nutrition