tbuckley/cabot-search huggingface dataset:
Genetic Association, Mutation Screening, and Functional Analysis of a Kozak Sequence Variant in the Metabotropic Glutamate Receptor 3 Gene in Bipolar Disorder
Authors: Radhika Kandaswamy, Andrew McQuillin, Sally I. Sharp, Alessia Fiorentino, Adebayo Anjorin, Robert A. Blizard, David Curtis, Hugh M. D. Gurling
Journal: JAMA Psychiatry (2013)

Genetic markers at the gene encoding the metabotropic glutamate receptor 3 (GRM3) showed allelic association with bipolar disorder.To screen the GRM3 gene and adjacent control regions of genomic DNA in volunteers with bipolar affective disorder for mutations increasing susceptibility to bipolar disorder.Sequencing and high-resolution melting curve analysis of DNA followed by genotyping was carried out in 1099 patients with bipolar affective disorder and 1152 healthy comparator individuals.Participants with bipolar disorder were recruited from National Health Service psychiatric services and from patient organizations.Individuals were included if they had Research Diagnostic Criteria diagnoses of bipolar I and bipolar II disorder and were of British or Irish ancestry.Identification of base pair changes in the GRM3 gene that affected expression or function of the GRM3 receptor that also showed an allelic association with bipolar disorder.A base pair variant (rs148754219) was found in the Kozak sequence of exon 1 of the GRM3 gene, 2 bases before the translation start codon of one of the receptor isoforms, in 23 of 2251 people who were screened and genotyped. Nineteen of the 1099 bipolar cases (1.7%) were mutation carriers compared with 4 of 1152 healthy comparators (0.3%). The variant was associated with bipolar disorder (P = .005; odds ratio, 4.20). Bioinformatic, electrophoretic mobility shift assay, and gene expression analysis found that the variant created a new transcription factor protein binding site and had a strong effect on gene transcription and translation.Confirmation of these findings is needed before the Kozak sequence variant can be accepted as a potential marker for personalized treatment of affective disorders with drugs targeting the metabotropic glutamate receptor 3.
Prostate Cancer Screening and Incidence: A Question of Causality
Authors: Jesse David Sammon, Shyam Sukumar, Quoc-Dien Trinh
Journal: JAMA Internal Medicine (2013)

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Racial Differences in End-Stage Renal Disease Rates in HIV Infection versus Diabetes
Authors: Andy I. Choi, Rudolph A. Rodriguez, Peter Bacchetti, Daniel Bertenthal, Paul A. Volberding, Ann M. O'Hare
Journal: Journal of the American Society of Nephrology (2007)

Few studies have compared the incidence of end-stage renal disease (ESRD) among individuals with the human immunodeficiency virus (HIV) and diabetes. We followed a national sample of 2,015,891 US veterans over a median peroid of 3.7 years for progression to ESRD. The age- and sex-adjusted incidence of ESRD (per 1000 person-years) among HIV-infected black patients was nearly an order of magnitude higher than among HIV-positive white patients, almost twice that of diabetic whites, and similar to that among diabetic blacks. In multivariate Cox proportional hazards analysis, diabetes was associated with an increased risk of ESRD among white patients, but HIV was not. Among black individuals, however, both HIV and diabetes conferred a similar increase in the risk of ESRD (4- to 5-fold increase compared to white individuals without HIV or diabetes). HIV and diabetes carry a similar risk of ESRD among black patients, highlighting the importance of developing strategies to prevent and treat renal disease among HIV-infected black individuals.
Retinoids are important cofactors in T cell activation.
Authors: A Garbe, J Buck, U Hämmerling
Journal: The Journal of Experimental Medicine (1992)

Murine thymic T cells depleted of antigen-presenting cells proliferate poorly in response to crosslinking anti-CD3 monoclonal antibodies or concanavalin A when cultured in conventional fetal calf serum-containing serum. However, in a serum-free medium formulated to contain, in addition to basic ingredients, insulin, transferrin, albumin, linoleic acid (ITLB), and retinol, proliferation is vigorous. The presence of retinol is critical, because when omitted, cells do not become activated. The subsets of T cells proliferating with the assistance of retinol cofactor are both CD4+ and CD8+ thymic T cells, and CD4+ peripheral T cells. Mature CD8+ T cells of lymph nodes can also be activated in ITLB medium plus retinol, provided that interleukin 2 (IL-2) is added. Retinol needs to be present at the time when T cell receptor triggering is initiated, suggesting that early activation events (G0 to G1 transition) are dependent on retinol. It is currently less clear whether or not subsequent events associated with G1 to S phase transition also require the presence of retinol. 14-hydroxy-retroretinol (14HRR) is a metabolic product of retinol in lymphocytes, and this retinoid effectively supports T cell activation in conjunction with a mitogen in lieu of retinol. Thus, while retinol and its intracellular product, 14HRR, are unable to activate T cells on their own, they are important cofactors. The requirement for retinol in CD3-mediated T cell activation cannot be satisfied by retinoic acid or ILs-1, 2, 4, and 6, and tumor necrosis factor-alpha whereas interferon gamma can substitute for retinol. Our experiments are compatible with the idea that retinol, in the course of cellular activation, is converted to 14HRR, which is needed as intracellular messenger. If substantiated by molecular studies now underway, our data should lead to the description of a new signal pathway distinct from the retinoic acid signal pathway observed in nonlymphoid cells, but perhaps functioning by a similar mechanism, i.e., ligand-assisted transcriptional regulation.
Maintenance of biologic-free remission with naproxen or no treatment in patients with early, active axial spondyloarthritis: results from a 6-month, randomised, open-label follow-up study, INFAST Part 2
Authors: J Sieper, J Lenaerts, J Wollenhaupt, M Rudwaleit, V I Mazurov, L Myasoutova, S Park, Y Song, R Yao, D Chitkara, N Vastesaeger
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objective</h3> To investigate whether biologic-free remission can be achieved in patients with early, active axial spondyloarthritis (SpA) who were in partial remission after 28 weeks of infliximab (IFX)+naproxen (NPX) or placebo (PBO)+NPX treatment and whether treatment with NPX was superior to no treatment to maintain disease control. <h3>Method</h3> Infliximab as First-Line Therapy in Patients with Early Active Axial Spondyloarthritis Trial (INFAST) Part 1 was a double-blind, randomised, controlled trial in biologic-naïve patients with early, active, moderate-to-severe axial SpA treated with either IFX 5 mg/kg+NPX 1000 mg/d or PBO+NPX 1000 mg/d for 28 weeks. Patients achieving Assessment of SpondyloArthritis international Society (ASAS) partial remission at week 28 continued to Part 2 and were randomised (1:1) to NPX or no treatment until week 52. Treatment group differences in ASAS partial remission and other efficacy variables were assessed through week 52 with Fisher exact tests. <h3>Results</h3> At week 52, similar percentages of patients in the NPX group (47.5%, 19/40) and the no-treatment group (40.0%, 16/40) maintained partial remission, p=0.65. Median duration of partial remission was 23 weeks in the NPX group and 12.6 weeks in the no-treatment group (p=0.38). Mean Bath Ankylosing Spondylitis Disease Activity Index scores were low at week 28, the start of follow-up treatment (NPX, 0.7; no treatment, 0.6), and remained low at week 52 (NPX, 1.2; no treatment, 1.7). <h3>Conclusions</h3> In axial SpA patients who reached partial remission after treatment with either IFX+NPX or NPX alone, disease activity remained low, and about half of patients remained in remission during 6 months in which NPX was continued or all treatments were stopped.
Adult familial cryptogenic fibrosing alveolitis in the United Kingdom
Authors: R. P Marshall
Journal: Thorax (2000)

<h3>BACKGROUND</h3> Familial cases of cryptogenic fibrosing alveolitis (CFA) have previously been reported; however, the prevalence and genetic background of this disorder are not known. The clinical and epidemiological findings of 25 families identified within the UK are reported. <h3>METHODS</h3> Adult pulmonary physicians in the UK were asked to identify all families under their care in which two or more individuals had been diagnosed with fibrosing alveolitis of unknown cause. A detailed structured questionnaire was sent to each proband to delineate possible environmental/occupational exposures and to obtain complete pedigree data. Physicians were also asked to provide clinical and diagnostic information. <h3>RESULTS</h3> Twenty five families were identified comprising 67 cases. Suitable data for analysis were available for 21 families (57 cases). The male:female ratio was 1.75:1 (p&lt;0.05). A high resolution computed tomographic (HRCT) scan was performed in 93% and a diagnosis of CFA confirmed on biopsy specimens in 32%. The mean age at diagnosis was 55.5 (2.5) years. Fifty percent of cases were ever smokers and 18% had been diagnosed as asthmatic. Exposure to known fibrogenic agents was recorded by 36% of patients. Clinical signs/symptoms and histological findings were indistinguishable from non-familial cases. <h3>CONCLUSIONS</h3> This study represents the largest cohort of familial CFA cases reported to date and confirms a prevalence of 1.34 cases per 10<sup>6</sup> in the UK population. Although rare, such cases represent an important subgroup in which a genetic susceptibility to pulmonary fibrosis is particularly evident. Familial patients are younger at diagnosis but otherwise indistinguishable from non-familial cases. The mode of inheritance is as yet unclear but a number of genetic loci are likely to be involved and are the subject of ongoing studies.
Intratracheal Transplantation of Alveolar Type II Cells Reverses Bleomycin-induced Lung Fibrosis
Authors: Anna Serrano-Mollar, Maria Nacher, Gemma Gay-Jordi, Daniel Closa, Antoni Xaubet, Oriol Bulbena
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Transplantation of stem cells has been proposed as a strategy for repair of lung fibrosis. Nevertheless, many studies have yielded controversial results that currently limit the potential use of these cells as an efficient treatment. Alveolar type II cells are the progenitor cells of the pulmonary epithelium and usually proliferate after epithelial cell injury. During lung fibrosis, however, the altered regeneration process leads to uncontrolled fibroblast proliferation.To investigate whether intratracheal transplantation of isolated alveolar type II cells can halt and reverse the fibrotic process in an experimental model of bleomycin-induced lung fibrosis in rats.Lung fibrosis was induced in syngeneic female Lewis rats by a single intratracheal instillation of bleomycin (2.5 U/kg). Animals were transplanted with alveolar type II cells from male animals at a dose of 2.5 x 10(6) cells per animal 3, 7, and 15 days after endotracheal bleomycin instillation. Animals were killed 21 days after the induction of lung fibrosis.Lung fibrosis was assessed by histologic study and determination of hydroxyproline content. Engraftment of transplanted cells was measured by real-time polymerase chain reaction for the Y chromosome and by fluorescence in situ hybridization for the Y chromosome. Transplantation of alveolar type II cells into damaged lung 3, 7, or 15 days after bleomycin instillation led to reduced collagen deposition, and reduction in the severity of pulmonary fibrosis.This study demonstrates the potential role of alveolar type II cell transplantation in designing future therapies for lung fibrosis.
Atorvastatin as a stable treatment in bronchiectasis: a randomised controlled trial
Authors: Pallavi Mandal, James D Chalmers, Catriona Graham, Catherine Harley, Manjit K Sidhu, Catherine Doherty, John W Govan, Tariq Sethi, Donald J Davidson, Adriano G Rossi, Adam T Hill
Journal: The Lancet Respiratory Medicine (2014)
Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease
Authors: Jeffrey C Barrett, Sarah Hansoul, Dan L Nicolae, Judy H Cho, Richard H Duerr, John D Rioux, Steven R Brant, Mark S Silverberg, Kent D Taylor, M Michael Barmada, Alain Bitton, Themistocles Dassopoulos, Lisa Wu Datta, Todd Green, Anne M Griffiths, Emily O Kistner, Michael T Murtha, Miguel D Regueiro, Jerome I Rotter, L Philip Schumm, A Hillary Steinhart, Stephan R Targan, Ramnik J Xavier, Cécile Libioulle, Cynthia Sandor, Mark Lathrop, Jacques Belaiche, Olivier Dewit, Ivo Gut, Simon Heath, Debby Laukens, Myriam Mni, Paul Rutgeerts, André Van Gossum, Diana Zelenika, Denis Franchimont, Jean-Pierre Hugot, Martine de Vos, Severine Vermeire, Edouard Louis, Lon R Cardon, Carl A Anderson, Hazel Drummond, Elaine Nimmo, Tariq Ahmad, Natalie J Prescott, Clive M Onnie, Sheila A Fisher, Jonathan Marchini, Jilur Ghori, Suzannah Bumpstead, Rhian Gwilliam, Mark Tremelling, Panos Deloukas, John Mansfield, Derek Jewell, Jack Satsangi, Christopher G Mathew, Miles Parkes, Michel Georges, Mark J Daly
Journal: Nature Genetics (2008)
Adiponectin and All-Cause Mortality in Elderly People With Type 2 Diabetes
Authors: Jessica R. Singer, Walter Palmas, Jeanne Teresi, Ruth Weinstock, Steven Shea, José A. Luchsinger
Journal: Diabetes Care (2012)

To assess the association between serum adiponectin level and all-cause mortality in people with type 2 diabetes. Because of the insulin-sensitizing, anti-inflammatory, and antiatherogenic effects of adiponectin, we hypothesized that higher adiponectin level would be associated with lower all-cause mortality.A total of 609 men and women aged 72 ± 6.3 years with type 2 diabetes and information on total and high molecular weight adiponectin were followed for a median of 5 years. The longitudinal association between adiponectin and all-cause mortality was analyzed with Cox proportional hazards models with time from adiponectin measurement to death as the time-to-event variable. Analyses were adjusted for demographic variables and significant diabetes parameters, significant cardiovascular parameters, and significant diabetes medications.Total and high molecular weight adiponectin were highly correlated. The highest adiponectin quartile was strongly associated with higher all-cause mortality compared with the lowest quartile (hazard ratio = 4.0 [95% CI: 1.7-9.2]) in the fully adjusted model. These results did not change in analyses stratified by sex and thiazolidinedione use, after exclusion of people who died within one year of adiponectin measurement, or when change in weight before adiponectin measurement was considered.Contrary to our hypothesis, higher adiponectin level was related to higher all-cause mortality. This association was not explained by confounding by other characteristics, including medications or preceding weight loss.
Leisure Time Physical Activity of Moderate to Vigorous Intensity and Mortality: A Large Pooled Cohort Analysis
Authors: Steven C. Moore, Alpa V. Patel, Charles E. Matthews, Amy Berrington de Gonzalez, Yikyung Park, Hormuzd A. Katki, Martha S. Linet, Elisabete Weiderpass, Kala Visvanathan, Kathy J. Helzlsouer, Michael Thun, Susan M. Gapstur, Patricia Hartge, I-Min Lee
Journal: PLoS Medicine (2012)

Analyzing data from over 650,000 individuals, Dr. Steven Moore and colleagues report that greater amounts of leisure-time physical activity were associated with higher life expectancy across a wide range of activity levels and body mass index groups.
Lipopolysaccharide Internalization Activates Endotoxin-Dependent Signal Transduction in Cardiomyocytes
Authors: Douglas B. Cowan, Sabrena Noria, Christof Stamm, Lina M. Garcia, Dimitrios N. Poutias, Pedro J. del Nido, Francis X. McGowan
Journal: Circulation Research (2001)

Abstract —We tested the hypothesis that bacterial lipopolysaccharide (LPS) must be internalized to facilitate endotoxin-dependent signal activation in cardiac myocytes. Fluorescently labeled LPS was used to treat primary cardiomyocyte cultures, perfused heart preparations, and the RAW264.7 macrophage cell line. Using confocal microscopy and spectrofluorometry, we found that LPS was rapidly internalized in cardiomyocyte cultures and Langendorff-perfused hearts. Although LPS uptake was also observed in macrophages, only a fraction of these cells were found to internalize endotoxin to the extent seen in cardiomyocytes. Colocalization experiments with organelle or structure-specific fluorophores showed that LPS was concentrated in the Golgi apparatus, lysosomes, and sarcomeres. Similar intracellular localization was demonstrated in cardiomyocytes by transmission electron microscopy using gold-labeled LPS. The internalization of LPS was dependent on endosomal trafficking, because an inhibitor of microfilament reorganization prevented uptake in both cardiomyocytes and whole hearts. Inhibition of endocytosis specifically restricted early activation of extracellular signal–regulated kinase proteins and nuclear factor-κB as well as later tumor necrosis factor-α production and inducible nitric oxide synthase expression. In conclusion, we have demonstrated that bacterial endotoxin is internalized and transported to specific intracellular sites in heart cells and that these events are obligatory for activation of LPS-dependent signal transduction.
All-Cause Mortality Risk Among a National Sample of Individuals With Diabetes
Authors: Karin M. Nelson, Edward J. Boyko, Thomas Koepsell
Journal: Diabetes Care (2010)

OBJECTIVE Little is known about the relative contributions of modifiable risk factors to overall diabetes mortality. The purpose of the current study is to 1) assess the association between modifiable risk factors and all-cause mortality among a nationally representative sample of individuals with diabetes and 2) determine the population-attributable risk percent (PAR%) for these factors. RESEARCH DESIGN AND METHODS We analyzed data from a nationally representative sample of 1,507 adults over the age of 17 years with a self-reported diagnosis of diabetes from the Third National Health and Nutrition Examination Survey (NHANES III) mortality study. Our main outcome measures were all-cause mortality and PAR%. We used the Cox proportional hazard analysis to determine hazard ratios (HRs) for known diabetes risks and calculated PAR%. RESULTS Among adults with diabetes, the HRs for all-cause mortality were significant for individuals who had an A1C ≥8% (HR 1.65, 95% CI 1.11–2.45) or reported no regular physical activity (1.58, 1.24–2.02) or current tobacco use (1.77, 1.15–2.73). The population-attributable risk was 15.3% for A1C value ≥8%, 16.4% for no regular physical activity, and 7.5% for current tobacco use. CONCLUSIONS Health systems may consider prioritizing care to include smoking cessation, increasing physical activity, and moderate glycemic control among patients with diabetes. This study suggests that focusing on these areas may result in significant reductions in mortality in individuals with diabetes.
USP21 negatively regulates antiviral response by acting as a RIG-I deubiquitinase
Authors: Yihui Fan, Renfang Mao, Yang Yu, Shangfeng Liu, Zhongcheng Shi, Jin Cheng, Huiyuan Zhang, Lei An, Yanling Zhao, Xin Xu, Zhenghu Chen, Mari Kogiso, Dekai Zhang, Hong Zhang, Pumin Zhang, Jae U. Jung, Xiaonan Li, Guotong Xu, Jianhua Yang
Journal: The Journal of Experimental Medicine (2014)

Lys63-linked polyubiquitination of RIG-I is essential in antiviral immune defense, yet the molecular mechanism that negatively regulates this critical step is poorly understood. Here, we report that USP21 acts as a novel negative regulator in antiviral responses through its ability to bind to and deubiquitinate RIG-I. Overexpression of USP21 inhibited RNA virus-induced RIG-I polyubiquitination and RIG-I-mediated interferon (IFN) signaling, whereas deletion of USP21 resulted in elevated RIG-I polyubiquitination, IRF3 phosphorylation, IFN-α/β production, and antiviral responses in MEFs in response to RNA virus infection. USP21 also restricted antiviral responses in peritoneal macrophages (PMs) and bone marrow-derived dendritic cells (BMDCs). USP21-deficient mice spontaneously developed splenomegaly and were more resistant to VSV infection with elevated production of IFNs. Chimeric mice with USP21-deficient hematopoietic cells developed virus-induced splenomegaly and were more resistant to VSV infection. Functional comparison of three deubiquitinases (USP21, A20, and CYLD) demonstrated that USP21 acts as a bona fide RIG-I deubiquitinase to down-regulate antiviral response independent of the A20 ubiquitin-editing complex. Our studies identify a previously unrecognized role for USP21 in the negative regulation of antiviral response through deubiquitinating RIG-I.
On the Futility of Screening for Genes That Make You Fat
Authors: J. Lennert Veerman
Journal: PLoS Medicine (2011)

An impressively large meta-analysis in this issue of PLoS Medicine shows that physical activity modifies the effect of a common genetic trait on body mass.It was already known that certain variants of the ''fat mass and obesity associated'' (FTO) gene predispose to weight gain, but this article shows that this effect is weaker among physically active persons [1].The authors argue that this is important because many people have a determinist view of genes and may think that when something is written in your genetic code, nothing can be done to alter the course of fate.The study shows that view to be overly simplistic: genes may predispose to weight gain, but this weight can be lost by extra physical activity.And in time, studies into the causes of this gene-behaviour interaction may lead to new treatments for obesity.