The rockefeller university

Background. Classic Kaposi sarcoma (cKS) is an inflammatory tumor caused by human herpesvirus 8 (HHV-8) commonly observed in elderly men of Mediterranean origin. We studied a Finnish family of 5 affected individuals in 2 generations. Except for atypical mycobacterial infection of the index case, the affected individuals did not have notable histories of infection. Methods.aEuro integral We performed genome and exome sequencing and mapped shared chromosomal regions to identify genetic predisposition in the family. Results.aEuro integral We identified 12 protein-coding candidate variants that segregated in the 3 affected cousins from whom we had samples. The affected mother of the index case was an obligatory carrier. Among the 12 candidates was a rare heterozygous substitution rs141331848 (c.1337C > T, p.Thr446Ile) in the DNA-binding domain of STAT4. The variant was not present in 242 Finnish control genomes or 180 additional regional controls. Activated T-helper cells from the HHV-8-negative variant carriers showed reduced interferon gamma production, compared with age and sex matched wild-type individuals. We screened STAT4 in additional 18 familial KS cases and the variant site from 56 sporadic KS cases but detected no pathogenic mutations. Conclusions.aEuro integral Our data suggest that STAT4 is a potential cKS-predisposition gene, but further functional and genetic validation is needed.

We must reliably map the interactomes of cellular macromolecular complexes in order to fully explore and understand biological systems. However, there are no methods to accurately predict how to capture a given macromolecular complex with its physiological binding partners. Here, we present a screening method that comprehensively explores the parameters affecting the stability of interactions in affinity-captured complexes, enabling the discovery of physiological binding partners in unparalleled detail. We have implemented this screen on several macromolecular complexes from a variety of organisms, revealing novel profiles for even well-studied proteins. Our approach is robust, economical and automatable, providing inroads to the rigorous, systematic dissection of cellular interactomes.

Type I interferon (IFN) is one of the first lines of cellular defense against viral pathogens. As a result of IFN signaling, a wide array of IFN-stimulated gene (ISG) products is upregulated to target different stages of the viral life cycle. We review recent findings implicating a subset of ISGs in translational regulation of viral and host mRNAs. Translation inhibition is mediated either by binding to viral RNA or by disrupting physiological interactions or levels of the translation complex components. In addition, many of these ISGs localize to translationally silent cytoplasmic granules, such as stress granules and processing bodies, and intersect with the microRNA (miRNA)-mediated silencing pathway to regulate translation of cellular mRNAs.

The process of translating scientific findings into clinical and public health settings has only recently received priority attention within the scientific community. Fueled by "Funding Opportunity Announcements" from the National Institutes of Health and Centers for Disease Control and Prevention, scientists have begun to explore the pathways to effectively "transfer" promising research accomplishments into effective and sustainable service programs within the health care delivery system. Using Glasgow's RE-AIM (Reach, Effectiveness, Adoption, Implementation and Maintenance) model as a guide, this research team enrolled 428 socially disadvantaged, culturally diverse women living with HIV/AIDS to test the dissemination and implementation of an evidence-based behavioral intervention designed to improve and sustain the physical and emotional health of participants into the Community Health Center (CHC) setting when conducted by trained CHC staff. Findings demonstrate the ability of trained CHC staff group leaders to attain results equivalent or superior to those achieved when conducted by research staff on the three principal study outcomes: depression, medication adherence and HIV viral load. Four of five CHCs involved in the study also identified and successfully obtained funding to continue to run intervention groups, supporting the adoption and sustainability components of the translation model. This study confirmed (a) the "translatability" of the Stress Management And Relaxation Training/Emotional Supportive Therapy (SMART/EST) Women's Program, from academic to CHC settings in two geographic regions with high HIV prevalence among women, (b) the ability of local staff (using the "train the trainer" model) to successfully achieve program fidelity and clinical outcomes, and (c) the sustainability the program beyond the auspices of research support, through supportive CHC leadership securing continued program funding.

If a person is trained to recognize or categorize objects or events using one sensory modality, the person can often recognize or categorize those same (or similar) objects and events via a novel modality. This phenomenon is an instance of cross-modal transfer of knowledge. Here, we study the Multisensory Hypothesis which states that people extract the intrinsic, modality-independent properties of objects and events, and represent these properties in multisensory representations. These representations underlie cross-modal transfer of knowledge. We conducted an experiment evaluating whether people transfer sequence category knowledge across auditory and visual domains. Our experimental data clearly indicate that we do. We also developed a computational model accounting for our experimental results. Consistent with the probabilistic language of thought approach to cognitive modeling, our model formalizes multisensory representations as symbolic "computer programs" and uses Bayesian inference to learn these representations. Because the model demonstrates how the acquisition and use of amodal, multisensory representations can underlie cross-modal transfer of knowledge, and because the model accounts for subjects' experimental performances, our work lends credence to the Multisensory Hypothesis. Overall, our work suggests that people automatically extract and represent objects' and events' intrinsic properties, and use these properties to process and understand the same (and similar) objects and events when they are perceived through novel sensory modalities.

Objective The aim of this study was to identify gene variants of DAT1 (SLC6A3) that modulate subjective responses to acute cocaine exposure. Methods Non-treatment-seeking volunteers (n=66) with cocaine use disorders received a single bolus infusion of saline and cocaine (40 mg, intravenous) in a randomized order. Subjective effects were assessed with visual analog scales administered before (-15 min) and up to 20 min after infusion. Ratings of subjective effects were normalized to baseline, and saline infusion values were subtracted. Data were analyzed using repeated measures analysis of variance. DNA from the participants was genotyped for the DAT1 intron 8 (rs3836790) and 3'-untranslated region (rs28363170) variable number of tandem repeats. Results Participants were mostly male (similar to 80%) and African American (similar to 70%). No differences were found among drug use variables between groups for either polymorphism. Carriers of the 9-allele of the DAT1 3'-untranslated region (9,9 and 9,10) exhibited greater responses to cocaine for 'high', 'any drug effect', 'anxious', and 'stimulated' (all P-values < 0.001) compared with individuals homozygous for the 10-allele. For the intron 8 polymorphism, individuals homozygous for the 6-allele exhibited greater responses for 'anxious' compared with carriers of the 5-allele (P<0.001). Individuals possessing the genotype pattern of 10,10 and at least one 5-allele reported lower responses to 'good effects', 'bad effects', 'depressed', and 'anxious' (all P-values < 0.01). Conclusion The data presented here show for the first time support for the hypothesis that genetic differences in DAT1 contribute to the variation in subjective responses to cocaine among participants with cocaine use disorders. Pharmacogenetics and Genomics 25: 296-304 Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved.

The performance and strategies used in electron reconstruction and selection at CMS are presented based on data corresponding to an integrated luminosity of 19.7 fb(-1), collected in proton-proton collisions at root s = 8TeV at the CERN LHC. The paper focuses on prompt isolated electrons with transverse momenta ranging from about 5 to a few 100 GeV. A detailed description is given of the algorithms used to cluster energy in the electromagnetic calorimeter and to reconstruct electron trajectories in the tracker. The electron momentum is estimated by combining the energy measurement in the calorimeter with the momentum measurement in the tracker. Benchmark selection criteria are presented, and their performances assessed using Z, SIC, and J/psi decays into e(+)+e(-) pairs. The spectra of the observables relevant to electron reconstruction and selection as well as their global efficiencies are well reproduced by Monte Carlo simulations. The momentum scale is calibrated with an uncertainty smaller than 0.3%. The momentum resolution for electrons produced in Z boson decays ranges from 1.7 to 4.5%, depending on electron pseudorapidity and energy loss through bremsstrahlung in the detector material.

Searches for third-generation squarks in fully hadronic final states are presented using data samples corresponding to integrated luminosities of 19.4 or 19.7 fb(-1), collected at a centre-of-mass energy of 8 TeV with the CMS detector at the LHC. Three mutually exclusive searches are presented, each optimized for a different decay topology. They include a multijet search requiring one fully reconstructed top quark, a dijet search requiring one or two jets originating from b quarks, and a monojet search. No excesses above the standard model expectations are seen, and limits are set on top and bottom squark production in the context of simplified models of supersymmetry.

Transposable elements comprise roughly 40% of mammalian genomes(1). They have an active role in genetic variation, adaptation and evolution through the duplication or deletion of genes or their regulatory elements(2-4), and transposable elements themselves can act as alternative promoters for nearby genes, resulting in noncanonical regulation of transcription(5,6). However, transposable element activity can lead to detrimental genome instability(7), and hosts have evolved mechanisms to silence transposable element mobility appropriately(8,9). Recent studies have demonstrated that a subset of transposable elements, endogenous retroviral elements (ERVs) containing long terminal repeats (LTRs), are silenced through trimethylation of histone H3 on lysine 9 (H3K9me3) by ESET (also known as SETDB1 or KMT1E)(10) and a co-repressor complex containing KRAB-associated protein 1 (KAP1; also known as TRIM28)(11) in mouse embryonic stem cells. Here we show that the replacement histone variant H3.3 is enriched at class I and class II ERVs, notably those of the early transposon (ETn)/MusD family and intracisternal A-type particles (IAPs). Deposition at a subset of these elements is dependent upon the H3.3 chaperone complex containing alpha-thalassaemia/mental retardation syndrome X-linked (ATRX) 12 and death-domain-associated protein (DAXX)(12-14). We demonstrate that recruitment of DAXX, H3.3 and KAP1 to ERVs is co-dependent and occurs upstream of ESET, linking H3.3 to ERV-associated H3K9me3. Importantly, H3K9me3 is reduced at ERVs upon H3.3 deletion, resulting in derepression and dysregulation of adjacent, endogenous genes, along with increased retrotransposition of IAPs. Our study identifies a unique heterochromatin state marked by the presence of both H3.3 and H3K9me3, and establishes an important role for H3.3 in control of ERV retrotransposition in embryonic stem cells.