The rockefeller university

Understanding the genetic and metabolic bases of obesity is helpful in planning and developing health strategies. Therefore, the first family-based joint linkage and linkage disequilibrium study was conducted in Iranian pedigrees to assess the relationship between obesity and single-nucleotide polymorphisms (SNPs) located in the 16q12.2 region. In the present study, a total of 13,344 individuals were included, of whom 12,502 individuals were within 3,109 pedigrees and 842 were unrelated singletons. To investigate the relationship between obesity and genetic variants, a joint model of linkage and linkage disequilibrium was applied. Moreover, a sequence kernel association test (SKAT) was used to evaluate the association of the SNP set with body size and lipid profile measurements. The joint model showed that rs13334070, in the intron 4 of the RPGRIP1L gene, has a significant association with obesity. According to the 4-gamete rule, which is a procedure for constructing SNP sets by considering recombination occurrence between SNPs, this polymorphism has a high correlation with six nearby SNPs that make an SNP set. SKAT showed that this SNP set has a significant association with body size factors, but almost no association with most of the lipid profile measurements. In conclusion, from the result of this study, it might be reasonable to consider RPGRIP1L as an important gene whose variations could be associated with obesity risk factors.

BackgroundPrompted by the revolution in high-throughput sequencing and its potential impact for treating cancer patients, we initiated a clinical research study to compare the ability of different sequencing assays and analysis methods to analyze glioblastoma tumors and generate real-time potential treatment options for physicians.MethodsA consortium of seven institutions in New York City enrolled 30 patients with glioblastoma and performed tumor whole genome sequencing (WGS) and RNA sequencing (RNA-seq; collectively WGS/RNA-seq); 20 of these patients were also analyzed with independent targeted panel sequencing. We also compared results of expert manual annotations with those from an automated annotation system, Watson Genomic Analysis (WGA), to assess the reliability and time required to identify potentially relevant pharmacologic interventions.ResultsWGS/RNAseq identified more potentially actionable clinical results than targeted panels in 90% of cases, with an average of 16-fold more unique potentially actionable variants identified per individual; 84 clinically actionable calls were made using WGS/RNA-seq that were not identified by panels. Expert annotation and WGA had good agreement on identifying variants [mean sensitivity=0.71, SD=0.18 and positive predictive value (PPV)=0.80, SD=0.20] and drug targets when the same variants were called (mean sensitivity=0.74, SD=0.34 and PPV=0.79, SD=0.23) across patients. Clinicians used the information to modify their treatment plan 10% of the time.ConclusionThese results present the first comprehensive comparison of technical and machine augmented analysis of targeted panel and WGS/RNA-seq to identify potential cancer treatments.

Introduction: Atopic dermatitis (AD) is the most common inflammatory skin disease, yet until recently there were no safe systemic therapies approved for the long-term management of AD in adult patients. A deeper understanding of disease pathogenesis and identification of molecular and cellular changes has resulted in a rapidly evolving pipeline of therapeutics that holds promise for safer long-term control. Areas covered: In this review, we highlight the growing arsenal of biologic and small molecule antagonists that target pathways implicated in AD pathogenesis. Evidence that AD is driven by multiple immune axes extending beyond the Th2 polarization has resulted in therapies targeting additional pathways, including the Th22, Th17/IL-23, and JAK-STAT pathways. Pruritus, a hallmark of AD, has been linked to multiple mechanisms and various therapeutics have emerged in response to alternative hypotheses. Expert opinion: Despite the assumption that AD has a common disease mechanism, recent studies indicate that the disorder is characterized by several phenotypes and therapy may need to be tailored to the unique immune traits of specific phenotypes. Targeted therapy should complement and expand our molecular map of AD across the various phenotypic iterations and help push AD pharmacotherapy into a new era of personalized medicine.

The direction of functional information flow in the sensory thalamocortical circuit may play a role in stimulus perception, but, surprisingly, this process is poorly understood. We addressed this problem by evaluating a directional information measure between simultaneously recorded neurons from somatosensory thalamus (ventral posterolateral nucleus, VPL) and somatosensory cortex (S1) sharing the same cutaneous receptive field while monkeys judged the presence or absence of a tactile stimulus. During stimulus presence, feed-forward information (VPL -> S1) increased as a function of the stimulus ampli- tude, while pure feed-back information (S1 -> VPL) was unaffected. In parallel, zero-lag interaction emerged with increasing stimulus amplitude, reflecting externally driven thalamocortical synchronization during stimulus processing. Furthermore, VPL -> S1 information decreased during error trials. Also, VPL -> S1 and zero-lag interaction decreased when monkeys were not required to report the stimulus presence. These findings provide evidence that both the direction of information flow and the instant synchronization in the sensory thalamocortical circuit play a role in stimulus perception.

Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of IFN-gamma immunity. Since 1996, disease-causing mutations have been found in 11 genes, which, through allelic heterogeneity, underlie 21 different genetic disorders. We briefly review here progress in the study of molecular, cellular and clinical aspects of MSMD since the last comprehensive review published in 2014. Highlights include the discoveries of (1) a new genetic etiology, autosomal recessive signal peptide peptidase-like 2 A deficiency, (2) TYK2-deficient patients with a clinical phenotype of MSMD, (3) an allelic form of partial recessive IFN-gamma R2 deficiency, and (4) two forms of syndromic MSMD: ROR gamma/ROR gamma T and JAK1 deficiencies. These recent findings illustrate how genetic and immunological studies of MSMD can shed a unique light onto the mechanisms of protective immunity to mycobacteria in humans.

Recent whole exome sequencing studies in humans have provided novel insight into the importance of the ephrinB2-EphB4-RASA1 signaling axis in cerebrovascular development, corroborating and extending previous work in model systems. Here, we aim to review the human cerebrovascular phenotypes associated with ephrinB2-EphB4-RASA1 mutations, including those recently discovered in Vein of Galen malformation: the most common and severe brain arteriovenous malformation in neonates. We will also discuss emerging paradigms of the molecular and cellular pathophysiology of disease-causing ephrinB2-EphB4-RASA1 mutations, including the potential role of somatic mosaicism. These observations have potential diagnostic and therapeutic implications for patients with rare congenital cerebrovascular diseases and their families.

The size of the membrane-bound nucleus scales with cell size in a wide range of cell types but the mechanisms determining overall nuclear size remain largely unknown. Here we investigate the role of fission yeast inner nuclear membrane proteins in determining nuclear size, and propose that the Lap2-Emerin-Manl domain protein Lem2 acts as a barrier to membrane flow between the nucleus and other parts of the cellular membrane system. Lem2 deletion increases membrane flow into and out of the nuclear envelope in response to changes in membrane synthesis and nucleocytoplasmic transport, altering nuclear size. The endoplasmic reticulum protein Lnp1 acts as a secondary barrier to membrane flow, functionally compensating for lack of Lem2. We propose that this is part of the mechanism that maintains nuclear size proportional to cellular membrane content and thus to cell size. Similar regulatory principles may apply to other organelles in the eukaryotic subcellular membrane network.

A search is presented for excited electrons and muons in final states at the LHC. The search is based on a data sample corresponding to an integrated luminosity of 35.9 fb(-1) of proton-proton collisions at a center-of-mass energy of 13 TeV, collected with the CMS detector in 2016. This is the first search for excited leptons at = 13 TeV. The observation is consistent with the standard model background prediction, and the most stringent exclusion limits to date are set on the excited lepton mass and the compositeness scale, at 95% confidence level. Excited electrons and muons are excluded for masses below 3.9 and 3.8 TeV, respectively, under the assumption that the excited lepton mass equals the compositeness scale. The best observed limit on the compositeness scale is obtained with an excited lepton mass of around 1.0 TeV, excluding values below 25 TeV for both excited electrons and muons.

The differentiation of self-renewing progenitor cells requires not only the regulation of lineage- and developmental stage-specific genes but also the coordinated adaptation of housekeeping functions from a metabolically active, proliferative state toward quiescence. How metabolic and cell-cycle states are coordinated with the regulation of cell type-specific genes is an important question, because dissociation between differentiation, cell cycle, and metabolic states is a hallmark of cancer. Here, we use a model system to systematically identify key transcriptional regulators of Ikaros-dependent B cell-progenitor differentiation. We find that the coordinated regulation of housekeeping functions and tissue-specific gene expression requires a feedforward circuit whereby Ikaros down-regulates the expression of Myc. Our findings show how coordination between differentiation and housekeeping states can be achieved by interconnected regulators. Similar principles likely coordinate differentiation and housekeeping functions during progenitor cell differentiation in other cell lineages.