The rockefeller university

Understanding how membrane nanoscale organization controls transmembrane receptors signaling activity remains a challenge. We studied interferon-gamma receptor (IFN-gamma R) signaling in fibroblasts from homozygous patients with a T168N mutation in IFNGR2. By adding a neo-N-glycan on IFN-gamma R2 subunit, this mutation blocks IFN-gamma activity by unknown mechanisms. We show that the lateral diffusion of IFN-gamma R2 is confined by sphingolipid/cholesterol nanodomains. In contrast, the IFN-gamma R2 T168N mutant diffusion is confined by distinct actin nanodomains where conformational changes required for Janus-activated tyrosine kinase/signal transducer and activator of transcription (JAK/STAT) activation by IFN-gamma could not occur. Removing IFN-gamma R2 T168N-bound galectins restored lateral diffusion in lipid nanodomains and JAK/STAT signaling in patient cells, whereas adding galectins impaired these processes in control cells. These experiments prove the critical role of dynamic receptor interactions with actin and lipid nanodomains and reveal a new function for receptor glycosylation and galectins. Our study establishes the physiological relevance of membrane nanodomains in the control of transmembrane receptor signaling in vivo.

We explore the momentum analyticity of the static transverse polarization tensor of a 2+1 dimensional holographic superconductor in its normal phase, aiming at finding the holographic counterpart of the singularities underlying the Friedel oscillations of an ordinary field theory. We prove that the polarization tensor is a meromorphic function with an infinite number of poles located on the complex momentum plane off real axis. With the aid of the WKB approximation these poles are found to lies asymptotically along two straight lines parallel to the imaginary axis for a large momentum magnitude. The similarity between the holographic Green's function and that of an weakly coupled ordinary field theory (e.g., 2+1 dimensional QED) regarding the location of the momentum singularities offers further support to the validity of the gauge/gravity duality.

The inelastic hadronic cross section in proton-lead collisions at a centre-of-mass energy per nucleon pair of 5.02 TeV is measured with the CMS detector at the LHC. The data sample, corresponding to an integrated luminosity of L = 12.6 +/- 0.4 nb(-1), has been collected with an unbiased trigger for inclusive particle production. The cross section is obtained from the measured number of proton-lead collisions with hadronic activity produced in the pseudorapidity ranges 3 < eta < 5 and/or -5 < eta < -3, corrected for photon-induced contributions, experimental acceptance, and other instrumental effects. The inelastic cross section is measured to be sigma(inel)(pPb) = 2061 +/- 3(stat) +/- 34(syst) +/- 72(lumi) mb. Various Monte Carlo generators, commonly used in heavy ion and cosmic ray physics, are found to reproduce the data within uncertainties. The value of sigma(inel)(pPb) is compatible with that expected from the proton-proton cross section at 5.02 TeV scaled up within a simple Glauber approach to account for multiple scatterings in the lead nucleus, indicating that further net nuclear corrections are small. (C) 2016 The Author. Published by Elsevier B.V. This is an open access article under the CC BY license (https://urldefense.proofpoint.com/v2/url?u=http-3A__creativecommons.org__licenses_by_4.0_&d=CwIDaQ&c=JeTkUgVztGMmhKYjxsy2rfoWYibK1YmxXez1G3oNStg&r=bWJiylK2oqB9vBxAFHE1PJcvSYL9TVkBaaVMsMDsLbs&m=SubwtCdzjsdA-PY9TmSH7PEXg4KtmcezMCn4fj9bcGg&s=HXkIJJX1CCeQzUTbvJBwbvJCpe5NkSxdcGF7odTZDwQ&e= ).

We present a measurement of the total WW and WZ production cross sections in p (p) over bar collision at root s = 1.96 TeV, in a final state consistent with leptonic W boson decay and jets originating from heavy-flavor quarks from either a W or a Z boson decay. This analysis uses the full data set collected with the CDF II detector during Run II of the Tevatron collider, corresponding to an integrated luminosity of 9.4 fb(-1). An analysis of the dijet mass spectrum provides 3.7 sigma evidence of the summed production processes of either WW or WZ bosons with a measured total cross section of sigma(WW+WZ) = 13.7 +/- 3.9 pb. Independent measurements of the WW and WZ production cross sections are allowed by the different heavy- flavor decay patterns of the W and Z bosons and by the analysis of secondary- decay vertices reconstructed within heavy- flavor jets. The productions of WW and of WZ dibosons are independently seen with significances of 2.9s and 2.1s, respectively, with total cross sections of sigma(WW) = 9.4 +/- 4.2 pb and sigma(WZ) = 3.7(-2.2)(+2.5) pb. The measurements are consistent with standard- model predictions.

Psoriasis is a chronic inflammatory disease associated with a variety of co-morbid conditions, including cardiovascular disease. Advancements in our understanding of the cellular and molecular mechanisms of psoriasis have led to a better understanding regarding its pathogenesis, which in turn has stimulated ongoing research to identify the underlying pathophysiology responsible for the increased risk of cardiovascular events associated with psoriasis. Although not yet fully elucidated, emerging evidence points to immune-mediated inflammation as a process that contributes to endothelial cell dysfunction, dyslipidemia, and atherosclerosis as key processes influencing cardiovascular disease in psoriasis. In particular, the dyslipidemia present in psoriasis may be associated with altered lipoprotein function and increased atherogenicity. Here, we review how the cytokine networks involved in lipoprotein metabolism and inflammation could impact on the cardiovascular disease risk for patients with psoriasis. Published by Elsevier Inc.

Repeated cocaine exposure regulates transcriptional regulation within the nucleus accumbens (NAc), and epigenetic mechanisms-such as histone acetylation and methylation on Lys residues-have been linked to these lasting actions of cocaine. In contrast to Lysmethylation, the role of histone Arg (R) methylation remains underexplored in addictionmodels. Here we show that protein-R-methyltransferase-6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the NAc of mice and rats after repeated cocaine exposure, including self-administration, and in the NAc of cocaine-addicted humans. Such PRMT6 down-regulation occurs selectively in NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2-MSNs), with opposite regulation occurring in D1-MSNs, and serves to protect against cocaine-induced addictive-like behavioral abnormalities. Using ChIP-seq, we identified Src kinase signaling inhibitor 1 (Srcin1; also referred to as p140Cap) as a key gene target for reduced H3R2me2a binding, and found that consequent Srcin1 induction in the NAc decreases Src signaling, cocaine reward, and the motivation to self-administer cocaine. Taken together, these findings suggest that suppression of Src signaling in NAc D2-MSNs, via PRMT6 and H3R2me2a down-regulation, functions as a homeostatic brake to restrain cocaine action, and provide novel candidates for the development of treatments for cocaine addiction.

In mammals the regulation of genomic instability plays a key role in tumor suppression and also controls genome plasticity, which is important for recombination during the processes of immunity and meiosis. Most studies to identify regulators of genomic instability have been performed in cells in culture or in systems that report on gross rearrangements of the genome, yet subtle differences in the level of genomic instability can contribute to whole organism phenotypes such as tumor predisposition. Here we performed a genome-wide association study in a population of 1379 outbred Crl: CFW(SW)-US_P08 mice to dissect the genetic landscape of micronucleus formation, a biomarker of chromosomal breaks, whole chromosome loss, and extranuclear DNA. Variation in micronucleus levels is a complex trait with a genome-wide heritability of 53.1%. We identify seven loci influencing micronucleus formation (false discovery rate <5%), and define candidate genes at each locus. Intriguingly at several loci we find evidence for sexual dimorphism in micronucleus formation, with a locus on chromosome 11 being specific to males.

Because the majority of environmental bacteria are not easily culturable, access to many bacterially encoded secondary metabolites will be dependent on the development of improved functional metagenomic screening methods. In this study, we examined a collection of diverse Streptomyces species for the best innate ability to heterologously express biosynthetic gene clusters. We then optimized methods for constructing high quality metagenomic cosmid libraries in the best Streptomyces host. An initial screen of a 1.5 million-membered metagenomic library constructed in Streptomyces albus, the species that exhibited the highest propensity for heterologous expression of gene clusters, led to the identification of the novel natural product metatricycloene (1). Metatricycloene is a tricyclic polyene encoded by a reductive, iterative polyketide-like gene cluster. Related gene clusters found in sequenced genomes appear to encode a largely unexplored collection of structurally diverse, polyene-based metabolites.

Proteins that associate with microtubules (MTs) are crucial to generate MT arrays and establish different cellular architectures. One example is PRC1 (protein regulator of cytokinesis 1), which cross-links antiparallel MTs and is essential for the completion of mitosis and cytokinesis. Here we describe a 4-angstrom-resolution cryo-EM structure of monomeric PRC1 bound to MTs. Residues in the spectrin domain of PRC1 contacting the MT are highly conserved and interact with the same pocket recognized by kinesin. We additionally found that PRC1 promotes MT assembly even in the presence of the MT stabilizer taxol. Interestingly, the angle of the spectrin domain on the MT surface corresponds to the previously observed cross-bridge angle between MTs cross-linked by full-length, dimeric PRC1. This finding, together with molecular dynamic simulations describing the intrinsic flexibility of PRC1, suggests that the MT-spectrin domain interface determines the geometry of the MT arrays cross-linked by PRC1.