The rockefeller university

While addition of the first-approved protease inhibitors (PIs), telaprevir and boceprevir, to pegylated interferon (PEG-IFN) and ribavirin (RBV) combination therapy significantly increased sustained virologic response (SVR) rates, PI-based triple therapy for the treatment of chronic hepatitis C virus (HCV) infection was prone to the emergence of resistant viral variants. Meanwhile, multiple direct acting antiviral agents (DAAs) targeting either the HCV NS3/4A protease, NS5A or NS5B polymerase have been approved and these have varying potencies and distinct propensities to provoke resistance. The pre-clinical in vivo assessment of drug efficacy and resistant variant emergence underwent a great evolution over the last decade. This field had long been hampered by the lack of suitable small animal models that robustly support the entire HCV life cycle. In particular, chimeric mice with humanized livers (humanized mice) and chimpanzees have been instrumental for studying HCV inhibitors and the evolution of drug resistance. In this review, we present the different in vivo HCV infection models and discuss their applicability to assess HCV therapy response and emergence of resistant variants.

Background: Though outcome models have been proposed previously, it is unknown whether cutoffs in clinical pregnancy and live birth rates at all ages are able to classify in vitro fertilization (IVF) patients into good-, intermediate-and poor prognosis. Methods: We here in 3 infertile patient cohorts, involving 1247, 1514 and 632 women, built logistic regression models based on 3 functional ovarian reserve (FOR) parameters, including (1) number of good quality embryos, (2) follicle stimulating hormone (FSH, mIU/mL) and (3) anti-Mullerian hormone (AMH, ng/mL), determining whether clinical pregnancy and live birth rates can discriminate between good, intermediate and poor prognosis patients. Results: All models, indeed, allowed at all ages for separation by prognosis, though cut offs changed with age. In the embryo model, increasing embryo production resulted in linear improvement of IVF outcomes despite transfer of similar embryo numbers; in the FSH model outcomes and FSH levels related inversely, while the association of AMH followed a bell-shaped polynomial pattern, demonstrating "best" outcomes at mid-ranges. All 3 models demonstrated increasingly poor outcomes with advancing ages, though "best" AMH even above age 43 was still associated with unexpectedly good pregnancy and delivery outcomes. Excessively high AMH, in contrast, was at all ages associated with spiking miscarriage rates. Conclusions: At varying peripheral serum concentrations, AMH, thus, demonstrates hithero unknown and contradictory effects on IVF outcomes, deserving at different concentrations investigation as a potential therapeutic agent, with pregnancy-supporting and pregnancy-interrupting properties.

Whole exome sequencing (WES) has proven an effective tool for the discovery of genetic defects in patients with primary immunodeficiencies (PIDs). However, success in dissecting the genetic etiology of common variable immunodeficiency (CVID) has been limited. We outline a practical framework for using WES to identify causative genetic defects in these subjects. WES was performed on 50 subjects diagnosed with CVID who had at least one of the following criteria: early onset, autoimmune/inflammatory manifestations, low B lymphocytes, and/or familial history of hypogammaglobulinemia. Following alignment and variant calling, exomes were screened for mutations in 269 PID-causing genes. Variants were filtered based on the mode of inheritance and reported frequency in the general population. Each variant was assessed by study of familial segregation and computational predictions of deleteriousness. Out of 433 variations in PID-associated genes, we identified 17 probable disease-causing mutations in 15 patients (30%). These variations were rare or private and included monoallelic mutations in NFKB1, STAT3, CTLA4, PIK3CD, and IKZF1, and biallelic mutations in LRBA and STXBP2. Forty-two other damaging variants were found but were not considered likely disease-causing based on the mode of inheritance and/or patient phenotype. WES combined with analysis of PID-associated genes is a cost-effective approach to identify disease-causing mutations in CVID patients with severe phenotypes and was successful in 30% of our cohort. As targeted therapeutics are becoming the mainstay of treatment for non-infectious manifestations in CVID, this approach will improve management of patients with more severe phenotypes.

Broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoprotein (Env) suppress viremia in animal models of HIV-1 and humans. To achieve potent activity without the emergence of viral escape mutants, co-administration of different bNAbs is necessary to target distinct epitopes essential for viral fitness. Here, we report the development of bispecific anti-Env neutralizing antibodies (biNAbs) with potent activity. Synergistic activity of biNAbs was achieved by combining an engineered hinge domain of IgG3 to increase Fab domain flexibility necessary for hetero-bivalent binding to the Env trimer while retaining the functional properties of the IgG1-Fc. Compared to unmodified biNAbs, hinge domain variants exhibited substantially improved neutralization activity, with particular combinations showing evidence of synergistic neutralization potency in vitro and enhanced in vivo therapeutic activity in HIV-1-infected humanized mice. These findings suggest innovative strategies for generating biNAbs with enhanced neutralization breadth and potency, representing ideal candidate molecules for the control of HIV-1 infection.

We measure the forward-backward asymmetry of the production of top-quark and antiquark pairs in proton-antiproton collisions at center-of-mass energy root s = 1.96 TeV using the full data set collected by the Collider Detector at Fermilab (CDF) in Tevatron Run II corresponding to an integrated luminosity of 9.1 fb(-1). The asymmetry is characterized by the rapidity difference between top quarks and antiquarks (Delta y) and measured in the final state with two charged leptons (electrons and muons). The inclusive asymmetry, corrected to the entire phase space at parton level, is measured to be A(FB)(t (t) over bar) = 0.12 +/- 0.13, consistent with the expectations from the standard model (SM) and previous CDF results in the final state with a single charged lepton. The combination of the CDF measurements of the inclusive A(FB)(t (t) over bar) in both final states yields A(FB)(t (t) over bar) 0.160 +/- 0.045, which is consistent with the SM predictions. We also measure the differential asymmetry as a function of Delta y. A linear fit to A(FB)(t (t) over bar) (vertical bar Delta y vertical bar),assuming zero asymmetry at Delta y = 0, yields a slope of alpha = 0.14 +/- 0.15, consistent with the SM prediction and the previous CDF determination in the final state with a single charged lepton. The combined slope of A(FB)(t (t) over bar) (vertical bar Delta y vertical bar) the two final states is alpha = 0.227 +/- 0.057, which is 2.0 sigma larger than the SM prediction.

Vocalizations produced by developing young early in life have simple acoustic features and are thought to be innate. Complex forms of early vocal learning are less likely to evolve in young altricial songbirds because the forebrain vocal-learning circuit is underdeveloped during the period when early vocalizations are produced. However, selective pressure experienced in early postnatal life may lead to early vocal learning that is likely controlled by a simpler brain circuit. We found the food begging calls produced by fledglings of the brown-headed cowbird (Molothrus ater), a generalist avian brood parasite, induced the expression of several immediate early genes and early circuit innervation in a forebrain vocal-motor pathway that is later used for vocal imitation. The forebrain neural activity was correlated with vocal intensity and variability of begging calls that appears to allow cowbirds to vocally match host nestmates. The begging-induced forebrain circuits we observed in fledgling cowbirds were not detected in nonparasitic passerines, including species that are close relatives to the cowbird. The involvement of forebrain vocal circuits during fledgling begging and its association with vocal learning plasticity may be an adaptation that provides young generalist brood parasites with a flexible signaling strategy to procure food from a wide range of heterospecific host parents. (c) 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 615-625, 2016

At the Fermilab Tevatron proton-antiproton (p (p) over bar) collider, Drell-Yan lepton pairs are produced in the process p (p) over bar -> e(+)e(-) + X through an intermediate gamma*/Z boson. The forward-backward asymmetry in the polar-angle distribution of the e(-) as a function of the e(+)e(-)-pair mass is used to obtain sin(2) theta(lept)(eff), the effective leptonic determination of the electroweak-mixing parameter sin(2) theta(W). The measurement sample, recorded by the Collider Detector at Fermilab (CDF), corresponds to 9.4 fb(-1) of integrated luminosity from p (p) over bar collisions at a center-of-momentum energy of 1.96 TeV, and is the full CDF Run II data set. The value of sin(2) theta(lept)(eff) is found to be 0.23248 +/- 0.00053. The combination with the previous CDF measurement based on mu(+)mu(-) pairs yields sin(2) theta(lept)(eff) = 0.23221 +/- 0.00046. This result, when interpreted within the specified context of the standard model assuming sin(2) theta(W) = 1 - M-W(2)/M-Z(2) and that the W- and Z-boson masses are on-shell, yields sin(2) theta(W) = 0.22400 +/- 0.00045, or equivalently a W-boson mass of 80.328 +/- 0.024 GeV/c(2).

The development of rapid, sensitive, and accurate mass spectrometric methods for measuring peptides, proteins, and even intact protein assemblies has made mass spectrometry (MS) an extraordinarily enabling tool for structural biology. Here, we provide a personal perspective of the increasingly useful role that mass spectrometric techniques are exerting during the elucidation of higher order protein structures. Areas covered in this brief perspective include MS as an enabling tool for the high resolution structural biologist, for compositional analysis of endogenous protein complexes, for stoichiometry determination, as well as for integrated approaches for the structural elucidation of protein complexes. We conclude with a vision for the future role of MS-based techniques in the development of a multi-scale molecular microscope.

A search for supersymmetry involving events with at least one photon, one electron or muon, and large missing transverse momentum has been performed by the CMS experiment. The data sample corresponds to an integrated luminosity of 19.7 fb(-1) of pp collisions at root s = 8 TeV, produced at the CERN LHC. No excess of events is observed beyond expectations from standard model processes. The result of the search is interpreted in the context of a general model of gauge-mediated supersymmetry breaking, where the charged and neutral winos are the next-to-lightest supersymmetric particles. Within this model, winos with a mass up to 360 GeV are excluded at the 95% confidence level. Two simplified models inspired by gauge-mediated supersymmetry breaking are also examined, and used to derive upper limits on the production cross sections of specific supersymmetric processes. (C) 2016 CERN for the benefit of the CMS Collaboration. Published by Elsevier B.V.

The aim of the present study was to investigate alterations in gene expression of opioid system components induced by extended access (18 h) cocaine self-administration and to determine the impact of genetic background in the vulnerability to escalate cocaine intake. Comparing two inbred rat strains, we previously reported that Lewis rats progressively escalated cocaine consumption compared to Fischer rats, in a new translational model of intravenous cocaine self-administration, which included 14 sessions of 18-h operant sessions in which rats were allowed to select the cocaine unit dose to self-administer. We compare here Fischer and Lewis rats in the gene expression of endogenous opioid peptides (Pomc, Penk, Pdyn) and cognate receptors (Oprm, Oprk and Oprd) in reward-related brain regions, after exposure to either cocaine self-administration or yoked-saline, in the aforementioned translational paradigm. We performed a correlation analysis between the mRNA level, found in the Dorsal Striatum (DS), Nucleus accumbens (NAcc) shell and core respectively, and individual cocaine intake. Our findings show that the gene expression of all the aforementioned opioid genes exhibit strain dependent differences in the DS, in absence of cocaine exposure. Also, different strain-specific cocaine-induced mRNA expression of Oprm and Oprk was found in DS. Only few differences were found in the ventral parts of the striatum. Moreover, gene expression level of Pdyn, Penk, Oprk, and Oprm in the DS was significantly correlated with cocaine intake only in Fischer rats. Overall, these data shed light on potential genetic differences which may predispose of subjects to initiate and escalate cocaine consumption. (C) 2016 Elsevier Ltd. All rights reserved.