The rockefeller university

While an essential role of HIV-1 integrase (IN) for integration of viral cDNA into human chromosome is established, studies with IN mutants and allosteric IN inhibitors (ALLINIs) have suggested that IN can also influence viral particle maturation. However, it has remained enigmatic as to how IN contributes to virion morphogenesis. Here, we demonstrate that IN directly binds the viral RNA genome in virions. These interactions have specificity, as IN exhibits distinct preference for select viral RNA structural elements. We show that IN substitutions that selectively impair its binding to viral RNA result in eccentric, non-infectious virions without affecting nucleocapsid-RNA interactions. Likewise, ALLINIs impair IN binding to viral RNA in virions of wildtype, but not escape mutant, virus. These results reveal an unexpected biological role of IN binding to the viral RNA genome during virion morphogenesis and elucidate the mode of action of ALLINIs.

Background and AimsFew randomized controlled trials have evaluated buprenorphine treatment interventions for opioid-dependent youth. Consequently, optimal administration strategies for this cohort are unclear. Our aim was to evaluate the relative efficacy of two different buprenorphine taper lengths in promoting abstinence from illicit opioids and treatment retention among opioid-dependent youth. DesignA double-blind, placebo controlled, multicenter randomized controlled trial. SettingTwo hospital-based research clinics (Manhattan and Brooklyn) in New York City, USA from 2005 to 2010. ParticipantsVolunteer sample of 53 primarily Caucasian participants between the ages of 16 and 24 (n=11 under age 18) who met DSM-IV opioid dependence criteria. InterventionParticipants were assigned randomly to either a 28-day buprenorphine taper (n=28) or 56-day buprenorphine taper (n=25) via a parallel-groups design during a 63-day period. Both groups received behavioral counseling and opioid abstinence incentives. Both taper conditions had a minimum of 1week of placebo dosing at the end of the taper. MeasurementsThe primary outcome was opioid abstinence measured as a percentage of scheduled urine toxicology tests documented to be negative for opioids. The secondary outcome was treatment retention, measured as number of days attended scheduled visits. FindingsIntent-to-treat analyses revealed that participants who received a 56-day buprenorphine taper had a significantly higher percentage of opioid-negative scheduled urine tests compared with participants who received a 28-day buprenorphine taper [35 versus 17%, P=0.039; Cohen's d=0.57, 95% confidence interval (CI)=0.02, 1.13]. Participants who received a 56-day buprenorphine taper were retained in treatment significantly longer than participants who received a 28-day buprenorphine taper (37.5 versus 26.4days, P=0.027; Cohen's d=0.63, 95% CI=0.06, 1.19). Daily attendance requirement was associated with decreased abstinence and shorter retention compared with a two to three times weekly attendance requirement, independent of taper duration. Follow-up data were insufficient to report. ConclusionLonger (56-day) buprenorphine taper produces better opioid abstinence and retention outcomes than shorter (28-day) buprenorphine taper for opioid-dependent youth.

The exclusive deep inelastic electroproduction of psi(2S) and J/psi (1S) at an ep centre-of-mass energy of 317 GeV has been studied with the ZEUS detector at HERA in the kinematic range 2 < Q(2) < 80 GeV2, 30 < W < 210 GeV and vertical bar t vertical bar < 1 GeV2, where Q(2) is the photon virtuality, W is the photon-proton centre-of-mass energy and t is the squared four-momentum transfer at the proton vertex. The data for 2 < Q(2) < 5 GeV2 were taken in the HERA I running period and correspond to an integrated luminosity of 114 pb(-1). The data for 5 < Q(2) < 80 GeV2 are from both HERA I and HERA II periods and correspond to an integrated luminosity of 468 pb(-1). The decay modes analysed were mu(+)mu(-) and J/psi(1S)pi(+)pi(-) for the psi(2S) and mu(+)mu(-) for the J/psi(1S). The cross-section ratio sigma(psi(2S))/sigma(J/psi(1S)) has been measured as a function of Q(2), W and t. The results are compared to predictions of QCD-inspired models of exclusive vector-meson production. (C) 2016 The Author(s). Published by Elsevier B.V.

Over the past 20 years, breakthrough discoveries of chromatin-modifying enzymes and associated mechanisms that alter chromatin in response to physiological or pathological signals have transformed our knowledge of epigenetics from a collection of curious biological phenomena to a functionally dissected research field. Here, we provide a personal perspective on the development of epigenetics, from its historical origins to what we define as 'the modern era of epigenetic research'. We primarily highlight key molecular mechanisms of and conceptual advances in epigenetic control that have changed our understanding of normal and perturbed development.

Tetherin encodes an interferon-inducible antiviral protein that traps a broad spectrum of enveloped viruses at infected cell surfaces. Despite the absence of any clearly related gene or activity, we describe possible scenarios by which tetherin arose that exemplify how protein modularity, evolvability, and robustness can create and preserve new functions. We find that tetherin genes in various organisms exhibit no sequence similarity and share only a common architecture and location in modern genomes. Moreover, tetherin is part of a cluster of three potential sister genes encoding proteins of similar architecture, some variants of which exhibit antiviral activity while others can be endowed with antiviral activity by a simple modification. Only in slowly evolving species (e.g., coelacanths) does tetherin exhibit sequence similarity to one potential sister gene. Neofunctionalization, drift, and genetic conflict appear to have driven a near complete loss of sequence similarity among modern tetherin genes and their sister genes.

All retroviruses package cellular RNAs into virions. Studies of murine leukemia virus (MLV) revealed that the major host cell RNAs encapsidated by this simple retrovirus were LTR retrotransposons and noncoding RNAs (ncRNAs). Several classes of ncRNAs appeared to be packaged by MLV shortly after synthesis, as precursors to tRNAs, small nuclear RNAs, and small nucleolar RNAs were all enriched in virions. To determine the extent to which the human immunodeficiency virus (HIV-1) packages similar RNAs, we used high-throughput sequencing to characterize the RNAs within infectious HIV-1 virions produced in CEM-SS T lymphoblastoid cells. We report that the most abundant cellular RNAs in HIV-1 virions are 7SL RNA and transcripts from numerous divergent and truncated members of the long interspersed element (LINE) and short interspersed element (SINE) families of retrotransposons. We also detected precursors to several tRNAs and small nuclear RNAs as well as transcripts derived from the ribosomal DNA (rDNA) intergenic spacers. We show that packaging of a pre-tRNA requires the nuclear export receptor Exportin 5, indicating that HIV-1 recruits at least some newly made ncRNAs in the cytoplasm. Together, our work identifies the set of RNAs packaged by HIV-1 and reveals that early steps in HIV-1 assembly intersect with host cell ncRNA biogenesis pathways.

A search for a narrow baryonic state in the pK(S)(0) and (p) over barK(S)(0) system has been performed in ep collisions at HERA with the ZEUS detector using an integrated luminosity of 358 pb(-1) taken in 2003-2007. The search was performed with deep inelastic scattering events at an ep centre-of-mass energy of 318 GeV for exchanged photon virtuality, Q(2), between 20 and 100 GeV2. Contrary to evidence presented for such a state around 1.52 GeV in a previous ZEUS analysis using a sample of 121 pb(-1) taken in 1996-2000, no resonance peak was found in the p((p) over bar )K-S(0) invariant-mass distribution in the range 1.45-1.7 GeV. Upper limits on the production cross section are set. (C) 2016 The Author(s). Published by Elsevier B.V.

Hair bundles are biological oscillators that actively transduce mechanical stimuli into electrical signals in the auditory, vestibular, and lateral-line systems of vertebrates. A bundle's function can be explained in part by its operation near a particular type of bifurcation, a qualitative change in behavior. By operating near different varieties of bifurcation, the bundle responds best to disparate classes of stimuli. We show how to determine the identity of and proximity to distinct bifurcations despite the presence of substantial environmental noise. Using an improved mechanical-load clamp to coerce a hair bundle to traverse different bifurcations, we find that a bundle operates within at least two functional regimes. When coupled to a high-stiffness load, a bundle functions near a supercritical Hopf bifurcation, in which case it responds best to sinusoidal stimuli such as those detected by an auditory organ. When the load stiffness is low, a bundle instead resides close to a subcritical Hopf bifurcation and achieves a graded frequency response-a continuous change in the rate, but not the amplitude, of spiking in response to changes in the offset force-a behavior that is useful in a vestibular organ. The mechanical load in vivo might therefore control a hair bundle's responsiveness for effective operation in a particular receptor organ. Our results provide direct experimental evidence for the existence of distinct bifurcations associated with a noisy biological oscillator, and demonstrate a general strategy for bifurcation analysis based on observations of any noisy system.

The impact of alpha linolenic acid (ALA), EPA, and DHA on obesity and metabolic complications was studied in mice fed a high-fat, high-sucrose (HF) diet. HF diets were supplemented with ALA, EPA, or DHA (1% w/w) and given to C57BL/6J mice for 16 weeks and to Ob/Ob mice for 6 weeks. In C57BL/6J mice, EPA reduced plasma cholesterol (-20%), limited fat mass accumulation (-23%) and adipose cell hypertrophy (-50%), and reduced plasma leptin concentration (-60%) compared with HF-fed mice. Furthermore, mice supplemented with EPA exhibited a higher insulin sensitivity (+24%) and glucose tolerance (+20%) compared with HF-fed mice. Similar effects were observed in EPA-supplemented Ob/Ob mice, although fat mass accumulation was not prevented. By contrast, in comparison with HF-fed mice, DHA did not prevent fat mass accumulation, increased plasma leptin concentration (+128%) in C57BL/6J mice, and did not improve glucose homeostasis in C57BL/6J and Ob/Ob mice. In 3T3-L1 adipocytes, DHA stimulated leptin expression whereas EPA induced adiponectin expression, suggesting that improved leptin/adiponectin balance may contribute to the protective effect of EPA.(jlr) In conclusion, supplementation with EPA, but not ALA and DHA, could preserve glucose homeostasis in an obesogenic environment and limit fat mass accumulation in the early stage of weight gain.-Pinel, A., E. Pitois, J-P. Rigaudiere, C. Jouve, S. De Saint-Vincent, B. Laillet, C. Montaurier, A. Huertas, B. Morio, and F. Capel. EPA prevents fat mass expansion and metabolic disturbances in mice fed with a Western diet.

Emerging evidence has shown that noncoding RNAs, particularly microRNAs (miRNAs), contribute to the pathogenesis of mood and anxiety disorders, although the molecular mechanisms are poorly understood. Here, we show that altered levels of miR17-92 in adult hippocampal neural progenitors have a significant impact on neurogenesis and anxiety and depression-related behaviors in mice. miR-1792 deletion in adult neural progenitors decreases neurogenesis in the dentate gyrus, while its overexpression increases neurogenesis. miR-17-92 affects neurogenesis by regulating genes in the glucocorticoid pathway, especially serum- and glucocorticoid- inducible protein kinase-1 (Sgk1). miR-17-92 knockout mice show anxiety-and depression-like behaviors, whereas miR-17-92 overexpressing mice exhibit anxiolytic and antidepression-like behaviors. Furthermore, we show that miR-17-92 expression in the adult mouse hippocampus responds to chronic stress, and miR-17-92 rescues proliferation defects induced by corticosterone in hippocampal neural progenitors. Our study uncovers a crucial role for miR-17-92 in adult neural progenitors through regulation of neurogenesis and anxiety-and depression-like behaviors.