The HIV-1 late domain-2 S40A polymorphism in antiretroviral (or ART)-exposed individuals influences protease inhibitor susceptibility.

BackgroundThe p6 region of the HIV-1 structural precursor polyprotein, Gag, contains two motifs, P7TAP11 and L35YPLXSL41, designated as late (L) domain-1 and -2, respectively. These motifs bind the ESCRT-I factor Tsg101 and the ESCRT adaptor Alix, respectively, and are critical for efficient budding of virus particles from the plasma membrane. L domain-2 is thought to be functionally redundant to PTAP. To identify possible other functions of L domain-2, we examined this motif in dominant viruses that emerged in a group of 14 women who had detectable levels of HIV-1 in both plasma and genital tract despite a history of current or previous antiretroviral therapy.ResultsRemarkably, variants possessing mutations or rare polymorphisms in the highly conserved L domain-2 were identified in seven of these women. A mutation in a conserved residue (S40A) that does not reduce Gag interaction with Alix and therefore did not reduce budding efficiency was further investigated. This mutation causes a simultaneous change in the Pol reading frame but exhibits little deficiency in Gag processing and virion maturation. Whether introduced into the HIV-1 NL4-3 strain genome or a model protease (PR) precursor, S40A reduced production of mature PR. This same mutation also led to high level detection of two extended forms of PR that were fairly stable compared to the WT in the presence of IDV at various concentrations; one of the extended forms was effective in trans processing even at micromolar IDV.ConclusionsOur results indicate that L domain-2, considered redundant in vitro, can undergo mutations in vivo that significantly alter PR function. These may contribute fitness benefits in both the absence and presence of PR inhibitor

Mesoscopic Fluctuations in Quantum Dots in the Kondo Regime

Properties of the Kondo effect in quantum dots depend sensitively on the coupling parameters and so on the realization of the quantum dot -- the Kondo temperature itself becomes a mesoscopic quantity. Assuming chaotic dynamics in the dot, we use random matrix theory to calculate the distribution of both the Kondo temperature and the conductance in the Coulomb blockade regime. We study two experimentally relevant cases: leads with single channels and leads with many channels. In the single-channel case, the distribution of the conductance is very wide as $T_K$ fluctuates on a logarithmic scale. As the number of channels increases, there is a slow crossover to a self-averaging regime.Comment: 4 pages, 3 figure

Reducing firearm access for youth at risk for suicide in a pediatric emergency department

BackgroundFirearm-related suicide is the second leading cause of pediatric firearm death. Lethal means counseling (LMC) can improve firearm safe-storage practices for families with youth at risk of suicide.ObjectivesThis study aims to evaluate the feasibility of pediatric emergency department (ED) behavioral mental health (BMH) specialists providing LMC to caregivers of youth presenting with BMH complaints and to test for changes in firearm safety practices, pre-post ED LMC intervention, as measures of preliminary efficacy.MethodsProspective pilot feasibility study of caregivers of youth presenting to a pediatric ED with BMH complaints. Caregivers completed an electronic survey regarding demographics and firearm safe-storage knowledge/practices followed by BMH specialist LMC. Firearm owners were offered a free lockbox and/or trigger lock. One-week follow-up surveys gathered self-reported data on firearm safety practices and intervention acceptability. One-month interviews with randomly sampled firearm owners collected additional firearm safety data. Primary outcomes were feasibility measures, including participant accrual/attrition and LMC intervention acceptability. Secondary outcomes included self-reported firearm safety practice changes. Feasibility benchmarks were manually tabulated, and Likert-scale acceptability responses were dichotomized to strongly agree/agree vs. neutral/disagree/strongly disagree. Descriptive statistics were used for univariate and paired data responses.ResultsIn total, 81 caregivers were approached; of which, 50 (81%) caregivers enrolled. A total of 44% reported having a firearm at home, 80% completed follow-up at one week. More than 80% affirmed that ED firearm safety education was useful and that the ED is an appropriate place for firearm safety discussions. In total, 58% of participants reported not having prior firearm safety education/counseling. Among firearm owners (n = 22), 18% reported rarely/never previously using a safe-storage device, and 59% of firearm owners requested safe storage devices.At 1-week follow-up (n = 40), a greater proportion of caregivers self-reported asking about firearms before their child visited other homes (+28%). Among firearm owners that completed follow-up (n = 19), 100% reported storing all firearms locked at one week (+23% post-intervention). In total, 10 caregivers reported temporarily/permanently removing firearms from the home.ConclusionIt is feasible to provide LMC in the pediatric ED via BMH specialists to families of high-risk youth. Caregivers were receptive to LMC and reported finding this intervention useful, acceptable, and appropriate. Additionally, LMC and device distribution led to reported changes in safe storage practices

Built-in and induced polarization across LaAlO3_3/SrTiO3_3 heterojunctions

Ionic crystals terminated at oppositely charged polar surfaces are inherently unstable and expected to undergo surface reconstructions to maintain electrostatic stability. Essentially, an electric field that arises between oppositely charged atomic planes gives rise to a built-in potential that diverges with thickness. In ultra thin film form however the polar crystals are expected to remain stable without necessitating surface reconstructions, yet the built-in potential has eluded observation. Here we present evidence of a built-in potential across polar \lao ~thin films grown on \sto ~substrates, a system well known for the electron gas that forms at the interface. By performing electron tunneling measurements between the electron gas and a metallic gate on \lao ~we measure a built-in electric field across \lao ~of 93 meV/\AA. Additionally, capacitance measurements reveal the presence of an induced dipole moment near the interface in \sto, illuminating a unique property of \sto ~substrates. We forsee use of the ionic built-in potential as an additional tuning parameter in both existing and novel device architectures, especially as atomic control of oxide interfaces gains widespread momentum.Comment: 6 pages, 4 figures. Submitted to Nature physics on May 1st, 201

TMEM106B a Novel Risk Factor for Frontotemporal Lobar Degeneration

Recently, the first genome-wide association (GWA) study in frontotemporal lobar degeneration (FTLD) identified common genetic variability at the TMEM106B gene on chromosome 7p21.3 as a potential important risk-modifying factor for FTLD with pathologic inclusions of TAR DNA-binding protein (FTLD-TDP), the most common pathological subtype in FTLD. To gather additional evidence for the implication of TMEM106B in FTLD risk, multiple replication studies in geographically distinct populations were set up. In this review, we revise all recent replication and follow-up studies of the FTLD-TDP GWA study and summarize the growing body of evidence that establish TMEM106B as a bona fide risk factor for FTLD. With the TMEM106B gene, a new player has been identified in the pathogenic cascade of FTLD which could hold important implications for the future development of disease-modifying therapies

Challenges Enrolling Children Into Traumatic Brain Injury Trials: An Observational Study

ObjectivesIn preparation for a clinical trial of therapeutic agents for children with moderate‐to‐severe blunt traumatic brain injuries (TBIs) in emergency departments (EDs), we conducted this feasibility study to (1) determine the number and clinical characteristics of eligible children, (2) determine the timing of patient and guardian arrival to the ED, and (3) describe the heterogeneity of TBIs on computed tomography (CT) scans.MethodsWe conducted a prospective observational study at 16 EDs of children ≤ 18 years of age presenting with blunt head trauma and Glasgow Coma Scale scores of 3–12. We documented the number of potentially eligible patients, timing of patient and guardian arrival, patient demographics and clinical characteristics, severity of injuries, and cranial CT findings.ResultsWe enrolled 295 eligible children at the 16 sites over 6 consecutive months. Cardiac arrest and nonsurvivable injuries were the most common characteristics that would exclude patients from a future trial. Most children arrived within 2 hours of injury, but most guardians did not arrive until 2–3 hours after the injury. There was a substantial range in types of TBIs, with subdural hemorrhages being the most common.ConclusionEnrolling children with moderate‐to‐severe TBI into time‐sensitive clinical trials will require large numbers of sites and meticulous preparation and coordination and will prove challenging to obtain informed consent given the timing of patient and guardian arrival. The Federal Exception from Informed Consent for Emergency Research will be an important consideration for enrolling these children.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135996/1/acem13085_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135996/2/acem13085.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135996/3/acem13085-sup-0001-DataSupplementS1.pd

LSST Science Book, Version 2.0

A survey that can cover the sky in optical bands over wide fields to faint magnitudes with a fast cadence will enable many of the exciting science opportunities of the next decade. The Large Synoptic Survey Telescope (LSST) will have an effective aperture of 6.7 meters and an imaging camera with field of view of 9.6 deg^2, and will be devoted to a ten-year imaging survey over 20,000 deg^2 south of +15 deg. Each pointing will be imaged 2000 times with fifteen second exposures in six broad bands from 0.35 to 1.1 microns, to a total point-source depth of r~27.5. The LSST Science Book describes the basic parameters of the LSST hardware, software, and observing plans. The book discusses educational and outreach opportunities, then goes on to describe a broad range of science that LSST will revolutionize: mapping the inner and outer Solar System, stellar populations in the Milky Way and nearby galaxies, the structure of the Milky Way disk and halo and other objects in the Local Volume, transient and variable objects both at low and high redshift, and the properties of normal and active galaxies at low and high redshift. It then turns to far-field cosmological topics, exploring properties of supernovae to z~1, strong and weak lensing, the large-scale distribution of galaxies and baryon oscillations, and how these different probes may be combined to constrain cosmological models and the physics of dark energy.Comment: 596 pages. Also available at full resolution at http://www.lsst.org/lsst/sciboo

Integrating Clinical Probability into the Diagnostic Approach to Idiopathic Pulmonary Fibrosis: An International Working Group Perspective

Background. When considering the diagnosis of idiopathic pulmonary fibrosis (IPF), experienced clinicians integrate clinical features that help to differentiate IPF from other fibrosing interstitial lung diseases, thus generating a “pre-test” probability of IPF. The aim of this international working group perspective was to summarize these features using a tabulated approach similar to chest HRCT and histopathologic patterns reported in the international guidelines for the diagnosis of IPF, and to help formally incorporate these clinical likelihoods into diagnostic reasoning to facilitate the diagnosis of IPF. Methods. The committee group identified factors that influence the clinical likelihood of a diagnosis of IPF, which was categorized as a pre-test clinical probability of IPF into “high” (70-100%), “intermediate” (30-70%), or “low” (0-30%). After integration of radiological and histopathological features, the post-test probability of diagnosis was categorized into “definite” (90-100%), “high confidence” (70-89%), “low confidence” (51-69%), or “low” (0-50%) probability of IPF. Findings. A conceptual Bayesian framework was created, integrating the clinical likelihood of IPF (“pre-test probability of IPF”) with the HRCT pattern, the histopathology pattern when available, and/or the pattern of observed disease behavior into a “post-test probability of IPF”. The diagnostic probability of IPF was expressed using an adapted diagnostic ontology for fibrotic interstitial lung diseases. Interpretation. The present approach will help incorporate the clinical judgement into the diagnosis of IPF, thus facilitating the application of IPF diagnostic guidelines and, ultimately improving diagnostic confidence and reducing the need for invasive diagnostic techniques

Deep Sequencing of the Nicastrin Gene in Pooled DNA, the Identification of Genetic Variants That Affect Risk of Alzheimer's Disease

Nicastrin is an obligatory component of the γ-secretase; the enzyme complex that leads to the production of Aβ fragments critically central to the pathogenesis of Alzheimer's disease (AD). Analyses of the effects of common variation in this gene on risk for late onset AD have been inconclusive. We investigated the effect of rare variation in the coding regions of the Nicastrin gene in a cohort of AD patients and matched controls using an innovative pooling approach and next generation sequencing. Five SNPs were identified and validated by individual genotyping from 311 cases and 360 controls. Association analysis identified a non-synonymous rare SNP (N417Y) with a statistically higher frequency in cases compared to controls in the Greek population (OR 3.994, CI 1.105–14.439, p = 0.035). This finding warrants further investigation in a larger cohort and adds weight to the hypothesis that rare variation explains some of genetic heritability still to be identified in Alzheimer's disease