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

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

SNPs Associated with Cerebrospinal Fluid Phospho-Tau Levels Influence Rate of Decline in Alzheimer's Disease

Alzheimer's Disease (AD) is a complex and multifactorial disease. While large genome-wide association studies have had some success in identifying novel genetic risk factors for AD, case-control studies are less likely to uncover genetic factors that influence progression of disease. An alternative approach to identifying genetic risk for AD is the use of quantitative traits or endophenotypes. The use of endophenotypes has proven to be an effective strategy, implicating genetic risk factors in several diseases, including anemia, osteoporosis and heart disease. In this study we identify a genetic factor associated with the rate of decline in AD patients and present a methodology for identification of other such factors. We have used an established biomarker for AD, cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (ptau181) levels as an endophenotype for AD, identifying a SNP, rs1868402, in the gene encoding the regulatory sub-unit of protein phosphatase B, associated with CSF ptau181 levels in two independent CSF series . We show no association of rs1868402 with risk for AD or age at onset, but detected a very significant association with rate of progression of disease that is consistent in two independent series . Our analyses suggest that genetic variants associated with CSF ptau181 levels may have a greater impact on rate of progression, while genetic variants such as APOE4, that are associated with CSF Aβ42 levels influence risk and onset but not the rate of progression. Our results also suggest that drugs that inhibit or decrease tau phosphorylation may slow cognitive decline in individuals with very mild dementia or delay the appearance of memory problems in elderly individuals with low CSF Aβ42 levels. Finally, we believe genome-wide association studies of CSF tau/ptau181 levels should identify novel genetic variants which will likely influence rate of progression of AD