Highly Pathogenic Avian Influenza A(H5N1) Virus Outbreak in New England Seals, United States

We report the spillover of highly pathogenic avian influenza A(H5N1) into marine mammals in the northeastern United States, coincident with H5N1 in sympatric wild birds. Our data indicate monitoring both wild coastal birds and marine mammals will be critical to determine pandemic potential of influenza A viruses

20 years of research on the Alcator C-Mod tokamak

The object of this review is to summarize the achievements of research on the Alcator C-Mod tokamak [Hutchinson et al., Phys. Plasmas 1, 1511 (1994) and Marmar, Fusion Sci. Technol. 51, 261 (2007)] and to place that research in the context of the quest for practical fusion energy. C-Mod is a compact, high-field tokamak, whose unique design and operating parameters have produced a wealth of new and important results since it began operation in 1993, contributing data that extends tests of critical physical models into new parameter ranges and into new regimes. Using only high-power radio frequency (RF) waves for heating and current drive with innovative launching structures, C-Mod operates routinely at reactor level power densities and achieves plasma pressures higher than any other toroidal confinement device. C-Mod spearheaded the development of the vertical-target divertor and has always operated with high-Z metal plasma facing components—approaches subsequently adopted for ITER. C-Mod has made ground-breaking discoveries in divertor physics and plasma-material interactions at reactor-like power and particle fluxes and elucidated the critical role of cross-field transport in divertor operation, edge flows and the tokamak density limit. C-Mod developed the I-mode and the Enhanced Dα H-mode regimes, which have high performance without large edge localized modes and with pedestal transport self-regulated by short-wavelength electromagnetic waves. C-Mod has carried out pioneering studies of intrinsic rotation and demonstrated that self-generated flow shear can be strong enough in some cases to significantly modify transport. C-Mod made the first quantitative link between the pedestal temperature and the H-mode's performance, showing that the observed self-similar temperature profiles were consistent with critical-gradient-length theories and followed up with quantitative tests of nonlinear gyrokinetic models. RF research highlights include direct experimental observation of ion cyclotron range of frequency (ICRF) mode-conversion, ICRF flow drive, demonstration of lower-hybrid current drive at ITER-like densities and fields and, using a set of novel diagnostics, extensive validation of advanced RF codes. Disruption studies on C-Mod provided the first observation of non-axisymmetric halo currents and non-axisymmetric radiation in mitigated disruptions. A summary of important achievements and discoveries are included.United States. Dept. of Energy (Cooperative Agreement DE-FC02-99ER54512)United States. Dept. of Energy (Cooperative Agreement DE-FG03-94ER-54241)United States. Dept. of Energy (Cooperative Agreement DE-AC02-78ET- 51013)United States. Dept. of Energy (Cooperative Agreement DE-AC02-09CH11466)United States. Dept. of Energy (Cooperative Agreement DE-FG02-95ER54309)United States. Dept. of Energy (Cooperative Agreement DE-AC02-05CH11231)United States. Dept. of Energy (Cooperative Agreement DE-AC52-07NA27344)United States. Dept. of Energy (Cooperative Agreement DE-FG02- 97ER54392)United States. Dept. of Energy (Cooperative Agreement DE-SC00-02060

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Human Achilles tendon mechanical behavior is more strongly related to collagen disorganization than advanced glycation end-products content

Diabetes is associated with impaired tendon homeostasis and subsequent tendon dysfunction, but the mechanisms underlying these associations is unclear. Advanced glycation end-products (AGEs) accumulate with diabetes and have been suggested to alter tendon function. In vivo imaging in humans has suggested collagen disorganization is more frequent in individuals with diabetes, which could also impair tendon mechanical function. The purpose of this study was to examine relationships between tendon tensile mechanics in human Achilles tendon with accumulation of advanced glycation end-products and collagen disorganization. Achilles tendon specimens (n = 16) were collected from individuals undergoing lower extremity amputation or from autopsy. Tendons were tensile tested with simultaneous quantitative polarized light imaging to assess collagen organization, after which AGEs content was assessed using a fluorescence assay. Moderate to strong relationships were observed between measures of collagen organization and tendon tensile mechanics (range of correlation coefficients: 0.570-0.727), whereas no statistically significant relationships were observed between AGEs content and mechanical parameters (range of correlation coefficients: 0.020-0.210). Results suggest that the relationship between AGEs content and tendon tensile mechanics may be masked by multifactorial collagen disorganization at larger length scales (i.e., the fascicle level)

Accuracy of selfreported cancer-screening histories: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2008; 17: 748–57

Abstract Background: Survey data used to study trends in cancer screening may overestimate screening utilization while potentially underestimating existing disparities in use. Methods: We did a literature review and meta-analysis of validation studies examining the accuracy of selfreported cancer-screening histories. We calculated summary random-effects estimates for sensitivity and specificity, separately for mammography, clinical breast exam (CBE), Pap smear, prostate-specific antigen testing (PSA), digital rectal exam, fecal occult blood testing, and colorectal endoscopy

Functionally Biased D2R Antagonists: Targeting the β‑Arrestin Pathway to Improve Antipsychotic Treatment

Schizophrenia is a severe neuropsychiatric disease that lacks completely effective and safe therapies. As a polygenic disorder, genetic studies have only started to shed light on its complex etiology. To date, the positive symptoms of schizophrenia are well-managed by antipsychotic drugs, which primarily target the dopamine D2 receptor (D2R). However, these antipsychotics are often accompanied by severe side effects, including motoric symptoms. At D2R, antipsychotic drugs antagonize both G-protein dependent (Gα_i/o) signaling and G-protein independent (β-arrestin) signaling. However, the relevant contributions of the distinct D2R signaling pathways to antipsychotic efficacy and on-target side effects (motoric) are still incompletely understood. Recent evidence from mouse genetic and pharmacological studies point to β-arrestin signaling as the major driver of antipsychotic efficacy and suggest that a β-arrestin biased D2R antagonist could achieve an additional level of selectivity at D2R, increasing the therapeutic index of next generation antipsychotics. Here, we characterize <b>BRD5814</b>, a highly brain penetrant β-arrestin biased D2R antagonist. <b>BRD5814</b> demonstrated good target engagement <i>via</i> PET imaging, achieving efficacy in an amphetamine-induced hyperlocomotion mouse model with strongly reduced motoric side effects in a rotarod performance test. This proof of concept study opens the possibility for the development of a new generation of pathway selective antipsychotics at D2R with reduced side effect profiles for the treatment of schizophrenia

Inhibitors of Glycogen Synthase Kinase 3 with Exquisite Kinome-Wide Selectivity and Their Functional Effects

The mood stabilizer lithium, the first-line treatment for bipolar disorder, is hypothesized to exert its effects through direct inhibition of glycogen synthase kinase 3 (GSK3) and indirectly by increasing GSK3’s inhibitory serine phosphorylation. GSK3 comprises two highly similar paralogs, GSK3α and GSK3β, which are key regulatory kinases in the canonical Wnt pathway. GSK3 stands as a nodal target within this pathway and is an attractive therapeutic target for multiple indications. Despite being an active field of research for the past 20 years, many GSK3 inhibitors demonstrate either poor to moderate selectivity versus the broader human kinome or physicochemical properties unsuitable for use in <i>in vitro</i> systems or <i>in vivo</i> models. A nonconventional analysis of data from a GSK3β inhibitor high-throughput screening campaign, which excluded known GSK3 inhibitor chemotypes, led to the discovery of a novel pyrazolo-tetrahydro­quinolinone scaffold with unparalleled kinome-wide selectivity for the GSK3 kinases. Taking advantage of an uncommon tridentate interaction with the hinge region of GSK3, we developed highly selective and potent GSK3 inhibitors, <b>BRD1652</b> and <b>BRD0209</b>, which demonstrated <i>in vivo</i> efficacy in a dopaminergic signaling paradigm modeling mood-related disorders. These new chemical probes open the way for exclusive analyses of the function of GSK3 kinases in multiple signaling pathways involved in many prevalent disorders