10 research outputs found
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
Epidemic Clostridium difficile Strains Demonstrate Increased Competitive Fitness Compared to Nonepidemic Isolates
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<sub>i/o</sub>) 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-tetrahydroÂquinolinone 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