Researchers explore Arctic freshwater\u27s role in ocean circulation

A critical, but insufficiently understood, component of global change is the influence of Arctic freshwater input on water mass exchange between the Arctic Ocean and Atlantic and Pacific Oceans. Four of the Earth\u27s 10 largest river systems, the Mackenzie, Ob,Yenisei, and Lena, contribute water to the Arctic shore (Figure 1) from a vast watershed that drains continental interiors. This river discharge flows into the world\u27s largest contiguous continental shelf and supplies over 50% (1823 km3 ) of the riverine input to the Arctic Ocean

High-throughput screening in larval zebrafish identifies novel potent sedative-hypnotics

BACKGROUND: Many general anesthetics were discovered empirically, but primary screens to find new sedative-hypnotics in drug libraries have not used animals, limiting the types of drugs discovered. The authors hypothesized that a sedative-hypnotic screening approach using zebrafish larvae responses to sensory stimuli would perform comparably to standard assays, and efficiently identify new active compounds. METHODS: The authors developed a binary outcome photomotor response assay for zebrafish larvae using a computerized system that tracked individual motions of up to 96 animals simultaneously. The assay was validated against tadpole loss of righting reflexes, using sedative-hypnotics of widely varying potencies that affect various molecular targets. A total of 374 representative compounds from a larger library were screened in zebrafish larvae for hypnotic activity at 10 µM. Molecular mechanisms of hits were explored in anesthetic-sensitive ion channels using electrophysiology, or in zebrafish using a specific reversal agent. RESULTS: Zebrafish larvae assays required far less drug, time, and effort than tadpoles. In validation experiments, zebrafish and tadpole screening for hypnotic activity agreed 100% (n = 11; P = 0.002), and potencies were very similar (Pearson correlation, r > 0.999). Two reversible and potent sedative-hypnotics were discovered in the library subset. CMLD003237 (EC50, ~11 µM) weakly modulated γ-aminobutyric acid type A receptors and inhibited neuronal nicotinic receptors. CMLD006025 (EC50, ~13 µM) inhibited both N-methyl-D-aspartate and neuronal nicotinic receptors. CONCLUSIONS: Photomotor response assays in zebrafish larvae are a mechanism-independent platform for high-throughput screening to identify novel sedative-hypnotics. The variety of chemotypes producing hypnosis is likely much larger than currently known.This work was supported by grants from Shanghai Jiaotong University School of Medicine, Shanghai, China, and the Chinese Medical Association, Beijing, China (both to Dr. Yang). The Department of Anesthesia, Critical Care and Pain Medicine of Massachusetts General Hospital, Boston, Massachusetts, supported this work through a Research Scholars Award and an Innovation Grant (both to Dr. Forman). Contributions to this research from the Boston University Center for Molecular Discovery, Boston, Massachusetts (to Drs. Porco, Brown, Schaus, and Xu, and to Mr. Trilles), were supported by a grant from the National Institutes of Health, Bethesda, Maryland (grant No. R24 GM111625). (Shanghai Jiaotong University School of Medicine, Shanghai, China; Chinese Medical Association, Beijing, China; Department of Anesthesia, Critical Care and Pain Medicine of Massachusetts General Hospital, Boston, Massachusetts; R24 GM111625 - National Institutes of Health, Bethesda, Maryland)Accepted manuscript2019-09-0

Association Between Passive and Active Smoking and Incident Type 2 Diabetes in Women

OBJECTIVE: Accumulating evidence has identified a positive association between active smoking and the risk of diabetes, but previous studies had limited information on passive smoking or changes in smoking behaviors over time. This analysis examined the association between exposure to passive smoke, active smoking, and the risk of incident type 2 diabetes among women. RESEARCH DESIGN AND METHODS: This is a prospective cohort study of 100,526 women in the Nurses’ Health Study who did not have prevalent diabetes in 1982, with follow-up for diabetes for 24 years. RESULTS: We identified 5,392 incident cases of type 2 diabetes during 24 years of follow-up. Compared with nonsmokers with no exposure to passive smoke, there was an increased risk of diabetes among nonsmokers who were occasionally (relative risk [RR] 1.10 [95% CI 0.94–1.23]) or regularly (1.16 [1.00–1.35]) exposed to passive smoke. The risk of incident type 2 diabetes was increased by 28% (12–50) among all past smokers. The risk diminished as time since quitting increased but still was elevated even 20–29 years later (1.15 [1.00–1.32]). Current smokers had the highest risk of incident type 2 diabetes in a dose-dependent manner. Adjusted RRs increased from 1.39 (1.17–1.64) for 1–14 cigarettes per day to 1.98 (1.57–2.36) for ≥25 cigarettes per day compared with nonsmokers with no exposure to passive smoke. CONCLUSIONS: Our study suggests that exposure to passive smoke and active smoking are positively and independently associated with the risk of type 2 diabetes

Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies

Accumulation of hyperphosphorylated, ubiquitinated and N-terminally truncated TAR DNA-binding protein (TDP-43) is the pathological hallmark lesion in most familial and sporadic forms of FTLD-U and ALS, which can be subsumed as TDP-43 proteinopathies. In order to get more insight into the role of abnormal phosphorylation in the disease process, the identification of specific phosphorylation sites and the generation of phosphorylation-specific antibodies are mandatory. Here, we developed and characterized novel rat monoclonal antibodies (1D3 and 7A9) raised against phosphorylated S409/410 of TDP-43. These antibodies were used to study the presence of S409/410 phosphorylation by immunohistochemistry and biochemical analysis in a large series of 64 FTLD-U cases with or without motor neuron disease including familial cases with mutations in progranulin (n=5), valosin-containing protein (n=4) and linkage to chromosome 9p (n=4), 18 ALS cases as well as other neurodegenerative diseases with concomitant TDP-43 pathology (n=5). Our data demonstrate that phosphorylation of S409/410 of TDP-43 is a highly consistent feature in pathologic inclusions in the whole spectrum of sporadic and familial forms of TDP-43 proteinopathies. Physiological nuclear TDP-43 was not detectable with these mAbs by immunohistochemistry and by immunoblot analyses. While the accumulation of phosphorylated C-terminal fragments was a robust finding in the cortical brain regions of FTLD-U and ALS, usually being much more abundant than the phosphorylated full-length TDP-43 band, spinal cord samples revealed a predominance of full-length TDP-43 over C-terminal fragments. This argues for a distinct TDP-43 species composition in inclusions in cortical versus spinal cord cells. Overall, these mAbs are powerful tools for the highly specific detection of disease-associated abnormal TDP-43 species and will be extremely useful for the neuropathological routine diagnostics of TDP-43 proteinopathies and for the investigation of emerging cellular and animal models for TDP-43 proteinopathie

A Deep Chandra Observation of the Distant Galaxy Cluster MS1137.5+6625

We present results from a deep Chandra observation of MS1137.5+66, a distant (z=0.783) and massive cluster of galaxies. Only a few similarly massive clusters are currently known at such high redshifts; accordingly, this observation provides much-needed information on the dynamical state of these rare systems. The cluster appears both regular and symmetric in the X-ray image. However, our analysis of the spectral and spatial X-ray data in conjunction with interferometric Sunyaev-Zel'dovich effect data and published deep optical imaging suggests the cluster has a fairly complex structure. The angular diameter distance we calculate from the Chandra and Sunyaev-Zel'dovich effect data assuming an isothermal, spherically symmetric cluster implies a low value for the Hubble constant for which we explore possible explanations.Comment: 16 pages, 6 figures, submitted to Ap

Near-Infrared Synchrotron Emission from Cas A

High energy observations of Cas A suggested the presence of synchrotron radiation, implying acceleration of cosmic rays by young supernova remnants. We detect synchrotron emission from Cas A in the near-infrared using Two Micron All Sky Survey (2MASS) and Palomar 200 inch PFIRCAM observations. The remnant is detected in J, H, and Ks bands, with Ks band brightest and J faint. In the J and H bands, bright [Fe II] lines (1.24um and 1.64um) are detected spectroscopically. The Palomar observations include Ks continuum, narrow-band 1.64um (centered on [Fe II]) and 2.12um (centered on H2(1-0)) images. While the narrow-band 1.64um image shows filamentary and knotty structures, similar to the optical image, the Ks image shows a relatively smooth, diffuse shell, remarkably similar to the radio image. The broad-band near-infrared fluxes of Cas A are generally consistent with, but a few tens of percent higher than, an extrapolation of the radio fluxes. The hardening to higher frequencies is possibly due to nonlinear shock acceleration and/or spectral index variation across the remnant. We show evidence of spectral index variation. The presence of near-infrared synchrotron radiation requires the roll-off frequency to be higher than 1.5e14 Hz, implying that electrons are accelerated to energies of at least 0.2 TeV. The morphological similarity in diffuse emission between the radio and Ks band images implies that synchrotron losses are not dominant. Our observations show unambiguous evidence that the near-infrared Ks band emission of Cas A is from synchrotron emission by accelerated cosmic-ray electrons.Comment: accepted by Ap

Sloshing Gas in the Core of the Most Luminous Galaxy Cluster RXJ1347.5-1145

We present new constraints on the merger history of the most X-ray luminous cluster of galaxies, RXJ1347.5-1145, based its unique multiwavelength morphology. Our X-ray analysis confirms the core gas is undergoing "sloshing" resulting from a prior, large scale, gravitational perturbation. In combination with extensive multiwavelength observations, the sloshing gas points to the primary and secondary clusters having had at least two prior strong gravitational interactions. The evidence supports a model in which the secondary subcluster with mass M=4.8+/-2.4 x 10(exp 14) Stellar Mass has previously (> or approx.=0.6 Gyr ago) passed by the primary cluster, and has now returned for a subsequent crossing where the subcluster's gas has been completely stripped from its dark matter halo. RXJ1347 is a prime example of how core gas sloshing may be used to constrain the merger histories of galaxy clusters through multiwavelength analyses

Genetic Predisposition to High Blood Pressure Associates With Cardiovascular Complications Among Patients With Type 2 Diabetes: Two Independent Studies

Hypertension and type 2 diabetes (T2D) commonly coexist, and both conditions are major risk factors for cardiovascular disease (CVD). We aimed to examine the association between genetic predisposition to high blood pressure and risk of CVD in individuals with T2D. The current study included 1,005 men and 1,299 women with T2D from the Health Professionals Follow-up Study and Nurses’ Health Study, of whom 732 developed CVD. A genetic predisposition score was calculated on the basis of 29 established blood pressure–associated variants. The genetic predisposition score showed consistent associations with risk of CVD in men and women. In the combined results, each additional blood pressure–increasing allele was associated with a 6% increased risk of CVD (odds ratio [OR] 1.06 [95% CI 1.03–1.10]). The OR was 1.62 (1.22–2.14) for risk of CVD comparing the extreme quartiles of the genetic predisposition score. The genetic association for CVD risk was significantly stronger in patients with T2D than that estimated in the general populations by a meta-analysis (OR per SD of genetic score 1.22 [95% CI 1.10–1.35] vs. 1.10 [1.08–1.12]; I2 = 71%). Our data indicate that genetic predisposition to high blood pressure is associated with an increased risk of CVD in individuals with T2D

Dietary fiber intake and mortality among survivors of myocardial infarction: prospective cohort study

Objective: To evaluate the associations of dietary fiber after myocardial infarction (MI) and changes in dietary fiber intake from before to after MI with all cause and cardiovascular mortality. Design: Prospective cohort study. Setting: Two large prospective cohort studies of US women and men with repeated dietary measurements: the Nurses’ Health Study and the Health Professionals Follow-Up Study. Participants: 2258 women and 1840 men who were free of cardiovascular disease, stroke, or cancer at enrollment, survived a first MI during follow-up, were free of stroke at the time of initial onset of MI, and provided food frequency questionnaires pre-MI and at least one post-MI. Main outcome measures Associations of dietary fiber post-MI and changes from before to after MI with all cause and cardiovascular mortality using Cox proportional hazards models, adjusting for drug use, medical history, and lifestyle factors. Results: Higher post-MI fiber intake was significantly associated with lower all cause mortality (comparing extreme fifths, pooled hazard ratio 0.75, 95% confidence interval 0.58 to 0.97). Greater intake of cereal fiber was more strongly associated with all cause mortality (pooled hazard ratio 0.73, 0.58 to 0.91) than were other sources of dietary fiber. Increased fiber intake from before to after MI was significantly associated with lower all cause mortality (pooled hazard ratio 0.69, 0.55 to 0.87). Conclusions: In this prospective study of patients who survived MI, a greater intake of dietary fiber after MI, especially cereal fiber, was inversely associated with all cause mortality. In addition, increasing consumption of fiber from before to after MI was significantly associated with lower all cause and cardiovascular mortality