Body composition estimated by bioelectrical impedance analyses is diminished by prenatal stress in neonatal lambs and by heat stress in feedlot wethers

Body composition correlates to carcass value in livestock, which makes the ability to accurately estimate body composition in the live animal beneficial (Berg and Marchello, 1994). Bioelectrical impedance analysis (BIA) is a clinical tool used to assess body composition in humans (Lukaski et al., 1985), but its use in livestock has been minimal. Lean and fat content contribute to profitability for livestock producers, and poor body composition can be caused by stress that occurs either during in utero development (De Blasio et al., 2007) or during postnatal growth (Boyd et al., 2015). Maternal hyperthermia-induced placental insufficiency (Brown et al., 2015) and sustained maternal inflammation (Cadaret et al., 2018) are two established causes of intrauterine growth restriction (IUGR). IUGR-born animals are characterized by asymmetrical growth restriction that alters lifelong body composition due to impaired muscle growth capacity (Yates et al., 2018). In addition, acute heat stress during periods of peak postnatal growth can alter body composition in livestock (Boyd et al., 2015). We postulate that BIA can detect these changes in the live animal. Thus, the objective of this study was to determine whether BIA measurements can predict changes to body composition in live neonatal lambs exposed to intrauterine stress and in heat-stressed feedlot lambs

Maternal inflammation at 0.7 gestation in ewes leads to intrauterine growth restriction and impaired glucose metabolism in offspring at 30 d of age

Fetal programming associated with intrauterine growth restriction (IUGR) leads to lifelong deficits in growth and metabolic function (Hales and Barker, 2013). IUGR arises when fetuses respond to poor in utero conditions by developing adaptations that repartition nutrients to critical tissues and away from skeletal muscle (Yates et al., 2012, 2018). This fetal programming is beneficial in utero but leads to persistent reductions in muscle mass and glucose homeostasis in offspring (DeFronzo et al., 1981). Recent studies by our laboratory in sheep and rats demonstrate that maternal inflammation during gestation induces fetal inflammatory adaptations that impair growth and disrupt muscle glucose metabolism (Cadaret et al., 2017, 2018). IUGR fetal skeletal muscle exhibits indicators of enhanced inflammatory sensitivity, which could disrupt glucose uptake and oxidation (Yates et al., 2016; Cadaret et al., 2018). Enhanced inflammatory responsiveness would help explain growth and metabolic deficits observed in IUGR offspring. We hypothesize that fetal programming induced by maternal inflammation persists in offspring and contributes to impaired growth and glucose metabolism at 30 d. Therefore, the objective of this study was to determine whether sustained maternal inflammation induced by bacterial endotoxin at 0.7 gestation leads to fetal programming that contributes to deficits in growth and glucose metabolism in offspring

Acid activation mechanism of the influenza A M2 proton channel

The homotetrameric influenza A M2 channel (AM2) is an acid-activated proton channel responsible for the acidification of the influenza virus interior, an important step in the viral lifecycle. Four histidine residues (His37) in the center of the channel act as a pH sensor and proton selectivity filter. Despite intense study, the pH-dependent activation mechanism of the AM2 channel has to date not been completely understood at a molecular level. Herein we have used multiscale computer simulations to characterize (with explicit proton transport free energy profiles and their associated calculated conductances) the activation mechanism of AM2. All proton transfer steps involved in proton diffusion through the channel, including the protonation/deprotonation of His37, are explicitly considered using classical, quantum, and reactive molecular dynamics methods. The asymmetry of the proton transport free energy profile under high-pH conditions qualitatively explains the rectification behavior of AM2 (i.e., why the inward proton flux is allowed when the pH is low in viral exterior and high in viral interior, but outward proton flux is prohibited when the pH gradient is reversed). Also, in agreement with electrophysiological results, our simulations indicate that the C-terminal amphipathic helix does not significantly change the proton conduction mechanism in the AM2 transmembrane domain; the four transmembrane helices flanking the channel lumen alone seem to determine the proton conduction mechanism.United States. National Institutes of Health (R01-GM088204

Resolution of Clinical and Laboratory Abnormalities after Diagnosis of Ventilator-Associated Pneumonia in Trauma Patients

Background: Guidelines advise that patients with ventilator-associated pneumonia (VAP) should respond clinically by Day 3 of antibiotics. White blood cell (WBC) count, maximum temperature (Tmax), and PaO2:FIO2 ratio are all said to respond significantly by Day 6. Resolution of abnormalities has not been evaluated in trauma patients. Methods: Retrospective review of trauma patients with VAP. The WBC count, Tmax, and PaO2:FIO2 were evaluated for 16 days after diagnosis. Patients were grouped into uncomplicated VAP, complicated VAP (those with inadequate empirical therapy [IEAT], VAP relapse/superinfection, or acute respiratory distress syndrome), and concurrent infection +VAP (those also infected at another site). Results: There were 126 patients (uncomplicated VAP= 29, complicated VAP = 69, and concurrent infection + VAP = 28). The mean Tmax in patients with uncomplicated VAP decreased significantly from diagnosis to Day 4 (Day 1: 39 – 0.5°C vs. Day 4: 38.6 – 0.7°C; p = 0.028) but never normalized. Their WBC counts and PaO2:FIO2 did not change significantly over the 16-day follow-up and never normalized.When comparing the three groups, the probability of resolving all three abnormalities was not different (p = 0.5). Conclusions: Clinical and laboratory abnormalities in critically injured patients with VAP do not resolve as quickly as suggested in the guidelines. Future studies should evaluate new methods to determine the response to antibiotic therapy in critically injured patients with VAP

Maternal inflammation at 0.7 gestation in ewes leads to intrauterine growth restriction and impaired glucose metabolism in offspring at 30 d of age

Fetal programming associated with intrauterine growth restriction (IUGR) leads to lifelong deficits in growth and metabolic function (Hales and Barker, 2013). IUGR arises when fetuses respond to poor in utero conditions by developing adaptations that repartition nutrients to critical tissues and away from skeletal muscle (Yates et al., 2012, 2018). This fetal programming is beneficial in utero but leads to persistent reductions in muscle mass and glucose homeostasis in offspring (DeFronzo et al., 1981). Recent studies by our laboratory in sheep and rats demonstrate that maternal inflammation during gestation induces fetal inflammatory adaptations that impair growth and disrupt muscle glucose metabolism (Cadaret et al., 2017, 2018). IUGR fetal skeletal muscle exhibits indicators of enhanced inflammatory sensitivity, which could disrupt glucose uptake and oxidation (Yates et al., 2016; Cadaret et al., 2018). Enhanced inflammatory responsiveness would help explain growth and metabolic deficits observed in IUGR offspring. We hypothesize that fetal programming induced by maternal inflammation persists in offspring and contributes to impaired growth and glucose metabolism at 30 d. Therefore, the objective of this study was to determine whether sustained maternal inflammation induced by bacterial endotoxin at 0.7 gestation leads to fetal programming that contributes to deficits in growth and glucose metabolism in offspring

Cadherin-10 maintains excitatory/inhibitory ratio through interactions with synaptic proteins

Appropriate excitatory/inhibitory (E/I) balance is essential for normal cortical function and is altered in some psychiatric disorders, including autism spectrum disorders (ASDs). Cell-autonomous molecular mechanisms that control the balance of excitatory and inhibitory synapse function remain poorly understood; no proteins that regulate excitatory and inhibitory synapse strength in a coordinated reciprocal manner have been identified. Using super-resolution imaging, electrophysiology, and molecular manipulations, we show that cadherin-10, encoded byCDH10within the ASD risk locus 5p14.1, maintains both excitatory and inhibitory synaptic scaffold structure in cultured cortical neurons from rats of both sexes. Cadherin-10 localizes to both excitatory and inhibitory synapses in neocortex, where it is organized into nanoscale puncta that influence the size of their associated PSDs. Knockdown of cadherin-10 reduces excitatory but increases inhibitory synapse size and strength, altering the E/I ratio in cortical neurons. Furthermore, cadherin-10 exhibits differential participation in complexes with PSD-95 and gephyrin, which may underlie its role in maintaining the E/I ratio. Our data provide a new mechanism whereby a protein encoded by a common ASD risk factor controls E/I ratios by regulating excitatory and inhibitory synapses in opposing directions.SIGNIFICANCE STATEMENTThe correct balance between excitatory/inhibitory (E/I) is crucial for normal brain function and is altered in psychiatric disorders such as autism. However, the molecular mechanisms that underlie this balance remain elusive. To address this, we studied cadherin-10, an adhesion protein that is genetically linked to autism and understudied at the cellular level. Using a combination of advanced microscopy techniques and electrophysiology, we show that cadherin-10 forms nanoscale puncta at excitatory and inhibitory synapses, maintains excitatory and inhibitory synaptic structure, and is essential for maintaining the correct balance between excitation and inhibition in neuronal dendrites. These findings reveal a new mechanism by which E/I balance is controlled in neurons and may bear relevance to synaptic dysfunction in autism.</jats:p

Nautical Research Platform for Water-Bound Experiments

Conducting research in lakes and rivers requires large crews and heavy-duty equipment, making even simple tests more costly and time consuming. Newer research methods are evolving constantly as new technology enables more precise and accessible experiments to be conducted. The need for simple execution of water-bound experiments exists and must be addressed to aid our understanding of these environments. We at the Microgravity Undergraduate Research Team have taken our previous research in autonomous Unmanned Surface Vehicles (USVs) and applied our efforts to relieving this problem. Our current research aims to provide a universal platform for research and experiments to be conducted in lakes and rivers, where we can then expand our efforts to more broad applications. The design allows for remote-control navigation by one user and easy portability. To address precision in experimentation, we have integrated autonomous GPS waypoint navigation which removes user error in sensitive measurements. The most important factor in its design is modularity; the ability to accommodate a wide range of equipment for research. Our platform succeeds in making water-bound experiments more accessible and more precise for a multitude of potential applications

The Ninth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the SDSS-III Baryon Oscillation Spectroscopic Survey

The Sloan Digital Sky Survey III (SDSS-III) presents the first spectroscopic data from the Baryon Oscillation Spectroscopic Survey (BOSS). This ninth data release (DR9) of the SDSS project includes 535,995 new galaxy spectra (median z=0.52), 102,100 new quasar spectra (median z=2.32), and 90,897 new stellar spectra, along with the data presented in previous data releases. These spectra were obtained with the new BOSS spectrograph and were taken between 2009 December and 2011 July. In addition, the stellar parameters pipeline, which determines radial velocities, surface temperatures, surface gravities, and metallicities of stars, has been updated and refined with improvements in temperature estimates for stars with T_eff<5000 K and in metallicity estimates for stars with [Fe/H]>-0.5. DR9 includes new stellar parameters for all stars presented in DR8, including stars from SDSS-I and II, as well as those observed as part of the SDSS-III Sloan Extension for Galactic Understanding and Exploration-2 (SEGUE-2). The astrometry error introduced in the DR8 imaging catalogs has been corrected in the DR9 data products. The next data release for SDSS-III will be in Summer 2013, which will present the first data from the Apache Point Observatory Galactic Evolution Experiment (APOGEE) along with another year of data from BOSS, followed by the final SDSS-III data release in December 2014.Comment: 9 figures; 2 tables. Submitted to ApJS. DR9 is available at http://www.sdss3.org/dr

Clustered mutations in the <i>GRIK2</i> kainate receptor subunit gene underlie diverse neurodevelopmental disorders

Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygous de novo variants in GRIK2 causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrent de novo variants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were homozygous for a previously reported variant (c.1969G&gt;A [p.Ala657Thr]). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that the GRIK2 variants are likely pathogenic. Analogous mutations introduced into recombinant GluK2 KAR subunits at sites within the M3 transmembrane domain (encoding p.Ala657Thr, p.Thr660Lys, and p.Thr660Arg) and the M3-S2 linker domain (encoding p.Ile668Thr) had complex effects on functional properties and membrane localization of homomeric and heteromeric KARs. Both p.Thr660Lys and p.Thr660Arg mutant KARs exhibited markedly slowed gating kinetics, similar to p.Ala657Thr-containing receptors. Moreover, we observed emerging genotype-phenotype correlations, including the presence of severe epilepsy in individuals with the p.Thr660Lys variant and hypomyelination in individuals with either the p.Thr660Lys or p.Thr660Arg variant. Collectively, these results demonstrate that human GRIK2 variants predicted to alter channel function are causative for early childhood development disorders and further emphasize the importance of clarifying the role of KARs in early nervous system development.</p

Clustered mutations in the <i>GRIK2</i> kainate receptor subunit gene underlie diverse neurodevelopmental disorders

Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygous de novo variants in GRIK2 causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrent de novo variants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were homozygous for a previously reported variant (c.1969G>A [p.Ala657Thr]). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that the GRIK2 variants are likely pathogenic. Analogous mutations introduced into recombinant GluK2 KAR subunits at sites within the M3 transmembrane domain (encoding p.Ala657Thr, p.Thr660Lys, and p.Thr660Arg) and the M3-S2 linker domain (encoding p.Ile668Thr) had complex effects on functional properties and membrane localization of homomeric and heteromeric KARs. Both p.Thr660Lys and p.Thr660Arg mutant KARs exhibited markedly slowed gating kinetics, similar to p.Ala657Thr-containing receptors. Moreover, we observed emerging genotype-phenotype correlations, including the presence of severe epilepsy in individuals with the p.Thr660Lys variant and hypomyelination in individuals with either the p.Thr660Lys or p.Thr660Arg variant. Collectively, these results demonstrate that human GRIK2 variants predicted to alter channel function are causative for early childhood development disorders and further emphasize the importance of clarifying the role of KARs in early nervous system development