Reduced regional brain cortical thickness in patients with heart failure.

AimsAutonomic, cognitive, and neuropsychologic deficits appear in heart failure (HF) subjects, and these compromised functions depend on cerebral cortex integrity in addition to that of subcortical and brainstem sites. Impaired autoregulation, low cardiac output, sleep-disordered-breathing, hypertension, and diabetic conditions in HF offer considerable potential to affect cortical areas by loss of neurons and glia, which would be expressed as reduced cortical thicknesses. However, except for gross descriptions of cortical volume loss/injury, regional cortical thickness integrity in HF is unknown. Our goal was to assess regional cortical thicknesses across the brain in HF, compared to control subjects.Methods and resultsWe examined localized cortical thicknesses in 35 HF and 61 control subjects with high-resolution T1-weighted images (3.0-Tesla MRI) using FreeSurfer software, and assessed group differences with analysis-of-covariance (covariates; age, gender; p<0.05; FDR). Significantly-reduced cortical thicknesses appeared in HF over controls in multiple areas, including the frontal, parietal, temporal, and occipital lobes, more markedly on the left side, within areas that control autonomic, cognitive, affective, language, and visual functions.ConclusionHeart failure subjects show reduced regional cortical thicknesses in sites that control autonomic, cognitive, affective, language, and visual functions that are deficient in the condition. The findings suggest chronic tissue alterations, with regional changes reflecting loss of neurons and glia, and presumably are related to earlier-described axonal changes. The pathological mechanisms contributing to reduced cortical thicknesses likely include hypoxia/ischemia, accompanying impaired cerebral perfusion from reduced cardiac output and sleep-disordered-breathing and other comorbidities in HF

Cdc13 OB2 Dimerization Required for Productive Stn1 Binding and Efficient Telomere Maintenance

SummaryCdc13 is an essential yeast protein required for telomere length regulation and genome stability. It does so via its telomere-capping properties and by regulating telomerase access to the telomeres. The crystal structure of the Saccharomyces cerevisiae Cdc13 domain located between the recruitment and DNA binding domains reveals an oligonucleotide-oligosaccharide binding fold (OB2) with unusually long loops extending from the core of the protein. These loops are involved in extensive interactions between two Cdc13 OB2 folds leading to stable homodimerization. Interestingly, the functionally impaired cdc13-1 mutation inhibits OB2 dimerization. Biochemical assays indicate OB2 is not involved in telomeric DNA or Stn1 binding. However, disruption of the OB2 dimer in full-length Cdc13 affects Cdc13-Stn1 association, leading to telomere length deregulation, increased temperature sensitivity, and Stn1 binding defects. We therefore propose that dimerization of the OB2 domain of Cdc13 is required for proper Cdc13, Stn1, Ten1 (CST) assembly and productive telomere capping

Global patterns of diapycnal mixing from measurements of the turbulent dissipation rate

The authors present inferences of diapycnal diffusivity from a compilation of over 5200 microstructure profiles. As microstructure observations are sparse, these are supplemented with indirect measurements of mixing obtained from (i) Thorpe-scale overturns from moored profilers, a finescale parameterization applied to (ii) shipboard observations of upper-ocean shear, (iii) strain as measured by profiling floats, and (iv) shear and strain from full-depth lowered acoustic Doppler current profilers (LADCP) and CTD profiles. Vertical profiles of the turbulent dissipation rate are bottom enhanced over rough topography and abrupt, isolated ridges. The geography of depth-integrated dissipation rate shows spatial variability related to internal wave generation, suggesting one direct energy pathway to turbulence. The global-averaged diapycnal diffusivity below 1000-m depth is O(10?4) m2 s?1 and above 1000-m depth is O(10?5) m2 s?1. The compiled microstructure observations sample a wide range of internal wave power inputs and topographic roughness, providing a dataset with which to estimate a representative global-averaged dissipation rate and diffusivity. However, there is strong regional variability in the ratio between local internal wave generation and local dissipation. In some regions, the depth-integrated dissipation rate is comparable to the estimated power input into the local internal wave field. In a few cases, more internal wave power is dissipated than locally generated, suggesting remote internal wave sources. However, at most locations the total power lost through turbulent dissipation is less than the input into the local internal wave field. This suggests dissipation elsewhere, such as continental margins

Three-Dimensional Double-Ridge Internal Tide Resonance in Luzon Strait

The three-dimensional (3D) double-ridge internal tide interference in the Luzon Strait in the South China Sea is examined by comparing 3D and two-dimensional (2D) realistic simulations. Both the 3D simulations and observations indicate the presence of 3D first-mode (semi)diurnal standing waves in the 3.6-km-deep trench in the strait. As in an earlier 2D study, barotropic-to-baroclinic energy conversion, flux divergence, and dissipation are greatly enhanced when semidiurnal tides dominate relative to periods dominated by diurnal tides. The resonance in the 3D simulation is several times stronger than in the 2D simulations for the central strait. Idealized experiments indicate that, in addition to ridge height, the resonance is only a function of separation distance and not of the along-ridge length; that is, the enhanced resonance in 3D is not caused by 3D standing waves or basin modes. Instead, the difference in resonance between the 2D and 3D simulations is attributed to the topographic blocking of the barotropic flow by the 3D ridges, affecting wave generation, and a more constructive phasing between the remotely generated internal waves, arriving under oblique angles, and the barotropic tide. Most of the resonance occurs for the first mode. The contribution of the higher modes is reduced because of 3D radiation, multiple generation sites, scattering, and a rapid decay in amplitude away from the ridge

Excess ribosomal protein production unbalances translation in a model of Fragile X Syndrome

Dysregulated protein synthesis is a core pathogenic mechanism in Fragile X Syndrome (FX). The mGluR Theory of FX predicts that pathological synaptic changes arise from the excessive translation of mRNAs downstream of mGlu1/5 activation. Here, we use a combination of CA1 pyramidal neuron-specific TRAP-seq and proteomics to identify the overtranslating mRNAs supporting exaggerated mGlu1/5 -induced long-term synaptic depression (mGluR-LTD) in the FX mouse model (Fmr1−/y). Our results identify a significant increase in the translation of ribosomal proteins (RPs) upon mGlu1/5 stimulation that coincides with a reduced translation of long mRNAs encoding synaptic proteins. These changes are mimicked and occluded in Fmr1−/y neurons. Inhibiting RP translation significantly impairs mGluR-LTD and prevents the length-dependent shift in the translating population. Together, these results suggest that pathological changes in FX result from a length-dependent alteration in the translating population that is supported by excessive RP translation

Sex ratio and the evolution of aggression in fruit flies

Aggressive behaviours are among the most striking displayed by animals, and aggression strongly impacts fitness in many species. Aggression varies plastically in response to the social environment, but we lack direct tests of how aggression evolves in response to intra-sexual competition. We investigated how aggression in both sexes evolves in response to the competitive environment, using populations of Drosophila melanogaster that we experimentally evolved under female-biased, equal, and male-biased sex ratios. We found that after evolution in a female-biased environment—with less male competition for mates—males fought less often on food patches, although the total frequency and duration of aggressive behaviour did not change. In females, evolution in a female-biased environment—where female competition for resources is higher—resulted in more frequent aggressive interactions among mated females, along with a greater increase in post-mating aggression. These changes in female aggression could not be attributed solely to evolution either in females or in male stimulation of female aggression, suggesting that coevolved interactions between the sexes determine female post-mating aggression. We found evidence consistent with a positive genetic correlation for aggression between males and females, suggesting a shared genetic basis. This study demonstrates the experimental evolution of a behaviour strongly linked to fitness, and the potential for the social environment to shape the evolution of contest behaviours

Breed-Specific Hematological Phenotypes in the Dog: A Natural Resource for the Genetic Dissection of Hematological Parameters in a Mammalian Species

Remarkably little has been published on hematological phenotypes of the domestic dog, the most polymorphic species on the planet. Information on the signalment and complete blood cell count of all dogs with normal red and white blood cell parameters judged by existing reference intervals was extracted from a veterinary database. Normal hematological profiles were available for 6046 dogs, 5447 of which also had machine platelet concentrations within the reference interval. Seventy-five pure breeds plus a mixed breed control group were represented by 10 or more dogs. All measured parameters except mean corpuscular hemoglobin concentration (MCHC) varied with age. Concentrations of white blood cells (WBCs), neutrophils, monocytes, lymphocytes, eosinophils and platelets, but not red blood cell parameters, all varied with sex. Neutering status had an impact on hemoglobin concentration, mean corpuscular hemoglobin (MCH), MCHC, and concentrations of WBCs, neutrophils, monocytes, lymphocytes and platelets. Principal component analysis of hematological data revealed 37 pure breeds with distinctive phenotypes. Furthermore, all hematological parameters except MCHC showed significant differences between specific individual breeds and the mixed breed group. Twenty-nine breeds had distinctive phenotypes when assessed in this way, of which 19 had already been identified by principal component analysis. Tentative breed-specific reference intervals were generated for breeds with a distinctive phenotype identified by comparative analysis. This study represents the first large-scale analysis of hematological phenotypes in the dog and underlines the important potential of this species in the elucidation of genetic determinants of hematological traits, triangulating phenotype, breed and genetic predisposition

Dose to level I and II axillary lymph nodes and lung by tangential field radiation in patients undergoing postmastectomy radiation with tissue expander reconstruction

<p>Abstract</p> <p>Background</p> <p>To define the dosimetric coverage of level I/II axillary volumes and the lung volume irradiated in postmastectomy radiotherapy (PMRT) following tissue expander placement.</p> <p>Methods and Materials</p> <p>Twenty-three patients were identified who had undergone postmastectomy radiotherapy with tangent only fields. All patients had pre-radiation tissue expander placement and expansion. Thirteen patients had bilateral expander reconstruction. The level I/II axillary volumes were contoured using the RTOG contouring atlas. The patient-specific variables of expander volume, superior-to-inferior location of expander, distance between expanders, expander angle and axillary volume were analyzed to determine their relationship to the axillary volume and lung volume dose.</p> <p>Results</p> <p>The mean coverage of the level I/II axillary volume by the 95% isodose line (V_D95%) was 23.9% (range 0.3 - 65.4%). The mean Ipsilateral Lung V_D50%was 8.8% (2.2-20.9). Ipsilateral and contralateral expander volume correlated to Axillary V_D95%in patients with bilateral reconstruction (p = 0.01 and 0.006, respectively) but not those with ipsilateral only reconstruction (p = 0.60). Ipsilateral Lung V_D50%correlated with angle of the expander from midline (p = 0.05).</p> <p>Conclusions</p> <p>In patients undergoing PMRT with tissue expanders, incidental doses delivered by tangents to the axilla, as defined by the RTOG contouring atlas, do not provide adequate coverage. The posterior-superior region of level I and II is the region most commonly underdosed. Axillary volume coverage increased with increasing expander volumes in patients with bilateral reconstruction. Lung dose increased with increasing expander angle from midline. This information should be considered both when placing expanders and when designing PMRT tangent only treatment plans by contouring and targeting the axilla volume when axillary treatment is indicated.</p

A warm Jet in a cold ocean

Unprecedented quantities of heat are entering the Pacific sector of the Arctic Ocean through Bering Strait, particularly during summer months. Though some heat is lost to the atmosphere during autumn cooling, a significant fraction of the incoming warm, salty water subducts (dives beneath) below a cooler fresher layer of near-surface water, subsequently extending hundreds of kilometers into the Beaufort Gyre. Upward turbulent mixing of these sub-surface pockets of heat is likely accelerating sea ice melt in the region. This Pacific-origin water brings both heat and unique biogeochemical properties, contributing to a changing Arctic ecosystem. However, our ability to understand or forecast the role of this incoming water mass has been hampered by lack of understanding of the physical processes controlling subduction and evolution of this this warm water. Crucially, the processes seen here occur at small horizontal scales not resolved by regional forecast models or climate simulations; new parameterizations must be developed that accurately represent the physics. Here we present novel high resolution observations showing the detailed process of subduction and initial evolution of warm Pacific-origin water in the southern Beaufort Gyre

Three-Dimensional Double-Ridge Internal Tide Resonance in Luzon Strait

The three-dimensional (3D) double-ridge internal tide interference in the Luzon Strait in the South China Sea is examined by comparing 3D and two-dimensional (2D) realistic simulations. Both the 3D simulations and observations indicate the presence of 3D first-mode (semi)diurnal standing waves in the 3.6-km-deep trench in the strait. As in an earlier 2D study, barotropic-to-baroclinic energy conversion, flux divergence, and dissipation are greatly enhanced when semidiurnal tides dominate relative to periods dominated by diurnal tides. The resonance in the 3D simulation is several times stronger than in the 2D simulations for the central strait. Idealized experiments indicate that, in addition to ridge height, the resonance is only a function of separation distance and not of the along-ridge length; that is, the enhanced resonance in 3D is not caused by 3D standing waves or basin modes. Instead, the difference in resonance between the 2D and 3D simulations is attributed to the topographic blocking of the barotropic flow by the 3D ridges, affecting wave generation, and a more constructive phasing between the remotely generated internal waves, arriving under oblique angles, and the barotropic tide. Most of the resonance occurs for the first mode. The contribution of the higher modes is reduced because of 3D radiation, multiple generation sites, scattering, and a rapid decay in amplitude away from the ridge.Keywords: Regional models, Numerical analysis/modeling, Models and modeling, Resonance, Circulation/Dynamics, Tides, Internal waves, Ocean models, Physical Meteorology and Climatology, Atm/Ocean Structure/Phenomen