Regulation and Maintenance of Vascular Tone and Patency in Cardiovascular Health and Disease

License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Despite numerous advances in health care practices, cardiovascular disease still remains the leading cause of morbidity and mortality worldwide. Perhaps the most important consequence of cardiovascular disease is the interruption of blood flow to organs such as the heart and brain, resulting in the clinical presentation of a heart attack or stroke. As such, the regulation of vascular tone and the maintenance of vascular patency are vital for the preservation of cardiovascular health. Central to this process is the vascular endothelium. The endothelium is vital for the regulation of vascular tone and the maintenance of vascular homeostasis, as it releases factors such as nitric oxide, hydrogen sulfide, endothelialdependent hyperpolarizing factor, and prostacyclin tha

Cluster Multi-spacecraft Determination of AKR Angular Beaming

Simultaneous observations of AKR emission using the four-spacecraft Cluster array were used to make the first direct measurements of the angular beaming patterns of individual bursts. By comparing the spacecraft locations and AKR burst locations, the angular beaming pattern was found to be narrowly confined to a plane containing the magnetic field vector at the source and tangent to a circle of constant latitude. Most rays paths are confined within 15 deg of this tangent plane, consistent with numerical simulations of AKR k-vector orientation at maximum growth rate. The emission is also strongly directed upward in the tangent plane, which we interpret as refraction of the rays as they leave the auroral cavity. The narrow beaming pattern implies that an observer located above the polar cap can detect AKR emission only from a small fraction of the auroral oval at a given location. This has important consequences for interpreting AKR visibility at a given location. It also helps re-interpret previously published Cluster VLBI studies of AKR source locations, which are now seen to be only a subset of all possible source locations. These observations are inconsistent with either filled or hollow cone beaming models.Comment: 5 pages, 4 figures. Geophys. Res. Letters (accepted

Attitudes of pregnant women and healthcare professionals towards clinical trials and routine implementation of antenatal vaccination against respiratory syncytial virus : a multicenter questionnaire study

Introduction: Respiratory syncytial virus (RSV) is a common cause of infant hospitalization and mortality. With multiple vaccines in development, we aimed to determine: (1) the awareness of RSV among pregnant women and healthcare professionals (HCPs), and (2) attitudes toward clinical trials and routine implementation of antenatal RSV vaccination.Methods: Separate questionnaires for pregnant women and HCPs were distributed within 4 hospitals in South England (July 2017–January 2018).Results: Responses from 314 pregnant women and 204 HCPs (18% obstetricians, 75% midwives, 7% unknown) were analyzed. Most pregnant women (88%) and midwives (66%) had no/very little awareness of RSV, unlike obstetricians (14%). Among pregnant women, 29% and 75% would likely accept RSV vaccination as part of a trial, or if routinely recommended, respectively. Younger women (16–24 years), those of 21–30 weeks’ gestation, and with experience of RSV were significantly more likely to participate in trials [odds ratio (OR): 1.42 (1.72–9.86); OR: 2.29 (1.22–4.31); OR: 9.07 (1.62–50.86), respectively]. White-British women and those of 21–30 weeks’ gestation were more likely to accept routinely recommended vaccination [OR: 2.16 (1.07–4.13); OR: 2.10 (1.07–4.13)]. Obstetricians were more likely than midwives to support clinical trials [92% vs. 68%, OR: 2.50 (1.01–6.16)] and routine RSV vaccination [89% vs. 79%, OR: 4.08 (1.53–9.81)], as were those with prior knowledge of RSV, and who deemed it serious.Conclusions: RSV awareness is low among pregnant women and midwives. Education will be required to support successful implementation of routine antenatal vaccination. Research is needed to understand reasons for vaccine hesitancy among pregnant women and HCPs, particularly midwives.<br/

Striated AKR Emission: A Remote Tracer of Ion Solitary Structures

We describe the statistical properties of narrowband drifting auroral kilometric radiation ('striated' AKR) based on observations from the Cluster wideband receiver during 2002-2005. We show that the observed characteristics, including frequency drift rate and direction, narrow bandwidth, observed intensity, and beaming angular sizes are all consistent with triggering by upward traveling ion solitary structures (`ion holes'). We calculate the expected perturbation of a horseshoe electron distribution function by an ion hole by integrating the resonance condition for a cyclotron maser instability (CMI) using the perturbed velocity distribution. We find that the CMI growth rate can be strongly enhanced as the horseshoe velocity distribution contracts inside the passing ion hole, resulting in a power gain increase greater than 100 dB. The gain curve is sharply peaked just above the R-mode cut-off frequency, with an effective bandwidth ~50 Hz, consistent with the observed bandwidth of striated AKR emission. Ion holes are observed in situ in the acceleration region moving upward with spatial scales and speeds consistent with the observed bandwidth and slopes of SAKR bursts. Hence, we suggest that SAKR bursts are a remote sensor of ion holes and can be used to determine the frequency of occurrence, locations in the acceleration region, and lifetimes of these structures.Comment: 10 pages, 10 figures. J .Geophys. Res. (in press

Changes in cortical and striatal neurons predict behavioral and electrophysiological abnormalities in a transgenic murine model of Huntington\u27s disease

Neurons in Huntington\u27s disease exhibit selective morphological and subcellular alterations in the striatum and cortex. The link between these neuronal changes and behavioral abnormalities is unclear. We investigated relationships between essential neuronal changes that predict motor impairment and possible involvement of the corticostriatal pathway in developing behavioral phenotypes. We therefore generated heterozygote mice expressing the N-terminal one-third of huntingtin with normal (CT18) or expanded (HD46, HD100) glutamine repeats. The HD mice exhibited motor deficits between 3 and 10 months. The age of onset depended on an expanded polyglutamine length; phenotype severity correlated with increasing age. Neuronal changes in the striatum (nuclear inclusions) preceded the onset of phenotype, whereas cortical changes, especially the accumulation of huntingtin in the nucleus and cytoplasm and the appearance of dysmorphic dendrites, predicted the onset and severity of behavioral deficits. Striatal neurons in the HD mice displayed altered responses to cortical stimulation and to activation by the excitotoxic agent NMDA. Application of NMDA increased intracellular Ca(2+) levels in HD100 neurons compared with wild-type neurons. Results suggest that motor deficits in Huntington\u27s disease arise from cumulative morphological and physiological changes in neurons that impair corticostriatal circuitry

A map of transcriptional heterogeneity and regulatory variation in human microglia.

Microglia, the tissue-resident macrophages of the central nervous system (CNS), play critical roles in immune defense, development and homeostasis. However, isolating microglia from humans in large numbers is challenging. Here, we profiled gene expression variation in primary human microglia isolated from 141 patients undergoing neurosurgery. Using single-cell and bulk RNA sequencing, we identify how age, sex and clinical pathology influence microglia gene expression and which genetic variants have microglia-specific functions using expression quantitative trait loci (eQTL) mapping. We follow up one of our findings using a human induced pluripotent stem cell-based macrophage model to fine-map a candidate causal variant for Alzheimer's disease at the BIN1 locus. Our study provides a population-scale transcriptional map of a critically important cell for human CNS development and disease

Compressed representation of a partially defined integer function over multiple arguments

In OLAP (OnLine Analitical Processing) data are analysed in an n-dimensional cube. The cube may be represented as a partially defined function over n arguments. Considering that often the function is not defined everywhere, we ask: is there a known way of representing the function or the points in which it is defined, in a more compact manner than the trivial one

Enhancing Quality and Impact of Early Phase Dose-Finding Clinical Trial Protocols:The SPIRIT DoseFinding Extension (SPIRIT-DEFINE) Guidance The SPIRIT-DEFINE Statement

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