Synaptic Vesicle Docking: Sphingosine Regulates Syntaxin1 Interaction with Munc18

Consensus exists that lipids must play key functions in synaptic activity but precise mechanistic information is limited. Acid sphingomyelinase knockout mice (ASMko) are a suitable model to address the role of sphingolipids in synaptic regulation as they recapitulate a mental retardation syndrome, Niemann Pick disease type A (NPA), and their neurons have altered levels of sphingomyelin (SM) and its derivatives. Electrophysiological recordings showed that ASMko hippocampi have increased paired-pulse facilitation and post-tetanic potentiation. Consistently, electron microscopy revealed reduced number of docked vesicles. Biochemical analysis of ASMko synaptic membranes unveiled higher amounts of SM and sphingosine (Se) and enhanced interaction of the docking molecules Munc18 and syntaxin1. In vitro reconstitution assays demonstrated that Se changes syntaxin1 conformation enhancing its interaction with Munc18. Moreover, Se reduces vesicle docking in primary neurons and increases paired-pulse facilitation when added to wt hippocampal slices. These data provide with a novel mechanism for synaptic vesicle control by sphingolipids and could explain cognitive deficits of NPA patients

Left ventricular volume: an optimal parameter to detect systolic dysfunction on prospectively triggered 64-multidetector row computed tomography: another step towards reducing radiation exposure

In this study, we define the correlation between LV volumes (both LV end-diastolic volume [LVEDV] and LV end-systolic volume [LVESV]) and ejection fraction (EF) on 64 slice multi-detector computed tomography (MDCT). We also determine the accuracy of all the LV volume (LVV) parameters to detect LV systolic dysfunction (LVSD) and investigate the feasibility of using LVV as a surrogate of LVSD on prospectively gated imaging to prevent the radiation exposure of retrospective imaging. 568 patients undergoing 64-detector MDCT were divided into 2 groups: Group 1—subjects without any heart disease and LVEF ≥ 50%; and Group 2—patients with coronary artery disease and LVEF < 50% (defined as LVSD). The LVV (LV cavity only) and Total LV volume (cavity + LV mass) at end-systole and end-diastole (LVESV, Total LVESV, LVEDV and Total LVEDV) were measured. The upper limit values (mean + 2 SD) of all LVV parameters in Group 1 were used as the reference criterion to diagnose LVSD in Group 2. An exponential correlation was found between LVEF and all the LVV parameters. The specificity to detect LVSD in Group 2 was >90% and the sensitivity was 88.9, 83.3, 61.3 and 74.9% by using LVESV, Total LVESV, LVEDV and Total LVEDV, respectively. Systolic and diastolic LV volumes had a high correlation with LVEF and a high accuracy to detect LVSD. Thus, on prospectively triggered imaging, ventricular volumes can predict patients with reduced LVEF, and appropriate referrals can be made

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Lipoprotein associated phospholipase A2: role in atherosclerosis and utility as a biomarker for cardiovascular risk

Atherosclerosis and its clinical manifestations are widely prevalent throughout the world. Atherogenesis is highly complex and modulated by numerous genetic and environmental risk factors. A large body of basic scientific and clinical research supports the conclusion that inflammation plays a significant role in atherogenesis along the entire continuum of its progression. Inflammation adversely impacts intravascular lipid handling and metabolism, resulting in the development of macrophage foam cell, fatty streak, and atheromatous plaque formation. Given the enormous human and economic cost of myocardial infarction, ischemic stroke, peripheral arterial disease and amputation, and premature death and disability, considerable effort is being committed to refining our ability to correctly identify patients at heightened risk for atherosclerotic vascular disease and acute cardiovascular events so that they can be treated earlier and more aggressively. Serum markers of inflammation have emerged as an important component of risk factor burden. Lipoprotein-associated phospholipase A2 (Lp-PLA2) potentiates intravascular inflammation and atherosclerosis. A variety of epidemiologic studies support the utility of Lp-PLA2 measurements for estimating and further refining cardiovascular disease risk. Drug therapies to inhibit Lp-PLA2 are in development and show considerable promise, including darapladib, a specific molecular inhibitor of the enzyme. In addition to substantially inhibiting Lp-PLA2 activity, darapladib reduces progression of the necrotic core volume of human coronary artery atheromatous plaque. The growing body of evidence points to an important role and utility for Lp-PLA2 testing in preventive and personalized clinical medicine

Validity and test-retest reliability of manual goniometers for measuring passive hip range of motion in femoroacetabular impingement patients.

<p>Abstract</p> <p>Background</p> <p>The aims of this study were to evaluate the construct validity (known group), concurrent validity (criterion based) and test-retest (intra-rater) reliability of manual goniometers to measure passive hip range of motion (ROM) in femoroacetabular impingement patients and healthy controls.</p> <p>Methods</p> <p>Passive hip flexion, abduction, adduction, internal and external rotation ROMs were simultaneously measured with a conventional goniometer and an electromagnetic tracking system (ETS) on two different testing sessions. A total of 15 patients and 15 sex- and age-matched healthy controls participated in the study.</p> <p>Results</p> <p>The goniometer provided greater hip ROM values compared to the ETS (range 2.0-18.9 degrees; <it>P </it>< 0.001); good concurrent validity was only achieved for hip abduction and internal rotation, with intraclass correlation coefficients (ICC) of 0.94 and 0.88, respectively. Both devices detected lower hip abduction ROM in patients compared to controls (<it>P </it>< 0.01). Test-retest reliability was good with ICCs higher 0.90, except for hip adduction (0.82-0.84). Reliability estimates did not differ between the goniometer and the ETS.</p> <p>Conclusions</p> <p>The present study suggests that goniometer-based assessments considerably overestimate hip joint ROM by measuring intersegmental angles (e.g., thigh flexion on trunk for hip flexion) rather than true hip ROM. It is likely that uncontrolled pelvic rotation and tilt due to difficulties in placing the goniometer properly and in performing the anatomically correct ROM contribute to the overrating of the arc of these motions. Nevertheless, conventional manual goniometers can be used with confidence for longitudinal assessments in the clinic.</p

Observation of a Self-Limiting, Shear-Induced Turbulent Inversion Layer Above Marine Stratocumulus

High-resolution measurements of thermodynamic, microphysical, and turbulence properties inside a turbulent inversion layer above a marine stratocumulus cloud layer are presented. The measurements are performed with the helicopter-towed measurement payload Airborne Cloud Turbulence Observation System (ACTOS), which allows for sampling with low true air speeds and steep profiles through cloud top. Vertical profiles show that the turbulent inversion layer consists of clear air above the cloud top, with nearly linear profiles of potential temperature, horizontal wind speed, absolute humidity, and concentration of interstitial aerosol. The layer is turbulent, with an energy dissipation rate nearly the same as that in the lower cloud, suggesting that the two are actively coupled, but with significant anisotropic turbulence at the large scales within the turbulent inversion layer. The turbulent inversion layer is traversed six times and the layer thickness is observed to vary between 37 and 85 m, whereas the potential temperature and horizontal wind speed differences at the top and bottom of the layer remain essentially constant. The Richardson number therefore increases with increasing layer thickness, from approximately 0. 2 to 0. 7, suggesting that the layer develops to the point where shear production of turbulence is sufficiently weak to be balanced by buoyancy suppression. This picture is consistent with prior numerical simulations of the evolution of turbulence in localized stratified shear layers. It is observed that the large eddy scale is suppressed by buoyancy and is on the order of the Ozmidov scale, much less than the thickness of the turbulent inversion layer, such that direct mixing between the cloud top and the free troposphere is inhibited, and the entrainment velocity tends to decrease with increasing turbulent inversion-layer thickness. Qualitatively, the turbulent inversion layer likely grows through nibbling rather than engulfment

An analysis of single amino acid repeats as use case for application specific background models

Background Sequence analysis aims to identify biologically relevant signals against a backdrop of functionally meaningless variation. Increasingly, it is recognized that the quality of the background model directly affects the performance of analyses. State-of-the-art approaches rely on classical sequence models that are adapted to the studied dataset. Although performing well in the analysis of globular protein domains, these models break down in regions of stronger compositional bias or low complexity. While these regions are typically filtered, there is increasing anecdotal evidence of functional roles. This motivates an exploration of more complex sequence models and application-specific approaches for the investigation of biased regions. Results Traditional Markov-chains and application-specific regression models are compared using the example of predicting runs of single amino acids, a particularly simple class of biased regions. Cross-fold validation experiments reveal that the alternative regression models capture the multi-variate trends well, despite their low dimensionality and in contrast even to higher-order Markov-predictors. We show how the significance of unusual observations can be computed for such empirical models. The power of a dedicated model in the detection of biologically interesting signals is then demonstrated in an analysis identifying the unexpected enrichment of contiguous leucine-repeats in signal-peptides. Considering different reference sets, we show how the question examined actually defines what constitutes the 'background'. Results can thus be highly sensitive to the choice of appropriate model training sets. Conversely, the choice of reference data determines the questions that can be investigated in an analysis. Conclusions Using a specific case of studying biased regions as an example, we have demonstrated that the construction of application-specific background models is both necessary and feasible in a challenging sequence analysis situation

Primary versus secondary source of data in observational studies and heterogeneity in meta-analyses of drug effects: a survey of major medical journals

The data from individual observational studies included in meta-analyses of drug effects are collected either from ad hoc methods (i.e. "primary data") or databases that were established for non-research purposes (i.e. "secondary data"). The use of secondary sources may be prone to measurement bias and confounding due to over-the-counter and out-of-pocket drug consumption, or non-adherence to treatment. In fact, it has been noted that failing to consider the origin of the data as a potential cause of heterogeneity may change the conclusions of a meta-analysis. We aimed to assess to what extent the origin of data is explored as a source of heterogeneity in meta-analyses of observational studies.publishe