Elucidating the genetic determinants of the archetypal complex disease hypertriglyceridemia

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in Canada. Among non-traditional risk factors, plasma triglyceride (TG) concentration is re-emerging as a significant risk factor. Patients with hypertriglyceridemia (HTG) – an archetypal complex phenotype defined by fasting plasma TG concentration \u3e95th percentile – thus have significantly increased CVD risk, compounded by associated co-morbidities such as obesity, metabolic syndrome and type 2 diabetes. However, the molecular pathways contributing to HTG susceptibility are incompletely defined. A better understanding of the genetic determinants that underlie the phenotypic spectrum of plasma TG and HTG susceptibility is necessary to identify novel genes and pathways that could be targeted to effectively lower plasma TG and improve cardiovascular risk. Accordingly, we sought to characterize the genetic architecture of HTG susceptibility and phenotypic heterogeneity using several modern genomic technologies, including high-density microarray genotyping and high-throughput resequencing of candidate genes in HTG patients and healthy controls. We demonstrate that a broad allelic spectrum of common small effect variants and rare large effect variants is associated with HTG. Furthermore, we demonstrate that significant overlap exists between genes and variants that modulate plasma TG and increase HTG susceptibility. Taken together, we suggest that HTG susceptibility is the result of a genetic burden of TG-raising alleles in genes that modulate plasma TG concentration. These findings provide a breadth of novel targets for pharmaceutical development in hopes of reducing plasma TG concentration and improve cardiovascular risk in HTG patients

Hypersonic Boundary Layer Measurements with Variable Blowing Rates Using Molecular Tagging Velocimetry

Measurements of mean and instantaneous streamwise velocity profiles in a hypersonic boundary layer with variable rates of mass injection (blowing) of nitrogen dioxide (NO2) were obtained over a 10-degree half-angle wedge model. The NO2 was seeded into the flow from a slot located 29.4 mm downstream of the sharp leading edge. The top surface of the wedge was oriented at a 20 degree angle in the Mach 10 flow, yielding an edge Mach number of approximately 4.2. The streamwise velocity profiles and streamwise fluctuating velocity component profiles were obtained using a three-laser NO2->NO photolysis molecular tagging velocimetry method. Observed trends in the mean streamwise velocity profiles and profiles of the fluctuating component of streamwise velocity as functions of the blowing rate are described. An effort is made to distinguish between the effect of blowing rate and wall temperature on the measured profiles. An analysis of the mean velocity profiles for a constant blowing rate is presented to determine the uncertainty in the measurement for different probe laser delay settings. Measurements of streamwise velocity were made to within approximately 120 gm of the model surface. The streamwise spatial resolution in this experiment ranged from 0.6 mm to 2.6 mm. An improvement in the spatial precision of the measurement technique has been made, with spatial uncertainties reduced by about a factor of 2 compared to previous measurements. For the quiescent flow calibration measurements presented, uncertainties as low as 2 m/s are obtained at 95% confidence for long delay times (25 gs). For the velocity measurements obtained with the wind tunnel operating, average single-shot uncertainties of less than 44 m/s are obtained at 95% confidence with a probe laser delay setting of 1 gs. The measurements were performed in the 31-inch Mach 10 Air Tunnel at the NASA Langley Research Center

Hypersonic Boundary Layer Transition Measurements Using NO2 approaches NO Photo-dissociation Tagging Velocimetry

Measurements of instantaneous and mean streamwise velocity profiles in a hypersonic laminar boundary layer as well as a boundary layer undergoing laminar-to-turbulent transition were obtained over a 10-degree half-angle wedge model. A molecular tagging velocimetry technique consisting of a NO2 approaches?NO photo-dissociation reaction and two subsequent excitations of NO was used. The measurement of the transitional boundary layer velocity profiles was made downstream of a 1-mm tall, 4-mm diameter cylindrical trip along several lines lying within a streamwise measurement plane normal to the model surface and offset 6-mm from the model centerline. For laminar and transitional boundary layer measurements, the magnitudes of streamwise velocity fluctuations are compared. In the transitional boundary layer the fluctuations were, in general, 2-4 times larger than those in the laminar boundary layer. Of particular interest were fluctuations corresponding to a height of approximately 50% of the laminar boundary layer thickness having a magnitude of nearly 30% of the mean measured velocity. For comparison, the measured fluctuations in the laminar boundary layer were approximately 5% of the mean measured velocity at the same location. For the highest 10% signal-to-noise ratio data, average single-shot uncertainties using a 1 ?Es and 50 ?Es interframe delay were ~115 m/s and ~3 m/s, respectively. By averaging single-shot measurements of the transitional boundary layer, uncertainties in mean velocity as low as 39 m/s were obtained in the wind tunnel. The wall-normal and streamwise spatial resolutions were 0.14-mm (2 pixel) and 0.82-mm (~11 pixels), respectively. These measurements were performed in the 31-inch Mach 10 Air Wind Tunnel at the NASA Langley Research Center

OH PLIF Visualization of a Premixed Ethylene-fueled Dual-Mode Scramjet Combustor

Hydroxyl radical (OH) planar induced laser fluorescence (PLIF) measurements have been performed in a small-scale scramjet combustor at the University of Virginia Aerospace Research Laboratory at nominal simulated Mach 5 enthalpy. OH lines were carefully chosen to have fluorescent signal that is independent of pressure and temperature but linear with mole fraction. The OH PLIF signal was imaged in planes orthogonal to and parallel to the freestream flow at different equivalence ratios. Flameout limits were tested and identified. Instantaneous planar images were recorded and analyzed to compare the results with width increased dual-pump enhanced coherent anti-Stokes Raman spectroscopy (WIDECARS) measurements in the same facility and large eddy simulation/Reynolds average Navier-Stokes (LES/RANS) numerical simulation. The flame angle was found to be approximately 10 degrees for several different conditions, which is in agreement with numerical predictions and measurements using WIDECARS. Finally, a comparison between NO PLIF non-combustion cases and OH PLIF combustion cases is provided: the comparison reveals that the dominant effect of flame propagation is freestream turbulence rather than heat release and concentration gradients

OH PLIF Visualization of the UVa Supersonic Combustion Experiment: Configuration A

Hydroxyl radical (OH) planar laser-induced fluorescence (PLIF) measurements were performed in the University of Virginia s dual-mode scramjet experiment. The test section was set up in configuration A, which includes a Mach 2 nozzle, combustor, and extender section. Hydrogen fuel was injected through an unswept compression ramp at two different equivalence ratios. Through the translation of the optical system and the use of two separate camera views, the entire optical range of the combustor was accessed. Single-shot, average, and standard deviation images of the OH PLIF signal are presented at several streamwise locations. The results show the development of a highly turbulent flame structure and provide an experimental database to be used for numerical model assessment

Endoplasmic reticulum-plasma membrane contact sites integrate sterol and phospholipid regulation

Tether proteins attach the endoplasmic reticulum (ER) to other cellular membranes, thereby creating contact sites that are proposed to form platforms for regulating lipid homeostasis and facilitating non-vesicular lipid exchange. Sterols are synthesized in the ER and transported by non-vesicular mechanisms to the plasma membrane (PM), where they represent almost half of all PM lipids and contribute critically to the barrier function of the PM. To determine whether contact sites are important for both sterol exchange between the ER and PM and intermembrane regulation of lipid metabolism, we generated Δ-super-tether (Δ-s-tether) yeast cells that lack six previously identified tethering proteins (yeast extended synatotagmin [E-Syt], vesicle-associated membrane protein [VAMP]-associated protein [VAP], and TMEM16-anoctamin homologues) as well as the presumptive tether Ice2. Despite the lack of ER-PM contacts in these cells, ER-PM sterol exchange is robust, indicating that the sterol transport machinery is either absent from or not uniquely located at contact sites. Unexpectedly, we found that the transport of exogenously supplied sterol to the ER occurs more slowly in Δ-s-tether cells than in wild-type (WT) cells. We pinpointed this defect to changes in sterol organization and transbilayer movement within the PM bilayer caused by phospholipid dysregulation, evinced by changes in the abundance and organization of PM lipids. Indeed, deletion of either OSH4, which encodes a sterol/phosphatidylinositol-4-phosphate (PI4P) exchange protein, or SAC1, which encodes a PI4P phosphatase, caused synthetic lethality in Δ-s-tether cells due to disruptions in redundant PI4P and phospholipid regulatory pathways. The growth defect of Δ-s-tether cells was rescued with an artificial "ER-PM staple," a tether assembled from unrelated non-yeast protein domains, indicating that endogenous tether proteins have nonspecific bridging functions. Finally, we discovered that sterols play a role in regulating ER-PM contact site formation. In sterol-depleted cells, levels of the yeast E-Syt tether Tcb3 were induced and ER-PM contact increased dramatically. These results support a model in which ER-PM contact sites provide a nexus for coordinating the complex interrelationship between sterols, sphingolipids, and phospholipids that maintain PM composition and integrity

OH PLIF Visualization of the UVa Supersonic Combustion Experiment: Configuration C

Non-intrusive hydroxyl radical (OH) planar laser-induced fluorescence (PLIF) measurements were obtained in configuration C of the University of Virginia supersonic combustion experiment. The combustion of hydrogen fuel injected through an unswept compression ramp into a supersonic cross-flow was imaged over a range of streamwise positions. Images were corrected for optical distortion, variations in the laser sheet profile, and different camera views. Results indicate an effect of fuel equivalence ratio on combustion zone shape and local turbulence length scale. The streamwise location of the reaction zone relative to the fuel injector was also found to be sensitive to the fuel equivalence ratio. The flow boundary conditions in the combustor section, which are sensitive to the fuel flow rate, are believed to have caused this effect. A combination of laser absorption and radiative trapping effects are proposed to have caused asymmetry observed in the images. The results complement previously published OH PLIF data obtained for configuration A along with other non-intrusive measurements to form a database for computational fluid dynamics (CFD) model validation

Critical success criteria for B2B E-commerce systems in Chinese medical supply chain.

The paper presents an exploratory investigation to determine and prioritise the critical success criteria, which can measure and guide the successful application and performance improvement of business to business e-commerce system (BBECS) in a medical supply chain's selling and buying functions, in the context of global business expansion. The research reveals that the buying and the selling functions have different prioritisations on the majority of the determined critical success measuring criteria. These criteria are categorised into three Critical Success Measuring Criteria Groups, for the selling and the buying functions, respectively, guiding medical supply chain members in harnessing the full advantage of a BBECS. For the selling function, the top critical success measuring criteria are as follows: integrating information searching/transmission and application processes, ensuring the reliability and timeliness of technical support, ensuring recognition and acceptance of e-commerce processes, displaying the organisation's business focus and product/service provisions online, securing a large scale/amount of business transactions, adjusting production outputs and inventory levels and having more registered users than competitors do. The top critical success measuring criteria for the buying function are as follows: securing the establishment of business relationships between businesses, displaying the measures ensuring mutual trust and cooperation online, ensuring employees' recognition of the benefit of e-commerce in increasing revenue, ensuring the contribution to the development and realisation of corporate strategy, achieving cost reduction for the organisation, making the purchase of famous brand products available/doable, securing a large scale/amount of business transactions, and ensuring the attainability of products/services at a lower price

Investigation of potential non-HLA rheumatoid arthritis susceptibility loci in a European cohort increases the evidence for nine markers

BACKGROUND: Genetic factors have a substantial role in determining development of rheumatoid arthritis (RA), and are likely to account for 50-60% of disease susceptibility. Genome-wide association studies have identified non-human leucocyte antigen RA susceptibility loci which associate with RA with low-to-moderate risk. OBJECTIVES: To investigate recently identified RA susceptibility markers using cohorts from six European countries, and perform a meta-analysis including previously published results. METHODS: 3311 DNA samples were collected from patients from six countries (UK, Germany, France, Greece, Sweden and Denmark). Genotype data or DNA samples for 3709 controls were collected from four countries (not Sweden or Denmark). Eighteen single nucleotide polymorphisms (SNPs) were genotyped using Sequenom MassArray technology. Samples with a >95% success rate and only those SNPs with a genotype success rate of >95% were included in the analysis. Scandinavian patient data were pooled and previously published Swedish control data were accessed as a comparison group. Meta-analysis was used to combine results from this study with all previously published data. RESULTS: After quality control, 3209 patients and 3692 controls were included in the study. Eight markers (ie, rs1160542 (AFF3), rs1678542 (KIF5A), rs2476601 (PTPN22), rs3087243 (CTLA4), rs4810485 (CD40), rs5029937 (6q23), rs10760130 (TRAF1/C5) and rs7574865 (STAT4)) were significantly associated with RA by meta-analysis. All 18 markers were associated with RA when previously published studies were incorporated in the analysis. Data from this study increased the significance for association with RA and nine markers. CONCLUSIONS: In a large European RA cohort further evidence for the association of 18 markers with RA development has been obtained