Panax Quinquefolius Saponin of Stem and Leaf Attenuates Intermittent High Glucose-Induced Oxidative Stress Injury in Cultured Human Umbilical Vein Endothelial Cells via PI3K/Akt/GSK-3 β

Panax quinquefolius saponin of stem and leaf (PQS), the effective parts of American ginseng, is widely used in China as a folk medicine for diabetes and cardiovascular diseases treatment. In our previous studies, we have demonstrated that PQS could improve the endothelial function of type II diabetes mellitus (T2DM) rats with high glucose fluctuation. In the present study, we investigated the protective effects of PQS against intermittent high glucose-induced oxidative damage on human umbilical vein endothelial cells (HUVECs) and the role of phosphatidylinositol 3-kinase kinase (PI3K)/Akt/GSK-3β pathway involved. Our results suggested that exposure of HUVECs to a high glucose concentration for 8 days showed a great decrease in cell viability accompanied by marked MDA content increase and SOD activity decrease. Moreover, high glucose significantly reduced the phosphorylation of Akt and GSK-3β. More importantly, these effects were even more evident in intermittent high glucose condition. PQS treatment significantly attenuated intermittent high glucose-induced oxidative damage on HUVECs and meanwhile increased cell viability and phosphorylation of Akt and GSK-3β of HUVECs. Interestingly, all these reverse effects of PQS on intermittent high glucose-cultured HUVECs were inhibited by PI3K inhibitor LY294002. These findings suggest that PQS attenuates intermittent-high-glucose-induced oxidative stress injury in HUVECs by PI3K/Akt/GSK-3β pathway

Chem2Bio2RDF: a semantic framework for linking and data mining chemogenomic and systems chemical biology data

<p>Abstract</p> <p>Background</p> <p>Recently there has been an explosion of new data sources about genes, proteins, genetic variations, chemical compounds, diseases and drugs. Integration of these data sources and the identification of patterns that go across them is of critical interest. Initiatives such as Bio2RDF and LODD have tackled the problem of linking biological data and drug data respectively using RDF. Thus far, the inclusion of chemogenomic and systems chemical biology information that crosses the domains of chemistry and biology has been very limited</p> <p>Results</p> <p>We have created a single repository called Chem2Bio2RDF by aggregating data from multiple chemogenomics repositories that is cross-linked into Bio2RDF and LODD. We have also created a linked-path generation tool to facilitate SPARQL query generation, and have created extended SPARQL functions to address specific chemical/biological search needs. We demonstrate the utility of Chem2Bio2RDF in investigating polypharmacology, identification of potential multiple pathway inhibitors, and the association of pathways with adverse drug reactions.</p> <p>Conclusions</p> <p>We have created a new semantic systems chemical biology resource, and have demonstrated its potential usefulness in specific examples of polypharmacology, multiple pathway inhibition and adverse drug reaction - pathway mapping. We have also demonstrated the usefulness of extending SPARQL with cheminformatics and bioinformatics functionality.</p

Use of \u3e100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations

Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged \u3e100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) \u3c 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11–34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count 86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations

Designing nano-aluminum laden fuel pump for aviation applications

In view of the fact that traditional liquid propellants cannot meet the design requirements of large-thrust flight vehicle, it has become a new trend to add nano-metal powder to liquid propellants to greatly increase density and specific impulse. In order to achieve the variable flow-rate and variable-proportion transportation of aviation fuel with nano-aluminum, a new type of solid-liquid mixing pumping system is designed, including powder conveying device, stirring device, pump and corresponding drive and transmission system. For the purpose of avoiding the frictional contact between the rotors, which will bring potential hazard to nano-aluminum powder, a non-contact twin-screw pump with synchronous gears is designed. Among them, based on the considerations of flow pulsation, volumetric efficiency and manufacturing difficulty, cycloid profile is adopted for screw rotors. After completing the functional design, geometric parameter design, structural design, 3D modeling, prototype manufacturing and preliminary performance estimation of the mixing pumping system, the performance of the screw feeder, agitator, screw pump was tested through experiments to meet the expected design requirements. The designed agitator can achieve sufficient mixing at 500 rpm in less than 10 s. Even though 50-micron clearances are designed with a relatively small rotor diameter, the volumetric efficiency of screw pump can reach above 50% when the discharge pressure is below 450 kPa and the flow rate is set as 10 L/min, the power of the screw pump is less than 700 W. This design facilitates the rapid real-time preparation of metallized propellants and provides a reference for further improving the design and control methods of nanoparticle two-phase flow pumping

The roles of SMYD4 in epigenetic regulation of cardiac development in zebrafish

SMYD4 belongs to a family of lysine methyltransferases. We analyzed the role of smyd4 in zebrafish development by generating a smyd4 mutant zebrafish line (smyd4L544Efs*1) using the CRISPR/Cas9 technology. The maternal and zygotic smyd4L544Efs*1 mutants demonstrated severe cardiac malformations, including defects in left-right patterning and looping and hypoplastic ventricles, suggesting that smyd4 was critical for heart development. Importantly, we identified two rare SMYD4 genetic variants in a 208-patient cohort with congenital heart defects. Both biochemical and functional analyses indicated that SMYD4(G345D) was pathogenic. Our data suggested that smyd4 functions as a histone methyltransferase and, by interacting with HDAC1, also serves as a potential modulator for histone acetylation. Transcriptome and bioinformatics analyses of smyd4L544Efs*1 and wild-type developing hearts suggested that smyd4 is a key epigenetic regulator involved in regulating endoplasmic reticulum-mediated protein processing and several important metabolic pathways in developing zebrafish hearts

East Asian Study of Tropospheric Aerosols and their Impact on Regional Clouds, Precipitation, and Climate (EAST-AIR_(CPC))

Aerosols have significant and complex impacts on regional climate in East Asia. Cloud‐aerosol‐precipitation interactions (CAPI) remain most challenging in climate studies. The quantitative understanding of CAPI requires good knowledge of aerosols, ranging from their formation, composition, transport, and their radiative, hygroscopic, and microphysical properties. A comprehensive review is presented here centered on the CAPI based chiefly, but not limited to, publications in the special section named EAST‐AIRcpc concerning (1) observations of aerosol loading and properties, (2) relationships between aerosols and meteorological variables affecting CAPI, (3) mechanisms behind CAPI, and (4) quantification of CAPI and their impact on climate. Heavy aerosol loading in East Asia has significant radiative effects by reducing surface radiation, increasing the air temperature, and lowering the boundary layer height. A key factor is aerosol absorption, which is particularly strong in central China. This absorption can have a wide range of impacts such as creating an imbalance of aerosol radiative forcing at the top and bottom of the atmosphere, leading to inconsistent retrievals of cloud variables from space‐borne and ground‐based instruments. Aerosol radiative forcing can delay or suppress the initiation and development of convective clouds whose microphysics can be further altered by the microphysical effect of aerosols. For the same cloud thickness, the likelihood of precipitation is influenced by aerosols: suppressing light rain and enhancing heavy rain, delaying but intensifying thunderstorms, and reducing the onset of isolated showers in most parts of China. Rainfall has become more inhomogeneous and more extreme in the heavily polluted urban regions

Catecholamine up-regulates MMP-7 expression by activating AP-1 and STAT3 in gastric cancer

<p>Abstract</p> <p>Background</p> <p>Stress, anxiety and depression can cause complex physiological and neuroendocrine changes, resulting in increased level of stress related hormone catecholamine, which may constitute a primary mechanism by which physiological factors impact gene expression in tumors. In the present study, we investigated the effects of catecholamine stimulation on MMP-7 expression in gastric cancer cells and elucidated the molecular mechanisms of the up-regulation of MMP-7 level by catecholamine through an adrenergic signaling pathway.</p> <p>Results</p> <p>Increased MMP-7 expression was identified at both mRNA and protein levels in the gastric cancer cells in response to isoproterenol stimulation. β2-AR antigonist effectively abrogated isoproterenol-induced MMP-7 expression. The activation of STAT3 and AP-1 was prominently induced by isoproterenol stimulation and AP-1 displayed a greater efficacy than STAT3 in isoproterenol-induced MMP-7 expression. Mutagenesis of three STAT3 binding sites in MMP-7 promoter failed to repress the transactivation of MMP-7 promoter and silencing STAT3 expression was not effective in preventing isoproterenol-induced MMP-7 expression. However, isoproterenol-induced MMP-7 promoter activities were completely disappeared when the AP-1 site was mutated. STAT3 and c-Jun could physically interact and bind to the AP-1 site, implicating that the interplay of both transcriptional factors on the AP-1 site is responsible for isoproterenol-stimulated MMP-7 expression in gastric cancer cells. The expression of MMP-7 in gastric cancer tissues was found to be at the site where β2-AR was overexpressed and the levels of MMP-7 and β2-AR were the highest in the metastatic locus of gastric cancer.</p> <p>Conclusions</p> <p>Up-regulation of MMP-7 expression through β2-AR-mediated signaling pathway is involved in invasion and metastasis of gastric cancer.</p

East Asian Study of Tropospheric Aerosols and their Impact on Regional Clouds, Precipitation, and Climate (EAST-AIR_(CPC))

Aerosols have significant and complex impacts on regional climate in East Asia. Cloud‐aerosol‐precipitation interactions (CAPI) remain most challenging in climate studies. The quantitative understanding of CAPI requires good knowledge of aerosols, ranging from their formation, composition, transport, and their radiative, hygroscopic, and microphysical properties. A comprehensive review is presented here centered on the CAPI based chiefly, but not limited to, publications in the special section named EAST‐AIRcpc concerning (1) observations of aerosol loading and properties, (2) relationships between aerosols and meteorological variables affecting CAPI, (3) mechanisms behind CAPI, and (4) quantification of CAPI and their impact on climate. Heavy aerosol loading in East Asia has significant radiative effects by reducing surface radiation, increasing the air temperature, and lowering the boundary layer height. A key factor is aerosol absorption, which is particularly strong in central China. This absorption can have a wide range of impacts such as creating an imbalance of aerosol radiative forcing at the top and bottom of the atmosphere, leading to inconsistent retrievals of cloud variables from space‐borne and ground‐based instruments. Aerosol radiative forcing can delay or suppress the initiation and development of convective clouds whose microphysics can be further altered by the microphysical effect of aerosols. For the same cloud thickness, the likelihood of precipitation is influenced by aerosols: suppressing light rain and enhancing heavy rain, delaying but intensifying thunderstorms, and reducing the onset of isolated showers in most parts of China. Rainfall has become more inhomogeneous and more extreme in the heavily polluted urban regions

The Polygenic and Monogenic Basis of Blood Traits and Diseases

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation. Analysis of blood cell traits in the UK Biobank and other cohorts illuminates the full genetic architecture of hematopoietic phenotypes, with evidence supporting the omnigenic model for complex traits and linking polygenic burden with monogenic blood diseases