Enteric microbiome metabolites correlate with response to simvastatin treatment

Although statins are widely prescribed medications, there remains considerable variability in therapeutic response. Genetics can explain only part of this variability. Metabolomics is a global biochemical approach that provides powerful tools for mapping pathways implicated in disease and in response to treatment. Metabolomics captures net interactions between genome, microbiome and the environment. In this study, we used a targeted GC-MS metabolomics platform to measure a panel of metabolites within cholesterol synthesis, dietary sterol absorption, and bile acid formation to determine metabolite signatures that may predict variation in statin LDL-C lowering efficacy. Measurements were performed in two subsets of the total study population in the Cholesterol and Pharmacogenetics (CAP) study: Full Range of Response (FR), and Good and Poor Responders (GPR) were 100 individuals randomly selected from across the entire range of LDL-C responses in CAP. GPR were 48 individuals, 24 each from the top and bottom 10% of the LDL-C response distribution matched for body mass index, race, and gender. We identified three secondary, bacterial-derived bile acids that contribute to predicting the magnitude of statin-induced LDL-C lowering in good responders. Bile acids and statins share transporters in the liver and intestine; we observed that increased plasma concentration of simvastatin positively correlates with higher levels of several secondary bile acids. Genetic analysis of these subjects identified associations between levels of seven bile acids and a single nucleotide polymorphism (SNP), rs4149056, in the gene encoding the organic anion transporter SLCO1B1. These findings, along with recently published results that the gut microbiome plays an important role in cardiovascular disease, indicate that interactions between genome, gut microbiome and environmental influences should be considered in the study and management of cardiovascular disease. Metabolic profiles could provide valuable information about treatment outcomes and could contribute to a more personalized approach to therapy.     

Travel patterns in China

The spread of infectious disease epidemics is mediated by human travel. Yet human mobility patterns vary substantially between countries and regions. Quantifying the frequency of travel and length of journeys in well-defined population is therefore critical for predicting the likely speed and pattern of spread of emerging infectious diseases, such as a new influenza pandemic. Here we present the results of a large population survey undertaken in 2007 in two areas of China: Shenzhen city in Guangdong province, and Huangshan city in Anhui province. In each area, 10,000 randomly selected individuals were interviewed, and data on regular and occasional journeys collected. Travel behaviour was examined as a function of age, sex, economic status and home location. Women and children were generally found to travel shorter distances than men. Travel patterns in the economically developed Shenzhen region are shown to resemble those in developed and economically advanced middle income countries with a significant fraction of the population commuting over distances in excess of 50 km. Conversely, in the less developed rural region of Anhui, travel was much more local, with very few journeys over 30 km. Travel patterns in both populations were well-fitted by a gravity model with a lognormal kernel function. The results provide the first quantitative information on human travel patterns in modern China, and suggest that a pandemic emerging in a less developed area of rural China might spread geographically sufficiently slowly for containment to be feasible, while spatial spread in the more economically developed areas might be expected to be much more rapid, making containment more difficult.     

COPS5 (Jab1) Protein Increases β Site Processing of Amyloid Precursor Protein and Amyloid β Peptide Generation by Stabilizing RanBP9 Protein Levels

Increased processing of amyloid precursor protein (APP) and accumulation of neurotoxic amyloid β peptide (Aβ) in the brain is central to the pathogenesis of Alzheimer''s disease (AD). Therefore, the identification of molecules that regulate Aβ generation is crucial for future therapeutic approaches for AD. We demonstrated previously that RanBP9 regulates Aβ generation in a number of cell lines and primary neuronal cultures by forming tripartite protein complexes with APP, low-density lipoprotein-related protein, and BACE1, consequently leading to increased amyloid plaque burden in the brain. RanBP9 is a scaffold protein that exists and functions in multiprotein complexes. To identify other proteins that may bind RanBP9 and regulate Aβ levels, we used a two-hybrid analysis against a human brain cDNA library and identified COPS5 as a novel RanBP9-interacting protein. This interaction was confirmed by coimmunoprecipitation experiments in both neuronal and non-neuronal cells and mouse brain. Colocalization of COPS5 and RanBP9 in the same subcellular compartments further supported the interaction of both proteins. Furthermore, like RanBP9, COPS5 robustly increased Aβ generation, followed by increased soluble APP-β (sAPP-β) and decreased soluble-APP-α (sAPP-α) levels. Most importantly, down-regulation of COPS5 by siRNAs reduced Aβ generation, implying that endogenous COPS5 regulates Aβ generation. Finally, COPS5 levels were increased significantly in AD brains and APΔE9 transgenic mice, and overexpression of COPS5 strongly increased RanBP9 protein levels by increasing its half-life. Taken together, these results suggest that COPS5 increases Aβ generation by increasing RanBP9 levels. Thus, COPS5 is a novel RanBP9-binding protein that increases APP processing and Aβ generation by stabilizing RanBP9 protein levels.     

A novel vaccine containing EphA2 epitope and LIGHT plasmid induces robust cellular immunity against glioma U251 cells

EphA2 is a receptor tyrosine kinase and can be acted as an attractive antigen for glioma vaccines. In addition, LIGHT plays an important role on enhancing T cell proliferation and cytokine production. To improve the CTL mediated immune response against glioma cells, we prepared the novel vaccine containing EphA2_883–891 peptide (TLADFDPRV) and LIGHT plasmid and utilized it to immunize the HLA-A2 transgenic HHD mice. In addition, trimera mice were immunized with the novel vaccine to elicit the antitumor immune response. The results demonstrated that the novel vaccine could induce robust cellular immunity against glioma U251 cells without lysing autologous lymphocytes. Moreover, the novel vaccine could significantly inhibit the tumor growth and prolong the life span of tumor bearing mice. These findings suggested that the novel vaccine containing EphA2 epitope and LIGHT plasmid could induce anti-tumor immunity against U251 cells expressing EphA2, and provided a promising strategy for glioma immunotherapy.     

五大连池火山熔岩台地草本层物种多样性及环境解释

五大连池火山熔岩台地是一种火山地貌, 研究熔岩台地草本物种分布及其环境解释, 对认识火山原生演替过程中植物群落空间格局形成及适应机制具有重要意义。本文以五大连池熔岩台地的草本物种为研究对象, 调查了苔藓、草本、灌丛、阔叶林和针阔混交林等不同植被类型中的草本层样方, 并测定样方中的土壤养分和水分等状况, 采用多样性指数、优势度指数、均匀度指数、物种丰富度评价草本层物种多样性, 通过典范对应分析方法研究了群落组成与土壤因子的关系。结果表明: (1)熔岩台地草本层物种丰富, 共56种, 占本研究调查区总物种数的82.35%, 草本样地的草本层物种多样性、优势度和均匀性高于其他植被类型。(2)熔岩台地土壤pH值对群落草本层物种丰富度和物种个体的空间分布均有较大影响。(3)土壤因子解释了群落分布的79.39%, 其中土壤pH值、速效磷、硝态氮、铵态氮所占的解释量比较大。(4)岩败酱(Patrinia rupestris)、万年蒿(Artemisia sacrorum)、硬质早熟禾(Poa sphondylodes)和中华苦荬菜(Ixeris chinensis)对环境要求较低, 能够适应熔岩台地土壤贫瘠恶劣的环境。熔岩台地不同植被类型表现出对环境资源的特定需求, 熔岩地貌导致了土壤pH值、养分、水分的差异, 并影响植物群落的分布。     

Molecular Characterization of Streptococcus agalactiae Isolated from Bovine Mastitis in Eastern China

One hundred and two Streptococcus agalactiae (group B streptococcus [GBS]) isolates were collected from dairy cattle with subclinical mastitis in Eastern China during 2011. Clonal groups were established by multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE), respectively. Capsular polysaccharides (CPS), pilus and alpha-like-protein (Alp) family genes were also characterized by molecular techniques. MLST analysis revealed that these isolates were limited to three clonal groups and were clustered in six different lineages, i.e. ST (sequence type) 103, ST568, ST67, ST301, ST313 and ST570, of which ST568 and ST570 were new genotypes. PFGE analysis revealed this isolates were clustered in 27 PFGE types, of which, types 7, 8, 14, 15, 16, 18, 23 and 25 were the eight major types, comprising close to 70% (71/102) of all the isolates. The most prevalent sequence types were ST103 (58% isolates) and ST568 (31% isolates), comprising capsular genotype Ia isolates without any of the detected Alp genes, suggesting the appearance of novel genomic backgrounds of prevalent strains of bovine S. agalactiae. All the strains possessed the pilus island 2b (PI-2b) gene and the prevalent capsular genotypes were types Ia (89% isolates) and II (11% isolates), the conserved pilus type providing suitable data for the development of vaccines against mastitis caused by S. agalactiae.     

Landscape Genetic Structure of a Streamside Tree Species Euptelea pleiospermum (Eupteleaceae): Contrasting Roles of River Valley and Mountain Ridge

We used landscape genetics and statistical models to test how landscape features influence connectivity or create barriers to dispersal for a mountain riparian tree species, Euptelea pleiospermum. Young leaves from 1078 individuals belonging to 36 populations at elevations of 900–2000 m along upper reaches of four rivers were genotyped using eight nuclear microsatellite markers. We found no evidence for the unidirectional dispersal hypothesis in E. pleiospermum within each river. The linear dispersal pattern along each river valley is mostly consistent with the “classical metapopulaton” model. Mountain ridges separating rivers were genetic barriers for this wind-pollinated tree species with anemochorous seeds, whereas river valleys provided important corridors for dispersal. Gene flow among populations along elevational gradients within each river prevails over gene flow among populations at similar elevations but from different rivers. This pattern of gene flow is likely to promote elevational range shifts of plant populations and to hinder local adaptation along elevational gradients. This study provides a paradigm to determine which of the two strategies (migration or adaptation) will be adopted by mountain riparian plants under climate warming.     

An Integrated Peptide-Antigen Microarray on Plasmonic Gold Films for Sensitive Human Antibody Profiling

High-throughput screening for interactions of peptides with a variety of antibody targets could greatly facilitate proteomic analysis for epitope mapping, enzyme profiling, drug discovery and biomarker identification. Peptide microarrays are suited for such undertaking because of their high-throughput capability. However, existing peptide microarrays lack the sensitivity needed for detecting low abundance proteins or low affinity peptide-protein interactions. This work presents a new peptide microarray platform constructed on nanostructured plasmonic gold substrates capable of metal enhanced NIR fluorescence enhancement (NIR-FE) by hundreds of folds for screening peptide-antibody interactions with ultrahigh sensitivity. Further, an integrated histone peptide and whole antigen array is developed on the same plasmonic gold chip for profiling human antibodies in the sera of systemic lupus erythematosus (SLE) patients, revealing that collectively a panel of biomarkers against unmodified and post-translationally modified histone peptides and several whole antigens allow more accurate differentiation of SLE patients from healthy individuals than profiling biomarkers against peptides or whole antigens alone.     

Improvement of high-yield pulp properties by using a small amount of bleached wheat straw pulp

In this study, the potential of using bleached wheat straw pulp (BWSP) was explored to improve the tensile strength of the high-yield pulp (HYP) while preserving its high bulk property. The results showed that with the addition of 5-10% refined BWSP, the HYP tensile strength can be increased by about 10-20% without sacrificing the bulk. Similar results were obtained by adding refined BWSP into a mixed furnish of bleached kraft pulps (BKPs) and HYP. The explanation was that micro fines from refined BWSP can act as binders to improve the HYP interfiber bonding, as a result, the HYP tensile strength can be improved by using a small amount of BWSP, while the HYP bulk is not significantly affected.     

P2Y(6) agonist uridine 5'-diphosphate promotes host defense against bacterial infection via monocyte chemoattractant protein-1-mediated monocytes/macrophages recruitment

Extracellular nucleotides are important messengers involved in series crucial physiological functions through the activation of P2 purinergic receptors. The detailed function and mechanism of the P2Y family in regulating immune response against invaded pathogens still remains unknown. In this study, the activation of purinoreceptor P2Y(6) by UDP was found to play a crucial role in promoting host defense against invaded bacteria through monocytes/macrophages recruitment. The expression level of P2Y(6) was much higher than other purinoreceptors in RAW264.7 cells, bone marrow macrophages, and peritoneal macrophages determined by real-time PCR. The supernatant of UDP (P2Y(6)-specific agonist)-treated RAW264.7 cells exhibited direct chemotaxis to monocytes/macrophages in vitro through Boyden Chambers assay. Meanwhile, the releasing of MCP-1 (MCP-1/CCL2) was enhanced obviously by UDP both in mRNA and protein level. Furthermore, the activation of P2Y(6) receptor by UDP also promotes ERK phosphorylation and AP-1 activation in a concentration- and time-dependent manner in RAW264.7 cells. This UDP-induced activation could be inhibited by P2Y(6) selectivity antagonist (MRS2578), MEK inhibitor (U0126), and MCP-1 blocking Ab, respectively. Moreover, i.p. injection with UDP resulted in a more efficacious clearance of invaded Escherichia coli and lower mortality in peritonitis mouse model. Together, our studies demonstrate that P2Y(6) receptor could be a novel mediator in upregulating innate immune response against the invaded pathogens through recruiting monocytes/macrophages.