CSE/H2S通路缺失影响小鼠肝脏胆固醇和脂肪酸代谢（英文）

肝脂质代谢异常导致过度肝脂肪沉积和脂肪变性是脂肪肝发展的关键环节.胱硫脒-伽马-裂解酶(CSE)是在肝脏中催化硫化氢(H2S)生成的酶之一.本研究的目的是研究CSE/H2S在调控肝脏胆固醇和脂肪酸代谢中的作用.用高脂饮食(HFD)喂食野生型(WT)和CSE敲除(KO)小鼠后,对小鼠肝形态学和生物化学变化进行了分析.与WT小鼠不同,HFD喂食显著增加CSE-KO小鼠的血浆和肝脏胆固醇水平以及肝和胆囊的大小.这些CSE-KO小鼠呈现典型的脂肪肝组织学和生物化学变化以及肝功能损害.血浆和肝脏甘油三酯水平也比HFD喂养WT小鼠显著降低.核受体转录因子LXRα以及它的靶基因,CYP7A1,在对照组和HFD组CSE-KO小鼠肝脏中的表达都低于相应WT小鼠的水平.这些异常阻碍胆固醇分解成胆汁并导致胆固醇蓄积在肝脏和胆囊.由于CSE/H2S通路缺失造成对HFD诱导的脂肪肝的高易感性,肝脏CSE/H2S通路可能是治疗脂肪肝损伤的一个新的靶向.     

Cooperative Sensor Anomaly Detection Using Global Information

Sensor networks are deployed in many application areas nowadays ranging from environment monitoring, industrial monitoring, and agriculture monitoring to military battlefield sensing. The accuracy of sensor readings is without a doubt one of the most important measures to evaluate the quality of a sensor and its network. Therefore, this work is motivated to propose approaches that can detect and repair erroneous (i.e., dirty) data caused by inevitable system problems involving various hardware and software components of sensor networks. As information about a single event of interest in a sensor network is usually reflected in multiple measurement points, the inconsistency among multiple sensor measurements serves as an indicator for data quality problem. The focus of this paper is thus to study methods that can effectively detect and identify erroneous data among inconsistent observations based on the inherent structure of various sensor measurement series from a group of sensors. Particularly, we present three models to characterize the inherent data structures among sensor measurement traces and then apply these models individually to guide the error detection of a sensor network. First, we propose a multivariate Gaussian model which explores the correlated data changes of a group of sensors. Second, we present a Principal Component Analysis (PCA) model which captures the sparse geometric relationship among sensors in a network. The PCA model is motivated by the fact that not all sensor networks have clustered sensor deployment and clear data correlation structure. Further, if the sensor data show non-linear characteristic, a traditional PCA model can not capture the data attributes properly. Therefore, we propose a third model which utilizes kernel functions to map the original data into a high dimensional feature space and then apply PCA model on the mapped linearized data. All these three models serve the purpose of capturing the underlying phenomenon of a sensor network from its global view, and then guide the error detection to discover any anomaly observations. We conducted simulations for each of the proposed models, and evaluated the performance by deriving the Receiver Operating Characteristic (ROC) curves.     

Systematic pathway analysis using high-resolution fitness profiling of combinatorial gene deletions

Systematic genetic interaction studies have illuminated many cellular processes. Here we quantitatively examine genetic interactions among 26 Saccharomyces cerevisiae genes conferring resistance to the DNA-damaging agent methyl methanesulfonate (MMS), as determined by chemogenomic fitness profiling of pooled deletion strains. We constructed 650 double-deletion strains, corresponding to all pairings of these 26 deletions. The fitness of single- and double-deletion strains were measured in the presence and absence of MMS. Genetic interactions were defined by combining principles from both statistical and classical genetics. The resulting network predicts that the Mph1 helicase has a role in resolving homologous recombination-derived DNA intermediates that is similar to (but distinct from) that of the Sgs1 helicase. Our results emphasize the utility of small molecules and multifactorial deletion mutants in uncovering functional relationships and pathway order.     

Acquisition of a multifunctional IgA+ plasma cell phenotype in the gut

The largest mucosal surface in the body is in the gastrointestinal tract, a location that is heavily colonized by microbes that are normally harmless. A key mechanism required for maintaining a homeostatic balance between this microbial burden and the lymphocytes that densely populate the gastrointestinal tract is the production and transepithelial transport of poly-reactive IgA (ref. 1). Within the mucosal tissues, B cells respond to cytokines, sometimes in the absence of T-cell help, undergo class switch recombination of their immunoglobulin receptor to IgA, and differentiate to become plasma cells. However, IgA-secreting plasma cells probably have additional attributes that are needed for coping with the tremendous bacterial load in the gastrointestinal tract. Here we report that mouse IgA(+) plasma cells also produce the antimicrobial mediators tumour-necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS), and express many molecules that are commonly associated with monocyte/granulocytic cell types. The development of iNOS-producing IgA(+) plasma cells can be recapitulated in vitro in the presence of gut stroma, and the acquisition of this multifunctional phenotype in vivo and in vitro relies on microbial co-stimulation. Deletion of TNF-α and iNOS in B-lineage cells resulted in a reduction in IgA production, altered diversification of the gut microbiota and poor clearance of a gut-tropic pathogen. These findings reveal a novel adaptation to maintaining homeostasis in the gut, and extend the repertoire of protective responses exhibited by some B-lineage cells.     

Novel aspects of glypican glycobiology

Mutations in glypican genes cause dysmorphic and overgrowth syndromes in men and mice, abnormal development in flies and worms, and defective gastrulation in zebrafish and ascidians. All glypican core proteins share a characteristic pattern of 14 conserved cysteine residues. Upstream from the C-terminal membrane anchorage are 3–4 heparan sulfate attachment sites. Cysteines in glypican-1 can become nitrosylated by nitric oxide in a copper-dependent reaction. When glypican-1 is exposed to ascorbate, nitric oxide is released and participates in deaminative cleavage of heparan sulfate at sites where the glucosamines have a free amino group. This process takes place while glypican-1 recycles via a nonclassical, caveolin-1-associated route. Glypicans are involved in growth factor signalling and transport, e.g. of polyamines. Cargo can be unloaded from heparan sulfate by nitric oxide-dependent degradation. How glypican and its degradation products and the cargo exit from the recycling route is an enigma.Received 27 November 2003; received after revision 8 January 2004; accepted 13 January 2004     

Oxysterols direct B-cell migration through EBI2

EBI2 (also called GPR183) is an orphan G-protein-coupled receptor that is highly expressed in spleen and upregulated upon Epstein-Barr-virus infection. Recent studies indicated that this receptor controls follicular B-cell migration and T-cell-dependent antibody production. Oxysterols elicit profound effects on immune and inflammatory responses as well as on cholesterol metabolism. The biological effects of oxysterols have largely been credited to the activation of nuclear hormone receptors. Here we isolate oxysterols from porcine spleen extracts and show that they are endogenous ligands for EBI2. The most potent ligand and activator is 7α,25-dihydroxycholesterol (OHC), with a dissociation constant of 450?pM for EBI2. In vitro, 7α,25-OHC stimulated the migration of EBI2-expressing mouse B and T cells with half-maximum effective concentration values around 500 pM, but had no effect on EBI2-deficient cells. In vivo, EBI2-deficient B cells or normal B cells desensitized by 7α,25-OHC pre-treatment showed reduced homing to follicular areas of the spleen. Blocking the synthesis of 7α,25-OHC in vivo with clotrimazole, a CYP7B1 inhibitor, reduced the content of 7α,25-OHC in the mouse spleen and promoted the migration of adoptively transferred pre-activated B cells to the T/B boundary (the boundary between the T-zone and B-zone in the spleen follicle), mimicking the phenotype of pre-activated B cells from EBI2-deficient mice. Our results show an unexpected causal link between EBI2, an orphan G-protein-coupled receptor controlling B-cell migration, and the known immunological effects of certain oxysterols, thus uncovering a previously unknown role for this class of molecules.