Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.     

超滤滞留物和浓缩乳蛋白对冰淇淋存施期质量的影响

用超滞留物浓缩三倍和浓缩乳蛋白取代香型冰淇淋中25、50或75％和25、50、75或100％的SNE（非脂肪固形物）。混合物制成的所有冰淇淋均含有12％的脂肪，9.7％的SNF，12％的蔗糖，4％的玉米汁固形物和0.3％的稳定乳化剂，对存放（硬化）24小时后的冰淇淋混合物的PH值和粘度作了测定。这些混合物通过一个HTST试验装置和一个4.73L批料冷凝器在超载80％下作了处理。同时测量了拨出温度，对存放期为1天、30天、90天的冰淇淋的化学成分，细菌含量以及口感性质作了鉴定。还对存放30天的冰淇淋的热冲击稳定性和溶化性能作了实验研究。研究结果指出：由超滤滞留物取代SNF制取的冰淇淋具有的香味、形体和组织优于用浓乳蛋白取代SNF制取的冰淇淋具有的香味、形体和组织优于用浓乳蛋白取代SNF制得的冰淇淋。用25％的超滤滞留物取代会获提平均8.31的最佳香味指数。     

Two new susceptibility loci for Kawasaki disease identified through genome-wide association analysis

To find new candidate loci predisposing individuals to Kawasaki disease, an acute vasculitis that affects children, we conducted a genome-wide association study in 622 individuals with Kawasaki disease (cases) and 1,107 controls in a Han Chinese population residing in Taiwan, with replication in an independent Han Chinese sample of 261 cases and 550 controls. We report two new loci, one at BLK (encoding B-lymphoid tyrosine kinase) and one at CD40, that are associated with Kawasaki disease at genome-wide significance (P < 5 × 10(-8)). Our findings may lead to a better understanding of the role of immune activation and inflammation in Kawasaki disease pathogenesis.     

Neurosteroid enhances glutamate release in rat prelimbic cortex via activation of α1-adrenergic and σ1 receptors

The present paper studied the effect and mechanism of neurosteroid pregnenolone sulfate (PREGS) on spontaneous glutamate release using electrophysiological and biochemical methods combined with a pharmacological approach. The results suggested that PREGS had a selective enhancing effect on spontaneous glutamate release in the prelimbic cortex and the hippocampus but not in the striatum. The effect of PREGS in the prelimbic cortex appeared to be via modulation of ₁-adrenergic and ₁ receptors, but in the hippocampus it might be dependent on ₁ receptors only. The activation of ₁-adrenergic receptors synergized ₁ receptor activation in the prelimbic cortex. Intracellular calcium released from the endoplasmic reticulum, protein kinase C, adenylyl cyclase and protein kinase A played a key role in the effect of PREGS. Intracellular calcium, protein kinase C and adenylyl cyclase might be upstream events in the activation of protein kinase A after PREGS.Received 7 January 2005; received after revision 19 February 2005; accepted 22 February 2005 Available online 29 March 2005     

APC/C regulation of axonal growth and synaptic functions in postmitotic neurons: the Liprin-{\varvec \alpha} connection

Protein ubiquitination has critical roles in neuronal physiology and defects in protein ubiquitination have been implicated in neurodegenerative pathology. The anaphase-promoting complex/cyclosome (APC/C) is one of two key E3 ubiquitin ligase complexes that functions in regulating cell cycle transitions in proliferating cells by acting on cyclins and components of the mitotic/meiotic apparatus. Documentation of APC/C's action beyond cell division is sparse. In the past year, however, novel and surprising roles for APC/C in postmitotic neurons, particularly in the modulation of axonal growth and synaptic functions, have been revealed. APC/C and its activator Cdh-1 are found in good abundance in neurons, and these seem to function at different cellular locations, modulating apparently diverse processes such as axonal growth and synaptic function. Interestingly, there also appears to be a single link to these apparently divergent actions of APC/C in neurons--the multi-domain, multi-functional scaffolding protein Liprin-alpha which is an APC/C substrate.     

Phospholipase C gamma 1 is a physiological guanine nucleotide exchange factor for the nuclear GTPase PIKE

Phospholipase C gamma 1 (PLC-gamma 1) hydrolyses phosphatidylinositol-4,5-bisphosphate to the second messengers inositol-1,4,5-trisphosphate and diacylglycerol. PLC-gamma 1 also has mitogenic activity upon growth-factor-dependent tyrosine phosphorylation; however, this activity is not dependent on the phospholipase activity of PLC-gamma 1, but requires an SH3 domain. Here, we demonstrate that PLC-gamma 1 acts as a guanine nucleotide exchange factor (GEF) for PIKE (phosphatidylinositol-3-OH kinase (PI(3)K) enhancer). PIKE is a nuclear GTPase that activates nuclear PI(3)K activity, and mediates the physiological activation by nerve growth factor (NGF) of nuclear PI(3)K activity. This enzymatic activity accounts for the mitogenic properties of PLC-gamma 1.     

Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes

Regulation of body fat storage involves signalling between centres that regulate feeding in the brain and sites of fat storage and use in the body. Here we describe an assay for analysing fat storage and mobilization in living Caenorhabditis elegans. By using RNA-mediated interference (RNAi) to disrupt the expression of each of the 16,757 worm genes, we have systematically screened the C. elegans genome for genes necessary for normal fat storage. We identify 305 gene inactivations that cause reduced body fat and 112 gene inactivations that cause increased fat storage. Analysis of the fat-reducing gene inactivations in insulin, serotonin and tubby signalling mutants of C. elegans, which have increased body fat, identifies a core set of fat regulatory genes as well as pathway-specific fat regulators. Many of the newly identified worm fat regulatory genes have mammalian homologues, some of which are known to function in fat regulation. Other C. elegans fat regulatory genes that are conserved across animal phylogeny, but have not previously been implicated in fat storage, may point to ancient and universal features of fat storage regulation, and identify targets for treating obesity and its associated diseases.     

Cloning and characterization of a glucose 6-phosphate／phosphate translocator from Oryza sativa

Plastids of nongreen tissues import carbon as a source of biosynthetic pathways and energy, and glucose 6-phosphate is the preferred hexose phosphate taken up by nongreen plastids. A cDNA clone encoding glucose 6-phosphate/phosphate translocator (GPT) was isolated from a cDNA library of immature seeds of rice and named as OsGPT. The cDNA has one uninterrupted open reading frame encoding a 42 kDa polypeptide possessing transit poptide consisting of 70 amino acid residues. The OsGPT gene maps on chromosome 8 of rice and is linked to the quantitative trait locus for 1000-grain weight. The expression of OsGPT is mainly re-stricted to heteretrephic tissues. These results suggest that glucose 6-phosphate imported via GPT can be used for starch biosynthesis in rice nongreen plastids