A two-stage meta-analysis identifies several new loci for Parkinson's disease

A previous genome-wide association (GWA) meta-analysis of 12,386 PD cases and 21,026 controls conducted by the International Parkinson''s Disease Genomics Consortium (IPDGC) discovered or confirmed 11 Parkinson''s disease (PD) loci. This first analysis of the two-stage IPDGC study focused on the set of loci that passed genome-wide significance in the first stage GWA scan. However, the second stage genotyping array, the ImmunoChip, included a larger set of 1,920 SNPs selected on the basis of the GWA analysis. Here, we analyzed this set of 1,920 SNPs, and we identified five additional PD risk loci (combined p<5×10⁻¹⁰, PARK16/1q32, STX1B/16p11, FGF20/8p22, STBD1/4q21, and GPNMB/7p15). Two of these five loci have been suggested by previous association studies (PARK16/1q32, FGF20/8p22), and this study provides further support for these findings. Using a dataset of post-mortem brain samples assayed for gene expression (n = 399) and methylation (n = 292), we identified methylation and expression changes associated with PD risk variants in PARK16/1q32, GPNMB/7p15, and STX1B/16p11 loci, hence suggesting potential molecular mechanisms and candidate genes at these risk loci.     

Methicillin-susceptible ST398 Staphylococcus aureus responsible for bloodstream infections: an emerging human-adapted subclone?

In the course of an annual 3-month bloodstream infections (BSI) survey conducted during a four-year period in 31 healthcare institutions located in three noncontiguous French regions, we report 18 ST398 Staphylococcus aureus BSI. ST398 BSI incidence showed a seven-fold increase during the study period (0.002 per 1,000 patient days in 2007 vs. 0.014 in 2010). ST398 BSI isolates differed from the pig-borne multiresistant clone: 17/18 BSI isolates were methicillin susceptible and none was of t011, t034 or t108 pig-borne spa-types. ST398 BSI isolates had homogenous resistance patterns (15/18 with only Ery(r)) and prophagic content (all harboured the hlb-converting Sau3int phage). The clustering of BSI and pig-borne isolates by spa-typing and MLVA, the occurrence of Sau3int phage in BSI isolates and the lack of this phage in pig-borne isolates suggest that the emergence of BSI isolates could have arisen from horizontal transfer, at least of the Sau3int phage, in genetically diverse MSSA ST398 isolates. The acquisition of the phage likely plays a role in the increasing ability of the lysogenic ST398 isolates to colonize human. The mode of acquisition of the non pig-borne ST398 isolates by our 18 patients remains unclear. ST398 BSI were diagnosed in patients lacking livestock exposure and were significantly associated with digestive portals of entry (3/18 [16.7%] for ST398 vs. 19/767 [2.5%] for non ST398 BSI; p?=?.012). This raises the question of possible foodborne human infections. We suggest the need for active surveillance to study and control the spread of this human-adapted subclone increasingly isolated in the hospital setting.     

Comparison of two management strategies for Helicobacter pylori treatment: clinical study and cost-effectiveness analysis

BACKGROUND: First-line proton pump inhibitor-based triple and quadruple therapies for Helicobacter pylori eradication present similar levels of efficacy. Cross-over treatment (quadruple following triple failure, and triple following quadruple failure) seems the most sensible approach to treatment failures, but the two strategies -'quadruple first' versus 'triple first'- have not been previously compared. The aims of our study were to assess the usefulness and the cost-effectiveness of the two treatment strategies. MATERIAL AND METHODS: Forty-nine out of 344 patients included in a previous study comparing triple therapy - 7 days of omeprazole, amoxicillin and clarithromycin twice a day - with quadruple therapy - 7 days of omeprazole twice a day, plus tetracycline, metronidazole and bismuth subcitrate three times a day - failed initial treatment and were assigned to cross-over therapy. Cure was determined by urea breath test. A decision analysis was performed to compare the two eradication strategies. RESULTS: Intention to treat cure rates were 46% (10/22 patients; 95% CI 24-68%) for second-line triple therapy and 63% (17/27 patients; 95% CI 42-81%) for second-line quadruple therapy. Per protocol cure rates were 71% and 85%, respectively. Intention to treat cure rates were 87% (95% CI 81-92%) for the 'triple first' versus 86% (95% CI 80-91%) for the 'quadruple first' strategy (p = .87). The 'quadruple first' strategy was more cost-effective. The incremental cost of 'triple first' strategy per person was 19 in the low-cost area and 65 US dollars in the high-cost area. CONCLUSIONS: The effectiveness of 'triple first' and 'quadruple first' strategies is similar, although the latter seems slightly more cost-effective.     

PHA-767491抑制多种肿瘤细胞生长

Cdc7激酶抑制剂PHA-767491是最新发现的一类抗肿瘤新药.本实验利用不同浓度的PHA-767491对肿瘤细胞进行抑制研究.实验结果显示,PHA-767491对肿瘤细胞有很强的生长抑制作用,且抑制效果随着药物浓度或时间的增加而增强;通过和化疗药物5-氟尿嘧啶对比发现,PHA-767491只需较低剂量就能发挥出抑制肿瘤的作用,且疗效远高于5-氟尿嘧啶.研究进一步还发现,PHA-767491可通过促使PARP和casepase3蛋白的剪切诱导肿瘤细胞凋亡,同时PHA-767491还可以引起肿瘤细胞自噬.综上研究表明,PHA-767491可以通过诱导细胞凋亡和引起细胞自噬作用对多种肿瘤细胞有较好的治疗效果,而对正常细胞毒性很低.因此该实验研究为今后抗肿瘤新药PHA-767491的进一步应用于癌症的临床治疗提供了重要的实验依据.     

在笼型蛋白和脂筏介导的两种内吞途径中nephrin的磷酸化修饰动力学不同

研究肾小球裂隙膜的主要成分nephrin分子在细胞内的转运途径及不同转运途径对nephrin磷酸化的影响.分别应用笼型蛋白介导的内吞(clathrin-mediated endocytosis,CME)和脂筏介导的内吞(raft-mediated endocytosis,RME)标记物转铁蛋白和霍乱毒素B亚基对nephrin的内吞过程进行分析,并进一步应用两种内吞途径阻断物EPS15Δ和Dyn2aK44A,研究阻断nephrin的内吞途径对其磷酸化水平的影响.结果显示,nephrin通过笼型蛋白和脂筏介导的两种内吞途径以不同速率进行内吞;与Src酪氨酸激酶家族成员Fyn共表达时,细胞内nephrin酪氨酸磷酸化被增强,而在Src家族激酶抑制剂PP2的作用下,nephrin酪氨酸磷酸化被减弱,表明nephrin的磷酸化过程是Fyn依赖的;内吞20min时,笼型蛋白介导的内吞途径的特异性阻断物EPS15Δ降低了nephrin磷酸化水平、笼型蛋白和脂筏介导的内吞途径的通用抑制剂Dyn2aK44A则增加了nephrin的磷酸化水平,综上结果表明:单独阻断脂筏介导的内吞可引起nephrin的磷酸化水平增加,脂筏介导的内吞对nephrin磷酸化过程起下调作用.     

VicRK(YycFG)双组分调节系统

细菌双组分调节系统,或称之为双组分信号转导系统,是细菌感应外界多变环境,维持自身存活和生长繁衍的重要感应系统.在这些调节系统中,最早发现于枯草芽孢杆菌的VicRK(YycFG)系统因与细胞存活密切相关而倍受关注.该系统存在于少数低G+C含量的革兰氏阳性菌中,包括金黄色葡萄球菌和肺炎链球菌等致病菌,高度保守.许多证据显示,VicRK(YycFG)具有调控细胞壁合成与代谢、胞膜完整、细胞分裂、脂类代谢、多糖合成与被膜形成以及细菌毒力等多种功能,参与细胞的生长、分裂与感染.该系统异常可导致细菌生活力严重下降,甚至死亡,因而成为防治该类病原菌的重要靶标.     

Ultraconserved elements in the human genome: association and transmission analyses of highly constrained single-nucleotide polymorphisms

Ultraconserved elements in the human genome likely harbor important biological functions as they are dosage sensitive and are able to direct tissue-specific expression. Because they are under purifying selection, variants in these elements may have a lower frequency in the population but a higher likelihood of association with complex traits. We tested a set of highly constrained SNPs (hcSNPs) distributed genome-wide among ultraconserved and nearly ultraconserved elements for association with seven traits related to reproductive (age at natural menopause, number of children, age at first child, and age at last child) and overall [longevity, body mass index (BMI), and height] fitness. Using up to 24,047 European-American samples from the National Heart, Lung, and Blood Institute Candidate Gene Association Resource (CARe), we observed an excess of associations with BMI and height. In an independent replication panel the most strongly associated SNPs showed an 8.4-fold enrichment of associations at the nominal level, including three variants in previously identified loci and one in a locus (DENND1A) previously shown to be associated with polycystic ovary syndrome. Finally, using 1430 family trios, we showed that the transmissions from heterozygous parents to offspring of the derived alleles of rare (frequency ≤0.5%) hcSNPs are not biased, particularly after adjusting for the rates of genotype missingness and error in the data. The lack of transmission bias ruled out an immediately and strongly deleterious effect due to the rare derived alleles, consistent with the observation that mice homozygous for the deletion of ultraconserved elements showed no overt phenotype. Our study also illustrated the importance of carefully modeling potential technical confounders when analyzing genotype data of rare variants.