Allelic association with SNPs: metrics, populations, and the linkage disequilibrium map

Comparison of different metrics, using three large samples of haplotypes from different populations, demonstrates that rho is the most efficient measure of association between pairs of single nucleotide polymorphisms (SNPs). Pairwise data can be modeled, using composite likelihood, to describe the decline in linkage disequilibrium with distance (the Malecot model). The evidence from more isolated populations (Finland, Sardinia) suggests that linkage disequilibrium extends to 427-893 kb but, even in samples representative of large heterogeneous populations, such as CEPH, the extent is 385 kb or greater. This suggests that isolated populations are not essential for linkage disequilibrium mapping of common diseases with SNPs. The in parameter of the Malecot model (recombination and time), evaluated at each SNP, indicates regions of the genome with extensive and less extensive disequilibrium (low and high values of in respectively). When plotted against the physical map, the regions with extensive and less extensive linkage disequilibrium may correspond to recombination cold and hot spots. This is discussed in relation to the Xq25 cytogenetic band and the HFE gene region.     

Role of JAK2 signal transductional pathway in activation and survival of human peripheral eosinophils by interferon-gamma (IFN-gamma)

The purpose of this study was to determine whether the JAK pathway is involved in eosinophil activation and survival through IFN-gamma receptor signalling in human peripheral eosinophils. Eosinophils were purified from the blood of six atopic disease patients by anti-CD16 magnetic bead-negative selection. IFN-gamma significantly up-regulated survival and CD69 expression in 24-48 h cultured eosinophils. Further, IFN-gamma induced tyrosine phosphorylation of JAK2 in eosinophils, as indicated by Western blot analysis. Finally, the specific JAK2 inhibitor AG-490 inhibited the tyrosine phosphorylation of JAK2, IFN-gamma-induced survival and CD69 expression in eosinophils. In conclusion, these results indicate that IFN-gamma induces eosinophil survival and CD69 expression through the activation of JAK2 in peripheral eosinophils, suggesting that JAK2 may play a significant role in eosinophil regulation by IFN-gamma-IFN-gammaR interaction.     

Characterization of IL-4 and IL-13 signals dependent on the human IL-13 receptor alpha chain 1: redundancy of requirement of tyrosine residue for STAT3 activation

IL-4 and IL-13 are pleiotropic cytokines whose biological activities overlap with each other. IL-13 receptor alpha chain 1 (IL-13R alpha 1) is necessary for binding to IL-13, and the heterodimer composed of IL-13R alpha 1 and IL-4R alpha chain transduces IL-13 and IL-4 signals; however, the functional mapping of the intracellular domain of IL-13R alpha 1 is not fully understood. In this study, we constructed wild and mutated types of human IL-13R alpha 1, and analyzed IL-4 and IL-13 signals using an IL-13R alpha 1-transfected human B cell line. Expression of IL-13R alpha 1 evoked STAT3 activation by IL-4 and IL-13, and in stimulated human B cells, on which IL-13R alpha 1 was highly expressed, IL-4 and IL-13 induced STAT3 activation. Replacement of the two tyrosine residues completely abolished STAT3 activation, although replacing either tyrosine residue alone retained it. Furthermore, we found that the Box1 region and the C-terminal tail of IL-13R alpha 1 were critical for binding to Tyk2, and activation of Jak1, Tyk2, the insulin receptor substrate-1 and STAT6 respectively. These results suggest that STAT3 activation is involved with IL-4 and IL-13 signals in human B cells along with the activation of STAT6, and that there is a unique sequence in IL-13R alpha 1 to activate STAT3.     

HIV阴性儿童马尔尼菲篮状菌病2例临床分析并文献复习

 目的 总结2例人类免疫缺陷病毒（HIV）阴性儿童马尔尼菲篮状菌病（TSM）患儿的临床特征。方法 分析某儿童医院收治的2例HIV阴性TSM患儿的临床特点及实验室资料、存在的基础疾病,并复习相关文献,总结TSM感染患儿的临床特征及诊治经验。结果 2例HIV阴性TSM患儿中病例1以右下肢肿块为首发症状,1个月余后才出现发热及咳嗽,误诊为结核感染;病例2以发热、三系减少及肝脾、淋巴结大等表现起病。病例1行基因检测为STAT1基因突变,病例2有反复灰指甲及口腔溃疡病史,均行血、骨髓培养及淋巴结活检确诊。病例1先后予以伏立康唑、两性霉素B脂质体静脉滴注,伊曲康唑口服维持治疗,共治疗1年后停药;病例2一直予以伏立康唑治疗（先静脉滴注后口服）,共7个月后停药,均无复发。结论 TSM可发生在HIV阴性儿童,且可存在STAT1基因突变。对于治疗效果差的患儿,应尽早行培养或组织活检以明确诊断,并积极查找TSM可能存在的基础疾病,以到达早期诊断、早期治疗和改善预后的目的。     

小檗碱通过抑制凋亡和炎症减轻大鼠慢性萎缩性胃炎病变的效果

目的：探究小檗碱对慢性萎缩性胃炎(CAG)的改善作用及其作用机制。方法：将SD大鼠随机分为对照组、模型组、小檗碱低剂量组、小檗碱中剂量组、小檗碱高剂量组和DUSP19组,每组9只。除对照组外均构建CAG模型,小檗碱低、中、高剂量分别灌胃给与25、50、100 mg/kg的小檗碱,DUSP19组灌胃给与100 mg/kg的小檗碱和尾静脉注射JAK激酶2/信号转导及转录激活因子3（JAK2/STAT3）通路激活剂DUSP19 100 μmol/L。苏木精-伊红（HE）染色法检测病理学变化;蛋白质印迹法检测JAK2/STAT3信号通路及凋亡相关蛋白表达;酶联免疫吸附试验（ELISA）检测血清相关因子表达水平;原位末端转移酶标记技术（TUNEL）检测胃黏膜细胞凋亡。结果：与模型组比较,小檗碱观察组磷酸化JAK2（p-JAK2）、磷酸化JAK3（p-JAK3）、胃动素（MTL）、肿瘤坏死因子-α（TNF-α）、白细胞介素6（IL-6）、白细胞介素-1β（IL-1β）、前列腺素E2（PGE2）、内皮素（ET）、B淋巴细胞瘤-2相关X蛋白（Bax）、裂解胱天蛋白酶3（Cl-caspase-3）、裂解胱天蛋白酶9（Cl-caspase-9）水平及细胞凋亡率显著降低(P<0.05),胃泌素（GAS）、分泌型免疫球蛋白A（sIgA）、谷胱甘肽（GSH）、B淋巴细胞瘤-2（Bcl-2）水平显著升高(P<0.05);JAK2/STAT3通路激活剂DUSP19可显著扭转小檗碱对上述指标的影响(P<0.05),且HE结果显示小檗碱可显著改善CAG大鼠胃组织病理病变。结论：小檗碱可通过JAK2/STAT3信号通路抑制细胞凋亡和炎症反应减轻大鼠慢性萎缩性胃炎。     

补中益气汤调控JAK2/STAT3信号通路对气虚发热证大鼠肠道菌群、免疫功能及神经功能的影响

目的:分析补中益气汤调控Janus激酶2(JAK2)/信号传导与活化转录因子3(STAT3)/STAT3信号通路对气虚发热证大鼠肠道菌群、免疫功能及神经功能的影响。方法:将30只大鼠随机分为正常组、气虚发热模型组、补中益气汤组,每组10只。气虚发热模型组、补中益气汤组大鼠用于建立气虚发热模型,第18天开始,补中益气汤组给予补中益气汤灌胃治疗5 d,气虚发热模型组给予等体积蒸馏水。16SrRNA基因序列分析技术检测大鼠肠道菌群;ELISA法检测CD4⁺、CD8⁺、补体C3水平、免疫球蛋白G(IgG)、免疫球蛋白M(IgM)水平;放免法测定乙酰胆碱(Ach)、环磷酸腺苷(cAMP)和环磷酸鸟苷(cGMP)水平;蛋白质印迹法(Western blot)检测p-JAK2、p-STAT3蛋白表达水平。结果:补中益气汤可改善气虚发热所致的疣微菌门、互养菌门菌落减少,螺旋体门、埃普西隆杆菌门菌落增多情况(P<0.05)。补中益气汤可改善气虚发热所致的血清CD4⁺、C3、IgM、IgG水平及淋巴细胞转化率降低,血清CD8^...