Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.     

广西崇左江州木榄山智人洞古人类遗址及其地质时代

关于现代智人起源的争论一直是国际古人类学研究的前沿与热点. 最近, 在广西崇左木榄山智人洞发现了具有现代人解剖特征初始状态的人类下颌骨化石及大量与之共生的哺乳动物化石. 木榄山智人洞哺乳动物群以江南象与初现的亚洲象及巨獏等组合为其特征, 截然不同于华南早更新世的巨猿动物群和中更新世的大熊猫-剑齿象动物群, 是典型亚洲象动物群的早期代表. 依动物群性质、地层对比及铀系年代测定木榄山化石智人和伴生的哺乳动物群的时代为距今约11万年的晚更新世早期. 该动物群主要由热带-亚热带型动物组成, 但木榄山动物群中森林型动物种类单调, 草地类型的动物相当多, 这表明当时的气候可能比以前干燥. 木榄山智人的发现对研究现代人起源及其环境背景具有非常重要的意义.     

The structural basis of agonist-induced activation in constitutively active rhodopsin

G-protein-coupled receptors (GPCRs) comprise the largest family of membrane proteins in the human genome and mediate cellular responses to an extensive array of hormones, neurotransmitters and sensory stimuli. Although some crystal structures have been determined for GPCRs, most are for modified forms, showing little basal activity, and are bound to inverse agonists or antagonists. Consequently, these structures correspond to receptors in their inactive states. The visual pigment rhodopsin is the only GPCR for which structures exist that are thought to be in the active state. However, these structures are for the apoprotein, or opsin, form that does not contain the agonist all-trans retinal. Here we present a crystal structure at a resolution of 3 ? for the constitutively active rhodopsin mutant Glu 113 Gln in complex with a peptide derived from the carboxy terminus of the α-subunit of the G protein transducin. The protein is in an active conformation that retains retinal in the binding pocket after photoactivation. Comparison with the structure of ground-state rhodopsin suggests how translocation of the retinal β-ionone ring leads to a rotation of transmembrane helix 6, which is the critical conformational change on activation. A key feature of this conformational change is a reorganization of water-mediated hydrogen-bond networks between the retinal-binding pocket and three of the most conserved GPCR sequence motifs. We thus show how an agonist ligand can activate its GPCR.     

T-cell-mediated enhancement of host-versus-graft reactivity in mice fed a diet enriched in vitamin A acetate

Retinol (vitamin A) and some of its derivatives have an important role in: (1) regulating growth, proliferation and differentiation of various tissues and (2) maintaining reproduction and visual function in man and higher animals. Vitamin A and retinoids are also known as potent immunoregulatory and antineoplastic agents. Their ability to increase reactivity to histoincompatible tissues is well documented but the mechanism of this action is unclear. Here we report that mice fed on an otherwise conventional diet supplemented with vitamin A acetate (VAA) respond to 10(5) semiallogeneic cells (a suboptimal dose) in a host-versus-graft (HvG) reaction, whereas mice on a conventional diet do not. It is possible to transfer this enhanced immune reactivity by injecting lymphoid cells from VAA-fed animals into those syngeneic mice maintained on the conventional diet. Using a positive selection technique, we demonstrate that the phenotype of the cell probably responsible for this phenomenon is Lyt 1+ 2-.     

The response of the adrenal gland to hypoglycaemia in the conscious calf

Résumé La sécrétion de glucocorticoides et de catécholamines par la glande surrénale droite fut observée chez des veaux conscients après une injection d'insuline. L'accroissement de la production de stéroides fut passagère malgré une hypoglycémie ininterrompue.

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Acknowledgements. This work was supported by grants from the Medical Research Council, the Smith, Kline & French Foundation and Twyford Pharmaceutical Services Ltd. We are also indebted to Dr.D. M. Burley (CIBA) for his continued assistance and to Dr.P. C. Risdall (Boots Co. Ltd.) who supplied the highly purified insulin. K.W.M. has been supported by the Agricultural Research Council. It is a particularly pleasure to acknowledge the skilled technical assistance provided by Mr.P.M.M. Bircham.