A high-density association screen of 155 ion transport genes for involvement with common migraine

The clinical overlap between monogenic Familial Hemiplegic Migraine (FHM) and common migraine subtypes, and the fact that all three FHM genes are involved in the transport of ions, suggest that ion transport genes may underlie susceptibility to common forms of migraine. To test this leading hypothesis, we examined common variation in 155 ion transport genes using 5257 single nucleotide polymorphisms (SNPs) in a Finnish sample of 841 unrelated migraine with aura cases and 884 unrelated non-migraine controls. The top signals were then tested for replication in four independent migraine case-control samples from the Netherlands, Germany and Australia, totalling 2835 unrelated migraine cases and 2740 unrelated controls. SNPs within 12 genes (KCNB2, KCNQ3, CLIC5, ATP2C2, CACNA1E, CACNB2, KCNE2, KCNK12, KCNK2, KCNS3, SCN5A and SCN9A) with promising nominal association (0.00041 < P < 0.005) in the Finnish sample were selected for replication. Although no variant remained significant after adjusting for multiple testing nor produced consistent evidence for association across all cohorts, a significant epistatic interaction between KCNB2 SNP rs1431656 (chromosome 8q13.3) and CACNB2 SNP rs7076100 (chromosome 10p12.33) (pointwise P = 0.00002; global P = 0.02) was observed in the Finnish case-control sample. We conclude that common variants of moderate effect size in ion transport genes do not play a major role in susceptibility to common migraine within these European populations, although there is some evidence for epistatic interaction between potassium and calcium channel genes, KCNB2 and CACNB2. Multiple rare variants or trans-regulatory elements of these genes are not ruled out.

MicroRNA-155 Is Required for Mycobacterium bovis BCG-Mediated Apoptosis of Macrophages

Pathogenic rnycobacteria, including Mycobacterium tuberculosis and Mycobacterium bovis, cause significant morbidity and mortality worldwide. However, the vaccine strain Mycobacterium bovis BCG, unlike virulent strains, triggers extensive apoptosis of infected macrophages, a step necessary for the elicitation of robust protective immunity. We here demonstrate that M. bovis BCG triggers Toll-like receptor 2 (TLR2)-dependent microRNA-155 (miR-155) expression, which involves signaling cross talk among phosphatidylinositol 3-kinase (PI3K), protein kinase C delta (PKC delta), and mitogen-activated protein kinases (MAPKs) and recruitment of NF-kappa B and c-ETS to miR-155 promoter. Genetic and signaling perturbations presented the evidence that miR-155 regulates PKA signaling by directly targeting a negative regulator of PKA, protein kinase inhibitor alpha (PKI-alpha). Enhanced activation of PKA signaling resulted in the generation of PKA C-alpha; phosphorylation of MSK1, cyclic AMP response element binding protein (CREB), and histone H3; and recruitment of phospho-CREB to the apoptotic gene promoters. The miR-155-triggered activation of caspase-3, BAK1, and cytochrome c translocation involved signaling integration of MAPKs and epigenetic or posttranslational modification of histones or CREB. Importantly, M. bovis BCG infection-induced apoptosis was severely compromised in macrophages derived from miR-155 knockout mice. Gain-of-function and loss-of-function studies validated the requirement of miR-155 for M. bovis BCG's ability to trigger apoptosis. Overall, M. bovis BCG-driven miR-155 dictates cell fate decisions of infected macrophages, strongly implicating a novel role for miR-155 in orchestrating cellular reprogramming during immune responses to mycobacterial infection.

Oncogenic MicroRNA-155 Down-regulates Tumor Suppressor CDC73 and Promotes Oral Squamous Cell Carcinoma Cell Proliferation IMPLICATIONS FOR CANCER THERAPEUTICS

The CDC73 gene is mutationally inactivated in hereditary and sporadic parathyroid tumors. It negatively regulates beta-catenin, cyclin D1, and c-MYC. Down-regulation of CDC73 has been reported in breast, renal, and gastric carcinomas. However, the reports regarding the role of CDC73 in oral squamous cell carcinoma (OSCC) are lacking. In this study we show that CDC73 is down-regulated in a majority of OSCC samples. We further show that oncogenic microRNA-155 (miR-155) negatively regulates CDC73 expression. Our experiments show that the dramatic up-regulation of miR-155 is an exclusive mechanism for down-regulation of CDC73 in a panel of human cell lines and a subset of OSCC patient samples in the absence of loss of heterozygosity, mutations, and promoter methylation. Ectopic expression of miR-155 in HEK293 cells dramatically reduced CDC73 levels, enhanced cell viability, and decreased apoptosis. Conversely, the delivery of a miR-155 antagonist (antagomir-155) to KB cells overexpressing miR-155 resulted in increased CDC73 levels, decreased cell viability, increased apoptosis, and marked regression of xenografts in nude mice. Cotransfection of miR-155 with CDC73 in HEK293 cells abrogated its pro-oncogenic effect. Reduced cell proliferation and increased apoptosis of KB cells were dependent on the presence or absence of the 3'-UTR in CDC73. In summary, knockdown of CDC73 expression due to overexpression of miR-155 not only adds a novelty to the list of mechanisms responsible for its down-regulation in different tumors, but the restoration of CDC73 levels by the use of antagomir-155 may also have an important role in therapeutic intervention of cancers, including OSCC.

Sapientia, 1985, Vol. XL, nº 155 (número completo)

Contenido: La verdad (I). La verdad en sí misma y en las cosas / Octavio N. Derisi -- Carácter racional de la libertad / Octavio N. Derisi -- Libertad política : liberalismo y tomismo / Héctor H. Hernández -- Hilemorfismo y corporalidad / J. E. Bolzán -- Fenomenología de la sensación / Gabriel Chalmeta -- La teoría relacional de la personalidad según J. Nuttin / William R. Darós -- Notas y comentarios -- Bibliografía

Diário da Constituinte [gravação de vídeo] : [programa n. 155]

Técnicos em reforma sanitária, representantes da Assembleia Nacional Constituinte (ANC) e o Ministro da Saúde, Sr. Roberto Santos, reuniram-se para debater o tema: a saúde e a Constituinte. Segundo o ministro Roberto Santos o projeto de Constituição atual é um avanço quando coloca a saúde como um direito do cidadão e dever do Estado. A questão da saúde faz parte do título geral do projeto de Constituição, que trata da ordem social. No Artigo 350 fica determinado que o Estado deve criar políticas para eliminar ou reduzir o risco de doenças e garantir o acesso universal e gratuito à saúde. O Deputado José Elias Murad (PTB-MG) esclarece que este princípio significa que, em qualquer parte do país, qualquer brasileiro terá direito ao atendimento médico gratuito. O Deputado Arnaldo Faria de Sá (PTB-SP) vai apresentar um projeto de decisão para colocar já em votação a duração do mandato do Presidente José Sarney. Segundo ele, é necessário votar logo esse tema para que a Constituinte possa trabalhar em paz. Segundo o Regimento da Comissão de Sistematização, um projeto de decisão é todo assunto que precisa ser discutido quando surgir uma ameaça aos trabalhos da Constituinte. O Deputado Nilson Gibson (PMDB-PE) declara que a questão do mandato do presidente como um fato jurídico constituído, um direito adquirido. O Deputado Adolfo Oliveira (PL-RJ) afirma que é preciso caminhar para uma Constituição nova, com tudo reformado, tudo revisado e votação direta para todos os cargos eletivos. O Deputado Augusto Carvalho (PCB-DF), em nome do partido, apoia as eleições diretas para presidente da república em 1988. O Deputado Virgildásio Sena (PMDB-BA) afirma que não é a hora de decidir o mandato do presidente, já que ainda não se decidiu nem o sistema de governo. O Deputado Euclides Scalco (PMDB-PR) entende que é o momento de discutir na Comissão de Sistematização a questão do mandato do presidente e do regime de governo. O Deputado Ulysses Guimarães (PMDB-SP) entende que o Plenário é o fórum próprio para discutir o mandato e o sistema de governo, quando for votado o substitutivo.

贵州凉风洞石笋的古气侯记录与古生态环境意义

自20世纪60年代以来，探索全球性气候变化规律和环境变迁史的研究工作在世界各国广泛开展。大规模的深海岩芯的研究、中国北方黄土的系统研究、大型湖泊沉积岩芯的研究及对树木年轮、泥炭、珊瑚、冰芯等“自然环境历史档案”开展的研究工作，都为重建古气候和古生态环境提供了大量的资料。洞穴化学沉积物（石笋）由于其特有的微层结构及其内的稳定氧、碳同位素和微量元素所蕴含的古气候与古生态环境信息，并且具有分布广、时间长、信息保存完整等特点，因此，它是研究地球环境变化很好的自然环境历史档案。本论文通过对凉风洞洞穴体系的综合研究和对凉风洞石笋（微层）生长特征及石笋的碳、氧稳定同位素组成的研究，系统探讨了贵州凉风洞石笋的古气候记录和古生态环境意义，得出以下主要结论：1，地表植被的类型及生物量等信息可综合反映于洞穴体系的不同组．分（气样、土样、水样）中。而洞穴的水动力条件也能很好的被洞穴滴水中所含微量（常量）元素记录。根据分析，洞穴综合体系对外界气候与生态环境的响应关系存在一定规律性。通过对比说明，我们所选的凉风洞基岩的溶蚀和缓冲对水体中的信息影响不大，即洞穴滴水较好的继承了土壤水所携带的地表气候与生态环境信息，是理想的研究对象。2．凉风洞石笋具有多个沉积旋回，不同沉积旋回的纹层组合及纹层结构存在一定的差异，指示不同的沉积环境。根据年龄数据判断，旋回①至旋回⑧之间年龄跨度为1570-8000 aBP，以呈缓平顶（柱）对称叠复状的沉积形态组合为主，示洞顶滴水量较大，滴水点相对稳定，且均匀，与全新世较为稳定的气候与环境变化的主旋律相一致。旋回⑧以下至底部石葡萄状沉积物之上部分之间年龄跨度为8000-14220 aBP，期间经历末次冰期晚期向全新世大暖期过渡，受诸如新仙女木事件（Younger Dryas）等的影响，气候变化幅度大，且经历多次反复，石笋生长的沉积学特征表现为斜锥（柱）、尖顶锥不对称叠复纹层组合，示洞顶滴水水量较小但变化较大，且洞穴滴水不稳（固）定。与此时间段内不稳定的气候与环境变化的主旋律也相一致。3．凉风洞石笋上段微层具有典型南方石笋微层发育的特性：微层发育较差，层面多弯曲，层间界面模糊等。下段因为沉积间断较多、风化层面厚及受到若干时段内碳酸钙重结晶而导致晶体穿插层位生长的影响，尽管在某些层位有微层发育，但无法对石笋微层作连续观察记录。根据高精度的石笋TIMS、ICP-MS测年数据和在显微镜下所数石笋微层数量的对比，扣除若干个沉积间断及风化层导致的微层缺失，以及显微镜下肉眼对细小微层计数的误差，我们认为，凉风洞石笋微层是年生长层的可能性较大。4，由于部分测年数据仍在测试中，目前无法精确控制石笋中沉积间断的存在导致的信息缺失，因此，我们仅仅根据部分石笋测年数据，建立了凉风洞石笋在不同时段的生长速率。全新世以来石笋的生长速率在22μm／yr-51μm／yr之间，明显高于末次冰期晚期向全新世过渡这一时间段内的石笋生长速率（16μm／yr）。这些数据间接印证了石笋生长响应于外界气候，尤其是降雨的变化。5．通过对洞穴体系的综合分析对比，我们判断凉风洞洞穴综合体系相对完整，洞穴化学沉积物的6先值较为直接的响应了土壤c压的61t值变化，即反映了地表的植被（c3植物和c；植物）的组成状况。贵州地区降雨80％集中在5-10月份，在此期间，基本受西南季风和东亚季风所控制。西南季风盛行时贵州各地的降雨频繁，是一年中雨量最集中的时期，在东亚季风影响时期，贵州多晴少雨，往往形成干早的天气。又西南季风控制区大气降雨创的值的加权平均值明显低于东亚季风控制区大气降雨δ18O值的加权平均值。因此，贵州地区年均降雨量和年均降雨δ18O值主要取决于西南（印度洋）季风的强弱：西南季风加强，降雨量增加，年均降雨剐、值偏负；西南季风减弱，降雨量减少，年均降雨δ18O值偏正。洞穴滴水的6旧O值变化基本继承了大气降水的别勿值变化。因此，对地处我国西南地区贵州南部的凉风洞，源于洞穴滴水的凉风洞石笋的别勺值变化直接响应了外界的大气降雨量的变化和西南季风与东亚季风相互的强弱交替。6．对凉风洞石笋碳、氧同位素组成的时间序列曲线作20点移动平均，发现，特别是进入全新世后，石笋的引3c值和扩、值几乎具有完全一致的同步变化，只是在变化幅度上在某些时段存在差异。说明在凉风洞石笋反映的14220-1570 aBP时间段内，尤其是10500-1570 aBP期间，本区域气候具有雨热（或干冷）同期的气候特征：在气温较高时间段，西南季风增强，气候湿润多雨，更有利于地表。植物的生长。气温降低时，随着东亚季风增强，西南季风减弱，气候干旱少雨，地表C；植物的生长占有一定的比例。据此重建和恢复了本地区14220-1570 aBP期间的古气候和古生态环境：（1）．14220-10500aBP，处于末次冰期晚期，气温较低。凉风洞石笋此时段的司、值都大于-9.8‰，最小值为-9.31‰，最大值达-7.290‰，平均值为-8.552‰。说明凉风洞洞穴地表的生长植被。植物占有一定的组分，石笋的δ18C值受C3植物和C4植物的共同影响。此时段内石笋6、值也存在一定的波动（-5.651‰－6.942‰），考虑到末次冰期晚期先全新世过渡期间气温变幅较大，O'Neil等（1969）所建立的氧同位素平衡分馏方程中的温度变化已不能忽略，并且大气降雨的温度效应作用也比较明显，因此我们对此时段的季风和大气降雨量的变化不作讨论。（2）. 10500-9300 aBP，新仙女木事件结束，进入全新世，气温逐渐回升。凉风洞石笋此时段的扩3c值大都小于-9.8‰，最小值为-10.377‰，最大值为-9.267‰，平均值为-9.910‰。凉风洞洞穴地表植被已逐渐由C3植物占主导。此时段石笋δ18C值明显卜降，最小值为-7.420‰，最大值为-6.077‰，平均值为-6.854‰。反映在全新世早期夏季风盛行，降雨量较大，西南季风对本地区全年降雨贡献率大。（3）．9300-8300 aBP，经历一段明显温度波动变化。仟3c值在-9.8‰上下波动，最小值为-10.155‰，最大值为-9.096‰，平均值为-9.712‰。凉风洞洞穴地表植被C4植物所占比例存在反复。此时段石笋岁a0值变化幅度不是很大，最小值为-6.796‰，最大值为-6.260‰，平均值为-6.490‰。受冬季风影响，夏季风有一定的减弱，总体降雨量一般，东亚季风对本地区全年降雨贡献率比全新世初期有所增大。（4）．8300-3l000BP，俗称全新世大暖期，此时段全球气温明显回升，石笋δ18C值总体逐渐降低，最小值为-n．926编，平均值为-10.496‰。凉风洞洞穴地表植被基本由C3植物所控制。但在扩飞值总体逐渐降低的趋势一F，也存在若干扩3c值明显增大时段，如7700-6700 aBP时段，61七值最大值达-8.110‰，地表C4植物所占比例已不能忽略。此时段石笋6150值变化幅度较大，最小值为-7.373‰，最大值为-5.047‰，平均值为-6.261‰。反映在全新世大暖期的大背景下西南季风和东亚季风的交替以及大气降雨量的变化存在较大的波动，说明了季风气候的不稳定性。（5）．3100-1570 aBP，在3100aBP前后，凉风洞石笋的δ18C值和δ18O值均急剧上升，标志进入晚全新世。此时段气温变幅很大，δ18C值总体虽然仍偏低，平均值为-10.275‰，但刻畜介于-6.495-12.097‰之间；δ18C值平均值为-6.184‰，变幅介于-4.677-8.65‰之间，均超过以往任何时段。此时段凉风洞洞穴地表植被基本上仍然由C。植物所控制，始于3100 aBP的急速降温事件使得在全新世晚期开始时段C4植物所占比例有一定的上升。此时段内西南季风和东亚季风反复多次交替，大气降雨量存在较大幅度的变化，说明了季风气候在此时段的很不稳定性。对于169于巧70 oBP百年时间段内石笋的δ18C值和司、值巨大幅度的急剧升高，有待进一步研究，也不排除石笋表层长期裸露受外界污染所致。

MicroRNA-155 Promotes Resolution of Hypoxia-Inducible Factor 1{alpha} Activity

The hypoxia-inducible factor (HIF) is a key regulator of the transcriptional response to hypoxia. While the mechanism underpinning HIF activation is well understood, little is known about its resolution. Both the protein and the mRNA levels of HIF-1a (but not HIF-2a) were decreased in intestinal epithelial cells exposed to prolonged hypoxia. Coincident with this, microRNA (miRNA) array analysis revealed multiple hypoxia-inducible miRNAs. Among these was miRNA-155 (miR-155), which is predicted to target HIF-1a mRNA. We confirmed the hypoxic upregulation of miR-155 in cultured cells and intestinal tissue from mice exposed to hypoxia. Furthermore, a role for HIF-1a in the induction of miR-155 in hypoxia was suggested by the identification of hypoxia response elements in the miR-155 promoter and confirmed experimentally. Application of miR-155 decreased the HIF-1a mRNA, protein, and transcriptional activity in hypoxia, and neutralization of endogenous miR-155 reversed the resolution of HIF-1a stabilization and activity. Based on these data and a mathematical model of HIF-1a suppression by miR-155, we propose that miR-155 induction contributes to an isoform-specific negative-feedback loop for the resolution of HIF-1a activity in cells exposed to prolonged hypoxia, leading to oscillatory behavior of HIF-1a-dependent transcription.

Resolución No. 155: Por la cual se acepta un desistimiento de un recurso de reposición y en subsidio de apelación

Servicios registrales

Street-level labour inspection in China and the implementation of ILO Convention No.155 concerning occupational safety and health

Les relations de travail et d'emploi sont devenues des enjeux importants en Chine. La Chine a ratifié 25 conventions internationales du travail et a travaillé en étroite collaboration avec l'OIT pour améliorer la sécurité et la santé au travail. Malgré ces efforts, la Chine est souvent critiquée pour des violations du travail. Face à ces problèmes, un système législatif d'administration de travail a été développé au niveau national. Mais l’application de ces règlements demeure problématique.. En particulier, les difficultés rencontrées par les inspecteurs du travail dans l'application de ces lois constituent un élément clé du problème. Notre mémoire s'intéresse essentiellement au rôle de l'inspecteur du travail dans l'administration publique de la sécurité du travail en Chine. Ces fonctionnaires jouent un rôle important et peuvent parfois exercer leur discrétion en tant qu'acteurs de première ligne, faisant d'eux de vrais décideurs politiques. Par conséquent, la compréhension de leur rôle et de leur discrétion dans l'application des normes du travail en Chine est cruciale. Notre mémoire est centré sur une étude de cas qualitative d'un bureau d'inspection du travail dans la région de Beijing. Dans le cadre de notre recherche nous avons examiné le rôle des inspecteurs du travail au moyen d’entretiens semi-structurés, d’une recherche documentaire ainsi qu’à l’occasion d’une brève observation des inspecteurs sur lors de la visite d’un lieu de travail. Les résultats démontrent que la définition du pouvoir discrétionnaire des inspecteurs du travail de première ligne en Chine est un enjeu très complexe. L’étude de cas permet cependant d’élaborer un cadre permettant l’identification des facteurs critiques déterminants pour l'évaluation et la compréhension de la nature du pouvoir discrétionnaire de l'inspecteur du travail en application de la loi.

Eficacia de los inhibidores selectivos de recaptación de serotonina en síntomas no cognitivos del alzhéimer: revisión sistemática

Introducción: El Alzhéimer tiene una prevalencia de 1,6% en las personas mayores de 65 años. Se caracteriza por la pérdida de memoria y otras funciones cognoscitivas, pero más del 70% de los afectados presentan síntomas no cognitivos entre los que se encuentran alteraciones del afecto, comportamiento y psicosis. Estos síntomas están asociados a mayores tasas de institucionalización, morbilidad y mortalidad. Métodos: Revisión sistemática de la literatura de artículos que proporcionaron información sobre la eficacia de los inhibidores selectivos de recaptación de serotonina en síntomas no cognitivos del Alzhéimer. Resultados: La búsqueda inicial arrojó un total de 495 resultados, 64 artículos fueron preseleccionados y 7 se incluyeron en la revisión; éstos se clasificaron como nivel de evidencia Ib; citalopram mostró ser más eficaz que el placebo y similar a antipsicóticos para síntomas comportamentales y psicóticos asociados al Alzhéimer con un perfil de efectos adversos más tolerable; sertralina no mostró eficacia en depresión y sí una mayor incidencia de efectos adversos con respecto al placebo. Discusión: Se obtuvieron resultados favorables en síntomas comportamentales y psicóticos pero no en afectivos. Las diferencias metodológicas de los estudios le dan complejidad a la interpretación de los resultados. Conclusión: La evidencia sugiere que el tratamiento con citalopram es eficaz en síntomas comportamentales y psicóticos asociados al Alzhéimer; para el tratamiento de la depresión asociado a esta demencia aún no existe un antidepresivo que pueda considerarse de elección.

Concediendo una subvención de 47.942,15 pesetas para el Instituto Católico de Arte e Industrias de Madrid, (I.C.A.I.).

Comunicación de la concesión de una subvención por un importe de 47.942,15 pesetas a favor del Instituto Católico de Artes e Industrias de Madrid, con cargo a los presupuestos del Ministerio de Educación Nacional.