Association between anthropometry and lifestyle factors and risk of B cell lymphoma: an exposome wide analysis.

To better understand the role of individual and lifestyle factors in human disease, an exposome-wide association study was performed to investigate within a single study anthropometry measures and lifestyle factors previously associated with B-cell lymphoma (BCL). Within the European Prospective Investigation into Cancer and nutrition study, 2,402 incident BCL cases were diagnosed from 475,426 participants that were followed-up on average 14 years. Standard and penalized Cox regression models as well as principal component (PC) analysis were used to evaluate 84 exposures in relation to BCL risk. Standard and penalized Cox regression models showed a positive association between anthropometric measures and BCL and multiple myeloma/plasma cell neoplasm (MM). The penalized Cox models additionally showed the association between several exposures from categories of physical activity, smoking status, medical history, socioeconomic position, and diet and BCL and/or the subtypes. PC analyses confirmed the individual associations but also showed additional observations. The PC5 including anthropometry, was positively associated with BCL, diffuse large B-cell lymphoma (DLBCL), and MM. There was a significant positive association between consumption of sugar and confectionary (PC11) and follicular lymphoma risk, and an inverse association between fish and shellfish and Vitamin D (PC15) and DLBCL risk. The PC1 including features of the Mediterranean diet and diet with lower inflammatory score showed an inverse association with BCL risk, while the PC7, including dairy, was positively associated with BCL and DLBCL risk. Physical activity (PC10) was positively associated with DLBCL risk among women. This study provided informative insights on the etiology of BCL

Expression analysis of the long non-coding RNA antisense to Uchl1 (AS Uchl1) during dopaminergic cells' differentiation in vitro and in neurochemical models of Parkinson's disease

Antisense (AS) transcripts are RNA molecules that are transcribed from the opposite strand to sense (S) genes forming S/AS pairs. The most prominent configuration is when a lncRNA is antisense to a protein coding gene. Increasing evidences prove that antisense transcription may control sense gene expression acting at distinct regulatory levels. However, its contribution to brain function and neurodegenerative diseases remains unclear. We have recently identified AS Uchl1 as an antisense to the mouse Ubiquitin carboxy-terminal hydrolase L1 (Uchl1) gene (AS Uchl1), the synthenic locus of UCHL1/PARK5. This is mutated in rare cases of early-onset familial Parkinson's Disease (PD) and loss of UCHL1 activity has been reported in many neurodegenerative diseases. Importantly, manipulation of UchL1 expression has been proposed as tool for therapeutic intervention. AS Uchl1 induces UchL1 expression by increasing its translation. It is the representative member of SINEUPs (SINEB2 sequence to UP-regulate translation), a new functional class of natural antisense lncRNAs that activate translation of their sense genes. Here we take advantage of FANTOM5 dataset to identify the transcription start sites associated to S/AS pair at Uchl1 locus. We show that AS Uchl1 expression is under the regulation of Nurr1, a major transcription factor involved in dopaminergic cells' differentiation and maintenance. Furthermore, AS Uch1 RNA levels are strongly down-regulated in neurochemical models of PD in vitro and in vivo. This work positions AS Uchl1 RNA as a component of Nurr1-dependent gene network and target of cellular stress extending our understanding on the role of antisense transcription in the brain

Prediction of cis-regulatory elements controlling genes differentially expressed by retinal and choroidal vascular endothelial cells

Cultured endothelial cells of the human retina and choroid demonstrate distinct patterns of gene expression. We hypothesized that differential gene expression reflected differences in the interactions of transcription factors and respective cis-regulatory motifs(s) in these two endothelial cell subpopulations, recognizing that motifs often exist as modules. We tested this hypothesis in silico by using TRANSFAC Professional and CisModule to identify cis-regulatory motifs and modules in genes that were differentially expressed by human retinal versus choroidal endothelial cells, as identified by analysis of a microarray data set. Motifs corresponding to eight transcription factors were significantly (p < 0.05) differentially abundant in genes that were relatively highly expressed in retinal (i.e., glucocorticoid receptor, high mobility group AT-hook 1, heat shock transcription factor 1, p53, vitamin D receptor) or choroidal (i.e., transcription factor E2F, Yin Yang 1, zinc finger 5) endothelial cells. Predicted cis-regulatory modules were quite different for these two groups of genes. Our findings raise the possibility of exploiting specific cis-regulatory motifs to target therapy at the ocular endothelial cells subtypes responsible for neovascular age-related macular degeneration or proliferative diabetic retinopathy

Ações de Prevenção da Deficiência Mental, dirigidas a Gestantes e Recém-Nascidos, no âmbito da Saúde Pública da Grande Vitória-ES

The accomplishment of prevention in Public Health requires a systematized knowledge for the proposition of a program and its evaluation. When it comes to the prevention of Mental Deficiency, which afflicts around 10% of the population, little is known in Brazil. By adopting a methodology for cataloging MD preventive actions in hospitals and health units, with pregnant women and newborns, it was possible to describe and analyze the actions of the public health system in Greater Vitoria/ES, indicating the levels of prevention which were most covered. Preventive actions (PA) of five large public hospitals, nine health units and six health offices, from 1996 to 1997 were studied. Data from 25 interviews show that these places made 51.5% of the 433 possible PA (57.4% of primary prevention and 45.5% of the secondary). Along with the particularization of the action of each municipality and place researched, the obtained data was useful for analyses and possible changes in maternal-infantile health indicators.Faire de la prévention dans la santé publique est conditionné par une très bonne connaissance afin de proposer des programmes et les évaluer. Au Brésil, on sait peu de choses sur la prévention de la déficience mentale, qui atteint pourtant 10 % de la population. Adoptant une méthodologie et pour faire un catalogue des actions préventives de déficience mentale dans les hôpitaux et les unités de santé, pour les femmes enceintes et les nouveau-nés, on a pu décrire et analyser les actions de santé publique dans la ville de Grande Vitoria (État du Espirito Santo), indiquant le niveau de prévention les plus couverts. On a regroupé les actions de prévention de cinq hôpitaux publics importants, neuf (31 %) unités de santé et six bureaux centralisateurs, entre 1996 et 97. Les données de vingt-cinq entrevues montrent que ces locaux réalisent 51,5 % des 433 actions de prévention possibles (57,4 % de prévention primaire et 45,5 % de secondaire). En détaillant les réalisations de chaque municipalité et local étudié, les chiffres fournissent des ressources pour des analyses et les modifications possibles dans les indicateurs de santé maternelle et infantile.Fazer prevenção em Saúde Pública implica em conhecimento sistematizado para a proposição de programas e sua avaliação. Quanto à prevenção de Deficiência Mental, que atinge cerca de 10% da população, pouco se conhece no país. Adotando uma metodologia para levantamento de ações preventivas de DM em hospitais e unidades de saúde, junto a gestantes e recém-nascidos, fo i possível descrever e analisar a atuação da rede pública de saúde da Grande Vitória/ES, indicando os níveis de prevenção mais atendidos. Foram levantadas as ações de prevenção (AP) de cinco hospitais públicos de grande porte, nove (31%) unidades de saúde e seis secretarias de saúde, entre 1996-97. Os dados de 25 entrevistas mostram que esses locais realizavam 51,5% das 433 AP possíveis (57,4% da prevenção primária e 45,5% da secundária). Particularizando a atuação de cada município e local pesquisado, os dados fornecem subsídios para análises e possíveis mudanças nos indicadores de saúde materno-infantil

Comparative genomics of small RNA regulatory pathway components in vector mosquitoes

<p>Abstract</p> <p>Background</p> <p>Small RNA regulatory pathways (SRRPs) control key aspects of development and anti-viral defense in metazoans. Members of the Argonaute family of catalytic enzymes degrade target RNAs in each of these pathways. SRRPs include the microRNA, small interfering RNA (siRNA) and PIWI-type gene silencing pathways. Mosquitoes generate viral siRNAs when infected with RNA arboviruses. However, in some mosquitoes, arboviruses survive antiviral RNA interference (RNAi) and are transmitted via mosquito bite to a subsequent host. Increased knowledge of these pathways and functional components should increase understanding of the limitations of anti-viral defense in vector mosquitoes. To do this, we compared the genomic structure of SRRP components across three mosquito species and three major small RNA pathways.</p> <p>Results</p> <p>The <it>Ae. aegypti, An. gambiae </it>and <it>Cx. pipiens </it>genomes encode putative orthologs for all major components of the miRNA, siRNA, and piRNA pathways. <it>Ae. aegypti </it>and <it>Cx. pipiens </it>have undergone expansion of Argonaute and PIWI subfamily genes. Phylogenetic analyses were performed for these protein families. In addition, sequence pattern recognition algorithms MEME, MDScan and Weeder were used to identify upstream regulatory motifs for all SRRP components. Statistical analyses confirmed enrichment of species-specific and pathway-specific cis-elements over the rest of the genome.</p> <p>Conclusion</p> <p>Analysis of Argonaute and PIWI subfamily genes suggests that the small regulatory RNA pathways of the major arbovirus vectors, <it>Ae. aegypti and Cx. pipiens</it>, are evolving faster than those of the malaria vector <it>An. gambiae </it>and <it>D. melanogaster</it>. Further, protein and genomic features suggest functional differences between subclasses of PIWI proteins and provide a basis for future analyses. Common UCR elements among SRRP components indicate that 1) key components from the miRNA, siRNA, and piRNA pathways contain NF-kappaB-related and Broad complex transcription factor binding sites, 2) purifying selection has occurred to maintain common pathway-specific elements across mosquito species and 3) species-specific differences in upstream elements suggest that there may be differences in regulatory control among mosquito species. Implications for arbovirus vector competence in mosquitoes are discussed.</p

The Cardiac Transcription Network Modulated by Gata4, Mef2a, Nkx2.5, Srf, Histone Modifications, and MicroRNAs

The transcriptome, as the pool of all transcribed elements in a given cell, is regulated by the interaction between different molecular levels, involving epigenetic, transcriptional, and post-transcriptional mechanisms. However, many previous studies investigated each of these levels individually, and little is known about their interdependency. We present a systems biology study integrating mRNA profiles with DNA–binding events of key cardiac transcription factors (Gata4, Mef2a, Nkx2.5, and Srf), activating histone modifications (H3ac, H4ac, H3K4me2, and H3K4me3), and microRNA profiles obtained in wild-type and RNAi–mediated knockdown. Finally, we confirmed conclusions primarily obtained in cardiomyocyte cell culture in a time-course of cardiac maturation in mouse around birth. We provide insights into the combinatorial regulation by cardiac transcription factors and show that they can partially compensate each other's function. Genes regulated by multiple transcription factors are less likely differentially expressed in RNAi knockdown of one respective factor. In addition to the analysis of the individual transcription factors, we found that histone 3 acetylation correlates with Srf- and Gata4-dependent gene expression and is complementarily reduced in cardiac Srf knockdown. Further, we found that altered microRNA expression in Srf knockdown potentially explains up to 45% of indirect mRNA targets. Considering all three levels of regulation, we present an Srf-centered transcription network providing on a single-gene level insights into the regulatory circuits establishing respective mRNA profiles. In summary, we show the combinatorial contribution of four DNA–binding transcription factors in regulating the cardiac transcriptome and provide evidence that histone modifications and microRNAs modulate their functional consequence. This opens a new perspective to understand heart development and the complexity cardiovascular disorders