Structure of human Cdc45 and implications for CMG helicase function.

Cell division cycle protein 45 (Cdc45) is required for DNA synthesis during genome duplication, as a component of the Cdc45-MCM-GINS (CMG) helicase. Despite its essential biological function, its biochemical role in DNA replication has remained elusive. Here we report the 2.1-Å crystal structure of human Cdc45, which confirms its evolutionary link with the bacterial RecJ nuclease and reveals several unexpected features that underpin its function in eukaryotic DNA replication. These include a long-range interaction between N- and C-terminal DHH domains, blocking access to the DNA-binding groove of its RecJ-like fold, and a helical insertion in its N-terminal DHH domain, which appears poised for replisome interactions. In combination with available electron microscopy data, we validate by mutational analysis the mechanism of Cdc45 association with the MCM ring and GINS co-activator, critical for CMG assembly. These findings provide an indispensable molecular basis to rationalize the essential role of Cdc45 in genomic duplication.We would like to thank Ben Luisi for help with X-ray data collection, Alessandro Costa for sharing the cryoEM data of the CMG complex before publication and Joseph Maman for help with the analysis of Cdc45-DNA interactions. This work was supported by a Wellcome Trust Senior Investigator award to LP (104641/Z/14/Z) and a Cambridge Gates PhD scholarship to ACS. VC is funded by the Associazione Italiana per Ricerca sul Cancro (AIRC), the European Research Council (ERC) consolidator grant (614541), the Association for International Cancer Research (AICR), the Giovanni-Armenise award to VC, the Epigen Progetto Bandiera and the Fondazione Telethon.This is the final version of the article. It first appeared from Nature via https://doi.org/10.1038/ncomms1163

Do isolacionismo ao intervencionismo: a participação dos Estados Unidos nas grandes guerras mundiais do século XX (1914 – 1944)

A influência norte-americana se dá praticamente em todo o sistema internacional. Para que os norte-americanos chegassem a essa posição, utilizaram, desde o final da Segunda Guerra Mundial, diversas ferramentas que lhes deram a oportunidade de obter e, posteriormente, consolidar sua capacidade de impor seus interesses sobre todo o sistema internacional, o que denota a habilidade do país na formação de novas diretrizes de poder. A potência passou por um longo processo de expansão, sobretudo no período entre guerras e durante a Segunda Guerra Mundial, que lhe permitiu emergir do conflito mundial com indeléveis vantagens em relação aos países da Europa. O objetivo deste artigo é analisar a participação dos EUA nos dois conflitos mundiais e como se deu a passagem de sua atuação de cenário internacional do isolacionismo para o intervencionismo

Processo decisório em política externa comercial : uma análise sobre a atuação do Brasil nas negociações agrícolas das rodadas Uruguai e Doha (1986-1990/2003-2008)

Orientador: Prof. Dr. Fabrício Ricardo de Limas TomioTese (doutorado) - Universidade Federal do Paraná, Setor de Ciências Humanas, Programa de Pós-Graduação em Ciência Política. Defesa : Curitiba, 30/11/2020Inclui referências: p. 142-148Resumo: Esta Tese de Doutorado tem como objetivo analisar, comparativamente, o processo decisório que delineou a atuação do Brasil nas negociações agrícolas do Sistema Multilateral de Comércio na Rodada Uruguai (1986-1990) e na Rodada Doha (2003-2008). Empregando-se o process tracing, buscar-se-á avaliar o papel do Ministério das Relações Exteriores e sua interação com os demais atores, nos dois momentos. Buscar-se-á responder se as mudanças ocasionadas nas estruturas políticas domésticas, a partir do processo de redemocratização, afetaram o papel da diplomacia na condução da política externa e como isso impactou na participação dos demais atores. Levanta-se a hipótese que, apesar de essas mudanças terem permitido o aumento da porosidade do MRE à participação de outros atores, tanto de outros órgãos do Governo como da sociedade civil interessada, o Ministério de Relações Exteriores continua sendo o ator central e que detém a palavra final processo decisório. Ou seja, a abertura a outros atores não implica na diminuição do seu peso no processo decisório. Palavras-Chave: Política Externa Comercial. Processo Decisório. Ministério de Relações Exteriores. Atores.Abstract: This Thesis aims to analyze, comparatively, the decision-making process that outlined Brazil's performance in the agricultural negotiations of the Multilateral Trade System in the Uruguay Round (1986-1990) and in the Doha Round (2003-2008). Using process tracing, the research will seek to evaluate the role of Itamaraty and its interaction with other actors, at both times. The main question is whether the changes brought about in domestic political structures, from the process of redemocratization, affected the role of diplomacy in the conduct of foreign policy and how it impacted the participation of other actors. The hypothesis raised is that, although these changes allowed the increase in the porosity of the MRE to the participation of other actors, both from Government structure and from civil society, Itamaraty remains the central actor and holds the final decision. In other words, openness to other actors does not imply a decrease in its weight in the decision-making process. Keywords: Foreign Trade Policy. Decision-Making Process. Itamaraty. Actors

0098: Erythrocyte membrane phospholipid fatty acids, dairy intakes and cardiovascular risk

IntroductionThe impact of dairy fats on cardiovascular risk has been debated. Circulating Pentadecanoic (15:0) and heptadecanoic (17:0) saturated fatty acids are good biomarkers of dairy product consumption as they are mainly provided by dairy fats. We described the prevalence of cardiovascular risk factors according to erythrocyte membrane phospholipid content in 15:0 and 17:0 fatty acids.Methods402 women and men aged 45-64 were randomly selected in 2005-2007, from the general population of three French areas. Nutritional data were collected through a 3-day food record. Fatty acid content was measured in erythrocyte membrane phospholipids.ResultsErythrocyte membrane contents in 15:0 and 17:0 fatty acids significantly increased with the consumption of dairy products collected during the 3-day food record. Prevalence of hypertension significantly decreased from the lowest to the highest quartile of 15:0 erythrocyte content (48.1%; 33.3%; 29.9%; 25.5%; p=0.005). A similar trend was observed for metabolic syndrome prevalence (39.4%; 28.1%; 25.2%; 21.3%; p=0.029). Prevalence of hypertension, hypertriglyceridaemia, overweight and metabolic syndrome significantly decreased from the lowest to the highest quartile of 17:0 erythrocyte content (44.1%; 36.5%; 28.1%; 25.6%; p=0.020 for hypertension; 30.3%; 15.4%; 16.9%; 16.7%; p=0.017 for hypertriglyceridaemia; 68.1%; 58.7%; 46.6%; 44.4%; p=0.002 for overweight; and 43.2%; 26.9%; 22.5%; 17.8%; p<0.001 for metabolic syndrome). All these relationships remained significant after adjustment for age and gender. The link did not reach significance level for diabetes.ConclusionElevated erythrocyte membrane phospholipid contents in 15:0 and 17:0 saturated fatty acids are associated with a lower prevalence of the metabolic syndrome and several of its components. These results suggest that saturated fat intake should not be systematically associated with high cardiovascular risk and can be considered as part of a balanced diet

Association of HPA axis-related genetic variation with stress reactivity and aggressive behaviour in pigs

<p>Abstract</p> <p>Background</p> <p>Stress, elicited for example by aggressive interactions, has negative effects on various biological functions including immune defence, reproduction, growth, and, in livestock, on product quality. Stress response and aggressiveness are mutually interrelated and show large interindividual variation, partly attributable to genetic factors. In the pig little is known about the molecular-genetic background of the variation in stress responsiveness and aggressiveness. To identify candidate genes we analyzed association of DNA markers in each of ten genes (<it>CRH </it>g.233C>T, <it>CRHR1 </it>c.*866_867insA, <it>CRHBP </it>c.51G>A, <it>POMC </it>c.293_298del, <it>MC2R </it>c.306T>G, <it>NR3C1 </it>c.*2122A>G, <it>AVP </it>c.207A>G, <it>AVPR1B </it>c.1084A>G, <it>UCN </it>g.1329T>C, <it>CRHR2 </it>c.*13T>C) related to the hypothalamic-pituitary-adrenocortical (HPA) axis, one of the main stress-response systems, with various stress- and aggression-related parameters at slaughter. These parameters were: physiological measures of the stress response (plasma concentrations of cortisol, creatine kinase, glucose, and lactate), adrenal weight (which is a parameter reflecting activity of the central branch of the HPA axis over time) and aggressive behaviour (measured by means of lesion scoring) in the context of psychosocial stress of mixing individuals with different aggressive temperament.</p> <p>Results</p> <p>The SNP <it>NR3C1 </it>c.*2122A>G showed association with cortisol concentration (p = 0.024), adrenal weight (p = 0.003) and aggressive behaviour (front lesion score, p = 0.012; total lesion score p = 0.045). The SNP <it>AVPR1B </it>c.1084A>G showed a highly significant association with aggressive behaviour (middle lesion score, p = 0.007; total lesion score p = 0.003). The SNP <it>UCN </it>g.1329T>C showed association with adrenal weight (p = 0.019) and aggressive behaviour (front lesion score, p = 0.029). The SNP <it>CRH </it>g.233C>T showed a significant association with glucose concentration (p = 0.002), and the polymorphisms <it>POMC </it>c.293_298del and <it>MC2R </it>c.306T>G with adrenal weight (p = 0.027 and p < 0.0001 respectively).</p> <p>Conclusions</p> <p>The multiple and consistent associations shown by SNP in <it>NR3C1 </it>and <it>AVPR1B </it>provide convincing evidence for genuine effects of their DNA sequence variation on stress responsiveness and aggressive behaviour. Identification of the causal functional molecular polymorphisms would not only provide markers useful for pig breeding but also insight into the molecular bases of the stress response and aggressive behaviour in general.</p