The intranuclear mobility of messenger RNA binding proteins is ATP dependent and temperature sensitive

fAter being released from transcription sites, messenger ribonucleoprotein particles (mRNPs) must reach the nuclear pore complexes in order to be translocated to the cytoplasm. Whether the intranuclear movement of mRNPs results largely from Brownian motion or involves molecular motors remains unknown. Here we have used quantitative photobleaching techniques to monitor the intranuclear mobility of protein components of mRNPs tagged with GFP. The results show that the diffusion coefficients of the poly(A)-binding protein II (PABP2) and the export factor TAP are significantly reduced when these proteins are bound to mRNP complexes, as compared with nonbound proteins. The data further show that the mobility of wild-type PABP2 and TAP, but not of a point mutant variant of PABP2 that fails to bind to RNA, is significantly reduced when cells are ATP depleted or incubated at 22°C. Energy depletion has only minor effects on the intranuclear mobility of a 2,000-kD dextran (which corresponds approximately in size to 40S mRNP particles), suggesting that the reduced mobility of PABP2 and TAP is not caused by a general alteration of the nuclear environment. Taken together, the data suggest that the mobility of mRNPs in the living cell nucleus involves a combination of passive diffusion and ATP-dependent processes

Acesso a Tratamento Endovascular para Acidente Vascular Cerebral Isquémico em Portugal

Introduction: Since the publication of endovascular treatment trials and European Stroke Guidelines, Portugal has re-organized stroke healthcare. The nine centers performing endovascular treatment are not equally distributed within the country, which may lead to differential access to endovascular treatment. Our main aim was to perform a descriptive analysis of the main treatment metrics regarding endovascular treatment in mainland Portugal and its administrative districts. Material and Methods: A retrospective national multicentric cohort study was conducted, including all ischemic stroke patients treated with endovascular treatment in mainland Portugal over two years (July 2015 to June 2017). All endovascular treatment centers contributed to an anonymized database. Demographic, stroke-related and procedure-related variables were collected. Crude endovascular treatment rates were calculated per 100 000 inhabitants for mainland Portugal, and each district and endovascular treatment standardized ratios (indirect age-sex standardization) were also calculated. Patient time metrics were computed as the median time between stroke onset, first-door, and puncture. Results: A total of 1625 endovascular treatment procedures were registered. The endovascular treatment rate was 8.27/100 000 inhabitants/year. We found regional heterogeneity in endovascular treatment rates (1.58 to 16.53/100 000/year), with higher rates in districts closer to endovascular treatment centers. When analyzed by district, the median time from stroke onset to puncture ranged from 212 to 432 minutes, reflecting regional heterogeneity. Conclusion: The overall national rate of EVT in the first two years after the organization of EVT-capable centers is one of the highest among European countries, however, significant regional disparities were documented. Moreover, stroke-onset-to-first-door times and in-hospital procedural times in the EVT centers were comparable to those reported in the randomized controlled trials performed in high-volume tertiary hospitals.Introdução: A aprovação do tratamento endovascular para o acidente vascular cerebral isquémico obrigou à reorganização dos cuidados de saúde em Portugal. Os nove centros que realizam tratamento endovascular não estão distribuídos equitativamente pelo território, o que poderá causar acesso diferencial a tratamento. O principal objetivo deste estudo é realizar uma análise descritiva da frequência e métricas temporais do tratamento endovascular em Portugal continental e seus distritos. Material e Métodos: Estudo de coorte nacional multicêntrico, incluindo todos os doentes com acidente vascular cerebral isquémico submetidos a tratamento endovascular em Portugal continental durante um período de dois anos (julho 2015 a junho 2017). Foram colhidos dados demográficos, relacionados com o acidente vascular cerebral e variáveis do procedimento. Taxas de tratamento endovascular brutas e ajustadas (ajuste indireto a idade e sexo) foram calculadas por 100 000 habitantes/ano para Portugal continental e cada distrito. Métricas de procedimento como tempo entre instalação, primeira porta e punção foram também analisadas. Resultados: Foram registados 1625 tratamentos endovasculares, indicando uma taxa bruta nacional de tratamento endovascular de 8,27/100 000 habitantes/ano. As taxas de tratamento endovascular entre distritos variaram entre 1,58 e 16,53/100 000/ano, com taxas mais elevadas nos distritos próximos a hospitais com tratamento endovascular. O tempo entre sintomas e punção femural entre distritos variou entre 212 e 432 minutos. Conclusão: Portugal continental apresenta uma taxa nacional de tratamento endovascular elevada, apresentando, contudo, assimetrias regionais no acesso. As métricas temporais foram comparáveis com as observadas nos ensaios clínicos piloto

Duox1-derived H2O2 modulates Cxcl8 expression and neutrophil recruitment via JNK/c-JUN/AP-1 signaling and chromatin modifications

Les auteurs Angelo Calado et Victoriano Mulero sont co-derniers auteurs.International audienceDUOX1-derived hydrogen peroxide (H2O2) and CXCL8 are two key neutrophil chemoattractants. H2O2 is critical at the early phase, whereas CXCL8 plays a key role in the late phases of recruitment, but the crosstalks between the two phases in vivo remain unknown. In this study using zebrafish, we report that H2O2 also contributes to neutrophil recruitment to injuries at the late phase as it induces Cxcl8 expression in vivo through a JNK/c-JUN/AP-1 signaling pathway. However, Erk and NF-kappa B signaling were not involved in this crosstalk. Strikingly, H2O2 also promotes cxcl8 expression through modulation of histone 3 lysine 4 trimethylation, histone 3 lysine 9 acetylation, and histone 3 lysine 9 trimethylation levels at its promoter. These results explain how early H2O2 signal regulates neutrophil recruitment at all phases, directly via Lyn oxidation or indirectly by modulating cxcl8 gene expression, via the activation of redox-sensitive signaling pathways, and further point out H2O2/DUOX1 as a key drug target for anti-inflammatory therapies

Additional file 1 of An admission control mechanism for dynamic QoS-enabled opportunistic routing protocols

Complete dataset of normality and inference tests of the performed experiments. The additional file presents the complete description of evaluated scenarios, the complete dataset of Student’s t test and the complete dataset of inference statistical tests

Aqueous-Phase Catalytic Chemical Reduction of p-Nitrophenol Employing Soluble Gold Nanoparticles with Different Shapes

Gold nanoparticles with different shapes were prepared and used as catalysts in the reduction of p-nitrophenol (PNP) in the aqueous phase and in the presence of sodium borohydride (NaBH4). Parameters such as the reaction temperature, substrate/NaBH4 molar ratio, and substrate/gold molar ratio were tested and evaluated. In this paper, we compare the catalytic reactivities of gold nanorods (AuNRs) and gold nanospheres (AuNSs), both synthesized by the seed-mediated method in the presence of cetyltrimethyl ammonium bromide (CTAB). Physical-chemical parameters such as the apparent rate constant (kapp) and activation energy (Ea) of the reactions were obtained for both systems. We observed that the catalytic system based on AuNRs is the most active. These colloidal dispersions were investigated and fully characterized by ultraviolet-visible absorption spectroscopy (UV–Vis) and transmission electron microscopy (TEM)

Saúde bucal no Programa Saúde da Família: uma avaliação do modelo assistencial Oral health in the Brazilian Family Health Program: a health care model evaluation

O objetivo deste estudo foi avaliar a incorporação da saúde bucal no Programa Saúde da Família no Rio Grande do Norte, com base na análise de fatores capazes de interferir no processo de mudança dos modelos assistenciais em saúde bucal. Esta avaliação tomou como referência três dimensões: o acesso, a organização do trabalho e as estratégias de programação. Foram sorteados 19 municípios no estado. Os instrumentos de coleta foram a entrevista estruturada aplicada a gestores e dentistas, a observação estruturada e a pesquisa documental. Foi possível identificar precariedade nas relações de trabalho e dificuldades no referenciamento para média e alta complexidade, na intersetorialidade, no diagnóstico epidemiológico e na avaliação das ações. A maioria dos municípios apresentou pouco ou nenhum avanço no modelo assistencial em saúde bucal. Os municípios que demonstraram avanços apresentaram alta expectativa de vida ao nascer, baixas taxas de mortalidade infantil, valores per capita entre os mais altos do Estado e altos valores de IDH-M. Concluiu-se que políticas públicas que contemplam aspectos além dos pertinentes ao setor saúde são decisivas para uma real mudança nos modelos assistenciais.<br>The purpose of this study was to evaluate the addition of oral health teams to the Family Health Program in the State of Rio Grande do Norte, Brazil, by analyzing factors that can affect the process of changing oral health care models. The evaluation involved three dimensions: access, work organization, and planning strategies. 19 counties (municipalities) were randomly selected. The data collection instruments were: structured interviews with health managers and dentists, structured observation, and documental research. The study identified a lack of formal employment contracts for dentists, difficulty in referring patients for high-complexity procedures, and problems with the development of inter-sector activities, epidemiological diagnoses, and work evaluation. Most of the counties showed little or no improvement in oral health care. The counties that had improved their oral health care were the same ones with higher life expectancy, lower infant mortality rates, higher per capita income, and higher human development index (HDI). In conclusion, public policies that include aspects beyond the health sector are decisive for a real change in health care models

Perspective of the GEMSTONE Consortium on Current and Future Approaches to Functional Validation for Skeletal Genetic Disease Using Cellular, Molecular and Animal-Modeling Techniques

The availability of large human datasets for genome-wide association studies (GWAS) and the advancement of sequencing technologies have boosted the identification of genetic variants in complex and rare diseases in the skeletal field. Yet, interpreting results from human association studies remains a challenge. To bridge the gap between genetic association and causality, a systematic functional investigation is necessary. Multiple unknowns exist for putative causal genes, including cellular localization of the molecular function. Intermediate traits (“endophenotypes”), e.g. molecular quantitative trait loci (molQTLs), are needed to identify mechanisms of underlying associations. Furthermore, index variants often reside in non-coding regions of the genome, therefore challenging for interpretation. Knowledge of non-coding variance (e.g. ncRNAs), repetitive sequences, and regulatory interactions between enhancers and their target genes is central for understanding causal genes in skeletal conditions. Animal models with deep skeletal phenotyping and cell culture models have already facilitated fine mapping of some association signals, elucidated gene mechanisms, and revealed disease-relevant biology. However, to accelerate research towards bridging the current gap between association and causality in skeletal diseases, alternative in vivo platforms need to be used and developed in parallel with the current -omics and traditional in vivo resources. Therefore, we argue that as a field we need to establish resource-sharing standards to collectively address complex research questions. These standards will promote data integration from various -omics technologies and functional dissection of human complex traits. In this mission statement, we review the current available resources and as a group propose a consensus to facilitate resource sharing using existing and future resources. Such coordination efforts will maximize the acquisition of knowledge from different approaches and thus reduce redundancy and duplication of resources. These measures will help to understand the pathogenesis of osteoporosis and other skeletal diseases towards defining new and more efficient therapeutic targets