Methyltrioxorhenium catalysed synthesis of highly oxidised aryltetralin lignans with anti-topoisomerase II and apoptogenic activities

A novel and efficient procedure to prepare highly oxidised aryltetralin lignans, such as isopodophyllotoxone and (-)-aristologone derivatives, by oxidation of podophyllotoxin and galbulin with methylrhenium trioxide (MTO) and novel MTO heterogeneous catalysts is reported. It is noteworthy that in the case of isopodophyllotoxone derivatives the functionalisation of the C-4 position of the C-ring and the ring-opening of the D-lactone moiety increased the activity against topoisomerase II while causing the undesired inhibition of tubulin polymerisation to disappear. The novel (-)-aristologone derivatives showed apoptogenic activity against resistant human lymphoma cell lines.L'articolo è disponibile sul sito dell'editore: http://www.sciencedirect.co

Effects of bone marrow mesenchymal stem cells (BM-MSCs) on rat pial microvascular remodeling after transient middle cerebral artery occlusion

Previous studies have shown that the pial microcirculation remodeling improves neurological outcome after middle cerebral artery occlusion (MCAO), accompanied by higher expression of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS), modulating in vivo angiogenesis. This study was aimed to assess the effects of bone marrow mesenchymal stem cells (BM-MSCs) infused after MCAO on rat pial microcirculation. Animals were subjected to 2 h MCAO followed by BM-MSCs infusion into internal carotid artery. Pial microcirculation was observed at different reperfusion times by fluorescence microscopy. Geometric characteristics of arteriolar networks, permeability increase, leukocyte adhesion, perfused capillary density, VEGF, and endothelial nitric oxide synthase (e-NOS) expression were evaluated. Green fluorescent protein (GFP)-BM-MSCs were used to evaluate their distribution and cell phenotype development during reperfusion. BM-MSCs stimulated a geometric rearrangement of pial networks with formation of new anastomotic vessels sprouting from preexistent arterioles in the penumbra at 7-14-28 days of reperfusion. At the same time VEGF and eNOS expression increased. GFP-BM-MSCs appear to be involved in endothelial and smooth muscle cell programming in the infarcted area. In conclusion, transient MCAO induced pial vascular remodeling characterized by arteriolar anastomotic arcades (originated from preexistent arterioles in penumbra area) able to overlap the ischemic core supplying blood to the neuronal tissue. BM-MSCs appear to accelerate angiogenic processes facilitating new vessel formation; this mechanism was promoted by an increase in VEGF and eNOS expression

Palytoxin and an Ostreopsis Toxin Extract Increase the Levels of mRNAs Encoding Inflammation-Related Proteins in Human Macrophages via p38 MAPK and NF-κB

BACKGROUND: Palytoxin and, likely, its analogues produced by the dinoflagellate genus Ostreopsis, represent a class of non-proteinaceous compounds displaying high toxicity in animals. Owing to the wide distribution and the poisonous effects of these toxins in humans, their chemistry and mechanism of action have generated a growing scientific interest. Depending on the exposure route, palytoxin and its Ostreopsis analogues may cause several adverse effects on human health, including acute inflammatory reactions which seem more typical of cutaneous and inhalation contact. These observations have led us to hypothesize that these toxins may activate pro-inflammatory signalling cascades. METHODOLOGY AND PRINCIPAL FINDINGS: Here we demonstrate that palytoxin and a semi-purified Ostreopsis cf. ovata toxin extract obtained from a cultured strain isolated in the NW Adriatic Sea and containing a putative palytoxin and all the ovatoxins so far known--including the recently identified ovatoxin-f--significantly increase the levels of mRNAs encoding inflammation-related proteins in immune cells, i.e. monocyte-derived human macrophages, as assessed by Real-Time PCR analysis. Western immunoblot and electrophoretic mobility shift assays revealed that nuclear transcription factor -κB (NF-κB) is activated in cells exposed to toxins in coincidence with reduced levels of the inhibitory protein IκB-α. Moreover, Mitogen-Activated Protein Kinases (MAPK) were phosphorylated in response to palytoxin, as also reported by others, and to the Ostreopsis toxin extract, as shown here for the first time. By using specific chemical inhibitors, the involvement of NF-κB and p38 MAPK in the toxin-induced transcription and accumulation of Cycloxigenase-2, Tumor Necrosis Factor-α, and Interleukin-8 transcripts has been demonstrated. CONCLUSIONS AND SIGNIFICANCE: The identification of specific molecular targets of palytoxin and its Ostreopsis analogues, besides contributing to expand the still limited knowledge of the intracellular signalling cascades affected by these toxins, may have important implications in setting up focused pharmacological interventions, replacing currently used symptomatic treatments

Dynamics of the transcriptional landscape during human fetal testis and ovary development

Acknowledgements We thank all members of the SEQanswers forums for helpful advice; Steven Salzberg and Cole Trapnell for continuous support with the ‘Tuxedo’ suite; and the UCSC Genome team members. Sequencing was performed by the GenomEast platform, a member of the ‘France Génomique’ consortium (ANR-10-INBS-0009). We thank Ms Linda Robertson, Ms Margaret Fraser, Ms Samantha Flannigan (University of Aberdeen) and the staff at Grampian NHS Pregnancy Counselling Service and all the staff of the Department of Obstetrics and Gynecology of the Rennes Sud Hospital for their expert assistance and help, and the participating women, without whom this study would not have been possible. The authors are grateful for Ms Gersende Lacombe and Mr Laurent Deleurme from the Biosit CytomeTri cytometry core facility of Rennes 1 University. Funding French National Institute of Health and Medical Research (Inserm); University of Rennes 1; French School of Public Health (EHESP); Swiss National Science Foundation [SNF n° CRS115_171007 to B.J.]; the French National Research Agency [ANR n° 16-CE14-0017-02 and n°18-CE14-0038-02 to F.C]; Medical Research Council [MR/L010011/1 to PAF]; European Community’s Seventh Framework Programme (FP7/2007–2013) [under grant agreement no 212885 to PAF]; European Union’s Horizon 2020 Research and Innovation Programme [under grant agreement no 825100 to P.A.F. and S.M.G.].Peer reviewedPostprin

Clamídia e infertilidade feminina: uma revisão abrangente da epidemiologia e implicações clínicas

A clamídia, causada pela bactéria Chlamydia trachomatis, é uma das infecções sexualmente transmissíveis mais prevalentes em todo o mundo. Sua associação com a infertilidade feminina é uma preocupação significativa de saúde pública, exigindo uma compreensão abrangente dos mecanismos subjacentes e estratégias de prevenção eficazes. Este estudo teve como objetivo investigar a epidemiologia da clamídia, os mecanismos pelos quais ela pode levar à infertilidade feminina, bem como o impacto desta infecção na saúde reprodutiva das mulheres. Foi realizada uma revisão abrangente da literatura científica disponível sobre clamídia e infertilidade feminina, utilizando bases de dados eletrônicas como PubMed, Scielo e LILACS. A revisão revelou uma alta prevalência de clamídia entre mulheres em idade reprodutiva e uma associação significativa com a infertilidade. Mecanismos patogênicos incluem inflamação crônica, lesões tubárias e disfunção ovariana. A detecção precoce é essencial para evitar danos irreversíveis à fertilidade. A clamídia representa uma importante causa de infertilidade feminina, destacando a necessidade de programas de rastreamento e intervenções precoces para prevenir complicações reprodutivas. Estratégias de prevenção, como educação sobre saúde sexual são fundamentais para reduzir a incidência dessa infecção. Além disso, são necessárias pesquisas contínuas para melhorar os métodos de diagnóstico, tratamento e prevenção da clamídia e suas complicações relacionadas à fertilidade

Sucessão familiar: os desafios ao longo das gerações / Family succession: the challenges throughout the generations

As empresas familiares, na sua grande maioria, começam suas atividades de forma bem pequena. Apresentam, inicialmente, poucos produtos, serviços e funcionários, e não possuem estrutura física e nem financeira estável. Porém, com o passar dos anos suas atividades atingem certo sucesso, e com o crescimento econômico das mesmas, há uma forte necessidade de melhoramento estrutural e profissional dos envolvidos, o que é fundamental para a continuidade da vida financeira de qualquer empresa. Portanto, o objetivo deste artigo é identificar quais foram às principais dificuldades encontradas no processo sucessório para o antecessor e sucessor de uma empresa familiar?  Foram realizadas entrevistas com cinco empresas familiares de Venda Nova do Imigrante, com aplicação de um questionário aos antecessores e sucessores da empresa, para avaliar suas dificuldades neste processo e as devidas contribuições. As principais dificuldades encontradas no processo de sucessão na visão do antecessor foram o medo da inovação e a dificuldade em acompanhar o raciocínio dos filhos

Preservação da fertilidade em oncologia: uma necessidade cada vez mais premente

A preservação da fertilidade em pacientes oncológicas tornou-se um tema de grande importância devido aos avanços no tratamento do câncer, que aumentaram significativamente a sobrevida dessas pacientes. Muitos dos tratamentos utilizados, como a quimioterapia e a radioterapia, podem causar danos aos ovários e reduzir a fertilidade. Portanto, é fundamental oferecer opções de preservação da fertilidade a essas pacientes antes do início do tratamento oncológico. O objetivo deste estudo foi revisar as principais estratégias de preservação da fertilidade em pacientes oncológicas, avaliando sua eficácia e segurança, bem como discutir as questões éticas e psicossociais relacionadas a esse tema. Foi realizada uma revisão sistemática da literatura através de estudos atualizados sobre preservação da fertilidade em pacientes oncológicas, incluindo estudos clínicos, revisões sistemáticas e diretrizes de sociedades médicas relevantes. Foram utilizadas bases de dados eletrônicas, como PubMed, Scielo e Lilacs, através de termos relacionados à infertilidade e oncologia. As estratégias de preservação da fertilidade em pacientes oncológicas têm demonstrado ser eficazes na manutenção da fertilidade e na melhoria da qualidade de vida dessas pacientes. A criopreservação de óvulos e embriões tem se mostrado segura e eficaz, permitindo que as pacientes realizem tratamentos de reprodução assistida após a conclusão do tratamento oncológico. Além disso, a utilização de inibidores da função ovariana durante a quimioterapia e a transposição dos ovários para um local fora do campo de irradiação durante radioterapia pélvica têm se mostrado também uma opção viável. A preservação da fertilidade em pacientes oncológicas é uma necessidade cada vez mais premente, pois permite que essas pacientes tenham a oportunidade de realizar o sonho da maternidade após o tratamento do câncer. Portanto, é fundamental que os profissionais de saúde estejam atentos a essa questão e ofereçam opções de preservação da fertilidade a todas as pacientes em idade fértil que serão submetidas a tratamento oncológico

Evaluation of individual and ensemble probabilistic forecasts of COVID-19 mortality in the United States

Short-term probabilistic forecasts of the trajectory of the COVID-19 pandemic in the United States have served as a visible and important communication channel between the scientific modeling community and both the general public and decision-makers. Forecasting models provide specific, quantitative, and evaluable predictions that inform short-term decisions such as healthcare staffing needs, school closures, and allocation of medical supplies. Starting in April 2020, the US COVID-19 Forecast Hub (https://covid19forecasthub.org/) collected, disseminated, and synthesized tens of millions of specific predictions from more than 90 different academic, industry, and independent research groups. A multimodel ensemble forecast that combined predictions from dozens of groups every week provided the most consistently accurate probabilistic forecasts of incident deaths due to COVID-19 at the state and national level from April 2020 through October 2021. The performance of 27 individual models that submitted complete forecasts of COVID-19 deaths consistently throughout this year showed high variability in forecast skill across time, geospatial units, and forecast horizons. Two-thirds of the models evaluated showed better accuracy than a naïve baseline model. Forecast accuracy degraded as models made predictions further into the future, with probabilistic error at a 20-wk horizon three to five times larger than when predicting at a 1-wk horizon. This project underscores the role that collaboration and active coordination between governmental public-health agencies, academic modeling teams, and industry partners can play in developing modern modeling capabilities to support local, state, and federal response to outbreaks

The United States COVID-19 Forecast Hub dataset

Academic researchers, government agencies, industry groups, and individuals have produced forecasts at an unprecedented scale during the COVID-19 pandemic. To leverage these forecasts, the United States Centers for Disease Control and Prevention (CDC) partnered with an academic research lab at the University of Massachusetts Amherst to create the US COVID-19 Forecast Hub. Launched in April 2020, the Forecast Hub is a dataset with point and probabilistic forecasts of incident cases, incident hospitalizations, incident deaths, and cumulative deaths due to COVID-19 at county, state, and national, levels in the United States. Included forecasts represent a variety of modeling approaches, data sources, and assumptions regarding the spread of COVID-19. The goal of this dataset is to establish a standardized and comparable set of short-term forecasts from modeling teams. These data can be used to develop ensemble models, communicate forecasts to the public, create visualizations, compare models, and inform policies regarding COVID-19 mitigation. These open-source data are available via download from GitHub, through an online API, and through R packages