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Previous research suggests that providing information about the health effects of climate change and the health benefits of climate action can increase public engagement with the issue. We sought to extend those findings with an experiment to test the motivational value of calling attention to opponents of climate action. In February, 2022, we conducted a survey experiment with adults from the USA, quota-sampled to represent the USA population (n=2201). Participants were randomly assigned to a no-message control condition, or one of four message conditions identified as authored by concerned health professionals. These messages warned recipients about the negative effects of climate change on health, and either made no mention of an opponent to climate action, or were messages augmented by identifying one of three opponents: (1) fossil fuel chief executive officers and their lobbyists, (2) politicians, or (3) a combination of the two. Portrayal of opponents to climate action increased attitudinal engagement, support for mitigation policies, and intentions to advocate for climate solutions, compared with message conditions not identifying an opponent-with the combined opponent portrayal tending to result in the largest effects; these effects were evident with audiences across political lines, especially political conservatives. Climate and health messages-with or without portrayal of an opponent-also increased trust in the messengers relative to the no-message control. These findings suggest that identifying opponents to climate action can be advantageous to building support for such action, reducing political issue polarisation, and fostering greater trust in health professionals as climate messengers.

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Introduction: Although dengue is the most common arbovirus infection worldwide, studies of severe dengue in Africa are lacking, and risk factors for severe dengue have been insufficiently described. This study was conducted in the context of the 2016 dengue epidemic in Burkina Faso to determine the prevalence of severe dengue, identify factors associated with severe dengue, and perform mapping of dengue cases in the country's capital, Ouagadougou. Methods: This cross-sectional study was conducted from November 2015 to January 2017. Data were collected in 15 public and private health centres, and included sociodemographic, clinical and patient outcome variables. Dengue was diagnosed using SD Bioline Dengue Duo rapid diagnostic tests. Data were analysed using Epi-Info Version 7. Logistic regression was used to identify predictors of severe dengue. P<0.05 was considered significant. Dengue case mapping was performed using Geographic Information System software (ArcGIS). Results: Of the 811 patients who tested positive for dengue, 609 (75%) had early dengue (AgNS1 positive) and 272 (33.5%) had severe dengue. Patient age ranged from 1 to 83 years (median 30.5 years) and 393 (48.3%) were female. Renal failure (13.1%) and severe bleeding (10.6%) were the most common signs of severe dengue. Risk factors for severe dengue included age, male sex, haemoglobin S, diabetes, hypertension, and primary dengue. Dengue cases were more concentrated  in sectors located in the centre of the city and close to the health centres. Conclusion: Dengue is increasingly common in Africa and factors associated with severity should be sought systematically as soon as a patient tests positive. Additional studies are needed to determine if the factors found to be associated with severity can be used to identify patients at risk for dengue-related complications, and to provide early and specialized management to reduce morbidity and mortality related to dengue in Africa.

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Eukaryotic gene expression is tightly regulated during translation of mRNA to protein. Mis-regulation of translation can lead to aberrant proteins which accumulate in cancers and cause neurodegenerative diseases. Foundational studies on model genes established fundamental roles for mRNA 5' transcript leader (TL) sequences in controlling ribosome recruitment, scanning, and initiation. TL cis-regulatory elements and their corresponding trans-acting factors control cap-dependent initiation under unstressed conditions. Under stress, cap-dependent initiation is suppressed, and specific mRNA structures and sequences promote translation of stress-responsive transcripts to remodel the proteome. In this review, we summarize current knowledge of TL functions in translation initiation. We focus on insights from high-throughput analyses of ribosome occupancy, mRNA structure, RNA Binding Protein occupancy, and massively parallel reporter assays. These data-driven approaches, coupled with computational analyses and modeling, have paved the way for a comprehensive understanding of TL functions. Finally, we will discuss areas of future research on the roles of mRNA sequences and structures in translation. This article is categorized under: Translation > Translation Mechanisms RNA Evolution and Genomics > Computational Analyses of RNA RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems.

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Mutations in the p53 tumor suppressor gene are the most frequent genetic alteration in cancer and are often associated with progression from benign to invasive stages with metastatic potential. Mutations inactivate tumor suppression by p53, and some endow the protein with novel gain of function (GOF) properties that actively promote tumor progression and metastasis. By comparative gene expression profiling of p53-mutated and p53-depleted cancer cells, we identified ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) as a mutant p53 target gene, which functions as a uridine 5'-diphosphatase (UDPase) in the endoplasmic reticulum (ER) to promote the folding of N-glycosylated membrane proteins. A comprehensive pan-cancer analysis revealed a highly significant correlation between p53 GOF mutations and ENTPD5 expression. Mechanistically, mutp53 is recruited by Sp1 to the ENTPD5 core promoter to induce its expression. We show ENTPD5 to be a mediator of mutant p53 GOF activity in clonogenic growth, architectural tissue remodeling, migration, invasion, and lung colonization in an experimental metastasis mouse model. Our study reveals folding of N-glycosylated membrane proteins in the ER as a mechanism underlying the metastatic progression of tumors with mutp53 that could provide new possibilities for cancer treatment.

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TP63, a member of the p53 gene family gene, encodes the ΔNp63 protein and is one of the most frequently amplified genes in squamous cell carcinomas (SCC) of the head and neck (HNSCC) and lungs (LUSC). Using an epiallelic series of siRNAs with intrinsically different knockdown abilities, we show that the complete loss of ΔNp63 strongly impaired cell proliferation, whereas partial ΔNp63 depletion rendered cells hypersensitive to cisplatin accompanied by an accumulation of DNA damage. Expression profiling revealed wide-spread transcriptional regulation of DNA repair genes and in particular Fanconi anemia (FA) pathway components such as FANCD2 and RAD18 - known to be crucial for the repair of cisplatin-induced interstrand crosslinks. In SCC patients ΔNp63 levels significantly correlate with FANCD2 and RAD18 expression confirming ΔNp63 as a key activator of the FA pathway in vivo Mechanistically, ΔNp63 bound an upstream enhancer of FANCD2 inactive in primary keratinocytes but aberrantly activated by ΔNp63 in SCC. Consistently, depletion of FANCD2 sensitized to cisplatin similar to depletion of ΔNp63. Together, our results demonstrate that ΔNp63 directly activates the FA pathway in SCC and limits the efficacy of cisplatin treatment. Targeting ΔNp63 therefore would not only inhibit SCC proliferation but also sensitize tumors to chemotherapy.

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Inactivation of the p53 tumor suppressor by Mdm2 is one of the most frequent events in cancer, so compounds targeting the p53-Mdm2 interaction are promising for cancer therapy. Mechanisms conferring resistance to p53-reactivating compounds are largely unknown. Here we show using CRISPR-Cas9-based target validation in lung and colorectal cancer that the activity of nutlin, which blocks the p53-binding pocket of Mdm2, strictly depends on functional p53. In contrast, sensitivity to the drug RITA, which binds the Mdm2-interacting N terminus of p53, correlates with induction of DNA damage. Cells with primary or acquired RITA resistance display cross-resistance to DNA crosslinking compounds such as cisplatin and show increased DNA cross-link repair. Inhibition of FancD2 by RNA interference or pharmacological mTOR inhibitors restores RITA sensitivity. The therapeutic response to p53-reactivating compounds is therefore limited by compound-specific resistance mechanisms that can be resolved by CRISPR-Cas9-based target validation and should be considered when allocating patients to p53-reactivating treatments.

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The health of populations depends on the availability of clean air, water, food, and sanitation, exposure to pathogens, toxins and environmental hazards, and numerous genetic, behavioral and social factors. For many thousands of years, human life expectancy was low, and population growth was slow. The development of technology-based civilizations facilitated what Abdel Omran called "epidemiological transition," with increasing life expectancy and rapid population growth. To a large extent, the spectacular growth of human populations during the past two centuries was made possible by the energy extracted from fossil fuels. We have now learned, however, that greenhouse gases from fossil fuel combustion are warming the planet's surface, causing changes in oceanic and atmospheric systems, and disrupting weather and hydrological patterns. Climate change poses unprecedented threats to human health by impacts on food and water security, heat waves and droughts, violent storms, infectious disease, and rising sea levels. Whether or not humanity can reduce greenhouse gas emissions quickly enough to slow climate change to a rate that will allow societies to successfully adapt is not yet known. This essay reviews the current state of relevant knowledge, and points in a few directions that those interested in human health may wish to consider.

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Tumours are heterogeneous cell populations that undergo clonal evolution during tumour progression, metastasis and response to therapy. Short hairpin RNAs (shRNAs) generate stable loss-of-function phenotypes and are versatile experimental tools to explore the contribution of individual genetic alterations to clonal evolution. In these experiments tumour cells carrying shRNAs are commonly tracked with fluorescent reporters. While this works well for cell culture studies and leukaemia mouse models, fluorescent reporters are poorly suited for animals with solid tumours--the most common tumour types in cancer patients. Here we develop a toolkit that uses secreted luciferases to track the fate of two different shRNA-expressing tumour cell clones competitively, both in vitro and in vivo. We demonstrate that secreted luciferase activities can be measured robustly in the blood stream of tumour-bearing mice to accurately quantify, in a minimally invasive manner, the dynamic evolution of two genetically distinct tumour subclones in preclinical mouse models of tumour development, metastasis and therapy.

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The tumor suppressor p53 provides exquisite protection from cancer by balancing cell survival and death in response to stress. Sustained stress or irreparable damage trigger p53's killer functions to permanently eliminate genetically-altered cells as a potential source of cancer. To prevent the unnecessary loss of cells that could cause premature aging as a result of stem cell attrition, the killer functions of p53 are tightly regulated and balanced against protector functions that promote damage repair and support survival in response to low stress or mild damage. In molecular terms these p53-based cell fate decisions involve protein interactions with cofactors and modifying enzymes, which modulate the activation of distinct sets of p53 target genes. In addition, we demonstrate that part of this regulation occurs at the level of DNA binding. We show that the killer function of p53 requires the four DNA binding domains within the p53 tetramer to interact with one another. These intermolecular interactions enable cooperative binding of p53 to less perfect response elements in the genome, which are present in many target genes essential for apoptosis. Modulating p53 interactions within the tetramer could therefore present a novel promising strategy to fine-tune p53-based cell fate decisions.

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p53 limits the proliferation of precancerous cells by inducing cell-cycle arrest or apoptosis. How the decision between survival and death is made at the level of p53 binding to target promoters remains unclear. Using cancer cell lines, we show that the cooperative nature of DNA binding extends the binding spectrum of p53 to degenerate response elements in proapoptotic genes. Mutational inactivation of cooperativity therefore does not compromise the cell-cycle arrest response but strongly reduces binding of p53 to multiple proapoptotic gene promoters (BAX, PUMA, NOXA, CASP1). Vice versa, engineered mutants with increased cooperativity show enhanced binding to proapoptotic genes, which shifts the cellular response to cell death. Furthermore, the cooperativity of DNA binding determines the extent of apoptosis in response to DNA damage. Because mutations, which impair cooperativity, are genetically linked to cancer susceptibility in patients, DNA binding cooperativity contributes to p53's tumor suppressor activity.

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PURPOSE: We have previously demonstrated that prostate tumors that highly express Bcl-2 are not only more tumorigenic, but also more angiogenic than low Bcl-2 expressing tumors. Observed increased rates of angiogenesis are likely due to the secretion of multiple factors from the tumor cells. EXPERIMENTAL DESIGN: Human endothelial cells were subjected to exogenous VEGF or conditioned media from PC-3 cells and assayed by several in vitro systems to better characterize the effects of tumor microenvironment on endothelial cells. RESULTS: VEGF stimulation increased Bcl-2 expression in human microvascular endothelial cells (HMVECs), at least partially through stabilization of Bcl-2 mRNA transcripts, and protected these cells from apoptosis. These effects were mimicked by treatment of HMVECs with conditioned media from cultured PC-3 prostate tumor cells manipulated to overexpress Bcl-2. Through the use of kinase inhibitors and molecular profiling, several distinct pathways were implicated in the regulation of Bcl-2 in HMVECs, including those involving PI3K/AKT, PKC, mTOR, STAT-1, and IL-8, factors associated with tumor survival and growth. CONCLUSIONS: This study identifies molecular elements of a link between Bcl-2 expression in distinct cell types within a tumor and reaffirms that strategies designed to target Bcl-2 are desirable as they might enhance treatment response through dual effects.

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Milk and dairy products are the main sources of calcium in western countries. In contrast, most calcium ingested in eastern and black African countries comes from vegetables and fish. Calcium is necessary for optimal bone metabolism and for many other biological systems. Recommended daily calcium intake differs among countries and even among institutions. Daily intake should be at least 1000 mg after the age of 10-12 years, and 1200-1500 mg/day for adolescents (14-18 years), pregnant women, and men over 65. There is no added benefit beyond 2000 mg, but intake should not fall below 700-800 mg/day. Three servings of dairy products are needed to meet recommended daily calcium intake. The importance of calcium in the management of osteoporosis is controversial. However, experts agree on the need to correct calcium deficiency, especially when associated with vitamin D deficiency Calcium and vitamin D supplementation is essential to prevent fractures in deficient elderly subjects. Calcium and vitamin D should be systematically added to treatments for patients with established osteoporosis and for those with risk factors.

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O presente relato descreve uma paciente com síndrome de Reiter e subluxaçäo atlanto-axial que desenvolveu compressäo da medula espinhal. A literatura sobre esse assunto é revisada

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As histiocitoses säo afecçöes caracterizadas pela proliferaçäo de células histiocitárias com atividade macrofágica a nível de órgäos ricos em células do sistema retículo endotelial, como fígado, baço, medula óssea, pulmöes, pele e ossos. Os autores relatam um caso de retículo-histiocitose multicêntrica, doença rara com alteraçöes clínico-radiológicas mimetizando outras patologias reumáticas

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Tendo em vista a alta incidência de recidiva da sinovite vilonodular pigmentada após sinovectomia, os autores fizeram estudo retrospectivo de seu tratamento nos casos observados no serviço entre 1975 e 1984. Foram estudados 17 casos, 15 referindo-se à articulaçäo do joelho e 2 à coxofemoral. Baseado nos resultados obtidos, os autores pensam que a sinoviortese pode ser útil como tratamento complementar da sinovite vilonodular pigmentada e propöem adotar a seguinte atitude terapêutica: sinovectomia inicial, a mais completa possível, seguida por sinoviortese isotópica três meses; em pacientes jovens, sinovectomia a mais completa possível, seguida por sinoviortese com ácido ósmico após três meses

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