Interaction of connexin43 and protein kinase C-delta during FGF2 signaling

<p>Abstract</p> <p>Background</p> <p>We have recently demonstrated that modulation of the gap junction protein, connexin43, can affect the response of osteoblasts to fibroblast growth factor 2 in a protein kinase C-delta-dependent manner. Others have shown that the C-terminal tail of connexin43 serves as a docking platform for signaling complexes. It is unknown whether protein kinase C-delta can physically interact with connexin43.</p> <p>Results</p> <p>In the present study, we investigate by immunofluorescent co-detection and biochemical examination the interaction between Cx43 and protein kinase C-delta. We establish that protein kinase C-delta physically interacts with connexin43 during fibroblast growth factor 2 signaling, and that protein kinase C delta preferentially co-precipitates phosphorylated connexin43. Further, we show by pull down assay that protein kinase C-delta associates with the C-terminal tail of connexin43.</p> <p>Conclusions</p> <p>Connexin43 can serve as a direct docking platform for the recruitment of protein kinase C-delta in order to affect fibroblast growth factor 2 signaling in osteoblasts. These data expand the list of signal molecules that assemble on the connexin43 C-terminal tail and provide a critical context to understand how gap junctions modify signal transduction cascades in order to impact cell function.</p

High mobility group A2 is a target for miRNA-98 in head and neck squamous cell carcinoma

BACKGROUND: HMGA2 expression has been shown to be associated with enhanced selective chemosensitivity towards the topoisomerase (topo) II inhibitor, doxorubicin, in cancer cells. Although the roles of signaling cascades and proteins as regulatory factors in development, neoplasia and adaptation to the environment are becoming well established, evidence for the involvement of regulatory small RNA molecules, such as microRNAs (miRNAs) as important regulators of both transcriptional and posttranscriptional gene silencing is presently mounting. RESULTS: Here we report that HMGA2 expression in head and neck squamous cell carcinoma (HNSCC) cells is regulated in part by miRNA-98 (miR-98). Albeit HMGA2 is associated with enhanced selective chemosensitivity towards topoisomerase (topo) II inhibitor, doxorubicin in HNSCC, the expression of HMGA2 is thwarted by hypoxia. This is accompanied by enhanced expression of miRNA-98 and other miRNAs, which predictably target HMGA2. Moreover, we show that transfection of pre-miR-98™ during normoxia diminishes HMGA2 and potentiates resistance to doxorubicin and cisplatin. These findings implicate the role of a miRNA as a key element in modulating tumors in variable microenvironments. CONCLUSION: These studies validate the observation that HMGA2 plays a prominent role in governing genotoxic responses. However, this may only represent cells growing under normal oxygen tensions. The demonstration that miRNA profiles are altered during hypoxia and repress a genotoxic response indicates that changes in microenvironment in eukaryotes mimic those of lower species and plants, where, for example, abiotic stresses regulate the expression of thousands of genes in plants at both transcriptional and posttranscriptional levels through a number of miRNAs and other small regulatory RNAs

Hypoxia-inducible factor-1α polymorphisms and TSC1/2 mutations are complementary in head and neck cancers

BACKGROUND: Polymorphisms or mutations in hypoxia inducible factor-1 alpha (HIF-1alpha) that increases its activity and stability under normoxia have recently been identified. Likewise, disruption of the TSC1/TSC2 complex through loss of TSC1 or TSC2 has been shown to result in abnormal accumulation of HIF-1α. Here, we investigate the novel polymorphisms in exon 12, that approximate the oxygen-dependent degradation domain of HIF-1alpha in five cell lines and 28 patients with oral squamous carcinomas. Moreover, we assess for the presence of polymorphisms and mutations in TSC1 and TSC2, to ascertain if dysregulation of such might complement HIF-1alpha expression. RESULTS: Denaturing high pressure liquid chromatography (DHPLC) analysis on PCR fragments in exon 12 of HIF-1alpha from 28 patients with OSCC revealed that 6 of 28 patients had mismatched heteroduplex patterns. Genomic DNA was extracted from peripheral blood leukocytes and direct sequencing showed that in 5 of the six cases these changes represented polymorphisms while, one case was a somatic mutation. Analyses of TSC1 and TSC2 revealed heteroduplexes in exons: TSC1 exon 17; TSC2 exons 36,40, and 41. The relative levels of HIF-1alpha were significantly greater for tumors possessing a HIF-1alpha polymorphism or mutation within exon 12, whereas tumors possessing a deletion or polymorphism in TSC1/TSC2 displayed a trend for higher levels of HIF-1alpha. Western blot analyses for HIF-1alpha, TSC1 and TSC2 in five SCC cell lines revealed high levels of HIF-1alpha in SCC cells possessing TSC1 and/or TSC2 mutations. Wild-type TSC2 cells targeted with siRNA to TSC2 exhibited increased levels of HIF-1alpha. Transfection of a HIF-1alpha mutant produced higher levels of HIF-1alpha in TSC1/TSC2 mutant cell lines than in wild type cells. TSC1/TSC2 mutant cell lines administered Rapamycin blocked S6 phorphorylation and diminished the levels of HIF-1alpha to those observed in cell lines with wild type TSC1/TSC2. CONCLUSION: Dysregulation of the TSC1/TSC2 complex by mutation compliments HIF-1α polymorphisms in the expression of HIF-1alpha in SCC of the head and neck, and may provide biomarkers to predict responses to specific therapies and overall disease prognosis

HOMOSSEXUALIDADE, FAMÍLIA E RELIGIÃO: UMA ANÁLISE PSICOSSOCIAL DE ORAÇÕES PARA BOBBY

Discute-se a relação entre homossexualidade, religião e família, a partir da Psicologia Sócio-histórica. Busca-se investigar, por meio de uma análise fílmica, os sentidos e significados apresentados pela família, em relação à homossexualidade. Para tanto, utiliza-se a produção filmográfica Orações para Bobby, como um documento cultural, datado historicamente, que permite evidenciar as formas de vivências psicossociais. Nesta proposição, metodologicamente são adotados procedimentos de identificação, recorte, descrição e interpretação de cenas emblemáticas. Desse modo, realizaram-se a identificação, o recorte e a localização temporal, a descrição detalhada de textos das cenas com seus aspectos visuais e auditivos e construíram-se três categorias de análise das 16 cenas emblemáticas selecionadas: significados de religião, homossexualidade e família; significado de homossexualidade e suicídio; e impactos intergeracionais do signo da homossexualidade. Os resultados indicam que a relação entre a homossexualidade assumida, dogmas religiosos e família tradicional podem desencadear atos suicidas com motivação volitiva e consciente; as acepções de signo, sentidos, significado, mediação e internalização contribuíram para compreender o impacto que os conceitos da homossexualidade, socialmente construídos, incidem na vivência da sexualidade de jovens homossexuais e seus relacionamentos afetivos no âmbito social e familiar. O significado da homossexualidade apresenta-se de forma pejorativa, com força de materialidade histórica e de manutenção hegemônica de ideias, por meio de grupos conservadores, que encontram na família um lugar afetuoso e subjetivo, de reprodução fértil, ao passo que coletivos identitários, como a comunidade LGBTQIA+, buscam espaços para o debate político com avanços e rupturas dessas noções, historicamente construídas, no processo de significação da sexualidade

Prognóstico do sistema de abastecimento e tratamento de água na área urbana em são Gonçalo do Rio Abaixo/MG

This article consists of a case study, where the objective was to perform a diagnosis of the system supply system and water treatment in the urban area of São Gonçalo do Rio Abaixo in Minas Gerais, exposing briefly the problems it currently presented , and consequently the predictability of actions with technical contributions, which can serve as aid to the municipal administration and civil society, in the elaboration of public policies and decision making, in the attempt to generate benefits for the entire population. Therefore, it was necessary to search for information in public documents, academic literature and current legislation to characterize the study area and collect data. And finally, presented a set of actions to be planned and you execute the immediate term, short, medium and long in order to promote the balance of the environment by means of a modifier and sustainable approach.En este artículo consiste en un estudio de caso, que se llevó a cabo el diagnóstico del sistema de suministro y tratamiento de agua en la zona urbana de São Gonçalo do Rio Abaixo en Minas Gerais, exponiendo brevemente los problemas que presenta actualmente y en consecuencia las acciones previsibilização con aportaciones técnicas, que pueden ser una ayuda para la administración municipal y la sociedad civil en el desarrollo de políticas públicas y la toma de decisiones en un intento de generar beneficios para todos sus habitantes. Por lo tanto, fue necesario buscar información en documentos públicos, literatura académica y legislación vigente para caracterizar el área de estudio y recopilar datos. Finalmente, se presentó un conjunto de acciones a ser planeadas y ejecutadas en el inmediato, corto, mediano y largo plazo para promover el equilibrio del medio ambiente a través de un enfoque modificador y sostenible.Este artigo constitui-se de um estudo de caso onde teve-se como objetivo realizar um diagnóstico do sistema de abastecimento e tratamento de água na área urbana do município de São Gonçalo do Rio Abaixo em Minas Gerais, expondo de forma sucinta os problemas por ele apresentados atualmente, e consequentemente a previsibilidade de ações com contribuições técnicas, que podem servir de auxílio à administração municipal e sociedade civil, na elaboração de políticas públicas e tomada de decisões, no intento de gerar benefícios para toda a sua população. Portanto, foi necessária a busca de informações em documentos públicos, literatura acadêmica e legislação vigente, para caracterizar a área de estudo e levantar dados. E, por fim, apresentou-se um conjunto de ações a serem planejadas e executas nos prazos imediato, curto, médio e longo, a fim de promover o equilíbrio do meio ambiente por meio de uma postura modificadora e sustentável

Perfil de pacientes geriátricos com hipertensão arterial: uma abordagem no cuidado farmacêutico

Objective: To study the profile of geriatric patients with hypertension. Methodology: A cross-sectional, analytical, prospective study with a predominantly quantitative approach, carried out from June to September, 2016 at the Pharmaceutical Supply Center (CAF) in the city of Banabuiú-CE. Results: Fifty-two elderly patients (62%) were women, aged 60-65 years 24 (48%), married 28 (56%) and illiterate 17 (34%). %). Smokers were 2 (4%), alcoholics 1 (2%) and 20 (40%) practiced exercise. Monotherapy was seen 26 (52%), with Losartan, Atenolol and Enalapril. The most frequent association was Hydrochlorothiazide with Losartan 8 (33%). 48 (96%) correctly followed the medical prescription. The most reported symptoms after the discovery were dizziness 15 (30%), altered cholesterol 14 (28%) and palpitation 10 (20%). Conclusion: Knowing the profile of the elderly, allows planning pharmaceutical care and directing them to the specific interventions in the implementation of their care.Objetivo: Estudar o perfil de pacientes geriátricos com hipertensão arterial. Metodologia: Estudo transversal, analítico, prospectivo, com abordagem predominantemente quantitativa, realizado no período de junho a setembro de 2016, na Central de Abastecimento Farmacêutico (CAF) na cidade de Banabuiú-CE. Resultados: Participaram do estudo 50 pacientes idosos em uso de anti-hipertensivos, em sua maioria 31 (62%) eram mulheres, faixa etária entre 60 a 65 anos 24 (48%), casados 28 (56%) e analfabetos 17 (34%). Os fumantes eram de 2 (4%), alcoólicos 1 (2%) e 20 (40%) praticavam exercícios. A monoterapia foi vista 26 (52%), com Losartana, Atenolol e Enalapril. A associação mais observada foi de Hidroclorotiazida com Losartana 8 (33%). 48 (96%) seguia corretamente a prescrição médica. Os sintomas mais relatados após a descoberta foram tontura 15 (30%), colesterol alterado 14 (28%) e palpitação 10 (20%). Conclusão: Conhecer o perfil dos idosos, possibilita planejar cuidados farmacêuticos e direcioná-los para as intervenções específicas na implementação de sua assistência

Convergent genetic and expression data implicate immunity in Alzheimer's disease

Background Late–onset Alzheimer's disease (AD) is heritable with 20 genes showing genome wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease we extended these genetic data in a pathway analysis. Methods The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (p = 3.27×10-12 after multiple testing correction for pathways), regulation of endocytosis (p = 1.31×10-11), cholesterol transport (p = 2.96 × 10-9) and proteasome-ubiquitin activity (p = 1.34×10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected p 0.002 – 0.05). Conclusions The immune response, regulation of endocytosis, cholesterol transport and protein ubiquitination represent prime targets for AD therapeutics

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation