The PPAR-gamma agonist pioglitazone protects cortical neurons from inflammatory mediators via improvement in peroxisomal function

<p>Abstract</p> <p>Background</p> <p>Inflammation is known to play a pivotal role in mediating neuronal damage and axonal injury in a variety of neurodegenerative disorders. Among the range of inflammatory mediators, nitric oxide and hydrogen peroxide are potent neurotoxic agents. Recent evidence has suggested that oligodendrocyte peroxisomes may play an important role in protecting neurons from inflammatory damage.</p> <p>Methods</p> <p>To assess the influence of peroxisomal activation on nitric oxide mediated neurotoxicity, we investigated the effects of the peroxisomal proliferator activated receptor (PPAR) gamma agonist, pioglitazone in primary cortical neurons that were either exposed to a nitric oxide donor or co-cultured with activated microglia.</p> <p>Results</p> <p>Pioglitazone protected neurons and axons against both nitric-oxide donor-induced and microglia-derived nitric oxide-induced toxicity. Moreover, cortical neurons treated with this compound showed a significant increase in the protein and gene expression of PPAR-gamma, which was associated with a concomitant increase in the enzymatic activity of catalase. In addition, the protection of neurons and axons against hydrogen peroxide-induced toxicity afforded by pioglitazone appeared to be dependent on catalase.</p> <p>Conclusions</p> <p>Collectively, these observations provide evidence that modulation of PPAR-gamma activity and peroxisomal function by pioglitazone attenuates both NO and hydrogen peroxide-mediated neuronal and axonal damage suggesting a new therapeutic approach to protect against neurodegenerative changes associated with neuroinflammation.</p

Cardiosphere-derived cells suppress allogeneic lymphocytes by production of PGE2 acting via the EP4 receptor

derived cells (CDCs) are a cardiac progenitor cell population, which have been shown to possess cardiac regenerative properties and can improve heart function in a variety of cardiac diseases. Studies in large animal models have predominantly focussed on using autologous cells for safety, however allogeneic cell banks would allow for a practical, cost-effective and efficient use in a clinical setting. The aim of this work was to determine the immunomodulatory status of these cells using CDCs and lymphocytes from 5 dogs. CDCs expressed MHC I but not MHC II molecules and in mixed lymphocyte reactions demonstrated a lack of lymphocyte proliferation in response to MHC-mismatched CDCs. Furthermore, MHC-mismatched CDCs suppressed lymphocyte proliferation and activation in response to Concanavalin A. Transwell experiments demonstrated that this was predominantly due to direct cell-cell contact in addition to soluble mediators whereby CDCs produced high levels of PGE2 under inflammatory conditions. This led to down-regulation of CD25 expression on lymphocytes via the EP4 receptor. Blocking prostaglandin synthesis restored both, proliferation and activation (measured via CD25 expression) of stimulated lymphocytes. We demonstrated for the first time in a large animal model that CDCs inhibit proliferation in allo-reactive lymphocytes and have potent immunosuppressive activity mediated via PGE2

Decolorization of synthetic melanoidins-containing wastewater by a bacterial consortium

The presence of melanoidins in molasses wastewater leads to water pollution both due to its dark brown color and its COD contents. In this study, a bacterial consortium isolated from waterfall sediment was tested for its decolorization. The identification of culturable bacteria by 16S rDNA based approach showed that the consortium composed of Klebsiella oxytoca, Serratia mercescens, Citrobacter sp. and unknown bacterium. In the context of academic study, prevention on the difficulties of providing effluent as well as its variations in compositions, several synthetic media prepared with respect to color and COD contents based on analysis of molasses wastewater, i.e., Viandox sauce (13.5% v/v), caramel (30% w/v), beet molasses wastewater (41.5% v/v) and sugarcane molasses wastewater (20% v/v) were used for decolorization using consortium with color removal 9.5, 1.13, 8.02 and 17.5%, respectively, within 2 days. However, Viandox sauce was retained for further study. The effect of initial pH and Viandox concentration on decolorization and growth of bacterial consortium were further determined. The highest decolorization of 18.3% was achieved at pH 4 after 2 day of incubation. Experiments on fresh or used medium and used or fresh bacterial cells, led to conclusion that the limitation of decolorization was due to nutritional deficiency. The effect of aeration on decolorization was also carried out in 2 L laboratory-scale suspended cell bioreactor. The maximum decolorization was 19.3% with aeration at KLa = 2.5836 h-1 (0.1 vvm)

Crisis Visits and Psychiatric Hospitalizations Among Patients Attending a Community Clinic in Rural Southern California

Ethnic minorities from disadvantaged socioeconomic backgrounds report increased utilization of mental health emergency services; however findings have been inconsistent across ethnic/racial groups. In this study we describe patients who present to a rural crisis unit in Southern California, examine rates of psychiatric hospitalizations across ethnic/racial groups, and investigate factors that are associated with increased psychiatric hospitalizations in this sample. This is a retrospective study of 451 racially and ethnically diverse patients attending a crisis unit in Imperial County, California. Chart review and data abstraction methods were used to characterize the sample and identify factors associated with psychiatric crises and subsequent hospitalizations. The sample was predominantly Latino/Hispanic (58.5%). Based on chart review, common psychosocial stressors which prompted a crisis center visit were: (a) financial problems; (b) homelessness; (c) partner or family conflict; (d) physical and health problems; (e) problems at school/work; (f) medication compliance; (g) aggressive behavior; (h) delusional behavior; (i) addiction and (j) anxiety/depression. Bivariate analyses revealed that Hispanics had a disproportionately lower rate of psychiatric hospitalizations while African Americans had a higher rate. Multivariate analyses which included demographic, clinical and psychosocial stressor variables revealed that being African American, having a psychotic disorder, and presenting as gravely disabled were associated with a higher likelihood of hospitalization while partner/family conflict was associated with a lesser likelihood in this rural community. These data elucidate the need for longitudinal studies to understand the interactions between psychosocial stressors, ethnicity and social support as determinants of psychiatric hospitalizations

Unveiling unconventional magnetism at the surface of Sr2RuO4.

Materials with strongly correlated electrons often exhibit interesting physical properties. An example of these materials is the layered oxide perovskite Sr2RuO4, which has been intensively investigated due to its unusual properties. Whilst the debate on the symmetry of the superconducting state in Sr2RuO4 is still ongoing, a deeper understanding of the Sr2RuO4 normal state appears crucial as this is the background in which electron pairing occurs. Here, by using low-energy muon spin spectroscopy we discover the existence of surface magnetism in Sr2RuO4 in its normal state. We detect static weak dipolar fields yet manifesting at an onset temperature higher than 50 K. We ascribe this unconventional magnetism to orbital loop currents forming at the reconstructed Sr2RuO4 surface. Our observations set a reference for the discovery of the same magnetic phase in other materials and unveil an electronic ordering mechanism that can influence electron pairing with broken time reversal symmetry

Primary healthcare and the construction of thematic health networks: what role can they play?

The enhancement of primary healthcare has been a core strategy for the empowerment of the Brazilian Unified Health System (SUS). Recent guidelines issued by OPAS and the Ministry of Health highlight the role it has played as a thematic communication network center, a regulating agent for the access and use of services required for comprehensive healthcare. Sponsored by PPSUS/Fapesp, this study examines the possibilities of the primary healthcare network exercising such a strategic function. Life narratives involving 15 regular users were produced in two cities of ABC Paulista, which have adopted the Family Health Strategy for the organization of their primary healthcare networks. The study presents three main findings: the primary healthcare network serves as an outpost of SUS by producing user values even for high complexity service users; the primary network is perceived is a place for simple care needs; there is shared impotence between users and teams when it comes to the network functioning as the coordinator of care, indicating that it does not possess the technological, operational and organizational material conditions or symbolic conditions (values, meanings, and representations) to be in a central position in the coordination of thematic healthcare networks.O fortalecimento da atenção básica tem sido valorizado como estratégia central para a construção do SUS. Diretrizes recentes emanadas pela OPAS e pelo MS destacam seu papel como centro de comunicação de redes temáticas, como reguladora do acesso e utilização dos serviços necessários para a integralidade do cuidado. O presente estudo, financiado com recursos PPSUS/Fapesp, problematiza as possibilidades da rede básica exercer tal função estratégica. Foram produzidas narrativas de vida de 15 usuários altamente utilizadores de serviços de saúde em dois municípios do ABC paulista, que adotaram a Estratégia de Saúde da Família para organização de suas redes básicas. O estudo apresenta três achados principais: a rede básica funciona como posto avançado do SUS, produzindo valores de uso mesmo para os pacientes utilizadores de serviços de alta complexidade; a rede básica é vista como lugar de coisas simples; há uma impotência compartilhada entre usuários e equipes quando se trata da rede básica funcionar como coordenadora do cuidado, indicando como ela não reúne condições materiais (tecnológicas, operacionais, organizacionais) e simbólicas (valores, significados e representações) de deter a posição central da coordenação das redes temáticas de saúde.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Departamento de Medicina PreventivaInstituto Superior de Ciências do Trabalho e da Empresa Instituto Universitário de Lisboa Faculdade de Ciências Médicas Departamento de Saúde ColetivaUniversidade Estadual de Campinas Faculdade de Ciências Médicas Departamento de Saúde ColetivaUNIFESP, EPM, Depto. de Medicina PreventivaSciEL

Self-assembled hydrogel fibers for sensing the multi-compartment intracellular milieu

Targeted delivery of drugs and sensors into cells is an attractive technology with both medical and scientific applications. Existing delivery vehicles are generally limited by the complexity of their design, dependence on active transport, and inability to function within cellular compartments. Here, we developed self-assembled nanofibrous hydrogel fibers using a biologically inert, low-molecular-weight amphiphile. Self-assembled nanofibrous hydrogels offer unique physical/mechanical properties and can easily be loaded with a diverse range of payloads. Unlike commercially available E. coli membrane particles covalently bound to the pH reporting dye pHrodo, pHrodo encapsulated in self-assembled hydrogel-fibers internalizes into macrophages at both physiologic (37°C) and sub-physiologic (4°C) temperatures through an energy-independent, passive process. Unlike dye alone or pHrodo complexed to E. coli, pHrodo-SAFs report pH in both the cytoplasm and phagosomes, as well the nucleus. This new class of materials should be useful for next-generation sensing of the intracellular milieu

FOXA1 repression is associated with loss of BRCA1 and increased promoter methylation and chromatin silencing in breast cancer

FOXA1 expression correlates with the breast cancer luminal subtype and patient survival. RNA and protein analysis of a panel of breast cancer cell lines revealed that BRCA1 deficiency is associated with the downregulation of FOXA1 expression. Knockdown of BRCA1 resulted in the downregulation of FOXA1 expression and enhancement of FOXA1 promoter methylation in MCF-7 breast cancer cells, whereas the reconstitution of BRCA1 in Brca1-deficent mouse mammary epithelial cells (MMECs) promoted Foxa1 expression and methylation. These data suggest that BRCA1 suppresses FOXA1 hypermethylation and silencing. Consistently, the treatment of MMECs with the DNA methylation inhibitor 5-aza-2'-deoxycitydine induced Foxa1 mRNA expression. Furthermore, treatment with GSK126, an inhibitor of EZH2 methyltransferase activity, induced FOXA1 expression in BRCA1-deficient but not in BRCA1-reconstituted MMECs. Likewise, the depletion of EZH2 by small interfering RNA enhanced FOXA1 mRNA expression. Chromatin immunoprecipitation (ChIP) analysis demonstrated that BRCA1, EZH2, DNA methyltransferases (DNMT)1/3a/3b and H3K27me3 are recruited to the endogenous FOXA1 promoter, further supporting the hypothesis that these proteins interact to modulate FOXA1 methylation and repression. Further co-immunoprecipitation and ChIP analysis showed that both BRCA1 and DNMT3b form complexes with EZH2 but not with each other, consistent with the notion that BRCA1 binds to EZH2 and negatively regulates its methyltransferase activity. We also found that EZH2 promotes and BRCA1 impairs the deposit of the gene silencing histone mark H3K27me3 on the FOXA1 promoter. These associations were validated in a familial breast cancer patient cohort. Integrated analysis of the global gene methylation and expression profiles of a set of 33 familial breast tumours revealed that FOXA1 promoter methylation is inversely correlated with the transcriptional expression of FOXA1 and that BRCA1 mutation breast cancer is significantly associated with FOXA1 methylation and downregulation of FOXA1 expression, providing physiological evidence to our findings that FOXA1 expression is regulated by methylation and chromatin silencing and that BRCA1 maintains FOXA1 expression through suppressing FOXA1 gene methylation in breast cancer.Oncogene advance online publication, 22 December 2014; doi:10.1038/onc.2014.421.published_or_final_versio

Population structure and genetic diversity in a commercial maize breeding program assessed with SSR and SNP markers

Information about the genetic diversity and population structure in elite breeding material is of fundamental importance for the improvement of crops. The objectives of our study were to (a) examine the population structure and the genetic diversity in elite maize germplasm based on simple sequence repeat (SSR) markers, (b) compare these results with those obtained from single nucleotide polymorphism (SNP) markers, and (c) compare the coancestry coefficient calculated from pedigree records with genetic distance estimates calculated from SSR and SNP markers. Our study was based on 1,537 elite maize inbred lines genotyped with 359 SSR and 8,244 SNP markers. The average number of alleles per locus, of group specific alleles, and the gene diversity (D) were higher for SSRs than for SNPs. Modified Roger’s distance (MRD) estimates and membership probabilities of the STRUCTURE matrices were higher for SSR than for SNP markers but the germplasm organization in four heterotic pools was consistent with STRUCTURE results based on SSRs and SNPs. MRD estimates calculated for the two marker systems were highly correlated (0.87). Our results suggested that the same conclusions regarding the structure and the diversity of heterotic pools could be drawn from both markers types. Furthermore, although our results suggested that the ratio of the number of SSRs and SNPs required to obtain MRD or D estimates with similar precision is not constant across the various precision levels, we propose that between 7 and 11 times more SNPs than SSRs should be used for analyzing population structure and genetic diversity

Declaração Internacional sobre o Direito ao Cuidado Nutricional e a Luta contra a Desnutrição

&nbsp; Faced with the need to promote the right to nutritional care, to fight against malnutrition and to advance in education and research in clinical nutrition, all the FELANPE’s societies signed on May 3 during an extraordinary assembly in the city of Cartagena, the International Declaration on the Right to Nutritional Care and the fight against Malnutrition, “Declaration of Cartagena”. The Declaration provides a coherent framework of thirteen principles which can serve as a guide for societies, schools and associations affiliated to FELANPE in the development of action plans. In addition, it will serve as an instrument to promote, through governments, the formulation of policies and legislation in the field of clinical nutrition. We believe that the general framework of principles proposed by the Declaration can contribute to raise awareness about the magnitude of this problem and to forge cooperation networks among Latin-American countries. Although this Declaration does not have a binding legal effect, it has undeniable moral force and can provide practical guidance to States. We will then be contributing to achieving the United Nations Sustainable Development Goals which aim to put an end to all forms of malnutrition by 2030.Frente a la necesidad de promover el derecho al cuidado nutricional, de luchar contra la malnutrición y de avanzar en temas de educación e investigación en nutrición clínica, las sociedades que constituyen la FELANPE firmaron la Declaración Internacional sobre el Derecho al Cuidado Nutricional y la lucha contra la Malnutrición, “Declaración de Cartagena”, en la asamblea extraordinaria que tuvo lugar el 3 de mayo del presente año en la ciudad de Cartagena. La Declaración proporciona un marco coherente de trece principios los cuales podrán servir de guía a las sociedades, los colegios y las asociaciones afiliadas a la FELANPE en el desarrollo de los planes de acción. Además, servirá como un instrumento para que promuevan, a través de los gobiernos, la formulación de políticas y legislaciones en el campo de la nutrición clínica. Consideramos que el marco general de principios propuesto por la Declaración puede contribuir a crear conciencia acerca de la magnitud de este problema y a forjar redes de cooperación entre los países de la región. Aunque esta Declaración no tiene un efecto jurídico vinculante (obligatorio), tiene una fuerza moral innegable y puede proporcionar orientación práctica a los Estados. Estaremos entonces contribuyendo a alcanzar los Objetivos de Desarrollo Sostenible de Naciones Unidas que buscan, para 2030, poner fin a todas las formas de malnutrición.&nbsp; Confrontados com a necessidade de promover o direito à assistência nutricional, para combater a desnutrição e favorecer o progresso na educação e na pesquisa em nutrição clínica, todas as companhias membros da FELANPE em data do 3 de maio 2019 numa reunião extraordinária, na cidade de Cartagena, reconhecem e suscrivem à Declaração Internacional sobre o Direito à Nutrição e o combate à desnutrição, “Declaração de Cartagena”. A Declaração fornece uma estrutura coerente de treze princípios que podem servir como um guia para sociedades, escolas e associações afiliadas à FELANPE no desenvolvimento de planos de ação. Além disso, servirá como instrumento para promover, através dos governos, a formulação de políticas e legislação no campo da nutrição clínica. Acreditamos que a estrutura geral de princípios proposta pela Declaração pode contribuir para aumentar a conscientização sobre a magnitude desse problema e forjar redes de cooperação entre os países da região. Embora esta Declaração não tenha um efeito legal vinculante, tem força moral inegável e pode fornecer orientação prática aos Estados. Vamos então contribuir para alcançar os Objetivos de Desenvolvimento Sustentável das Nações Unidas que visam, até 2030, pôr fim a todas as formas de desnutrição