Identification of New SRF Binding Sites in Genes Modulated by SRF Over-Expression in Mouse Hearts

Background To identify in vivo new cardiac binding sites of serum response factor (SRF) in genes and to study the response of these genes to mild over-expression of SRF, we employed a cardiac-specific, transgenic mouse model, with mild over-expression of SRF (Mild-O SRF Tg). Methodology Microarray experiments were performed on hearts of Mild-O-SRF Tg at 6 months of age. We identified 207 genes that are important for cardiac function that were differentially expressed in vivo. Among them the promoter region of 192 genes had SRF binding motifs, the classic CArG or CArG-like (CArG-L) elements. Fifty-one of the 56 genes with classic SRF binding sites had not been previously reported. These SRF-modulated genes were grouped into 12 categories based on their function. It was observed that genes associated with cardiac energy metabolism shifted toward that of carbohydrate metabolism and away from that of fatty acid metabolism. The expression of genes that are involved in transcription and ion regulation were decreased, but expression of cytoskeletal genes was significantly increased. Using public databases of mouse models of hemodynamic stress (GEO database), we also found that similar altered expression of the SRF-modulated genes occurred in these hearts with cardiac ischemia or aortic constriction as well. Conclusion and significance SRF-modulated genes are actively regulated under various physiological and pathological conditions. We have discovered that a large number of cardiac genes have classic SRF binding sites and were significantly modulated in the Mild-O-SRF Tg mouse hearts. Hence, the mild elevation of SRF protein in the heart that is observed during typical adult aging may have a major impact on many SRF-modulated genes, thereby affecting Cardiac structure and performance. The results from our study could help to enhance our understanding of SRF regulation of cellular processes in the aged heart

Proteomic characterization of HIV-modulated membrane receptors, kinases and signaling proteins involved in novel angiogenic pathways

<p>Abstract</p> <p>Background</p> <p>Kaposi's sarcoma (KS), hemangioma, and other angioproliferative diseases are highly prevalent in HIV-infected individuals. While KS is etiologically linked to the human herpesvirus-8 (HHV8) infection, HIV-patients without HHV-8 and those infected with unrelated viruses also develop angiopathies. Further, HIV-Tat can activate protein-tyrosine-kinase (PTK-activity) of the vascular endothelial growth factor receptor involved in stimulating angiogenic processes. However, Tat by itself or HHV8-genes alone cannot induce angiogenesis <it>in vivo </it>unless specific proteins/enzymes are produced synchronously by different cell-types. We therefore tested a hypothesis that <it>chronic </it>HIV-<it>replication in non-endothelial cells </it>may produce novel factors that provoke angiogenic pathways.</p> <p>Methods</p> <p>Genome-wide proteins from HIV-infected and uninfected T-lymphocytes were tested by subtractive proteomics analyses at various stages of virus and cell growth <it>in vitro </it>over a period of two years. Several thousand differentially regulated proteins were identified by mass spectrometry (MS) and >200 proteins were confirmed in multiple gels. Each protein was scrutinized extensively by protein-interaction-pathways, bioinformatics, and statistical analyses.</p> <p>Results</p> <p>By functional categorization, 31 proteins were identified to be associated with various signaling events involved in angiogenesis. 88% proteins were located in the plasma membrane or extracellular matrix and >90% were found to be essential for regeneration, neovascularization and angiogenic processes during embryonic development.</p> <p>Conclusion</p> <p>Chronic HIV-infection of T-cells produces membrane receptor-PTKs, serine-threonine kinases, growth factors, adhesion molecules and many diffusible signaling proteins that have not been previously reported in HIV-infected cells. Each protein has been associated with endothelial cell-growth, morphogenesis, sprouting, microvessel-formation and other biological processes involved in angiogenesis (p = 10^-4to 10^-12). Bioinformatics analyses suggest that overproduction of PTKs and other kinases in HIV-infected cells has <it>suppressed </it>VEGF/VEGFR-PTK expression and promoted <it>VEGFR-independent </it>pathways. This unique mechanism is similar to that observed in neovascularization and angiogenesis during embryogenesis. Validation of clinically relevant proteins by gene-silencing and translational studies <it>in vivo </it>would identify specific targets that can be used for early diagnosis of angiogenic disorders and future development of inhibitors of angiopathies. This is the first comprehensive study to demonstrate that HIV-infection alone, without any co-infection or treatment, can induce numerous "embryonic" proteins and kinases capable of generating novel <it>VEGF-independent </it>angiogenic pathways.</p

De la «Educación de Adultos» a la «Educación para todos, a lo largo de toda la vida» en Uruguay (From «Adult Education» to «a Lifelong Process of Education for Everybody» in Uruguay)

This article is the result of collective work of a group of teachers from the UNESCO Chair of Young and Adult Education in the Institute of Education at the University of the Republic, Uruguay. Its central aim is to describe and analyze how the evolution that the idea of adult education has developed in the historical context of education in Uruguay. In the first place, a historical review of the concept of adult education in Uruguay is carried out, identifying the organizational institutions and other associations dealing with the subject. Secondly, the authors present some significant experiences and reflections on the history of these educational policies and practices with both adults and young people.Theoretical and Experimental Linguistic

Collaborative and Collective: Reflexive Coordination and the Dynamics of Open Innovation in the Digital Industry Clusters of the Paris Region

International audienceEconomic geography increasingly conceptualises innovation as a collective action. However, the literature on clusters often reduces the collective dimension to the circulation of knowledge between local and regional organisations based on various forms of (market, organisational, social, institutional or cognitive) co-ordination. This paper diverges from this grass-roots perspective by discussing the role of collective actions in clusters--i.e. actions developed by a large number of cluster members acting as a group. Empirical evidence drawing on a study of three digital clusters in the Paris region shows that the cluster as a collective entity holds agency and-- thanks to reflexive co-ordination--can contribute to open innovation, including innovation-seeking partnerships in the early stages of cluster life cycles

Kinetics of FKBP12.6 Binding to Ryanodine Receptors in Permeabilized Cardiac Myocytes and Effects on Ca Sparks

The Inquisition took place in Mexico from 1571 to 1820. The Antiguo Palacio de la Inquisicion was built in the first third of the 18th century by Pedro de Arrieta who introduced such innovations as the octagonal entrance and the interlaced arches with unsupported junctures located in the building's courtyard. The current building houses a museum devoted to history of medicine Mexico. When the Federal District was created in 1824, the State government needed to move from the building (to Texcoco), to be outside the Federal District.; The Inquisition took place in Mexico from 1571 to 1820. The Antiguo Palacio de la Inquisicion was built in the first third of the 18th century by Pedro de Arrieta who introduced such innovations as the octagonal entrance and the interlaced arches with unsupported junctures located in the building's courtyard. The current building houses a museum devoted to history of medicine Mexico. When the Federal District was created in 1824, the State government needed to move from the building (to Texcoco), to be outside the Federal District

Annexin A6 modifies muscular dystrophy by mediating sarcolemmal repair

Many monogenic disorders, including the muscular dystrophies, display phenotypic variability despite the same disease-causing mutation. To identify genetic modifiers of muscular dystrophy and its associated cardiomyopathy, we used quantitative trait locus mapping and whole genome sequencing in a mouse model. This approach uncovered a modifier locus on chromosome 11 associated with sarcolemmal membrane damage and heart mass. Whole genome and RNA sequencing identified Anxa6, encoding annexin A6, as a modifier gene. A synonymous variant in exon 11 creates a cryptic splice donor, resulting in a truncated annexin A6 protein called ANXA6N32. Live cell imaging showed that annexin A6 orchestrates a repair zone and cap at the site of membrane disruption. In contrast, ANXA6N32 dramatically disrupted the annexin A6-rich cap and the associated repair zone, permitting membrane leak. Anxa6 is a modifier of muscular dystrophy and membrane repair after injury

Exclusão e educação social: conceitos em superfície e fundo Exclusion and social education: superficial and thorough concepts

O artigo trata da relação entre exclusão e educação social. Objetiva trazer elementos que permitam uma discussão sobre a realidade e as concepções de exclusão/inclusão e educação social, com o fim de re-velar ideologias e interesses que as informam. Trabalha com a hipótese de que existe uma disputa entre projetos sociais e educacionais contraditórios, resultando, daí, estratégias de combate à exclusão e promotoras de inclusão, encarnadas em concepções e práticas de educação social, como resposta às demandas de políticas sociais públicas provenientes das populações de crianças e jovens em situação de vulnerabilidade. A problematização desses conceitos - exclusão e educação social - poderá contribuir à formulação de políticas para a educação pública.<br>This paper approaches the relationship between exclusion and social education. It aims at bringing out elements that lead to discuss reality and conceptions of social exclusion/inclusion and social education to dis-close the ideologies and interests that inform them. It develops the hypothesis that some kind of dispute between contradictory social and educational projects have resulted in strategies to fight exclusion and promote inclusion that are based on social education practices, as a response to the public social policies claimed by children and young people at risk. Problemizing these concepts - exclusion and social education - may bring some contributions to the formulation of public education policies