New approaches to data access in large-scale distributed system

Mención Internacional en el título de doctorA great number of scientific projects need supercomputing resources, such as, for example, those carried out in physics, astrophysics, chemistry, pharmacology, etc. Most of them generate, as well, a great amount of data; for example, a some minutes long experiment in a particle accelerator generates several terabytes of data. In the last years, high-performance computing environments have evolved towards large-scale distributed systems such as Grids, Clouds, and Volunteer Computing environments. Managing a great volume of data in these environments means an added huge problem since the data have to travel from one site to another through the internet. In this work a novel generic I/O architecture for large-scale distributed systems used for high-performance and high-throughput computing will be proposed. This solution is based on applying parallel I/O techniques to remote data access. Novel replication and data search schemes will also be proposed; schemes that, combined with the above techniques, will allow to improve the performance of those applications that execute in these environments. In addition, it will be proposed to develop simulation tools that allow to test these and other ideas without needing to use real platforms due to their technical and logistic limitations. An initial prototype of this solution has been evaluated and the results show a noteworthy improvement regarding to data access compared to existing solutions.Un gran número de proyectos científicos necesitan recursos de supercomputación como, por ejemplo, los llevados a cabo en física, astrofísica, química, farmacología, etc. Muchos de ellos generan, además, una gran cantidad de datos; por ejemplo, un experimento de unos minutos de duración en un acelerador de partículas genera varios terabytes de datos. Los entornos de computación de altas prestaciones han evolucionado en los últimos años hacia sistemas distribuidos a gran escala tales como Grids, Clouds y entornos de computación voluntaria. En estos entornos gestionar un gran volumen de datos supone un problema añadido de importantes dimensiones ya que los datos tienen que viajar de un sitio a otro a través de internet. En este trabajo se propondrá una nueva arquitectura de E/S genérica para sistemas distribuidos a gran escala usados para cómputo de altas prestaciones y de alta productividad. Esta solución se basa en la aplicación de técnicas de E/S paralela al acceso remoto a los datos. Así mismo, se estudiarán y propondrán nuevos esquemas de replicación y búsqueda de datos que, en combinación con las técnicas anteriores, permitan mejorar las prestaciones de aquellas aplicaciones que ejecuten en este tipo de entornos. También se propone desarrollar herramientas de simulación que permitan probar estas y otras ideas sin necesidad de recurrir a una plataforma real debido a las limitaciones técnicas y logísticas que ello supone. Se ha evaluado un prototipo inicial de esta solución y los resultados muestran una mejora significativa en el acceso a los datos sobre las soluciones existentes.Programa Oficial de Doctorado en Ciencia y Tecnología InformáticaPresidente: David Expósito Singh.- Secretario: María de los Santos Pérez Hernández.- Vocal: Juan Manuel Tirado Mart

Control of Liver Gene Expression by Sex Steroids and Growth Hormone Interplay

Sex steroids have important physiological actions, which are not limited to reproductive organs, in both females and males. They exert important physiological roles, including the regulation of somatotropic-liver axis, intermediate metabolism, or gender dimorphism. This is in part because the liver is a sex steroid-responsive organ where sex steroid- and growth hormone (GH)-dependent signaling pathways connect to regulate complex gene expression networks. Sex steroids can impact liver gene expression by a direct, through hepatic estrogen receptor (ER)α and androgen receptor (AR), or indirect mechanisms, by modulation of pituitary GH secretion and/or interaction with the GHR-STAT5b signaling pathway. Therefore, deficiency of sex steroid- and GH-dependent signaling pathways might cause a dramatic impact on mammalian liver physiology. In this chapter, we will focus our attention on main concepts and paradigms involved in the role and interplay between sex steroid- and GH-dependent signaling to regulate gene expression networks in the mammalian liver. A better understanding of how sex steroids and interactions with GH-STAT5b signaling pathway influence physiological and pathological states in the liver will contribute to improve clinical management of patients with disorders in body growth, development, and metabolism

Escrevendo a história com a comunidade: a experiência em Cotogchoa, Pichincha-Equador

Este artículo trata sobre la investigación realizada en la parroquia Cotogchoa, en la provincia de Pichincha-Ecuador, a partir del propio emprendimiento de sus dirigentes para escribir su historia. La labor de investigación historiográfica ha implicado la revisión de diferentes fuentes entre lo escritural, oral y visual para el análisis de la relación entre pasado y presente, historia y memoria, de una parroquia expuesta a fenómenos cambiantes de emigración y de urbanización./nLa investigación encierra una mirada a largo plazo con datos desde épocas tempranas, pasando por la relación laboral y social con la hacienda hasta la influencia de la Reforma Agraria y sus consecuencias visibles hasta hoy en el uso de la tierra. La emigración y la creciente urbanización han sido factores decisivos para emprender el análisis historiográfico de Cotogchoa.This article is about the research carried out in the parish of Cotogchoa, in the province of Pichincha-Ecuador, based on the undertaking of its leaders to write its history. The historiographic research work has entailed a revision of different sources between the scriptural, oral and visual for the analysis of the relationship between past and present, history and memory, of a parish exposed to changing phenomena of emigration and urbanization./nThe research encompasses a long-term view with data from early times, through the labor and social relationship with the hacienda to the influence of the Agrarian Reform and its visible consequences until today in land use. Emigration and increasing urbanization have been decisive factors in the historiographic analysis of Cotogchoa.Este artigo é sobre a pesquisa realizada na paróquia Cotogchoa, na província de Pichincha-Equador, com base no empreendedorismo de seus líderes para escrever sua história. O trabalho de pesquisa historiográfica envolveu a revisão de diferentes fontes entre as escrituras, a oral e a visual para a análise da relação entre passado e presente, história e memória de uma paróquia exposta a fenômenos mutantes de emigração e urbanização./nA pesquisa tem uma perspectiva de longo prazo com dados desde os primeiros tempos, através do relacionamento trabalhista e social com a fazenda até a influência da Reforma Agrária e suas conseqüências visíveis até hoje no uso da terra. A emigração e a crescente urbanização foram fatores decisivos para a análise historiográfica de Cotogchoa

JAK, an Oncokinase in Hematological Cancer

Janus kinases (JAKs) play an essential role in the regulation of cytokine signaling. They control cell survival, proliferation, differentiation, immune response, and hematopoiesis. Deregulation of JAK signaling has been associated to the pathogenesis of numerous immune-inflammatory diseases, hematological malignancies, and solid tumors. Thus, JAK proteins have emerged as attractive therapeutic targets in the last decade. The discovery of the gain-of-function JAK2 mutation (JAK2 V617F) as the main cause of polycythemia vera—a chronic myeloproliferative syndrome—led to the development of the JAK inhibitor ruxolitinib. This key finding opened the door to the search for new therapeutic agents able to suppress the constitutive activation of JAK signaling in hematological cancers and other tumors. However, given the conserved nature of the kinase domain among JAK family members, and the interrelated roles of JAK kinases in many physiological processes, including hematopoiesis and immunity, the broad usage of JAK inhibitors in hematology is challenged by their narrow therapeutic window. Novel therapies are, therefore, needed. This chapter focuses on the understanding of the complex signaling of JAK proteins in cancerous cells, the various JAK aberrations implicated in myeloproliferative neoplasms, leukemia, and lymphoma, and the clinically available JAK inhibitors in cancer therapy

Neuroendocrine effects of quetiapine in healthy volunteers

The present study measured prolactin, cortisol, ACTH and growth hormone in healthy male volunteers following an acute oral administration of quetiapine, an atypical antipsychotic with high affinity for H, and moderate affinity for sigma, sigma(1), 5-HT2, alpha(2) and D-2 receptors. Fifteen male volunteers entered this randomized double-blind, cross-over, placebo-controlled study. Blood samples were drawn every 30 min from 09:00 hours to 13:00 hours. the first samples were drawn immediately before the administration of 150 mg quetiapine or placebo. Mean results for each hormone and ANOVA for repeated measures were performed. the area under the curve (AUC) hormonal values were calculated and compared by paired t test. the ANOVA showed an increase of prolactin after quetiapine administration from time 60 min up to the end of the observation period. Cortisol decreased after quetiapine administration from time 150 min to time 240 min. ACTH secretion showed no difference compared to placebo. There was a late increase in growth hormone secretion, significant in comparison with placebo only at time 210 min. the AUC values were statistically different for prolactin and cortisol compared to placebo. A single dose of quetiapine (150 mg) increased prolactin secretion probably due to a transiently high D, receptor occupancy at the anterior pituitary. Cortisol secretion decreased as was expected from quetiapine's pharmacodynamic profile. the lack of response of ACTH might be, at least in part, explained by the low hormonal assay sensitivity. the late growth hormone increase might have been due to quetiapine's antagonism of H, receptors.Universidade Federal de São Paulo, Dept Psychobiol, São Paulo Sch Med, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, São Paulo Sch Med, BR-04023062 São Paulo, BrazilWeb of Scienc

Neurogenesis and depression: etiology or new ilusion?

New hippocampal neurons are continuously generated in the adult brain of several animal species. Several studies have demonstrated that a variety of enviromental factors, including stress, influence the proliferation of hippocampal cells. Thus, stress induced decrease of hippocampal neurogenesis seem to be an important factor in the etiology of depression. In this review the relationship between neurogenesis and depression has been emphasized.Novos neurônios continuam sendo gerados no cérebro adulto de diversas espécies animais. Muitos estudos têm demonstrado que diversos fatores ambientais, inclusive o estresse, influenciam a proliferação de células hipocampais. Nesse sentido, a diminuição da neurogênese induzida pelo estresse parece ser um importante fator na etiologia da depressão. Nessa revisão, a relação entre neurogênese e depressão é enfatizada.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de MedicinaUniversidade de Mogi das Cruzes Núcleo de Pesquisas TecnológicasUniversidade Federal de São Paulo (UNIFESP) Departamento de PsicobiologiaUNIFESP, EPMUNIFESP, Depto. de PsicobiologiaSciEL

Growth Hormone Receptor Signaling Pathways and its Negative Regulation by SOCS2

Growth hormone (GH) is a critical regulator of linear body growth during childhood but continues to have important metabolic actions throughout life. The GH receptor (GHR) is ubiquitously expressed, and deficiency of GHR signaling causes a dramatic impact on normal physiology during somatic development, adulthood, and aging. GHR belongs to a family of receptors without intrinsic kinase activity. However, GH binding to homodimers of GHR results in a conformational change in the receptors and the associated tyrosine kinase Janus kinase 2 (JAK2) molecules. Activated JAK2 phosphorylates the GHR cytoplasmic domain on tyrosine residues, and subsequent JAK2-dependent and JAK2-independent intracellular signal transduction pathways evoke cell responses including changes in gene transcription, proliferation, cytoskeletal reorganization, and lipid and glucose metabolism. JAK2 phosphorylates STAT5b, which is a key transcription factor in GH regulation of target genes associated with body growth, intermediate metabolism, and gender dimorphism; although STAT1, 3, and 5a have also been shown to be recruited by the GHR. In addition, many transcripts are regulated independently of STAT5b as a result of GHR activation of Src, ERK, and PI3K-mTOR signaling pathways. The analysis of molecular mechanisms involved in inactivation of GHR-dependent signaling pathway is also imperative for understanding GH physiology. This is clearly illustrated in the case of hepatic GHR-JAK2-STAT5b activation where signal duration regulates gender differences in liver gene expression. An early step in the termination of GH-dependent signaling is removal of GHRs by endocytosis and ubiquitination. The level of ubiquitin ligase SOCS2 is constitutively low, but its expression is rapidly induced by GH. SOCS2 binding to GHR complex promotes their ubiquitination and subsequent proteasomal degradation, contributing to the termination of the GH intracellular signaling. Clinically relevant, SOCS2 is a key negative regulator of GH-dependent body growth and lipid and glucose homeostasis. Furthermore, several cytokines, growth factors, xenobiotics, and sex hormones can regulate SOCS2 protein level, which provides a mechanism for cross-talking where multiple factors can regulate GHR signaling during somatic development. A better understanding of this complex regulation in physiological and pathological states will contribute to prevent health damage and improve clinical management of patients with growth and metabolic disorders

O transtorno bipolar na mulher

Gender differences, described in several psychiatric disorders, seem to be also present in bipolar disorder (BD). The prevalence of bipolar I disorder is equally distributed between women and men. Women seem to be at higher risk for rapid cycling and mixed mania, conditions that could make BD a disorder with a more severe course in the female sex. A marked depressive diathesis among women, greatest use of antidepressants and hormonal differences have been mentioned as hypotheses to explain these phenomenological differences. However, women and men seem to respond equally to medication. The indication of anticonvulsivants as first-line treatment in women is controversial, except for the treatment of mixed mania and, probably, rapid cycling.BD treatment during pregnancy must take into account risks related to medication effects as well as to the mother's illness. Prophylaxis in the postpartum is strongly recommended due to a great risk of recurrence in this period. Although psychotropic medication is generally contraindicated during lactation, among mood stabilizers, carbamazepine and valproate seem safer than lithium. Further studies are needed to confirm BD's course differences between women and men and to investigate possible impact on treatment effectiveness.Diferenças sexuais, descritas em vários transtornos psiquiátricos, também parecem estar presentes no transtorno afetivo bipolar (TAB). A prevalência do TAB tipo I se distribui igualmente entre mulheres e homens. Mulheres parecem estar sujeitas a um risco maior de ciclagem rápida e mania mista, condições que fariam do TAB um transtorno com curso mais prejudicial no sexo feminino. Uma diátese depressiva mais marcante, uso excessivo de antidepressivos e diferenças hormonais surgem como hipóteses para explicar essas diferenças fenomenológicas, apesar das quais, mulheres e homens parecem responder igualmente ao tratamento medicamentoso. A indicação de anticonvulsivantes como primeira escolha em mulheres é controversa, a não ser para o tratamento da mania mista e, talvez, da ciclagem rápida. O tratamento do TAB na gravidez deve levar em conta tanto os riscos de exposição aos medicamentos quanto à doença materna. A profilaxia do TAB no puerpério está fortemente indicada em decorrência do grande risco de recorrência da doença nesse período. Embora, de modo geral, as medicações psicotrópicas estejam contra-indicadas durante a amamentação, entre os estabilizadores do humor, a carbamazepina e o valproato são mais seguros do que o lítio. Mais estudos são necessários para a confirmação das diferenças de curso do TAB entre mulheres e homens e a investigação de possíveis diferenças na efetividade dos tratamentos

SkyCDS: A resilient content delivery service based on diversified cloud storage

Cloud-based storage is a popular outsourcing solution for organizations to deliver contents to end-users. However, there is a need for contingency plans to ensure service provision when the provider either suffers outages or is going out of business. This paper presents SkyCDS: a resilient content delivery service based on a publish/subscribe overlay over diversified cloud storage. SkyCDS splits the content delivery into metadata and content storage flow layers. The metadata flow layer is based on publish-subscribe patterns for insourcing the metadata control back to content owner. The storage layer is based on dispersal information over multiple cloud locations with which organizations outsource content storage in a controlled manner. In SkyCDS, the content dispersion is performed on the publisher side and the content retrieving process on the end-user side (the subscriber), which reduces the load on the organization side only to metadata management. SkyCDS also lowers the overhead of the content dispersion and retrieving processes by taking advantage of multi-core technology. A new allocation strategy based on cloud storage diversification and failure masking mechanisms minimize side effects of temporary, permanent cloud-based service outages and vendor lock-in. We developed a SkyCDS prototype that was evaluated by using synthetic workloads and a study case with real traces. Publish/subscribe queuing patterns were evaluated by using a simulation tool based on characterized metrics taken from experimental evaluation. The evaluation revealed the feasibility of SkyCDS in terms of performance, reliability and storage space profitability. It also shows a novel way to compare the storage/delivery options through risk assessment. (C) 2015 Elsevier B.V. All rights reserved.The work presented in this paper has been partially supported by EU under the COST programme Action IC1305, Network for Sustainable Ultrascale Computing (NESUS)