Lipotoxicity: the obese and endurance-trained paradox

The potential lipotoxic effect of intramyocellular triglyceride (IMTG) accumulation has been suggested to be a major component in the development of insulin resistance. Increased levels of IMTGs correlate with insulin resistance in both obese and diabetic patients, but this relationship does not exist in endurance trained (ETr) subjects. This may be, in part, related to differences in the gene expression and activities of key enzymes involved in fatty acid transport and oxidation as well as in the perodixation status of the IMTGs in obese/diabetic patients as compared with ETr subjects. Disruptions in fat and lipid homeostasis in skeletal muscle have been shown to activate protein kinase C (PKC), which acts on several downstream signalling pathways, including the insulin and the IB kinase (IKK)/NFB signalling pathways. Additionally, an increased peroxidation of IMTGs may reduce insulin sensitivity by increasing TNF, which is known to increase the expression of suppressor of cytokine signalling proteins (SOCS). A common characteristic observed when activating both PKC and TNF/SOCS3 is the inhibition of tyrosine phosphorylation of IRS-1 and subsequently an inhibition of its activation of downstream signalling molecules. These may be important players in the development of insulin resistance and understanding their activation and expression in both obese and ETr humans should assist in understanding how and why IMTGs become lipotoxic.

Blind source separation using second-order cyclostationary statistics

This paper studies the blind source separation (BSS) problem with the assumption that the source signals are cyclostationary. Identifiability and separability criteria based on second-order cyclostationary statistics (SOCS) alone are derived. The identifiability condition is used to define an appropriate contrast function. An iterative algorithm (ATH2) is derived to minimize this contrast function. This algorithm separates the sources even when they do not have distinct cycle frequencies .

The myeloproliferative disorder-associated JAK2 V617F mutant escapes negative regulation by suppressor of cytokine signaling 3

The somatic JAK2 valine-to-phenylalanine (V617F) mutation has been detected in up to 90% of patients with polycythemia and in a sizeable proportion of patients with other myeloproliferative disorders such as essential thrombocythemia and idiopathic myelofibrosis. Suppressor of cytokine signaling 3 (SOCS3) is known to be a strong negative regulator of erythropoietin (EPO) signaling through interaction with both the EPO receptor (EPOR) and JAK2. We report here that JAK2 V617F cannot be regulated and that its activation is actually potentiated in the presence of SOCS3. Instead of acting as a suppressor, SOCS3 enhanced the proliferation of cells expressing both JAK2 V617F and EPOR. Additionally, although SOCS1 and SOCS2 are degraded in the presence of JAK2 V617F, turnover of SOCS3 is inhibited by the JAK2 mutant kinase and this correlated with marked tyrosine phosphorylation of SOCS3 protein. We also observed constitutive tyrosine phosphorylation of SOCS3 in peripheral blood mononuclear cells (PBMCs) derived from patients homozygous for the JAK2 V617F mutant. These findings suggest that the JAK2 V617F has overcome normal SOCS regulation by hyperphosphorylating SOCS3, rendering it unable to inhibit the mutant kinase. Thus, JAK2 V617F may even exploit SOCS3 to potentiate its myeloproliferative capacity.

Exercise-induced activation of STAT3 signaling is increased with age

Activation of the transcription factor signal transducers and activators of transcription (STAT) 3 is common to many inflammatory cytokines and growth factors, with recent evidence of involvement in skeletal muscle regeneration. The purpose of this study was to determine whether STAT3 signaling activation is regulated differentially, at rest and following intense resistance exercise, in aged human skeletal muscle. Skeletal muscle biopsies were harvested from healthy younger (n = 11, 20.4 ± 0.8 years) and older men (n = 10, 67.4 ± 1.3 years) under resting conditions and 2 h after the completion of resistance exercise. No differences were evident at rest, whereas the phosphorylation of STAT3 was significantly increased in old (23-fold) compared to young (5-fold) subjects after exercise. This correlated with significantly higher induction of the STAT3 target genes including; interleukin-6 (IL-6), JUNB, c-MYC, and suppressor of cytokine signaling (SOCS) 3 mRNA in older subjects following exercise. Despite increased SOCS3 mRNA, cellular protein abundance was suppressed. SOCS3 protein is an important negative regulator of STAT3 activation and cytokine signaling. Thus, in aged human muscle, elevated responsiveness of the STAT3 signaling pathway and suppressed SOCS3 protein are evident following resistance exercise. These data suggest that enhanced STAT3 signaling responsiveness to proinflammatory factors may impact on mechanisms of muscle repair and regeneration.

Stat5 as a diagnostic marker for leukemia

The Jak-Stat-Socs pathway is an important component of cytokine receptor signaling. Not surprisingly, perturbation of this pathway is implicated in diseases of hematopoietic and immune origin, including leukemia, lymphoma and immune deficiencies. This review examines the role of a key component of this pathway, Stat5. This has been shown to be activated in a variety of leukemias and myeloproliferative disorders, including downstream of a range of key oncogenes where it has been shown to play an important role in mediating their effects. Therefore, Stat5 represents a useful pan-leukemia/myeloproliferative disorder diagnostic marker and key therapeutic end point, as well as representing an attractive therapeutic target for these disorders.

Suppressors of cytokine signaling : functions in normal biology and roles in disease

Suppressor of cytokine signaling (SaCS) proteins have been identified as key negative regulators of cytokine and growth factor signaling. Therefore, given the diverse roles played by cytokines and growth factors in development and disease, it is not surprising that the sacs proteins themselves possess equally diverse and important functions, such as the control of hematopoiesis, immune function, growth and placental development. Significantly, more recent studies are increaSingly highlighting the crucial roles played by SOCS proteins in disease, particularly their tumor suppressor and anti-infammatory functions. Collectively, this research has served to confirm the importance of this class of proteins and suggests that therapeutic strategies for modulating SOCS proteins might be relevant for a range of diseases.

Evolution of JAK-STAT pathway components : mechanisms and role in immune system development

Background
Lying downstream of a myriad of cytokine receptors, the Janus kinase (JAK) – Signal transducer and activator of transcription (STAT) pathway is pivotal for the development and function of the immune system, with additional important roles in other biological systems. To gain further insight into immune system evolution, we have performed a comprehensive bioinformatic analysis of the JAK-STAT pathway components, including the key negative regulators of this pathway, the SH2-domain containing tyrosine phosphatase (SHP), Protein inhibitors against Stats (PIAS), and Suppressor of cytokine signaling (SOCS) proteins across a diverse range of organisms.

Results
Our analysis has demonstrated significant expansion of JAK-STAT pathway components co-incident with the emergence of adaptive immunity, with whole genome duplication being the principal mechanism for generating this additional diversity. In contrast, expansion of upstream cytokine receptors appears to be a pivotal driver for the differential diversification of specific pathway components.

Conclusion
Diversification of JAK-STAT pathway components during early vertebrate development occurred concurrently with a major expansion of upstream cytokine receptors and two rounds of whole genome duplications. This produced an intricate cell-cell communication system that has made a significant contribution to the evolution of the immune system, particularly the emergence of adaptive immunity.

Evolution of the JAK-STAT pathway

The JAK-STAT pathway represents a finely tuned orchestra capable of rapidly facilitating an exquisite symphony of responses from a complex array of extracellular signals. This review explores the evolution of the JAK-STAT pathway: the origins of the individual domains from which it is constructed, the formation of individual components from these basic building blocks, the assembly of the components into a functional pathway, and the subsequent reiteration of this basic template to fulfill a variety of roles downstream of cytokine receptors.

Modelos para o mapeamento de aplicações em infra-estruturas de comunicação intrachip

O projeto de sistemas intrachip (SoCs) é uma atividade de alto grau de complexidade, dados a dimensão de SoCs, na ordem do bilhão de transistores, os requisitos de tempo de desenvolvimento e de consumo de energia, entre outros fatores. A forma de dominar a complexidade de projeto de SoCs inclui dividir a funcionalidade do sistema em módulos de menor complexidade, denominados de núcleos de propriedade intelectual (núcleos IP), interligados por uma infra-estrutura de comunicação. Enquanto núcleos IP podem ser reusados de outros projetos ou adquiridos de terceiros, a infra-estrutura de comunicação deve sempre ser desenvolvida de forma personalizada para cada SoC. O presente trabalho volta-se para o projeto de infraestruturas de comunicação eficientes. Questões importantes neste contexto são a eficiência da comunicação, refletida e.g. em medidas de vazão e latência, a redução de área de silício para implementar a comunicação, e a redução da energia consumida na comunicação. Estas questões dependem da escolha da infra-estrutura de comunicação. Barramentos são as infra-estruturas mais usadas nas comunicações intrachip, mas têm sido consideradas como pouco adequadas para servir a necessidade de comunicação de SoCs futuros. Redes intrachip vêm emergindo como um possível melhor candidato. Nesta infra-estrutura de comunicação, um problema a ser resolvido é o posicionamento relativo de núcleos IP dentro da rede, visando otimizar desempenho e reduzir o consumo de energia, no que se denomina aqui problema de mapeamento. Dada a complexidade deste problema, considera-se fundamental dispor de modelos para capturar as características da infra-estrutura de comunicação, bem como da aplicação que a emprega A principal contribuição deste trabalho é propor e avaliar um conjunto de modelos de computação voltados para a solução do problema de mapeamento de núcleos de propriedade intelectual sobre uma infra-estrutura de comunicação. Três modelos são propostos (CDM, CDCM e ECWM) e comparados, entre si e com três outros disponíveis na literatura (CWM, CTM e ACPM). Embora os modelos sejam genéricos, os estudos de caso restringem-se aqui a infra-estruturas de comunicação do tipo rede intrachip. Dada a diversidade de modelos de mapeamento, propõe-se uma segunda contribuição, o metamodelo Quantidade, Ordem, Dependência (QOD), que relaciona modelos de mapeamento usando os critérios expressos na denominação QOD. Considerando o alto grau de abstração dos modelos empregados, julga-se necessário prover uma conexão com níveis inferiores da hierarquia de projeto. Neste sentido, uma terceira contribuição original do presente trabalho é a proposta de modelos de consumo de energia e tempo de comunicação para redes intrachip. Visando demonstrar a validade de todos os modelos propostos, foram desenvolvidos métodos de uso destes na solução do problema de mapeamento, o que constitui uma quarta contribuição. Estes métodos incluem algoritmos de mapeamento, estimativas de tempo de execução, consumo de energia e caminhos críticos em infra-estruturas de comunicação. Como quinta contribuição, propõe-se o framework CAFES, que integra os métodos desenvolvidos e os modelos de mapeamento em algoritmos computacionais. Uma última contribuição do presente trabalho é um método habilitando a estimativa de consumo de energia para infra-estruturas de comunicação e sua implementação como uma ferramenta computacional.

Redes-em-chip de baixo custo

Com as recentes tecnologias de fabricação é possível integrar milhões de transistores em um único chip, permitindo a criação dos chamados System-on-Chip (SoCs), que integram em um único chip um grande número de componentes (tipicamente blocos reutilizáveis conhecidos por núcleos). Quanto mais complexos forem estes sistemas, melhores técnicas de projeto serão necessárias para também reduzir o tempo e custo do projeto. Uma destas técnicas, chamada de Network-on-Chip (NoC), permite melhorar a performance da comunicação entre os núcleos e, ao mesmo tempo, fornecer uma plataforma de comunicação escalável e que pode ser reutilizada para um grande número de sistemas. Uma NoC pode ser definida como uma estrutura de roteadores e canais ponto-a-ponto que interconectam os núcleos de um sistema, provendo o suporte de comunicação entre eles. Os dados são transmitidos pela rede na forma de mensagens, que podem ser divididas em unidades menores chamadas de pacote. Uma das desvantagens desta plataforma de comunicação é o impacto na área do sistema causado pelos roteadores. Dentro deste contexto, este trabalho apresenta uma arquitetura de roteador de baixo custo, com o objetivo de permitir o uso de NoCs em sistemas onde a área do roteador representará um grande impacto no custo do sistema. A arquitetura deste roteador, chamado de Tonga, é baseada em um roteador chamado RASoC, um soft-core para SoCs. Nesta dissertação será apresentada também uma rede heterogênea, baseada na rede SoCIN, e composta por dois tipos de roteadores – RASoC e Tonga. Estes roteadores visam diferentes objetivos: Rasoc alcança uma maior performance comparada ao Tonga, mas ocupa área consideravelmente maior. Potencialmente, uma NoC heterogênea otimizada pode ser desenvolvida combinando estes roteadores, procurando o melhor compromisso entre área e latência. Os modelos desenvolvidos permitem a estimativa de área e do desempenho das arquiteturas de comunicação propostas e são apresentados resultados de performance para algumas aplicações.

Estudo da viabilidade do desenvolvimento de sistemas integrados baseados em redes em chip sem processadores: sistema IPNoSys

The increase of capacity to integrate transistors permitted to develop completed systems, with several components, in single chip, they are called SoC (System-on-Chip). However, the interconnection subsystem cans influence the scalability of SoCs, like buses, or can be an ad hoc solution, like bus hierarchy. Thus, the ideal interconnection subsystem to SoCs is the Network-on-Chip (NoC). The NoCs permit to use simultaneous point-to-point channels between components and they can be reused in other projects. However, the NoCs can raise the complexity of project, the area in chip and the dissipated power. Thus, it is necessary or to modify the way how to use them or to change the development paradigm. Thus, a system based on NoC is proposed, where the applications are described through packages and performed in each router between source and destination, without traditional processors. To perform applications, independent of number of instructions and of the NoC dimensions, it was developed the spiral complement algorithm, which finds other destination until all instructions has been performed. Therefore, the objective is to study the viability of development that system, denominated IPNoSys system. In this study, it was developed a tool in SystemC, using accurate cycle, to simulate the system that performs applications, which was implemented in a package description language, also developed to this study. Through the simulation tool, several result were obtained that could be used to evaluate the system performance. The methodology used to describe the application corresponds to transform the high level application in data-flow graph that become one or more packages. This methodology was used in three applications: a counter, DCT-2D and float add. The counter was used to evaluate a deadlock solution and to perform parallel application. The DCT was used to compare to STORM platform. Finally, the float add aimed to evaluate the efficiency of the software routine to perform a unimplemented hardware instruction. The results from simulation confirm the viability of development of IPNoSys system. They showed that is possible to perform application described in packages, sequentially or parallelly, without interruptions caused by deadlock, and also showed that the execution time of IPNoSys is more efficient than the STORM platform

Simulação de reservatórios de petróleo em ambiente MPSoC

The constant increase of complexity in computer applications demands the development of more powerful hardware support for them. With processor's operational frequency reaching its limit, the most viable solution is the use of parallelism. Based on parallelism techniques and the progressive growth in the capacity of transistors integration in a single chip is the concept of MPSoCs (Multi-Processor System-on-Chip). MPSoCs will eventually become a cheaper and faster alternative to supercomputers and clusters, and applications developed for these high performance systems will migrate to computers equipped with MP-SoCs containing dozens to hundreds of computation cores. In particular, applications in the area of oil and natural gas exploration are also characterized by the high processing capacity required and would benefit greatly from these high performance systems. This work intends to evaluate a traditional and complex application of the oil and gas industry known as reservoir simulation, developing a solution with integrated computational systems in a single chip, with hundreds of functional unities. For this, as the STORM (MPSoC Directory-Based Platform) platform already has a shared memory model, a new distributed memory model were developed. Also a message passing library has been developed folowing MPI standard

Expression of the Interleukin-10 Signaling Pathway Genes in Individuals With Down Syndrome and Periodontitis

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)