REST: transcriptional and epigenetic regulator

Acquisition and maintenance of cell fate and potential are dependent on the complex interplay of extracellular signaling, gene regulatory networks and epigenetic states. During embryonic development, embryonic stem cells become progressively more restricted along specific lineages, ultimately giving rise to the diversity of cell types in the adult mammalian organism. Recent years have seen major advances in our understanding of the mechanisms that regulate the underlying transcriptional programmes during development. In particular, there has been a significant increase in our knowledge of how epigenetic marks on chromatin can regulate transcription by generating more or less permissive chromatin conformations. This article focuses on how a single transcription factor, repressor element-1 silencing transcription factor, can function as both a transcriptional and epigenetic regulator, controlling diverse aspects of development. We will discuss how the elucidation of repressor element-1 silencing transcription factor function in both normal and disease conditions has provided valuable insights into how the epigenome and transcriptional regulators might cooperatively orchestrate correct development.

Rescue of gene expression by modified REST decoy oligonucleotides in a cellular model of Huntington's disease

Transcriptional dysfunction is a prominent hallmark of Huntington's disease (HD). Several transcription factors have been implicated in the aetiology of HD progression and one of the most prominent is repressor element 1 (RE1) silencing transcription factor (REST). REST is a global repressor of neuronal gene expression and in the presence of mutant Huntingtin increased nuclear REST levels lead to elevated RE1 occupancy and a concomitant increase in target gene repression, including brain-derived neurotrophic factor. It is of great interest to devise strategies to reverse transcriptional dysregulation caused by increased nuclear REST and determine the consequences in HD. Thus far, such strategies have involved RNAi or mutant REST constructs. Decoys are double-stranded oligodeoxynucleotides corresponding to the DNA-binding element of a transcription factor and act to sequester it, thereby abrogating its transcriptional activity. Here, we report the use of a novel decoy strategy to rescue REST target gene expression in a cellular model of HD. We show that delivery of the decoy in cells expressing mutant Huntingtin leads to its specific interaction with REST, a reduction in REST occupancy of RE1s and rescue of target gene expression, including Bdnf. These data point to an alternative strategy for rebalancing the transcriptional dysregulation in HD.

The role of REST in transcriptional and epigenetic dysregulation in Huntington's disease

Huntington's disease (HD) is a devastating disorder that affects approximately 1 in 10,000 people and is accompanied by neuronal dysfunction and neurodegeneration. HD manifests as a progressive chorea, a decline in mental abilities accompanied by behavioural, emotional and psychiatric problems followed by, dementia, and ultimately, death. The molecular pathology of HD is complex but includes widespread transcriptional dysregulation. Although many transcriptional regulatory molecules have been implicated in the pathogenesis of HD, a growing body of evidence points to the pivotal role of RE1 Silencing Transcription Factor (REST). In HD, REST, translocates from the cytoplasm to the nucleus in neurons resulting in repression of key target genes such as BDNF. Since these original observations, several thousand direct target genes of REST have been identified, including numerous non-coding RNAs including both microRNAs and long non-coding RNAs, several of which are dysregulated in HD. More recently, evidence is emerging that hints at epigenetic abnormalities in HD brain. This in turn, promotes the notion that targeting the epigenetic machinery may be a useful strategy for treatment of some aspects of HD. REST also recruits a host of histone and chromatin modifying activities that can regulate the local epigenetic signature at REST target genes. Collectively, these observations present REST as a hub that coordinates transcriptional, posttranscriptional and epigenetic programmes, many of which are disrupted in HD. We identify several spokes emanating from this REST hub that may represent useful sites to redress REST dysfunction in HD.

Reward, rest, and antidepressant drug action

Purpose of the study: Reduced subjective experience of reward (anhedonia) is a key symptom of major depression. We have developed a human model of reward processing to investigate the neural correlates of anhedonia. Methods: We report the data from studies that examined reward processing using functional magnetic resonance imaging (fMRI) in those vulnerable to depression. We also report the effects of antidepressant medications on our neural model of reward processing and on the resting state in healthy volunteers. Results: Our results thus far indicate that deficits in reward processing are apparent in those vulnerable to depression, and also that antidepressant medication modulates reward processing and resting state functional connectivity in parts of the brain consistent with serotonin and catecholamine transmitter pathways in healthy volunteers. Conclusions: We conclude that this type of human model of reward processing might be useful in detecting biomarkers for depression and also in illuminating why antidepressant medications may not be very effective in treating anhedonia.

Day of rest - Peter Fry

[Parte 2: Filme "Day of Rest"]

Why the ‘Rest’ doesn’t need foreign finance

The Rest will be able to catch up and grow faster than the West only if it goes against a “received truth”, namely that capital-rich countries should transfer their capital to capital-poor countries. This intuitive truth is the mantra that the West cites to justify its occupation of the markets of developing countries with its finance and its multinationals. Classical Developmentalism successfully criticized the unequal exchange involved in trade liberalization, but it didn’t succeed in criticizing foreign finance. This task has been recently achieved by New Developmentalism and its developmental macroeconomics, which shows that countries will invest and grow more if they don’t run current account deficits, even when these deficits are financed by foreign direct investment

Tábula: uma framework para o desenvolvimento de aplicações REST

O desenvolvimento de aplicações web nos nossos dias é uma área importante, devido à disseminação do acesso à Internet e à utilização do browser como uma aplicação cliente universal. A aplicação web típica em HTML está sendo desafiada por tecnologias que permitem interfaces ricas que comunicam com um backend através de serviços. As ferramentas existentes para criar aplicações web ainda não adoptaram esta abordagem e o suporte existente é omissa em oferecer programadores ferramentas dinâmicas e fáceis de usar. Web Services tradicionais baseados em SOAP e Representacional State Transfer (REST) são alternativas para a comunicação entre o frontend e no backend. O REST ganhou recentemente visibilidade e a sua menor dificuldade de aprendizagem parece adequada para muitas aplicações. No entanto, a falta de normas leva a implementar serviços REST de muitas formas diferentes, mesmo na mesma plataforma, não existindo um acordo comum sobre como descrevê-los. Nesta dissertação, propomos uma nova framework para o desenvolvimento rápido de aplicações baseadas em REST. Para esse efeito, especificações e serviços de administração são apresentadas a fim de resolver os problemas de configuração de uma camada de serviços baseada em REST. Além disso, é apresentada uma nova abordagem para processar os pedidos, permitindo também a aplicação dos princípios AOP. Finalmente, é apresentada a implementação de uma framework que suporte estas especificações. Neste âmbito, temos por objectivo expor as potencialidades dinâmicas desta framework, tendo em vista a maximização da produtividade do programador na criação de aplicações baseadas em REST, minimizando o reinício do servidor e suportando dinamicamente uma ampla gama de mudanças.

Preliminary Study of the Gastric Acidity in Thoroughbred Horses at Rest after Enteral Administration of Esomeprazole Magnesium (Nexium)

The regulation of gastric secretion is of crucial importance to the equilibrium of the gastroenteric system. Despite the large number of factors involved in the causes of peptic illnesses, pH = 4 is considered the threshold between physiologic and deleterious effects of stomach acid secretion. With the aim of maintaining pH greater than 4, proton-pump inhibitors, such as esomeprazole magnesium (NEXIUM), have shown excellent results in the control of acid secretion. Aimed at examining the action of this drug in the control of pH levels of gastric secretion in thoroughbreds, a single dose of 40 or 80 mg of esomeprazole magnesium was administered daily, and pH was determined serially for 5 consecutive days. The results obtained corroborated the efficacy of esomeprazole magnesium in the control of gastric pH at both doses tested, with 100% of the mean pH being greater than 5. Moreover, no statistical difference was noted between the two doses tested.

Effect of occlusal splint thickness on electrical masticatory muscle activity during rest and clenching

The extent of separation between the maxillary and mandibular teeth in the fabrication of interocclusal splints designed to achieve efficiency and muscle relaxation is controversial and undefined in the literature. Based on this premise, the aim of this study was to evaluate the effect of interocclusal splint thicknesses of 3 and 6 millimeters on the electrical activity of the anterior temporal and masseter muscles during rest and dental clenching. Twenty asymptomatic individuals (10 males and 10 females) were selected using the Research Diagnostic Criteria (RDC). Electromyography (EMG) was performed both with and without the 3- and 6-mm splints using the Bio EMG software package, which recorded values given in microvolts (mu V). The results, which were assessed using analysis of variance (ANOVA) to a 5% significance level (p < 0.05), showed increased electrical activity of the masticatory muscles during dental clenching compared with at rest, with greater activity in the masseter muscle. The electrical activity did not differ according to the thickness of the splints or between males and females. We can conclude that both splint thicknesses are effective in treating muscle hyperactivity given their similar clinical behavior for asymptomatic individuals.

Manipulation of Rest Period Length Induces Different Causes of Fatigue in Vertical Jumping

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Quality of natural coffee subjected to different rest periods during the drying process

O parcelamento da secagem pode ser eficiente tanto no que diz respeito à qualidade final do café, quanto na redução do consumo específico de energia. Diante disso, objetivou-se, com o presente trabalho, avaliar o efeito do teor de água dos frutos no momento da interrupção da secagem e do período de repouso até a retomada da secagem na qualidade do café natural, por meio da análise sensorial e dos testes de condutividade elétrica e lixiviação de potássio. Frutos de café maduros foram colhidos manual e seletivamente e, em seguida, secados ao sol em terreiros de concreto por dois dias e, então, submetidos à secagem mecânica em secadores de camada fixa. Quando o café atingiu os teores de água de 20%, 17% e 14% (base úmida, bu), a secagem foi interrompida e o café permaneceu em repouso por cinco, quinze e trinta dias e, posteriormente, foi secado em secadores mecânicos até o teor de água de 11% (bu). O controle constituiu-se na secagem completa em terreiro. Observou-se que as combinações entre o menor teor de água e o maior período de repouso e entre o maior teor de água e o menor período de repouso, proporcionam menores valores de lixiviação de potássio. A qualidade da bebida melhora progressivamente com o aumento do período de repouso. A interrupção da secagem com teores de água de 17% e 20% (bu) não altera a qualidade do café natural, comparativamente à secagem completa em terreiro.

Electromyographic study of the temporal, masseter and suprahyoid muscles in the mandibular rest position

The temporal muscles (anterior position), and the masseter and suprahyoid muscles were studied electromyographically in 15 subjects with ages ranging from 18 to 35 years, showing normal occlusion (Class I of angle), complete dentition and no dysfunction of the stomatognathic system. The volunteers sat comfortably in a chair, keeping the Frankfurt plane parallel to the boor; the muscles were analysed in the mandibular resting position through a number of stages: with minimum exteroceptive stimuli, relaxation with soft music, abolition of the intrabuccal negative pressure through a plastic tube, stress provoked by an electronic game, disocclusion of posterior teeth using the occlusal splint and finally withdrawal of this device. The electromyographic results were analysed statistically. The samples, were analysed for all of the frequencies of motor units, in a 1-min period. It was found that there were statistically significant difference between the relaxation stages as compared with the withdrawal of negative intraoral pressure and mainly with the stress phase, being this only on the suprahyoid muscles, with 5% significance.