Allosteric activation of Hsp70 reduces mutant huntingtin levels, the clustering of N-terminal fragments, and their nuclear accumulation

AIMS: Huntington's disease (HD) is caused by a mutant huntingtin protein that misfolds, yields toxic N-terminal fragments, aggregates, and disrupts proteostasis. The Hsp70 chaperone is a potential therapeutic target as it prevents proteotoxicity by favouring protein folding, disaggregation, or degradation. We tested the hypothesis that allosteric Hsp70 activation with a pharmacological mimetic of the Hsp70 co-chaperone Hip, YM-1, could modulate huntingtin proteostasis. MAIN METHODS: We used HD cell models expressing either N-terminal or full-length huntingtin. Using single-cell analysis we studied huntingtin aggregation in different cellular compartments by fluorescence microscopy. Protein interaction was evaluated by immunoprecipitation, while protein levels were quantified by immunofluorescence and western-blot. KEY FINDINGS: N-terminal huntingtin interacted with Hsp70 and increased its levels. Treatment with YM-1 reduced N-terminal huntingtin clustering and nuclear aggregation. Full-length mutant huntingtin also interacted with Hsp70, and treatment with YM-1 reduced huntingtin levels when combined with Hsp70 induction by heat shock. Mechanistically, YM-1 increases the Hsp70 affinity for substrates, promoting their proteasomal degradation. Consistently, YM-1 reduced the levels of ubiquitinated proteins. Interestingly, YM-1 accumulated in mitochondria, interfered with its Hsp70 isoform involved in protein import, and increased NRF1 levels, a regulator of proteasome genes. We thus suggest that YM-1 may trigger the coordination of mitochondrial and cytosolic proteostasis, enhancing protein degradation. SIGNIFICANCE: Our findings show that the strategy of allosteric Hsp70 activation holds potential for HD. While drug efficacy may be limited to tissues with elevated Hsp70, combined therapies with Hsp70 elevating strategies could harness the full potential of allosteric Hsp70 activators for HD

Safe Parallelism: Compiler Analysis Techniques for Ada and OpenMP

There is a growing need to support parallel computation in Ada to cope with the performance requirements of the most advanced functionalities of safety-critical systems. In that regard, the use of parallel programming models is paramount to exploit the benefits of parallelism. Recent works motivate the use of OpenMP for being a de facto standard in high-performance computing for programming shared memory architectures. These works address two important aspects towards the introduction of OpenMP in Ada: the compatibility of the OpenMP syntax with the Ada language, and the interoperability of the OpenMP and the Ada runtimes, demonstrating that OpenMP complements and supports the structured parallelism approach of the tasklet model. This paper addresses a third fundamental aspect: functional safety from a compiler perspective. Particularly, it focuses on race conditions and considers the fine-grain and unstructured capabilities of OpenMP. Hereof, this paper presents a new compiler analysis technique that: (1) identifies potential race conditions in parallel Ada programs based on OpenMP or Ada tasks or both, and (2) provides solutions for the detected races.This work was supported by the Spanish Ministry of Science and Innovation under contract TIN2015-65316-P, and by the FCT (Portuguese Foundation for Science and Technology) within the CISTER Research Unit (CEC/04234).Peer ReviewedPostprint (author's final draft

An architecture for reliable distributed computer-controlled systems

In Distributed Computer-Controlled Systems (DCCS), both real-time and reliability requirements are of major concern. Architectures for DCCS must be designed considering the integration of processing nodes and the underlying communication infrastructure. Such integration must be provided by appropriate software support services. In this paper, an architecture for DCCS is presented, its structure is outlined, and the services provided by the support software are presented. These are considered in order to guarantee the real-time and reliability requirements placed by current and future systems

A serious game enhancing social tenants' behavioral change towards energy efficiency

The energy consumption of the current building stock represents about 40% of the total final energy consumption in Europe. New gamification techniques may play a significant role in helping users adopt new and more energy efficient behaviours. This paper presents the advances achieved within the context of the EU-funded project EnerGAware - Energy Game for Awareness of energy efficiency in social housing communities. The main objective of the project, funded by the European Union under the Horizon2020 programme, is to reduce the energy consumption and carbon emissions in a sample of European social housing by changing the energy efficiency behaviour of the social tenants through the implementation of a serious game linked to the real energy use of the participants' homes

OpenMP tasking model for Ada: safety and correctness

22nd International Conference on Reliable Software Technologies (Ada-Europe 2017). 12 to 16, Jun, 2017. Vienna, Austria.The safety-critical real-time embedded domain increasingly demands the use of parallel architectures to fulfill performance requirements. Such architectures require the use of parallel programming models to exploit the underlying parallelism. This paper evaluates the applicability of using OpenMP, a widespread parallel programming model, with Ada, a language widely used in the safety-critical domain. Concretely, this paper shows that applying the OpenMP tasking model to exploit fine-grained parallelism within Ada tasks does not impact on programs safeness and correctness, which is vital in the environments where Ada is mostly used. Moreover, we compare the OpenMP tasking model with the proposal of Ada extensions to define parallel blocks, parallel loops and reductions. Overall, we conclude that the OpenMP tasking model can be safely used in such environments, being a promising approach to exploit fine-grain parallelism in Ada tasks, and we identify the issues which still need to be further researched.info:eu-repo/semantics/publishedVersio

District Health Managers' Perceptions of Supervision in Malawi and Tanzania.

Mid-level cadres are being used to address human resource shortages in many African contexts, but insufficient and ineffective human resource management is compromising their performance. Supervision plays a key role in performance and motivation, but is frequently characterised by periodic inspection and control, rather than support and feedback to improve performance. This paper explores the perceptions of district health management teams in Tanzania and Malawi on their role as supervisors and on the challenges to effective supervision at the district level. This qualitative study took place as part of a broader project, "Health Systems Strengthening for Equity: The Power and Potential of Mid-Level Providers". Semi-structured interviews were conducted with 20 district health management team personnel in Malawi and 37 council health team members in Tanzania. The interviews covered a range of human resource management issues, including supervision and performance assessment, staff job descriptions and roles, motivation and working conditions. Participants displayed varying attitudes to the nature and purpose of the supervision process. Much of the discourse in Malawi centred on inspection and control, while interviewees in Tanzania were more likely to articulate a paradigm characterised by support and improvement. In both countries, facility level performance metrics dominated. The lack of competency-based indicators or clear standards to assess individual health worker performance were considered problematic. Shortages of staff, at both district and facility level, were described as a major impediment to carrying out regular supervisory visits. Other challenges included conflicting and multiple responsibilities of district health team staff and financial constraints. Supervision is a central component of effective human resource management. Policy level attention is crucial to ensure a systematic, structured process that is based on common understandings of the role and purpose of supervision. This is particularly important in a context where the majority of staff are mid-level cadres for whom regulation and guidelines may not be as formalised or well-developed as for traditional cadres, such as registered nurses and medical doctors. Supervision needs to be adequately resourced and supported in order to improve performance and retention at the district level

Acesso a Tratamento Endovascular para Acidente Vascular Cerebral Isquémico em Portugal

Introduction: Since the publication of endovascular treatment trials and European Stroke Guidelines, Portugal has re-organized stroke healthcare. The nine centers performing endovascular treatment are not equally distributed within the country, which may lead to differential access to endovascular treatment. Our main aim was to perform a descriptive analysis of the main treatment metrics regarding endovascular treatment in mainland Portugal and its administrative districts. Material and methods: A retrospective national multicentric cohort study was conducted, including all ischemic stroke patients treated with endovascular treatment in mainland Portugal over two years (July 2015 to June 2017). All endovascular treatment centers contributed to an anonymized database. Demographic, stroke-related and procedure-related variables were collected. Crude endovascular treatment rates were calculated per 100 000 inhabitants for mainland Portugal, and each district and endovascular treatment standardized ratios (indirect age-sex standardization) were also calculated. Patient time metrics were computed as the median time between stroke onset, first-door, and puncture. Results: A total of 1625 endovascular treatment procedures were registered. The endovascular treatment rate was 8.27/100 000 inhabitants/year. We found regional heterogeneity in endovascular treatment rates (1.58 to 16.53/100 000/year), with higher rates in districts closer to endovascular treatment centers. When analyzed by district, the median time from stroke onset to puncture ranged from 212 to 432 minutes, reflecting regional heterogeneity. Discussion: Overall endovascular treatment rates and procedural times in Portugal are comparable to other international registries. We found geographic heterogeneity, with lower endovascular treatment rates and longer onset-to-puncture time in southern and inner regions. Conclusion: The overall national rate of EVT in the first two years after the organization of EVT-capable centers is one of the highest among European countries, however, significant regional disparities were documented. Moreover, stroke-onset-to-first-door times and in-hospital procedural times in the EVT centers were comparable to those reported in the randomized controlled trials performed in high-volume tertiary hospitals.info:eu-repo/semantics/publishedVersio

Motivos e consequências da baixa adesão às precauções padrão pela equipe de enfermagem

As precauções padrão (PP) são recomendações para prevenir infecções e proteger os trabalhadores de saúde durante a prestação de cuidados. Porém, constata-se baixa adesão a estas recomendações.Objetivo: Analisar os motivos e as consequências da baixa adesão às PP pela equipe de enfermagem.Método: Revisão integrativa da literatura, busca em sete bases de dados, período de 2005 a 2014.Resultados: 30 artigos foram selecionados para análise. Os motivos da baixa adesão evidenciados relacionam-se a práticas deficitárias de educação permanente, comportamentos de risco de trabalhadores, provisão de material e equipamentos de proteção inadequados e condições de trabalho inadequadas. As consequências são os acidentes e as doenças do trabalho. Os estudos de intervenção são escassos e limitam-se à educação dos profissionais.Conclusões: A baixa adesão às PP está vinculada a aspectos individuais dos trabalhadores e às instituições empregadoras e formadoras. As estratégias de intervenção realizadas mostram-se pouco eficientes por focar apenas o trabalhador.Palavras-chave: Precauções padrão. Precauções universais. Saúde ocupacional. Prevenção de acidentes. Equipe de enfermagem

Epigenetic change in e-cardherin and COX-2 to predict chronic periodontitis

<p>Abstract</p> <p>Background</p> <p>DNA methylation of certain genes frequently occurs in neoplastic cells. Although the cause remains unknown, many genes have been identified with such atypical methylation in neoplastic cells. The hypermethylation of E-Cadherin and Cyclooxygenase 2 (COX-2) in chronic inflammation such as chronic periodontitis may demonstrate mild lesion/mutation epigenetic level. This study compares the hypermethylation status of E-Cadherin and COX-2 genes which are often found in breast cancer patients with that in chronic periodontitis.</p> <p>Methods</p> <p>Total DNA was extracted from the blood samples of 108 systemically healthy non-periodontitis subjects, and the gingival tissues and blood samples of 110 chronic periodontitis patient as well as neoplastic tissues of 106 breast cancer patients. Methylation-specific PCR for E-Cadherin and COX-2 was performed on these samples and the PCR products were analyzed on 2% agarose gel.</p> <p>Results</p> <p>Hypermethylation of E-Cadherin and COX-2 was observed in 38% and 35% of the breast cancer samples, respectively. In chronic periodontitis patients the detection rate was 25% and 19% respectively, and none was found in the systemically healthy non-periodontitis control subjects. The hypermethylation status was shown to be correlated among the three groups with statistical significance (p < 0.0001). The methylation of CpG islands in E-Cadherin and COX-2 genes in periodontitis patients occurs more frequently in periodontitis patients than in the control subjects, but occurs less frequently than in the breast cancer patients.</p> <p>Conclusions</p> <p>This set of data shows that the epigenetic change in E-Cadherin and Cyclooxygenase-2 is associated with chronic periodontitis. The epigenetic changes presented in chronic inflammation patients might demonstrate an irreversible destruction in the tissues or organs similar to the effects of cancer. Chronic periodontitis to some extent might be associated with DNA hypermethylation which is related to cancer risk factors.</p

Frequency and genotypic distribution of GB virus C (GBV-C) among Colombian population with Hepatitis B (HBV) or Hepatitis C (HCV) infection

<p>Abstract</p> <p>Background</p> <p>GB virus C (GBV-C) is an enveloped positive-sense ssRNA virus belonging to the <it>Flaviviridae </it>family. Studies on the genetic variability of the GBV-C reveals the existence of six genotypes: genotype 1 predominates in West Africa, genotype 2 in Europe and America, genotype 3 in Asia, genotype 4 in Southwest Asia, genotype 5 in South Africa and genotype 6 in Indonesia. The aim of this study was to determine the frequency and genotypic distribution of GBV-C in the Colombian population.</p> <p>Methods</p> <p>Two groups were analyzed: i) 408 Colombian blood donors infected with HCV (n = 250) and HBV (n = 158) from Bogotá and ii) 99 indigenous people with HBV infection from Leticia, Amazonas. A fragment of 344 bp from the 5' untranslated region (5' UTR) was amplified by nested RT PCR. Viral sequences were genotyped by phylogenetic analysis using reference sequences from each genotype obtained from GenBank (n = 160). Bayesian phylogenetic analyses were conducted using Markov chain Monte Carlo (MCMC) approach to obtain the MCC tree using BEAST v.1.5.3.</p> <p>Results</p> <p>Among blood donors, from 158 HBsAg positive samples, eight 5.06% (n = 8) were positive for GBV-C and from 250 anti-HCV positive samples, 3.2%(n = 8) were positive for GBV-C. Also, 7.7% (n = 7) GBV-C positive samples were found among indigenous people from Leticia. A phylogenetic analysis revealed the presence of the following GBV-C genotypes among blood donors: 2a (41.6%), 1 (33.3%), 3 (16.6%) and 2b (8.3%). All genotype 1 sequences were found in co-infection with HBV and 4/5 sequences genotype 2a were found in co-infection with HCV. All sequences from indigenous people from Leticia were classified as genotype 3. The presence of GBV-C infection was not correlated with the sex (p = 0.43), age (p = 0.38) or origin (p = 0.17).</p> <p>Conclusions</p> <p>It was found a high frequency of GBV-C genotype 1 and 2 in blood donors. The presence of genotype 3 in indigenous population was previously reported from Santa Marta region in Colombia and in native people from Venezuela and Bolivia. This fact may be correlated to the ancient movements of Asian people to South America a long time ago.</p