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A presente investigação é uma revisão integrativa que objetivou avaliar as evidências científicas disponíveis referentes a utilização das práticas integrativas e complementares em saúde dentro do cuidado paliativo. Para a seleção dos artigos utilizou-se duas bases de dados, Biblioteca Virtual em Saúde (BVS) e Medline. A amostra desta pesquisa consistiu-se em 15 artigos. Após a leitura e análise das pesquisas incluídas na revisão, observou-se que em geral as práticas integrativas e complementares em saúde refletem em melhoria dos sintomas em pacientes de cuidados paliativos, sendo o principal sintoma a dor. As práticas integrativas e complementares mais utilizadas nas pesquisas foram medicina tradicional chinesa, aromaterapia, massagem, reflexologia, terapia com animais e musicoterapia.

International audience; Background and Aims: Hepatitis E virus (HEV) is one of the most common causes of acute hepatitis worldwide. Its positive-strand RNA genome encodes three open reading frames (ORF). ORF1 is translated into a large protein composed of multiple domains and known as the viral replicase. The RNA-dependent RNA polymerase (RdRp) domain is responsible for the synthesis of viral RNA.Approach and Results: Here, we identified a highly conserved α-helix located in the RdRp thumb subdomain. Nuclear magnetic resonance demonstrated an amphipathic α-helix extending from amino acids 1628 to 1644 of the ORF1 protein. Functional analyses revealed a dual role of this helix in HEV RNA replication and virus production, including assembly and release. Mutations on the hydrophobic side of the amphipathic α-helix impaired RNA replication and resulted in the selection of a second-site compensatory change in the RdRp palm subdomain. Other mutations enhanced RNA replication but impaired virus assembly and/or release.Conclusions: Structure-function analyses identified a conserved amphipathic α-helix in the thumb subdomain of the HEV RdRp with a dual role in viral RNA replication and infectious particle production. This study provides structural insights into a key segment of the ORF1 protein and describes the successful use of reverse genetics in HEV, revealing functional interactions between the RdRp thumb and palm subdomains. On a broader scale, it demonstrates that the HEV replicase, similar to those of other positive-strand RNA viruses, is also involved in virus production

O seguinte relato de prática pedagógica trata de um projeto interdisciplinar entre os componentes de língua portuguesa, literatura e biologia, realizado com duas turmas de segundo ano do ensino médio em uma escola pública de Porto Alegre, intitulado: “A polêmica da vacina: entre verdades e mentiras”. A aplicação ocorreu com a participação de bolsistas do projeto de “Residência pedagógica” da Universidade Federal do Rio Grande do Sul (UFRGS). Para o planejamento deste projeto, teve-se como base a Aprendizagem Baseada em Projetos (ABP), que, de acordo com Bender (2014), propõe que se trabalhe a partir de problemas reais, com materiais e discussões que possibilitem o desenvolvimento e engajamento dos alunos ao longo do processo de aprendizagem. O projeto foi realizado na modalidade de Ensino Remoto Emergencial (ERE) e ancora-se em perspectivas teóricas que partem de uma abordagem linguística, a qual contribui para as relações dos sujeitos falantes, considerando o contexto social e histórico onde estão inseridos.

Purpose– This article aims to assess the influence of cost strategy policies on the performance of sole traders, small and medium-sized companies in the civil construction sector in Curitiba and the Metropolitan Region (southern Brazil). Design/methodology/approach– Using a questionnaire, the survey collected data from 95 companies. The data has been analyzed based on descriptive statistics and multivariate analysis using discriminant analysis. Findings– Results showed that a lack of a strategic process is more evident in companies classified as low to medium performance companies. Only 36% of companies are positioned for only one of the positioning strategies. The cost strategy variable, which had the greatest impact on performance, was the policy with “greater simplification/standardization of products/services” compared to the other variables analyzed in the study. Originality/value– Results imply that most companies do not have a strategic position and that it is possible to obtain better performance through strategic management, encouraging the development of this perspective in companies in the sector. Keywords - Construction Industry; Strategy; Strategic management; Cost strategy; Survey.

Background Myostatin and activin A induce muscle wasting by activating the ubiquitin proteasome system and inhibiting the Akt/mammalian target of rapamycin pathway. In chronic kidney disease (CKD), myostatin and activin A plasma concentrations are increased, but it is unclear if there is increased production or decreased renal clearance. Methods We measured myostatin and activin A concentrations in 232 CKD patients and studied their correlation with estimated glomerular filtration rate (eGFR). We analyzed the myostatin gene (MSTN) expression in muscle biopsies of hemodialysis (HD) patients. We then measured circulating myostatin and activin A in plasma and the Mstn and Inhba expression in muscles, kidney, liver and heart of two CKD mice models (adenine and 5/6 nephrectomy models). Finally, we analyzed whether the uremic toxin indoxyl sulfate (IS) increased Mstn expression in mice and cultured muscle cells. Results In patients, myostatin and activin A were inversely correlated with eGFR. MSTN expression was lower in HD patients’ muscles (vastus lateralis) than in controls. In mice with CKD, myostatin and activin A blood concentrations were increased. Mstn was not upregulated in CKD mice tissues. Inha was upregulated in kidney and heart. Exposure to IS did not induce Mstn upregulation in mouse muscles and in cultured myoblasts and myocytes. Conclusion During CKD, myostatin and activin A blood concentrations are increased. Myostatin is not overproduced, suggesting only an impaired renal clearance, but activin A is overproduced in the kidney and heart. We propose to add myostatin and activin A to the list of uremic toxins.

The identification of underlying genes of genetic conditions has expanded greatly in the past decades, which has broadened the field of genes responsible for inherited neuromuscular diseases. We aimed to investigate mutations associated with neuromuscular disorders phenotypes in 2 Moroccan families. Next-generation sequencing combined with Sanger sequencing could assist with understanding the hereditary variety and underlying disease mechanisms in these disorders. Two novel homozygous mutations were described in this study. The SIL1 mutation is the first identified in the Moroccan population, the mutation was identified as the main cause of Marinesco-Sjogren syndrome in one patient. While the second mutation identified in the fatty acid 2-hydroxylase gene (FA2H) was associated with the Spastic paraplegia 35 in another patient, both transmitted in an autosomal recessive pattern. These conditions are extremely rare in the North African population and may be underdiagnosed due to overlapping clinical characteristics and heterogeneity of these diseases. We have reported in this studymutations associated with the diseases found in the patients. In addition, we have narrowed the phenotypic spectrum, as well as the diagnostic orientation of patients with neuromuscular disorders, who might have very similar symptoms to other disease groups.Keywords: Neuromuscular Disorders; Next-Generation Sequencing; Hereditary Spastic Paraplegia Type 35; North Africa; Marinesco-Sjogren syndrome.

International audience; Exon skipping is a promising therapeutic approach. One important condition for this approach is that the exon-skipped form of the gene can at least partially perform the required function and lead to improvement of the phenotype. It is therefore critical to identify the exons that can be skipped without a significant deleterious effect on the protein function. Pathogenic variants in the DMD gene are responsible for Duchenne muscular dystrophy (DMD). We report for the first time a deletion of the in-frame exon 49 associated with a strikingly normal muscular phenotype. Based on this observation, and on previously known therapeutic approaches using exon skipping in DMD for other single exons, we aimed to extend the clinical use of exon skipping for patients carrying truncating mutations in exon 49. We first determined the precise genomic position of the exon 49 deletion in our patients. We then demonstrated the feasibility of skipping exon 49 using an in vitro AON (antisense oligonucleotide) approach in human myotubes carrying a truncating pathogenic variant as well as in healthy ones. This work is a proof of concept aiming to expand exon-skipping approaches for DMD exon 49.

International audience; Background and aims: The identification of underlying genes of genetic conditions has expanded greatly in the past decades, which has broadened the field of genes responsible for inherited neuromuscular diseases. We aimed to investigate mutations associated with neuromuscular disorders phenotypes in 2 Moroccan families.Material and methods: Next-generation sequencing combined with Sanger sequencing could assist with under-standing the hereditary variety and underlying disease mechanisms in these disorders. Results: Two novel homozygous mutations were described in this study. The SIL1 mutation is the first identified in the Moroccan population, the mutation was identified as the main cause of Marinesco-Sjogren syndrome in one patient. While the second mutation identified in the fatty acid 2-hydroxylase gene (FA2H) was associated with the Spastic paraplegia 35 in another patient, both transmitted in an autosomal recessive pattern.Discussion and conclusions: These conditions are extremely rare in the North African population and may be underdiagnosed due to overlapping clinical characteristics and heterogeneity of these diseases. We have reported in this study mutations associated with the diseases found in the patients. In addition, we have narrowed the phenotypic spectrum, as well as the diagnostic orientation of patients with neuromuscular disorders, who might have very similar symptoms to other disease groups.

International audience; STIM1, the stromal interaction molecule 1, is the key protein for maintaining calciumconcentration in the endoplasmic reticulum by triggering the Store Operated CalciumEntry (SOCE). Bi-allelic mutations in STIM1 gene are responsible for a loss-offunctionin patients affected with a CRAC channelopathy syndrome in which severecombined immunodeficiency syndrome (SCID-like), autoimmunity, ectodermal dysplasiaand muscle hypotonia are combined. Here, we studied two siblings from a consanguineousSyrian family, presenting with muscle weakness, hyperlaxity, elastic skin,tooth abnormalities, dysmorphic facies, hypoplastic patellae and history of respiratoryinfections. Using exome sequencing, we have identified a new homozygous frameshiftmutation in STIM1: c.685delT [p.(Phe229Leufs*12)], leading to a complete lossof STIM1 protein. In this study, we describe an unusual phenotype linked to STIM1mutations, combining clinical signs usually observed in different STIM1-related diseases.In particular, we confirmed that the complete loss of STIM1 function is notalways associated with severe immune disorders. Altogether, our results broaden thespectrum of phenotypes associated with mutations in STIM1 and opens new perspectiveson the pathological mechanisms associated with a defect in the proteins constitutingthe SOCE complex.

Plant viruses cause massive crop yield loss worldwide. Most plant viruses are RNA viruses, many of which contain a functional tRNA-like structure. RNase P has the enzymatic activity to catalyze the 5′ maturation of precursor tRNAs. It is also able to cleave tRNA-like structures. However, RNase P enzymes only accumulate in the nucleus, mitochondria, and chloroplasts rather than cytosol where virus replication takes place. Here, we report a biotechnology strategy based on the re-localization of plant protein-only RNase P to the cytosol (CytoRP) to target plant viruses tRNA-like structures and thus hamper virus replication. We demonstrate the cytosol localization of protein-only RNase P in Arabidopsis protoplasts. In addition, we provide in vitro evidences for CytoRP to cleave turnip yellow mosaic virus and oilseed rape mosaic virus. However, we observe varied in vivo results. The possible reasons have been discussed. Overall, the results provided here show the potential of using CytoRP for combating some plant viral diseases., New approaches to plant disease control are important for pathogens that are difficult to control by existing methods. Here, the authors report a potential strategy to combat plant viruses by cytosolic expressed protein-only RNase P and show its ability for in vitro cleavage of tRNA-like structures existing in many plant viruses.

Improving the accuracy of variant interpretation during diagnostic sequencing is a major goal for genomic medicine. In order to explore an often overlooked splicing effect of missense variants, we developed the functional assay (“minigene”) for the majority of exons of CAPN3, the gene responsible for Limb Girdle Muscular Dystrophy (LGMD). By systematically screening 21 missense variants distributed along the gene, we found that eight clinically relevant missense variants located at a certain distance from the exon/intron borders (deep exonic missense variants) disrupted normal splicing of CAPN3 exons. Several recent machine learning based computational tools failed to predict splicing impact for the majority of these deep exonic missense variants, highlighting the importance of including variants of this type in the training sets during the future algorithm development. Overall, 24 variants in CAPN3 gene were explored, leading to the change in the ACMG classification of seven of them when results of the “minigene” functional assay were taken into account. Our findings reveal previously unknown splicing impact of several clinically important variants in CAPN3 and draw attention to the existence of deep exonic variants with a disruptive effect on gene splicing that could be overlooked by the current approaches in clinical genetics.

Hepatitis E virus (HEV) infection is an important cause of acute hepatitis and may lead to chronic infection in immunocompromised patients. Knowledge of the viral life cycle is incomplete due to the limited availability of functional tools. In particular, low levels of expression of the ORF1 protein or limited sensitivity of currently available antibodies or both limit our understanding of the viral replicase. Here, we report the successful establishment of subgenomic HEV replicons and full-length genomes harboring an epitope tag or a functional reporter in the ORF1 protein. These novel tools should allow further characterization of the HEV replication complex and to improve our understanding of the viral life cycle., Hepatitis E virus (HEV) is one of the most common causes of acute hepatitis and jaundice in the world. Current understanding of the molecular virology and pathogenesis of hepatitis E is incomplete, due particularly to the limited availability of functional tools. Here, we report the development of tagged HEV genomes as a novel tool to investigate the viral life cycle. A selectable subgenomic HEV replicon was subjected to random 15-nucleotide sequence insertion using transposon-based technology. Viable insertions in the open reading frame 1 (ORF1) protein were selected in a hepatoblastoma cell line. Functional insertion sites were identified downstream of the methyltransferase domain, in the hypervariable region (HVR), and between the helicase and RNA-dependent RNA polymerase domains. HEV genomes harboring a hemagglutinin (HA) epitope tag or a small luciferase (NanoLuc) in the HVR were found to be fully functional and to allow the production of infectious virus. NanoLuc allowed quantitative monitoring of HEV infection and replication by luciferase assay. The use of HA-tagged replicons and full-length genomes allowed localization of putative sites of HEV RNA replication by the simultaneous detection of viral RNA by fluorescence in situ hybridization and of ORF1 protein by immunofluorescence. Candidate HEV replication complexes were found in cytoplasmic dot-like structures which partially overlapped ORF2 and ORF3 proteins as well as exosomal markers. Hence, tagged HEV genomes yield new insights into the viral life cycle and should allow further investigation of the structure and composition of the viral replication complex. IMPORTANCE Hepatitis E virus (HEV) infection is an important cause of acute hepatitis and may lead to chronic infection in immunocompromised patients. Knowledge of the viral life cycle is incomplete due to the limited availability of functional tools. In particular, low levels of expression of the ORF1 protein or limited sensitivity of currently available antibodies or both limit our understanding of the viral replicase. Here, we report the successful establishment of subgenomic HEV replicons and full-length genomes harboring an epitope tag or a functional reporter in the ORF1 protein. These novel tools should allow further characterization of the HEV replication complex and to improve our understanding of the viral life cycle.

A indústria da construção civil é conhecida por ser um setor altamente dinâmico e competitivo. Diante de um cenário econômico de incertezas, a busca por melhores resultados se tornou cada vez mais significativa. Este trabalho tem como propósito avaliar a influência das práticas atuais de gestão estratégica no desempenho das micro, pequenas e médias empresas do ramo da construção civil em Curitiba e Região Metropolitana. A pesquisa foi realizada por meio de um Survey que levantou dados de 95 empresas. Os dados foram analisados com base na estatística descritiva e pela análise multivariada por meio da análise discriminante. Os resultados evidenciaram que a falta de um processo estratégico nas empresas é mais evidente nas empresas classificadas com desempenho menor. As variáveis como: metas e objetivos claramente definidos; nível de conhecimento dos colaboradores em relação às estratégias de gestão adotadas pela empresa e conhecimento pleno dos concorrentes existentes do mercado foram 3 das 6 variáveis que apresentaram influência na performance das empresas. Além disso, poucas empresas apresentaram um posicionamento estratégico. Dessa forma, verifica-se que a gestão estratégica tem relação com melhor desempenho, logo, a tese incentiva o desenvolvimento dessa perspectiva de maneira a melhorar a performance das empresas do ramo criando perenidade, sustentabilidade dos negócios e melhoria dos resultados no setor da construção civil. The construction industry is known to be a highly dynamic and competitive industry. Faced with an economic scenario of uncertainties, the search for better results has become increasingly significant. This thesis aims to evaluate the influence of current strategic management practices on the micro, small and medium enterprises performance in the construction sector in Curitiba and Região Metropolitana. The survey collected data from 95 companies. The data has been analyzed based on descriptive statistics and multivariate analysis through the discriminant analysis. The results showed that the lack of a strategic process is more evident in the companies with lower performance. The variables such as: to have clearly defined goals and objectives, level of employees knowledge in management strategies adopted by the company and full knowledge of the existing market competitors were 3 of the 6 variables that had the greatest impact on performance. Besides, few companies presented a strategic positioning. It turns out that strategy management is related to better performance, so the thesis encourages the development of this perspective in order to improve the performance of companies in the industry by creating business continuity and sustainability and improving results in the construction sector.

Summary A functional bipolar spindle is essential to segregate chromosomes correctly during mitosis. Across organisms and cell types, spindle architecture should be optimized to promote error-free divisions. However, it remains to be investigated whether mitotic spindle morphology adapts to changes in tissue properties, typical of embryonic development, in order to ensure different tasks, such as spindle positioning and chromosome segregation. We have characterized mitotic spindles in neural stem cells (NSCs) of the embryonic developing mouse neocortex. Surprisingly, we found a switch in spindle morphology from early to late neurogenic stages, which relies on an increase in inner spindle microtubule density and stability. Mechanistically, we identified the microtubule-associated protein TPX2 as one determinant of spindle shape, contributing not only to its robustness but also to correct chromosome segregation upon mitotic challenge. Our findings highlight a possible causal relationship between spindle architecture and mitotic accuracy with likely implications in brain size regulation.

Contains fulltext : 154354.pdf (Publisher’s version ) (Closed access) Premature aging syndromes are rare genetic disorders mimicking clinical and molecular features of aging. A recently identified group of premature aging syndromes is linked to mutation of the LMNA gene encoding lamins A and C, and is associated with nuclear deformation and dysfunction. Hutchinson-Gilford progeria syndrome (HGPS) was the first premature aging syndrome linked to LMNA mutation and its molecular bases have been deeply investigated. It is due to a recurrent de novo mutation leading to aberrant splicing and the production of a truncated and toxic nuclear lamin A precursor (prelamin ADelta50), also called progerin. In this work and based on the literature data, we propose to distinguish two main groups of premature aging laminopathies: (1) HGPS and HGP-like syndromes, which share clinical features due to hampered processing and intranuclear toxic accumulation of prelamin A isoforms; and (2) APS (atypical progeria syndromes), due to dominant or recessive missense mutations affecting lamins A and C. Among HGPS-like patients, several deleted prelamin A transcripts (prelamin ADelta50, ADelta35 and ADelta90) have been described. The purpose of this work was to characterize those transcripts in eight patients affected with HGP-like rare syndromes. When fibroblasts were available, the relationships between the presence and ratios of these transcripts and other parameters were studied, aiming to increase our understanding of genotype-phenotype relationships in HGPS-like patients. Altogether our results evidence that progerin accumulation is the major pathogenetic mechanism responsible for HGP-like syndromes due to mutations near the donor splice site of exon 11.

There is great concern worldwide about increased greenhouse gas emissions and the consequences of climate change. Photovoltaic solar energy emerges as an alternative source of renewable energy with low environmental impacts. Through a bibliographical review on the subject, this paper presents an analysis of the scale insertion of this energy in Brazil, demonstrating the benefits that can be generated of this technology, impediments and future perspectives. The conclusion is that Brazil has great potential for the energy generation, collaborating to reduce the environmental impacts as a reduction of the greenhouse gases emission. The barriers to introducing photovoltaic solar energy have been lack of investment, lack of more aggressive incentive programs, technological capacity and professional training.

Considerando o impacto da estratégia nas empresas do setor da construção civil, o artigo, a partir de estudo empírico, foca nas variáveis associadas à estratégia que resultam em uma organização com melhor visão e posicionamento estratégico consolidados. A pesquisa foi baseada em um survey que levantou dados de 125 empresas no Brasil. Os dados, relacionados a nove variáveis dividas em dois grupos e três categorias, foram analisados com base na análise multivariada por meio da análise discriminante múltipla. Os resultados mostraram que quanto maior a presença da análise do ambiente de atuação da empresa, da análise da necessidade dos clientes e da análise de desempenho com base em metas e/ou indicadores, maior a tendência da organização de possuir visão e o posicionamento estratégico altamente definidos. Nesse sentido, o artigo incentiva o desenvolvimento da estratégia de forma a criar perenidade e sustentabilidade dos negócios, melhorando resultados no setor da construção civil.