FoxO3a overexpression prevents both glycogen overload and autophagic buildup in skeletal muscle of Pompe disease

FoxO3a overexpression prevents both glycogen overload and autophagic buildup in skeletal muscle of Pompe disease. 6eme congrès international de Myologi

In Vivo bone tissue induction by freeze-dried collagen-nanohydroxyapatite matrix loaded with BMP2/NS1 mRNAs lipopolyplexes

Messenger RNA (mRNA) activated matrices (RAMs) are interesting to orchestrate tissue and organ regeneration due to the in-situ and sustained production of functional proteins. However, the immunogenicity of in vitro transcribed mRNA and the paucity of proper in vivo mRNA delivery vector need to be overcome to exert the therapeutic potential of RAM. We developed a dual mRNAs system for in vitro osteogenesis by co-delivering NS1 mRNA with BMP2 mRNA to inhibit RNA sensors and enhance BMP-2 expression. Next, we evaluated a lipopolyplex (LPR) formulation platform for in vivo mRNA delivery and adapted the LPRs for RAM preparation. The LPR formulated BMP2/NS1 mRNAs were incorporated into an optimized collagen-nanohydroxyapatite scaffold and freeze-dried to prepare ready-to-use RAMs. The loaded BMP2/NS1 mRNAs lipopolyplexes maintained their spherical morphology in the RAM, thanks to the core-shell structure of LPR. The mRNAs release from RAMs lasted for 16 days resulting in an enhanced prolonged transgene expression period compared to direct cell transfection. Once subcutaneously implanted in mice, the BMP2/NS1 mRNAs LPRs containing RAMs (RAM-BMP2/NS1) induced significant new bone tissue than those without NS1 mRNA, eight weeks post implantation. Overall, our results demonstrate that the BMP2/NS1 dual mRNAs system is suitable for osteogenic engagement, and the freeze-dried RAM-BMP2/NS1 could be promising off-the-shelf products for clinical orthopedic practice.info:eu-repo/semantics/publishedVersio

Observation of the spread of slow deformation in Greece following the breakup of the slab

International audienc

Satellite cells fail to contribute to muscle repair but are functional in Pompe disease (glycogenosis type II)

Satellite cells fail to contribute to muscle repair but are functional in Pompe disease (glycogenosis type II). 6eme congrés international de Myologi

Cadeia produtiva do gengibre (Zingiber officinale ROSCOE) no estado do Paraná : análise e recomendações para melhoria da qualidade

Orientador : Raquel R.B.NegrelleCo-orientadores: Luiz Doni Filho, Neusa G.A. RuckerTese (doutorado) - Universidade Federal do Paraná. Setor de Ciências Agrárias. Curso de Pós-Graduação em Agronomia - área de concentração Produção Vegetal, Departamento de Fitotecnia e FitossanitarismoInclui bibliografia e glossárioResumo: O presente trabalho teve como objetivo o estudo prospectivo da cadeia produtiva do Zingiber officinale Roscoe no Estado do Paraná, identificando os principais agentes envolvidos e paralelamente proceder análise dos pontos de estrangulamentos, especificamente no que concerne à qualidade microbiológica deste produto em todos os níveis, desde a produção até a fase final da comercialização, visando identificar causas e propor soluções no sentido da melhoria do sistema como um todo. Este estudo foi desenvolvido no período de 2000 a 2002 englobando pesquisa de campo, entrevistas abertas com representantes de estabelecimentos de comercialização, produtores e demais atores da cadeia produtiva, além de análises laboratoriais do produto "in natura" disponível no mercado consumidor da Região Metropolitana de Curitiba - PR. Este documento está organizado em 9 capítulos, que apresentam vastas informações englobando aspectos botânicos, ecológicos, fisico-químicos e farmacológicos do gengibre, e que estão incluídas nos capítulos 1 e 2. O capítulo 3 apresenta características gerais da principal região produtora brasileira, Morretes - PR, englobando localização, aspectos sócio-econômicos, geológicos e geomorfológicos e caracterização climática. O capítulo 4 apresenta o estudo prospectivo da cadeia produtiva do gengibre no Estado do Paraná, que engloba panorama mundial, brasileiro e paranaense do volume de produção agrícola de gengibre. Inclui-se também caracterização da comunidade produtora agrícola do litoral paranaense, além da identificação e caracterização dos outros diferentes níveis da cadeia produtiva do gengibre e a detecção dos principais pontos de estrangulamento nos diferentes níveis desta cadeia produtiva. A caracterização do cultivo e beneficiamento do gengibre no litoral paranaense é apresentada no capítulo 5, evidenciando suas particularidades frente ao descrito na literatura especializada. No capítulo 6 avaliou-se as condições higiênico-sanitárias dos estabelecimentos produtores, do processo de beneficiamento pós-colheita (lavagem, limpeza, secagem e embalagem) e das condições de manipulação do gengibre "in natura" no litoral paranaense. De maneira geral, as condições de higiene e limpeza observadas foram consideradas precárias, determinando alta potencialidade de contaminação do gengibre com agentes que poderiam colocar em risco a saúde do consumidor. No capítulo 7 são apresentados os resultados dos estabelecimentos de comercialização da Região Metropolitana de Curitiba - PR, no que tange à qualidade e adequação às normas vigentes. Dos aspectos observados, as condições dos vestuários e dos equipamentos de proteção individual (manipuladores) foram considerados precários, o que pode potencializar a contaminação do produto e colocar em risco a saúde do consumidor. O capítulo 8 teve como objetivo caracterizar o perfil microbiológico do gengibre "in natura" comercializado na Região Metropolitana de Curitiba - PR, tendo como base a Resolução - CNPPA n. 12 - Brasil, 1978 e a Resolução - RDC n. 12 - Brasil, 2001. Para tanto, foram realizadas a determinação do número mais provável (NMP) de coliformes totais, coliformes a 45° C/g e Escherichia coli, e a presença de Salmonella sp em 25 gramas. Sintetizando, um conjunto de propostas e recomendações aos agentes econômicos que atuam e processam a cadeia produtiva do gengibre no Estado do Paraná, em especial o município de Morretes - PR, é apresentado no capítulo 9Abstract: Prospective studies of the productive chain of the Zingiber officinale Roscoe on Parana State identifying the main agents envolved and parallel procedure analysis of the strangulation points, in order to microbiology qualify this product in whole levels from the production until commercialization last phase, aiming identify causes and propose solutions to the improvement of the system in general. This survey developed from 2000 to 2002 involved field research, interviews with representative of the commercialization establishments, producers and others actors of the productive chain, besides made in laboratories of the quality of crude product available to the consumer market in Curitiba. This paper is organized in nine chapters that present information involving botanical, ecological, physique-chemical and pharmacological aspects of ginger that are included in chapters 1 and 2. The chapter 3 presents the characteristics of the main brazilian productive area, embody localization, social and economic aspects, geologycal, geomorphologycal and climate characterization. The chapter 4 the study of the productive chain of this product in Parana State, which includes the paranaense, the brazilian and the worldwide panoramic view of the production volume and commercialization of the ginger; characterization of the agricultural community; identification and characterization of others different levels of the productive chain and also, the main strangulation points on these different levels of the productive chain. In the chapter 5 the agricultural process of the ginger benefit and cultivation in Morretes Town, Paraná, Brazil was caracterized. In the chapter 6 the hygienic-sanitary conditions of the producers establishments, postharvest benefit system and manipulation conditions of crude ginger in the paranaense coastland, Brazil were evaluated with an aim to subsidy the ofert of the best quality product to consumer market. In general, the cleaning and hygienic conditions were precarious, determining a high potential of ginger contamination with agents that can put in risk the consumers' health. The chapter 7 presents the results of the commercialization establishments in the metropolitan area of Curitiba considering adequation to the current norm. Of the observed items, the manipulation conditions was considered precarious due to the inadequate conditions that contributes to contamination, bringing about serious problems to consumers' health. The chapter 8 aimed the microbiological quality of the ginger market in the metropolitan area of Curitiba based on the Brazilian legislation. The microbiological analysis found total coliforms, 45° C/g coliforms, Escherichia coli most probable number (MPN) and Salmonella sp presence. Synthetizing, a group of considerations and recommendations to economic agents that actuate and carry on the productive chain of the ginger in the Parana State, specially in Morretes Town, is presented in the chapter

Solving patients with rare diseases through programmatic reanalysis of genome-phenome data.

Funder: EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health); doi: https://doi.org/10.13039/100011272; Grant(s): 305444, 305444Funder: Ministerio de Economía y Competitividad (Ministry of Economy and Competitiveness); doi: https://doi.org/10.13039/501100003329Funder: Generalitat de Catalunya (Government of Catalonia); doi: https://doi.org/10.13039/501100002809Funder: EC | European Regional Development Fund (Europski Fond za Regionalni Razvoj); doi: https://doi.org/10.13039/501100008530Funder: Instituto Nacional de Bioinformática ELIXIR Implementation Studies Centro de Excelencia Severo OchoaFunder: EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health)Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP's Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Solve-RD: systematic pan-European data sharing and collaborative analysis to solve rare diseases.

For the first time in Europe hundreds of rare disease (RD) experts team up to actively share and jointly analyse existing patient's data. Solve-RD is a Horizon 2020-supported EU flagship project bringing together >300 clinicians, scientists, and patient representatives of 51 sites from 15 countries. Solve-RD is built upon a core group of four European Reference Networks (ERNs; ERN-ITHACA, ERN-RND, ERN-Euro NMD, ERN-GENTURIS) which annually see more than 270,000 RD patients with respective pathologies. The main ambition is to solve unsolved rare diseases for which a molecular cause is not yet known. This is achieved through an innovative clinical research environment that introduces novel ways to organise expertise and data. Two major approaches are being pursued (i) massive data re-analysis of >19,000 unsolved rare disease patients and (ii) novel combined -omics approaches. The minimum requirement to be eligible for the analysis activities is an inconclusive exome that can be shared with controlled access. The first preliminary data re-analysis has already diagnosed 255 cases form 8393 exomes/genome datasets. This unprecedented degree of collaboration focused on sharing of data and expertise shall identify many new disease genes and enable diagnosis of many so far undiagnosed patients from all over Europe

Solving unsolved rare neurological diseases-a Solve-RD viewpoint.

Funder: Durch Princess Beatrix Muscle Fund Durch Speeren voor Spieren Muscle FundFunder: University of Tübingen Medical Faculty PATE programFunder: European Reference Network for Rare Neurological Diseases | 739510Funder: European Joint Program on Rare Diseases (EJP-RD COFUND-EJP) | 44140962