Elevated α-synuclein caused by SNCA gene triplication impairs neuronal differentiation and maturation in Parkinson's patient-derived induced pluripotent stem cells

We have assessed the impact of a-synuclein overexpression on the differentiation potential and phenotypic signatures of two neural-committed induced pluripotent stem cell lines derived from a Parkinson's disease patient with a triplication of the human SNCA genomic locus. In parallel, comparative studies were performed on two control lines derived from healthy individuals and lines generated from the patient iPS-derived neuroprogenitor lines infected with a lentivirus incorporating a small hairpin RNA to knock down the SNCA mRNA. The SNCA triplication lines exhibited a reduced capacity to differentiate into dopaminergic or GABAergic neurons and decreased neurite outgrowth and lower neuronal activity compared with control cultures. This delayed maturation phenotype was confirmed by gene expression profiling, which revealed a significant reduction in mRNA for genes implicated in neuronal differentiation such as delta-like homolog 1 (DLK1), gamma-aminobutyric acid type B receptor subunit 2 (GABABR2), nuclear receptor related 1 protein (NURR1), G-protein-regulated inward-rectifier potassium channel 2 (GIRK-2) and tyrosine hydroxylase (TH). The differentiated patient cells also demonstrated increased autophagic flux when stressed with chloroquine. We conclude that a two-fold overexpression of a-synuclein caused by a triplication of the SNCA gene is sufficient to impair the differentiation of neuronal progenitor cells, a finding with implications for adult neurogenesis and Parkinson's disease progression, particularly in the context of bioenergetic dysfunction.Instituto de Investigaciones Bioquímicas de La Plat

Efeito da radiação gama em melão fresco minimamente processado

Beja – Portugal, Março de 2007EncontroOs produtos hortofrutícolas estão frequentemente em contacto com o solo, insectos, animais e seres humanos não só durante o desenvolvimento e colheita como por vezes na indústria de processamento. Por essas razões as camadas superfíciais dos produtos podem estar expostas a contaminantes naturais, chegando a atingir 104 a 106 microrganismos por grama. Embora as bactérias saprófitas, os bolores e as leveduras sejam a flora dominante, os microrganismos patogénicos também podem estar presentes. Nos últimos anos tem havido um aumento de surtos de toxi-infecções associados ao consumo de frutos e vegetais crus. Surtos de toxi-infecções provocados por Salmonella (Chester, Poona e Enteritidis), Escherichia coli O157:H7, Shigella, Campylobacter spp. e virus Norwalk têm sido associados ao consumo de melão. Os frutos submetidos ao processamento mínimo são mais perecíveis do que os produtos intactos donde provêm, pois o corte aumenta a deterioração microbiana, pela transferência de microrganismos do exterior para o interior, sendo a lavagem dos frutos inteiros com água clorada aplicada para reduzir a contaminação, contudo esta redução pode não ser suficiente. Assim, a irradiação é um processo alternativo, que pode ser aplicado, após a embalagem final do produto, evitando recontaminações. O objectivo deste trabalho foi a avaliação do efeito da irradiação gama na descontaminação do melão (Cucumis melo L. cv. Piel de Sapo) minimamente processado, para aumentar o tempo de vida útil. O melão inteiro foi lavado com água clorada a 125 ppm, descascado, cortado em cubos, colocado em caixas de Nutrip-PS (polistireno) e seguidamente embalado em filme polimérico (PE) com aplicação de atmosfera modificada passiva. As amostras foram submetidas a radiação gama, com doses de 0,5 e 1 kGy. Foram avaliados parâmetros microbiológicos, físico-químicos e sensoriais ao longo do período de conservação (11 dias). Os resultados evidenciam que a irradiação provocou uma redução de 1,5 log na carga microbiana, sem alteração da qualidade organoléptica do produtoDTPA, Estação Agronómica Nacional - INIAP, Quinta do Marquês, 2784-505 Oeiras, Portugal Instituto Tecnológico e Nuclear, E.N. 10, 2696 Sacavém, Portugal Faculdade de Medicina Veterinária, UTL, Lisboa, Portuga

Elevated α-synuclein caused by SNCA gene triplication impairs neuronal differentiation and maturation in Parkinson's patient-derived induced pluripotent stem cells

We have assessed the impact of a-synuclein overexpression on the differentiation potential and phenotypic signatures of two neural-committed induced pluripotent stem cell lines derived from a Parkinson's disease patient with a triplication of the human SNCA genomic locus. In parallel, comparative studies were performed on two control lines derived from healthy individuals and lines generated from the patient iPS-derived neuroprogenitor lines infected with a lentivirus incorporating a small hairpin RNA to knock down the SNCA mRNA. The SNCA triplication lines exhibited a reduced capacity to differentiate into dopaminergic or GABAergic neurons and decreased neurite outgrowth and lower neuronal activity compared with control cultures. This delayed maturation phenotype was confirmed by gene expression profiling, which revealed a significant reduction in mRNA for genes implicated in neuronal differentiation such as delta-like homolog 1 (DLK1), gamma-aminobutyric acid type B receptor subunit 2 (GABABR2), nuclear receptor related 1 protein (NURR1), G-protein-regulated inward-rectifier potassium channel 2 (GIRK-2) and tyrosine hydroxylase (TH). The differentiated patient cells also demonstrated increased autophagic flux when stressed with chloroquine. We conclude that a two-fold overexpression of a-synuclein caused by a triplication of the SNCA gene is sufficient to impair the differentiation of neuronal progenitor cells, a finding with implications for adult neurogenesis and Parkinson's disease progression, particularly in the context of bioenergetic dysfunction.Instituto de Investigaciones Bioquímicas de La Plat

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362