Synergistic binding of transcription factors to cell-specific enhancers programs motor neuron identity

Efficient transcriptional programming promises to open new frontiers in regenerative medicine. However, mechanisms by which programming factors transform cell fate are unknown, preventing more rational selection of factors to generate desirable cell types. Three transcription factors, Ngn2, Isl1 and Lhx3, were sufficient to program rapidly and efficiently spinal motor neuron identity when expressed in differentiating mouse embryonic stem cells. Replacement of Lhx3 by Phox2a led to specification of cranial, rather than spinal, motor neurons. Chromatin immunoprecipitation–sequencing analysis of Isl1, Lhx3 and Phox2a binding sites revealed that the two cell fates were programmed by the recruitment of Isl1-Lhx3 and Isl1-Phox2a complexes to distinct genomic locations characterized by a unique grammar of homeodomain binding motifs. Our findings suggest that synergistic interactions among transcription factors determine the specificity of their recruitment to cell type–specific binding sites and illustrate how a single transcription factor can be repurposed to program different cell types.Project ALS FoundationNational Institutes of Health (U.S.) (Grant P01 NS055923

Combined microfluidics/protein patterning platform for pharmacological interrogation of axon pathfinding

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Genetically-Modified Human Pluripotent Stem Cells: New Hopes for the Understanding and the Treatment of Neurological Diseases?

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DGT : EQS adaptation for Nickel, Cadmium and Lead

As DGT results cannot be directly compared to marine water AA-EQS, the general objective of this document is to propose a methodology so that DGT results can be applied in a regulatory context for waterbody quality assessment. Using a pragmatic approach applied to the context of the WFD, this methodology is based on the study of European reports, European technical and scientific guidance documents, publications of network of experts and processing of MONITOOL dataset. For this purpose, the document is organised in two parts: - a bibliographic part with a review of the derivation process of EQSs, a description of the differences between DGT and spot sampling based measurements, the proposed methodology for the use of DGT results in a regulatory framework, by comparing DGT results to EQS ; - a data processing part carried out using MONITOOL datasets in order to adapt EQS marine water in EQSDGT for Cd, Ni and Pb. Moreover, another methodology is proposed, which is to predict the concentrations measured by DGT into its corresponding dissolved concentrations, so they can be directly compared to EQSmarine water

DGT thresholds adaptation. Cobalt - copper - manganese - zinc

As DGT results cannot be directly compared to marine water thresholds, the specific objectives of this document is i) to propose a methodology so that DGT results can be applied in a regulatory context notably for establishing the ecological status of waterbodies as regard specific pollutants and ii) to adapt existing thresholds, defined in marine water at national level by a Member State, into DGT thresholds, for cobalt, copper, iron, zinc and manganese. In order to reach these objectives, an overview of existing thresholds defined for Co, Cu, Fe, Zn and Mn was done, based both on a threshold research in existing databases and on a survey carried on among the MONITOOL partners on the specific pollutant they have defined. The methodology defined for Pb, Cd, and Ni (WP6 ] action 1) is declined for Co, Cu, Fe, Zn and Mn. Based on the robust MONITOOL database of dissolved and labile metal concentrations in transitional and coastal waters, a data processing was done in order to propose adapted DGT thresholds

Preparation of functionalized aryl- and heteroarylpyridazines by nickel-catalyzed electrochemical cross-coupling reactions

0022-3263International audienceA general efficient electrochemical method for the preparation of aryl- and heteroarylpyridazines in a nickel-catalyzed cross-coupling reaction of 3-chloro-6-methoxypyridazine and 3-chloro-6-methylpyridazine with a range of functionalized aryl or heteroaryl halides is reported

Identifying health conditions associated with Alzheimer's disease up to 15 years before diagnosis: an agnostic study of French and British health records

BACKGROUND: The identification of modifiable risk factors for Alzheimer's disease is paramount for early prevention and the targeting of new interventions. We aimed to assess the associations between health conditions diagnosed in primary care and the risk of incident Alzheimer's disease over time, up to 15 years before a first Alzheimer's disease diagnosis. METHODS: In this agnostic study of French and British health records, data from 20 214 patients with Alzheimer's disease in the UK and 19 458 patients with Alzheimer's disease in France were extracted from The Health Improvement Network database. We considered data recorded from Jan 1, 1996, to March 31, 2020 in the UK and from Jan 4, 1998, to Feb 20, 2019, in France. For each Alzheimer's disease case, a control was randomly assigned after matching for sex and age at last visit. We agnostically tested the associations between 123 different diagnoses of the International Classification of Diseases, 10th revision, extracted from health records, and Alzheimer's disease, by running a conditional logistic regression to account for matching of cases and controls. We focused on three time periods before diagnosis of Alzheimer's disease, to separate risk factors from early symptoms and comorbidities. FINDINGS: Unadjusted odds ratios (ORs) and 95% CIs for the association between Alzheimer's disease and various health conditions were estimated, and p values were corrected for multiple comparisons. In both the British and French studies, ten health conditions were significantly positively associated with increased Alzheimer's disease risk, in a window of exposure from 2-10 years before Alzheimer's disease diagnosis, comprising major depressive disorder (UK OR 1·34, 95% CI 1·23-1·46; France OR 1·73, 1·57-1·91), anxiety (UK OR 1·36, 1·25-1·47; France OR 1·50, 1·36-1·65), reaction to severe stress and adjustment disorders (UK OR 1·40, 1·24-1·59; France OR 1·83, 1·55-2·15), hearing loss (UK OR 1·19, 1·11-1·28; France OR 1·51, 1·21-1·89), constipation (UK OR 1·31, 1·22-1·41; France OR 1·59, 1·44-1·75), spondylosis (UK OR 1·26, 1·14-1·39; France OR 1·62, 1·44-1·81), abnormal weight loss (UK OR 1·47, 1·33-1·63; France OR 1·88, 1·56-2·26), malaise and fatigue (UK OR 1·23, 1·14-1·32; France OR 1·59, 1·46-1·73), memory loss (UK OR 7·63, 6·65-8·76; France OR 4·41, 3·07-6·34), and syncope and collapse (UK OR 1·23, 1·10-1·37; France OR 1·57, 1·26-1·96). Depression was the first comorbid condition associated with Alzheimer's disease, appearing at least 9 years before the first clinical diagnosis, followed by anxiety, constipation, and abnormal weight loss. INTERPRETATION: These results from two independent primary care databases provide new evidence on the temporality of risk factors and early signs of Alzheimer's disease that are observable at the general practitioner level. These results could guide the implementation of new primary and secondary prevention policies. FUNDING: Agence Nationale de la Recherche.PaRis Artificial Intelligence Research InstitutEInstitut de Neurosciences Translationnelles de Pari

Substances prioritaires DCE : Etude de détermination de facteurs de bioaccumulation (BAF) sur les mollusques en milieu marin

Pour permettre d’évaluer la qualité chimique des masses d’eau en utilisant les résultats de la surveillance opérée sur les bivalves via le ROCCH ou le RINBIO, il est nécessaire de transposer les seuils existants applicables dans les eaux marines en seuils « mollusques » et ainsi d’adapter les NQE eau marine (Normes de Qualité Environnementale) en VGE mollusques (Valeur Guide Environnementale). Cette adaptation nécessite d’utiliser des facteurs de conversion eau-biote : les facteurs de bioconcentration (BCF) ou les facteurs de bioaccumulation (BAF) spécifiques de couples substance-espèce. Les BAF sont les facteurs à privilégier autant que possible car plus représentatifs de ce qui se passe dans le milieu avec notamment la prise en compte des différentes voies d’exposition des organismes aquatiques aux contaminants, i.e. la voie directe (eau) et la voie trophique (ingestion de proies contaminées). Cette démarche de détermination de VGE mollusques est engagée par Ifremer - OFB depuis 2015, et plusieurs étapes ont été réalisées : proposition de VGE mollusques (1) sur la base de données existantes, élaboration d’une méthodologie de détermination de BAF pour les mollusques en milieu marin afin d’acquérir des données BAF terrain. Cette étude de détermination des BAF sur les mollusques en milieu marin a été conduite entre 2016 et 2019, elle concerne 27 substances prioritaires : 3 composés métalliques et 24 substances organiques. Sept sites ont été échantillonnés en parallèle sur les matrices eau marine et mollusques. Suivant les points, les mollusques échantillonnés étaient des moules sauvages (ou d’élevage) et / ou des moules encagés, et deux sites disposaient en plus d’huîtres encagées. Les concentrations dans l’eau marine ont été mesurées sur eau brute et / ou eau filtrée. En dépit des nombreuses difficultés logistiques rencontrées, cette étude souligne d’un point de vue technique, l’intérêt de la SBSE (Stir Bar Sorptive Extraction), pour la recherche de certaines substances organiques dans l’eau marine, la pertinence de rechercher ces substances sur eau brute mais également sur eau filtrée. Cette étude permet de disposer de résultats acquis en parallèle à la fois sur moules encagées, sur moules sauvages ou d’élevage et de mesurer des BAF pour 10 substances : Cd, Ni, Pb, anthracène, PBDE, DDT total, HCH, naphtalène, octylphénol, TBT, permettant d’affiner les VGE mollusques

An Alternative Splicing Switch Regulates Embryonic Stem Cell Pluripotency and Reprogramming

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