Pour une politique ambitieuse des données publiques

Ce rapport présente une étude sur la réutilisation des données publiques, menée pour la Délégation aux usages de l’Internet du Ministère de l’Enseignement supérieur et de la Recherche dans le cadre du Master d’Action Publique de l’École des Ponts ParisTech. Il met en perspective la problématique et les enjeux de l’Open Data, propose un état des lieux de la réutilisation des données publiques en France, et dessine trois scénarios prospectifs pour l’évolution future de ce mouvement. Elle présente seize propositions pour une politique nationale ambitieuse d’ouverture et de réutilisation des données publiques. Quatre élèves de l’École des Ponts ParisTech, Pierre-Henri Bertin, Romain Lacombe, François Vauglin et Alice Vieillefosse ont mené cette analyse de septembre 2010 à janvier 2011, en rencontrant les acteurs clés de la réutilisation des données publiques, en prenant part à des colloques internationaux, et en s’appuyant sur la bibliographie existante

Identification of the Toxoplasma gondii mitochondrial ribosome, and characterisation of a protein essential for mitochondrial translation

Apicomplexan parasites cause diseases such as malaria and toxoplasmosis. The apicomplexan mitochondrion shows striking differences from common model organisms, including fundamental processes such as mitochondrial translation. Despite evidence that mitochondrial translation is essential for parasite survival, it is largely understudied. Progress has been restricted by the absence of functional assays to detect apicomplexan mitochondrial translation, a lack of knowledge of proteins involved in the process and the inability to identify and detect mitoribosomes. We report the localization of 12 new mitochondrial proteins, including 6 putative mitoribosomal proteins. We demonstrate the integration of three mitoribosomal proteins in macromolecular complexes, and provide evidence suggesting these are apicomplexan mitoribosomal subunits, detected here for the first time. Finally, a new analytical pipeline detected defects in mitochondrial translation upon depletion of the small subunit protein 35 (TgmS35), while other mitochondrial functions remain unaffected. Our work lays a foundation for the study of apicomplexan mitochondrial translation

ATP synthase hexamer assemblies shape cristae of Toxoplasma mitochondria

Mitochondrial ATP synthase plays a key role in inducing membrane curvature to establish cristae. In Apicomplexa causing diseases such as malaria and toxoplasmosis, an unusual cristae morphology has been observed, but its structural basis is unknown. Here, we report that the apicomplexan ATP synthase assembles into cyclic hexamers, essential to shape their distinct cristae. Cryo-EM was used to determine the structure of the hexamer, which is held together by interactions between parasite-specific subunits in the lumenal region. Overall, we identified 17 apicomplexan-specific subunits, and a minimal and nuclear-encoded subunit-a. The hexamer consists of three dimers with an extensive dimer interface that includes bound cardiolipins and the inhibitor IF1. Cryo-ET and subtomogram averaging revealed that hexamers arrange into ~20-megadalton pentagonal pyramids in the curved apical membrane regions. Knockout of the linker protein ATPTG11 resulted in the loss of pentagonal pyramids with concomitant aberrantly shaped cristae. Together, this demonstrates that the unique macromolecular arrangement is critical for the maintenance of cristae morphology in Apicomplexa

Two ancient membrane pores mediate mitochondrial-nucleus membrane contact sites

Coordination between nucleus and mitochondria is essential for cell survival, and thus numerous communication routes have been established between these two organelles over eukaryotic cell evolution. One route for organelle communication is via membrane contact sites, functional appositions formed by molecular tethers. We describe a novel nuclear-mitochondrial membrane contact site in the protozoan Toxoplasma gondii. We have identified specific contacts occurring at the nuclear pore and demonstrated an interaction between components of the nuclear pore and the mitochondrial protein translocon, highlighting them as molecular tethers. Genetic disruption of the nuclear pore or the TOM translocon components, TgNup503 or TgTom40, respectively, result in contact site reduction, supporting their potential involvement in this tether. TgNup503 depletion further leads to specific mitochondrial morphology and functional defects, supporting a role for nuclear-mitochondrial contacts in mediating their communication. The discovery of a contact formed through interaction between two ancient mitochondrial and nuclear complexes sets the ground for better understanding of mitochondrial-nuclear crosstalk in eukaryotes

Finger creases lend a hand in Kabuki syndrome.

International audienceKabuki syndrome (KS) is a rare syndrome associating malformations with intellectual deficiency and numerous visceral, orthopedic, endocrinological, immune and autoimmune complications. The early establishment of a diagnostic of KS leads to better care of the patients and therefore prevents complications such as perception deafness, severe complications of auto-immune diseases or obesity. However, the diagnosis of KS remains difficult because based on the appreciation of facial features combined with other highly variable features. We describe a novel sign, namely the attenuation and/or congenital absence of the IPD crease of the third and fourth fingers associated with limitation of flexion of the corresponding joints, which seems to be specific of KS and could help the clinician to diagnose KS

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

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

Alien Registration- Lacombe, Alice (Lewiston, Androscoggin County)

https://digitalmaine.com/alien_docs/28599/thumbnail.jp

Mitochondrial translation in Toxoplasma gondii: Establishing tools, and characterizing essential mitoribosomal components

Apicomplexan parasites cause diseases such as malaria and toxoplasmosis. These parasites are obligate intracellular pathogen and divergent organisms whose cellular machineries often composed of unique structures of functions compared to model organisms. Studying fundamental mitochondrial biology in these organisms means defining the ancestral core of eukaryotic pathways while simultaneously identifying organism specific traits, that may also inspire drug discovery. Organellar translation has been a focus for the latter in recent years. Due to extreme gene transfer to the nuclear genome, the apicomplexan mitochondrial genome encodes only three proteins: COXI, COXIII and COB, and a series of indirect evidence suggest active mitochondrial translation of these proteins. Evidence also point to several divergent features in this pathway compared to model organism, primarily the reliance on the import of the full set of tRNAs from the cytosol, and the unusual ribosome composition. Progress has been hampered by the lack of functional assays to detect apicomplexan mitochondrial translation, a shortage of knowledge of proteins involved in this process and the incapacity to detect mitoribosomes. We investigate the molecular detail of translation in apicomplexan organisms using Toxoplasma gondii as a model. tRNA affinity pull down identified 7 candidate proteins with potential role in mitochondrial tRNA import. Using a bioinformatics screen based on mRNA expression patterns, 279 candidate mitochondrial housekeeping components were identified in Toxoplasma. 11 were validated, including the mitoribosomal small subunit protein 35 (TgmS35). The small subunit of the mitoribosome was detected for the first time in apicomplexans through TgmS35 triple HA tagging. A new analytical pipeline detected defects in mitochondrial translation upon TgmS35 depletion, while other mitochondrial functions remain unaffected. Our findings provide further support for the divergent nature of apicomplexan mitochondrial translation and lay a foundation for the study of apicomplexan mitochondrial translation

Alien Registration- Lacombe, Alice (Lewiston, Androscoggin County)

https://digitalmaine.com/alien_docs/28599/thumbnail.jp