Identification de nouveaux gènes impliqués dans des maladies ophtalmologiques rares en utilisant la CGH-array

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Étude des régions sub-télomériques par MLPA chez 1041 patients présentant un retard mental non spécifique

Environ 3% de la population pédiatrique présente un retard mental (RM). La revue des cas publiés réalisée en 2003 par de Vries estime que 5% des patients présentant un RM sont porteurs d une anomalie subtélomérique. Cependant, la majorité des études rapportées ont été réalisées sur des populations de patients hautement sélectionnés cliniquement en raison de la lourdeur et du coût des kits de sondes FISH spécifiques des subtéloméres. Les objectifs de ce travail sont d établir la fréquence des microremaniements subtélomériques dans une large population de patients présentant un RM et d affiner la description des phénotypes associés à chaque microremaniement. Dans ce but, nous avons développé une stratégie de dépistage systématique des anomalies subtélomériques par une technique de PCR quantitative par MLPA (multiplex ligation dependent probe amplification). Une confirmation de l anomalie retrouvée par un second panel de sondes MLPA, puis par FISH subtélomérique a été réalisée secondairement. Cette stratégie a été appliquée à une population de 1041 patients présentant un RM de tout niveau, en s affranchissant des critères de présélection cliniques publiés qui ne nous semblaient pas satisfaisants. Un réarrangement subtélomérique a été mis en évidence par MLPA et confirmé par hybridation in situ chez 28 patients (soit 2,7%). Les résultats discordants ont été caractérisés en développant des techniques complémentaires (sondes FISH locales, PCR quantitative en temps réel). Dans un dernier temps, nous avons tenté d établir des corrélations entre le phénotype et le remaniement détecté en intégrant les données cliniques de la littérature aux observations issues de nos patientsPARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Top-m identification for linear bandits

International audienceMotivated by an application to drug repurposing, we propose the first algorithms to tackle the identification of the m ≥ 1 arms with largest means in a linear bandit model, in the fixed-confidence setting. These algorithms belong to the generic family of Gap-Index Focused Algorithms (GIFA) that we introduce for Top-m identification in linear bandits. We propose a unified analysis of these algorithms, which shows how the use of features might decrease the sample complexity. We further validate these algorithms empirically on simulated data and on a simple drug repurposing task

Top-m identification for linear bandits

International audienceMotivated by an application to drug repurposing, we propose the first algorithms to tackle the identification of the m ≥ 1 arms with largest means in a linear bandit model, in the fixed-confidence setting. These algorithms belong to the generic family of Gap-Index Focused Algorithms (GIFA) that we introduce for Top-m identification in linear bandits. We propose a unified analysis of these algorithms, which shows how the use of features might decrease the sample complexity. We further validate these algorithms empirically on simulated data and on a simple drug repurposing task

The molecular pathophysiology of mood disorders: From the analysis of single molecular layers to multi-omic integration

International audienceNext-generation sequencing now enables the rapid and affordable production of reliable biological data at multiple molecular levels, collectively referred to as "omics". To maximize the potential for discovery, computational biologists have created and adapted integrative multi-omic analytical methods. When applied to diseases with traceable pathophysiology such as cancer, these new algorithms and statistical approaches have enabled the discovery of clinically relevant molecular mechanisms and biomarkers. In contrast, these methods have been much less applied to the field of molecular psychiatry, although diagnostic and prognostic biomarkers are similarly needed. In the present review, we first briefly summarize main findings from two decades of studies that investigated single molecular processes in relation to mood disorders. Then, we conduct a systematic review of multi-omic strategies that have been proposed and used more recently. We also list databases and types of data available to researchers for future work. Finally, we present the newest methodologies that have been employed for multi-omics integration in other medical fields, and discuss their potential for molecular psychiatry studies

Impact of Fetal Growth Restriction on the Neonatal Microglial Proteome in the Rat

Microglial activation is a key modulator of brain vulnerability in response to intra-uterine growth restriction (IUGR). However, the consequences of IUGR on microglial development and the microglial proteome are still unknown. We used a model of IUGR induced by a gestational low-protein diet (LPD) in rats. Microglia, isolated from control and growth-restricted animals at P1 and P4, showed significant changes in the proteome between the two groups. The expression of protein sets associated with fetal growth, inflammation, and the immune response were significantly enriched in LPD microglia at P1 and P4. Interestingly, upregulation of protein sets associated with the oxidative stress response and reactive oxygen species production was observed at P4 but not P1. During development, inflammation-associated proteins were upregulated between P1 and P4 in both control and LPD microglia. By contrast, proteins associated with DNA repair and senescence pathways were upregulated in only LPD microglia. Similarly, protein sets involved in protein retrograde transport were significantly downregulated in only LPD microglia. Overall, these data demonstrate significant and multiple effects of LPD-induced IUGR on the developmental program of microglial cells, leading to an abnormal proteome within the first postnatal days

Accelerated aging in bipolar disorders: An exploratory study of six epigenetic clocks

Bipolar disorder (BD) is a chronic and severe psychiatric disorder associated with significant medical morbidity and reduced life expectancy. In this study, we assessed accelerated epigenetic aging in individuals with BD using various DNA methylation (DNAm)-based markers. For this purpose, we used five epigenetic clocks (Horvath, Hannum, EN, PhenoAge, and GrimAge) and a DNAm-based telomere length clock (DNAmTL). DNAm profiles were obtained using Infinium MethylationEPIC Arrays from whole-blood samples of 184 individuals with BD. We also estimated blood cell counts based on DNAm levels for adjustment. Significant correlations between chronological age and each epigenetic age estimated using the six different clocks were observed. Following adjustment for blood cell counts, we found that the six epigenetic AgeAccels (age accelerations) were significantly associated with the body mass index. GrimAge AgeAccel was significantly associated with male sex, smoking status and childhood maltreatment. DNAmTL AgeAccel was significantly associated with smoking status. Overall, this study showed that distinct epigenetic clocks are sensitive to different aspects of aging process in BD. Further investigations with comprehensive epigenetic clock analyses and large samples are required to confirm our findings of potential determinants of an accelerated epigenetic aging in BD

WWOX -related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation

International audienceBACKGROUND:Homozygous mutations in WWOX were reported in eight individuals of two families with autosomal recessive spinocerebellar ataxia type 12 and in two siblings with infantile epileptic encephalopathy (IEE), including one who deceased prior to DNA sampling.METHODS:By combining array comparative genomic hybridisation, targeted Sanger sequencing and next generation sequencing, we identified five further patients from four families with IEE due to biallelic alterations of WWOX.RESULTS:We identified eight deleterious WWOX alleles consisting in four deletions, a four base-pair frameshifting deletion, one missense and two nonsense mutations. Genotype-phenotype correlation emerges from the seven reported families. The phenotype in four patients carrying two predicted null alleles was characterised by (1) little if any psychomotor acquisitions, poor spontaneous motility and absent eye contact from birth, (2) pharmacoresistant epilepsy starting in the 1st weeks of life, (3) possible retinal degeneration, acquired microcephaly and premature death. This contrasted with the less severe autosomal recessive spinocerebellar ataxia type 12 phenotype due to hypomorphic alleles. In line with this correlation, the phenotype in two siblings carrying a null allele and a missense mutation was intermediate.CONCLUSIONS:Our results obtained by a combination of different molecular techniques undoubtedly incriminate WWOX as a gene for recessive IEE and illustrate the usefulness of high throughput data mining for the identification of genes for rare autosomal recessive disorders. The structure of the WWOX locus encompassing the FRA16D fragile site might explain why constitutive deletions are recurrently reported in genetic databases, suggesting that WWOX-related encephalopathies, although likely rare, may not be exceptional