De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits:report of 25 new individuals and review of the literature

TBR1, a T-box transcription factor expressed in the cerebral cortex, regulates the expression of several candidate genes for autism spectrum disorders (ASD). Although TBR1 has been reported as a high-confidence risk gene for ASD and intellectual disability (ID) in functional and clinical reports since 2011, TBR1 has only recently been recorded as a human disease gene in the OMIM database. Currently, the neurodevelopmental disorders and structural brain anomalies associated with TBR1 variants are not well characterized. Through international data sharing, we collected data from 25 unreported individuals and compared them with data from the literature. We evaluated structural brain anomalies in seven individuals by analysis of MRI images, and compared these with anomalies observed in TBR1 mutant mice. The phenotype included ID in all individuals, associated to autistic traits in 76% of them. No recognizable facial phenotype could be identified. MRI analysis revealed a reduction of the anterior commissure and suggested new features including dysplastic hippocampus and subtle neocortical dysgenesis. This report supports the role of TBR1 in ID associated with autistic traits and suggests new structural brain malformations in humans. We hope this work will help geneticists to interpret TBR1 variants and diagnose ASD probands

Skrekkelementenes funksjon i Maurits Hansens Othar av Bretagne (1819)

Denne bacheloroppgaven tar utgangspunkt i en nærlesing av noen sentrale skrekkelementer i romanen Othar av Bretagne (1819). Skrekkelementene vil studeres med utgangspunkt i følgende problemstilling: Hvilken funksjon har skrekkelementene i Othar av Bretagne? (1819). Denne problemstillingen vil drøftes ut i fra min hypotese om at skrekken først og fremst er der av estetiske grunner. For å besvare disse spørsmålene vil jeg studere Othar av Bretagne i lys av tre ulike ytringer fra samtiden som alle tilfører noe til debatten om skrekkens rolle i litteraturen. Skrekkelementene kan kobles til det sublime og til et fantastisk og overnaturlig modus som har til hensikt å vekke nysgjerrighet og innbilningskraften til leseren

Evaluation d'une procédure d'insémination des ovocytes en fécondation in vitro classique tenant compte de la morphologie des spermatozoïdes sélectionnés

PARIS7-Xavier Bichat (751182101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Plasma or serum? A qualitative study on rodents and humans using high-throughput microRNA sequencing for circulating biomarkers

International audienceAbstract microRNAs are small non-coding RNAs gaining interest for their potential roles as reliable biomarkers for the diagnosis and therapeutics of numerous pathologies, ranging from cancer to neurodegenerative or psychiatric disorders. Indeed, microRNAs are present in various accessible biofluids, including peripheral blood, and specific dysregulation of their expression may be associated with these different pathological conditions. microRNAs can be isolated from plasma or serum for sequencing with commercial kits. However, these two biofluids might exhibit some differences in their microRNA contents, due notably to the coagulation process occurring during serum collection. It remains unclear from previous studies and commercial recommendations which blood fraction is preferable. Because of the small amount of circulating microRNAs in a given blood volume, this question appears crucial for qualitative and quantitative optimization of microRNA profiling, especially in animal models used for investigating the pathophysiological relevancy of this approach. We therefore evaluated the efficiency of RNA isolation and microRNA levels from plasma and sera isolated from rats and humans, with a widely used extraction kit (QIAGEN miRNeasy), and assessed microRNA quality and quantity with high-throughput sequencing. Fewer reads with length corresponding to non-miRNAs sequences were observed in plasma than in serum, both from rats and humans. Moreover, rat plasma produced twice as many aligned reads compared to sera, as well as more aligned reads corresponding to microRNAs (84.6% against 38.7%), differences that were not find in human samples. Our results, therefore, clearly indicate that plasma should be preferred for miRNA investigations, particularly for translational studies

Modèle de gestions différenciées de vergers à graines : le merisier

[Notes_IRSTEA]Convention 61.45.80.31/02 notifiée le 9/12/2002 [Departement_IRSTEA]GT [TR1_IRSTEA]SET / BIOFORExtrait de documentLe but du projet était de comparer la diversité et les flux de gènes dans trois modalités de vergers expérimentaux de merisier et dans un peuplement classé. Certaines variétés forestières garantissent par construction la stabilité et la qualité de leur composition génétique : les cultivars reproduits végétativement à l'identique, les graines issus de croisements contrôlés. Dans un verger à graines de plein air le producteur peut maîtriser la quantité de graines récoltée sur chaque mère, par contre la composition paternelle ne lui est pas connue. La composition pollinique peut être variable selon les pères potentiels, variable selon les années, et selon le degré d'isolement du verger, des pères extérieurs peuvent contribuer au nuage pollinique. Pour les graines récoltées directement dans un peuplement, pères et mères sont également inconnus. Pour évaluer la qualité des croisements et la diversité en verger à graines demerisier, trois modes de gestion ont été testés en 2001 : un verger de plein air abrité par un filet anti-oiseaux, un verger sous serre tunnel hors gel avec introduction simultanée de tous les clones, un verger sous serre avec introduction des clones les plus tardifs en premier pour augmenter la période de recouvrement des floraisons. L'hypothèse à tester est que le verger à floraison synchronisée doit permettre l'amélioration de la panmixie par le contrôle de l'époque de floraison de chaque clone composant le verger. Les vergers à graines peuvent être l'objet de pollinisation par des arbres ne composant pas le verger, car les abeilles introduites dans chacun des vergers sous serre avaient la possibilité d'en sortir (contrairement à ce qui était prévu au départ), et des merisiers en collection étaient présents sur le domaine de la pépinière. Après avoir regroupé les arbres de verger dans la même modalité en verger de plein air, la pollution génétique a été plus particulièrement évaluée. Enfin, à titre de comparaison, la diversité a été également étudiée en peuplement classé. Nous avons analysé l'étendue des taches de drageonnage dans la population et comparé l'hétérozygotie et le nombre d'allèles entre les individus parents récoltés par les grimpeurs et un échantillon du lot de graines récolté. Nous avons également essayé de retrouver le père et la mère des graines de ce lot

Donor Dependent Variations in Hematopoietic Differentiation among Embryonic and Induced Pluripotent Stem Cell Lines

International audienceHematopoiesis generated from human embryonic stem cells (ES) and induced pluripotent stem cells (iPS) are unprecedented resources for cell therapy. We compared hematopoietic differentiation potentials from ES and iPS cell lines originated from various donors and derived them using integrative and non-integrative vectors. Significant differences in differentiation toward hematopoietic lineage were observed among ES and iPS. The ability of engraftment of iPS or ES-derived cells in NOG mice varied among the lines with low levels of chimerism. iPS generated from ES cell-derived mesenchymal stem cells (MSC) reproduce a similar hematopoietic outcome compared to their parental ES cell line. We were not able to identify any specific hematopoietic transcription factors that allow to distinguish between good versus poor hematopoiesis in undifferentiated ES or iPS cell lines. There is a relatively unpredictable variation in hematopoietic differentiation between ES and iPS cell lines that could not be predicted based on phenotype or gene expression of the undifferentiated cells. These results demonstrate the influence of genetic background in variation of hematopoietic potential rather than the reprogramming process

Efficacy and safety of methotrexate versus placebo as add-on therapy to H1 antihistamines for patients with difficult-to-treat chronic spontaneous urticaria: A randomized, controlled trial

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Evaluation of a low-dose methotrexate added to h1-antihistamines regimen for severe chronic spontaneous urticaria: a phase III, randomized, placebo-controlled trial

International audienceIntroduction: H1-antihistamines (anti-H1) are the first-line treatment for chronic spontaneous urticaria (CSU). Immunosuppressive drugs may be proposed in case of incomplete improvement of CSU. Objective: To evaluate the efficacy of a low-dose methotrexate added to H1-antihistamines regimen for CSU resistant to anti-H1 treatment, compared with anti-H1 monotherapy in a randomized, placebo-controlled trial. Materials and Methods: Patients with CSU resistant to at least a 3 month-period of anti-H1 were randomly assigned to receive either low-dose methotrexate (0.2 mg/kg/week) or placebo in addition to anti-H1. Primary outcome was the proportion of patient with complete remission of CSU after 18 weeks (W18), defined as no urticarial lesion within the previous 30 days. Intention to treat analyses were performed (failure was considered when data on primary outcome were missing). Results: From November 2011 to May 2016, 75 patients were randomized: 39 were allocated to methotrexate and 36 to placebo. In the intention to treat population, 3 patients in the methotrexate group (7.9%) and 0 patient in the placebo group (0.0%) had a complete remission at W18 (difference, 7.9 percentage points, [95% confidence interval (CI) -4.0 to 20.8], p=0.24). Eleven patients in the methotrexate group (29.0%) and 6 patients in the placebo group (18.8%) had less than 7 days with urticarial lesions within the 30 days before W18 (difference, 10.2 percentage points, [95% CI -10.2 to 28.8], p=0.40). Clinical adverse events occurred in 56.4% of patients in the methotrexate group and 50.0% in the placebo group (p=0.58), mostly gastrointestinal symptoms. Biological adverse events occurred in 59.0% of patients in the methotrexate group and 30.6% in the placebo group (p=0.01), mainly increased blood level of transaminases. Conclusions: We did not evidence any superiority of a low dose methotrexate added to anti-H1, compared with anti-H1 monotherapy, for patients with chronic spontaneous urticarial

Human engraftment of NOG mice transplanted with ES or iPS cells.

<p>Human engraftment of NOG mice transplanted with ES or iPS cells.</p

Hematopoietic differentiation potential among four ES cell lines.

<p>(A) Protocol schematic for hematopoietic differentiation by EB and OP9 co-cultures methods. ES cell lines are cultured on MEF with bFGF, treated with collagenase IV, broken into small clumps and plated for hematopoiesis induction. Clumps are seeded in EB differentiation media in ultra low attachment plates incubate at 37°C in 5% CO₂ for 16 days, media was change 2–3 times. For OP9 co-culture, clumps are seeded in hematopoiesis differentiation media on OP9 grown to confluence and media changed at days 4, 6 and 8 cultured at 37°C in 5% CO₂ for 13 days. At day 16 (EB) and day 13 (OP9 co-culture), cells were disrupt to single cell suspension and plate for CFC, analyze flow cytometry, Q-RT-PCR, or mouse reconstitution assay analysis. B-F) by the EB method. (B) Number of CFC counted and classified according to morphology. Each assay was performed in triplicate, data is shown as mean ± s.d. of n = 27, 34, 3 and 3 independent experiments for SA01, H1, H9 and CL01 respectively. There is no statistically significant difference for CFC number when comparing SA01 <i>vs</i> H1 and H9 <i>vs</i> CL01 (p>0.05), in contrast to SA01 <i>vs</i> H9, SA01 <i>vs</i> CL01, H1 <i>vs</i> H9, H1 <i>vs</i> CL01 are statistically significant different (*<i>p</i><0.05). (C) Types of CFC (CFU-E, BFU-E, CFU-GM and CFU-GEMM). (D) Flow cytometric analysis of the percentage of CD34+ cells in EB-derived ES cells n = 12, 22, 3 and 3 for SA01, H1, H9 and CL01 respectively. Differences of expression of CD34 for SA01 <i>vs</i> H1, SA01 <i>vs</i> H9, SA01 <i>vs</i> CL01, H1 <i>vs</i> H9, H1 <i>vs</i> CL01 were statistically significant (*p<0.05). (E) EB-derived cells from SA01, H1 and H9 cell lines co-expressed CD34/CD45, CD34/CD43 and CD45/CD43 hematopoietic markers n = 4, 8 and 3, respectively. (F) Representative FACS analysis for EB-derived cells from H1 cell line co-expressed CD34/CD45, CD34/CD43 and CD45/CD43 hematopoietic markers. G-I) on OP9 co-cultures, (G) Number of CFC generated, SA01 n = 6, H1 n = 8, H9 n = 3 and CL01 n = 3, CFC number from SA01 was significantly different from that obtained from the 3 others ES cell lines (*<i>p</i><0.05). (H) Distribution of CFC types. (I) Flow cytometric analysis of the percentage of CD34+ cells after OP9 differentiation, SA01 n = 6, H1 n = 8, H9 n = 7 and CL01 n = 3 were not statistically significant (p>0.05).</p