Rôle des anomalies de TET2 dans la transformation tumorale lymphoïde et myéloïde

Les enzymes de la famille Ten-Eleven-Translocation (TET) sont des oxygénases dépendantes du 2-oxoglutarate et du Fe (II) capables d hydroxyler les cytosines méthylées. La conversion en 5-hydroxyméthylcytosines constituerait une étape vers la déméthylation et les protéines TET seraient donc impliquées dans le contrôle épigénétique de la transcription. Des mutations inactivatrices acquises du gène TET2 ont été décrites dans environ 20% des hémopathies myéloïdes humaines. L'analyse de deux modèles murins d invalidation de Tet2 montre que Tet2 contrôle l'hydroxyméthylation et l homéostasie du compartiment hématopoïétique. Son inactivation entraine des anomalies pléiotropiques des stades précoces et tardifs de l hématopoïèse et le développement d'hémopathies myéloïdes. L'étude du statut de TET2 chez une grande série de patients porteurs d'hémopathies lymphoïdes matures retrouve des mutations de ce gène chez 12% des cas de lymphomes T. Celles-ci sont significativement associées aux mutations du gène DNMT3A et sont plus fréquemment observées au sein de deux sous-types, le lymphome T angio-immunoblastique et le lymphome T périphérique non spécifié. L analyse de populations triées montre la préexistence des mutations de TET2 ou de DNMT3A dans les progéniteurs hématopoïétiques chez certains patients.En conclusion, les mutations de TET2 peuvent survenir dans des progéniteurs précoces, leur conférer un avantage sélectif par rapport aux progéniteurs sauvages et conduire au développement d une hématopoïèse clonale. Des anomalies génétiques additionnelles semblent nécessaires à la transformation tumorale aussi bien myéloïde que lymphoïde. Ces deux types d hémopathies pourraient donc se développer à partir d une même atteinte du compartiment des cellules souches hématopoïétiques.The Ten-Eleven-Translocation (TET) enzymes belong to a family of oxygenases that are dependent on 2-oxoglutarate and Fe (II) and are able to oxidize methylcytosines. This may represent a step toward DNA demethylation and as such these proteins are involved in the epigenetic control of transcription. Acquired TET2 loss-of-function mutations have been reported in about 20% of human myeloid malignancies.Analysis of two Tet2-deficiency mouse models shows that Tet2 controls hydroxymethylation and homeostasis in the hematopoietic compartment. Tet2 deficiency results in pleiotropic abnormalities of both early and late steps of hematopoiesis and leads to the development of myeloid disorders. The sequencing of TET2 in a large series of patients with mature lymphoproliferations identifies TET2 mutations in 12% of T-cell lymphoma. They are significantly associated with DNMT3A mutations and are more frequently observed in two subtypes, the angioimmunoblastic T-cell lymphoma and the peripheral T-cell lymphoma, not other specified. Analysis of flow-sorted populations shows the presence of TET2 and DNMT3A alterations in hematopoietic progenitors in some patients. In summary, TET2 mutations may affect early progenitors, confer a selective advantage compared with controls progenitors and result in a clonal hematopoiesis. Some additional genetic events are likely required to the myeloid or lymphoid transformation. Both diseases could therefore arise from a common alteration of the hematopoietic stem cell compartment.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

Predicting the Progression of Mild Cognitive Impairment Using Machine Learning: A Systematic and Quantitative Review

Context. Automatically predicting if a subject with Mild Cognitive Impairment (MCI) is going to progress to Alzheimer's disease (AD) dementia in the coming years is a relevant question regarding clinical practice and trial inclusion alike. A large number of articles have been published, with a wide range of algorithms, input variables, data sets and experimental designs. It is unclear which of these factors are determinant for the prediction, and affect the predictive performance that can be expected in clinical practice. We performed a systematic review of studies focusing on the automatic prediction of the progression of MCI to AD dementia. We systematically and statistically studied the influence of different factors on predictive performance. Method. The review included 172 articles, 93 of which were published after 2014. 234 experiments were extracted from these articles. For each of them, we reported the used data set, the feature types (defining 10 categories), the algorithm type (defining 12 categories), performance and potential methodological issues. The impact of the features and algorithm on the performance was evaluated using t-tests on the coefficients of mixed effect linear regressions. Results. We found that using cognitive, fluorodeoxyglucose-positron emission tomog-raphy or potentially electroencephalography and magnetoencephalography variables significantly improves predictive performance compared to not including them (p=0.046, 0.009 and 0.003 respectively), whereas including T1 magnetic resonance imaging, amyloid positron emission tomography or cerebrospinal fluid AD biomarkers does not show a significant effect. On the other hand, the algorithm used in the method does not have a significant impact on performance. We identified several methodological issues. Major issues, found in 23.5% of studies, include the absence of a test set, or its use for feature selection or parameter tuning. Other issues, found in 15.0% of studies, pertain to the usability of the method in clinical practice. We also highlight that short-term predictions are likely not to be better than predicting that subjects stay stable over time. Finally, we highlight possible biases in publications that tend not to publish methods with poor performance on large data sets, which may be censored as negative results. Conclusion. Using machine learning to predict MCI to AD dementia progression is a promising and dynamic field. Among the most predictive modalities, cognitive scores are the cheapest and less invasive, as compared to imaging. The good performance they offer question the wide use of imaging for predicting diagnosis evolution, and call for further exploring fine cognitive assessments. Issues identified in the studies highlight the importance of establishing good practices and guidelines for the use of machine learning as a decision support system in clinical practice

Activating mutations and translocations in the guanine exchange factor VAV1 in peripheral T-cell lymphomas.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of non-Hodgkin lymphomas frequently associated with poor prognosis and for which genetic mechanisms of transformation remain incompletely understood. Using RNA sequencing and targeted sequencing, here we identify a recurrent in-frame deletion (VAV1 Δ778-786) generated by a focal deletion-driven alternative splicing mechanism as well as novel VAV1 gene fusions (VAV1-THAP4, VAV1-MYO1F, and VAV1-S100A7) in PTCL. Mechanistically these genetic lesions result in increased activation of VAV1 catalytic-dependent (MAPK, JNK) and non-catalytic-dependent (nuclear factor of activated T cells, NFAT) VAV1 effector pathways. These results support a driver oncogenic role for VAV1 signaling in the pathogenesis of PTCL

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

The complete sequence of human chromosome 5

Chromosome 5 is one of the largest human chromosomes yet has one of the lowest gene densities. This is partially explained by numerous gene-poor regions that display a remarkable degree of noncoding and syntenic conservation with non-mammalian vertebrates, suggesting they are functionally constrained. In total, we compiled 177.7 million base pairs of highly accurate finished sequence containing 923 manually curated protein-encoding genes including the protocadherin and interleukin gene families and the first complete versions of each of the large chromosome 5 specific internal duplications. These duplications are very recent evolutionary events and play a likely mechanistic role, since deletions of these regions are the cause of debilitating disorders including spinal muscular atrophy (SMA)

Sur les grands clusters en percolation

NOUS ETUDIONS LES GRANDS CLUSTERS EN PERCOLATION BERNOULLI? EN PERCOLATION FK ET EN PERCOLATION ORIENTEE.EN PERCOLATION BERNOULLI, LES CLUSTERS SATISFONT UN PRINCIPE DE GRANDES DEVIATIONS. LA FONCTION DE TAUX EST LA MESURE DE HAUSDORFF 1-DIMENSIONNELLE ASSOCIEE A LA FONCTION DE CONNECTIVITE.EN PERCOLATION FK EN DIMENSION DEUX, LE CLUSTER MAXIMAL DANS UNE BOITE A LA DENSITE DU CLUSTER INFINI ET L'UNION DES CLUSTERS INTERMEDIAIRES EST DE TAILLE NEGLIGEABLE A DES DEVIATIONS SURFACIQUES PRES.LES GRADS CLUSTERS FINIS EN PERCOLATIN FK SONT DISTRIBUES COMME UN PROCESSUS DE POISSON SPATIAL. LA METHODE CHEN-STEIN EST APPLIQUEE AU PROCESSUS DES CENTRES DE GRAVITES DES GRANDS CLUSTERS FINIS ET NOUS TRAVAILLONS SOUS L'HYPOTHESE D'UNE PROPRIETE DE MELANGE FAIBLE POUR CONTROLER LES INTERACTIONS ENTRE LES CLUSTERS.LA MESURE EMPIRIQUE DU CLUSTER DE 0 SATISFAIT UN PRINCIPE DE GRANDES DEVIATIONS EN PERCOLATION ORIEN-TEE. LE SCHEMA EST CELUI DU CAS NON-ORIENTE. BIEN QUE LE PROCESSUS SOIT MARKOVIEN, DES DIFFICULTES SURGISSENT, PARTICULEREMENT A CAUSE DE LA NON-EQUIVALENCE ENTRE L'ENERGIE DE SURFACE ET LE PERIMETRE.WE STUDY LARGE CLUSTERS IN BERNOULLI PERCOLATION, FK PERCOLATION AND ORIENTED PERCOLATION.IN BERNOULLI PERCOLATION, CLUSTERS SATISFY A LARGE DEVIATION PRINCIPLE. THE RATE FUNCTIONIS THE 1-DIMENSIONAL HAUSDORFF MEASURE ASSOCIATED TO THE CONNECTIVITY FUNCTION.IN 2D-FK PERCOLATION THE MAXIMAL CLUSTER IN A BOX HAS THE DENSITY OF THE INFINITE CLUSTERAND THE SET OF INTERMEDIATE CLUSTERS HAS A NEGLIGIBLE VOLUME UP TO LARGE DEVIATIONS OF LINEAR ORDER.LARGE FINITE CLUSTERS ARE SPATIALLY DISTRIBUTED AS A POISSON PROCESS IN FK PERCOLATION. WE APPLY THE CHEN-STEIN METHODTO THE PROCESS OF THE MASS CENTERS OF LARGE FINITE CLUSTERS. WE REQUIRE A MIXING PROPERTY TO CONTROL INTERACTIONS BETWEEN CLUSTERS.THE EMPIRICAL MEASURE OF THE CLUSTER OF 0 SATISFIES A LARGE DEVIATION PRINCIPLE IN OREINTED PERCOLATION. THE SHEME OF THE PROOF IS LIKE IN THE UNORIENTED CASE. DESPITE THE MARKOVIAN ASPECT OF THE ORIENTED PROCESS, WE HAVE TO HANDLE SEVERAL DIFFICULTIES, IN PARTICULAR THE NON-EQUIVLALENCE BETWEEN THE SURFACE ENERGY AND THE PERIMETER.ORSAY-PARIS 11-BU Sciences (914712101) / SudocORSAY-PARIS 11-Bib. Maths (914712203) / SudocSudocFranceF

An ab initio and DFT study of (N2)2 dimers

The structure of van der Waals dimers (N2)2 is studied using ab initio and density functional calculations. The potential energy surfaces corrected a priori for basis set superposition errors are necessary for determining both the geometries and the vibrational frequencies. With both ab initio MP2, MP4 and DFT PW91–PW91 levels of theory, the T-shaped and canted conformations appear to be the most stable, within 1–5 cm−1 of each other. The DFT PW91–PW91 dissociation energy is 67 cm−1 and an upper limit to the barrier to internal motion is 30 cm−1, both in excellent agreement with the values deduced from IR measurements

Mapping cis-Regulatory Domains in the Human Genome Using Multi-Species Conservation of Synteny

Our inability to associate distant regulatory elements with the genes that they regulate has largely precluded their examination for sequence alterations contributing to human disease. One major obstacle is the large genomic space surrounding targeted genes in which such elements could potentially reside 1. In order to delineate gene regulatory boundaries we used whole-genome human-mouse-chicken (HMC) and human-mouse-frog (HMF) multiple alignments to compile conserved blocks of synteny (CBS), under the hypothesis that these blocks have been kept intact throughout evolution at least in part by the requirement of regulatory elements to stay linked to the genes that they regulate. A total of 2,116 and 1,942 CBS >200 kb were assembled for HMC and HMF respectively, encompassing 1.53 and 0.86 Gb of human sequence. To support the existence of complex long-range regulatory domains within these CBS we analyzed the prevalence and distribution of chromosomal aberrations leading to position effects (disruption of a gene s regulatory environment) 1,2, observing a clear bias not only for mapping onto CBS but also for longer CBS size. Our results provide a genome wide dataset characterizing the regulatory domains of genes and the conserved regulatory elements within them