Two-sided cells of Weyl groups and certain splitting Whittaker polynomials

Consider the subset of a Weyl group with a fixed descent set. For Weyl groups of classical types, we determine the number of two-sided cells this subset intersect. Moreover, we apply this result to prove that certain rational Whittaker polynomials associated with covering groups split over the field of rational numbers

Izraženost surfaktantnog proteina B u bronhoalveolarnom ispirku terminske novorođenčadi sa sindromom respiracijskog distresa

The aim was to investigate the surfactant protein B (SP-B) expression in the bronchoalveolar lavage fluid (BALF ) of full-term neonates with respiratory distress syndrome (RD S). The enzyme-linked immunosorbent assay was performed to assess SP-B expression in BALF of 60 full-term neonates with RD S and 23 healthy neonates and correlation of SP-B level with RD S classification according to chest x-ray findings and PaO2/FiO2 before mechanical ventilation in neonates with RD S. The SP-B level was significantly lower in the RD S group (17.63±6.80 ng/mL) than in healthy neonates (103.95±6.38 ng/mL) (P<0.001). The SP-B level correlated positively with PaO2/ FiO2 before mechanical ventilation (r=0.838, P<0.001). Moreover, the lower the SP-B level, the more severe was the RD S as determined by chest x-ray (P<0.001). In conclusion, full-term neonates with RD S had reduced SP-B in BALF , which was related to the severity of RD S, suggesting that SP-B supplement may be an effective strategy in the treatment of RD S in full-term neonates.Cilj studije bio je ispitati izraženost surfaktantnog proteina B (SP-B) u bronhoalveolarnom ispirku (BALF ) terminske novorođenčadi sa sindromom respiracijskog distresa (SRD ). Izraženost SP-B određena je testom ELI SA u BALF 60 terminske novorođenčadi sa SRD i 23 zdrave novorođenčadi. Utvrđena je korelacija razine SP-B s klasifikacijom SRD prema rendgenskoj snimci prsišta i vrijednosti PaO2/FiO2 prije mehaničke ventilacije u novorođenčadi sa SRD . U skupini novorođenčadi sa SRD razina SP-B bila je značajno niža (17,63±6,80 ng/mL) od one u zdrave novorođenčadi (103,95±6,38 ng/ mL) (P<0,001). Utvrđena je pozitivna korelacija razine SP-B i PaO2/FiO2 prije mehaničke ventilacije (r=0,838, P<0,001). Štoviše, što je bila niža razina SP-B, to je teži bio SRD procijenjen prema rendgenskoj snimci prsišta (P<0,001). Zaključuje se da terminska novorođenčad sa SRD ima sniženu razinu SP-B u BALF i to je povezano s težinom SRD . Ovi nalazi ukazuju na to da bi dodatak SP-B mogla biti učinkovita strategija u liječenju SRD kod terminske novorođenčadi

CRISPR/Cas9 screen in human iPSC‐derived cortical neurons identifies NEK6 as a novel disease modifier of C9orf72 poly(PR) toxicity

Introduction The most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are hexanucleotide repeats in chromosome 9 open reading frame 72 (C9orf72). These repeats produce dipeptide repeat proteins with poly(PR) being the most toxic one. Methods We performed a kinome-wide CRISPR/Cas9 knock-out screen in human induced pluripotent stem cell (iPSC) -derived cortical neurons to identify modifiers of poly(PR) toxicity, and validated the role of candidate modifiers using in vitro, in vivo, and ex-vivo studies. Results Knock-down of NIMA-related kinase 6 (NEK6) prevented neuronal toxicity caused by poly(PR). Knock-down of nek6 also ameliorated the poly(PR)-induced axonopathy in zebrafish and NEK6 was aberrantly expressed in C9orf72 patients. Suppression of NEK6 expression and NEK6 activity inhibition rescued axonal transport defects in cortical neurons from C9orf72 patient iPSCs, at least partially by reversing p53-related DNA damage. Discussion We identified NEK6, which regulates poly(PR)-mediated p53-related DNA damage, as a novel therapeutic target for C9orf72 FTD/ALS

DeepDyve: Dynamic Verification for Deep Neural Networks

Deep neural networks (DNNs) have become one of the enabling technologies in many safety-critical applications, e.g., autonomous driving and medical image analysis. DNN systems, however, suffer from various kinds of threats, such as adversarial example attacks and fault injection attacks. While there are many defense methods proposed against maliciously crafted inputs, solutions against faults presented in the DNN system itself (e.g., parameters and calculations) are far less explored. In this paper, we develop a novel lightweight fault-tolerant solution for DNN-based systems, namely DeepDyve, which employs pre-trained neural networks that are far simpler and smaller than the original DNN for dynamic verification. The key to enabling such lightweight checking is that the smaller neural network only needs to produce approximate results for the initial task without sacrificing fault coverage much. We develop efficient and effective architecture and task exploration techniques to achieve optimized risk/overhead trade-off in DeepDyve. Experimental results show that DeepDyve can reduce 90% of the risks at around 10% overhead

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

Tissue-specific gain of wild-type RTK levels combined with screen strategies identify new mechanisms of cell vulnerability in developmental and tumorigenic programs

Pour étudier la capacité cellulaire à s’adapter aux changements de signalisation dépendante des RTKs, nous utilisons un modèle de souris où l’expression du RTK Met sauvage peut être accrue dans un tissu spécifique. La plupart des tissus se protègent contre cette expression anormale des RTK. Mais certains types cellulaires sont sensibles aux altérations des RTKs, c’est le cas du mésenchyme du membre pendant l’embryogenèse. En effet, l’expression de certains gènes du mésenchyme est modifiée et celui-ci n’est plus accessible aux myoblastes qui le colonisent, conduisant à des déficits des muscles du membre. Chez l’adulte une augmentation de l’expression de Met dans le foie (Alb-R26Met) perturbe l’homéostasie tissulaire, conduisant à la tumorigenèse. Pour identifier des gènes qui coopèrent avec les RTKs pendant l’initiation de la tumorigenèse, nous avons combiné les souris Alb-R26Met avec le système de mutagenèse Sleeping Beauty (SB) transposon. 285 gènes putatifs liés au cancer ont été identifiés. Certains sont des proto-oncogènes ou suppresseurs de tumeurs déjà connus, validant le système. D’autres gènes n’avaient, jusqu’à présent, jamais été associés à ce processus. 9 candidats ont été fonctionnellement validés. Pour identifier des signaux assurant le maintien de la tumeur, nous avons analysé le phosphokinome, testé l’efficacité de composés et identifié de nouvelles combinaisons de drogues qui agissent en synergie pour tuer les cellules cancéreuses dérivées de Alb-R26Met. En conclusion, ces travaux montrent qu’une approche génétique non-biaisée combinée à une approche génomique permet d’identifier de nouveaux mécanismes pertinents pour la biologie du cancer.We explore the cell competence to deal with slight changes in RTK inputs during embryogenesis and tissue homeostasis using a mouse model in which wild-type RTK Met levels can be moderately enhanced in a tissue specific manner. Most tissues buffer enhanced RTK levels thus avoiding perturbation of developmental programs and tissue homeostasis. Nevertheless, certain cell types are vulnerable to RTK levels. During embryogenesis, the limb mesenchyme is sensitive to alterations of the spatial distribution of RTKs, as illustrated by gene expression changes and by loss of accessibility to incoming myoblasts, which lead to limb muscle defects. At adulthood, liver enhanced Met levels (Alb-R26Met) perturbs tissue homeostasis, leading to tumorigenesis. To uncover new genes that cooperate with RTKs during tumour initiation, we combined Alb-R26Met mice with the Sleeping Beauty (SB) transposon mutagenesis system. 285 putative cancer-related genes have been identified. Some correspond to known proto-oncogenes or tumour suppressors, thus validating the overall strategy we employed for cancer gene discovery. Others have not been previously linked to cancer. 9 new tumour suppressors have been functionally validated, demonstrating the validity of our screen strategy. To identify signals involved in tumour maintenance, we employed a phosphokinome-guided drug screen and identified new synergistic drugs deleterious for cancer cells modelled by the Alb-R26Met genetic setting. The overall strategy and outcomes strengthen the value of combining unbiased genetic and genomic approaches to identify new mechanisms relevant for cancer biology and new therapeutic interventions

Systematic study of microRNAs in within-species and cross-species interactions

MicroRNAs (miRNAs) are small noncoding RNAs that play important roles in post-transcriptional gene regulation in eukaryotic cells. They target mRNAs to suppress gene expression by inhibition of translation or promotion of mRNA decay. miRNAs have emerged as key gene regulators in diverse biological pathways, with over half of the human transcriptome predicted to be under miRNA regulation. In conjunction with other post-transcriptional control pathways, the majority of the gene expression cascade can be under direct or indirect miRNA regulation. Given this far-reaching role, it is not surprising that disruption of miRNA functions can contribute to many human diseases. Both computational and experimental methods are now available for identifying miRNA target sites. Many tools have been developed for functional analysis of miRNA targets to help understand miRNA functions. Exosomes are small (50-90 nm) extracellular vesicles (EVs) composed of lipids, proteins, and genetic materials that can mediate communications between cells. Such communications can play important roles in the regulation of physiology and pathological processes. Recently, some studies have demonstrated that exosomes containing small noncoding RNAs from pathogens have potential to regulate the host immune response, and gut microbiota can also be affected by host exosomal miRNAs. Lastly, exosomal miRNAs originating from foreign organisms (xeno-miRNAs), have been detected in the host's circulatory system. Therefore, exosomal miRNAs can potentially play important roles in cross-species interactions.The central objective of my thesis project is to develop bioinformatics tools to help better understand the roles of miRNAs in both within- and cross-species gene regulations. I worked on three different sub-projects to achieve this goal. Firstly, I developed the miRNet web application to perform miRNA functional study within species. It currently integrates 11 miRNA-target interaction databases and supports comprehensive expression data analysis and flexible interactive network visualization; Secondly, I developed the Xeno-miRNet database application combining known and predicted xeno-miRNAs and their targets to allow researchers to explore the potential functions of xeno-miRNAs originating from different species in several selected hosts. Finally, to explore the modulation of gut microbiota by host exosomal miRNAs, I performed miRNA target prediction against 806 gut bacteria genomes, followed by experimental validations of several selected miRNAs and target bacteria.Les micro-ARN (miARN) sont de petits ARN non codants qui jouent un roleimportant dans la régulation génique post-transcriptionnelle dans les cellules eucaryotes. Ils ciblent les ARNm pour supprimer l'expression génique par l'inhibition de la traduction ou la promotion de la dégradation de l'ARNm. Les miARN ont émergé en tant que régulateurs principaux de gène dans diverses voies biologiques, avec plus de la moitié de la transcriptome humaine étant prédite pour être sous la régulation de miARN. En conjonction avec d'autres voies de contrôle post-transcription, la majorité de la cascade d'expression de gène peut être sous la régulation directe ou indirecte de miARN. Compte tenu de ce rôle de grande envergure, il n'est pas surprenant que la perturbation de la fonction Mirna peut contribuer à de nombreuses maladies humaines. De nombreux outils ont également été développés pour l'analyse de l'enrichissement fonctionnel des cibles de miARN pour aider à comprendre les fonctions de miARN. Actuellement, des méthodes informatiques et expérimentales sont maintenant disponibles pour identifier les sites cibles de miARN.Les exosomes sont de petites (50-90 nm) vésicules extracellulaires (VE) composées de lipides, de protéines et de matériel génétique, qui peuvent servir de médiateurs pour faciliter la communication entre les cellules. Une telle communication peut jouer un rôle important dans la régulation de la physiologie et des processus pathologiques. Récemment, certaines études ont démontré que les exosomes contenant de petits ARN non codants provenant de pathogènes ont le potentiel de réguler la réponse immunitaire de l'hôte. De plus, le microbiote intestinal peut également être médié par les miARN exosomaux de l'hôte. Enfin, des miARN exosomaux d'organismes étrangers, appelés xéno-miARN, ont également été détectés dans le système circulatoire de l'hôte. Par conséquent, les miARN exosomiques peuvent potentiellement jouer un rôle vital dans les interactions inter-espèces.L'objectif central de mon projet de thèse est de développer des outils bioinformatiques pour aider à mieux comprendre le rôle des miARN dans la régulation des gènes intra- et inter-espèces. J'ai travaillé sur trois sous-projets différents pour atteindre cet objectif. Tout d'abord, j'ai développé l'application du site internet miRNet pour effectuer une étude fonctionnelle de miARN au sein des espèces. miRNet intègre actuellement 11 bases de données d'interaction miARN-cible et prend en charge l'analyse complète des données d'expression et la visualisation de réseau interactif flexible. Deuxièmement, j'ai développé l'application de base de données Xeno-miRNet combinant des xéno-miARN connus et prédits et leurs cibles pour permettre aux chercheurs d'explorer les fonctions potentielles des xéno-miARN provenant de différentes espèces dans plusieurs hôtes sélectionnés. Enfin, pour explorer la modulation du microbiote intestinal par les miARN exosomaux de l'hôte, la prédiction de cible de miRNA a été réalisée et effectuée contre 806 génomes de bactéries intestinales, suivie par des validations expérimentales pour plusieurs miARN et bactéries sélectionnés