HCV genotyping using statistical classification approach

The genotype of Hepatitis C Virus (HCV) strains is an important determinant of the severity and aggressiveness of liver infection as well as patient response to antiviral therapy. Fast and accurate determination of viral genotype could provide direction in the clinical management of patients with chronic HCV infections. Using publicly available HCV nucleotide sequences, we built a global Position Weight Matrix (PWM) for the HCV genome. Based on the PWM, a set of genotype specific nucleotide sequence "signatures" were selected from the 5' NCR, CORE, E1, and NS5B regions of the HCV genome. We evaluated the predictive power of these signatures for predicting the most common HCV genotypes and subtypes. We observed that nucleotide sequence signatures selected from NS5B and E1 regions generally demonstrated stronger discriminant power in differentiating major HCV genotypes and subtypes than that from 5' NCR and CORE regions. Two discriminant methods were used to build predictive models. Through 10 fold cross validation, over 99% prediction accuracy was achieved using both support vector machine (SVM) and random forest based classification methods in a dataset of 1134 sequences for NS5B and 947 sequences for E1. Prediction accuracy for each genotype is also reported

Peter, le langage qui n’existe pas...

“Inside every large language is a small language struggling to get out ...” [Igarashi et al. 2001]“... and inside every small language is a sharp extension looking for better expressivity ...” [Liquori & Spiwack 2008]It is my privilege and pleasure to introduce Peter, the language that does not exist... The Peter language contains almost the linguistic features I have introduced and investigated in the field of functional and object-oriented programming, plus some new features not published yet. In Peter’s Habilitation, I will try to limit as much as possible the mathematical overhead and the technicalities (e.g. full set of rules, full proofs of theorems, etc.). In my opinion, the habilitation thesis should not be a mere translation of the candidate’s most successful papers (3), nor a commented curriculum vitæ, nor a survey of all the related works in his scientific area (4), just to mention a few “classic Habilitation styles”. It is my opinion that it should be short in length since it is experienced that a very few Habilitation thesis are really downloaded, cited and read. Oftenly, habilitation thesis are not even made accessible on the Web. Peter’s Habilitation will be based on the following three points: • (Modularity) I will present a (Turing complete) kernel of Peter, called Baby Peter, and I will continue in the rest of the Habilitation to extend it in a modular fashion until the final extension, called Wise Peter. Baby Peter is a functional language with object-oriented features equipped with a sound type system. Peter bears some similarities to Atsushi, Benjamin and Phil’s Featherweight Java [IPW01] and Alonso Church’s typed lambda calculus [Chu41]. The main difference lies in an ad hoc exception-handling mechanism allowing the programmer to choose the type system according to her/his necessities and goals. Even more, it allows the programmer to write her/his own type system (see item (Type-programmable)). Some chapters will focus on operational semantics, some others on type systems, some others on both. All topics will be treated in a “lightweight fashion”. Examples of extensions are for instance mixing class-based and pure object-based features, but also improving proof languages à la LF with pattern matching facilities and including those metalanguages to Peter in order to mix algorithms and their correctness proofs. • (Verbatim-like) Instead of annoying the reader with a plain French translation of some of my most relevant papers (6), I will show, for each extension, only some key rules of the operational semantics or of the type system (every system has at least a key rule...) and some motivating examples. I do not plan to prove type soundness for each extension of Peter: the whole soundness of Wise Peter is left as a challenge for the “next” user friendly proof assistant.• (Type-programmable) Type systems for programming languages and proof languages are fixed a priori by language designers; type systems are not first class citizens. To my little knowledge, no language allows the programmer to build, choose, or mix type systems. The idea of modifying the type discipline at compile time is not completely new; a quite inspiring work has been done by the “visionary-6-pages” paper by Gilad in 2004 [Bra04] called Pluggable Type Systems. The possibility to mixing type systems and using it as a first class citizens is an interesting research strand that will constitute an original contribution in Peter’s Habilitation. With the intention of disseminating science in a simple, clear and pedagogical way, and inspired by the works of Kim [Bru99, TKB01, BDKT03, RBC+ 05, Bru02] and Gilles [Dow03, Dow07], I wish you a very nice reading of the Peter’s Habilitation. 3 Although certain parts are taken of my articles. 4 The typographic convention is that references to my papers are in “numeric” style while references to other papers are in “alphanumeric” style. 6 We provide a CD and a Web site with all my papers.C’est mon privilege et plaisir d’introduire Peter, le langage qui n’existe pas... Le langage Peter contient quasiment tous les aspects linguistiques que j’ai introduits et étudiés dans le domaine de la programmation fonctionnelle et objets, ainsi que quelques idées qui n’ont pas encore été publiées. Dans l’habilitation de Peter, la démarche que je suivrai consiste à essayer de limiter les détails concernant les aspects théoriques et techniques (c-à-d. les ensembles complets des règles de typage, suites de théorèmes abscons, etc.). Mon mémoire d’habilitation ne sera pas une traduction brutale des différents articles publiés (1), ni un curriculum vitæ commenté, ni un panorama de tous les articles dans un domaine scientifique (2), pour ne citer que quelques styles classiques de thèses d’habilitation. Tout d’abord elle sera courte car l’expérience enseigne que très peu de thèses d’habilitation sont réellement téléchargées, citées et lues. Très souvent, les thèses d’habilitation ne sont même pas accessibles sur le Web. L’Habilitation de Peter sera fondée sur les trois « dogmes » suivants: • (Modularité) Je commencerai par le plus petit fragment complet (au sens de Turing) de Peter, appelée Baby Peter et je continuerai de façon modulaire, d’extension en extension, jusqu’à l’extension finale appelée Sage Peter. Baby Peter est un langage fonctionnel avec des constructions linguistiques orientées objet et un système de types correct. Peter partage quelques similitudes avec Featherweight Java de Atsushi, Benjamin et Phil [IPW01] et le lambda calcul typé de Alonso (Church) [Chu41]. La différence principale entre Featherweight Java et Peter, est un mécanisme d’exceptions ad hoc, qui permet au programmeur de décider quel système de types sera le plus adapté à l’egard de ses nécessités et objectifs. En plus, ce mécanisme permet au programmeur d'écrire son système de types (voir point Type-programmable). Certains chapitres seront focalisés sur un nouveau système de types, tandis que, dans d’autres chapitres, l’extension sera associée à une extension de la syntaxe et du système de types. Tous les arguments seront traités d’une façon accessible au plus grand nombre de lecteurs. Comme exemples d’extensions, je citerai une forme nouvelle d'héritage multiple, une extension de Peter qui permettra à un objet de « s'échapper de sa classe », une extension de Peter avec filtrage évolué et enfin une extension de Peter qui permettra de mélanger algorithmes et preuves de correction d’algorithmes.• (Verbatim-like) Plutôt que d'asséner à mes lecteurs une traduction française mot-à-mot de mes articles scientifiques (5), j’ai privilegié une présentation simple de chaque extension, utilisant uniquement quelques règles clés de la sémantique opérationnelle ou du système de types (il y a toujours une règle clé...), en ajoutant immédiatement des exemples pour motiver et comprendre son utilisation correcte. Je ne prouverai pas la propriété de complétude de chaque système de types qui étend Peter : la complétude de Sage Peter est proposée en défi au prochain assistant à la preuve convivial. • (Type-programmable) Les systèmes de types pour les langages de programmation et pour la preuve sont fixés a priori par leurs concepteurs et ne sont pas des objets de première classe pouvant être modifiés ou simplement utilisés par le programmeur qui en subit les qualités et les faiblesses. À ma connaissance, aucun langage ne permet au programmeur de « programmer » sa discipline de types personnelle. L’idée de modifier la discipline de typage à la compilation n’est pas très nouvelle ; un article « visionnaire » de 6 pages, qui m'a eclairé, a été Pluggable Type System de Gilad [Bra04] sorti en 2004. La possibilité de permettre au programmeur d'écrire sa propre discipline de typage et de l’utiliser à la volée est par elle-même une contribution originale dans l’habilitation de Peter. Avec l’envie de diffuser la connaissance scientifique de façon simple, claire et pédagogique, inspiré par les ouvrages de Kim [Bru99,TKB01, BDKT03, RBC+ 05, Bru02] et Gilles [Dow03, Dow07], il ne me reste plus qu'à vous souhaiter une bonne lecture de l’habilitation de Peter. 1. Bien que certaines parties soient tirées de mes articles. 2. La convention typographique est que les référence à mes articles soit en style « numérique » tandis que les références à d’autres articles soit en « alphanumérique ». 5 Un CD et un site web contiendront tous mes articles. <br

Understanding Neuromuscular Health and Disease: Advances in Genetics, Omics, and Molecular Function

This compilation focuses on recent advances in the molecular and cellular understandingof neuromuscular biology, and the treatment of neuromuscular disease.These advances are at the forefront of modern molecular methodologies, oftenintegrating across wet-lab cell and tissue models, dry-lab computational approaches,and clinical studies. The continuing development and application ofmultiomics methods offer particular challenges and opportunities in the field,not least in the potential for personalized medicine

Safe Automated Refactoring for Intelligent Parallelization of Java 8 Streams

Streaming APIs are becoming more pervasive in mainstream Object-Oriented programming languages and platforms. For example, the Stream API introduced in Java 8 allows for functional-like, MapReduce-style operations in processing both finite, e.g., collections, and infinite data structures. However, using this API efficiently involves subtle considerations such as determining when it is best for stream operations to run in parallel, when running operations in parallel can be less efficient, and when it is safe to run in parallel due to possible lambda expression side-effects. ics-preserving fashion. The approach, based on a novel data ordering and typestate analysis, consists of preconditions and transformations for automatically determining when it is safe and possibly advantageous to convert sequential streams to parallel and unorder or de-parallelize already parallel streams. The approach was implemented as a plug-in to the popular Eclipse IDE, uses the WALA and SAFE analysis frameworks, and was evaluated on 18 Java projects consisting of ∼1.65M lines of code. We found that 116 of 419 candidate streams (27.68%) were refactorable, and an average speedup of 3.49 on performance tests was observed. The results indicate that the approach is useful in optimizing stream code to their full potential

Programming Languages and Systems

This open access book constitutes the proceedings of the 30th European Symposium on Programming, ESOP 2021, which was held during March 27 until April 1, 2021, as part of the European Joint Conferences on Theory and Practice of Software, ETAPS 2021. The conference was planned to take place in Luxembourg and changed to an online format due to the COVID-19 pandemic. The 24 papers included in this volume were carefully reviewed and selected from 79 submissions. They deal with fundamental issues in the specification, design, analysis, and implementation of programming languages and systems

Foundations of Software Science and Computation Structures

This open access book constitutes the proceedings of the 23rd International Conference on Foundations of Software Science and Computational Structures, FOSSACS 2020, which took place in Dublin, Ireland, in April 2020, and was held as Part of the European Joint Conferences on Theory and Practice of Software, ETAPS 2020. The 31 regular papers presented in this volume were carefully reviewed and selected from 98 submissions. The papers cover topics such as categorical models and logics; language theory, automata, and games; modal, spatial, and temporal logics; type theory and proof theory; concurrency theory and process calculi; rewriting theory; semantics of programming languages; program analysis, correctness, transformation, and verification; logics of programming; software specification and refinement; models of concurrent, reactive, stochastic, distributed, hybrid, and mobile systems; emerging models of computation; logical aspects of computational complexity; models of software security; and logical foundations of data bases.

Serotonin and Social Competency

Despite the fact that serotonergic drugs are called upon to treat a myriad of psychopathologies, the effect of serotonin on core behaviors and cognitive abilities are poorly understood. This is especially true for cognitive functions which underlie socially competent behavior. This dissertation aims to increase understanding of the role of serotonin in other monitoring and social competency throughout development. Species of primates, including humans, that live in complex social environments must allocate extensive cognitive resources to monitor conspecifics. However, they must balance the benefits of gathering social information with the need to monitor their non-social environments. Social monitoring strategies vary across species, populations of the same species, and even within populations. This variation seems to be dependent upon the amount of social monitoring that is required for an individual to avoid conflict and maintain its dominance rank. The serotonergic system has a history connecting it to socially competent behavior, like other monitoring, although its causal role is not understood. Therefore, better understanding how increasing concentrations of serotonin impact other monitoring behaviors will clarify serotonin’s role in psychopathology and may help clinicians predict how serotonergic interventions will influence pathologies. Furthermore, better understanding how the relationship between early life stress and serotonin impacts social competency will improve our understanding of psychiatric disorders and help develop novel interventions.In Chapter 2 of the present dissertation, the role of serotonin in the allocation of attention to social images, a core component of social monitoring, was studied by assaying rhesus macaques’ unconstrained looking to social and non-social stimuli using a free viewing paradigm (Dal Monte et al., 2014). We used a quantitative, repeated, within-subject, design to test how increasing central concentrations of serotonin would impact social looking behavior. Importantly, we found that increasing central concentrations of serotonin with its direct precursor, 5-Hydroxytrypotophan (5-HTP), modulated looking duration relative to individual differences in looking. 5-HTP decreased looking duration in animals with high baseline attention, but increased looking duration in low baseline attention animals. 5-HTP’s effects were also reflected in how engaged individuals were in the task and how they allocated attention to salient facial features—the eyes and mouth—of stimulus animals. Individual differences seem to be based in serotonergic function. Compared to low baseline animals, high baseline looking animals exhibited higher baseline concentrations of 5-HTP and serotonin and lower 5-HIAA to serotonin ratios indicating central serotonergic functioning may underlie and predict variation in serotonin’s effects on cognitive operation. The individual differences in 5-HTPs effects on looking increased our interest in serotonin’s role in balancing the costs and benefits of monitoring others (Weinberg‐Wolf and Chang, 2019). In Chapter 3, we tested the effect of 5-HTP on macaque’s abilities to flexibly switch between two actions: orienting to faces, or, at other times, inhibiting orientation towards faces. Critically, we found that 5-HTP also only impaired the ability to inhibit orientation to faces, but did not impact inhibition performance on trials with control images. It also seems that 5-HTP made animals less flexible, causing them to persevere in actions more. Furthermore, 5-HTP’s effects on performance are likely due to changes in arousal and motivation state as 5-HTP’s impairments were linked to increased reaction time, animals taking longer to initiate trials, and a constricted pupil. Serotonin is also implicated in the development of psychiatric disorders, especially Autism Spectrum Disorders. In Chapter 4, we examined the relationship between infant serotonergic function, assayed via CSF concentrations of 5-HIAA, and the acquisition of social status. We found that neonatal (11-32 days) 5-HIAA concentrations positively predict eventual, acquired, social rank. Furthermore, this relationship was strongest amongst macaques who had been reared by their mothers compared to those reared without mothers. In addition, mother reared infants exhibited higher concentrations of CSF 5-HIAA and attained higher social rank than their peers. These finds support the relationship between serotonin and early social experience in socially competent development. By considering the findings presented in Chapters 2, 3 and 4, we discuss, in Chapter 5, the role of serotonin in competent social monitoring and its development. We also discuss a plausible evolutionary explanation for variability in other monitoring behaviors and for variable effects of serotonin on cognition and behavior. Finally, we consider future directions researchers should explore as the field progresses

Classification et caractérisation des cancers colorectaux par approches omiques

Colon cancer (CC) is one of the most frequent and most deadly cancer in France and worldwide. Nearly half of patients die within 5 years after diagnosis. Clinical stage based on histological features and molecular classification based genomic instabilities (microsatellite instability (MSI), chromosomal instability (CIN) and hypermethylation of the promoters (ICPM)) are not sufficient to define homogeneous molecular entities and to predict recurrence effectively. To improve patient care, it is essential to better understand the diversity of the disease so that effective prognostic and predictive markers could be found. My PhD work has been focused on studying the diversity of CC at the molecular level through the use of omics approaches on a large cohort of tumor samples. It led to the establishment of a robust transcriptomic classification of these cancers, validated on independent data sets, and to a detailed characterization of each of the subtypes. Six subtypes have been defined and were associated with distinct clinicopathological characteristics and molecular alterations, specific enrichments of supervised gene expression signatures related to cell and lesions of origin, specific deregulated signaling pathways and distinct survival. The results of this work have been strengthened by a consensus classification defined by an international consortium working group in which I've been involved. These results confirm that colorectal cancer is an heterogeneous disease. They provide a renewed framework to develop prognostic signatures, discover new treatment targets, identify new therapeutic strategies and assess response to treatment in clinical trials.Le cancer du côlon (CC) est l'un des cancers les plus fréquents et les plus mortels en France et dans le monde. Près de la moitié des patients décèdent dans les 5 ans suivant le diagnostic. La classification clinique en stade histologique et la classification moléculaire selon les formes d'instabilité du génome (l'instabilité des microsatellites (MSI), l'instabilité chromosomique (CIN) et l'hyperméthylation des promoteurs (CIMP)) ne suffisent pas à définir des entités homogènes du point de vue moléculaire et à prédire de manière efficace la récidive. Pour améliorer la prise en charge des patients, il apparaît indispensable de mieux appréhender la diversité de la maladie afin de trouver des marqueurs pronostiques et prédictifs efficaces. Mon travail de thèse a donc été d'étudier la diversité des CC à l'échelle moléculaire par l'utilisation d'approches omiques sur une large cohorte de patients. Il a abouti à l'établissement d'une classification transcriptomique robuste de ce cancer dans son ensemble, validée sur des données indépendantes, et à la caractérisation fine de chacun des sous-types. Six sous-types ont ainsi été définis présentant des caractéristiques clinico-pathologiques, des altérations moléculaires de l'ADN, des enrichissements de signatures liées aux lésions et cellules d'origines, des voies de signalisation dérégulées et des survies bien distinctes. Les résultats de ce travail ont été confortés par un travail de classification consensus mis en place avec un consortium de travail international auquel j'ai participé. Ces résultats ont permis de confirmer que le cancer colorectal n'est pas une maladie homogène. Ils ouvrent de nouvelles perspectives pour l'établissement de signatures pronostiques et la recherche de cibles pour de nouveaux traitements ainsi que pour l'évaluation de la réponse au traitement au sein d'essais cliniques