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The problem of reconstructing the duplication history of a set of tandemly repeated sequences was first introduced by Fitch (1977). Many recent works deal with this problem, showing the validity of the unequal recombination model proposed by Fitch, describing numerous inference algorithms, and exploring the combinatorial properties of these new mathematical objects, which are duplication trees (DT). In this paper, we deal with the topological rearrangement of these trees. Classical rearrangements used in phylogeny (NNI, SPR, TBR, ...) cannot be applied directly on DT. We demonstrate that restricting the neighborhood defined by the SPR (Subtree Pruning and Re-grafting) rearrangement to valid duplication trees, allows exploring the whole space of DT. We use these restricted rearrangements in a local search method which improves an initial tree via successive rearrangements and optimizes the parsimony criterion. We show through simulations that this method improves all existing programs for both reconstructing the initial tree and recovering its duplication events.

Melanoma is the malignant tumor of melanocytes and considered as one of the most aggressive human cancers. While the worldwide incidence rate of melanoma has increased during the last decade, current therapies for melanoma do not provide long-term effect. The highly heterogeneous expression signature of melanoma underlies the inefficient therapy and accentuates the inevitability of profound molecular understanding of melanoma, its maintenance and progression. In this study, we aimed to reveal the complex patterns of distinct molecular mechanisms underlying the progression and maintenance of melanoma using high-throughput sequencing technologies. Series of melanoma tumor tissues representing discrete stages of the malignant progression were deeply sequenced. Integrative analysis revealed hard-wired genomic aberrations and associated transcriptomic consequences. These genomic aberrations included clusters of oncogenes brought together by structural variations, which cooperated in their amplifications and subsequent up-regulated expressions. We believe that these hard-wired genetic changes are biologically significant; they sustain the survival of the tumor and offer the advantage of the distant metastasis. We reconstituted the architecture of melanoma progression and maintenance and we identified gene cassettes with a putative role in sustaining tumor growth. The correlation of these gene cassettes with the cancer phenotype and the feasibility of these putative oncogenes as candidates for targeted therapy were addressed using cell-based assays on a high content screening platform. Analysis of the matched cell lines derived from the same patient offered a valuable resource for in vitro manipulation, testing of drugs and functional validation. A detailed molecular characterization of the functionally validated genes and their contribution in the cancer signaling pathways will provide a better understanding of the molecular basis of tumor evolution. Citation Format: Faranak Ghazi Sherbaf, Koichiro Inaki, Denis Bertrand, Xing Yi Woo, Dave Hoon, Axel Hillmer, Edison Liu. Genomic signatures of melanoma maintenance. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3414. doi:10.1158/1538-7445.AM2014-3414

The molecular complexity of cancer still remains as the limiting factor for developing efficient therapies with minimal side effects. However, scientists succeeded in determining common alterations in most human cancer types. Each of these alterations results from disruption of an anti-cancer regulation mechanism and/or activation of cancer-promoting networks by genetic and epigenetic changes. As a consequence, cancer cells become capable of mimicking stem cells’ ability to proliferate indefinitely while maintaining their cellular identity, or to self-renew, which is crucial for any type of stem cell. Indeed, some of the networks which are deregulated in cancer normally regulate self-renewal in stem cells. However, self-renewal is tightly regulated in stem cells, while cancer cells manage to escape the internal and external regulation mechanisms. Hence, cancer cells differ from stem cells by displaying disruptions in feedback mechanism controlling the rate of cell division, aberrant differentiation programs and error-prone replication, so they become invasive and even metastatic. We hypothesize that the stemness regulatory “cassette” that serves limitless replicative potential and undifferentiated state is a measure of cancer virulence and progression. We believe that this gene cassette is established through different mechanisms in each cell type, so it can be separated from invasion and instability in a precise and defined manner. To test our hypotheses, we set up a system reconstruction model consisting of induced pluripotent cells and transformed cells as stem and cancer cell models respectively, and their source of primary mouse embryonic fibroblast cells. From this model system, we created a system's map for transformation using differential expression patterns from whole genome expression arrays. We discovered gene networks that are common between stem and cancer cells, but different from their primary cells of origin. We also found deregulated/activated cassettes which are unique for cancer cells and which are hardwired by genomic rearrangements (copy number and structural variations) identified by DNA paired end tag (DNA-PET) sequencing and single nucleotide variations using RNA sequencing. We are now investigating the role of candidate genes selected from this analysis in cancer and stem cell maintenance through a high content siRNA screening. Citation Format: Gaye Saginc, Leena Ukil, Xingyi Woo, Francesca Menghi, Denis Bertrand, Charlie Wah Heng Lee, Koichiro Inaki, Edison Tak Bun Liu. In vitro tool for discovering oncogenes and tumor suppressor genes in a system's manner. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3180. doi:10.1158/1538-7445.AM2013-3180

Melanoma is one of the most aggressive human cancers. The worldwide incidence rate of melanoma has increased during the last decade but with few FDA approved therapeutic options. Patients with lymph node metastasis can show highly variable clinical outcomes, from several years disease free survival after excision of the primary lesion to extremely aggressive metastatic disease; while patients with distant metastasis show poor clinical outcome. Outstanding outcomes using target therapies such as B-RAF V600E inhibitor (Vemurafenib) bring hope for possibility of melanoma cure. Alternatively, since melanoma acquires resistance to Vemurafenib, the necessity of searching for other candidates and simultaneously targeting several pathways for long-term survival is inevitable. Better understanding of the genomic signatures of melanoma progression and maintenance provides new opportunities for developing novel therapeutic targets for successful management of this fatal disease. In this study, we aim to reveal the complex patterns of distinct molecular aberrations and mechanisms underlying the progression and maintenance of melanoma using high-throughput sequencing approaches. Our hypothesis is that there are genetic changes in melanoma which suggest the survival of the distant metastasis; these genetic changes include activated oncogenes and suppressed tumor suppressor genes correlated with melanoma progression and maintenance. As a proof of principal we initiated this study with a poor prognosis melanoma patient; a 46 year old man diagnosed with lymph node metastasis and treated with T-cell vaccination (TCV), who showed the tumor distant metastasis to lung, 14.8 months after complete lymph node dissection. The availability of primary cell lines established from both lymph node and lung metastatic tissues represents a major advantage for the functional validation of individual candidate genes which may serve as novel targets for cancer therapy. Integration of copy number with structural variation data showed a great selection for cell lines generation (derived from lymph node and lung tumors) and we observed that this selection was for a similar clone embedded in lymph node and lung metastatic tumors. With this data, we hypothesized that common sets of events which cut across all samples in this case identify the core sets of putative oncogenes and tumor suppressor genes which drive this patient's cancer cells. The correlation of these genes with the cancer phenotype will be addressed. Citation Format: Faranak Ghazi Sherbaf, Charlie LEE Wah Heng, Xing Yi Woo, Denis Bertrand, Koichiro Inaki, Kelly Chong Chong, Donald Morton, Sharon Huang, Dave Hoon, Edison Liu. Genomic signatures of melanoma progression and maintenance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2001. doi:10.1158/1538-7445.AM2013-2001

Ovarian cancer affects ∼ 204,000 women each year, and it is one of the leading causes of cancer-related death among women world-wide, as most patients present with advanced stage (III/IV) tumours, and only 40% survive 5 years after diagnosis. Improvement in the clinical management of ovarian patients is likely to derive from a better understanding of the molecular aberrations which initiate and maintain tumour growth as well as from the discovery of novel drug-able targets for the development of personalised targeted therapies. In this study, we comprehensively characterised the cancer genome of a patient diagnosed with grade III serous ovarian carcinoma, using a combination of massive-parallel sequencing technologies, including long distance DNA Paired-End-Tag (DNA-PET) sequencing, RNA-sequencing and exome-capture sequencing. This approach ensures deep coverage (from 50-180X) of critical mutational elements in a cancer genome. By comparing the genomic abnormalities identified in the tumour sample with those found in its normal counterpart (peripheral blood lymphocytes), we were able to compile a catalogue of all of the somatic events which occurred during oncogenesis and to define the overall complexity of this specific cancer genome. Interestingly, chromosomal arm loss appeared to be the predominant feature of this tumour, with more than 30% of the haploid genome being affected by a decrease in copy number. This associated with a prevalence of inter-chromosomal rearrangements, suggesting chromosomal translocations as a preferred consequence of genomic instability. Here we describe some examples of somatic translocation events causing the loss of tumour suppressor genes. Using this genotype as a possible model of ovarian carcinoma evolution, we aim to explain a subset of ovarian cancers displaying a similar chromosomal profile by applying an analysis of copy number variations, and to define common mechanisms of cancer gene loss. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5107. doi:1538-7445.AM2012-5107

BACKGROUND: Gastric cancer is the second highest cause of global cancer mortality. To explore the complete repertoire of somatic alterations in gastric cancer, we combined massively parallel short read and DNA paired-end tag sequencing to present the first whole-genome analysis of two gastric adenocarcinomas, one with chromosomal instability and the other with microsatellite instability. RESULTS: Integrative analysis and de novo assemblies revealed the architecture of a wild-type KRAS amplification, a common driver event in gastric cancer. We discovered three distinct mutational signatures in gastric cancer--against a genome-wide backdrop of oxidative and microsatellite instability-related mutational signatures, we identified the first exome-specific mutational signature. Further characterization of the impact of these signatures by combining sequencing data from 40 complete gastric cancer exomes and targeted screening of an additional 94 independent gastric tumors uncovered ACVR2A, RPL22 and LMAN1 as recurrently mutated genes in microsatellite instability-positive gastric cancer and PAPPA as a recurrently mutated gene in TP53 wild-type gastric cancer. CONCLUSIONS: These results highlight how whole-genome cancer sequencing can uncover information relevant to tissue-specific carcinogenesis that would otherwise be missed from exome-sequencing data.

Background Tandemly Arrayed Gene (TAG) clusters are groups of paralogous genes that are found adjacent on a chromosome. TAGs represent an important repertoire of genes in eukaryotes. In addition to tandem duplication events, TAG clusters are affected during their evolution by other mechanisms, such as inversion and deletion events, that affect the order and orientation of genes. The DILTAG algorithm developed in 1 makes it possible to infer a set of optimal evolutionary histories explaining the evolution of a single TAG cluster, from an ancestral single gene, through tandem duplications (simple or multiple, direct or inverted), deletions and inversion events. Results We present a general methodology, which is an extension of DILTAG, for the study of the evolutionary history of a set of orthologous TAG clusters in multiple species. In addition to the speciation events reflected by the phylogenetic tree of the considered species, the evolutionary events that are taken into account are simple or multiple tandem duplications, direct or inverted, simple or multiple deletions, and inversions. We analysed the performance of our algorithm on simulated data sets and we applied it to the protocadherin gene clusters of human, chimpanzee, mouse and rat. Conclusions Our results obtained on simulated data sets showed a good performance in inferring the total number and size distribution of duplication events. A limitation of the algorithm is however in dealing with multiple gene deletions, as the algorithm is highly exponential in this case, and becomes quickly intractable.

Sur l’horizon du debat qui traverse la semiotique contemporaine – opposant une expression sensible somatique du sens a une mediation discursive de cette expression – l’article tente d’articuler les deux paradigmes en montrant leur etroite imbrication dans le discours en acte. Deux exemples sont proposes a l’appui de cette these, associant, autour d’un meme phenomene, un extrait de Du cote de Guermantes de Proust, et des fragments de recits d’enfance de personnalites politiques contemporaines. Ce phenomene est celui de la suspension momentanee d’un role thematique, definissant le statut social des enonciateurs, au profit d’une parole sensible apparemment disjointe de ce role. L’analyse montre, non seulement que les deux formes de discours interagissent en profondeur, mais qu’un evenement particulier de langage, un « connecteur sensible », assurant la mediation entre l’une et l’autre, libere l’expression somatique. Outre le probleme theorique pose, l’etude cherche a montrer comment, a partir d’un cas concret, la semiotique permet d’etablir des liens entre la litterature et les discours sociaux.

A qualitative pre-test study, employing the structured semiotic methodology of Greimas and the Paris school, was conducted on four print advertisements conceived for a Black & White whisky campaign, and this article presents the major findings. Both the content and expression of the advertisements are examined, in terms of elementary oppositions, of narrative organization, of cultural values, and of linguistic and plastic manifestations. Finally, the ironic quality of the enunciation, playing on cultural stereotypes, is shown to demonstrate an equivalence between the ‘author’ of the campaign and the target public envisaged.

Bertrand Denis. Sémiotique du discours et lecture des textes. In: Langue française, n°61, 1984. Sémiotique et enseignement du français. pp. 9-26.

La semiotique a-t-elle quelque chose a dire sure la litterature en tant que sœur des ‘beaux-arts’? Peut-elle rendre compte des raisons d’une reussite d’ecriture? – Intention naive, dira-t-on, que de vouloir decourvrir, sure la base des seules methodes structurales, pourquoi une œuvre nous captive. Si le probleme, et son enjeu, sont immenses (car il y va de la constitution d’une esthetique structurale), le terrain choisi pour l’aborder est, lui, partiellement defriche: l’ecriture dite ‘realiste’ releve d’une poetique dotee de ses mechanismes propres. A la suite notamment de A.J. Greimas, de H. Mitterand et de Ph. Hamon, D. Bertrand en reprend ici l’ analyse et en approfondit la portee grâce a une exploration systematique des figures de la spatialite dans le Germinal de Zola. Transcendant les distinctions entre figurativite et abstraction, un imaginaire topologique regit les divers niveaux de signification du roman et en garandit l’efficacite symbolique.

Cet article s’appuie sur des données colligées lors d'une enquête effectuée auprès des professeurs des universités québécoises ; il identifie les tendances fondamentales de la transformation actuelle du travail professoral et propose une série de mesures pour mieux concilier les exigences du monde universitaire et la spécificité du travail professoral. D'une part, il rappelle que la charge de travail des professeurs est lourde, que les tâches sont plus ou moins bien intégrées, et que diverses transformations qualitatives s’imposent aux tâches d'enseignement et de recherche. D'autre part, il propose de délester certaines activités de gestion courante, de mieux identifier les compétences requises dans le nouveau contexte et de reconnaître davantage le caractère organisationnel et collectif du travail et l'existence de plusieurs types d’aménagements des tâches professorales., This article presents data from a survey of Quebec university professors, identifies the fundamental tendencies of the current transformation of professor’s work, and proposes a series of measures that could better reconcile the demands of the university and the specificity of professors’ work. The author notes, on one hand, that professors have a heavy workload, that the tasks are more or less integrated, and that various qualitative transformations are required for both functions of teaching and research. On the other hand, he proposes to alleviate certain current management activities, to better identify those competencies required in this new context, and to better recognize the organizational and collective characteristic of work and the existence of several types of professors., Este artículo se apoya sobre los datos colegidos durante un estudio realizado con profesores de universidades quebequenses ; identifica luego las tendencias fundamentales de la transformación actual del trabajo académico y propone una serie de medidas que tienen como objetivo conciliar las exigencias del mundo universitario y las especificidad del trabajo profesoral. Por una parte, el estudio recuerda que la carga de trabajo de profesores es dura, que las tareas son más o menos integradas y que se imponen algunas tranformaciones cualitativas a las cargas de enseñanza y de investigación. Por otra parte, se propone liberar ciertas actividades de gestión corriente, identificar mejor las competencias requeridas dentro del nuevo contexto y tener en cuenta el carácter organizativo y colectivo del trabajo así como la existencia de varios tipos de profesores., Dieser Beitrag stützt sich auf Daten, die im Rahmen einer Umfrage unter Québecker Universitätsprofessoren ermittelt wurden. Er identifiziert die Grundtendenzen der gegenwärtigen Veränderungen der akademischen Arbeit und erwägt eine Reihe von Maßnahmen, um die Forderungen des Universitätslebens mit der spezifischen professoralen Tätigkeit besser in Einklang zu bringen. Es wird zunächst ausgeführt, dass die Arbeitslast der Professoren eine sehr schwere ist, dass die Tätigkeit mehr oder weniger integriert ist und dass die Lehr- und Forschungsarbeit verschiedenen qualitativen Veränderungen unterworfen ist. Darüber hinaus wird vorgeschlagen, bestimmte routinemäßige Verwaltungs-aufgaben abzuschütteln, die für die veränderte akademische Umwelt notwendigen Kompetenzen genauer zu definieren und den organisato-rischen und kollektiven Charakter der Tätigkeit sowie die Tat-sache, dass es verschiedene Typen von Professoren gibt, mit in Betracht zu ziehen.

The assembly of large, repeat-rich eukaryotic genomes continues to represent a significant challenge in genomics. While long-read technologies have made the high-quality assembly of small, microbial genomes increasingly feasible, data generation can be prohibitively expensive for larger genomes. Fundamental advances in assembly algorithms are thus essential to exploit the characteristics of short and long-read sequencing technologies to consistently and reliably provide high-qualities assemblies in a cost-efficient manner. Here we present a scalable, exact algorithm (OPERA-LG) for the scaffold assembly of large, repeat-rich genomes that exhibits almost an order of magnitude improvement over the state-of-the-art programs in both correctness (>5X on average) and contiguity (>10X). This provides a systematic approach for combining data from different sequencing technologies, as well as a rigorous framework for scaffolding of repetitive sequences. OPERA-LG represents the first in a new class of algorithms that can efficiently assemble large genomes while providing formal guarantees about assembly quality, providing an avenue for systematic augmentation and improvement of 1000s of existing draft eukaryotic genome assemblies.

Comment peut-on parler d’« émotion éthique » et dépasser le caractère paradoxal de cette expression ? Après avoir évoqué l’apparente incompatibilité conceptuelle entre éthique et émotion, l’étude cherche à identifier les différentes localisations du pathémique dans la trame de la signification éthique. Elle y reconnaît ainsi une véritable syntagmatique de l’émotion, en une succession de séquences. Elle se fonde tout d’abord sur le concept de transduction (G. Simondon) pour analyser le rôle de l’émotion dans le passage du pré-individuel à l’individuel et au trans-individuel. Elle développe ensuite la thèse de Lévinas qui fonde la responsabilité éthique sur l’émotion du visage de l’autre. Elle analyse enfin l’éthique sensitive de Jean-Jacques Rousseau en amont des obligations morales. Cette reconnaissance de l’émotion éthique permet de dégager la spécificité d’une approche sémiotique des axiologies de la responsabilité : elle approfondit le lien entre structures discursives, assomption subjective et valeurs., How can we talk about “ethical emotion” beyond the paradoxical meaning of this expression? After referring to the apparent conceptual incompatibility between ethics and emotion, the article seeks to identify the different locations of pathemic contents in the structure of ethical significance. A real syntagmatic process of emotion, as a consistent succession of sequences, appears. It is based firstly on the concept of transduction (G. Simondon) which allows the description of the role of emotion in the transition from pre-individual to individual and trans-individual. It then meets the theory of Levinas who founded the ethical responsibility upon the emotion generated by the face of the other. It analyzes finally Jean-Jacques Rousseau’s sensitive ethics above moral obligations. This recognition of the ethical emotion shows the specificity of semiotic approach to the axiology of responsibility: it deepens the relationship between discourse structures, subjective assumption and values.

International audience; En étudiant la perception esthétique, cet article est centré sur ce point de rencontre entre l’esthésie et l’esthétique que Valéry appelle la « poïétique ». En particulier, on analyse la prégnance de ce que nous appelons les « phénomènes cadentiels » dans la perception esthétique des formes (plastiques, musicales, poétiques) qui se déploient dans le temps.

Réunir les sémiotiques, conjuguer les approches structuraliste et pragmatiste, c'est conjurer la partition entre les deux courants moteurs de la recherche sémiotique, et enrichir leurs liens réciproques avec les sciences sociales. Partant d'une discussion entre ces perspectives théoriques, cet ouvrage entend mettre en lumière les différentes interprétations possibles de ce qui devient une exigence dans la recherche universitaire : l'engagement. Ou plutôt l'implication socio-politique des recherches au sein de disciplines sémiotiques, caractérisées par la distanciation conceptuelle.

International audience

Réunir les sémiotiques, conjuguer les approches structuraliste et pragmatiste, c'est conjurer la partition entre les deux courants moteurs de la recherche sémiotique, et enrichir leurs liens réciproques avec les sciences sociales. Partant d'une discussion entre ces perspectives théoriques, cet ouvrage entend mettre en lumière les différentes interprétations possibles de ce qui devient une exigence dans la recherche universitaire : l'engagement. Ou plutôt l'implication socio-politique des recherches au sein de disciplines sémiotiques, caractérisées par la distanciation conceptuelle.