Search

Abstract Background Solving the structure of mRNA transcripts is a major challenge for both research and molecular diagnostic purposes. Current approaches based on short-read RNA sequencing and RT-PCR techniques cannot fully explore the complexity of transcript structure. The emergence of third-generation long-read sequencing addresses this problem by solving this sequence directly. However, genes with low expression levels are difficult to study with the whole transcriptome sequencing approach. To fix this technical limitation, we propose a novel method to capture transcripts of a gene panel using a targeted enrichment approach suitable for Pacific Biosciences and Oxford Nanopore Technologies platforms. Results We designed a set of probes to capture transcripts of a panel of genes involved in hereditary breast and ovarian cancer syndrome. We present SOSTAR (iSofOrmS annoTAtoR), a versatile pipeline to assemble, quantify and annotate isoforms from long read sequencing using a new tool specially designed for this application. The significant enrichment of transcripts by our capture protocol, together with the SOSTAR annotation, allowed the identification of 1,231 unique transcripts within the gene panel from the eight patients sequenced. The structure of these transcripts was annotated with a resolution of one base relative to a reference transcript. All major alternative splicing events of the BRCA1 and BRCA2 genes described in the literature were found. Complex splicing events such as pseudoexons were correctly annotated. SOSTAR enabled the identification of abnormal transcripts in the positive controls. In addition, a case of unexplained inheritance in a family with a history of breast and ovarian cancer was solved by identifying an SVA retrotransposon in intron 13 of the BRCA1 gene. Conclusions We have validated a new protocol for the enrichment of transcripts of interest using probes adapted to the ONT and PacBio platforms. This protocol allows a complete description of the alternative structures of transcripts, the estimation of their expression and the identification of aberrant transcripts in a single experiment. This proof-of-concept opens new possibilities for RNA structure exploration in both research and molecular diagnostics.

Le contexte choisi est celui de l’ultime séance de débat à l'Assemblée nationale française le 23 avril 2013, avant le vote établissant dans le droit le « mariage pour tous » compris comme œuvre de justice sociétale. Cette nouvelle loi sera la réalisation majeure du gouvernement socialiste de l’époque. Alors même que le résultat du vote est acquis compte tenu de l’état des forces politiques et de la domination de la gauche, le débat préalable a lieu avec toute la force de ses arguments contradictoires. On analyse alors quelques courts extraits des discours prononcés à la tribune par des députés favorables ou opposés à cette loi, en nous interrogeant sur la pertinence d’un tel débat dont on sait que l’effet pragmatique sera nul. Cet épisode remarquable nous conduit à interroger les trois piliers de la rhétorique classique — les « genres » judiciaire, épidictique et délibératif — du point de vue sémiotique de la véridiction et sur l’horizon du discours juridique dans le rituel législatif fondateur du Droit. Ce discours, loin d’être exclusivement concerné par le genre judiciaire, se situe plutôt à la croisée de la célèbre tripartition générique. Entre vérité attestée (le judiciaire), vérité exaltée (l’épidictique) et vérité projetée (le délibératif), c’est dans l’entrelacs du pathémique que le discours du Droit construit ses modalités d’énonciation pour imposer ses énoncés normatifs et contribuer ainsi à l’édification du collectif. Notre hypothèse consiste alors à chercher dans ce syncrétisme générique la raison de la pertinence des prises de parole politico-juridiques « de circonstance » : leur visée, loin de l’effet pragmatique primaire d’un succès dans les urnes, serait de faire apparaître un « point de justesse » dont l’effet est de consolider le collectif et de contribuer à son institution à travers un rituel énonciatif qui semble à lui-même sa propre fin.

Abstract Background Cholangiocarcinoma (CCA) is a fatal cancer of the bile duct with a poor prognosis owing to limited therapeutic options. The incidence of intrahepatic CCA (iCCA) is increasing worldwide, and its molecular basis is emerging. Environmental factors may contribute to regional differences in the mutation spectrum of European patients with iCCA, which are underrepresented in systematic genomic and transcriptomic studies of the disease. Methods We describe an integrated whole‐exome sequencing and transcriptomic study of 37 iCCAs patients in Germany. Results We observed as most frequently mutated genes ARID1A (14%), IDH1, BAP1, TP53, KRAS, and ATM in 8% of patients. We identified FGFR2::BICC1 fusions in two tumours, and FGFR2::KCTD1 and TMEM106B::ROS1 as novel fusions with potential therapeutic implications in iCCA and confirmed oncogenic properties of TMEM106B::ROS1 in vitro. Using a data integration framework, we identified PBX1 as a novel central regulatory gene in iCCA. We performed extended screening by targeted sequencing of an additional 40 CCAs. In the joint analysis, IDH1 (13%), BAP1 (10%), TP53 (9%), KRAS (7%), ARID1A (7%), NF1 (5%), and ATM (5%) were the most frequently mutated genes, and we found PBX1 to show copy gain in 20% of the tumours. According to other studies, amplifications of PBX1 tend to occur in European iCCAs in contrast to liver fluke‐associated Asian iCCAs. Conclusions By analyzing an additional European cohort of iCCA patients, we found that PBX1 protein expression was a marker of poor prognosis. Overall, our findings provide insight into key molecular alterations in iCCA, reveal new targetable fusion genes, and suggest that PBX1 is a novel modulator of this disease.

Chaque période de la sémiotique, à travers l’un et l’autre de ses courants majeurs, a connu son modèle spatial emblématique, véritable signature épistémique de la mise en forme théorique : carré, hexagone, cercle, strates feuilletées, ellipse, aile de papillon, courbes entre abscisse et ordonnée, spirales, bulles, sphères, etc. On s’intéresse ici à l’une des représentations les plus largement répandues : celle des niveaux entre surface et profondeur. Si la linguistique générative et la sémiotique greimassienne à sa suite, mais dans une autre perspective, ont popularisé le schéma des structures profondes opposables aux structures de surface, elles n’ont fait que prolonger un dispositif spatial qui était transversal à bien d’autres disciplines : sens immanent et sens transcendant ; sens explicite et sens caché ; contenu manifeste et contenu latent ; saillance et prégnance. En recherchant les raisons d’un motif formel aussi récurrent, notre exploration de cette modélisation spatiale interroge l’hypothèse localiste, qui postule la spatialisation comme une isotopie sémantique première et modélisante, se présentant comme un signifiant disponible pour la formation des contenus non spatiaux. Le « catachrésisme » spatial régirait la formation du langage. On revient alors sur le parcours génératif de la signification pour tenter de comprendre les raisons de son succès pédagogique et de son relatif insuccès scientifique. Les procédures de conversion qui assurent le passage d’un niveau à l’autre transforment le statisme des niveaux en dynamisme des échanges. Les strates opèrent comme des filtres à mailles progressives : les très grosses mailles des structures profondes s’affinant peu à peu pour ne plus laisser passer, en surface que les sèmes à mailles fines. Une nouvelle figure spatiale refait alors son apparition, la densité sémique, et la syntagmatique du parcours l’emporte sur la paradigmatique des niveaux. C’est donc pour finir ce mot « parcours » qui nous arrête, avec la mouvance indéterminée et sans bord qui lui est inhérente. Cela implique une instance mobile qui prend en charge ce parcours, un randonneur énonciatif du faire scientifique. On place alors l’énonciation comme centre opérateur du parcours, muni de ses composantes liées : sensible, par l’ancrage somatique de toute énonciation possible (cf. la phusis), et cognitive, par une projection des formants dont la générativité peut donner l’image. Soumis au primat de la perspective, ce sont les différents régimes sémiotiques de sélection des formes d’expression et des formes de contenu qui modélisent, in fine, le, ou plutôt les, parcours.

Reference genomes for gut microbiomes help unravel microbial “dark matter” and serve as valuable resource for disease-focused studies. Here, the authors perform short and long read metagenomics and metagenome-assembled genomes analyses to profile the gut microbiome of Southeast Asian populations, revealing significant species and strain-level diversity, with thousands of previously uncharacterized biosynthetic gene clusters.

Abstract Background The transient and fragmented nature of the deep-sea hydrothermal environment made of ridge subduction, plate collision and the emergence of new rifts is currently acting to separate of vent populations, promoting local adaptation and contributing to bursts of speciation and species specialization. The tube-dwelling worms Alvinella pompejana called the Pompeii worm and its sister species A. caudata live syntopically on the hottest part of deep-sea hydrothermal chimneys along the East Pacific Rise. They are exposed to extreme thermal and chemical gradients, which vary greatly in space and time, and thus represent ideal candidates for understanding the evolutionary mechanisms at play in the vent fauna evolution. Results We explored genomic patterns of divergence in the early and late stages of speciation of these emblematic worms using transcriptome assemblies and the first draft genome to better understand the relative role of geographic isolation and habitat preference in their genome evolution. Analyses were conducted on allopatric populations of Alvinella pompejana (early stage of separation) and between A. pompejana and its syntopic species Alvinella caudata (late stage of speciation). We first identified divergent genomic regions and targets of selection as well as their position in the genome over collections of orthologous genes and, then, described the speciation dynamics by documenting the annotation of the most divergent and/or positively selected genes involved in the isolation process. Gene mapping clearly indicated that divergent genes associated with the early stage of speciation, although accounting for nearly 30% of genes, are highly scattered in the genome without any island of divergence and not involved in gamete recognition or mito-nuclear incompatibilities. By contrast, genomes of A. pompejana and A. caudata are clearly separated with nearly all genes (96%) exhibiting high divergence. This congealing effect however seems to be linked to habitat specialization and still allows positive selection on genes involved in gamete recognition, as a possible long-duration process of species reinforcement. Conclusion Our analyses highlight the non-negligible role of natural selection on both the early and late stages of speciation in the iconic thermophilic worms living on the walls of deep-sea hydrothermal chimneys. They shed light on the evolution of gene divergence during the process of speciation and species specialization over a very long period of time.

Parmi les nombreuses innovations théoriques de Jean-Marie Floch, sa redécouverte de Wölfflin a marqué une date dans l’histoire de la théorie sémiotique ; redécouverte d’un structuralisme pré-structural accompagné d’un développement théorique considérable, dans l’œuvre de Floch, permettant l’extension de la « vision baroque » opposable à la « vision classique » bien au-delà du domaine qui lui a donné naissance, au delà même des univers esthétiques, pour entrer de plain-pied dans le champ de la communication sociale (médiatique, technique, politique, etc.) contemporaine. Or, les propositions de Claude Zilberberg (notamment dans « Présence de Wölfflin », n° 23-24 des Nouveaux Actes Sémiotiques, 1992) ont profondément modifié la perspective théorique sur l’héritage du célèbre historien de l’art, suscitant un désaccord avec Floch. En interrogeant le statut du débat au sein de la communauté sémiotique, illustré ici par les divergences tues entre les sémioticiens, on analyse ces deux « lectures » de Wölfflin, leurs différences formelles, leurs rapports respectifs avec le sensible, leurs horizons théoriques – catégoriel d’un côté, tensif de l’autre. On met alors l’accent sur deux points de divergence, concernant le statut de l’affect et le problème de la profondeur. On montre les empiètements entre les deux approches et leur profonde convergence. Mais surtout on suggère ici un dépassement possible de la controverse en analysant la distinction classique / baroque sur fond de perception et en termes de « rythme », c’est-à-dire comme variation de tension entre les événements accentuels d’une série syntagmatique. On fait ainsi intervenir la question de la nuance, celle de la non-résolution de syntagmes accentuels, voire de la discordance entre niveaux accentuels. Cette contribution à la connaissance d’un phénomène essentiel dans l’histoire des formes permet aussi de reposer la question de sa dénomination. Comment nommer en effet ce qui constitue, à travers tant de matériaux langagiers (non verbal et verbal), tant de domaines de communication, tant de moments et de contextes historiques, une trame insistante au sein de la culture occidentale, au cœur même de sa « grammaire d'expression » dont l’opposition «classique/baroque » n’est au fond qu’une émergence exceptionnelle, mais locale ?

Objectives: Hypermucoviscous Klebsiella pneumoniae is an emerging cause of community-acquired liver abscess. The aim of this study was to investigate whether hypermucoviscous strains could be shared among households. Methods: The clinical K. pneumoniae isolates from a cohort of 24 patients with Klebsiella liver abscess were genotyped, and the stool metagenomes of the index patients and their cohabiting domestic partners were analyzed. Results: K. pneumoniae was identified in 33% of index patient stools, and one index patient’s clinical isolate was identified in their domestic partner’s stool. Conclusions: This could represent a transmission event or could represent exposure to a common environmental source.

Methods for assembly, taxonomic profiling and binning are key to interpreting metagenome data, but a lack of consensus about benchmarking complicates performance assessment. The Critical Assessment of Metagenome Interpretation (CAMI) challenge has engaged the global developer community to benchmark their programs on highly complex and realistic data sets, generated from ∼700 newly sequenced microorganisms and ∼600 novel viruses and plasmids and representing common experimental setups. Assembly and genome binning programs performed well for species represented by individual genomes but were substantially affected by the presence of related strains. Taxonomic profiling and binning programs were proficient at high taxonomic ranks, with a notable performance decrease below family level. Parameter settings markedly affected performance, underscoring their importance for program reproducibility. The CAMI results highlight current challenges but also provide a roadmap for software selection to answer specific research questions.

Abstract Background Whole genome sequencing of cultured pathogens is the state of the art public health response for the bioinformatic source tracking of illness outbreaks. Quasimetagenomics can substantially reduce the amount of culturing needed before a high quality genome can be recovered. Highly accurate short read data is analyzed for single nucleotide polymorphisms and multi-locus sequence types to differentiate strains but cannot span many genomic repeats, resulting in highly fragmented assemblies. Long reads can span repeats, resulting in much more contiguous assemblies, but have lower accuracy than short reads. Results We evaluated the accuracy of Listeria monocytogenes assemblies from enrichments (quasimetagenomes) of naturally-contaminated ice cream using long read (Oxford Nanopore) and short read (Illumina) sequencing data. Accuracy of ten assembly approaches, over a range of sequencing depths, was evaluated by comparing sequence similarity of genes in assemblies to a complete reference genome. Long read assemblies reconstructed a circularized genome as well as a 71 kbp plasmid after 24 h of enrichment; however, high error rates prevented high fidelity gene assembly, even at 150X depth of coverage. Short read assemblies accurately reconstructed the core genes after 28 h of enrichment but produced highly fragmented genomes. Hybrid approaches demonstrated promising results but had biases based upon the initial assembly strategy. Short read assemblies scaffolded with long reads accurately assembled the core genes after just 24 h of enrichment, but were highly fragmented. Long read assemblies polished with short reads reconstructed a circularized genome and plasmid and assembled all the genes after 24 h enrichment but with less fidelity for the core genes than the short read assemblies. Conclusion The integration of long and short read sequencing of quasimetagenomes expedited the reconstruction of a high quality pathogen genome compared to either platform alone. A new and more complete level of information about genome structure, gene order and mobile elements can be added to the public health response by incorporating long read analyses with the standard short read WGS outbreak response.

To determine the duration of carbapenemase-producing Enterobacteriaceae (CPE) carriage, we studied 21 CPE carriers for »1 year. Mean carriage duration was 86 days; probability of decolonization in 1 year was 98.5%, suggesting that CPE-carriers’ status can be reviewed yearly. Prolonged carriage was associated with use of antimicrobial drugs.

A reflexão aqui proposta parte das perturbações causadas pela pandemia de Covid-19 e procura entender se ela produz um “mundo” paradigmaticamente distinto. Assim, são estudadas a flutuação do gênero, a disseminação do Destinador, a proliferação de variantes de antissujeitos. São, porém, a crise da verdade e o desaparecimento das certezas que, acima de tudo, marcam o possível surgimento de uma subcultura alternativa àquela que precedeu o início da pandemia. Mais precisamente, são examinadas a transformação radical das relações proxêmicas ou, ainda, as modificações, devido ao uso da máscara, na qualidade fática das interações. No entanto, apesar das recategorizações impostas, essa pandemia poderia provocar a ressurreição da Humanidade, unidade actancial coletiva engajada unissonamente, dentro de uma nova cultura e de uma nova narrativa, na luta contra um inimigo muito mais perigoso que ameaça o mundo, a mudança climática.

Après avoir rappelé la généalogie théorique de la sémiotique, entre linguistique, anthropologie et phénoménologie, nous souhaitons mettre en évidence les propriétés de la sémiotique post-greimassienne en montrant que la « signification en acte », son objet, implique simultanément la saisie des formants, leur structuration, leur énonciation, leur mise en perspective, leurs implications dans le champ social et leurs enjeux anthropologiques. Nous nous appuyons sur deux exemples, l’un textuel, l’autre lexical. Le premier aura pour objet une lecture sémiotique transversale d’un texte de Victor Hugo, « L’archipel de la Manche », prologue de son roman Les Travailleurs de la mer (1866, éd. de 1883) : nous montrons comment la grande trame pluri-disciplinaire des sciences naturelles, humaines et sociales prend corps dans ce texte travers une poétique et une politique de l’énonciation, discipline première et ultime. Le second exemple a pour objet l’actant collectif à travers la saisie du pronom « nous », entre inclusion et exclusion. Nous prenons alors appui sur le texte ultime de Paolo Fabbri (à paraître), « Les identités collectives », pour interroger les nombreuses voies de passage entre la forme langagière et les politiques de l’altérité qu’elle induit. Cette conférence est donnée en hommage à ce grand sémioticien italien, disparu le 2 juin 2020.

Treatment response in patient-derived models may serve as a biomarker for response in the clinic. Here, the authors use paired patient-derived mouse xenografts and patient-derived primary culture models from head and neck squamous cell carcinomas, including metastasis, as models for high-throughput screening of anti-cancer drugs.

Copyright of Gériatrie et Psychologie Neuropsychiatrie du Vieillissement is the property of John Libbey Eurotext Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Cholangiocarcinoma (CCA) is the primary cancer of the bile duct system. The role of bile duct tissue microbiomes in CCA tumorigenesis is unestablished. To address this, sixty primary CCA tumors and matched normals, from both liver fluke (Opisthorchis viverrini) associated (OVa, n = 28) and non-O. viverrini associated (non-OVa, n = 32) cancers, were profiled using high-throughput 16S rRNA sequencing. A distinct, tissue-specific microbiome dominated by the bacterial families Dietziaceae, Pseudomonadaceae and Oxalobacteraceae was observed in bile duct tissues. Systemic perturbation of the microbiome was noted in tumor and paired normal samples (vs non-cancer normals) for several bacterial families with a significant increase in Stenotrophomonas species distinguishing tumors vs paired normals. Comparison of parasite associated (OVa) vs non-associated (non-OVa) groups identified enrichment for specific enteric bacteria (Bifidobacteriaceae, Enterobacteriaceae and Enterococcaceae). One of the enriched families, Bifidobacteriaceae, was found to be dominant in the O. viverrini microbiome, providing a mechanistic link to the parasite. Functional analysis and comparison of CCA microbiomes revealed higher potential for producing bile acids and ammonia in OVa tissues, linking the altered microbiota to carcinogenesis. These results define how the unique microbial communities resident in the bile duct, parasitic infections and the tissue microenvironment can influence each other, and contribute to cancer.

Barrett’s oesophagus is a precancerous intestinal metaplasia that can progress to oesophageal adenocarcinoma. In this study, the authors isolate and characterize human Barrett’s stem cells and identify a specific genomic pedigree that supports the potential role of these cells as precursors of oesophageal adenocarcinoma.

Greimas atribuía sua opção pela língua francesa à “escrita de aço de Flaubert”. De igual modo, o edifício conceitual e analítico de Semântica estrutural dá à forma do conteúdo uma tal materialidade que esta também pode ser denominada “de aço”. Interrogaremos essa sensibilidade material que orienta a reconstrução científica do semantismo e a consideraremos uma poética. Esse procedimento libera efetivamente as potencialidades interpretativas do texto dos enclaves em que se encontra sua essência, tornando-as, então, formalmente descritíveis – ao mesmo tempo que assume sua parcela inevitável de elipse e imperfeição. Sobre essa base, interrogaremos, no centro de Semântica estrutural, a passagem da construção analítica à expressão literária e, particularmente, ao imaginário de Bermanos estudado por Tashun Yücel e, daí, à introdução de Sobre o sentido, que surgiria alguns anos mais tarde, ela própria intitulada “Sobre o sentido”.

Genome rearrangements, a hallmark of cancer, can result in gene fusions with oncogenic properties. Using DNA paired-end-tag (DNA-PET) whole-genome sequencing, we analyzed 15 gastric cancers (GCs) from Southeast Asians. Rearrangements were enriched in open chromatin and shaped by chromatin structure. We identified seven rearrangement hot spots and 136 gene fusions. In three out of 100 GC cases, we found recurrent fusions between CLDN18, a tight junction gene, and ARHGAP26, a gene encoding a RHOA inhibitor. Epithelial cell lines expressing CLDN18-ARHGAP26 displayed a dramatic loss of epithelial phenotype and long protrusions indicative of epithelial-mesenchymal transition (EMT). Fusion-positive cell lines showed impaired barrier properties, reduced cell-cell and cell-extracellular matrix adhesion, retarded wound healing, and inhibition of RHOA. Gain of invasion was seen in cancer cell lines expressing the fusion. Thus, CLDN18-ARHGAP26 mediates epithelial disintegration, possibly leading to stomach H+ leakage, and the fusion might contribute to invasiveness once a cell is transformed.

In the general framework of the relations between semiotics and literature and, more widely, between literary semiotics and plastic language, our aim is to argue, through a concrete case, the contribution of semiotics in the clarification of a literary and art history problem. The study concerns the break-up between two friends, Zola and Cézanne, after the publication, by the first one, of his novel L’Œuvre. The confrontation of painting descriptions in the fiction with Cézanne’s words about the artist activity allows us to bring out more profoundly the theoretical differences of conception regarding the act of painting and its aim, through the figurative question of representation, the aspectual problem of realization and the phenomenological dimension of sensation. More generally, and beyond the studied case, our objective is to show how semiotics processes may contribute to the dialogue between arts.