SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response.

SF3B1 hotspot mutations are associated with a poor prognosis in several tumor types and lead to global disruption of canonical splicing. Through synthetic lethal drug screens, we identify that SF3B1 mutant (SF3B1MUT) cells are selectively sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi), independent of hotspot mutation and tumor site. SF3B1MUT cells display a defective response to PARPi-induced replication stress that occurs via downregulation of the cyclin-dependent kinase 2 interacting protein (CINP), leading to increased replication fork origin firing and loss of phosphorylated CHK1 (pCHK1; S317) induction. This results in subsequent failure to resolve DNA replication intermediates and G2/M cell cycle arrest. These defects are rescued through CINP overexpression, or further targeted by a combination of ataxia-telangiectasia mutated and PARP inhibition. In vivo, PARPi produce profound antitumor effects in multiple SF3B1MUT cancer models and eliminate distant metastases. These data provide the rationale for testing the clinical efficacy of PARPi in a biomarker-driven, homologous recombination proficient, patient population

The Effect of Modularity Representation and Presentation Medium on the Understandability of Business Process Models in BPMN

Many factors influence the creation of understandable business process models for an appropriate audience. Understandability of process models becomes critical particularly when a process is complex and its model is large in structure. Using modularization to represent such models hierarchically (e.g. using sub-processes) is considered to contribute to the understandability of these models. To investigate this assumption, we conducted an experiment that involved 2 large-scale real-life business process models that were modeled using BPMN v2.0 (Business Process Model and Notation). Each process was modeled in 3 modularity forms: fully-flattened, flattened where activities are clustered using BPMN groups, and modularized using separately viewed BPMN sub-processes. The objective is to investigate if and how different forms of modularity representation in BPMN collaboration diagrams influence the understandability of process models. In addition to the forms of modularity representation, we also looked into the presentation medium (paper vs. computer) as a factor that potentially influences model comprehension. Sixty business practitioners from a large organization participated in the experiment. The results of our experiment indicate that for business practitioners, to optimally understand a BPMN model in the form of a collaboration diagram, it is best to present the model in a ‘fully-flattened’ fashion (without using collapsed sub-processes in BPMN) in the ‘paper’ format

Theories in Business and Information Systems Engineering

Even though the idea of science enjoys an impressive reputation, there seems to be no precise conception of science. On the one hand, there is no unified definition of the extension of activities subsumed under the notion of science. According to the narrow conception that is common in Anglo-Saxon countries, science is restricted to those disciplines that investigate nature and aim at explanation and prediction of natural phenomena. A wider conception that can be found in various European countries includes social sciences, the humanities and engineering. On the other hand and related to the first aspect, there is still no general consensus on the specific characteristics of scientific discoveries and scientific knowledge

Utilisation du pénétromètre dynamique du type PANDA en milieu urbain pour l'évaluation et la caractérisation du dépôt archéologique

National audienceL'utilisation du pénétromètre PANDA à l'occasion d'une fouille à Tours a suscité la mise en place de méthodes descriptives et statistiques liant données géotechniques et archéologiques. Un premier objectif consiste à distinguer le dépôt archéologique du toit des alluvions qui forment le sol géologique. Cet objectif se révèle accessible sans trop de difficultés et les données du pénétromètre peuvent être confirmées par géo-endoscopie. Les résultats obtenus ouvrent la possibilité de réaliser un maillage pour restituer l'épaisseur du dépôt archéologique et le modelé du toit des alluvions à l'échelle de la ville. Un deuxième objectif, plus lointain, est de caractériser le sol traversé par le pénétromètre. Les travaux en cours portent sur la définition d'une échelle d'interprétation compatible avec celles de l'archéologie et de la géotechnique. Pour définir cette échelle, l'hypothèse retenue est que la variété stratigraphique reflète l'intensité de l'activité le plus souvent humaine, parfois d'origine naturelle. Par la construction d'un référentiel lié à la résistance des différents types de couches archéologiques et par l'étude de l'intensité de la variation du signal enregistré, il est envisagé de subdiviser l'ensemble d'une stratification de plusieurs mètres en tranches affectées d'un indice de complexité reflétant le tauxd'activité. L'analyse de la structuration spatiale des mesures pénétrométriques permet aussi de faire la part de l'agitation aléatoire, résultant de bruits de mesures, d'une agitation structurée, révélatrice des propriétés du milieu traversé. Elle permet d'attacher un indice de qualité à chaque série de mesures. Une caractérisation plus fine de ces tranches nécessitera une autre méthode d'investigation paranalyse géoendoscopique

Characterizing referenda with quorums via strategy-proofness

<p>The paper works with a formal model of referenda, where a finite number of voters can choose between two options and abstention. A referendum will be invalid if too many voters abstain, otherwise the referendum will return one of the two options. We consider quorum rules where an option is chosen if it is preferred by the majority of voters and if at least a certain number of voters (the quorum) votes for the alternative. The paper characterizes these rules as the only referenda which are strategy-proof over certain preferences.</p>

GTPase-activating protein oligophrenin 1 is a new partner of multifunctional adapter protein intersectin 1

Intersectin 1 (ITSN1) is a multifunctional adaptor protein which is involved in endocytosis, exocytosis and cellular signaling and it is also associated with such pathologies as Down syndrome and Alzheimer’s disease. The aim of this study was to identify new ITSN1 protein partners which are implicated in membrane trafficking. Methods. In silico analysis by Scansite online resource had identified a GTPase activating protein oligophrenin 1 (OPHN1) as a potential partner of ITSN1 SH3A domain. GST pull-down and immunoprecipitation were used to prove complex formation between ITSN1 and OPHN1. Subcellular protein localization was determined by immunofluorescence and confocal microscopy. Results. We have shown that brain-specific and ubiquitously expressed SH3A domain isoforms of ITSN1 interact with OPHN1. ITSN1 and OPHN1 form complexes in both resting and stimulated to exocytosis PC12 cell line. Conclusions. GTPase activating protein OPHN1 and adaptor protein ITSN1 interact in PC12 cell line independently of exocytosis stimulation