Phorbolester-activated Munc13-1 and ubMunc13-2 exert opposing effects on dense-core vesicle secretion

Munc13 proteins are priming factors for SNARE-dependent exocytosis, which are activated by diacylglycerol (DAG)-binding to their C1-domain. Several Munc13 paralogs exist, but their differential roles are not well understood. We studied the interdependence of phorbolesters (DAG mimics) with Munc13-1 and ubMunc13-2 in mouse adrenal chromaffin cells. Although expression of either Munc13-1 or ubMunc13-2 stimulated secretion, phorbolester was only stimulatory for secretion when ubMunc13-2 expression dominated, but inhibitory when Munc13-1 dominated. Accordingly, phorbolester stimulated secretion in wildtype cells, or cells overexpressing ubMunc13-2, but inhibited secretion in Munc13-2/Unc13b knockout (KO) cells or in cells overexpressing Munc13-1. Phorbolester was more stimulatory in the Munc13-1/Unc13a KO than in WT littermates, showing that endogenous Munc13-1 limits the effects of phorbolester. Imaging showed that ubMunc13-2 traffics to the plasma membrane with a time-course matching Ca2+-dependent secretion, and trafficking is independent of Synaptotagmin-7 (Syt7). However, in the absence of Syt7, phorbolester became inhibitory for both Munc13-1 and ubMunc13-2-driven secretion, indicating that stimulatory phorbolester x Munc13-2 interaction depends on functional pairing with Syt7. Overall, DAG/phorbolester, ubMunc13-2 and Syt7 form a stimulatory triad for dense-core vesicle priming

Recognizing Members of the Tournament Equilibrium Set is NP-hard

A recurring theme in the mathematical social sciences is how to select the "most desirable" elements given a binary dominance relation on a set of alternatives. Schwartz's tournament equilibrium set (TEQ) ranks among the most intriguing, but also among the most enigmatic, tournament solutions that have been proposed so far in this context. Due to its unwieldy recursive definition, little is known about TEQ. In particular, its monotonicity remains an open problem up to date. Yet, if TEQ were to satisfy monotonicity, it would be a very attractive tournament solution concept refining both the Banks set and Dutta's minimal covering set. We show that the problem of deciding whether a given alternative is contained in TEQ is NP-hard.Comment: 9 pages, 3 figure

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

Full vs Partial Market Coverage with Minimum Quality Standards

The consequences of the adoption of quality standards on the extent of market coverage is investigated by modelling a game between regulator and low-quality firm in a vertically differentiated duopoly. The game has a unique equilibrium in the most part of the parameter range. There exists a non-negligible range where the game has no equilibrium in pure strategies. This result questions the feasibility of MQS regulation when firms endogenously determine market coverage

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

Outils de prévision de la demande (OPD) et pratiques de réduction des stocks

National audienceIl apparait intuitif de considérer qu’une entreprise multi-produit ayant la possibilité de prévoir de manière plus précise la structure de sa demande a moins besoin de se protéger en constituant des stocks de précaution puisque la composition de sa demande devient prévisible. De manière symétrique, il semble intuitif de penser qu'une firme multi-produit qui se protégerait davantage en constituant des stocks de précaution plus nombreux aura moins besoin de prévoir la composition de sa demande. Les Outils de Prévision de la Demande (OPD) et les stocks seraient alors substituables. L’objectif de cet article est de jeter le doute sur cette hypothèse de substituabilité entre les OPD et les stocks. Nous montrons en effet dans cet article qu’il existe des situations ou les comportements de protection (constitution de stocks de précaution) et de prévision (acquisition d’un OPD) sont complémentaires pour une entreprise

A characterization of majority voting rules with quorums

Voting rules, Majority voting rules with Quorums, D71,