Presuppositions in Context: Constructing Bridges

About the book: The First International and Interdisciplinary Conference on Modelling and Using Context, Rio de Janeiro, January 1997, gave rise to the present book, which contains a selection of the papers presented there, thoroughly refereed and revised. The treatment of contexts as bona fide objects of logical formalisation has gained wide acceptance, following the seminal impetus given by McCarthy in his Turing Award address. The field of natural language offers a particularly rich variety of examples and challenges to researchers concerned with the formal modelling of context, and several chapters in the volume deal with contextualisation in the setting of natural language. Others adopt a purely formal-logical viewpoint, seeking to develop general models of even wider applicability. The 12 chapters are organised in three groups: formalisation of contextual information in natural language understanding and generation, the application of context in mechanised reasoning domains, and novel non-classical logics for contextual application

USP49 deubiquitinase regulates the mitotic spindle checkpoint and prevents aneuploidy.

The spindle assembly checkpoint (SAC) is an essential mechanism that ensures the accurate chromosome segregation during mitosis, thus preventing genomic instability. Deubiquitinases have emerged as key regulators of the SAC, mainly by determining the fate of proteins during cell cycle progression. Here, we identify USP49 deubiquitinase as a novel regulator of the spindle checkpoint. We show that loss of USP49 in different cancer cell lines impairs proliferation and increases aneuploidy. In addition, USP49-depleted cells overcome the arrest induced by the SAC in the presence of nocodazole. Finally, we report new binding partners of USP49, including ribophorin 1, USP44, and different centrins.We thank A.P. Ugalde, D. Rodríguez, J.G. Pérez-Silva, Y. Español and F. Rodríguez for helpful comments and advice. We also thank S.A. Miranda, D. Álvarez-Puente and C. Garabaya for excellent technical assistance, as well as the staff of the scientific core facilities from the University of Oviedo (Unidad de Ensayos Biotecnológicos y Biomédicos, Servicios Científico-Técnicos). This work was supported by the Ministerio de Ciencia e Innovación (SAF2017-87655-R, PDI2020-118394RB-100 and PGC2018- 097019-B-I00), “la Caixa” Banking Foundation (project code HR17-00247), and the European Research Council (742067, DeAge). The IUOPA is funded by the Asturian Government and Fundación Cajastur-Liberbank.S

Attitudes of Germans towards distributive issues in the German health system

Social health care systems are inevitably confronted with the scarcity of resources and the resulting distributional challenges. Since prioritization implies distributional effects, decisions on respective rules should take citizens’ preferences into account. Thus, knowledge about citizens’ attitudes and preferences regarding different distributional issues implied by the type of financing health care is necessary to judge the public acceptance of a health system. In this study we concentrate on two distributive issues in the German health system: First, we analyse the acceptance of prioritizing decisions concerning the treatment of certain patient groups, in this case patients who all need a heart operation. Here we focus on the fact that a patient is strong smoker or a non-smoker, the criteria of age or the fact that a patient has or does not have young children. Second, we investigate Germans’ opinions towards income dependent health services. The results reveal strong effects of individuals’ attitudes regarding general aspects of the health system on priorities, e.g. that individuals behaving health demanding should not be preferred. In addition, experiences of limited access to health services are found to have a strong influence on citizens’ attitudes, too. Finally, decisions about different prioritization criteria are found to be not independent.

Activation of Serine One-Carbon Metabolism by Calcineurin A beta 1 Reduces Myocardial Hypertrophy and Improves Ventricular Function

Background In response to pressure overload, the heart develops ventricular hypertrophy that progressively decompensates and leads to heart failure. This pathological hypertrophy is mediated, among others, by the phosphatase calcineurin and is characterized by metabolic changes that impair energy production by mitochondria. Objectives The authors aimed to determine the role of the calcineurin splicing variant CnAβ1 in the context of cardiac hypertrophy and its mechanism of action. Methods Transgenic mice overexpressing CnAβ1 specifically in cardiomyocytes and mice lacking the unique C-terminal domain in CnAβ1 (CnAβ1Δi12 mice) were used. Pressure overload hypertrophy was induced by transaortic constriction. Cardiac function was measured by echocardiography. Mice were characterized using various molecular analyses. Results In contrast to other calcineurin isoforms, the authors show here that cardiac-specific overexpression of CnAβ1 in transgenic mice reduces cardiac hypertrophy and improves cardiac function. This effect is mediated by activation of serine and one-carbon metabolism, and the production of antioxidant mediators that prevent mitochondrial protein oxidation and preserve ATP production. The induction of enzymes involved in this metabolic pathway by CnAβ1 is dependent on mTOR activity. Inhibition of serine and one-carbon metabolism blocks the beneficial effects of CnAβ1. CnAβ1Δi12 mice show increased cardiac hypertrophy and declined contractility. Conclusions The metabolic reprogramming induced by CnAβ1 redefines the role of calcineurin in the heart and shows for the first time that activation of the serine and one-carbon pathway has beneficial effects on cardiac hypertrophy and function, paving the way for new therapeutic approaches

Boolean Game with Prioritized Norms

In this paper we study boolean game with prioritized norms. Norms distinguish illegal strategies from legal strategies. Notions like legal strategy and legal Nash equilibrium are introduced. Our formal model is a combination of (weighted) boolean game and so called (prioritized) input/output logic. After formally presenting the model, we use examples to show that non-optimal Nash equilibrium can be avoided by making use of norms.We study various complexity issues related to legal strategy and legal Nash equilibrium

Activation of Serine One-Carbon Metabolism by Calcineurin A beta 1 Reduces Myocardial Hypertrophy and Improves Ventricular Function

BACKGROUND In response to pressure overload, the heart develops ventricular hypertrophy that progressively decompensates and leads to heart failure. This pathological hypertrophy is mediated, among others, by the phosphatase calcineurin and is characterized by metabolic changes that impair energy production by mitochondria. OBJECTIVES The authors aimed to determine the role of the calcineurin splicing variant CnA beta 1 in the context of cardiac hypertrophy and its mechanism of action. METHODS Transgenic mice overexpressing CnAb1 specifically in cardiomyocytes and mice lacking the unique C-terminal domain in CnA beta 1 (CnA beta 1(Delta i12) mice) were used. Pressure overload hypertrophy was induced by transaortic constriction. Cardiac function was measured by echocardiography. Mice were characterized using various molecular analyses. RESULTS In contrast to other calcineurin isoforms, the authors show here that cardiac-specific overexpression of CnA beta 1 in transgenic mice reduces cardiac hypertrophy and improves cardiac function. This effect is mediated by activation of serine and one-carbon metabolism, and the production of antioxidant mediators that prevent mitochondrial protein oxidation and preserve ATP production. The induction of enzymes involved in this metabolic pathway by CnAb1 is dependent on mTOR activity. Inhibition of serine and one-carbon metabolism blocks the beneficial effects of CnA beta 1. CnA beta 1(Delta i12) mice show increased cardiac hypertrophy and declined contractility. CONCLUSIONS The metabolic reprogramming induced by CnAb1 redefines the role of calcineurin in the heart and shows for the first time that activation of the serine and one-carbon pathway has beneficial effects on cardiac hypertrophy and function, paving the way for new therapeutic approaches. (J Am Coll Cardiol 2018; 71: 654-67) (C) 2018 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).This work was supported by grants from the European Union (CardioNeT-ITN-289600 and CardioNext-608027 to Dr. Lara-Pezzi; Meet-ITN-317433 to Dr. Enriquez; UE0/MCA1108 to Dr. Acin-Perez), from the Spanish Ministry of Economy and Competitiveness (SAF2015-65722-R and SAF2012-31451 to Dr. Lara-Pezzi; SAF2015-71521-REDC, BFU2013-50448, and SAF2012-32776 to Dr. Enriquez; RyC-2011-07826 to Dr. Acin-Perez; BIO2012-37926 and BIO2015-67580-P to Dr. Vazquez), from the Spanish Carlos III Institute of Health (CPII14/00027 to Dr. Lara-Pezzi; RD12/0042/066 to Drs. Garcia-Pavia and Lara-Pezzi), from the Regional Government of Madrid (2010-BMD-2321 ``Fibroteam´´ to Dr. Lara-Pezzi; 2011-BMD-2402 ``Mitolab´´ to Dr. Enriquez) and the FIS-ISCIII (PRB2-IPT13/0001 and RD12/0042/0056-RIC-RETICS to Dr. Vazquez). This work was also supported by the Plan Estatal de IthornDthornI 2013-2016-European Regional Development Fund (FEDER) ``A way of making Europe,´´ Spain. The CNIC is supported by the Spanish Ministry of Economy and Competitiveness and by the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). Drs. Vazquez and Garcia-Pavia have served as consultants for VL39. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Padron-Barthe, Villalba-Orero, and Gomez-Salinero contributed equally to this work and are joint first authors. Robyn Shaw, MD, PhD, served as Guest Editor for this paper.S