La Investigación como modus vivendi

Asociación Argentina para el Progreso de las Ciencias, merecida o no, me produce cierto halago y quiero agradecer a quienes me consideraron para hacerla. Sin embargo, para que la misma adquiera algún sentido, quisiera que esta pequeña crónica de mi camino en la investigación pueda significar algo menos mezquino que la satisfacción de mi ego y sirva para motivar y alentar a los jóvenes que se inician en este camino. Intentaré describir, lo más objetivamente posible el camino que inicié hace más de 50 años intentando develar los mecanismos básicos de la función cardíaca, camino que sigo transitando con entusiasmo. A los datos precisos he agregado algunas anécdotas contadas tal como han quedado en mi memoria después de tantos años.Fil: Mattiazzi, Ramona Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentin

The role of CaMKII regulation of phospholamban activity in heart disease

Phospholamban (PLN) is a phosphoprotein in cardiac sarcoplasmic reticulum (SR) that is a reversible regulator of the Ca(2)(+)-ATPase (SERCA2a) activity and cardiac contractility. Dephosphorylated PLN inhibits SERCA2a and PLN phosphorylation, at either Ser(16) by PKA or Thr(17) by Ca(2)(+)-calmodulin-dependent protein kinase (CaMKII), reverses this inhibition. Through this mechanism, PLN is a key modulator of SR Ca(2)(+) uptake, Ca(2)(+) load, contractility, and relaxation. PLN phosphorylation is also the main determinant of β1-adrenergic responses in the heart. Although phosphorylation of Thr(17) by CaMKII contributes to this effect, its role is subordinate to the PKA-dependent increase in cytosolic Ca(2)(+), necessary to activate CaMKII. Furthermore, the effects of PLN and its phosphorylation on cardiac function are subject to additional regulation by its interacting partners, the anti-apoptotic HAX-1 protein and Gm or the anchoring unit of protein phosphatase 1. Regulation of PLN activity by this multimeric complex becomes even more important in pathological conditions, characterized by aberrant Ca(2)(+)-cycling. In this scenario, CaMKII-dependent PLN phosphorylation has been associated with protective effects in both acidosis and ischemia/reperfusion. However, the beneficial effects of increasing SR Ca(2)(+) uptake through PLN phosphorylation may be lost or even become deleterious, when these occur in association with alterations in SR Ca(2)(+) leak. Moreover, a major characteristic in human and experimental heart failure (HF) is depressed SR Ca(2)(+) uptake, associated with decreased SERCA2a levels and dephosphorylation of PLN, leading to decreased SR Ca(2)(+) load and impaired contractility. Thus, the strategy of altering SERCA2a and/or PLN levels or activity to restore perturbed SR Ca(2)(+) uptake is a potential therapeutic tool for HF treatment. We will review here the role of CaMKII-dependent phosphorylation of PLN at Thr(17) on cardiac function under physiological and pathological conditions

Decomposition of Feynman Integrals on the Maximal Cut by Intersection Numbers

We elaborate on the recent idea of a direct decomposition of Feynman integrals onto a basis of master integrals on maximal cuts using intersection numbers. We begin by showing an application of the method to the derivation of contiguity relations for special functions, such as the Euler beta function, the Gauss ${}_2F_1$ hypergeometric function, and the Appell $F_1$ function. Then, we apply the new method to decompose Feynman integrals whose maximal cuts admit 1-form integral representations, including examples that have from two to an arbitrary number of loops, and/or from zero to an arbitrary number of legs. Direct constructions of differential equations and dimensional recurrence relations for Feynman integrals are also discussed. We present two novel approaches to decomposition-by-intersections in cases where the maximal cuts admit a 2-form integral representation, with a view towards the extension of the formalism to $n$-form representations. The decomposition formulae computed through the use of intersection numbers are directly verified to agree with the ones obtained using integration-by-parts identities.Comment: 115 pages, 29 figures; references added; additional examples added; matches published versio

The role of CaMKII regulation of phospholamban activity in heart disease

Phospholamban (PLN) is a phosphoprotein in cardiac sarcoplasmic reticulum (SR) that is a reversible regulator of the Ca2+-ATPase (SERCA2a) activity and cardiac contractility. Dephosphorylated PLN inhibits SERCA2a and PLN phosphorylation, at either Ser16 by PKA or Thr17 by Ca2+-calmodulin-dependent protein kinase (CaMKII), reverses this inhibition. Through this mechanism, PLN is a key modulator of SR Ca2+ uptake, Ca2+ load, contractility, and relaxation. PLN phosphorylation is also the main determinant of ß1-adrenergic responses in the heart. Although phosphorylation of Thr17 by CaMKII contributes to this effect, its role is subordinate to the PKA-dependent increase in cytosolic Ca2+, necessary to activate CaMKII. Furthermore, the effects of PLN and its phosphorylation on cardiac function are subject to additional regulation by its interacting partners, the anti-apoptotic HAX-1 protein and Gm or the anchoring unit of protein phosphatase 1. Regulation of PLN activity by this multimeric complex becomes even more important in pathological conditions, characterized by aberrant Ca2+-cycling. In this scenario, CaMKII-dependent PLN phosphorylation has been associated with protective effects in both acidosis and ischemia/reperfusion. However, the beneficial effects of increasing SR Ca2+ uptake through PLN phosphorylation may be lost or even become deleterious, when these occur in association with alterations in SR Ca2+ leak. Moreover, a major characteristic in human and experimental heart failure (HF) is depressed SR Ca2+ uptake, associated with decreased SERCA2a levels and dephosphorylation of PLN, leading to decreased SR Ca2+ load and impaired contractility. Thus, the strategy of altering SERCA2a and/or PLN levels or activity to restore perturbed SR Ca2+ uptake is a potential therapeutic tool for HF treatment. We will review here the role of CaMKII-dependent phosphorylation of PLN at Thr17 on cardiac function under physiological and pathological conditions.Facultad de Ciencias MédicasCentro de Investigaciones Cardiovasculare

Targeting late ICaL to close the window to ventricular arrhythmias

Triggered arrhythmias originate from aberrant cell membrane depolarizations that occur during or after completion of the cardiac action potential (AP). Although the phenomenon was recognized early and associated with cardiac arrhythmias in recordings relying on monophasic APs (Segers, 1941; Bozler, 1943), the concept of triggered activity was coined several decades later by Paul Cranefield (Cranefield, 1975) who, incidentally, served as editor-in-chief of this journal for more than 25 yr. This new term aimed to differentiate the slow membrane depolarization that depends on a previous AP (triggered activity) from automaticity, a slow membrane depolarization with different properties like the rhythmicity and spontaneity and independence on a preceding AP. Cranefield also originated the term “afterdepolarizations” for this triggered activity and described what are now traditionally known as early afterdepolarizations (EADs) “…that appears before the membrane potential has returned to the level it had at the beginning of the upstroke of the action potential,” and delayed afterdepolarizations (DADs), which occur “…after repolarization is complete i.e., after the membrane potential has returned to the level seen before the action potential” (Cranefield, 1975, 1977).Fil: Gonano, Luis Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; ArgentinaFil: Mattiazzi, Ramona Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentin

Tracking nitroxyl-derived posttranslational modifications of phospholamban in cardiac myocytes

Cardiovascular disease is the leading cause of morbidity and mortality worldwide. Calcium (Ca2+) mishandling is one of the most striking abnormalities in this wide spectrum of pathologies, among which heart failure (HF) remains the leading cause of death in developed countries (Benjamin et al., 2018). A hallmark of HF in both human and animal models is impaired Ca2+ sequestration into the SR, which contributes to the decreased contractile performance in this disease (Gwathmey et al., 1987; Meyer et al., 1995; del Monte et al., 2002). Not surprisingly, this defective mechanism has been targeted with novel therapeutic strategies that are now undergoing experimental and clinical testing in animals and patients (Pfeffer et al., 2015; Hulot et al., 2016, 2017; Motloch et al., 2018). In this issue of JGP, Keceli et al. provide novel insights into the molecular mechanism from which nitroxyl (HNO), nitric oxide (NO)´s one-electron-reduced and protonated sibling, recently emerged as a promising candidate for HF treatment.Fil: Mundiña, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; ArgentinaFil: Mattiazzi, Ramona Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentin

SERCA is critical to control the Bowditch effect in the heart

The Bowditch effect or staircase phenomenon is the increment or reduction of contractile force when heart rate increases, defined as either a positive or negative staircase. The healthy and failing human heart both show positive or negative staircase, respectively, but the causes of these distinct cardiac responses are unclear. Different experimental approaches indicate that while the level of Ca2+ in the sarcoplasmic reticulum is critical, the molecular mechanisms are unclear. Here, we demonstrate that Drosophila melanogaster shows a negative staircase which is associated to a slight but significant frequency-dependent acceleration of relaxation (FDAR) at the highest stimulation frequencies tested. We further showed that the type of staircase is oppositely modified by two distinct SERCA mutations. The dominant conditional mutation SERCAA617T induced positive staircase and arrhythmia, while SERCAE442K accentuated the negative staircase of wild type. At the stimulation frequencies tested, no significant FDAR could be appreciated in mutant flies. The present results provide evidence that two individual mutations directly modify the type of staircase occurring within the heart and suggest an important role of SERCA in regulating the Bowditch effect.Fil: Balcazar, Dario Emmanuel. Universidad Nacional de La Plata; ArgentinaFil: Regge, María Victoria. Universidad Nacional de La Plata; ArgentinaFil: Santalla, Manuela. Universidad Nacional de La Plata; ArgentinaFil: Behrensmeyer, Anna Kay. Universität Osnabrück;Fil: Achimón, Fernanda. Universität Osnabrück;Fil: Mattiazzi, Ramona Alicia. Universidad Nacional de La Plata; ArgentinaFil: Ferrero, Paola Viviana. Universidad Nacional de La Plata; Argentin

Cidadania, migração e agentes políticos no séc. XXI

The paper considers the deep transformations regarding meanings of citizenship in contemporary age and political challenges derived. Special issue is represented by citizenship grant as form of swift enfranchisement of migrants in XXI century Europe. Keywords: Citizenship and Nation-State, Post-modernisms and Post- Colonialisms, Political Participation, International Migration. O artigo considera as profundas transformações da noção de cidadania e os desafios políticos que estas mudanças comportam. Uma atenção especial é dada ao uso do dispositivo da concessão da cidadania como forma de rápida integração dos migrantes na Europa do séc. XXI. Palavras-chave: Cidadania e Estado-Nacional, Pós-modernidades e Pós- colonialismos, Participação Política, Migrações Internacionais.The paper considers the deep transformations regarding meanings of citizenship in contemporary age and political challenges derived. Special issue is represented by citizenship grant as form of swift enfranchisement of migrants in XXI century Europe. Keywords: Citizenship and Nation-State, Post-modernisms and Post- Colonialisms, Political Participation, International Migration. O artigo considera as profundas transformações da noção de cidadania e os desafios políticos que estas mudanças comportam. Uma atenção especial é dada ao uso do dispositivo da concessão da cidadania como forma de rápida integração dos migrantes na Europa do séc. XXI. Palavras-chave: Cidadania e Estado-Nacional, Pós-modernidades e Pós- colonialismos, Participação Política, Migrações Internacionais

Ca2+/calmodulin-dependent protein kinase: A key component in the contractile recovery from acidosis

Intracellular acidosis exerts substantial effects on the contractile performance of the heart. Soon after the onset of acidosis, contractility diminishes, largely due to a decrease in myofilament Ca2+ responsiveness. This decrease in contractility is followed by a progressive recovery that occurs despite the persistent acidosis. This recovery is the result of different mechanisms that converge to increase diastolic Ca2+ levels and Ca2+ transient amplitude. Recent experimental evidence indicates that activation of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) is an essential step in the sequence of events that increases the Ca2+ transient amplitude and produces contractile recovery. CaMKII may act as an amplifier, providing compensatory pathways to offset the inhibitory effects of acidosis on many of the Ca2+ handling proteins. CaMKII-induced phosphorylation of the SERCA2a regulatory protein phospholamban (PLN) has the potential to promote an increase in sarcoplasmic reticulum (SR) Ca2+ uptake and SR Ca2+ load, and is a likely candidate to mediate the mechanical recovery from acidosis. In addition, CaMKII-dependent phosphorylation of proteins other than PLN may also contribute to this recovery.Facultad de Ciencias Médica