Applying computational approaches to the understanding of the consequences and opportunities of ion channel properties in atrial fibrillation

Cardiac arrhythmias are disorders of the electrical system of the heart and an often clinically-challenging group of disorders. Atrial fibrillation (AF) is the most common cardiac arrhythmia in the general population; it is associated with significant morbidity and mortality. Available antiarrhythmic drugs (AADs) for the treatment of AF are older molecules with sub- optimal efficacy and safety profiles. Recent advances in basic electrophysiology and the development of sophisticated mathematical modeling approaches could help in expanding our understanding of the basic mechanisms of AF and assist in the development of novel AF- selective AADs. The purpose of this thesis was to utilize computational approaches to the understanding of the consequences and opportunities of ion channel properties, with a special emphasis on AF. The cardiac action potential is the basic functional unit of the electrical system of the heart and is the manifestation of coordinated current fluxes through specialized proteins known as ion channels. Antiarrhythmic drugs act through modulation of ion channel properties. We hypothesized that mathematical modeling could be used to study and optimize the pharmacodynamic properties of AADs for the treatment of AF. We demonstrated that the pharmacodynamic properties (binding/unbinding characteristics) of a state-dependent Na+- channel blocker modulate the drug’s anti-/proarrhythmic actions with inactivated-state blockers being optimally AF-selective. The optimized drug’s selectivity for AF was the result of its rate- selectivity (stronger effects at fast vs slow cardiomyocyte activation rates) with relatively mild atrial-selective (stronger effects in atrial vs ventricular cardiomyocytes) actions. We found that the optimally AF-selective Na+-channel blocker had sub-optimal anti-AF efficacy, but that slightly less selective drugs had favorable AF-termination rates. We then sought to explore potential current-block combinations with synergistic AF- selective properties. Using mathematical modeling and laboratory experiments, we demonstrated that the combination of optimized state-dependent Na+-channel block and K+- channel block had synergistic effects, significantly augmenting AF termination rates for any level of AF-selectivity vs pure Na+-channel block. The mechanisms of these synergistic effects were found to be mediated by the functional interaction between the action potential prolonging- v effects of K+-channel block, the Na+-channel blocker’s voltage-dependent binding/unbinding properties and the Na+ channel’s inactivation characteristics, highlighting the non-linear nature of the cardiac action potential’s dynamics. Traditional K+ currents targeted by AADs have significant ventricular proarrhythmic liabilities. Using recent experimental observations, we updated the mathematic formulation for the inactivation dynamics of the ultra-rapid delayed-rectifier K+ current (IKur), an atrial-specific current. Using this model, we showed that, contrary to what had been proposed in the published literature, IKur rate-dependent properties are mediated by its activation properties with minimal contribution from inactivation, under physiological conditions. We also demonstrated that the contribution of IKur to action potential repolarization is preserved, or even increased, in the setting of electrical remodeling-induced IKur downregulation. Finally, we described the mechanisms of the forward rate-dependent of IKur block, mediated by functional non-linear interactions with the rapid delayed inward-rectifier K+ current (IKr), the only K+ current with such properties. Until recently, fibroblasts were considered to be electrically inactive. More recently, experimental work demonstrated the presence of functional ionic current on the fibroblast and possible cardiomyocyte-fibroblast coupling. Here, we described a novel kind of heart failure- induced electrical remodeling involving the fibroblasts ion channels. This was characterized by downregulation of the fibroblast voltage-dependent K+ current (IKv,fb) and upregulation of the fibroblast inward-rectifier K+ current (IKir,fb). We then implemented our experimental findings into a mathematical model of cardiomyocyte-fibroblast coupling and found fibroblast electrical remodeling to have significant effects on the cardiomyocyte’s electrophysiological properties. In a 2-dimension model of simulated AF, downregulation of IKv,fb had an antiarrhythmic effect whereas IKir,fb upregulation was found to be proarrhythmic. The studies presented here utilized mathematical modeling to study non-linear systems in cardiac electrophysiology to tackle questions that would have been difficult to approach with traditional laboratory-based experimentation. They also showcased how theoretical results can help orient and receive confirmation with subsequent experimental work or, conversely, novel experimental findings results be implemented into a mathematical model to investigate potential consequences. Mathematical modeling is a promising tool to help in studying the complex and vi non-linear effects of pharmacological modulation of ion channel properties and assist in the development of optimized antiarrhythmics for the treatment of AF, a major unmet need in clinical medicine. As models increase in sophistication to better represent the cardiomyocyte’s electrophysiology, they will almost certainly play an ever-growing role in expanding our understanding of the mechanisms of complex arrhythmias.Les arythmies cardiaques représentent une famille de pathologies du système électrique cardiaque. La fibrillation auriculaire (FA), est l’arythmie cardiaque la plus fréquente dans la population générale et est associée à un fardeau de morbidité et mortalité cardiovasculaire important. Les médicaments antiarythmiques utilisées dans le traitement de la FA sont de vieilles molécules avec une efficacité sous-optimale et des effets secondaires importants. Les avancées récentes en électrophysiologie cardiaque fondamentale et le développement d’outils de modélisation mathématique ont le potentiel d’élargir notre compréhension des mécanismes pathophysiologiques en FA et contribuer au développement de nouveaux médicaments antiarythmiques optimisés pour le traitement de la FA. L’objectif global de cette thèse est d’utiliser les méthodes de modélisation mathématique pour étudier les conséquences et opportunités thérapeutiques de la modulation des canaux ioniques cardiaques, avec une emphase sur la FA. Le potentiel d’action cardiaque est l’unité fonctionnelle de base du système électrique cardiaque ; il est le résultat du flux coordonné de courants électriques à travers de protéines spécialisées, les canaux ioniques. Les molécules antiarythmiques agissent à travers la modulation des canaux ioniques cardiaques. Nous avons posé l’hypothèse que des modèles mathématiques pourraient être utilisés pour étudier et optimiser les propriétés pharmacodynamiques d’un médicament antiarythmique pour le traitement de la FA. Nous avons démontré que les propriétés pharmacodynamiques (propriétés de liage et déliage) d’un bloqueur des canaux Na+ état-dépendant modulent les effets anti- et pro-arythmiques de la molécule ; un bloqueur Na+ sélectif pour l’état inactivé du canal serait maximalement FA-sélectif. Cette sélectivité pour la FA est la conséquence de la sélectivité pour la fréquence (effet thérapeutique plus important à des fréquences d’activation du cardiomyocyte élevées vs basses) avec une contribution relativement faible de la sélectivité auriculaire (effet thérapeutique plus important sur les cardiomyocytes auriculaires vs ventriculaires). Par la suite, nous avons exploré des combinaisons de bloqueurs ioniques ayant des propriétés anti-FA synergiques. En utilisant des modèles mathématiques et des expériences en laboratoire, nous avons démontré que la combinaison d’un bloqueur des canaux Na+ et d’un iii bloqueur des canaux K+ a des effets synergiques, augmentant de façon importante l’efficacité anti-FA pour un même degré de sélectivité vs un bloqueur des canaux Na+ seul. Le mécanisme de synergie a été élucidé et consiste d’effets fonctionnels médiés par l’interaction du prolongement de la durée du potentiel d’action causé par le bloque des canaux K+, les propriétés voltage-dépendantes du liage et déliage du bloqueur des canaux Na+ ainsi que des propriétés d’inactivation des canaux Na+, démontrant la nature hautement non-linéaire des dynamiques du potentiel d’action cardiaque. Les courants K+ ciblés par les médicaments antiarythmiques ont des effets proarythmiques ventriculaires importants. En utilisant des données expérimentales récentes, nous avons proposé une formulation mise à jour des dynamiques d’inactivation du courant K+ IKur, un courant auriculo-sélectif. En utilisant ce modèle, nous avons démontré que, contrairement à ce qui avait été précédemment proposé, les propriétés fréquence-dépendantes du courant IKur dépendent de ses caractéristiques d’activation avec une contribution négligeable de ses propriétés d’inactivation, sous conditions physiologiques normales. Nous avons également démontré que la contribution de IKur à la repolarisation du potentiel d’action est maintenue, voir augmentée, dans le contexte de la diminution de IKur en situation de remodelage électrique induit par la FA. Finalement, nous avons décrit le mécanisme qui sous-tend les propriétés fréquence-dépendantes du bloque de IKur, l’unique courant K+ avec de telles caractéristiques. Jusqu’à très récemment, les fibroblastes cardiaques étaient considérés comme électriquement inactifs. Des travaux expérimentaux ont démontré la présence de canaux ioniques sur la surface de ces fibroblastes ainsi que la possibilité de couplage électrique entre cardiomyocytes et fibroblastes. Nous avons décrit un nouveau type de remodelage électrique en situation d’insuffisance cardiaque, le remodelage des courants ioniques des fibroblastes cardiaques. Ce remodelage est caractérisé par une diminution du courant K+ voltage-dépendant IKv,fb et une augmentation du courant K+ IKir,fb. Nous avons par la suite incorporé ces trouvailles expérimentales dans un modèle mathématique simulant l’interaction électrique entre cardiomyocytes et fibroblastes et montré que le remodelage électrique des fibroblastes peut avoir un impact important sur les propriétés électrophysiologiques des cardiomyocytes. Dans iv un modèle 2-dimensionel de FA, nous avons trouvé que la diminution de IKv,fb a un effet antiarythmique alors que l’augmentation de IKir,fb a des effets proarythmiques. Les études ici présentées utilisent les méthodes de modélisation mathématique pour l’étude de systèmes non-linéaires en électrophysiologie cardiaque et aborder des avenues de recherche difficilement accessibles aux méthodes de laboratoire traditionnelles. Elles démontrent également comment des résultats théoriques peuvent orienter et trouver confirmation dans des travaux expérimentaux subséquents ou, à l’inverse, des trouvailles expérimentales peuvent être implémentées dans les modèles mathématiques pour investiguer les conséquences de celles-ci. La modélisation mathématique est un outil prometteur pour l’étude des effets complexes et non-linéaires de la modulation pharmacologique des canaux ioniques et ainsi contribuer au développement de médicaments antiarythmiques optimisés pour le traitement de la FA, un besoin clinique majeur

Graffiti art and self-identity: Leaving their mark

This project focuses on graffiti art as not an unconstructive form of artwork as society might assume, but a way of coping and establishing an identity for youth mostly males who are searching for who they are

PREPARACIÓN DE MEMBRANAS HÍBRIDAS POLÍMERO/ZIFs PARA LA PERMEACIÓN DE CO2

APARTIR DE LA RECUPERACIóN DE LDPE SE SINTETIZARON MEMBRANAS DE ZIF PARA ADSORCIóN DE CO2El presente trabajo se centró en las membranas híbridas o membranas de matriz mixta (MMMs, por sus siglas en inglés), las cuales cuentan con un alto potencial en la investigación y desarrollo en la separación de gases en virtud de su alta selectividad en gases puros o mezclados. Los materiales que las componen tienen diversos tamaños de poro lo que hace que funcione como un tamiz específico para la separación de gases. Se sintetizaron MMMs para la permeación de Bióxido de Carbono (CO2) compuestas de tres materiales: ZIF-8 (por sus siglas en inglés, Zeolitic Imidazolate Framework) el cual está formado por iones de zinc y 2-metilimidazol (ligando), polietileno de baja densidad (LDPE, por sus siglas en inglés, Low Density Polyethylene) el cual es un polímero que se utiliza como soporte y por ultimo una malla de acero inoxidable para dar una resistencia mecánica al soporte. El LDPE y la malla de acero inoxidable se utilizaron como soporte de la membrana híbrida polímero/ZIFs para dar las dimensiones (espesor y diámetro) y morfología de la MMMs a través de una técnica de procesamiento llamado recubrimiento por centrifugación (spin coating, en inglés) que ofrece un potencial alto para la fabricación de membranas libres de defectos, el polímero fue depositado sobre una malla de acero inoxidable para cubrirla por completo y de esta manera obtener los soportes. Las MMMs fueron sintetizadas mediante un proceso de crecimiento solvotermal in-situ; donde se realiza la funcionalización de la superficie del soporte generado por spin coating, para posteriormente caracterizarlas y realizarles las pruebas de permeación de CO2. Los resultados muestran una membrana híbrida completamente integrada, sin fracturas ni defectos (evaluada por microscopía electrónica de barrido), su fase establecida (mediante difracción de rayos X) y una estabilidad térmica de 300 °C (mediante análisis Termogravimétrico). Posteriormente se realizaron las pruebas de permeación de gases; lo cual confirma la permeación de CO2.CONACYT, UAEME

Little Higgs models with a light T quark

We study Little Higgs models based on a SU(3)_1 x SU(3)_2 global symmetry and with two scales (the two vacuum expectation values f_{1,2}) substantially different. We show that all the extra vector boson fields present in these models may be much heavier than the vectorlike T quark necessary to cancel top-quark quadratic corrections. In this case the models become an extension of the standard model with a light (500 GeV) T quark and a scalar Higgs field with a large singlet component. We obtain that the Yukawa and the gauge couplings of the Higgs are smaller than in the standard model, a fact that reduces significantly the Higgs production rate through glu-glu and WW fusion. The T-quark decay into Higgs boson becomes then a dominant Higgs production channel in hadron colliders.Comment: 16 pages, version to appear in NP

Two-loop SUSY QCD corrections to the neutralino masses in the MSSM

We have calculated the two-loop strong interaction corrections to the neutralino pole masses in the DRbar'-scheme in the Minimal Supersymmetric Standard Model (MSSM). We have performed a detailed numerical analysis for a particular point in the parameter space and found corrections of a few tenths of a percent. We agree with previously derived analytic formulae for two-loop corrections to fermion masses.Comment: 10 pages, 10 eps figures, figure 10 replace

In vitro activity of bedaquiline against rapidly growing nontuberculous mycobacteria

Bedaquiline (BDQ) has been proven to be effective in the treatment of multidrug-resistant tuberculosis. We hypothesized that BDQ could be a potential agent to treat nontuberculous mycobacterial (NTM) infection. The objective of this study was to evaluate the in vitro activity of BDQ against rapidly growing mycobacteria by assessing the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) against 18 NTM strains. For MIC determination we performed the resazurin microtitre assay broth dilution, and for the MBC the c.f.u. was determined. BDQ exhibited a strong inhibitory effect against most NTM tested; however, for some NTM strains the MBC was significantly higher than the MIC. A new finding is that Mycobacterium flavescens has a mutation in the gene atpE associated with natural resistance to BDQ. These preliminary promising results demonstrate that BDQ could be potentially useful for the treatment of NTM

Wheelchair Tire Change

This project consists of a rear wheel wheelchair lift to be designed and created by a Cal Poly senior project team. This project was created for injured veteran Ms. Landeen who has the trouble of tracking mud into her house because of dirty wheelchair tires. The project was presented by the non-profit organization The Quality of Life Plus (QL+) Program. Much like when you remove your shoes coming into your home, Ms. Landeen needs a way to exchange her outdoor wheels for her clean indoor wheels. The expected outcome of this project is a fully functioning device that will safely and effectively allow Ms. Landeen to independently change her tires. The following report details the problem given, background research on current products, initial analysis to define the problem, the ideation process performed by the team, concept and prototype designs, design iteration, manufacturing, design verification, and testing of the final design prototype

Superovulation, in vivo Embryo Recovery and Cryopreservation for Aoudad (Ammotragus Lervia) Females Using Osmotic Pumps and Vitrification : A Preliminary Experience and its Implications for Conservation

We thank all of the administrative, veterinary and animal keeper staff of the Leon Zoological Park and the embryologists (especially to Claudia Gonzalez) of the Instituto de Ciencias en Reproducción Humana, also to J.I Castillo-Quan for critical reading of the manuscript. This work was partially supported by grants 0105961/10110/194/09 to RF, 59716 to JPRU from CONACYT and grant 107996 to JPRU from FOMIXYucatán 2008. JLS was supported by a doctoral scholarship from CONACYT (240847).Peer reviewedPublisher PD

MSSM Higgs-boson mass predictions and two-loop non-supersymmetric counterterms

The evaluation of Yukawa-enhanced two-loop contributions to the MSSM Higgs-boson mass is considered. We prove the common assumption that regularization by dimensional reduction preserves supersymmetry at the required level. Thus generating counterterms by multiplicative renormalization is correct. Technically, we identify a suitable Slavnov-Taylor identity, use a recently developed method to evaluate it at the two-loop level, and show that it is valid in dimensional reduction.Comment: 14 pages, 2 figure

Twelve-month utilization rates and adequacy of treatment for mental health and substance use disorders in Argentina

OBJECTIVE: To estimate the 12-month prevalence of mental health services utilization (overall and by type of service sector), the adequacy of treatment provided, and sociodemographic correlates in the Argentinean Study of Mental Health Epidemiology (ASMHE). METHODS: The ASMHE is a multistage probability household sample representative of adults in urban areas of Argentina. The World Health Organization World Mental Health Composite International Diagnostic Interview (WMH-CIDI) was used to evaluate psychiatric diagnosis and service utilization. RESULTS: Among those with a disorder, 27.6% received any treatment in the prior 12 months. Of these, 78.3% received minimally adequate treatment using a broad definition and only 43.6% using a stringent definition. For individuals with a disorder, more services were provided by mental health professionals (17.7%) than by general medical professionals (11.5%) or non-healthcare sectors (2.6%). Younger individuals with low education and income were less likely to receive treatment; those never married and those with an anxiety or mood disorder were more likely to receive treatment. Among those in treatment, treatment was least adequate among younger individuals with low education and low income. CONCLUSIONS: Policies to increase access to services for mental health disorders in Argentina are needed, as is training for primary care practitioners in the early detection and treatment of psychiatric disorders.Fil: Cia, Alfredo H.. Centro de Investigaciones Médicas En Ansiedad; ArgentinaFil: Stagnaro, Juan C.. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Aguilar Gaxiola, Sergio. University of California; Estados UnidosFil: Sustas, Sebastián Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Serfaty, Edith. Centro de Estudios Epidemiológicos; ArgentinaFil: Nemirovsky, Martin. Proyecto SUMA; ArgentinaFil: Kessler, Ronald C.. Harvard Medical School; Estados UnidosFil: Benjet, Corina. Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz; Méxic