Prediction of the effects of drugs on cardiac activity using computer simulations

[ES] Las enfermedades cardiovasculares siguen siendo la principal causa de muerte en Europa. Las arritmias cardíacas son una causa importante de muerte súbita, pero sus mecanismos son complejos. Esto denota la importancia de su estudio y prevención. La investigación sobre electrofisiología cardíaca ha demostrado que las anomalías eléctricas causadas por mutaciones que afectan a canales cardíacos pueden desencadenar arritmias. Sorprendentemente, se ha descubierto una gran variedad de fármacos proarrítmicos, incluidos aquellos que usamos para prevenirlas. Las indicaciones de uso de fármacos actuales intentaron solucionar este problema diseñando una prueba para identificar aquellos fármacos que podían ser peligrosos basado en el bloqueo de un solo canal iónico. El estudio de las interacciones fármaco-canal ha revelado la existencia no sólo de compuestos que bloquean múltiples canales, sino también una gran complejidad en esas interacciones. Esto podría explicar por qué algunos medicamentos pueden mostrar efectos muy diferentes en la misma enfermedad. Existen dos desafíos importantes con respecto a los efectos de los fármacos en la electrofisiología cardíaca. Por un lado, las empresas y entidades reguladoras están buscando una herramienta de alto rendimiento que mejore la detección del potencial proarrítmico durante el desarrollo de fármacos. Por otro lado, los pacientes con anomalías eléctricas a menudo requieren tratamientos personalizados más seguros. Las simulaciones computacionales contienen un poder sin precedentes para abordar fenómenos biofísicos complejos. Deberían ser de utilidad a la hora de determinar las características que definen tanto los efectos beneficiosos como no deseados de los fármacos mediante la reproducción de datos experimentales y clínicos. En esta tesis doctoral, se han utilizado modelos computacionales y simulaciones para dar respuesta a estos dos desafíos. El estudio de los efectos de los fármacos sobre la actividad cardíaca se dividió en el estudio de su seguridad y de su eficacia, respectivamente. Para dar respuesta al primer desafío, se adoptó un enfoque más amplio y se generó un nuevo biomarcador fácil de usar para la clasificación del potencial proarrítmico de los fármacos utilizando modelos del potencial de acción de células y tejidos cardíacos humanos. Se integró el bloqueo de múltiples canales a través de IC50 y el uso de concentraciones terapéuticas con el fin de mejorar el poder predictivo. Luego, se entrenó el biomarcador cuantificando el potencial proarrítmico de 84 fármacos. Los resultados obtenidos sugieren que el biomarcador podría usarse para probar el potencial proarrítmico de nuevos fármacos. Respecto al segundo desafío, se adoptó un enfoque más específico y se buscó mejorar la terapia de pacientes con anomalías eléctricas cardíacas. Por lo tanto, se creó un modelo detallado de la mutación V411M del canal de sodio, causante del síndrome de QT largo, reproduciendo datos clínicos y experimentales. Se evaluaron los posibles efectos beneficiosos de ranolazina, a la par que se aportó información sobre los mecanismos que impulsan la efectividad de la flecainida. Los resultados obtenidos sugieren que, si bien ambos fármacos mostraron diferentes mecanismos de bloqueo de los canales de sodio, un tratamiento con ranolazina podría ser beneficioso en estos pacientes.[CA] Les malalties cardiovasculars continuen sent la principal causa de mort a Europa. Les arrítmies cardíaques són una causa important de mort sobtada, però els seus mecanismes són complexos. Això denota la importància del seu estudi i prevenció. La investigació sobre electrofisiologia cardíaca ha demostrat que les anomalies elèctriques que afecten a canals cardiacs poden desencadenar arrítmies. Sorprenentment, s'ha descobert una gran varietat de fàrmacs proarrítmics, inclosos aquells que utilitzem per a previndre-les. Les indicacions d'ús de fàrmacs actuals van intentar solucionar aquest problema dissenyant una prova per a identificar aquells fàrmacs que podien ser perillosos basada en el bloqueig d'un sol canal iònic. L'estudi de les interaccions fàrmac-canal ha revelat l'existència no sols de compostos que bloquegen múltiples canals, sinó també una gran complexitat en aquestes interaccions. Això podria explicar per què alguns medicaments poden mostrar efectes molt diferents en la mateixa malaltia. Existeixen dos desafiaments importants respecte als efectes dels fàrmacs en la electrofisiologia cardíaca. D'una banda, les empreses i entitats reguladores estan buscant una eina d'alt rendiment que millore la detecció del potencial proarrítmic durant el desenvolupament de fàrmacs. D'altra banda, els pacients amb anomalies elèctriques sovint requereixen tractaments personalitzats més segurs. Les simulacions computacionals contenen un poder sense precedents per a abordar fenòmens biofísics complexos. Haurien de ser d'utilitat a l'hora de determinar les característiques que defineixen tant els efectes beneficiosos com no desitjats dels fàrmacs mitjançant la reproducció de dades experimentals i clíniques. En aquesta tesi doctoral, s'han utilitzat models computacionals i simulacions per a donar resposta a aquests dos desafiaments. L'estudi dels efectes dels fàrmacs sobre l'activitat cardíaca es va dividir en l'estudi de la seva seguretat i la seva eficacia. Per a donar resposta al primer desafiament, es va adoptar un enfocament més ampli i es va generar un nou biomarcador fàcil d'usar per a la classificació del potencial proarrítmic dels fàrmacs utilitzant models del potencial d'acció de cèl·lules i teixits cardíacs humans. Es va integrar el bloqueig de múltiples canals a través d'IC50 i l'ús de concentracions terapèutiques amb la finalitat de millorar el poder predictiu. Després, es va entrenar el biomarcador quantificant el potencial proarrítmic de 84 fàrmacs. Els resultats obtinguts suggereixen que el biomarcador podria usar-se per a provar el potencial proarrítmic de nous fàrmacs. Respecte al segon desafiament, es va adoptar un enfocament més específic i es va buscar millorar la teràpia de pacients amb anomalies elèctriques cardíaques. Per tant, es va crear un model detallat de la mutació V411M del canal de sodi, causant de la síndrome de QT llarg, reproduint dades clíniques i experimentals. Es van avaluar els possibles efectes beneficiosos de ranolazina, a l'una que es va aportar informació sobre els mecanismes que impulsen l'efectivitat de la flecainida. Els resultats obtinguts suggereixen que, si bé tots dos fàrmacs van mostrar diferents mecanismes de bloqueig dels canals de sodi, un tractament amb ranolazina podria ser beneficiós en aquests pacients.[EN] Cardiovascular disease remains the main cause of death in Europe. Cardiac arrhythmias are an important cause of sudden death, but their mechanisms are complex. This denotes the importance of their study and prevention. Research on cardiac electrophysiology has shown that electrical abnormalities caused by mutations in cardiac channels can trigger arrhythmias. Surprisingly, a wide variety of drugs have also shown proarrhythmic potential, including those that we use to prevent arrhythmia. Current guidelines designed a test to identify dangerous drugs by assessing their blocking power on a single ion channel to address this situation. Study of drug-channel interactions has revealed not only compounds that block multiple channels but also a great complexity in those interactions. This could explain why similar drugs can show vastly different effects in some diseases. There are two important challenges regarding the effects of drugs on cardiac electrophysiology. On the one hand, companies and regulators are in search of a high throughput tool that improves proarrhythmic potential detection during drug development. On the other hand, patients with electrical abnormalities often require safer personalized treatments owing to their condition. Computer simulations provide an unprecedented power to tackle complex biophysical phenomena. They should prove useful determining the characteristics that define the drugs' beneficial and unwanted effects by reproducing experimental and clinical observations. In this PhD thesis, we used computational models and simulations to address the two abovementioned challenges. We split the study of drug effects on the cardiac activity into the study of their safety and efficacy, respectively. For the former, we took a wider approach and generated a new easy-to-use biomarker for proarrhythmic potential classification using cardiac cell and tissue human action potential models. We integrated multiple channel block through IC50s and therapeutic concentrations to improve its predictive power. Then, we quantified the proarrhythmic potential of 84 drugs to train the biomarker. Our results suggest that it could be used to test the proarrhythmic potential of new drugs. For the second challenge, we took a more specific approach and sought to improve the therapy of patients with cardiac electrical abnormalities. Therefore, we created a detailed model for the long QT syndrome-causing V411M mutation of the sodium channel reproducing clinical and experimental data. We tested the potential benefits of ranolazine, while giving insights into the mechanisms that drive flecainide's effectiveness. Our results suggest that while both drugs showed different mechanisms of sodium channel block, ranolazine could prove beneficial in these patients.This PhD thesis was developed within the following projects: Ministerio de Economía y Competitividad and Fondo Europeo de Desarrollo Regional (FEDER) DPI2015-69125-R (MINECO/FEDER, UE): Simulación computacional para la predicción personalizada de los efectos de los fármacos sobre la actividad cardiaca. Dirección General de Política Científica de la Generalitat Valenciana (PROMETEU2016/088): “Modelos computacionales personalizados multiescala para la optimización del diagnóstico y tratamiento de arritmias cardiacas (personalised digital heart). Vicerrectorado de Investigación, Innovación y Transferencia de la Universitat Politècnica de València, Ayuda a Primeros Proyectos de Investigación (PAID-06-18), and by Memorial Nacho Barberá. Instituto de Salud Carlos III (La Fe Biobank PT17/0015/0043).Cano García, J. (2021). Prediction of the effects of drugs on cardiac activity using computer simulations [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/164094TESI

Functional Characterization of Regulatory Macrophages That Inhibit Graft-reactive Immunity

Macrophage accumulation in transplanted organs has long been recognized as a feature of allograft rejection1. Immunogenic monocytes infiltrate the allograft early after transplantation, mount a graft reactive response against the transplanted organ, and initiate organ rejection2. Recent data suggest that suppressive macrophages facilitate successful long-term transplantation3 and are required for the induction of transplantation tolerance4. This suggests a multidimensional concept of macrophage ontogeny, activation, and function, which demands a new roadmap for the isolation and analysis of macrophage function5. Due to the plasticity of macrophages, it is necessary to provide a methodology to isolate and characterize macrophages, depending on the tissue environment, and to define their functions according to different scenarios. Here, we describe a protocol for immune characterization of graft-infiltrating macrophages and the methods we used to functionally evaluate their capacity to inhibit CD8+ T proliferation and to promote CD4+Foxp3+ Treg expansion in vitro.We acknowledge the technical contributions of the Flow Cytometry, Microsurgery, and Bio- repository/Pathology Centers of Research Excellence at Mount Sinai. This work was supported by the COST Action BM1305: Action to Focus and Accelerate Cell Tolerogenic Therapies (A FACTT), the Mount Sinai Recanati/Miller Transplantation Institute developmental funds, Ministerio de Ciencia e Innovacion SAF2013-48834-R and SAF2016-80031-R J.O.S

Escenes domèstiques al carrer

El treball pretén estudiar els diferents espais col·lectius a partir de les escenes urbanes que es produeixen al carrer a les Festes Patronals de Benidorm. A través d’una anàlisi de les transformacions urbanes que es produeixen a les festivitats, es fa èmfasi en les qualitats i les característiques de l’arquitectura que afavoreixen l’aparició d’interaccions humanes tant de baixa intensitat, com veure, escoltar, trobar-se...; així com les d’alta intensitat, com parlar, seure..., o en els casos d’estudi, dinar al carrer. L’anàlisi dels espais col·lectius ha estat dividit en quatre capítols: El primer explica el context i la diferència entre un dia normal i un dia de festes. En el segon capítol s’exposen els diferents tipus d’espais i la varietat d’ocupacions que trobem. En el tercer capítol s’exposen 5 casos d’estudi, que representin i mostrin les interaccions analitzades. En últim lloc, el resultat final d’aquest treball és donar eines als arquitectes basades en la multitud d’experiències acumulades durant anys que han fet que es continuï produint una activitat tan domèstica com menjar, al carrer.El trabajo pretende estudiar los diferentes espacios colectivos a partir de las escenas urbanas que se producen en la calles durante las Fiestas Patronales de Benidorm. A través de un análisis de las transformaciones urbanas que se producen en las festividades, se enfatiza en las cualidades y características de la arquitectura que favorecen la aparición de interacciones humanas tanto de baja intensidad, como ver, escuchar, encontrarse...; así como las de alta intensidad, como hablar, sentarse..., o en los casos de estudio, comer en la calle. Este análisis de los espacios colectivos de divide en cuatro capítulos: El primero explica el contexto y la diferencia entre un dia normal y un dia de fiestas. El segundo capítulo expone los diferentes tipos de espacios y la variedad de ocupaciones que encontramos. En el tercer capítulo se exponen 5 casos de estudio que representen y muestren las interacciones analizadas. En último lugar, el resultado final de este trabajo es dar herramientas a los arquitectos basadas en la multitud de experiencias acumuladas durante años que han hecho que se continúe produciendo una actividad tan doméstica como comer, en la calle.The work aims to study the different collective spaces based on the urban scenes that take place in the streets during the Benidorm Patron Saint's Festivities. Through an analysis of the urban transformations that take place during the festivities, emphasis is placed on the qualities and characteristics of the architecture that favour the appearance of human interactions of both low intensity, such as seeing, listening, meeting...; as well as those of high intensity, such as talking, sitting..., or in the case studies, eating in the street. This analysis of collective spaces is divided into four chapters: The first explains the context and the difference between a normal day and a holiday. The second chapter explains the different types of spaces and the variety of occupations we find. The third chapter presents 5 case studies that represent and show the interactions analysed. Finally, the end result of this work is to provide architects with tools based on the multitude of experiences accumulated over the years that have led to the continuation of such a domestic activity as eating in the street

Influència de la mineralogia en la durabilitat de les roques toves: aplicació a talussos de Gipúskoa

Català: Aquest treball neix amb la intenció d’afegir un granet de sorra a un projecte d’investigació sobre la degradació de talussos de carretera situats en dos municipis del País Basc dut a terme per Joan Martínez-Bofill en col·laboració amb el Departament de Cristal·lografia i Mineralogia de la Universitat de Barcelona, el Departament d’Enginyeria del Terreny de la Universitat Politècnica de Catalunya i la Diputació Foral de Gipúzkoa. L’aportació fonamental al projecte és bàsicament la realització d’un estudi amb detall de la microtextura i la mineralogia de mostres extretes de sondeigs a peu de talús per mirar d’aprofundir en les causes de les patologies de degradabilitat que presenten els materials aflorants. Per fer-ho s’ha plantejat l’ús de la microscòpia electrònica d’escombrat (BSESEM/EDS) amb anàlisi d’energies dispersives i s’ha intentat justificar l’ús d’aquesta tecnologia en projectes d’aquest tipus, per a adquirir un grau de coneixement del terreny més profund i detallat del que permet la tradicional microscòpia òptica. Els resultats obtinguts d’aquestes anàlisis microtexturals s’han correlacionat amb els resultats obtinguts mitjançant els estudis d’ús habitual en aquest tipus de projectes i han servit per a establir una complementació mútua molt útil de cara a futures investigacions.Anglés: The aim of this work is to make a contribution to a research project that deals with the deterioration of road slopes located in two municipalities of the Basque Country. Said research project is carried out by Joan Martinez-Bofill, in collaboration with the Department of crystallography and Mineralogy of the University of Barcelona, the Department of Geotechnical Engineering of the Polytechnic University of Catalonia and the Provincial Government of Gipuzkoa. The main contribution to the project is basically a detailed microtextural and mineralogical study of samples taken from on-site surveys to try to explore in greater depth the causes leading to outcropping materials pathologies. To do so we have considered the use of scanning electron microscopy (BSE-SEM/EDS) with energy-dispersive spectroscopy, and sought to justify the use of this technology in this type of projects, in order to acquire a deeper knowledge and detail of the terrain than that allowed by traditional optical microscopy. The results of these microtextural analyses have been correlated with results of studies commonly used in projects of this kind, and they have helped to establish a degree of mutual complementation that will be useful for future research

Red de Bibliotecas Municipales de la provincia de Barcelona

The Public Library Network of the province of Barcelona has extensive experience in the field of collaborative work. The key to its success is not just the important historical events that helped to shape the present library system in the province of Barcelona. It is also the dissemination of collaborative values among libraries and library staff. After years of hard work, there are new challenges to meet, without forgetting the firm commitment to provide high quality library services that meet people’s needs and expectations

Immunotherapy with myeloid cells for tolerance induction

PURPOSE OF REVIEW: Understanding the interplay between myeloid dendritic cells and T cells under tolerogenic conditions, and whether their interactions induce the development of antigen-specific regulatory T cells (Tregs) is critical to uncover the mechanisms involved in the induction of indefinite allograft survival. RECENT FINDINGS: Myeloid dendritic cell-T-cell interactions are seminal events that determine the outcome of the immune response, and multiple in-vitro protocols suggest the generation of tolerogenic myeloid dendritic cells that modulate T-cell responses, and determine the outcome of the immune response to an allograft following adoptive transfer. We believe that identifying specific conditions that lead to the generation of tolerogenic myeloid dendritic cells and Tregs are critical for the manipulation of the immune response towards the development of transplantation tolerance. SUMMARY: We summarize recent findings regarding specific culture conditions that generate tolerogenic myeloid dendritic cells that induce T-cell hyporesponsiveness and Treg development, which represents a novel immunotherapeutic approach to promote the induction of indefinite graft survival prolongation. The interpretations presented here illustrate that different mechanisms govern the generation of tolerogenic myeloid dendritic cells, and we discuss the concomitant therapeutic implications.This work was supported by the Programa Ramón y Cajal RYC-2006-1588, Ministerio de Educa-ción y Ciencia SAF2007-63579, Programa José Castillejo JC2008-00065, and Programa de Investigación de Grupos Emergentes del ISCIII (to J.C.O.), and NIH R01 AI-41428, AI-72039, and the Emerald Foundation (to J.S.B.).S

Abellaite, NaPb2(CO3)2(OH), a new supergene mineral from the Eureka mine, Lleida province, Catalonia, Spain

The new mineral abellaite (IMA 2014-111), ideally NaPb2 (CO3)2 (OH), is a supergene mineral that was found in one of the galleries of the long-disused Eureka mine, in the southern Pyrenees (Lleida province), Catalonia, Spain. Abellaite is found as sparse coatings on the surface of the primary mineralization, it forms subhedral crystals not larger than 10μm as well as larger pseudohexagonal platelets up to ~ 30μm. Individual crystals commonly have a tabular to lamellar habit and form fairly disordered aggregates. The mineral is associated with a large number of primary minerals (roscoelite, pyrite, uraninite, coffinite, 'carbon', galena, sphalerite, nickeloan cobaltite, covellite, tennantite and chalcopyrite) and supergene minerals (hydrozincite, aragonite, gordaite, As-rich vanadinite andersonite, čejkaite, malachite and devilline). Abellaite is colourless to white, with a vitreous to nacreous lustre. The mineral is translucent, has a white streak and is non-fluorescent. The aggregates of microcrystals are highly friable. The calculated density using the ideal formula is 5.93 g/cm3. The chemical composition of the mineral (the mean of 10 electron microprobe analyses) is Na 3.88, Ca 0.29, Pb 72.03, C 4.17, O 19.47 and H 0.17, total 100.00 wt% (H, C and O by stoichiometry assuming the ideal formula). On the basis of 7 O atoms, the empirical formula of abellaite is Na0.96 Ca0.04 Pb1.98 (CO3)2 (OH). The simplified formula of the mineral is NaPb2 (CO3)2 (OH). The mineral is hexagonal, space group P 63 mc, a = 5.254(2), c = 13.450(5) Å, V = 321.5(2) Å3 and Z = 2. The strongest powder-diffraction lines [d in Å (I) (h k l)] are: 3.193 (100) (0 1 3), 2.627 (84) (1 1 0), 2.275 (29) (0 2 0), 2.242 (65) (0 2 1, 0 0 6), 2.029(95) (0 2 3). Abellaite has a known synthetic analogue, and the crystal structure of the mineral was refined by using crystallographic data of the synthetic phase. The mineral is named in honour of the mineralogist and gemmologist Joan Abella i Creus (b. 1968), who has long studied the deposits of the Eureka mine and who collected the mineral

Diagnostic criteria for bruxism: A scoping review

Background: A scoping review was conducted to explore all the methods and criteria used in primary research on bruxism diagnosis. Methods: A pre-defined and validated search was carried out in the PubMed, CINAHL, PsycInfo, Scopus, PeDro, LILACS, and Epistemonikos databases. Primary studies conducted on bruxism as primary condition in the adult population were included. The selection phases were carried out by peers, and conflicts were resolved by a third reviewer or by consensus. Data extraction and manual tracing were done in order to identify the relevant studies. Results: The search and selection strategy identified 472 publications, and after manual tracing, 423 studies were selected for analysis. The results on diagnostic methods were grouped into 10 categories. Different subcategories were described within these categories, resulting in a total of 73 diagnostic methods: physical examination (n = 11), questionnaires (n = 12), polysomnography (n = 13), electromyography (n = 5), the International Classification for Sleep Disorders from the American Association of Sleep Medicine (ICSD-AASM) (n = 3), intraoral devices (n = 10), history (n = 7), audio-video recordings (n = 3), smartphone applications (n = 2), and others (n = 7). In addition, the combinations of methods used in the primary research were also analyzed. The prevalence of use was calculated for all diagnostic categories and subcategories, as well as for the combinations. Conclusion: There was high heterogeneity in primary research regarding the diagnosis of bruxism. There is evidence that not all diagnostic methods are properly validated. Future research should focus on validating these methods and developing the best tool in terms of reliability and cost-effectiveness for the diagnosis of bruxism

The BCG Vaccine for COVID-19: First Verdict and Future Directions.

Despite of the rapid development of the vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it will take several months to have enough doses and the proper infrastructure to vaccinate a good proportion of the world population. In this interim, the accessibility to the Bacille Calmette-Guerin (BCG) may mitigate the pandemic impact in some countries and the BCG vaccine offers significant advantages and flexibility in the way clinical vaccines are administered. BCG vaccination is a highly cost-effective intervention against tuberculosis (TB) and many low-and lower-middle-income countries would likely have the infrastructure, and health care personnel sufficiently familiar with the conventional TB vaccine to mount full-scale efforts to administer novel BCG-based vaccine for COVID-19. This suggests the potential for BCG to overcome future barriers to vaccine roll-out in the countries where health systems are fragile and where the effects of this new coronavirus could be catastrophic. Many studies have reported cross-protective effects of the BCG vaccine toward non-tuberculosis related diseases. Mechanistically, this cross-protective effect of the BCG vaccine can be explained, in part, by trained immunity, a recently discovered program of innate immune memory, which is characterized by non-permanent epigenetic reprogramming of macrophages that leads to increased inflammatory cytokine production and consequently potent immune responses. In this review, we summarize recent work highlighting the potential use of BCG for the treatment respiratory infectious diseases and ongoing SARS-CoV-2 clinical trials. In situations where no other specific prophylactic tools are available, the BCG vaccine could be used as a potential adjuvant, to decrease sickness of SARS-CoV-2 infection and/or to mitigate the effects of concurrent respiratory infections.The authors' work is supported by National Institutes of Health grants R01 AI139623AI and Ministerio de Ciencia e Innovación PID2019-110015RB-I00 (JO); PID2019-105761RB-100 (EN-V). MG-P is funded from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 860003.S