The mitochondrial stress response and its impact on prohibitin-mediated aging phenotypes

Programa de Doctorado en Biotecnología y Tecnología QuímicaLínea de Investigación: Modelos Animales en Biotecnología y BiomedicinaClave Programa: DBICódigo Línea: 22Aging is a natural progression that affects all living organisms from birth, through maturity, to old age. It is characterized by a decline of the physiological integrity and it is accompanied by a higher incidence of age-related diseases, which represent nowadays the most common reason of death. Understanding the aging process has always been of interest. Initially it was thought to be the result of stochastic degradation but, nowadays, it is widely acknowledged that aging is controlled, at least in part, by genetic pathways and biochemical mechanisms. In this work, we focus in mitochondrial dysfunction as one of the most important processes regulating aging. Proper mitochondrial activity is preserved through regulation of mitochondrial dynamics and mitophagy and through proper maintenance of mitochondrial homeostasis. Under proteotoxic conditions the mitochondrial unfolded protein response, UPRmt, is activated to maintain mitochondrial proteostasis by inducing the expression of mitochondrial chaperones and proteases that control protein folding, assembly and degradation. The mitochondrial prohibitin, PHB, complex is a ring-like structure sitting in the inner mitochondrial membrane. It is composed of two subunits, PHB-1 and PHB-2, that are highly evolutionary conserved. PHBs have been related with many different functions: maintenance of nucleoids organization and stability, protection of newly synthesized mitochondrial proteins, assistance in folding and formation of the respiration super-complexes or acting as scaffold protein. Lack of PHB results in embryonic lethality in Caenorhabditis elegans, while homozygous PHB deletion mutants develop into sterile adults due to maternal contribution. In addition, deletion of PHB induces a very strong mitochondrial stress response. In this work, we show that the induction of UPRmt upon PHB deletion does not require the canonical components of the stress response, suggesting an alternative signalling mechanism. We present a sorting strategy capable of selecting homozygous mutants carrying the UPRmt-GFP stress reporter from GFP-balanced animals at the second larval stage. Because sorting is not completely error-free, we developed an automated high-throughput image analysis protocol that identifies and discards animals carrying the chromosome balancer. This method allows the study of balanced lethal mutations in a high-throughput manner. It can be easily adapted depending on the user¿s requirements and should serve as a useful resource for the C. elegans community for probing new biological aspects of essential nematode genes as well as the generation of more comprehensive genetic networks. In a chromosome-wide RNAi screen for C. elegans genes having human orthologues, we uncovered both known and new PHB genetic interactors affecting the UPRmt and growth. Interestingly, depletion of PHB shows an opposite effect on aging: it shortens lifespan in wild-type worms while it dramatically extends the longevity of the already long-lived insulin/IGF-1 signaling (IIS) pathway mutants. Moreover, the strong mitochondrial stress response elicited upon PHB depletion is remarkably reduced in IIS mutants. We aim at identifying new pathways involved in the regulation of the PHB-mediated mitochondrial stress response, as well as mechanisms responsible for the opposite longevity outcomes of PHB depletion. Towards this aim, we carried out genome-wide RNAi screens in PHB-depleted wild type animals and PHB-depleted IIS mutants. By performing GO term enrichment analysis, we identify inhibition of protein degradation, disruption of mitochondrial integrity and impairment of ATP synthesis as processes increasing the mitochondrial stress response. Moreover, we report a boost in the mitochondrial stress response as a mechanism to cope with the inhibition of other stress responses, such as nutrient sensing or defense response. Besides, inhibition of processes that are very energy consuming, such as protein biogenesis or ATP hydrolysis, reduced the mitochondrial stress response. In particular, we describe two new regulators of the mitochondrial stress response, two transcription factors, C16A3.4 and TLF-1. Furthermore, a new role for chromatin organization emerge in the regulation of the UPRmt and lifespan in an insulin dependent manner. We identify USP-48, a deubiquitinase, as an important factor for the enhanced lifespan of daf-2 mutants. Additionally, we establish a histone H2A, HIS-65, as a modulator of the mitochondrial stress response and aging in PHB-depleted daf-2 mutants. In this work thus, we pinpoint new players involved in the regulation of the mitochondrial stress response. These results will unveil the molecular pathways regulating mitochondrial quality control mechanisms and shed some light on the processes contributing to the differential effect in aging of PHB depletion in wild type and metabolically compromised animals.Universidad Pablo de Olavide de Sevilla. Departamento de Biología Molecular e Ingeniería BioquímicaPostprin

La Tecnología Blockchain en los videojuegos

La tecnología blockchain es un criterio que expone una gigantesca revolución no solo en la industria de los videojuegos sino en otros entornos. Este trabajo se realizó por medio de una investigación descriptiva de cualquier cosa de costo podría ser rastreada y comercializada en una red de blockchain, disminuyendo el peligro y los precios para todos los relacionados, puede compararse con información descriptiva, incorruptible y específica, que corrobora el historial de cierto tipo de información de interés, llevando esta tecnología por el lado de la industria de los videojuegos afortunadamente, blockchain provee resoluciones a las inquietudes de la industria mundial juegos completos tienen la posibilidad de ser propagados por una cadena de bloques. La ejecución adecuada de la blockchain en los juegos en línea indica que los jugadores podrían interactuar unos con otros y los juegos se desarrollaran de una forma en la que jamás nuevos géneros de juegos destacando los recursos de gameplay que son únicos de esta. &nbsp

High arrhythmic risk in antero-septal acute myocardial ischemia is explained by increased transmural reentry occurrence

Acute myocardial ischemia is a precursor of sudden arrhythmic death. Variability in its manifestation hampers understanding of arrhythmia mechanisms and challenges risk stratification. Our aim is to unravel the mechanisms underlying how size, transmural extent and location of ischemia determine arrhythmia vulnerability and ecG alterations. High performance computing simulations using a human torso/biventricular biophysically-detailed model were conducted to quantify the impact of varying ischemic region properties, including location (LAD/LcX occlusion), transmural/subendocardial ischemia, size, and normal/slow myocardial propagation. ecG biomarkers and vulnerability window for reentry were computed in over 400 simulations for 18 cases evaluated. Two distinct mechanisms explained larger vulnerability to reentry in transmural versus subendocardial ischemia. Macro-reentry around the ischemic region was the primary mechanism increasing arrhythmic risk in transmural versus subendocardial ischemia, for both LAD and LcX occlusion. transmural micro-reentry at the ischemic border zone explained arrhythmic vulnerability in subendocardial ischemia, especially in LAD occlusion, as reentries were favoured by the ischemic region intersecting the septo-apical region. St elevation reflected ischemic extent in transmural ischemia for LCX and LAD occlusion but not in subendocardial ischemia (associated with mild St depression). the technology and results presented can inform safety and efficacy evaluation of anti-arrhythmic therapy in acute myocardial ischemia

MRI-Based Computational Torso/Biventricular Multiscale Models to Investigate the Impact of Anatomical Variability on the ECG QRS Complex

Aims:Patient-to-patient anatomical differences are an important source of variability in the electrocardiogram, and they may compromise the identification of pathological electrophysiological abnormalities. This study aims at quantifying the contribution of variability in ventricular and torso anatomies to differences in QRS complexes of the 12-lead ECG using computer simulations. Methods:A computational pipeline is presented that enables computer simulations using human torso/biventricular anatomically based electrophysiological models from clinically standard magnetic resonance imaging (MRI). The ventricular model includes membrane kinetics represented by the biophysically detailed O’Hara Rudy model modified for tissue heterogeneity and includes fiber orientation based on the Streeter rule. A population of 265 torso/biventricular models was generated by combining ventricular and torso anatomies obtained from clinically standard MRIs, augmented with a statistical shape model of the body. 12-lead ECGs were simulated on the 265 human torso/biventricular electrophysiology models, and QRS morphology,duration and amplitude were quantified in each ECG lead for each of the human torso-biventricular models. Results:QRS morphologies in limb leads are mainly determined by ventricular anatomy,while in the precordial leads, and especially V1 to V4, they are determined by heart position within the torso. Differences in ventricular orientation within the torso can explain morphological variability from monophasic to biphasic QRS complexes. QRS duration ismainly influenced by myocardial volume, while it is hardly affected by the torso anatomyor position. An average increase of 0.12±0.05 ms in QRS duration is obtained for eachcm3of myocardial volume across all the leads while it hardly changed due to changes in torso volume. Conclusion:Computer simulations using populations of human torso/biventricular models based on clinical MRI enable quantification of anatomical causes of variability in the QRS complex of the 12-lead ECG. The human models presented also pave theway toward their use as testbeds in silico clinical trial

Prácticas responsables de gestión humana y su relación con la retención del personal de seguridad de la empresa Grupo Zeus Service S.A.C en el distrito de Trujillo en el I semestre 2018

El presente estudio se ha realizado para determinar de qué manera las prácticas responsables de gestión humana se relacionan con la retención del personal de seguridad de la empresa Grupo Zeus Service S.A.C. Trujillo 2018. El enunciado del problema fue ¿De qué manera las prácticas responsables de gestión humana se relacionan con la retención del personal de seguridad de la empresa Grupo Zeus Service S.A.C en el distrito de Trujillo en el I semestre 2018? y cuya hipótesis fue: Las prácticas responsables de gestión humana se relacionan de manera significativa con la retención de personal de seguridad de la empresa Grupo Zeus Service S.A.C en el distrito de Trujillo en el I semestre 2018. Asimismo, tiene un diseño descriptivo transversal correlacional; para ello se utilizó la técnica de la encuesta y como instrumento al cuestionario para poder obtener la información pertinente. Por otro lado, se consideró como población a los trabajadores de seguridad de la empresa Grupo Zeus Service S.A.C, la cual, estuvo conformada por un total de 53 trabajadores de seguridad, y, debido a que, por ser un monto menor a 100 trabajadores, no se utilizó la fórmula de poblaciones finitas ya que se trabajó con el total de la población para obtener un mejor resultado; por lo que, cada uno de ellos fue encuestado para poder obtener una información más clara. Se concluye que las buenas prácticas de gestión humana se relacionan de manera significativa con la retención del personal de seguridad de la empresa Grupo Zeus Service SAC dando por confirmada la H1, mediante la chi cuadrada.The present study has been carried out to determine how responsible practices of human management are related to the retention of security personnel of the company Grupo Zeus Service S.A.C. Trujillo 2018. The statement of the problem was: How are the responsible practices of human management related to the retention of security personnel of the company Grupo Zeus Service S.A.C in the district of Trujillo in the first half of 2018? and whose hypothesis was: The practices responsible for human management are significantly related to the retention of security personnel of the company Grupo Zeus Service S.A.C in the district of Trujillo in the first half of 2018. It also has a cross-sectional descriptive design; To do this, the survey technique was used and the questionnaire was used to obtain the pertinent information. On the other hand, it was considered as a population to the security workers of the company Zeus Service SAC, which consisted of a total of 53 security workers, and, because it is less than 100 workers, the formula for finite populations was not used since the total population was used to obtain a better result; therefore, each one of them was surveyed in order to obtain a clearer information. It is concluded that: Good human management practices are significantly related to the retention of security personnel of the Zeus Service SAC company, confirming the H1, using the square chi.Tesi

Gestión curricular y gestión de aprendizaje en docentes de dos instituciones educativas públicas, San Juan de Lurigancho. Lima, 2023

El presente trabajo de investigación estudió la gestión curricular y gestión de aprendizaje, como objetivo se planteó determinar la influencia de la gestión curricular en la gestión de aprendizaje en docentes. La metodología del presente trabajo tiene como tipo de investigación aplicada, nivel explicativo, enfoque cuantitativo, método hipotético-deductivo y diseño no- experimental. La población estuvo conformada por 67 docentes de dos instituciones educativas públicas y la muestra conformada por 67 docentes que representan la totalidad de la población, por lo que se realizó un censo. La técnica de recopilación de datos para las dos variables fue la encuesta y el cuestionario se utilizó como instrumento, lo que fue validado por expertos y su confiabilidad fue dada por el coeficiente de Alfa de Cronbach. Los resultados obtenidos luego de realizar la prueba de regresión logística ordinal arrojaron un p-valor= 0,000 menor a 0,05, probando que la gestión curricular es explicada por la gestión de aprendizaje, obteniendo un Pseudo R2 de Cox y Snell de 99,5 % y de Nagelkerke de 99,8 %, concluyendo que la gestión curricular influye significativamente en la gestión de aprendizaje en docentes de dos instituciones educativas públicas de San Juan de Lurigancho, 2023