Linking Induction and Transrepression of PPARβ/δ with Cellular Function

The copyrights of all papers published in this journal are retained by the respective authors as per the 'Creative Commons Attribution License' (http://creativecommons.org/licenses/by/3.0/).Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors and members of the nuclear hormone receptor superfamily. PPARβ/δ is ubiquitously expressed and has a central role in homeostasis, and has been suggested as a therapeutic target for a number of metabolic and cardiovascular disorders. This important nuclear receptor controls transcription under different modes of molecular activity which directly control the cellular function and fate of tissues. This complex activity of induction and transrepression of gene expression (with and without exogenous ligands) is poorly understood and yet understanding this molecular control through novel drug development would led to control over a key molecular switch in all cells. This review outlines the main molecular mechanisms of PPARβ/δ, and links the modes of activity to the signalling pathways in inflammation, proliferation and senescence, with the goal to understand how this will translate into novel drug design to control the PPARβ/δ molecular switch.Peer reviewe

The Effects of PPARβ/δ Ligands on Lung Inflammation and Vascular Reactivity

The peroxisome proliferator activated receptor beta/delta (PPARβ/δ) is a transcription factor ubiquitously expressed in cells, although more highly active in skeletal muscle, arteries and endothelium. Signalling via PPARβ/δ is involved in lipid metabolism, glucose metabolism, insulin sensitivity, inflammation, and cell proliferation and therefore it is emerging as a therapeutic target for the treatment of disorders associated with metabolic syndrome or diabetes. However, there are great discrepancies in the literature about the role of PPARβ/δ and scientists describe both anti- and pro-effects on inflammation, cell migration and cell proliferation after ligand-activation of PPARβ/δ. Understanding the PPARβ/δ mode of action is of great interest and may provide new molecular mechanisms for treating a variety of inflammation-related diseases. This thesis aims to expand the knowledge on PPARβ/δ to better understand its mechanism of action at genomic and non-genomic level, which might give some clues for new therapeutic drug developments targeting PPARβ/δ. Methods: Pharmacological techniques including organ bath and myography were used for the study of the non-genomic effects of PPARβ/δ on vascular tone, comparing aorta and mesenteric arteries as a model of systemic and resistance vasculature respectively from healthy and streptozotocin (STZ)-induced diabetic rats. Molecular biology techniques including Griess assay, ELISA and qRT-PCR were used for the study of the regulation of lung inflammation by PPARβ/δ, focusing on the PPARβ/δ molecular switch between induction and trans-repression, two different pathways of gene regulation. Computational methods such as docking were used for the study of the PPARβ/δ binding pocket and how PPARβ/δ is activated/repressed after ligand binding as well as the possibility of accommodating more than one ligand simultaneously into the binding pocket. Results: In large STZ-diabetic systemic aorta arteries, PPARβ/δ inhibits the contraction through the PI3K/Akt/eNOS pathway. GW0742, a PPARβ/δ agonist, improves vasodilation through the RhoA/ROCK pathway in Naïve aorta and through potassium channels in STZ-diabetic aorta. In resistance arteries such as mesenteric arteries, PPARβ/δ inhibits the contraction through the PI3K/Akt/eNOS pathway in Naïve and possibly STZ-diabetic tissues. In contrast, GW0742 inhibits the RhoA/ROCK pathway on STZ-diabetic mesentery arteries and regulates the potassium channels in Naïve mesenteric arteries in a PPARβ/δ independent manner. In the model of lung inflammation used, the presence of agonist (GW0742 or L-165041) and antagonist (GSK3787 or GSK0660) at same time has anti-inflammatory effects and switches the PPARβ/δ mode of action from induction to trans-repression, therefore it was concluded that, at least in this model, the PPARβ/δ induction mode of action is pro-inflammatory and the trans-repression anti-inflammatory. PPARβ/δ agonists and antagonists bind differently to the PPARβ/δ receptor pocket. PPARβ/δ agonists form polar interactions with the residues His287, His413 and Tyr437 whilst PPARβ/δ antagonists form polar interactions with the residues Thr252 and Asn307. Further, our modelling indicates favourable binding energies and the feasibility of two ligands binding at same time into the PPARβ/δ binding pocket. Conclusion: A multidisciplinary approach was designed for the study of PPARβ/δ and provided novel information about its functioning both at genomic and non-genomic level. The findings of this thesis can help the drug discovery industry for a better prediction of the modelling behaviour of new PPARβ/δ drugs and can support the rationale for developing new treatments targeting PPARβ/δ for hypertension and/or cardiovascular complications

Neoliberal Dystopias: Postmodern Aesthetics and a Modern Ethic in Four Pairs of Plays by Argentine and Irish Playwrights (1990-2003)

This project is an exploration of eight plays, four from Argentina, four from Ireland, comprehending the period between 1990 and 2003. Both countries share a strong tradition of national theatre that, from its beginnings, was closely intertwined with the development of the nation state. Theatre functions in Argentina and Ireland as a medium through which representations of what it means to be Irish or Argentine have been explored, questioned, and contested. It is the aim of this project to examine how the apparently non-political and ahistorical theater of the playwrights I will examine is indeed a response to a contextualized sense of political, social, and economic uncertainty, fueled by globalization. The postmodern aesthetics of the plays go beyond the playful to question how community, identity, and meaning are articulated in a world where national frameworks are being replaced by transnational movements (both economic and cultural). The impact of neoliberal economic policies implemented on Argentina and Ireland in the 90s and the severe displacement and rise of inequality of large sections of the population in both countries is contested, critiqued, and examined in all the plays of my study. In both the Argentine and Irish cases, lingering repressive practices responsible for human rights violations coexisted with an economic neoliberal agenda that generated its own particular set of discriminations, abuses, and diminish citizenships. This project analyzes how the chosen plays establish links between present and former instances of repression, violence, and abuse--underscoring for audiences unaddressed haunting human rights concerns in late twentieth-century Argentina and Ireland

Determination of priority conservation areas in the Puna and Prepuna of northern Argentina

Actualmente existe una gran preocupación debido a la pérdida de la biodiversidad como resultado de la destrucción y modificación de los hábitats naturales causada por las actividades del hombre. Una de las soluciones más comunes a este problema es el establecimiento de redes de áreas protegidas, con el objetivo de conservar la mayor cantidad y diversidad de hábitats posibles. El objetivo de este trabajo fue realizar una determinación de áreas de endemismo y riqueza específica para 16 especies de peces, 11 especies de anfibios, 24 especies de reptiles y 46 especies de plantas en la región de Puna y Prepuna del Noroeste Argentino. Se identificaron áreas de endemismo utilizando el criterio de endemicidad implementado en el programa NDM, y para la estimación de riqueza se utilizó el programa DIVA-GIS. Las áreas identificadas mediante los dos análisis son congruentes entre sí, resultando en 5 áreas, donde 4 de ellas coinciden con áreas que ya poseen políticas de conservación, mientras que 1 no coincide con ninguna reserva, por lo que a futuro podría ser considerada en nuevos planes de conservación. Este enfoque constituye un aporte novedoso para abordar una planificación sistemática de Áreas Prioritarias que junto a otros aportes filogenéticos, geográficos, ecológicos conformen una herramienta eficaz y útil, para los organismos encargados de la toma de decisiones en políticas de conservación.There exists a great concern about the loss of biodiversity as a result of destruction and modification of natural habitats caused by human activities. One of the most common solutions to this problem is to establish protected area networks to conserve as many habitats as possible. The objective of this work was to determine areas of endemism and specific richness for 16 species of fish, 11 of amphibians, 24 of reptiles, and 46 species of plants in the Puna and Prepuna region of Northwestern Argentina. Areas of endemism were identified using the endemicity criterion implemented in the software NDM, and DIVA-GIS was used for richness estimation. Five congruent areas were identified by the two analyses, four of them coincide with areas that already have conservation policies, while one does not coincide with any protected area. In the future this area could be considered in new conservation programs. This approach constitutes a novel contribution to a systematic planning of Priority Areas, which together with other contributions (ecological, geographic, and phylogenetic) constitute an effective and useful tool for decision-making agencies in conservation policies.Fil: Portelli, Sabrina Noelia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Bio y Geociencias del NOA. Universidad Nacional de Salta. Facultad de Ciencias Naturales. Museo de Ciencias Naturales. Instituto de Bio y Geociencias del NOA; ArgentinaFil: Diaz Gomez, Juan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Bio y Geociencias del NOA. Universidad Nacional de Salta. Facultad de Ciencias Naturales. Museo de Ciencias Naturales. Instituto de Bio y Geociencias del NOA; Argentin

Programa de gestión estratégica basado en el modelo de liderazgo de David Fischman para mejorar las relaciones interpersonales del personales directivo, docente y administrativo de la institución educativa N° 10158 ¨Julio C. Tello¨ del centro poblado Cruz del Medano, del distrito de Mórrope

El presente Trabajo de Investigación simplifica en su contenido un Programa de Gestión Estratégica basado en el Modelo de Liderazgo de David Fischman para mejorar las relaciones interpersonales del personal directivo, docente y administrativo de la Institución Educativa N° 10158 “Julio C. Tello” del centro poblado Cruz del Médano, distrito de Mórrope considerando que al realizar el correspondiente análisis de la problemática se constató que, en efecto existe un endeble ejercicio de las relaciones interpersonales, que limita el desarrollo de los procesos de gestión de la organización educativa. Ante el problema se ha trazado como objetivo principal, precisamente, demostrar que la aplicación de un Programa de Gestión Estratégica basado en el Modelo de Liderazgo de David Fischman mejora las relaciones interpersonales del personal directivo , docente y administrativo de la Institución Educativa N° 10158 “Julio C.Tello”, que fundamentado en la Teoría de la Motivación Humana de Maslow, Teoría del Liderazgo Personal e Interpersonal de David Fischman, Teoría de las Relaciones Humanas de Elton Mayo y Teoría del Liderazgo Participativo y Democrático de Rensis Likert y a partir de la contrastación de la hipótesis se espera lograr un aporte teórico que contribuya a la solución de la problemática existente, no sólo en la Institución Educativa N° 10158 “Julio C. Tello", sino también en las demás instituciones del país

Reforma procesal o cambio de código: Una mirada fiscal desde el distrito de Lima Este

La autora analiza los aspectos que deben comprenderse para la reforma procesal penal y los contrasta con el proceso de implementación que se viene realizando en el distrito judicial de Lima Este. Además, expone la poca importancia que se le ha brindado al rol que cumple el Ministerio Público en el proceso de reforma. Finalmente, señala las dificultades que deben afrontar los fiscales en la aplicación del nuevo modelo procesal penal, como el consiguiente riesgo del fracaso de la pretendida reforma.DOIhttps://doi.org/10.24265/voxjuris.2020.v38n1.0

Predicción empresarial II

En el presente trabajo se estudió temas relacionados con la predicción empresarial, para poder afrontar con eficiencia las incertidumbres que se pueden presentar en la vida de una empresa. En el primer punto tenemos a la programación lineal, es una técnica matemática que consiste en una serie de métodos y procedimientos que permiten resolver problemas de optimización lo que ha permitido a empresas y organizaciones importantes beneficios. En el siguiente capítulo podemos observar al PERT y CPM; en el primero permite dirigir la programación de un proyecto. Consiste en la representación gráfica de una red de tareas, que, cuando se colocan en una cadena, permiten alcanzar los objetivos de un proyecto. CPM Una herramienta que permite estimar el tiempo más corto en el que es posible completar un proyecto. Existe una teoría que explica el conjunto matemático y describe un sistema de líneas de esperas, a este se le denomina “Teoría de Colas” y el objetivo de este es encontrar un estado estable del sistema y determinar una capacidad de servicio apropiada. La teoría de la formación de colas busca una solución al problema de la espera prediciendo primero el comportamiento del sistema. Dentro de un modelo de colas existen elementos como la fuente de entrada o población potencial, el cliente, la capacidad de la cola y la disciplina de la cola. Para finalizar hablamos sobre el software para resolver problemas de predicción empresarial, este software informática (Wingsb) es muy utilizado para construir modelos matemáticos que permite tomar decisiones específicamente en el área de administración y economía.Trabajo de suficiencia profesiona

Co-Incubation with PPARβ/δ Agonists and Antagonists Modeled Using Computational Chemistry: Effect on LPS Induced Inflammatory Markers in Pulmonary Artery

© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)Peroxisome proliferator activated receptor beta/delta (PPARβ/δ) is a nuclear receptor ubiquitously expressed in cells, whose signaling controls inflammation. There are large discrepan-cies in understanding the complex role of PPARβ/δ in disease, having both anti‐ and pro‐effects on inflammation. After ligand activation, PPARβ/δ regulates genes by two different mechanisms; induction and transrepression, the effects of which are difficult to differentiate directly. We studied the PPARβ/δ‐regulation of lipopolysaccharide (LPS) induced inflammation (indicated by release of nitrite and IL‐6) of rat pulmonary artery, using different combinations of agonists (GW0742 or L−165402) and antagonists (GSK3787 or GSK0660). LPS induced release of NO and IL‐6 is not significantly reduced by incubation with PPARβ/δ ligands (either agonist or antagonist), however, co-incubation with an agonist and antagonist significantly reduces LPS‐induced nitrite production and Nos2 mRNA expression. In contrast, incubation with LPS and PPARβ/δ agonists leads to a significant increase in Pdk−4 and Angptl−4 mRNA expression, which is significantly decreased in the presence of PPARβ/δ antagonists. Docking using computational chemistry methods indicates that PPARβ/δ agonists form polar bonds with His287, His413 and Tyr437, while antagonists are more promiscuous about which amino acids they bind to, although they are very prone to bind Thr252 and Asn307. Dual binding in the PPARβ/δ binding pocket indicates the ligands retain similar binding energies, which suggests that co‐incubation with both agonist and antagonist does not prevent the specific binding of each other to the large PPARβ/δ binding pocket. To our knowledge, this is the first time that the possibility of binding two ligands simultaneously into the PPARβ/δ binding pocket has been explored. Agonist binding followed by antagonist simultaneously switches the PPARβ/δ mode of action from induction to transrepression, which is linked with an increase in Nos2 mRNA expression and nitrite production.Peer reviewedFinal Published versio