Nogo-B Receptor Stabilizes Niemann-Pick Type C2 Protein and Regulates Intracellular Cholesterol Trafficking

SummaryThe Nogo-B receptor (NgBR) is a recently identified receptor for the N terminus of reticulon 4B/Nogo-B. Other than its role in binding Nogo-B, little is known about the biology of NgBR. To elucidate a basic cellular role for NgBR, we performed a yeast two-hybrid screen for interacting proteins, using the C-terminal domain as bait, and identified Niemann-Pick type C2 protein (NPC2) as an NgBR-interacting protein. NPC2 protein levels are increased in the presence of NgBR, and NgBR enhances NPC2 protein stability. NgBR localizes primarily to the endoplasmic reticulum (ER) and regulates the stability of nascent NPC2. RNAi-mediated disruption of NgBR or genetic deficiency in NgBR lead to a decrease in NPC2 levels, increased intracellular cholesterol accumulation, and a loss of sterol sensing, all hallmarks of an NPC2 mutation. These data identify NgBR as an NPC2-interacting protein and provide evidence of a role for NgBR in intracellular cholesterol trafficking

La imagen y la narrativa como herramientas para el abordaje psicosocial en escenarios de violencia. Departamentos de La Guajira y Atlántico

En el presente trabajo, se muestra la observación que se tuvo desde una mirada psicológica el cual, se encaminaron en los escenarios de violencia que vive Colombia actualmente, dónde se comprendió los contextos sociales, políticos y culturales, también se realizó un análisis de la dimensión psicosocial para buscar estrategias como medio de solución para que la víctima pueda enfrentar los eventos que le han generado trauma y así contribuir a un mejoramiento en la calidad de vida, donde la persona pueda construir un proyecto de vida y una vida exitosa. Las herramientas que el diplomado brindó permitió el poder ver los diferentes escenarios de violencia que muchos pobladores en el país viven como se puede ver en el desplazamiento forzoso explicando de una mejor manera las vivencias que ha tenido que llevar junto con la familia, dejando a un lado las actividades que realizaban a nivel social, cultural y económicas. En los relatos se puede ver que, en Colombia muchos grupos poblacionales han sido afectados por conflictos de larga duración, que han acarreado consecuencias negativas a nivel psicosocial como producto de los eventos traumáticos. Esta situación ha repercutido de manera adversa en la población general a un sentir de intimidación, puesto que, estos hechos han dejado a su paso impactos negativos que han afectado la integridad de quienes sufren estos flagelos.In the present work, the observation that was made from a psychological perspective is shown, which was directed towards the scenes of violence that Colombia is currently experiencing, where the social, political and cultural contexts were understood, an analysis of the dimension was also carried out. psychosocial to seek strategies as a means of solution so that the victim can face the events that have generated trauma and thus contribute to an improvement in the quality of life, where the person can build a life project and a successful life. The tools that the graduate provided allowed us to see the different scenarios of violence that many residents of the country experience, as can be seen in forced displacement, explaining in a better way the experiences that they have had to carry with their families, leaving a besides the activities they carried out at a social, cultural and economic level. In the reports it can be seen that, in Colombia, many population groups have been affected by long-term conflicts, which have had negative consequences at the psychosocial level as a result of traumatic events. This situation has adversely affected the general population to a feeling of intimidation, since these events have left behind negative impacts that have affected the integrity of those who suffer these scourges

miR-27b Modulates Insulin Signaling in Hepatocytes by Regulating Insulin Receptor Expression

Insulin resistance (IR) is one of the key contributing factors in the development of type 2 diabetes mellitus (T2DM). However, the molecular mechanisms leading to IR are still unclear. The implication of microRNAs (miRNAs) in the pathophysiology of multiple cardiometabolic pathologies, including obesity, atherosclerotic heart failure and IR, has emerged as a major focus of interest in recent years. Indeed, upregulation of several miRNAs has been associated with obesity and IR. Among them, miR-27b is overexpressed in the liver in patients with obesity, but its role in IR has not yet been thoroughly explored. In this study, we investigated the role of miR-27b in regulating insulin signaling in hepatocytes, both in vitro and in vivo. Therefore, assessment of the impact of miR-27b on insulin resistance through the hepatic tissue is of special importance due to the high expression of miR-27b in the liver together with its known role in regulating lipid metabolism. Notably, we found that miR-27b controls post-transcriptional expression of numerous components of the insulin signaling pathway including the insulin receptor (INSR) and insulin receptor substrate 1 (IRS1) in human hepatoma cells. These results were further confirmed in vivo showing that overexpression and inhibition of hepatic miR-27 enhances and suppresses hepatic INSR expression and insulin sensitivity, respectively. This study identified a novel role for miR-27 in regulating insulin signaling, and this finding suggests that elevated miR-27 levels may contribute to early development of hepatic insulin resistance.This work was supported by the Basque Government (Grupos Consolidados IT-1264-19). A.B.-V. was supported by Programa de especialización de Personal Investigador Doctor en la UPV/EHU (2019) 2019-2020. U.G-G. was supported by Fundación Biofísica Bizkaia. S.J. was supported by a grant PIF (2017–2018), Gobierno Vasco. We sincerely thank Haziq Siddiqi (Harvard Medical School) for his critical reading and editing of this manuscript

Suppressing miR-21 activity in tumor-associated macrophages promotes an antitumor immune response

microRNA-21 (miR-21) is the most commonly upregulated miRNA in solid tumors. This cancer-associated microRNA (oncomiR) regulates various downstream effectors associated with tumor pathogenesis during all stages of carcinogenesis. In this study, we analyzed the function of miR-21 in noncancer cells of the tumor microenvironment to further evaluate its contribution to tumor progression. We report that the expression of miR-21 in cells of the tumor immune infiltrate, and in particular in macrophages, was responsible for promoting tumor growth. Absence of miR-21 expression in tumor- associated macrophages (TAMs), caused a global rewiring of their transcriptional regulatory network that was skewed toward a proinflammatory angiostatic phenotype. This promoted an antitumoral immune response characterized by a macrophage-mediated improvement of cytotoxic T-cell responses through the induction of cytokines and chemokines, including IL-12 and C-X-C motif chemokine 10. These effects translated to a reduction in tumor neovascularization and an induction of tumor cell death that led to decreased tumor growth. Additionally, using the carrier peptide pH (low) insertion peptide, we were able to target miR-21 in TAMs, which decreased tumor growth even under conditions where miR-21 expression was deficient in cancer cells. Consequently, miR-21 inhibition in TAMs induced an angiostatic and immunostimulatory activation with potential therapeutic implications

Inhibition of profibrotic microRNA-21 affects platelets and their releasate.

Fibrosis is a major contributor to organ disease for which no specific therapy is available. MicroRNA-21 (miR-21) has been implicated in the fibrogenetic response, and inhibitors of miR-21 are currently undergoing clinical trials. Here, we explore how miR-21 inhibition may attenuate fibrosis using a proteomics approach. Transfection of miR-21 mimic or inhibitor in murine cardiac fibroblasts revealed limited effects on extracellular matrix (ECM) protein secretion. Similarly, miR-21-null mouse hearts showed an unaltered ECM composition. Thus, we searched for additional explanations as to how miR-21 might regulate fibrosis. In plasma samples from the community-based Bruneck Study, we found a marked correlation of miR-21 levels with several platelet-derived profibrotic factors, including TGF-β1. Pharmacological miR-21 inhibition with an antagomiR reduced the platelet release of TGF-β1 in mice. Mechanistically, Wiskott-Aldrich syndrome protein, a negative regulator of platelet TGF-β1 secretion, was identified as a direct target of miR-21. miR-21-null mice had lower platelet and leukocyte counts compared with littermate controls but higher megakaryocyte numbers in the bone marrow. Thus, to our knowledge this study reports a previously unrecognized effect of miR-21 inhibition on platelets. The effect of antagomiR-21 treatment on platelet TGF-β1 release, in particular, may contribute to the antifibrotic effects of miR-21 inhibitors

Efectos de la inhibición de la síntesis de colesterol sobre la actividad del receptor LDL y la proliferación celular 'in vitro'

Tesis doctoral inédita leida en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 28-05-200

Diseño del micropavimento para el mantenimiento del pavimento flexible de la Avenida Guillermo Billinghurst en San Juan de Miraflores – 2020

El presente trabajo de investigación tuvo como objetivo general determinar la influencia del micropavimento en el mantenimiento de la carpeta asfáltica, buscando comprobar que esta tiene un efecto positivo que mejora las características y prolonga el tiempo de vida del pavimento. Esta es una investigación aplicada porque se utiliza manuales ya existentes y es de tipo experimental porque evaluaremos la influencia de la variable independiente (micropavimento) en la dependiente (mantenimiento de la carpeta asfáltica). Para los resultados se trabajó con 4 muestras con diferentes porcentajes de emulsión asfáltica, estos porcentajes fueron 6.9%, 8.1%, 9.4% y 10.6% de asfalto en la mezcla, obteniendo resultados de desgaste por abrasión de 348.7 g/m2 , 220.4 g/m2 , 141.5 g/m2 y 108.6 g/m2 respectivamente, y una absorción de arena de 311.1 g/m2 , 394.1 g/m2 , 467.3g/m2 y 526.2 g/m2 respectivamente, obteniendo así una cantidad optima de asfalto de 8.1% de la mezcla. Como conclusión tenemos que el micropavimento influye de manera favorable en el mantenimiento de la carpeta asfáltica, pero se debe recalcar que para lograr ese optimo resultado es importante que este sea aplicado al inicio de la aparición de las fallas en el pavimento, así mismo, es fundamental el cumplimiento de las normas establecidas tanto en la selección de los materiales, diseño, y ejecución

LA ECOLOGIA B-LEARNING: ESCENARIO PARA EL APRENDIZAJE DE LA ASIGNATURA FISICA II EN LA FACULTAD DE INGENIERÍA DE LA UNIVERSIDAD DE CARABOBO

La investigación consistió en el  desarrollo de un entorno ecológico bajo B-learning 2.0 para el aprendizaje de la Física  II en la Facultad de Ingeniería de la Universidad de Carabobo. Se fundamenta en las teorías de: aprendizaje colaborativo de Lev Vygotsky, inteligencias múltiples de Howard Gardner, Conectivismo de George Siemens y el B-learning 2.0; enmarcada en el paradigma cuantitativo en tipo proyecto factible, apoyado en un diagnóstico de campo bajo diseño no experimental estructurado en tres fases: diseño de contenidos, arquitectura del entorno e implementación. La  población en estudio estuvo formada por setecientos noventa y cinco (795) estudiantes que cursaron la asignatura Física II en el primer semestre lectivo del año 2012, la muestra se constituyó con ciento setenta y cinco (175) estudiantes a quienes se aplicó un cuestionario. La validez del instrumento se determinó desde el contenido y para la confiabilidad se utilizó el coeficiente de correlación de Pearson obteniendo un valor de 0.991. El resultado obtenido al aplicar el modelo demostró la influencia positiva en el aumento del dominio cognoscitivo del estudiante de Física II

miR‐33 in cardiometabolic diseases: lessons learned from novel animal models and approaches

Abstract miRNAs have emerged as critical regulators of nearly all biologic processes and important therapeutic targets for numerous diseases. However, despite the tremendous progress that has been made in this field, many misconceptions remain among much of the broader scientific community about the manner in which miRNAs function. In this review, we focus on miR‐33, one of the most extensively studied miRNAs, as an example, to highlight many of the advances that have been made in the miRNA field and the hurdles that must be cleared to promote the development of miRNA‐based therapies. We discuss how the generation of novel animal models and newly developed experimental techniques helped to elucidate the specialized roles of miR‐33 within different tissues and begin to define the specific mechanisms by which miR‐33 contributes to cardiometabolic diseases including obesity and atherosclerosis. This review will summarize what is known about miR‐33 and highlight common obstacles in the miRNA field and then describe recent advances and approaches that have allowed researchers to provide a more complete picture of the specific functions of this miRNA

Control of cholesterol metabolism and plasma high-density lipoprotein levels by microRNA-144

PMCID: PMC3929583.-- et al.[Rationale]: Foam cell formation because of excessive accumulation of cholesterol by macrophages is a pathological hallmark of atherosclerosis, the major cause of morbidity and mortality in Western societies. Liver X nuclear receptors (LXRs) regulate the expression of the adenosine triphosphate-binding cassette (ABC) transporters, including adenosine triphosphate-binding cassette transporter A1 (ABCA1) and adenosine triphosphate-binding cassette transporter G1 (ABCG1). ABCA1 and ABCG1 facilitate the efflux of cholesterol from macrophages and regulate high-density lipoprotein (HDL) biogenesis. Increasing evidence supports the role of microRNA (miRNAs) in regulating cholesterol metabolism through ABC transporters. [Objective]: We aimed to identify novel miRNAs that regulate cholesterol metabolism in macrophages stimulated with LXR agonists. [Methods and Results]: To map the miRNA expression signature of macrophages stimulated with LXR agonists, we performed an miRNA profiling microarray analysis in primary mouse peritoneal macrophages stimulated with LXR ligands. We report that LXR ligands increase miR-144 expression in macrophages and mouse livers. Overexpression of miR-144 reduces ABCA1 expression and attenuates cholesterol efflux to apolipoproteinA1 in macrophages. Delivery of miR-144 oligonucleotides to mice attenuates ABCA1 expression in the liver, reducing HDL levels. Conversely, silencing of miR-144 in mice increases the expression of ABCA1 and plasma HDL levels. Thus, miR-144 seems to regulate both macrophage cholesterol efflux and HDL biogenesis in the liver. [Conclusions]: miR-144 regulates cholesterol metabolism via suppressing ABCA1 expression and modulation of miRNAs may represent a potential therapeutical intervention for treating dyslipidemia and atherosclerotic vascular disease. © 2013 American Heart Association, Inc.This work was supported by grants from the National Institutes of Health (R01HL107953 and R01HL106063 to C. Fernández-Hernando, R01HL105945 to Y. Suárez, and P30NS069329 to J. Kim) and the Spanish Ministry of I+D (grant SAF2008-00057 and SAF2011-29244 to A. Castrillo). C.M. Ramírez was supported by a postdoctoral fellowship from the American Heart Association (12POST9780016), D. Cirera-Salinas was supported by the Deutsche Forschunqsqemeinschaft, and A. Wanschel was supported by Capes Foundation, Ministry of Education of Brazil, Brazil. N. Rotllan was supported by a postdoctoral fellowship from Spanish Ministry of I+D. E. Araldi is a Howard Hughes Institute International Student Research Fellow.Peer Reviewe