Vascular smooth muscle cell NAD(P)H oxidase activity during the development of hypertension: Effect of angiotensin II and role of insulinlike growth factor-1 receptor transactivation

We investigated whether angiotensin II (Ang II)-induced reactive oxygen species (ROS) generation is altered in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR) during the phases of prehypertension, developing hypertension, and established hypertension and assessed the putative role of insulinlike growth factor-1 receptor (IGF-1R) in Ang II-mediated actions. The VSMCs from SHR and Wistar-Kyoto rats (WKY) aged 4 (prehypertensive), 9 (developing hypertension), and 16 (established hypertension) weeks were studied. The ROS production and NAD(P)H oxidase activation were determined by fluorescence and chemiluminescence, respectively. The role of IGF-1R was assessed with the selective inhibitor AG1024. The ROS bioavailability was manipulated with Tiron (10-5 mol/L) and diphenylene iodonium (DPI) (10-6 mol/L). Angiotensin II dose dependently increased ROS production in WKY and SHR at all ages. The Ang II-induced responses were greater in SHR versus WKY at 9 and 16 weeks (P < .05). The Ang II-stimulated ROS increase was greater in 9- and 16-week-old SHR versus 4-week SHR (P < .05). These effects were reduced by AG 1024. Basal NAD(P)H oxidase activity was higher in VSMCs from 9-week-old SHR versus 4-week-old rats (P < .05). Angiotensin II induced a significant increase in oxidase activity in VSMCs from 9- and 16-week-old SHR (P < .001), without influencing responses in cells from 4-week-old SHR. Pretreatment of 9- and 16-week-old SHR cells with AG1024 reduced Ang II-mediated NAD(P)H oxidase activation (P < .05). Basal and Ang II-induced NAD(P)H-driven ROS generation are enhanced in VSMCs from SHR during development of hypertension, but not in cells from prehypertensive rats. Transactivation of IGF-1R by Ang II may be important in vascular oxidative excess in the development of hypertension in SHR.Fil: Cruzado, Montserrat Cecilia. Universidad Nacional de Cuyo; Argentina. Universidad de Mendoza; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Risler, Norma Raquel. Universidad Nacional de Cuyo; ArgentinaFil: Miatello, Roberto Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Yao, Guoying. Institut de Recherches Cliniques de Montréal; CanadáFil: Schiffrin, Ernesto L.. Institut de Recherches Cliniques de Montréal; CanadáFil: Touyz, Rhian M.. Institut de Recherches Cliniques de Montréal; Canad

Galectin-3 shapes toxic alpha-synuclein strains in Parkinson's disease.

Parkinson's Disease (PD) is a neurodegenerative and progressive disorder characterised by intracytoplasmic inclusions called Lewy bodies (LB) and degeneration of dopaminergic neurons in the substantia nigra (SN). Aggregated α-synuclein (αSYN) is known to be the main component of the LB. It has also been reported to interact with several proteins and organelles. Galectin-3 (GAL3) is known to have a detrimental function in neurodegenerative diseases. It is a galactose-binding protein without known catalytic activity and is expressed mainly by activated microglial cells in the central nervous system (CNS). GAL3 has been previously found in the outer layer of the LB in post-mortem brains. However, the role of GAL3 in PD is yet to be elucidated. In post-mortem samples, we identified an association between GAL3 and LB in all the PD subjects studied. GAL3 was linked to less αSYN in the LB outer layer and other αSYN deposits, including pale bodies. GAL3 was also associated with disrupted lysosomes. In vitro studies demonstrate that exogenous recombinant Gal3 is internalised by neuronal cell lines and primary neurons where it interacts with endogenous αSyn fibrils. In addition, aggregation experiments show that Gal3 affects spatial propagation and the stability of pre-formed αSyn fibrils resulting in short, amorphous toxic strains. To further investigate these observations in vivo, we take advantage of WT and Gal3KO mice subjected to intranigral injection of adenovirus overexpressing human αSyn as a PD model. In line with our in vitro studies, under these conditions, genetic deletion of GAL3 leads to increased intracellular αSyn accumulation within dopaminergic neurons and remarkably preserved dopaminergic integrity and motor function. Overall, our data suggest a prominent role for GAL3 in the aggregation process of αSYN and LB formation, leading to the production of short species to the detriment of larger strains which triggers neuronal degeneration in a mouse model of PD

Cellular Immunity to Predict the Risk of Cytomegalovirus Infection in Kidney Transplantation: A Prospective, Interventional, Multicenter Clinical Trial

Background: Improving cytomegalovirus (CMV) immune-risk stratification in kidney transplantation is highly needed to establish guided preventive strategies. Methods: This prospective, interventional, multicenter clinical trial assessed the value of monitoring pretransplant CMV-specific cell-mediated immunity (CMI) using an interferon-γrelease assay to predict CMV infection in kidney transplantation. One hundred sixty donor/recipient CMV-seropositive (D+/R+) patients, stratified by their baseline CMV (immediate-early protein 1)-specific CMI risk, were randomized to receive either preemptive or 3-month antiviral prophylaxis. Also, 15-day posttransplant CMI risk stratification and CMI specific to the 65 kDa phosphoprotein (pp65) CMV antigen were investigated. Immunosuppression consisted of basiliximab, tacrolimus, mycophenolate mofetil, and corticosteroids in 80% of patients, whereas 20% received thymoglobulin induction therapy. Results: Patients at high risk for CMV based on pretransplant CMI developed significantly higher CMV infection rates than those deemed to be at low risk with both preemptive (73.3% vs 44.4%; odds ratio [OR], 3.44 [95% confidence interval {CI}, 1.30-9.08]) and prophylaxis (33.3% vs 4.1%; OR, 11.75 [95% CI, 2.31-59.71]) approaches. The predictive capacity for CMV-specific CMI was only found in basiliximab-treated patients for both preemptive and prophylaxis therapy. Fifteen-day CMI risk stratification better predicted CMV infection (81.3% vs 9.1%; OR, 43.33 [95% CI, 7.89-237.96]). Conclusions: Pretransplant CMV-specific CMI identifies D+/R+ kidney recipients at high risk of developing CMV infection if not receiving T-cell-depleting antibodies. Monitoring CMV-specific CMI soon after transplantation further defines the CMV infection prediction risk. Monitoring CMV-specific CMI may guide decision making regarding the type of CMV preventive strategy in kidney transplantation. Clinical Trials Registration: NCT02550639

Capacitando comunidades marginales a través de un medio masivo de comunicación

Se toma como muestra al partido de La Matanza situado en la provincia de Buenos Aires, el cual cuenta con más de 1.500.000 habitantes. Esta población que supera en número a la de 19 provincias tomadas separadamente, es solo inferior a la Ciudad Autónoma de la Provincia de Buenos Aires y las provincias de Buenos Aires, Córdoba, Santa Fe y Mendoza. Dentro de este Partido conviven comunidades residenciales junto a marginales, por ello se hace un estudio a fin de cuantificar la brecha tecnológica y luego aplicar una metodología que permita acercar el conocimiento a las zonas más marginales a fin de disminuir dicha brecha e incluir a las mismas en la sociedad del conocimiento.Eje: Tecnología Informática Aplicada en EducaciónRed de Universidades con Carreras en Informática (RedUNCI

Implementación de una estrategia para reducir la brecha tecnológica

En el presente artículo se muestra la existencia de la brecha tecnológica entre las comunidades que utilizan las TICs (Tecnologías de la Información y Comunicación) como parte de su vida cotidiana y aquellas que no poseen ningún tipo de conocimiento al respecto. Es posible a través de los resultados arrojados por un relevamiento realizado en comunidades con características socio-culturales distintas evidenciar la distancia en materia de tecnología que separa a las comunidades. Tomando conciencia de la existencia de la brecha tecnológica, en este trabajo se presentan los resultados de implementar una estrategia que les permita a los ciudadanos con escasos recursos, que residen en las zonas más marginales, acceder al conocimiento.Presentado en el VIII Workshop Tecnología Informática aplicada en Educación (WTIAE)Red de Universidades con Carreras en Informática (RedUNCI

Evaluación de la toxicidad sub aguda del Camu Camu (Myrciaria dubia) administrado por vía oral en ratas.

Introducción: Camu-Camu, es un árbol frutal, oriundo de la amazonla sudamericana que crece en las orillas anegables de rlos amazónicos. Pertenece al genero Myrciaria, especie dubia. Presenta una gran importancia nutritiva. Su alto contenido en ácido ascórbico (2780 mg/lOO g de pulpa) le confieren propiedades antioxidantes.Objetivo: Evaluar la toxicidad subaguda (30 días) del Camu-Camu.Material y método: Utilizamos 33 ratas albinas. macho, Holt&lt;;man, distribuidas en 3 grupos equitativos: Grupo I (grupo control), se leadministró agua destilada, Grupo 11 y Grupo 111, se les administró por vía oral el extracto seco de Camu-Camu a las dosis de 100 y 200mg/Kg, respectivamente. Al inicio del experimento (basal), a los 15 y a los 30 días, se determinó: hemoglobina, WBC, urea, albúmina, creatinina, proteínas, GOT, TGP, TGO, en sangre, y peso corporal; además, serealizó el examen histológico de higado, riñones, bazo y esrómago al finalizar el esnldio(30dlas).Resultados: Los valores de hemoglobina, albúmina y prmeinas, fueron mayores que las del grupocoOlrol (p&lt;0.05); a su vez, los valores de GOTfueron menores que los del grupo cotrol (p&lt;0.05). No encontramos evidencias de mxicidad sub-aguda, en ninguno de los 2 grupos expuestos, en el examen histopatológico.Conclusión: El Camu-Camu, a las dosis y formas de administración, delpresente trabajo, carece de efectos tóxicos para las Taras

Reconstructing native American migrations from whole-genome and whole-exome data.

There is great scientific and popular interest in understanding the genetic history of populations in the Americas. We wish to understand when different regions of the continent were inhabited, where settlers came from, and how current inhabitants relate genetically to earlier populations. Recent studies unraveled parts of the genetic history of the continent using genotyping arrays and uniparental markers. The 1000 Genomes Project provides a unique opportunity for improving our understanding of population genetic history by providing over a hundred sequenced low coverage genomes and exomes from Colombian (CLM), Mexican-American (MXL), and Puerto Rican (PUR) populations. Here, we explore the genomic contributions of African, European, and especially Native American ancestry to these populations. Estimated Native American ancestry is 48% in MXL, 25% in CLM, and 13% in PUR. Native American ancestry in PUR is most closely related to populations surrounding the Orinoco River basin, confirming the Southern American ancestry of the Taíno people of the Caribbean. We present new methods to estimate the allele frequencies in the Native American fraction of the populations, and model their distribution using a demographic model for three ancestral Native American populations. These ancestral populations likely split in close succession: the most likely scenario, based on a peopling of the Americas 16 thousand years ago (kya), supports that the MXL Ancestors split 12.2kya, with a subsequent split of the ancestors to CLM and PUR 11.7kya. The model also features effective populations of 62,000 in Mexico, 8,700 in Colombia, and 1,900 in Puerto Rico. Modeling Identity-by-descent (IBD) and ancestry tract length, we show that post-contact populations also differ markedly in their effective sizes and migration patterns, with Puerto Rico showing the smallest effective size and the earlier migration from Europe. Finally, we compare IBD and ancestry assignments to find evidence for relatedness among European founders to the three populations