Gene transfer of wild-type apoA-I and apoA-I Milano reduce atherosclerosis to a similar extent

<p>Abstract</p> <p>Background</p> <p>The atheroprotective effects of systemic delivery of either apolipoprotein A-I (wtApoA-I) or the naturally occurring mutant ApoA-I Milano (ApoA-I_M) have been established in animal and human trials, but direct comparison studies evaluating the phenotype of ApoA-I or ApoAI-Milano knock-in mice or bone marrow transplantated animals with selectively ApoA-I or ApoAI-Milano transduced macrophages give conflicting results regarding the superior performance of either one. We therefore sought to compare the two forms of apoA-I using liver-directed somatic gene transfer in hypercholesterinemic mice – a model which is most adequately mimicking the clinical setting.</p> <p>Methods and results</p> <p>Vectors based on AAV serotype 8 (AAV2.8) encoding wtApoA-I, ApoA-I_Mor green fluorescent protein (GFP) as control were constructed. LDL receptor deficient mice were fed a Western Diet. After 8 weeks the AAV vectors were injected, and 6 weeks later atherosclerotic lesion size was determined by aortic <it>en face </it>analysis. Expression of wtApoA-I reduced progression of atherosclerosis by 32% compared with control (p = 0.02) and of ApoA-I_Mby 24% (p = 0.04). There was no significant difference between the two forms of ApoA-I in inhibiting atherosclerosis progression.</p> <p>Conclusion</p> <p>Liver-directed AAV2.8-mediated gene transfer of wtApoA-I and ApoA-I_Meach significantly reduced atherosclerosis progression to a similar extent.</p

Interleukin-36beta provides protection against HSV-1 infection, but does not modulate initiation of adaptive immune responses

Interleukin-36 (IL-36) represents three cytokines, IL-36alpha, IL-36beta and IL-36gamma, which bind to the same receptor, IL-1RL2; however, their physiological function(s) remain poorly understood. Here, the role of IL-36 in immunity against HSV-1 was examined using the flank skin infection mouse model. Expression analyses revealed increased levels of IL-36alpha and IL-36beta mRNA in infected skin, while constitutive IL-36gamma levels remained largely unchanged. In human keratinocytes, IL-36alpha mRNA was induced by HSV-1, while IL-1beta and TNFalpha increased all three IL-36 mRNAs. The dominant alternative splice variant of human IL-36beta mRNA was isoform 2, which is the ortholog of the known mouse IL-36beta mRNA. Mice deficient in IL-36beta, but not IL-36alpha or IL-36gamma, succumbed more frequently to HSV-1 infection than wild type mice. Furthermore, IL-36beta(-/-) mice developed larger zosteriform skin lesions along infected neurons. Levels of HSV-1 specific antibodies, CD8(+) cells and IFNgamma-producing CD4(+) cells were statistically equal in wild type and IL-36beta(-/-) mice, suggesting similar initiation of adaptive immunity in the two strains. This correlated with the time at which HSV-1 genome and mRNA levels in primary skin lesions started to decline in both wild type and IL-36beta(-/-) mice. Our data indicate that IL-36beta has previously unrecognized functions protective against HSV-1 infection

Evaluación de dos dietas alternativas para cerdos en la etapa de engorde

Swine production food represents 70 to 80 % of costs in developing countries can not be based on cereal imports , by instability of supply and prices. The objective is to determine the effect of two alternative diets pig fattening stage on zootechnical parameters ; The pig farm Abejonal was conducted in the municipality of San José Valle ( Santander) located at 1,250 meters above sea level , temperature of 23 ° C and precipitation is 1,717 mm. Crossing twelve pigs ( Landrace X Duroc X Pietrain ) three months, average weight of 70kg were used ; the animals were kept in separate cages , the experimental period was 38 days with eight days of habituation . Weight measurements were performed every eight days. Witness or commercial feed and two alternative diets isonitrogenous and isocaloric with bore and fish silage , respectively treatments as provided . The experimental design was completely random. As a result , no differences between the experimental diets (p &gt; 0.05 ) treatment with fish silage were observed feed efficiency was higher than the other treatments but the cost-benefit ratio is higher in the bore diet. Therefore the use of raw materials in the region in the diet of fattening pigs does not affect your weight gain or becoming productive behavior efficient economic alternative.La producción de cerdos la alimentación representa del 70 al 80% de los costos en países en desarrollo no puede sustentarse en la importación de cereales, por inestabilidad de oferta y precios. El Objetivo es determinar el efecto de dos dietas alternativas para cerdos etapa engorde sobre los parámetros zootécnicos; Se realizó granja porcina El Abejonal, del municipio Valle de San José (Santander) ubicada a 1.250 msnm, temperatura de 23 °C y precipitación 1.717 mm. Se utilizaron doce porcinos de cruce (Duroc X Landrace X Pietrain) de tres meses, peso medio de 70kg; los animales permanecieron en jaulas separadas, el periodo experimental fue 38 días con 8 días de acostumbramiento. Se realizaron pesajes cada ocho días. Se proporcionó tratamientos como: testigo o alimento comercial y dos dietas alternativas isoproteicas e isoenergéticas con bore y ensilaje de pescado, respectivamente. El diseño experimental empleado fue completamente al azar. Como resultado, no se observaron diferencias entre las dietas experimentales (p&gt;0.05) el tratamiento con ensilaje de pescado la eficiencia alimenticia fue mayor a los otros tratamientos pero la relación costo beneficio es mayor en la dieta bore. Por lo cual el uso de materias primas de la región en la dieta de los cerdos en ceba no afecta su ganancia de peso ni su comportamiento productivo convirtiéndose en una alternativa económica eficient

Adeno-Assocated Virus (AAV) Serotype 9 Provides Global Cardiac Gene Transfer Superior to AAV1, AAV6, AAV7, and AAV8 in the Mouse and Rat

Heart disease is the leading cause of morbidity and mortality. Cardiac gene transfer may serve as a novel therapeutic approach. This investigation was undertaken to compare cardiac tropisms of adeno-associated virus (AAV) serotypes 1, 6, 7, 8, and 9. Neonatal mice were injected with 2.5 × 1011 genome copies (GC) of AAV serotype 1, 6, 7, 8, or 9 expressing LacZ under the control of the constitutive chicken β-actin promoter with cytomegalovirus enhancer promoter via intrapericardial injection and monitored for up to 1 year. Adult rats were injected with 5 × 1011 GC of the AAV vectors via direct cardiac injection and monitored for 1 month. Cardiac distribution of LacZ expression was assessed by X-Gal histochemistry, and β-galactosidase activity was quantified in a chemiluminescence assay. Cardiac functional data and biodistribution data were also collected in the rat. AAV9 provided global cardiac gene transfer stable for up to 1 year that was superior to other serotypes. LacZ expression was relatively cardiac specific, and cardiac function was unaffected by gene transfer. AAV9 provides high-level, stable expression in the mouse and rat heart and may provide a simple alternative to the creation of cardiac-specific transgenic mice. AAV9 should be used in rodent cardiac studies and may be the vector of choice for clinical trials of cardiac gene transfer

Percutaneous Transendocardial Delivery of Self-complementary Adeno-associated Virus 6 Achieves Global Cardiac Gene Transfer in Canines

Achieving efficient cardiac gene transfer in a large animal model has proven to be technically challenging. Previous strategies have used cardiopulmonary bypass or dual catheterization with the aid of vasodilators to deliver vectors, such as adenovirus, adeno-associated virus (AAV), or plasmid DNA. Although single-stranded AAV (ssAAV) vectors have shown the greatest promise, they suffer from delayed expression, which might be circumvented using self-complementary vectors. We sought to optimize cardiac gene transfer using a percutaneous transendocardial injection catheter to deliver adeno-associated viral vectors to the canine myocardium. Four vectors were evaluated-ssAAV9, self-complementary AAV9 (scAAV9), scAAV8, scAAV6-so that comparison could be made between single-stranded and self-complementary vectors as well as among serotypes 9, 8, and 6. We demonstrate that scAAV is superior to ssAAV and that AAV 6 is superior to the other serotypes evaluated. Biodistribution studies revealed that vector genome copies were 15-4,000 times more abundant in the heart than in any other organ for scAAV6. Percutaneous transendocardial injection of scAAV6 is a safe, effective method to achieve efficient cardiac gene transfer

Long-term Restoration of Cardiac Dystrophin Expression in Golden Retriever Muscular Dystrophy Following rAAV6-mediated Exon Skipping

Although restoration of dystrophin expression via exon skipping in both cardiac and skeletal muscle has been successfully demonstrated in the mdx mouse, restoration of cardiac dystrophin expression in large animal models of Duchenne muscular dystrophy (DMD) has proven to be a challenge. In large animals, investigators have focused on using intravenous injection of antisense oligonucleotides (AO) to mediate exon skipping. In this study, we sought to optimize restoration of cardiac dystrophin expression in the golden retriever muscular dystrophy (GRMD) model using percutaneous transendocardial delivery of recombinant AAV6 (rAAV6) to deliver a modified U7 small nuclear RNA (snRNA) carrying antisense sequence to target the exon splicing enhancers of exons 6 and 8 and correct the disrupted reading frame. We demonstrate restoration of cardiac dystrophin expression at 13 months confirmed by reverse transcription-PCR (RT-PCR) and immunoblot as well as membrane localization by immunohistochemistry. This was accompanied by improved cardiac function as assessed by cardiac magnetic resonance imaging (MRI). Percutaneous transendocardial delivery of rAAV6 expressing a modified U7 exon skipping construct is a safe, effective method for restoration of dystrophin expression and improvement of cardiac function in the GRMD canine and may be easily translatable to human DMD patients

Dilemas de la paz territorial en los tiempos del post-acuerdo: Experiencias territoriales en la región del eje cafetero

El presente libro, tejido a múltiples voces, perspectivas, abordajes teóricos y metodológicos, se inscribe en los proyectos editoriales de la región eje cafetero que se alejan de las lecturas dicotómicas o categóricas, por el contrario, transita los laberintos que se abren camino cuando una sociedad se traza la difícil tarea de construir una paz territorial en medio de los escenarios de la guerra. La memoria social, las voces de sobrevivientes, organizaciones sociales, medios de comunicación, posturas oficiales y cívicas, las apuestas pedagógicas por la paz, las lecturas territoriales del conflicto y las múltiples secuelas de las variadas violencias constituyen los horizontes temáticos de los 12 capítulos del presente libro, interpretando las complejas realidades presentes en el corazón de la región cafetera. Resultado de multiplicidad de voces, formaciones disciplinares y experiencias vitales, así como de la diversidad de organizaciones, entidades y universidades que acogieron el llamado del ¨Programa de Investigación en Transiciones, Violencias y Memoria¨ para construir una apuesta editorial recreada en los marcos de la sociología relacional, las cuales, a partir de perspectivas históricas, críticas y situadas, adelantaron análisis situados en la región cafetera en los tiempos del postacuerdo.Ruta Pacífica de las Mujeres ; Sistema Universitario del Eje Cafetero ; Universidad Católica de Manizales ; Universidad Católica de Pereira ; Vicerrectoría de Investigaciones, Innovación y Extensión Editorial Universidad Tecnológica de Pereira Pereira, Colombia.CONTENIDO Prólogo ....................................................................................................................6 Jefferson Jaramillo Marín Encrucijadas de una paz inacabada. A manera de introducción.....................12 Por: Luis Adolfo Martínez Herrera y Oscar Arango Gaviria PARTE I................................................................................................................20 Las tensiones de la memoria histórica y de los medios de comunicación en el contexto regional ..................................................................................................20 CAPÍTULO UNO.................................................................................................21 La memoria histórica en la región......................................................................22 Alberto Berón Ospina CAPÍTULO DOS .................................................................................................38 La mutación del periodismo en tiempos transicionales....................................39 Juan Antonio Ruiz Romero PARTE II..............................................................................................................73 Excombatientes, reintegrados y sobrevivientes del conflicto armado..............73 CAPÍTULO TRES...............................................................................................74 Una guerra silenciada: enunciaciones iniciales sobre los actores ...................75 y las dinámicas del conflicto armado en el Eje Cafetero ..................................75 Oscar Fernando Martínez Herrera y Miguel Gómez Bermeo CAPÍTULO CUATRO .....................................................................................106 Experiencia institucional de la Agencia para la Reincorporación y la Normalización en la atención de personas que se acogen a procesos de desarme, desmovilización, reintegración y reincorporación en el Eje Cafetero: 2003- 2020 .....................................................................................................................107 José Luis Medrano Benavides, Lina Marcela Duque Ossa, Oscar Fernando Sanmiguel CAPÍTULO CINCO..........................................................................................137 Entre víctimas y victimarios. Percepciones sociales de sobrevivientes del conflicto armado ................................................................................................................138 Luis Adolfo Martínez Herrera y Nicolás Muñoz Giraldo CAPÍTULO SEIS...............................................................................................173 Transición y reincorporación desde el Jimmy Tatamá: entre retórica y territorialidad.....................................................................................................174 Julio César Murillo García PARTE III...........................................................................................................197 Organizaciones sociales, historias y pedagogías regionales para la paz .......197 CAPÍTULO SIETE............................................................................................198 La Unión Patriótica: notas históricas sobre su acción política en el departamento de Risaralda, marzo 28 de 1984 - enero 6 de 1989 ..........................................199 Jahir Rodríguez Rodriguez CAPÍTULO OCHO ...........................................................................................250 Quinchía: memoria latente de un pueblo ultrajado. Reflexiones sobre la reparación simbólica..........................................................................................251 Gina M. Arias-Rodríguez y Érika V. Tobón-González CAPÍTULO NUEVE .........................................................................................279 La escuela de liderazgo para la paz: seis años al servicio dela educación para la paz ...................................................................................................................280 Oscar Arango Gaviria CAPÍTULO DIEZ..............................................................................................313 Una experiencia de formación para la paz ......................................................314 Claudia Mónica Londoño V. y Claudia Patricia Herrera G.. ........................314 PARTE IV...........................................................................................................338 Secuelas del conflicto armado y redefiniciones de las nociones de memoria y transiciones..........................................................................................................338 CAPÍTULO ONCE............................................................................................339 Comprensiones psicosociales sobre la desaparición forzada en Colombia...340 Mitzin Guadalupe Mata Mata y Mauricio Orozco Vallejo CAPÍTULO DOCE............................................................................................362 Narrativas, obsolescencias y hegemonías.........................................................363 Camilo Lozano River

Variable effects of forest canopies on snow processes in a valley of the central Spanish Pyrenees

Snowpacks and forests have complex interactions throughout the large range of altitudes where they co‐occur. However, there are no reliable data on the spatial and temporal interactions of forests with snowpacks, such as those that occur in nearby areas that have different environmental conditions and those that occur during different snow seasons. This study monitored the interactions of forests with snowpacks in four forest stands in a single valley of the central Spanish Pyrenees during three consecutive snow seasons (2015/2016, 2016/2017 and 2017/2018). Daily snow depth data from time‐lapse cameras were compared with snow data from field surveys that were performed every 10–15 days. These data thus provided information on the spatial and temporal changes of snow–water equivalent (SWE). The results indicated that forest had the same general effects on snowpack in each forest stand and during each snow season. On average, forest cover reduced the duration of snowpack by 17 days, reduced the cumulative SWE of the snowpack by about 60% and increased the spatial heterogeneity of snowpack by 190%. Overall, forest cover reduced SWE total accumulation by 40% and the rate of SWE accumulation by 25%. The forest‐mediated reduction of the accumulation rate, in combination with the occasional forest‐mediated enhancement of melting rate, explained the reduced duration of snowpacks beneath forest canopies. However, the magnitude and timing of certain forest effects on snowpack had significant spatial and temporal variations. This variability must be considered when selecting the location of an experimental site in a mountainous area, because the study site should be representative of surrounding areas. The same considerations apply when selecting a time period for study.Ministerio de Educación, Cultura y Deporte, Grant/Award Number: FPU16/00902; Ministry of Economy and Competitiveness, Grant/Award Numbers: CGL2017‐82216‐R, CGL2014‐52599‐P; Ministry of Education, Culture and Sports, Grant/Award Numbers: FPU15, FPU16