Identification of novel genes interacting with DVAP, the causative gene of ALS8 in humans

Amyotrophic lateral sclerosis (ALS) is a major neurodegenerative disease caused by the death of motor neurons leading to paralysis. Mechanisms underlying the pathogenesis of the disease remain unknown but with the identification of causative genes from ALS patients, some processes have been linked to the disease. One of these genes is VAPB, a highly conserved protein involved in lipid transfer, vesicle metabolism and synaptic morphology. We modeled in Drosophila the disease-linked P56S mutation (DVAP-P58S) and observed with the expression of this allele neurodegeneration in the eye and loss of motor performance. These phenotypes provide an excellent opportunity to use fly’s genetics to find novel genetic interactors of DVAP and understand ALS pathomechanism. Therefore, we carried out a large scale genetic screen by crossing the ALS model with a collection of P-element overexpression lines. After the analysis of 1183 lines, we obtained 71 modifier lines that suppress DVAP-induced neurodegeneration and 14 lines that enhance this phenotype, decreasing furthermore the eye size and viability of the offspring. To confirm that the effect of modifier lines was caused by a specific gene, we validated them with independent alleles of those genes. Using different sources, we were able to confirm the effect of 63 of the 85 modifiers, providing a strong confirmation of their effect. When we studied the effect of the modifier genes co-expressed with DVAP-P58S in the nervous system, we detected that 46 lines presented the same modifying effect in adult viability and 58 in the motor performance of the adult offspring. Considering the stronger readouts, we obtained 42 genes as novel high confidence DVAP genetic interactors. To understand furthermore the way they are affecting DVAP neurodegeneration, we carried out a series of bioinformatic analyses using Drosophila and human databases. Lipid droplets, vesicle metabolism and cell proliferation appear as the most important categories found in the screen, all processes conserved when analysed with human orthologs of the modifiers. Further characterisation of the endocytosis-linked modifier Rab5 and the predicted DVAP-interactors Rab7 and Rab11, showed that the suppression effect is not only confirmed in vivo but is also conserved in human tissue from ALS patients. These data validate our genetic screen and at the same time open novel opportunities to understand ALS mechanisms and find possible therapeutic targets

Utilización de Naive Bayes para predicción de victorias en jugadores de la Asociación de Tenistas Profesionales

86 p.La predicción de juegos deportivos es un tema de interés para el mundo de las apuestas, ya sea para beneficiar a los apostadoros o maximizar las ganancias de las casas de apuestas. Las distintas asociaciones de deportes han almacenado información detallada respecto al desempeño de jugadores, incluyendo resultados de enfrentamientos contra adversarios y detalles del desempeño individual, etc. Frecuentemente,mucha de esta información se encuentra públicamente disponible en los respectivos sitios web de las asociaciones deportivas.El problema a resolver consiste en utilizar esta información histórica para predecir el resultado mal de un encuentro de tenis entre dos oponentes.Para lograr el objetivo propuesto, se obtuvieron datos disponibles públicamente desde el sitio web de la Asociación de Tenistas Profesionales (ATP)1. Estos datos contienen información estadística respecto a encuentros individuales entre dos oponentes e información cuantitativa del desempeño de un jugador durante una temporada. Estos datos fueron debidamente transformados y posteriormente utilizados para construir un modelo de clasificación. Se entrenó el modelo con datos de la temporada 2012, identificando que es posible predecir dependiendo del contexto, hasta con un 80% de efectividad, quién obtendrá la victoria en juegos de una misma temporada. Adicionalmente, se detectó que la superficie en la que se juega, es determinante en el proceso de predicción. Otro conjunto de experimento, consideró utilizar el modelo de aprendizaje generado a partir de datos de la temporada 2012 para predecir las temporadas 2013 y 2014. En este caso obtuvimos precisiones del orden del 65 %, lo que es superior a una predicción puramente aleatoria. En opinión de este autor, estos resultados hacen evidente el potencial de la minería de datos para anticipar resultados de eventos deportivos. Este caso se enfoca particularmente en el tenis, pero se estima que la metodología expuesta en el presente documento es suficientemente genérica para ser aplicada en otros contextos

Why Quantification Matters: Characterization of Phenotypes at the <em>Drosophila</em> Larval Neuromuscular Junction

Most studies on morphogenesis rely on qualitative descriptions of how anatomical traits are affected by the disruption of specific genes and genetic pathways. Quantitative descriptions are rarely performed, although genetic manipulations produce a range of phenotypic effects and variations are observed even among individuals within control groups. Emerging evidence shows that morphology, size and location of organelles play a previously underappreciated, yet fundamental role in cell function and survival. Here we provide step-by-step instructions for performing quantitative analyses of phenotypes at the Drosophila larval neuromuscular junction (NMJ). We use several reliable immuno-histochemical markers combined with bio-imaging techniques and morphometric analyses to examine the effects of genetic mutations on specific cellular processes. In particular, we focus on the quantitative analysis of phenotypes affecting morphology, size and position of nuclei within the striated muscles of Drosophila larvae. The Drosophila larval NMJ is a valuable experimental model to investigate the molecular mechanisms underlying the structure and the function of the neuromuscular system, both in health and disease. However, the methodologies we describe here can be extended to other systems as well

Gain-of-function mutations in the ALS8 causative gene VAPB have detrimental effects on neurons and muscles

Summary Amyotrophic Lateral Sclerosis (ALS) is a motor neuron degenerative disease characterized by a progressive, and ultimately fatal, muscle paralysis. The human VAMP-Associated Protein B (hVAPB) is the causative gene of ALS type 8. Previous studies have shown that a loss-of-function mechanism is responsible for VAPB-induced ALS. Recently, a novel mutation in hVAPB (V234I) has been identified but its pathogenic potential has not been assessed. We found that neuronal expression of the V234I mutant allele in Drosophila (DVAP-V260I) induces defects in synaptic structure and microtubule architecture that are opposite to those associated with DVAP mutants and transgenic expression of other ALS-linked alleles. Expression of DVAP-V260I also induces aggregate formation, reduced viability, wing postural defects, abnormal locomotion behavior, nuclear abnormalities, neurodegeneration and upregulation of the heat-shock-mediated stress response. Similar, albeit milder, phenotypes are associated with the overexpression of the wild-type protein. These data show that overexpressing the wild-type DVAP is sufficient to induce the disease and that DVAP-V260I is a pathogenic allele with increased wild-type activity. We propose that a combination of gain- and loss-of-function mechanisms is responsible for VAPB-induced ALS

Impact of Obstructive Sleep Apnea (OSA) in COVID-19 Survivors, Symptoms Changes Between 4-Months and 1 Year After the COVID-19 Infection

Objective: To determine the association between Obstructive Sleep Apnea (OSA) with long-term symptoms and inflammatory cytokines, exploring the changes between 4-months and 1-year after COVID-19 infection. Methods: We conducted an observational, prospective cohort study, including patients ≥18 years old with confirmed diagnosis of COVID-19 between April to July 2020. All participants underwent two clinical follow-up visits, the first at 4-months (Visit 1) and the second at 1 year, after SARS-CoV-2 infection (Visit 2). Plasma glucose, total cholesterol, HDL, and triglycerides. Regarding pulmonary function, spirometry and lung diffusion capacity tests were assessed. For mental and neurocognitive evaluation, a short-form (SF-12), Beck depression and Hospital-Anxiety depression questionnaires were conducted at both time-points, whereas the Montreal Cognitive assessment was conducted during the second follow-up. Regarding to sleep evaluation, Epworth Sleepiness Scale, Insomnia Severity index and STOP-BANG questionnaire were conducted. Additionally, a home sleep apnea test and 7-day wrist actigraphy were performed in all participants. Inflammatory cytokines were measured using an inflammatory cytokine bead array kit. p-values < 0.05 were considered statistically significant and statistical analyses were performed using R software. Results: A total of 60 patients were included in the first follow-up, from which 57 completed the second follow-up. The mean age was 46.4 years-old (SD ± 13.1) and 53.3% were male. 30% of cases reported mild COVID-19 infection, 28.3% with moderate illness, and 41.6% with severe illness. Moreover, 56.6% of them were admitted to the ICU. Regarding to metabolic values, the OSA group showed higher values of insulin resistance (IR) (27%), systolic blood pressure (SBP) 135.2 (±19.1), dyslipidemia (67.5%), total cholesterol 202.1 (±60.5), triglycerides 176.1 (±119.0) and HOMA-IR 9.0 (±18.8) in comparison with the non-OSA group. 1 year after COVID-19 infection, DLCO test remains abnormal in OSA patients (25% OSA vs. 3.6% non-OSA, p = 0.02). Finally, those participants with OSA who develop ARDS reported an adjusted OR 20.4 (95%-CI, 1.04-504) risk of neurocognitive impairment. Discussion: Among patients with previous COVID-19, OSA impact the development of incident glycemic, neurocognitive impairment, and abnormal functional pulmonary changes that persist up to 1 year since acute phase.This study was supported by the Agencia Nacional de Investigación y Desarrollo (ANID, COVID1005), Chilean Government. GL declares funding for research by the American Academy of Sleep Medicine (AASM, 254-FP-21). JG, FB, and AT declare funded by ISCIII (CIBERESUCICOVID, COV20/00110). EN-L, SS, CC, RQ and BA were funded by Fondecyt 1211480 and COVID-19 Genomics Network (C19-GenoNet) ACT210085. Figure 1 was created with BioRender.com and Flow Cytometer was funded by EQM150061 (FONDEQUIP-ANID)

CÁNCER DE COLON Y EMBARAZO: REPORTE DE CASO Y REVISIÓN DE LA LITERATURA

El cáncer colorrectal asociado al embarazo es una patología extremadamente infrecuente. Se presenta el caso de una paciente de 38 años con antecedentes familiares de cáncer de colon, cursando un embarazo de 35 semanas en la que se diagnosticó un cáncer de colon derecho. Se efectúa una revisión de la literatura en relación al diagnóstico y manejo de esta rara entida

Mitochondria and Calcium Regulation as Basis of Neurodegeneration Associated With Aging

Age is the main risk factor for the onset of neurodegenerative diseases. A decline of mitochondrial function has been observed in several age-dependent neurodegenerative diseases and may be a major contributing factor in their progression. Recent findings have shown that mitochondrial fitness is tightly regulated by Ca2+ signals, which are altered long before the onset of measurable histopathology hallmarks or cognitive deficits in several neurodegenerative diseases including Alzheimer’s disease (AD), the most frequent cause of dementia. The transfer of Ca2+ from the endoplasmic reticulum (ER) to the mitochondria, facilitated by the presence of mitochondria-associated membranes (MAMs), is essential for several physiological mitochondrial functions such as respiration. Ca2+ transfer to mitochondria must be finely regulated because excess Ca2+ will disturb oxidative phosphorylation (OXPHOS), thereby increasing the generation of reactive oxygen species (ROS) that leads to cellular damage observed in both aging and neurodegenerative diseases. In addition, excess Ca2+ and ROS trigger the opening of the mitochondrial transition pore mPTP, leading to loss of mitochondrial function and cell death. mPTP opening probably increases with age and its activity has been associated with several neurodegenerative diseases. As Ca2+ seems to be the initiator of the mitochondrial failure that contributes to the synaptic deficit observed during aging and neurodegeneration, in this review, we aim to look at current evidence for mitochondrial dysfunction caused by Ca2+ miscommunication in neuronal models of neurodegenerative disorders related to aging, with special emphasis on AD

Polymorphism of viral dsRNA in Xanthophyllomyces dendrorhous strains isolated from different geographic areas

<p>Abstract</p> <p>Background</p> <p>Strains of the astaxanthin producing yeast <it>Xanthophyllomyces dendrorhous </it>have been isolated from different cold regions around the earth, and the presence of double stranded RNA (dsRNA) elements was described in some isolates. This kind of viruses is widely distributed among yeasts and filamentous fungi and, although generally are cryptic in function, their studies have been a key factor in the knowledge of important fungi. In this work, the characterization and genetic relationships among dsRNA elements were determined in strains representatives of almost all regions of the earth where <it>X. dendrorhous </it>have been isolated.</p> <p>Results</p> <p>Almost all strains of <it>X. dendrorhous </it>analyzed carry one, two or four dsRNA elements, of molecular sizes in the range from 0.8 to 5.0 kb. Different dsRNA-patterns were observed in strains with different geographic origin, being L1 (5.0 kb) the common dsRNA element. By hybridization assays a high genomic polymorphism was observed among L1 dsRNAs of different <it>X. dendrorhous </it>strains. Contrary, hybridization was observed between L1 and L2 dsRNAs of strains from same or different regions, while the dsRNA elements of minor sizes (M, S1, and S2) present in several strains did not show hybridization with neither L1 or L2 dsRNAs. Along the growth curve of UCD 67-385 (harboring four dsRNAs) an increase of L2 relative to L1 dsRNA was observed, whiles the S1/L1 ratio remains constant, as well as the M/L1 ratio of Patagonian strain. Strains cured of S2 dsRNA were obtained by treatment with anisomycin, and comparison of its dsRNA contents with uncured strain, revealed an increase of L1 dsRNA while the L2 and S1 dsRNA remain unaltered.</p> <p>Conclusion</p> <p>The dsRNA elements of <it>X. dendrorhous </it>are highly variable in size and sequence, and the dsRNA pattern is specific to the geographic region of isolation. Each L1 and L2 dsRNA are viral elements able to self replicate and to coexist into a cell, and L1 and S2 dsRNAs elements could be part of a helper/satellite virus system in <it>X. dendrorhous</it>.</p

Enfermedades crónicas

Adherencia al tratamiento farmacol&oacute;gico y relaci&oacute;n con el control metab&oacute;lico en pacientes con DM2Aluminio en pacientes con terapia de reemplazo renal cr&oacute;nico con hemodi&aacute;lisis en Bogot&aacute;, ColombiaAmputaci&oacute;n de extremidades inferiores: &iquest;est&aacute;n aumentando las tasas?Consumo de edulcorantes artificiales en j&oacute;venes universitariosC&oacute;mo crecen ni&ntilde;os normales de 2 a&ntilde;os que son sobrepeso a los 7 a&ntilde;osDiagn&oacute;stico con enfoque territorial de salud cardiovascular en la Regi&oacute;n MetropolitanaEfecto a corto plazo de una intervenci&oacute;n con ejercicio f&iacute;sico, en ni&ntilde;os con sobrepesoEfectos de la cirug&iacute;a bari&aacute;trica en pacientes con s&iacute;ndrome metab&oacute;lico e IMC &lt; 35 KG/M2Encuesta mundial de tabaquismo en estudiantes de profesiones de saludEnfermedades cr&oacute;nicas no transmisibles: Consecuencias sociales-sanitarias de comunidades rurales en ChileEpidemiolog&iacute;a de las muertes hospitalarias por patolog&iacute;as relacionadas a muerte encef&aacute;lica, Chile 2003-2007Estado nutricional y conductas alimentarias en adolescentes de 4&ordm; medio de la Regi&oacute;n de CoquimboEstudio de calidad de vida en una muestra del plan piloto para hepatitis CEvaluaci&oacute;n del proceso asistencial y de resultados de salud del GES de diabetes mellitus 2Factores de riesgo cardiovascular en poblaci&oacute;n universitaria de la Facsal, universidad de Tarapac&aacute;Implicancias psicosociales en la g&eacute;nesis, evoluci&oacute;n y tratamiento de pacientes con hipertensi&oacute;n arterial esencialInfarto agudo al miocardio (IAM): Realidad en el Hospital de Puerto Natales, 2009-2010Introducci&oacute;n de nuevas TIC y mejor&iacute;a de la asistencia a un programa de saludNi&ntilde;os obesos atendidos en el Cesfam de Puerto Natales y su entorno familiarPerfil de la mortalidad por c&aacute;ncer de cuello uterino en R&iacute;o de JaneiroPerfil del paciente primo-consultante del Programa de Salud Cardiovascular, Consultorio Cordillera Andina, Los AndesPrevalencia de automedicaci&oacute;n en mujeres beneficiarias del Hospital Comunitario de Til-TiPrevalencia de caries en poblaci&oacute;n preescolar y su relaci&oacute;n con malnutrici&oacute;n por excesoPrevalencia de retinopat&iacute;a diab&eacute;tica en comunas dependientes del Servicio de Salud Metropolitano Occidente (SSMOC)Problemas de adherencia farmacol&oacute;gica antihipertensiva en poblaci&oacute;n mapuche: Un estudio cualitativoRol biol&oacute;gico de los antioxidantes innatos en pacientes portadores de VIH/SidaSobrepeso en empleados de un restaurante de una universidad p&uacute;blica del estado de S&atilde;o Paul