Influence of paraoxonase-1 deficiency on metabolic alterations and inflammation

Les malalties cròniques no infecciones i no transmissibles (diabetis, càncer i malalties cardiovasculars) compateixen mecanismes moleculars com l’estrès oxidatiu, la inflamació i les alteracions metabòliques. Les complicacions derivades poden incrementar el risc de desenvolupar altres comorbiditats com la malaltia del fetge gras no alcohòlic (EHNA) i l’aterosclerosi. La EHNA s’associa a resistència a la insulina i a aterosclerosi subclínica, que juntament amb l’estrès oxidatiu, es consideren els principals factors en la progressió de la EHNA cap a esteatohepatitis. La família d’enzims paraoxonasa (PON) és un sistema endogen antioxidant molt important implicat en la protecció front els processos oxidants, contribueixen a la immunitat innata, la bioactivació de fàrmacs, la detoxificació de molècules reactives, la modulació de l’estrès de reticle i la regulació de la proliferació/apoptosi cel·lular. Creiem que la deficiència de PON1 s’associa a problemes metabòlics severs que poden estar lligats a inflamació i a comorbiditats com la EHNA i l’aterosclerosi. A l’estudi 1, vam investigar l’efecte de la deficiència de PON1 en el fetge de ratolins alimentats amb dieta rica en greix. Els resultats van mostrar que PON1 sembla tenir un important paper protector en el fetge, fet que comporta una rellevància clínica ja que una activitat de PON1 disminuïda és una alteració primerenca en pacients amb dany hepàtic. En l’estudi 2 vam investigar la influència de PON1 en les alteracions metabòliques quan cèl·lules endotelials incubades amb oxLDL. Els resultats mostraven que les HDL de ratolins deficients en PON1 tenien menor capacitat de protegir a aquestes cèl·lules de les oxLDL, provocant importants problemes metabòlics. Els efectes de la metformina en pacients amb problemes hepàtics generen controvèrsia. A l’estudi 3 vam testar els seus efectes en fetges de ratolins deficients en PON1, evidenciant els efectes indesitjats del fàrmac en el fetge dels animals, agreujant inflamació i esteatosi hepàtica.Las enfermedades no infecciosas y no transmisibles crónicas (diabetes, cáncer y enfermedades cardiovasculares) comparten mecanismos moleculares como estrés oxidativo, inflamación y alteraciones metabólicas. Las complicaciones derivadas de estas enfermedades están relacionadas e incrementan el riesgo de desarrollar otras comorbilidades, como la enfermedad hepática no alcohólica (EHNA) y la aterosclerosis. La EHNA se relaciona con resistencia a la insulina y aterosclerosis, que junto con el estrés oxidativo participan en su progresión a esteatohepatitis no alcohólica. La familia de enzimas paraoxonasa es un sistema antioxidante endógeno implicado en la protección contra el daño oxidativo y la peroxidación lipídica, participa en inmunidad innata, bioactivación de drogas, detoxificación de moléculas reactivas, modulación del estrés en retículo endoplamático y regulación de la proliferación celular/apoptosis. Creemos que la deficiencia de PON1 está asociada a graves alteraciones hepáticas y podría estar relacionada con inflamación y comorbilidades de enfermedades como la EHNA y la aterosclerosis. Inicialmente (estudio 1), investigamos como la deficiencia de PON1 afecta histológica y metabólicamente al hígado de ratones alimentados con dieta rica en grasa. Concluimos que PON1 tiene un importante papel protector en hígado pudiendo tener relevancia clinica, ya que una menor actividad de PON1 es una de las primeras alteraciones detectadas en pacientes con daño hepático. Seguidamente (estudio2), investigamos la influencia de PON1 en las alteraciones metabólicas de células endoteliales incubadas con LDL oxidadas (LDLox). Los resultados mostraron que las HDL de estos ratones tenían menor capacidad de protección frente a las LDLox, llevando a importantes alteraciones metabólicas. Debido a la controversia de resultados sobre los efectos de la metformina en pacientes con daño hepático, en el estudio 3 testamos los efectos de la metformina en hígado de ratones deficientes en PON1, concluyendo que la administración de metformina produce efectos negativos en los hígados de estos ratones, agravando la inflamación y la esteatosis.Non-communicable diseases (NCD) are non-infectious and non-transmissible chronic diseases, such as diabetes, cancer and cardiovascular disease. They share common molecular mechanisms including oxidative stress, inflammation and metabolic alterations. NCD complications are interrelated, increasing risk to develop other comorbidities such as non-alcoholic fatty liver disease (NAFLD) and atherosclerosis.. NAFLD is associated with insulin resistance and subclinical atherosclerosis, that together with oxidative stress are considered driving factors in the progression of NAFLD to NASH (non-alcoholic steatohepatitis). The paraoxonase (PON) family of enzymes is an important endogenous antioxidant system implicated in protection against oxidative damage and lipid peroxidation, contribution to innate immunity, bioactivation of drugs, detoxification of reactive molecules, modulation of endoplasmic reticulum stress, and regulation of cell proliferation/apoptosis. We hypothesize that PON1 deficiency is associated to severe metabolic disturbances that may be related to inflammation and the comorbidities of some NCD, such as NAFLD and atherosclerosis. In Study 1, we investigated the effect of PON1 deficiency on histological alterations and hepatic metabolism in mice fed a high-fat high-cholesterol diet. Results showed that PON1 seems to have an important protective role in the liver which may have clinical relevance since reduced serum and liver PON1 activity is an early alteration in patients with liver impairment. In Study 2 we investigated the influence of PON1 on metabolic alterations when endothelial cells are incubated with oxLDL . The results showed that HDL from PON1 deficient mice has an impaired capacity to protect endothelial cells from oxLDL, triggering important metabolic disturbances. As there are controversial results about the effects of metformin in patients with liver impairment, in Study 3, we wanted to test metformin effects on the liver of PON1 deficient mice. Results showed that metformin administration produces undesirable effects in the liver of PON1 deficient mice, aggravating inflammation and steatosis

Recaudación arbitrio municipal limpieza pública y su incidencia en calidad del servicio brindado por Segat - distrito Trujillo 2021 - 2022

Esta investigación fue desarrollada con el propósito principal de evaluar como la recaudación del arbitrio municipal de limpieza pública incidía en la calidad del servicio brindado por SEGAT - Distrito de Trujillo 2021-2022. Fue de tipo aplicada y con un diseño no experimental (Correlacional causal). La muestra fue de 120 viviendas del distrito de Trujillo. Se empleó método del muestreo no probabilístico por conveniencia para su estimación. Aplicamos cuestionario a jefes de hogar y a funcionarios una entrevista. Tuvo un enfoque cuantitativo y se utilizó el modelo de Regresión Logística Ordinal que permitió medir el nivel de incidencia entre las variables. También la prueba de Negelkerke que corrigió la escala del estadístico, coeficiente de Spearman que midió la fuerza y dirección de incidencia entre las variables y el coeficiente tau-b de Kendal para hallar el nivel de variación entre variables. Para procesar utilizamos (SPSS) - versión 27, y software estadístico R. Con esta coherencia de procedimiento el principal resultado fue demostrar que la recaudación del arbitrio municipal de limpieza pública incide de manera directa y altamente significativa en un 74.5% sobre la calidad del servicio brindado por SEGAT, con ello se alcanzó el propósito estimado

Crops gone wild: evolution of weeds and invasives from domesticated ancestors.

The evolution of problematic plants, both weeds and invasives, is a topic of increasing interest. Plants that have evolved from domesticated ancestors have certain advantages for study. Because of their economic importance, domesticated plants are generally well-characterized and readily available for ecogenetic comparison with their wild descendants. Thus, the evolutionary history of crop descendants has the potential to be reconstructed in some detail. Furthermore, growing crop progenitors with their problematic descendants in a common environment allows for the identification of significant evolutionary differences that correlate with weediness or invasiveness. We sought well-established examples of invasives and weeds for which genetic and/or ethnobotanical evidence has confirmed their evolution from domesticates. We found surprisingly few cases, only 13. We examine our list for generalizations and then some selected cases to reveal how plant pests have evolved from domesticates. Despite their potential utility, crop descendants remain underexploited for evolutionary study. Promising evolutionary research opportunities for these systems are abundant and worthy of pursuit

Benchmarking of single‐virus genomics: a new tool for uncovering the virosphere

Metagenomics and single‐cell genomics have enabled the discovery of relevant uncultured microbes. Recently, single‐virus genomics (SVG), although still in an incipient stage, has opened new avenues in viral ecology by allowing the sequencing of one single virus at a time. The investigation of methodological alternatives and optimization of existing procedures for SVG is paramount to deliver high‐quality genomic data. We report a sequencing dataset of viral single‐amplified genomes (vSAGs) from cultured and uncultured viruses obtained by applying different conditions in each SVG step, from viral preservation and novel whole‐genome amplification (WGA) to sequencing platforms and genome assembly. Sequencing data showed that cryopreservation and mild fixation were compatible with WGA, although fresh samples delivered better genome quality data. The novel TruPrime WGA, based on primase‐polymerase features, and WGA‐X employing a thermostable phi29 polymerase, were proven to be with sufficient sensitivity in SVG. The Oxford Nanopore (ON) sequencing platform did not provide a significant improvement of vSAG assembly compared to Illumina alone. Finally, the SPAdes assembler performed the best. Overall, our results represent a valuable genomic dataset that will help to standardized and advance new tools in viral ecology.This work has been supported by Gordon and Betty Moore Foundation (grant 5334) and Spanish Ministry of Economy and Competitiveness (refs CGL2013‐40564‐R, RTI2018‐094248‐B‐I00 and SAF2013‐49267‐EXP). Work at CRG, BIST and UPF was in part funded by the Spanish Ministry of Economy and Competitiveness, ‘Centro de Excelencia Severo Ochoa 2013‐2017’ and the Spanish Ministry of Economy and Competitiveness, ‘Centro de Excelencia Maria de Maeztu 2016‐2019’

Microfossils of the Yangtzeplacognathus crassus zone in the middle darriwilian of the argentine precordillera

The San Juan Formation of the Eastern and Central Precordillera is composed mainly of fossiliferous limestone and marly limestone. The conodont biostratigraphy of the very top of this unit has been studied on several localities such as: Don Braulio, La Pola, Cecilia and Del Aluvión creeks, recording the Y. crassus Zone for this levels (Mestre, 2010; Mestre, 2013, Heredia and Mestre, 2013). The microfossils associated to this conodont biozone are represented by spicules, foraminifers and protoconchs, which are reported and figured in this work.Fil: Mestre Garcia, Ana Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Juan. Centro de Investigaciones de la Geosfera y Biosfera; ArgentinaFil: Beresi, Matilde Sylvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Científico Tecnológico Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; ArgentinaFil: Heredia, Susana Emma. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Juan. Centro de Investigaciones de la Geosfera y Biosfera; ArgentinaFil: Nestell, G.. University Of Texas; Estados Unido

Avaliação da utilização de exames genéticos complementares previstos na portaria número 199/14 no diagnóstico de doenças genéticas no Hospital Universitário de Brasília

Dissertação (mestrado)—Universidade de Brasília, Faculdade de Medicina, Programa de Pós-Graduação em Ciências Médicas, 2018.Cada ano nascem, no mundo, 7,6 milhões de crianças com algum defeito congênito ou doença genética. Estima-se que no Brasil, sejam 13 milhões de pessoas afetadas. No início dos anos 2000, movimentos sociais e a pressão de pacientes e familiares levaram a que a questão das doenças raras entrasse na agenda da saúde pública e, em 2014, foi publicada pelo Ministério da Saúde do Brasil, a Portaria GM/MS n° 199, que institui a Política Nacional de Atenção Integral às Pessoas com Doenças Raras. Nela ficam estabelecidos os princípios e diretrizes para o atendimento integral a estas pessoas no âmbito do Sistema Único de Saúde, incluindo os exames disponibilizados. O objetivo deste trabalho foi estabelecer a contribuição das diferentes metodologias de diagnóstico clínico, citogenético e molecular na elucidação diagnóstica em pacientes atendidos no Serviço de Genética Médica do Hospital Universitário de Brasília, visando avaliar a melhora no diagnóstico com a implantação dessa Portaria. Para isso, foram analisados os prontuários de 299 pacientes, quanto à sexo, idade, motivo do encaminhamento, exames genéticos complementares e se foi possível realizar o diagnóstico baseado nessas metodologias ou pelo quadro clínico. O diagnóstico clínico foi possível em 17,7% dos pacientes. O cariótipo contribuiu para o diagnóstico em 14%, a análise cromossômica por microarranjos (CMA) em 6,35%, a pesquisa de mutações em FMR1 para pesquisa da Síndrome do X-frágil em 0,66% e a amplificação de múltiplas sondas dependente de ligação multiplex (MLPA) em 0,33%. Sessenta por cento dos pacientes ficaram sem diagnóstico. O rendimento diagnóstico dos exames foi concordante com os previstos pela literatura. Os exames previstos na Portaria GM/MS n° 199/2014 aumentaram a possibilidade diagnóstica, porém, a demora na publicação da Portaria, fez com que não fossem contemplados exames genéticos mais atuais, que aumentariam ainda mais a chance de diagnóstico, principalmente para as doenças gênicas.Every year, 7.6 million children worldwide are born with a birth defect or genetic disease. It is estimated that in Brazil, 13 million people are affected. In the early 2000s, social movements and patient and family pressure, led to the inclusion of rare diseases in the public health agenda and, in 2014, Brazil’s Ministry of Health published the Ordinance n ° 199, which established the National Comprehensive Care for People with Rare Diseases. It established the principles and guidelines for the integral care of these patients within the scope of the Unified Health System, and which diagnosis methods should be available. The aim of this work was to establish the contribution of the different methodos for cytogenetic, molecular and clinical diagnosis, in the diagnostic elucidation of patients assisted at the Medical Genetic Service of the Hospital Universitário de Brasília, aiming to evaluate the improvement in diagnosis with the implementation of this Ordinance. For that, we evaluated medical records of 299 patients, regarding sex, age, reason for referral, complementary genetic tests and whether diagnostic was conclusive based on these methodos or clinical presentation. Clinical diagnosis was possible in 17.7% of the patients. The karyotype contributed to the diagnosis in 14%, chromosomal analysis by microarray (CMA) in 6.35%, mutation screening in FMR1 to investigate the Fragile- X syndrome in 0.66%, Multiplex Ligation-dependent Probe Amplification (MLPA) in 0,33%. Sixty percent of the patients remained undiagnosed. The diagnostic yield of these tests was in agreement with those published elsewhere in literature. The examinations provided in Ordinance GM/MS n° 199/2014 increased the diagnostic possibility, but the delay in Ordinance’s publication meant led to newest genetic tests being left out, which would increase the chance of diagnosis, especially for the monogenic diseases

Three Cases of Canine Dermatomyositis-Like Disease

Background: Dermatomyositis is an idiopathic, inflammatory/immunemediated disease of the skin, muscles and bloodvessels of hereditary nature and unclear pathogenesis. This familial disease has been described in certain breeds, especially collies and Shetland sheep dogs and is of rare occurrence in mongrel dogs. To describe and discuss three clinical cases of dermatomyositis-like disease and provide a brief review of the literature.Cases: Three young mongrel dogs are included in this report. Case 1: Mandarino, a 4-year-old mongrel dog, having a history of skin lesions for at least a year. Showed an underweight patient, skin ulcers, crusts, alopecia, peri-ocular scarring causing severe lagophthalmia and a corneal ulcer. Muscle atrophy was most notable in the head and legs; the dog haddifficulty and pain walking. Treatment was initialised with cephalexin 30 mg/kg BID, pentoxifylline 25 mg/kg BID, and prednisone 2.2 mg/kg SID. The patient was presented after two weeks for follow up; the anaemia and skin condition had improved, the weight had increased by 2 kg, dysphagia and locomotor abnormalities were not present. Case 2: Milagros,a mongrel female dog approximately two years of age, rescued from a shelter. Physical examination showed facial alopecia, erythema and scarring of the periocular skin, crusting and scaling in alopecic areas, pinnae tip necrosis and crusting, ear alopecia, tail tip necrosis and crusting. Also present were distal limb alopecia, crusting and ulcers in areas of trauma in the hock and carpal surfaces; some nails presented onychorhexis and onychoschizia. The patient has been treated for12 months with a good clinical outcome, with pentoxifylline, azathioprine 2.2 mg/kg EOD alternating with prednisone 1 mg/kg EOD. Case 3: Chuchito, an 11-month-old male mongrel rescued dog had been previously hospitalised due to his skin condition. Physical examination showed depigmented and alopecic areas in the nasal planum, perioral and periocular areas, and inflammation of the palpebral tissues. Necrosis of the distal pinnae, alopecia and scales were evident, along with sloughing of scales and ulcers. Skin lesions were also present in the distal limbs, and alopecia, erythema and some crusting and scales in the carpal, tarsal and digital areas. Onychodystrophy was present in several digits. This study describes the physical examination and the clinical pathological findings, including skin scrapings, fungal cultures, and skin biopsies, in three dogs with dermatomyositis-like disease, as well as the clinical outcomes after slightly different treatment protocols were used. The biopsy results of two dogs showed ischaemic dermatopathy.Discussion: The most common initial signs of the disease are erythema, desquamation and alopecia in the facial area, ears, distal limbs and pinnae in young puppies aged between two and six months of age, followed by pigmentary changes. Muscular lesions are uncommon; when present, they represent the most severe form of this disease. Dysphagia is a common sign and mega-oesophagus may be present. Patients with muscular disease can manifest difficulty walking, with a stiff high gait. The immune mediated pathogenesis of dermatomyositis can relate to triggering factors in some dogs, such as drugs, infections, paraneoplasms, or toxins. Other potential inducing stressors include oestrus, whelping and excessive solar exposure. Dermatomyositis-like or familiar dermatomyositis is diagnosed using clinical findings, histopathologyof skin and muscle, and muscle physiology studies. Electromyography, breed predisposition and genetic background can be helpful in some cases. The clinical findings and response to the treatment of all three cases were compatible with dermatomyositis-like disease in mongrel dogs.Keywords: dermatomyositis, dermatopathy, vascular disease, inflammatory myopathies, mongrel dog

Overview of low GWP mixtures for the replacement of HFC refrigerants: R134a, R404A and R410A

The current European F-gas regulation establishes restrictions in the use of fluoride refrigerants with a high global warming potential (GWP) in applications of refrigeration and air conditioning (RAC) systems. Moreover, a gradual limitation on the GWP weight of the fluoride refrigerants placed on the market is ongoing and will end with approximately one-fifth of today's offer. In this context, many of the RAC systems operate with refrigerants R134a, R404A, and R410A that have GWP values of 1300, 3943 and 2088, respectively, are being forced to be replaced by environmentally friendly alternatives, like hydrofluoroolefin (HFO) refrigerants and their mixtures with hydrofluorocarbons (HFC), which can be designed to present intermediate characteristics and become the ideal candidate many RAC applications. This work presents the most recent HFC/HFO/HC/R744 refrigerant mixture options for an alternative to the refrigerants mentiond above and compares their energetic and performance with the early developed mixture prototypes

Sistema de Gestión de Seguridad y Salud en el trabajo para reducir la accidentabilidad en una empresa de construcción, Lima 2022

La investigación titulada “Sistema de Gestión de Seguridad y Salud en el Trabajo para reducir la accidentabilidad en una empresa de construcción, Lima 2022”, tuvo como objetivo analizar de qué manera el SGSST reduce la accidentabilidad en una constructora, Lima 2022. La metodología fue de tipo aplicada, nivel explicativo, enfoque cuantitativo y diseño pre experimental, asimismo la muestra fue los 87 días laborales de medición de lesiones que fueron medidos a través de la técnica de la observación y análisis documental con los instrumentos de la ficha de registro y check list. En los resultados, en el pretest el índice de la accidentabilidad fue 300.8508 y con la implementación de SGSST en el postest fue 49.0383, además en la prueba wilcoxon la significancia fue 0.038 < 0.050 (se rechazó la hipótesis nula). En conclusión, el sistema de Gestión de Seguridad y Salud en el Trabajo redujo la accidentabilidad en una empresa de construcción, Lima 2022