Potential Role of Atp8a1 as Plasma Membrane Aminophospholipid Translocase in Proliferating Neuronal Cells

La actividad enzimática responsable de la localización de la membrana interna de la fosfatidilserina (PS) es la aminofosfolipido translocasa (PLAPLT). Basándonos en nuestros estudios anteriores que muestran que la sobreexpresión de Atp8a1 en células de neuroblastoma hibrido en proliferación provoca un aumento de la actividad de PLAPLT, propusimos que Atp8a1 funciona como PLAPLT solo en células de división rápida, como células neurotumorales. Como confirmación de estas hipótesis, expresamos mutante del sitio de fosforilacion de Atp8a1 en células N18 disminuyendo el valor Vmax de PLAPLT, sin alterar significativamente el valor de Km. La eliminación de Atp8a1 también debería causar exposición a PS en neuroblastos albergados dentro del giro dentado (DG), que es un nicho proliferativo dentro del centro de memoria denominado hipocampo. Dicha extemalizacion de PS debería desencadenar la fagocitosis de las células DG, lo que a su vez podría conseguir a una pérdida de la función del hipocampo. En apoyo de esta hipótesis, se observó que los ratones Atp8a1 (-/-) sufren posiblemente de defectos de aprendizaje relacionados con el hipocampo. Nuestro estudio revela una estrategia potencial para la eliminación selectiva de las tumorales del cerebro mediante la supresión dirigida de la actividad de Atp8a1.Tesi

Factores de mortalidad asociados con la COVID-19 en la Sierra Central del Perú: Huánuco, 2020-2021

Objetivo. Determinar los factores asociados con la mortalidad por la COVID-19 en la Sierra Central del Perú; específicamente en el Departamento de Huánuco durante 2020-2021. Métodos. Este estudio cuantitativo, observacional, analítico y retrospectivo recopiló historias clínicas de 903 pacientes tratados en el Centro de Atención y Aislamiento Temporal (CAAT) Amarilis del Hospital Materno Infantil (HMI) Carlos Showing Ferrari, en Huánuco, Perú. El análisis inferencial involucró un modelo de regresión logística bivariada y un modelo predictivo multivariado, para asociar varios factores con la mortalidad por la COVID-19. Resultados. El modelo predictivo de regresión logística identificó una tasa de mortalidad por la COVID-19 del 8,19 % (74 pacientes). Los factores significativamente asociados con un aumento de la mortalidad incluyeron la edad avanzada (OR = 3,24; IC = 1,83 – 5,75), la saturación de oxígeno mínima al ingreso (OR = 4,25; IC = 1,79 – 10,10), la hipertensión (OR = 2,01; IC = 1,17 - 3,45), la sepsis durante la hospitalización (OR = 1,97; IC = 1,09 – 3,55) y el género masculino (OR = 1,77; IC = 1,03 – 3,04). Conclusión. Los factores asociados con un aumento de la mortalidad por la COVID-19 en la Sierra Central del Perú incluyen la edad avanzada, la baja saturación de oxígeno al ingreso, la sepsis durante la hospitalización y el género masculino

High-velocity fragmentation of titanium alloy rings and cylinders produced using Field-Assisted Sintering Technology

This paper explores the mechanics of high velocity impact fragmentation in titanium alloys produced by Field-Assisted Sintering Technology. For that purpose, we have utilized the experimental setups recently developed by Nieto-Fuentes et al. (J Mech Phys Solids 174:105248, 2023a; Int J Impact Eng 180:104556, 2023b) for conducting dynamic expansion tests on rings and cylinders. The experiments involve firing a conical-nosed cylindrical projectile using a single-stage ight-gas gun against the stationary ring/cylinder at velocities ranging from≈ 248 m/s to≈390 m/s, corresponding to estimated strain rates in the specimen varying from ≈ 10050 s−1 to ≈ 19125 s−1. The diameter of the cylindrical part of the projectile exceeds the inner diameter of the ring/cylinder, causing the latter to expand as the projectile moves forward, resulting in the formation of multiple necks and fragments. Two different alloys have been tested: Ti6Al4V and Ti5Al5V5Mo3Cr. These materials are widely utilized in aeronautical and aerospace industries for constructing structural elements such as compressor parts (discs and blades) and Whipple shields, which are frequently exposed to intense mechanical loading, including high-velocity impacts. However, despite the scientific and technological significance of Ti6Al4V and Ti5Al5V5Mo3Cr, and the extensive research on their mechanical and fracture behaviors, to the best of the authors’ knowledge, no systematic study has been conducted thus far on the dynamic fragmentation behavior of these alloys. Hence, this paper presents an ambitious fragmentation testing program, encompassing a total of 27 and 29 experiments on rings and cylinders, respectively. Monolithic and multimaterial samples—half specimen of Ti6Al4V and half specimen of Ti5Al5V5Mo3Cr—have been tested, taking advantage of the ability of Field-Assisted Sintering Technology to produce multimaterial parts. The fragments have been collected, weighed, sized, and analyzed using scanning electron microscopy. The experiments have shown that the number of necks, the number of fragments, and the proportion of necks developing into fragments generally increase with expansion velocity. The average distance between necks has been assessed against the predictions of a linear stability analysis (Zhou et al. in Int J Impact Eng 33:880–891 2006; Vaz-Romero et al. in Int J Solids Struct 125:232–243, 2017), revealing satisfactory agreement between theoretical predictions and experimental results. In addition, the experimental results have been compared with tests reported in the literature for various metals and alloys (Nieto-Fuentes et al. in J Mech Phys Solids 174:105248, 2023a; Zhang and Ravi-Chandar in Int J Fract 142:183–217, 2006, Zhang and Ravi-Chandar in Int J Fract 150:3–36, 2008) to examine the influence of material behavior on the statistics of fragments size and necks spacing

Biochemical and genetic analysis of butyrylcholinesterase (BChE) in a family, due to prolonged neuromuscular blockade after the use of succinylcholine

Butyrylcholinesterase (BChE) is a plasma enzyme that catalyzes the hydrolysis of choline esters, including the muscle-relaxant succinylcholine and mivacurium. Patients who present sustained neuromuscular blockade after using succinylcholine usually carry BChE variants with reduced enzyme activity or an acquired BChE deficiency. We report here the molecular basis of the BCHE gene underlying the slow catabolism of succinylcholine in a patient who underwent endoscopic nasal surgery. We measured the enzyme activity of BChE and extracted genomic DNA in order to study the promoter region and all exons of the BCHE gene of the patient, her parents and siblings. PCR products were sequenced and compared with reference sequences from GenBank. We detected that the patient and one of her brothers have two homozygous mutations: nt1615 GCA > ACA (Ala539Thr), responsible for the K variant, and nt209 GAT > GGT (Asp70Gly), which produces the atypical variant A. Her parents and two of her brothers were found to be heterozygous for the AK allele, and another brother is homozygous for the normal allele. Sequence analysis of exon 1 including 5′UTR showed that the proband and her brother are homozygous for –116GG. The AK/AK genotype is considered the most frequent in hereditary hypocholinesterasemia (44%). This work demonstrates the importance of defining the phenotype and genotype of the BCHE gene in patients who are subjected to neuromuscular block by succinylcholine, because of the risk of prolonged neuromuscular paralysis

Allele-specific differences in ryanodine receptor 1 mRNA expression levels may contribute to phenotypic variability in malignant hyperthermia

<p>Abstract</p> <p>Background</p> <p>Malignant hyperthermia (MH) is a dominantly inherited skeletal muscle disorder that can cause a fatal hypermetabolic reaction to general anaesthetics. The primary locus of MH (MHS1 locus) in humans is linked to chromosome 19q13.1, the position of the gene encoding the ryanodine receptor skeletal muscle calcium release channel (RyR1).</p> <p>Methods</p> <p>In this study, an inexpensive allele-specific PCR (AS-PCR) assay was designed that allowed the relative quantification of the two RyR1 transcripts in heterozygous samples found to be susceptible to MH (MHS). Allele-specific differences in RyR1 expression levels can provide insight into the observed variable penetrance and variations in MH phenotypes between individuals. The presence/absence of the H4833Y mutation in <it>RYR</it>1 transcripts was employed as a marker that allowed discrimination between the two alleles.</p> <p>Results</p> <p>In four skeletal muscle samples and two lymphoblastoid cell lines (LCLs) from different MHS patients, the wild type allele was found to be expressed at higher levels than the mutant RyR1 allele. For both LCLs, the ratios between the wild type and mutant <it>RYR</it>1 alleles did not change after different incubation times with actinomycin D. This suggests that there are no allele-specific differences in RyR1 mRNA stability, at least in these cells.</p> <p>Conclusion</p> <p>The data presented here revealed for the first time allele-specific differences in <it>RYR</it>1 mRNA expression levels in heterozygous MHS samples, and can at least in part contribute to the observed variable penetrance and variations in MH clinical phenotypes.</p

Genetics and genomics in Peru: Clinical and research perspective

Peruvians currently preserve in their DNA the history of 2.5 million years of human evolution and 150,000 years of migration from Africa to Peru or the Americas. The development of Genetics and Genomics in the clinical and academic field is shown in this review