Altered Kv2.1 functioning promotes increased excitability in hippocampal neurons of an Alzheimer's disease mouse model.

Altered neuronal excitability is emerging as an important feature in Alzheimer's disease (AD). Kv2.1 potassium channels are important modulators of neuronal excitability and synaptic activity. We investigated Kv2.1 currents and its relation to the intrinsic synaptic activity of hippocampal neurons from 3xTg-AD (triple transgenic mouse model of Alzheimer's disease) mice, a widely employed preclinical AD model. Synaptic activity was also investigated by analyzing spontaneous [Ca(2+)]i spikes. Compared with wild-type (Non-Tg (non-transgenic mouse model)) cultures, 3xTg-AD neurons showed enhanced spike frequency and decreased intensity. Compared with Non-Tg cultures, 3xTg-AD hippocampal neurons revealed reduced Kv2.1-dependent Ik current densities as well as normalized conductances. 3xTg-AD cultures also exhibited an overall decrease in the number of functional Kv2.1 channels. Immunofluorescence assay revealed an increase in Kv2.1 channel oligomerization, a condition associated with blockade of channel function. In Non-Tg neurons, pharmacological blockade of Kv2.1 channels reproduced the altered pattern found in the 3xTg-AD cultures. Moreover, compared with untreated sister cultures, pharmacological inhibition of Kv2.1 in 3xTg-AD neurons did not produce any significant modification in Ik current densities. Reactive oxygen species (ROS) promote Kv2.1 oligomerization, thereby acting as negative modulator of the channel activity. Glutamate receptor activation produced higher ROS levels in hippocampal 3xTg-AD cultures compared with Non-Tg neurons. Antioxidant treatment with N-Acetyl-Cysteine was found to rescue Kv2.1-dependent currents and decreased spontaneous hyperexcitability in 3xTg-AD neurons. Analogous results regarding spontaneous synaptic activity were observed in neuronal cultures treated with the antioxidant 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox). Our study indicates that AD-related mutations may promote enhanced ROS generation, oxidative-dependent oligomerization, and loss of function of Kv2.1 channels. These processes can be part on the increased neuronal excitability of these neurons. These steps may set a deleterious vicious circle that eventually helps to promote excitotoxic damage found in the AD brain

Facteurs d’affiliation aux pairs sont étroitement associés à la criminalité des jeunes incarcérés à la prison centrale de Kinshasa : Affiliation Factors to Peers are strongly associated to the Criminality among the Youth of the Central Prison of Kinshasa

Context and objective. Increasing crime is one of the major social problems facing in the context of armed conflicts of various kinds. The objective of this study is to investigate the determinants of the peer affiliation domain of criminal and violent criminal behavior. Methods. We undertook a case-control study included 500 subjects: 297 incarcerated criminals (189 violent criminals, as crime against a person and 108 non-violent criminals, as crime against property) against 203 noncriminal subjects, between August 2015 and December 2016. We selected control subjects from general population of the city of Kinshasa and matched them with cases according to gender, age (± 2 years) and geographical origin. Logistic regression analysis was used to investigate the determinants of criminality and of violent criminality. Results. Compared to noncriminals, criminals were significantly gang members (55.6% versus 4.9%, p<0.001), carry guns (40.1% versus 7.9%, p<0.001), attend parties with friends without parental supervision (69.7% versus 34%, p<0.001), and have friends who sell drugs (44.4% versus 14.8%, p<0.001). Compared to non-violent criminals, violent criminals were significantly more likely to be gang members (60.8% versus 46.3%, p=0.015), carry weapons (46.6% versus 28.7%, p=0.003) and have friends who sell heroin (50.3% versus 34.3%, p=0.008). In multivariate logistic regression analyse, being a gang member (ORa 13.6; 95% CI: 6.76-27.67), carrying a weapon (ORa 2.85; 95% CI: 1.5-5.42) and unsupervised parties (ORa 1.95; 95% CI: 1.25-3.02) were the independently associated with crime. Only carrying weapons (ORa 1.87; 95% CI: 1.05-3.32) emerged as an independent determinant of violent crime. Conclusion. Violent and non-violent crime is a continuum in which the former differs from the latter in terms of carrying a weapon. Gang involvement, social gatherings with friends and carrying weapons are the common threads of their criminal behavior. Contexte et objectif. La criminalité croissante compte parmi les problèmes sociaux majeurs en République Démocratique du Congo aux prises à des conflits armés de diverse nature. Cette étude a pour objectif de rechercher les déterminants du domaine d’affiliation aux pairs du comportement criminel et criminel violent. Méthodes. Nous avons entrepris une étude cas-témoin enrôlant 500 sujets : 297 criminels incarcérés (189 criminels violents, crime contre la personne et 108 criminels non violents, crime contre la propriété) contre 203 sujets non criminels, entre août 2015 et décembre 2016. Les témoins ont été recrutés dans la population générale de la ville de Kinshasa et appariés aux cas, selon le sexe (même), l’âge (± 2 ans) et la provenance géographique. L’analyse de régression logistique a été utilisée pour rechercher les déterminants de la criminalité. Résultats. Comparés aux non criminels, les criminels étaient significativement membres de gang (55,6% versus 4,9%, p < 0,001), porteurs des armes (40,1% versus 7,9% ; p <0,001), dans des soirées entre amissans supervision parentale (69,7% versus 34%, p<0,001), et  avaient des amis vendeurs de drogues (44,4% versus 14,8%, p<0,001). Par rapport aux criminels non violents, les criminels violents étaient significativement membres de gang (60,8% versus 46,3%, p=0,015), porteurs des armes (46,6% versus 28,7%, p=0,003) et avaient des amis vendeurs de drogues (50,3% versus 34,3%, p=0,008). En analyse de régression logistique multivariée, être membre de gang (ORa 13,6; IC 95% : 6,76-27,67), porter une arme (ORa 2,85; IC 95% : 1,5-5,42) et assister dans les soirées sans supervision (ORa 1,95; IC 95% : 1,25-3,02) constituaient les déterminants indépendamment associés à la criminalité. Seul porter des armes (ORa 1,87; IC 95% : 1,05-3,32) a émergé comme déterminant indépendant de la criminalité violente. Conclusion. La criminalité violente et non violente constitue un continuum dans lequel la première se différencie de la deuxième par le port d’arme. La participation à un gang, les soirées entre amis et le port d’arme constituent le fils conducteur de leur comportement criminel. &nbsp

Rare and common genetic determinants of metabolic individuality and their effects on human health

Garrod’s concept of ‘chemical individuality’ has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant–metabolite associations (P < 1.25 × 10−11) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant–metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships

Fish Oil Enhances Recovery of Intestinal Microbiota and Epithelial Integrity in Chronic Rejection of Intestinal Transplant

The intestinal chronic rejection (CR) is the major limitation to long-term survival of transplanted organs. This study aimed to investigate the interaction between intestinal microbiota and epithelial integrity in chronic rejection of intestinal transplantation, and to find out whether fish oil enhances recovery of intestinal microbiota and epithelial integrity.. In addition, CR rats showed pronounced alteration of tight junction, depicted by marked changes in epithelial cell ultrastructure and redistribution of occuldin and claudins as well as disruption in TJ barrier function. Fish oil administration ameliorated disruption of epithelial integrity in CR, which was associated with an improvement of the mucosal structure leading to improved tight junctions.Our study have presented novel evidence that fish oil is involved in the maintenance of epithelial TJ integrity and recovery of gut microbiota, which may have therapeutic potential against CR in intestinal transplantation

Latin Americans show wide-spread Converso ancestry and imprint of local Native ancestry on physical appearance

Historical records and genetic analyses indicate that Latin Americans trace their ancestry mainly to the intermixing (admixture) of Native Americans, Europeans and Sub-Saharan Africans. Using novel haplotype-based methods, here we infer sub-continental ancestry in over 6,500 Latin Americans and evaluate the impact of regional ancestry variation on physical appearance. We find that Native American ancestry components in Latin Americans correspond geographically to the present-day genetic structure of Native groups, and that sources of non-Native ancestry, and admixture timings, match documented migratory flows. We also detect South/East Mediterranean ancestry across Latin America, probably stemming mostly from the clandestine colonial migration of Christian converts of non-European origin (Conversos). Furthermore, we find that ancestry related to highland (Central Andean) versus lowland (Mapuche) Natives is associated with variation in facial features, particularly nose morphology, and detect significant differences in allele frequencies between these groups at loci previously associated with nose morphology in this sample

Rare and common genetic determinants of metabolic individuality and their effects on human health

Garrod’s concept of ‘chemical individuality’ has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant–metabolite associations (P < 1.25 × 10−11) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant–metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships

Potential neoplastic evolution of Vero cells: in vivo and in vitro characterization

Vero cell lines are extensively employed in viral vaccine manufacturing. Similarly to all established cells, mutations can occur during Vero cells in vitro amplification which can result in adverse features compromising their biological safety. To evaluate the potential neoplastic evolution of these cells, in vitro transformation test, gene expression analysis and karyotyping were compared among low- (127 and 139 passages) and high-passage (passage 194) cell lines, as well as transformed colonies (TCs). In vivo tumorigenicity was also tested to confirm preliminary in vitro data obtained for low passage lines and TCs. Moreover, Vero cells cultivated in foetal bovine serum-free medium and derived from TCs were analysed to investigate the influence of cultivation methods on tumorigenic evolution. Low-passage Vero developed TCs in soft agar, without showing any tumorigenic evolution when inoculated in the animal model. Karyotyping showed a hypo-diploid modal chromosome number and rearrangements with no difference among Vero cell line passages and TCs. These abnormalities were reported also in serum-free cultivated Vero. Gene expression revealed that high-passage Vero cells had several under-expressedand a few over-expressed genes compared to low-passage ones.Gene ontology revealed no significant enrichment of pathways related to oncogenic risk. These findings suggest that in vitro high passage, and not culture conditions, induces Vero transformation correlated to karyotype and gene expression alterations. These data, together with previous investigations reporting tumour induction in high-passage Vero cells, suggest the use of low-passage Vero cells or cell lines other than Vero to increase the safety of vaccine manufacturing

Facteurs d’affiliation aux pairs sont étroitement associés à la criminalité des jeunes incarcérés à la prison centrale de Kinshasa

info:eu-repo/semantics/publishe