Genetic variation in autophagy-related genes influences the risk and phenotype of Buruli ulcer

Introduction Buruli ulcer (BU) is a severe necrotizing human skin disease caused by Mycobacterium ulcerans. Clinically, presentation is a sum of these diverse pathogenic hits subjected to critical immune-regulatory mechanisms. Among them, autophagy has been demonstrated as a cellular process of critical importance. Since microtubules and dynein are affected by mycolactone, the critical pathogenic exotoxin produced by M. ulcerans, cytoskeleton-related changes might potentially impair the autophagic process and impact the risk and progression of infection. Objective Genetic variants in the autophagy-related genes NOD2, PARK2 and ATG16L1 has been associated with susceptibility to mycobacterial diseases. Here, we investigated their association with BU risk, its severe phenotypes and its progression to an ulcerative form. Methods Genetic variants were genotyped using KASPar chemistry in 208 BU patients (70.2% with an ulcerative form and 28% in severe WHO category 3 phenotype) and 300 healthy endemic controls. Results The rs1333955 SNP in PARK2 was significantly associated with increased susceptibility to BU [odds ratio (OR), 1.43; P = 0.05]. In addition, both the rs9302752 and rs2066842 SNPs in NOD2 gee significantly increased the predisposition of patients to develop category 3 (OR, 2.23; P = 0.02; and OR 12.7; P = 0.03, respectively, whereas the rs2241880 SNP in ATG16L1 was found to significantly protect patients from presenting the ulcer phenotype (OR, 0.35; P = 0.02). Conclusion Our findings indicate that specific genetic variants in autophagy-related genes influence susceptibility to the development of BU and its progression to severe phenotypes.The research leading to these results received funding from the Health Services of the Fundação Calouste Gulbenkian under the grant Proc.N°94776 LJ; from the Fundação para a Ciência e Tecnologia (FCT), cofunded by Programa Operacional Regional do Norte (ON.2—O Novo 267 Norte); from the Quadro de Referência Estratégico Nacional (QREN) through the Fundo Europeu de Desenvolvimento Regional (FEDER) and from the Projeto Estratégico – LA 26 – 2013–2014 (PEst-C/SAU/LA0026/2013). JFM received an individual QREN fellowship (UMINHO/BPD/14/2014); CCu and AGF received an individual FCT fellowship (SFRH/BPD/96176/2013 and SFRH/BPD/68547/2010, respectively); and AC received an FCT contract (IF/00735/2014). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript

Genetic Variation in Autophagy-Related Genes Influences the Risk and Phenotype of Buruli Ulcer

Abstract Introductio

Epigenetic loss of RNA‑methyltransferase NSUN5 in glioma targets ribosomes to drive stress adaptive translational program

Tumors have aberrant proteomes that often do not match their corresponding transcriptome profiles. One possible cause of this discrepancy is the existence of aberrant RNA modification landscapes in the so-called epitranscriptome. Here, we report that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate RNA methyltransferase for 5-methylcytosine. In this setting, NSUN5 exhibits tumor-suppressor characteristics in vivo glioma models. We also found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA that drives an overall depletion of protein synthesis, and leads to the emergence of an adaptive translational program for survival under conditions of cellular stress. Interestingly, NSUN5 epigenetic inactivation also renders these gliomas sensitive to bioactivatable substrates of the stress-related enzyme NQO1. Most importantly, NSUN5 epigenetic inactivation is a hallmark of glioma patients with long-term survival for this otherwise devastating disease

Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program

Altres ajuts: This work was supported by the Obra Social "La Caixa" (to M. Esteller).Tumors have aberrant proteomes that often do not match their corresponding transcriptome profiles. One possible cause of this discrepancy is the existence of aberrant RNA modification landscapes in the so-called epitranscriptome. Here, we report that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate RNA methyltransferase for 5-methylcytosine. In this setting, NSUN5 exhibits tumor-suppressor characteristics in vivo glioma models. We also found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA that drives an overall depletion of protein synthesis, and leads to the emergence of an adaptive translational program for survival under conditions of cellular stress. Interestingly, NSUN5 epigenetic inactivation also renders these gliomas sensitive to bioactivatable substrates of the stress-related enzyme NQO1. Most importantly, NSUN5 epigenetic inactivation is a hallmark of glioma patients with long-term survival for this otherwise devastating disease

Evaluación a los dos meses del alta hospitalaria tras la primera ola de COVID-19: presencia de síntomas persistentes

Introduction: a series of symptoms have been reported after COVID-19, which have been encompassed in the so-named “postCOVID syndrome”. PostCOVID syndrome is a heterogeneous disorder with an uncertain pathophysiology. The aim of this study is to describe the characteristics and frequence of symptoms after COVID-19 discharge and to analyze the possible implicated factors. Methods: this is an observational propective study with COVID-19 patients hospitalized from March to April 2020. Patients were assessed in an outpatient clinic two months after discharge, and serological, radiological and laboratory workup was conducted. Previous medical history, length of stay (LOS) and intensive care unit (ICU) admission were recorded. Persistent symptons (PS) were defined as those appearing after the acute infection and present at follow-up. Results: 74 patients were included. Mean age was 66±13 years, and 54.4% patients were men. Six (8.1%) patients needed ICU admission, and median LOS was 8 (6-12) days. Forty (54.8%) patients presented PS, the most frequent being fatigue and dyspnea (20.3% each). 77% patients presented laboratory abnormalities but just in 11 cases (15.1%) were they severe. Ten (13.5%) had radiological abnormalities. 71 (95.9%) had positive IgG serology. There were no differences between patients with and without PS regarding previous medical history or acute infection course. PS patients had a higher heart rate 83 (75-93) vs 76 65-85) bpm; p=0.038) at assessment. Conclusion: symptoms and laboratory abnormalities are frequent two months after COVID-19, although usually mild. No predictors were found for the presence of PS, but larger studies are needed to ascertain this aseverationIntroducción: se han notificado tras el alta por COVID-19 una serie de síntomas englobados dentro del llamado “síndrome post-COVID”, un cuadro heterogéneo cuya fisiopatología es incierta. Nuestro objetivo es describir las características y frecuencia de síntomas tras el alta y analizar los posibles factores relacionados. Métodos: estudio observacional prospectivo con pacientes ingresados por COVID-19 durante marzo-abril de 2020. Se evaluó en consulta a los dos meses tras el alta con valoración clínica, analítica, serología y radiografía de tórax. Se recogieron los antecedentes, la estancia hospitalaria y la necesidad de UCI. Se definieron síntomas persistentes (SP) como síntomas que aparecieron desde la infección aguda y que se mantenían al seguimiento. Resultados: se revisaron 74 pacientes. La edad media fue 66±13 años, siendo un 51,4% hombres. Seis (8,1%) ingresaron en UCI, y la mediana de estancia fue 8 (6-12) días. Cuarenta (54,8%) presentaron SP, siendo los más frecuentes astenia y disnea (20,3% ambos). Un 77% tenía alteraciones analíticas pero solo en 11 (15,1%) fueron relevantes. Diez (13,5%) presentaban alteraciones radiológicas y 71 (95,9%) tenían IgG positiva. No hubo diferencias entre los pacientes con y sin SP en sus antecedentes o evolución hospitalaria. Los pacientes con SP estaban más taquicárdicos [83 (75-93) lpm vs 76 (65-85) lpm; p=0,038], no existiendo diferencias significativas en el resto de variables. Conclusión: al seguimiento tras la COVID-19 es frecuente la presencia de síntomas o alteraciones analíticas, aunque no suelen traducir gravedad. No encontramos variables que predijeran la presencia de los mismos, pero sería interesante analizar cohortes más amplia

General characteristics of Buruli ulcer (BU) patients and healthy controls.

<p>General characteristics of Buruli ulcer (BU) patients and healthy controls.</p

Haploview pairwise analysis of Linkage Disequilibrium (LD) between NOD2 gene SNPs (A) and PARK2 gene SNPs (B).

<p>The r2 colour scheme was used. Measures of r2 = 0 are represented in white (not significant); 0</p

Genotype distributions and association test results of SNPs in the <i>PARK2</i> gene among BU patients and age- and gender-matched healthy controls.

<p>Genotype distributions and association test results of SNPs in the <i>PARK2</i> gene among BU patients and age- and gender-matched healthy controls.</p

Efficacy of Telemedicine and At-Home Telemonitoring following Hospital Discharge in Patients with COVID-19

Aim: This work aims to evaluate the safety and utility of an at-home telemedicine with telemonitoring program for discharged COVID-19 patients. Methods: This is a retrospective cohort study of all patients discharged home in Galicia between 6 March 2020 and 15 February 2021. We evaluated a structured, proactive monitoring program conducted by the ASLAM (&Aacute;rea Sanitaria de Lugo, A Mari&ntilde;a y Monforte de Lemos) Healthcare Area team compared to patients discharged in the rest of the Autonomous Community of Galicia. Results: During the study period, 10,517 patients were hospitalized for COVID-19 and 8601 (81.8%) were discharged. Of them, 738 (8.6%) were discharged in ASLAM and 7863 (91.4%) were discharged in the rest of Galicia. Of those discharged in ASLAM, 475 (64.4%) patients were monitored. Compared to patients in the rest of Galicia, the group monitored via telemedicine had a significantly shorter first hospital stay (p &lt; 0.0001), a lower readmission rate (p = 0.05), and a shorter second hospital stay (p = 0.04), with no differences in emergency department visits or 90-day all-cause mortality. Conclusion: A structured, proactive telemedicine with telemonitoring program for discharged COVID-19 patients is a safe, useful tool that reduces the mean length of hospital stay and readmissions