Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

I diritti dei bambini e degli adolescenti. Una ricerca sui progetti legati alla legge 285

Il volume propone un'analisi dei progetti proposti e fnianziati in base alla legge 285 del 1997, Disposizioni per la promozione di diritti e ed opportunità per l'infanzia e l'adolescenza. Nei diversi saggi, basati su un approccio teorico alla valutazione, questi progetti sono stati analizzati per quel che riguarda la cornice giuridica, le azioni prevalenti, tipologie e l'organizzazione delle attività specifiche, il contesto territoriali, le basi teoriche, gli obiettivi, i destinatari, la metodologia, i modi di valutazione interna, le caratteristiche della promozione della partecipazione. Il volume propone quindi una serie di interrogativi fondamentali che riguarda la qualità della progettazione rivolta a bambini e adolescenti, con particolare riferimento alla promozione della loro partecipazione

P2 receptors in human heart : upregulation of P2X6 in patients undergoing heart transplantation, interaction with TNF\u3b1 and potential role in myocardial cell death

ATP acts as a neurotransmitter via seven P2X6 receptor-channels for Na + and Ca2+, and eight G-protein-coupled P2Y receptors. Despite evidence suggesting roles in human heart, the map of myocardial P2 receptors is incomplete, and their involvement in chronic heart failure (CHF) has never received adequate attention. In left myocardia from five to nine control and 5-12 CHF subjects undergoing heart transplantation, we analyzed the full repertoire of P2 receptors and of 10 "orphan" P2Y-like receptors. All known P2Y receptors (i.e. P2Y1,2,4,6,11,12,13,14) and two P2Y-like receptors (GPR91 and GPR17) were detected in all subjects. All known P2X1-7 receptors were also detected; of these, only P2X6 was upregulated in CHF, as confirmed by quantitative real time-PCR. The potential significance of this change was studied in primary cardiac fibroblasts freshly isolated from young pigs. Exposure of cardiac fibroblasts to ATP or its hydrolysis-resistant-analog benzoylATP induced apoptosis. TNF\u3b1 (a cytokine implicated in CHF progression) exacerbated cell death. Similar effects were induced by ATP and TNF\u3b1 in a murine cardiomyocytic cell line. In cardiac fibroblasts, TNF\u3b1 inhibited the downregulation of P2X6 mRNA associated to prolonged agonist exposure, suggesting that, by preventing ATP-induced P2X6 desensitization, TNF\u3b1 may abolish a defense mechanism meant at avoiding Ca2+ overload and, ultimately, Ca 2+-dependent cell death. This may provide a basis for P2X6 upregulation in CHF. In conclusion, we provide the first characterization of P2 receptors in the human heart and suggest that the interaction between TNF\u3b1 and the upregulated P2X6 receptor may represent a novel pathogenic mechanism in CHF. (copyright) 2005 Elsevier Ltd. All rights reserved

Una nuova dedica a Ercole da un manoscritto di Bonifacius Amerbach

The manuscript C VI a 77, once belonged to the XVIth century humanist Bonifacius Amerbach and now preserved in the Universitätsbibliothek Basel, is not a high quality epigraphic manuscript, but includes at least a couple of Roman inscriptions elsewhere unknown. One of them, already published in the previous years, is a dedication to Iuppiter Optimus Maximus set by an eques singularis; the other one is a dedication to Hercules Invictus – here published for the first time - set, when he was an urban praetor, by L. Turranius Venustus Gratianus, member of a well known senatorial family of the III/IV century AD

The contribution of the European high containment laboratories during the 2014-2015 Ebola Virus Disease emergency

Since December 2013, the world has experienced the worst ever epidemic of Ebola virus disease (EVD), which has caused thousands of deaths in several West African countries. When the epidemic began, the European Union (EU) was not unprepared, thanks to the 10-year-long commitment of the European Commission (EC) to fund several networks in the area of highly infectious diseases. The European Network of Biosafety-Level 4 (BSL-4) laboratories (Euronet-P4, later called ENP4-Lab) was one of them; it has been operating since 2004, bringing together the facilities where RiskGroup 4 (RG-4) pathogens such as Ebola virus can be safely handled. In 2010, with the aim of increasing European preparedness in the fight against highly infectious trans-border threats, a new Joint Action was launched, resulting from the union of the networks that had previously worked on the diagnostics of highly infectious viruses and bacteria: ENP4-Lab and EQADeBa (Establishment of Quality Assurance for Detection of Highly Pathogenic Bacteria of Potential Bioterrorism Risk). (...)The authors are grateful to the European Commission and CHAFEA for financially and technically supporting the following Networks: EURONET-P4 2003214, ENP4Lab 2006208, QUANDHIP 2010-21-02, and EMLab (European Mobile Laboratory Project). Part of this work was also supported by the Italian Ministry of Health, ‘Ricerca Corrente’ grants awarded to the ‘Lazzaro Spallanzani’ National Institute for Infectious Diseases-IRCCS, Rome, Italy.info:eu-repo/semantics/acceptedVersio