An explainable model of host genetic interactions linked to COVID-19 severity

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as "Respiratory or thoracic disease", supporting their link with COVID-19 severity outcome.A multifaceted computational strategy identifies 16 genetic variants contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing dataset of a cohort of Italian patients

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Author response: Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study

n/

The HERMES-technologic and scientific pathfinder

HERMES-TP/SP (High Energy Rapid Modular Ensemble of Satellites Technologic and Scientific Pathfinder) is a constellation of six 3U nano-satellites hosting simple but innovative X-ray detectors, characterized by a large energy band and excellent temporal resolution, and thus optimized for the monitoring of Cosmic High Energy transients such as Gamma Ray Bursts and the electromagnetic counterparts of Gravitational Wave Events, and for the determination of their positions. The projects are funded by the Italian Ministry of University and Research and by the Italian Space Agency, and by the European Union's Horizon 2020 Research and Innovation Program under Grant Agreement No. 821896. HERMES-TP/SP is an in-orbit demonstration, that should be tested starting from 2022. It is intrinsically a modular experiment that can be naturally expanded to provide a global, sensitive all sky monitor for high-energy transients

The scientific payload on-board the HERMES-TP and HERMES-SP CubeSat missions

none103siHERMES (High Energy Rapid Modular Ensemble of Satellites) Technological and Scientific pathfinder is a space borne mission based on a LEO constellation of nano-satellites. The 3U CubeSat buses host new miniaturized detectors to probe the temporal emission of bright high-energy transients such as Gamma-Ray Bursts (GRBs). Fast transient localization, in a field of view of several steradians and with arcmin-level accuracy, is gained by comparing time delays among the same event detection epochs occurred on at least 3 nano-satellites. With a launch date in 2022, HERMES transient monitoring represents a keystone capability to complement the next generation of gravitational wave experiments. In this paper we will illustrate the HERMES payload design, highlighting the technical solutions adopted to allow a wide-energy-band and sensitive X-ray and gamma-ray detector to be accommodated in a CubeSat 1U volume together with its complete control electronics and data handling system.noneEvangelista, Yuri; Fiore, Fabrizio; Fuschino, Fabio; Campana, Riccardo; Ceraudo, Francesco; Demenev, Evgeny; Guzman, Alejandro; Labanti, Claudio; La Rosa, Giovanni; Fiorini, Mauro; Gandola, Massimo; Grassi, Marco; Mele, Filippo; Morgante, Gianluca; Nogara, Paolo; Piazzolla, Raffaele; Pliego Caballero, Samuel; Rashevskaya, Irina; Russo, Francesco; Sciarrone, Giulia; Sottile, Giuseppe; Milankovich, Dorottya; Pál, András; Ambrosino, Filippo; Auricchio, Natalia; Barbera, Marco; Bellutti, Pierluigi; Bertuccio, Giuseppe; Borghi, Giacomo; Cao, Jiewei; Chen, Tianxiang; Dilillo, Giuseppe; Feroci, Marco; Ficorella, Francesco; Lo Cicero, Ugo; Malcovati, Piero; Morbidini, Alfredo; Pauletta, Giovanni; Picciotto, Antonino; Rachevski, Alexandre; Santangelo, Andrea; Tenzer, Chistoph; Vacchi, Andrea; Wang, Lingjun; Xu, Yupeng; Zampa, Gianluigi; Zampa, Nicola; Zorzi, Nicola; Burderi, Luciano; Lavagna, Michèle; Bertacin, Roberto; Lunghi, Paolo; Monge, Angel; Negri, Barbara; Pirrotta, Simone; Puccetti, Simonetta; Sanna, Andrea; Amarilli, Fabrizio; Amelino-Camelia, Giovanni; Bechini, Michele; Citossi, Marco; Colagrossi, Andrea; Curzel, Serena; Della Casa, Giovanni; Cinelli, Marco; Del Santo, Melania; Di Salvo, Tiziana; Feruglio, Chiara; Ferrandi, Fabrizio; Fiorito, Michele; Gacnik, Dejan; Galgóczi, Gabor; Gambino, Angelo Francesco; Ghirlanda, Giancarlo; Gomboc, Andreja; Karlica, Mile; Efremov, Pavel; Kostic, Uros; Clerici, Aurora; Lopez Fernandez, Borja; Maselli, Alessandro; Nava, Lara; Ohno, Masanori; Ottolina, Daniele; Pasquale, Andrea; Perri, Matteo; Piccinin, Margherita; Prinetto, Jacopo; Riggio, Alessandro; Ripa, Jakub; Papitto, Alessandro; Piranomonte, Silvia; Scala, Francesca; Selcan, David; Silvestrini, Stefano; Rotovnik, Tomaz; Virgilli, Enrico; Troisi, Ivan; Werner, Norbert; Zanotti, Giovanni; Anitra, Alessio; Manca, Arianna; Clerici, AuroraEvangelista, Yuri; Fiore, Fabrizio; Fuschino, Fabio; Campana, Riccardo; Ceraudo, Francesco; Demenev, Evgeny; Guzman, Alejandro; Labanti, Claudio; La Rosa, Giovanni; Fiorini, Mauro; Gandola, Massimo; Grassi, Marco; Mele, Filippo; Morgante, Gianluca; Nogara, Paolo; Piazzolla, Raffaele; Pliego Caballero, Samuel; Rashevskaya, Irina; Russo, Francesco; Sciarrone, Giulia; Sottile, Giuseppe; Milankovich, Dorottya; Pál, András; Ambrosino, Filippo; Auricchio, Natalia; Barbera, Marco; Bellutti, Pierluigi; Bertuccio, Giuseppe; Borghi, Giacomo; Cao, Jiewei; Chen, Tianxiang; Dilillo, Giuseppe; Feroci, Marco; Ficorella, Francesco; Lo Cicero, Ugo; Malcovati, Piero; Morbidini, Alfredo; Pauletta, Giovanni; Picciotto, Antonino; Rachevski, Alexandre; Santangelo, Andrea; Tenzer, Chistoph; Vacchi, Andrea; Wang, Lingjun; Xu, Yupeng; Zampa, Gianluigi; Zampa, Nicola; Zorzi, Nicola; Burderi, Luciano; Lavagna, Michèle; Bertacin, Roberto; Lunghi, Paolo; Monge, Angel; Negri, Barbara; Pirrotta, Simone; Puccetti, Simonetta; Sanna, Andrea; Amarilli, Fabrizio; Amelino-Camelia, Giovanni; Bechini, Michele; Citossi, Marco; Colagrossi, Andrea; Curzel, Serena; Della Casa, Giovanni; Cinelli, Marco; Del Santo, Melania; Di Salvo, Tiziana; Feruglio, Chiara; Ferrandi, Fabrizio; Fiorito, Michele; Gacnik, Dejan; Galgóczi, Gabor; Gambino, Angelo Francesco; Ghirlanda, Giancarlo; Gomboc, Andreja; Karlica, Mile; Efremov, Pavel; Kostic, Uros; Clerici, Aurora; Lopez Fernandez, Borja; Maselli, Alessandro; Nava, Lara; Ohno, Masanori; Ottolina, Daniele; Pasquale, Andrea; Perri, Matteo; Piccinin, Margherita; Prinetto, Jacopo; Riggio, Alessandro; Ripa, Jakub; Papitto, Alessandro; Piranomonte, Silvia; Scala, Francesca; Selcan, David; Silvestrini, Stefano; Rotovnik, Tomaz; Virgilli, Enrico; Troisi, Ivan; Werner, Norbert; Zanotti, Giovanni; Anitra, Alessio; Manca, Arianna; Clerici, Auror

Timing techniques applied to distributed modular high-energy astronomy: the H.E.R.M.E.S. project

The association of GW170817 with GRB170817A proved that electromagnetic counterparts of gravitational wave events are the key to deeply understand the physics of NS-NS merges. Upgrades of the existing GW antennas and the construction of new ones will allow to increase sensitivity down to several hundred Mpc vastly increasing the number of possible electromagnetic counterparts. Monitoring of the hard X-ray/soft gamma-ray sky with good localisation capabilities will help to effectively tackle this problem allowing to fully exploit multi-messenger astronomy. However, building a high energy all-sky monitor with large collective area might be particularly challenging due to the need to place the detectors onboard satellites of limited size. Distributed astronomy is a simple and cheap solution to overcome this difficulty. Here we discuss in detail dedicated timing techniques that allow to precisely locate an astronomical event in the sky taking advantage of the spatial distribution of a swarm of detectors orbiting Earth