41 research outputs found
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
The reference site collaborative network of the european innovation partnership on active and healthy ageing
Seventy four Reference Sites of the European Innovation
Partnership on Active and Healthy Ageing (EIP on AHA)
have been recognised by the European Commission in
2016 for their commitment to excellence in investing and
scaling up innovative solutions for active and healthy
ageing. The Reference Site Collaborative Network
(RSCN) brings together the EIP on AHA Reference Sites
awarded by the European Commission, and Candidate
Reference Sites into a single forum. The overarching goals
are to promote cooperation, share and transfer good
practice and solutions in the development and scaling up
of health and care strategies, policies and service delivery
models, while at the same time supporting the action
groups in their work. The RSCN aspires to be recognized
by the EU Commission as the principal forum and
authority representing all EIP on AHA Reference Sites.
The RSCN will contribute to achieve the goals of the EIP
on AHA by improving health and care outcomes for
citizens across Europe, and the development of sustainable
economic growth and the creation of jobs
Characterization of the Danube River sediments using the PMF multivariate approach
Chemical composition data for the Danube River and its tributaries sediments were analyzed using positive matrix factorization (PMF). The objective was to identify both natural and anthropogenic sources affecting the catchment area of the river. During the Joint Danube Survey 2 (JDS2) campaign 148 bottom sediments samples were collected. The following elements were analyzed by means of the X-Ray fluorescence (XRF) technique: Al, As, Ca, Cd, Cl, Co, Cr, Cu, Fe, K, Mg, Mn, Na, Ni, P, Pb, S, Si, Ti, V and Zn. Mercury was determined by cold vapour atomic absorption spectrometry (CV-AAS).
Three factors were obtained considering the whole data set (Danube and tributaries), identified as: (1) a carbonate component characterized by Ca and Mg; (2) an alumino-silicate component dominated by Si and Al content and the presence of some metals attributed to natural processes; (3) an anthropogenic source identified by Hg, S, P and some heavy metals load.
To better characterize the role of tributaries, the Danube and tributaries data sets, were also analyzed separately. The same three source factors were identified in the Danube data set. For the tributaries, a four-factor source model gave one further factor dominated by S and P, which could be attributed to the use of fertilizers in agriculture.JRC.H.1-Water Resource
Versatile grafting of polysaccharides in homogeneous mild conditions by using atom transfer radical polymerization
A versatile atom transfer radical polymerization (ATRP) method for polysaccharide grafting in homogeneous mild conditions without using protecting group chemistry is presented. Water/DMF mixtures with different compositions were used as the solvent. The "grafting-from" approach was used in order to prepare suitable pullulan and dextran ATRP macroinitiators with a well controlled degree of functionalization. Methacrylate and acrylamide monomers were grafted obtaining good control over the number, molecular weight and polydispersity of the grafted chains without homopolymer formation and polysaccharide degradation. The versatility of this method allowed us to prepare comblike derivatives with a wide range of properties (amphiphilic, ionic, and ther-moresponsive) by simply changing the solvent composition and the catalyst. This could make possible the synthesis of new interesting biomaterials starting from a wide range of polysaccharides