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Additional file 1: Tables S1: Demographics, clinical baseline characteristics, therapy and cause of death of COVID-19 patients.

Additional file 1. Scoping review protocol. Working method and tools used by the domain groups. Table S1. Selected articles catalogued by domain. Table S2. Tables of evidence. A) Virus characterization and viral entry: B) Host signature: C) Pathways: D. Phenotypes. Table S3. B) Conceptual table: SARS-CoV-2 entry. Tabla S4. Immune response to SARS-CoV-2 infection in lung and other tissues (A), peripheral blood (B) and specific cell types in blood immune cells (C). Pathways, host signature (differentially expressed genes and proteins) and body districts, subset per specific omics data: host proteomics, bulk RNAseq and scRNAseq. Table S5. Pathogenic mechanisms in COVID-19 phenotype: SARS-CoV-2���host interactions in the lung. (A), DEG and DEP analysis in other organs and tissues (B) Hub genes and pathway of innate immune response (C), Comorbidities COVID-19 associated not sharing COVID-19 pathogenesis (D), Comorbidities associated and related to COVID-19 pathway (E). Omics and pathway involved were split by different phenotypes: severe, mild/asymptomatic and other Infections. Annexes: Annex 1���Report from Working Group 1: Molecular characterisation of the virus; Annex 2���Report from Working Group 2���Pathways; Annex 3���Report from Working Group 3- Host signatures; Annex 4���Report from Working Group 4���Phenotype. Glossary.

Table S1. Exosome proteins enriched within the EV fraction of the whole ADSC secretome. Table S2. Soluble and EV GO-MF terms enrichment. Table S3 EV fraction GO-MF terms enrichment. Table S4. Top 20 significantly enriched GO BP terms secretome-wide. Table S5. Top 20 significantly enriched GO BP terms in ADSC and AFS EV fractions. Table S6. Top significantly enriched GO BP terms in ADSC and AFS soluble fractions. Table S7. Comparison of miRNA cargo between different ADSC and AFS cell types and secretome pre-conditioning methods. (DOCX 51 kb)

The secretome of human amniotic fluid stem cells (AFSC) has great potential as a therapeutic agent in regenerative medicine. However it must be produced in a clinically compliant manner before it can be used in humans. Here we developed a means of producing a biologically active secretome from AFSCs that is free of all exogenous molecules. We demonstrate that the full secretome is capable of promoting stem cell proliferation, migration and protection of cells against senescence. Furthermore, it has significant anti-inflammatory properties. Most importantly we show that it promotes tissue regeneration in a model of muscle damage. We then demonstrate that the secretome contains extracellular vesicles (EV) that harbour much but not all the biological activity of the whole secretome. Proteomic characterisation of the EV and free secretome fraction show the presence of numerous molecules specific to each fraction that could be key regulators of tissue regeneration. Intriguingly we show that the EVs only contain miRNA and not mRNA. This suggests tissue regeneration in the host is mediated by the action of EVs modifying existing, rather than the imposition of new, signalling pathways. The EVs harbour significant anti-inflammatory activity as well as promoting angiogenesis; the latter may be the mechanistic explanation for their ability to promote muscle regeneration after cardiotoxin injury.

Seuls les 100 premiers auteurs dont les auteurs INRA ont été entrés dans la notice. La liste complète des auteurs et de leurs affiliations est accessible sur la publication.

Most patients infected with SARS-CoV-2 display mild symptoms with good prognosis, while 20% of patients suffer from severe viral pneumonia and up to 5% may require intensive care unit (ICU) admission due to severe acute respiratory syndrome, which could be accompanied by multiorgan failure.Plasma proteomics provide valuable and unbiased information about disease progression and therapeutic candidates. Recent proteomic studies have identified molecular changes in plasma of COVID-19 patients that implied significant dysregulation of several aspects of the inflammatory response accompanied by a general metabolic suppression. However, which of these plasma alterations are associated with disease severity remains only partly characterized.A known limitation of proteomic studies of plasma samples is the large difference in the macromolecule abundance, with concentration spanning at least 10 orders of magnitude. To improve the coverage of plasma contents, we performed a deep proteomic analysis of plasma from 10 COVID-19 patients with severe/fatal pneumonia compared to 10 COVID-19 patients with pneumonia who did not require ICU admission (non-ICU). To this aim, plasma samples were first depleted of the most abundant proteins, trypsin digested and peptides subjected to a high pH reversed-phase peptide fractionation before LC–MS analysis.These results highlighted an increase of proteins involved in neutrophil and platelet activity and acute phase response, which is significantly higher in severe/fatal COVID-19 patients when compared to non-ICU ones. Importantly, these changes are associated with a selective induction of complement cascade factors in severe/fatal COVID-19 patients. Data are available via ProteomeXchange with identifier PXD036491. Among these alterations, we confirmed by ELISA that higher levels of the neutrophil granule proteins DEFA3 and LCN2 are present in COVID-19 patients requiring ICU admission when compared to non-ICU and healthy donors.Altogether, our study provided an in-depth view of plasma proteome changes that occur in COVID-19 patients in relation to disease severity, which can be helpful to identify therapeutic strategies to improve the disease outcome.

Stem cell research & therapy 10(1), 116 (2019). doi:10.1186/s13287-019-1213-1, Published by BioMed Central, London

International audience; Une lecture en contexte historique et sytématique du célèbre texte de Simmel sur la ville et la mentalité moderne

// Gustavo J. S. Pereira 1 , Manuela Antonioli 2, 3 , Hanako Hirata 1 , Rodrigo P. Ureshino 1 , Aline R. Nascimento 1 , Claudia Bincoletto 1 , Tiziana Vescovo 3 , Mauro Piacentini 2, 3 , Gian Maria Fimia 3, 4 , Soraya S. Smaili 1 1 Department of Pharmacology, Federal University of Sao Paulo, (UNIFESP), Sao Paulo, Brazil 2 Department of Biology, University of Rome “Tor Vergata”, Rome, Italy 3 Department of Epidemiology and Preclinical Research, National Institute for Infectious Diseases IRCCS 'Lazzaro Spallanzani', Rome, Italy 4 Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Lecce, Italy Correspondence to: Soraya S. Smaili, email: ssmaili@unifesp.br Gian Maria Fimia, email: gianmaria.fimia@inmi.it Keywords: autophagy, glutamate, NAADP, two-pore channels, AMPK Received: August 20, 2016 Accepted: December 27, 2016 Published: December 31, 2016 ABSTRACT NAADP (nicotinic acid adenine dinucleotide phosphate) has been proposed as a second messenger for glutamate in neuronal and glial cells via the activation of the lysosomal Ca 2+ channels TPC1 and TPC2. However, the activities of glutamate that are mediated by NAADP remain unclear. In this study, we evaluated the effect of glutamate on autophagy in astrocytes at physiological, non-toxic concentration. We found that glutamate induces autophagy at similar extent as NAADP. By contrast, the NAADP antagonist NED-19 or SiRNA-mediated inhibition of TPC1/2 decreases autophagy induced by glutamate, confirming a role for NAADP in this pathway. The involvement of TPC1/2 in glutamate-induced autophagy was also confirmed in SHSY5Y neuroblastoma cells. Finally, we show that glutamate leads to a NAADP-dependent activation of AMPK, which is required for autophagy induction, while mTOR activity is not affected by this treatment. Taken together, our results indicate that glutamate stimulates autophagy via NAADP/TPC/AMPK axis, providing new insights of how Ca 2+ signalling glutamate-mediated can control the cell metabolism in the central nervous system.

Inhibition of a main regulator of cell metabolism, the protein kinase mTOR, induces autophagy and inhibits cell proliferation. However, the molecular pathways involved in the cross-talk between these two mTOR-dependent cell processes are largely unknown. Here we show that the scaffold protein AMBRA1, a member of the autophagy signalling network and a downstream target of mTOR, regulates cell proliferation by facilitating the dephosphorylation and degradation of the proto-oncogene c-Myc. We found that AMBRA1 favours the interaction between c-Myc and its phosphatase PP2A and that, when mTOR is inhibited, it enhances PP2A activity on this specific target, thereby reducing the cell division rate. As expected, such a de-regulation of c-Myc correlates with increased tumorigenesis in AMBRA1-defective systems, thus supporting a role for AMBRA1 as a haploinsufficient tumour suppressor gene.

Autophagy is a major degradative process activated in a rapid and transient manner to cope with stress conditions. Whether autophagy is beneficial or detrimental depends upon the rate of induction and the appropriateness of the duration. Alterations in both autophagy initiation and termination predispose the cell to death, and affect the execution of other inducible processes such as inflammation. In this review we discuss how stress signaling pathways dynamically control the activity of the autophagy machinery by mediating post-translational modifications and regulatory protein interactions. In particular, we highlight the emerging role of TRIM and CULLIN families of ubiquitin ligases which play opposite roles in the autophagy response by promoting or inhibiting, respectively, the activity of the autophagy initiation complex.

Numerous studies are revealing a role of exosomes in intercellular communication, and growing evidence indicates an important function for these vesicles in the progression and pathogenesis of cancer and neurodegenerative diseases. However, the biogenesis process of exosomes is still unclear. Tissue transglutaminase (TG2) is a multifunctional enzyme with different subcellular localizations. Particularly, under stressful conditions, the enzyme has been also detected in the extracellular matrix, but the mechanism(s) by which TG2 is released outside the cells requires further investigation. Therefore, the goal of the present study was to determine whether exosomes might be a vehicle for TG2 to reach the extracellular space, and whether TG2 could be involved in exosomes biogenesis. To address this issue, we isolated and characterized exosomes derived from cells either expressing or not TG2, under stressful conditions (i.e. proteasome impairment or expressing a mutated form of huntingtin (mHtt) containing 84 polyglutamine repeats). Our results show that TG2 is present in the exosomes only upon proteasome blockade, a condition in which TG2 interacts with TSG101 and ALIX, two key proteins involved in exosome biogenesis. Interestingly, we found that TG2 favours the assembly of a protein complex including mHtt, ALIX, TSG101 and BAG3, a co-chaperone involved in the clearance of mHtt. The formation of this complex is paralleled by the selective recruitment of mHtt and BAG3 in the exosomes derived from TG2 proficient cells only. Overall, our data indicate that TG2 is an important player in the biogenesis of exosomes controlling the selectivity of their cargo under stressful cellular conditions. In addition, these vesicles represent the way by which cells can release TG2 into the extracellular space under proteostasis impairment.