UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma

Although clonal neo-antigen burden is associated with improved response to immune therapy, the functional basis for this remains unclear. Here we study this question in a novel controlled mouse melanoma model that enables us to explore the effects of intra-tumor heterogeneity (ITH) on tumor aggressiveness and immunity independent of tumor mutational burden. Induction of UVB-derived mutations yields highly aggressive tumors with decreased anti-tumor activity. However, single-cell-derived tumors with reduced ITH are swiftly rejected. Their rejection is accompanied by increased T cell reactivity and a less suppressive microenvironment. Using phylogenetic analyses and mixing experiments of single-cell clones, we dissect two characteristics of ITH: the number of clones forming the tumor and their clonal diversity. Our analysis of melanoma patient tumor data recapitulates our results in terms of overall survival and response to immune checkpoint therapy. These findings highlight the importance of clonal mutations in robust immune surveillance and the need to quantify patient ITH to determine the response to checkpoint blockade

Human protein reference database—2006 update

Human Protein Reference Database (HPRD) () was developed to serve as a comprehensive collection of protein features, post-translational modifications (PTMs) and protein–protein interactions. Since the original report, this database has increased to >20 000 proteins entries and has become the largest database for literature-derived protein–protein interactions (>30 000) and PTMs (>8000) for human proteins. We have also introduced several new features in HPRD including: (i) protein isoforms, (ii) enhanced search options, (iii) linking of pathway annotations and (iv) integration of a novel browser, GenProt Viewer (), developed by us that allows integration of genomic and proteomic information. With the continued support and active participation by the biomedical community, we expect HPRD to become a unique source of curated information for the human proteome and spur biomedical discoveries based on integration of genomic, transcriptomic and proteomic data

Multi-omics analysis reveals the influence of genetic and environmental risk factors on developing gut microbiota in infants at risk of celiac disease

none38siBackground: Celiac disease (CD) is an autoimmune digestive disorder that occurs in genetically susceptible individuals in response to ingesting gluten, a protein found in wheat, rye, and barley. Research shows that genetic predisposition and exposure to gluten are necessary but not sufficient to trigger the development of CD. This suggests that exposure to other environmental stimuli early in life, e.g., cesarean section delivery and exposure to antibiotics or formula feeding, may also play a key role in CD pathogenesis through yet unknown mechanisms. Here, we use multi-omics analysis to investigate how genetic and early environmental risk factors alter the development of the gut microbiota in infants at risk of CD. Results: Toward this end, we selected 31 infants from a large-scale prospective birth cohort study of infants with a first-degree relative with CD. We then performed rigorous multivariate association, cross-sectional, and longitudinal analyses using metagenomic and metabolomic data collected at birth, 3 months and 6 months of age to explore the impact of genetic predisposition and environmental risk factors on the gut microbiota composition, function, and metabolome prior to the introduction of trigger (gluten). These analyses revealed several microbial species, functional pathways, and metabolites that are associated with each genetic and environmental risk factor or that are differentially abundant between environmentally exposed and non-exposed infants or between time points. Among our significant findings, we found that cesarean section delivery is associated with a decreased abundance of Bacteroides vulgatus and Bacteroides dorei and of folate biosynthesis pathway and with an increased abundance of hydroxyphenylacetic acid, alterations that are implicated in immune system dysfunction and inflammatory conditions. Additionally, longitudinal analysis revealed that, in infants not exposed to any environmental risk factor, the abundances of Bacteroides uniformis and of metabolite 3-3-hydroxyphenylproprionic acid increase over time, while those for lipoic acid and methane metabolism pathways decrease, patterns that are linked to beneficial immunomodulatory and anti-inflammatory effects. Conclusions: Overall, our study provides unprecedented insights into major taxonomic and functional shifts in the developing gut microbiota of infants at risk of CD linking genetic and environmental risk factors to detrimental immunomodulatory and inflammatory effects. [MediaObject not available: see fulltext.].noneLeonard M.M.; Karathia H.; Pujolassos M.; Troisi J.; Valitutti F.; Subramanian P.; Camhi S.; Kenyon V.; Colucci A.; Serena G.; Cucchiara S.; Montuori M.; Malamisura B.; Francavilla R.; Elli L.; Fanelli B.; Colwell R.; Hasan N.; Zomorrodi A.R.; Fasano A.; Piemontese P.; Calvi A.; Baldassarre M.; Norsa L.; Trovato C.M.; Raguseo C.L.; Passaro T.; Roggero P.; Crocco M.; Morelli A.; Perrone M.; Chieppa M.; Scala G.; Lionetti M.E.; Catassi C.; Serretiello A.; Vecchi C.; De Villsante G.C.Leonard, M. M.; Karathia, H.; Pujolassos, M.; Troisi, J.; Valitutti, F.; Subramanian, P.; Camhi, S.; Kenyon, V.; Colucci, A.; Serena, G.; Cucchiara, S.; Montuori, M.; Malamisura, B.; Francavilla, R.; Elli, L.; Fanelli, B.; Colwell, R.; Hasan, N.; Zomorrodi, A. R.; Fasano, A.; Piemontese, P.; Calvi, A.; Baldassarre, M.; Norsa, L.; Trovato, C. M.; Raguseo, C. L.; Passaro, T.; Roggero, P.; Crocco, M.; Morelli, A.; Perrone, M.; Chieppa, M.; Scala, G.; Lionetti, M. E.; Catassi, C.; Serretiello, A.; Vecchi, C.; De Villsante, G. C

Nickel oxide (NiO) nanoparticles disturb physiology and induce cell death in the yeast Saccharomyces cerevisiae

The increasing use of nanoparticles (NPs) has spurred concerns about their toxic effects. This work aimed to assess the potential hazards of nickel oxide (NiO) NPs using the yeast Saccharomyces cerevisiae as a cell model. Yeast cells exposed for 6 h to 100 mg/L NiO NPs presented reduced metabolic activity (esterase activity and FUN-1 dye processing) and enhanced accumulation of reactive oxygen species. NiO NPs induced the loss of cell viability in a dose-dependent manner. Study of the dissolution of NiO NPs in aqueous media, together with the toxicological data, suggests that the nickel released by the NPs cannot explain all the toxic effects observed in S. cerevisiae caused by the NPs. Transmission electron microscopy observations revealed that NiO NPs were adsorbed onto cell surface but did not enter into yeast cells. Isogenic mutants (cwp1? and cwp2?) with increased cell wall porosity did not display enhanced susceptibility to NiO NPs compared to the wild type strain. Our results suggest that NiO NPs exert their toxic effect by an indirect mechanism. This work contributes to knowledge of the potential hazards of NiO NPs and to the elucidation of their mechanisms of toxic action.This work was performed in the framework of the financing by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit, COMPETE 2020 (POCI-01-0145-FEDER-006684), and BioTecNorte operation (NORTE-01-0145-FEDER-000004) funded by the European Regional Development Fund under the scope of Norte2020—Programa Operacional Regional do Norte and LAQV (UID/QUI/50006/2013—POCI/01/0145/FEDER/007265)withfinancial support from FCT/MEC through national funds and co-financed by FEDER, under the Partnership Agreement PT2020.info:eu-repo/semantics/publishedVersio