Micro- and nano-plastics (MNPs) pollution has become a pressing global environmental issue, with growing concerns regarding its impact on human health. However, evidence on the effects of MNPs on... Show moreMicro- and nano-plastics (MNPs) pollution has become a pressing global environmental issue, with growing concerns regarding its impact on human health. However, evidence on the effects of MNPs on human health remains limited. This paper reviews the three routes of human exposure to MNPs, which include ingestion, inhalation, and dermal contact. It further discusses the potential routes of translocation of MNPs in human lungs, intestines, and skin, analyses the potential impact of MNPs on the homeostasis of human organ systems, and provides an outlook on future research priorities for MNPs in human health. There is growing evidence that MNPs are present in human tissues or fluids. Lab studies, including in vivo animal models and in vitro human-derived cell cultures, revealed that MNPs exposure could negatively affect human health. MNPs exposure could cause oxidative stress, cytotoxicity, disruption of internal barriers like the intestinal, the air–blood and the placental barrier, tissue damage, as well as immune homeostasis imbalance, endocrine disruption, and reproductive and developmental toxicity. Limitedly available epidemiological studies suggest that disorders like lung nodules, asthma, and blood thrombus might be caused or exacerbated by MNPs exposure. However, direct evidence for the effects of MNPs on human health is still scarce, and future research in this area is needed to provide quantitative support for assessing the risk of MNPs to human health. Show less
Leaders can launch hostile attacks on out-groups and organize in-group defence. Whether groups settle the confict in their favour depends, however, on whether followers align with leader’s... Show moreLeaders can launch hostile attacks on out-groups and organize in-group defence. Whether groups settle the confict in their favour depends, however, on whether followers align with leader’s initiatives. Yet how leader and followers coordinate during intergroup confict remains unknown. Participants in small groups elected a leader and made costly contributions to intergroup confict while dorsolateral prefrontal cortex (DLPFC) activity was simultaneously measured. Leaders were more sacrifcial and their contribution infuenced group survival to a greater extent during in-group defence than during out-group attacks. Leaders also had increased DLPFC activity when defending in-group, which predicted their comparatively strong contribution to confict; followers reciprocated their leader’s initiatives the more their DLPFC activity synchronized with that of their leader. When launching attacks, however, leaders and followers aligned poorly at behavioural and neural levels, which explained why out-group attacks often failed. Our results provide a neurobehavioural account of leader–follower coordination during intergroup confict and reveal leader–follower behavioural/neural alignment as pivotal for groups settling conficts in their favour. Show less
Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently... Show moreBackground: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk. Show less
A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million... Show moreA major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology. Show less
Unlike cutaneous melanoma, uveal melanoma (UM) is characterized by mutations in GNAQ and GNA11 and remains a fatal disease because there is essentially no effective targeted therapy or... Show moreUnlike cutaneous melanoma, uveal melanoma (UM) is characterized by mutations in GNAQ and GNA11 and remains a fatal disease because there is essentially no effective targeted therapy or immunotherapy available. We report the discovery of the copper ionophore elesclomol as a GNAQ/11-specific UM inhibitor. Elesclomol was identified in a differential cytotoxicity screen of an in-house tool compound library, and its in vivo pharmacological efficacy was further confirmed in zebrafish and mouse UM models. Mechanistically, elesclomol transports copper to mitochondria and produces a large amount of reactive oxygen species (ROS) as Cu(II) is reduced to Cu(I) in GNAQ/11-mutant UM cells, which selectively activates LATS1 kinase in the Hippo signaling pathway and consequently promotes YAP phosphorylation and inhibits its nuclear accumulation. The inactivation of YAP downregulates the expression of SNAI2, which in turn suppresses the migration of UM cells. These findings were cross validated by our clinical observation that YAP activation was found specifically in UM samples with a GNAQ/11 mutation. Furthermore, addition of binimetinib, a MEK inhibitor, to elesclomol increased its synthetic lethality to GNAQ/11-mutant UM cells, thereby overriding drug resistance. This effect was confirmed in an orthotopic xenograft model and in a patient-derived xenograft model of UM. These studies reveal a novel mechanistic basis for repurposing elesclomol by showing that copper homeostasis is a GNAQ/11-specific vulnerability in UM. Elesclomol may provide a new therapeutic path for selectively targeting malignant GNAQ/11-mutant UM. Show less
Bischetti, M.; Feruglio, C.; D'Odorico, V.; Arav, N.; Banados, E.; Becker, G.; ... ; Fiore, F. 2022
Bright quasars, powered by accretion onto billion-solar-mass black holes, already existed at the epoch of reionization, when the Universe was 0.5-1 billion years old(1). How these black holes... Show moreBright quasars, powered by accretion onto billion-solar-mass black holes, already existed at the epoch of reionization, when the Universe was 0.5-1 billion years old(1). How these black holes formed in such a short time isthe subject of debate, particularly asthey lie above the correlation between black-hole mass and galaxy dynamical mass(2,3) in the local Universe. What slowed down black-hole growth, leading towards the symbioticgrowth observed in the local Universe, and when this process started, has hitherto not been known, although black-hole feedback is a likely driver(4). Here we report optical and near-infrared observations of a sample of quasars at redshifts 5.8 less than or similar to z less than or similar to 6.6. About half ofthe quasar spectra reveal broad, blueshifted absorption line troughs, tracing black-hole-driven winds with extreme outflowvelocities, up to 17% of the speed of light. The fraction of quasars with such outflow winds at z greater than or similar to 5.8 approximate to 2.4 is times higher than at z approximate to 2-4. We infer that outflows at z greater than or similar to 5.8 inject large amounts of energy into the interstellar medium and suppress nuclear gas accretion, slowing down black-hole growth. The outflow phase may then mark the beginning of substantial black-hole feedback. The red optical colours of outflow quasars at z greater than or similar to 5.8 indeed suggest that these systems are dusty and may be caught during an initial quenching phase of obscured accretion(5). Show less
Emerging research supports that triclosan (TCS), an antimicrobial agent found in thousands of consumer products, exacerbates colitis and colitis-associated colorectal tumorigenesis in animal models... Show moreEmerging research supports that triclosan (TCS), an antimicrobial agent found in thousands of consumer products, exacerbates colitis and colitis-associated colorectal tumorigenesis in animal models. While the intestinal toxicities of TCS require the presence of gut microbiota, the molecular mechanisms involved have not been defined. Here we show that intestinal commensal microbes mediate metabolic activation of TCS in the colon and drive its gut toxicology. Using a range of in vitro, ex vivo, and in vivo approaches, we identify specific microbial β-glucuronidase (GUS) enzymes involved and pinpoint molecular motifs required to metabolically activate TCS in the gut. Finally, we show that targeted inhibition of bacterial GUS enzymes abolishes the colitis-promoting effects of TCS, supporting an essential role of specific microbial proteins in TCS toxicity. Together, our results define a mechanism by which intestinal microbes contribute to the metabolic activation and gut toxicity of TCS, and highlight the importance of considering the contributions of the gut microbiota in evaluating the toxic potential of environmental chemicals. Show less
