889 research outputs found

    Host behaviour and exposure risk in an insect-pathogen interaction

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    1. Studies of variability in host resistance to disease generally emphasize variability in susceptibility given exposure, neglecting the possibility that hosts may vary in behaviours that affect the risk of exposure. 2. In many insects, horizontal transmission of baculoviruses occurs when larvae consume foliage contaminated by the cadavers of virus-infected conspecific larvae; so, host behaviour may have a strong effect on the risk of infection. 3. We studied variability in the behaviour of gypsy moth (Lymantria dispar) larvae, which are able to detect and avoid virus-contaminated foliage. 4. Our results show that detection ability can be affected by the family line that larvae originate from, even at some distance froma virus-infected cadaver, and suggest that cadaver-detection ability may be heritable. 5. There is thus the potential for natural selection to act on cadaver-detection ability, and thereby to affect the dynamics of pathogen-driven cycles in gypsy moth populations. 6. We argue that host behaviour is a neglected component in studies of variability in disease resistance. © 2010 The Authors. Journal compilation © 2010 British Ecological Society

    TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression.

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    Background & Aims: Cholangiocarcinoma (CCA) is a cancer of the hepatic bile ducts that is rarely resectable and is associated with poor prognosis. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) is known to signal via its receptor fibroblast growth factor-inducible 14 (Fn14) and induce cholangiocyte and myofibroblast proliferation in liver injury. We aimed to characterise its role in CCA. Methods: The expression of the TWEAK ligand and Fn14 receptor was assessed immunohistochemically and by bulk RNA and single cell transcriptomics of human liver tissue. Spatiotemporal dynamics of pathway regulation were comprehensively analysed in rat and mouse models of thioacetamide (TAA)-mediated CCA. Flow cytometry, qPCR and proteomic analyses of CCA cell lines and conditioned medium experiments with primary macrophages were performed to evaluate the downstream functions of TWEAK/Fn14. In vivo pathway manipulation was assessed via TWEAK overexpression in NICD/AKT-induced CCA or genetic Fn14 knockout during TAA-mediated carcinogenesis. Results: Our data reveal TWEAK and Fn14 overexpression in multiple human CCA cohorts, and Fn14 upregulation in early TAA-induced carcinogenesis. TWEAK regulated the secretion of factors from CC-SW-1 and SNU-1079 CCA cells, inducing polarisation of proinflammatory CD206+ macrophages. Pharmacological blocking of the TWEAK downstream target chemokine monocyte chemoattractant protein 1 (MCP-1 or CCL2) significantly reduced CCA xenograft growth, while TWEAK overexpression drove cancer-associated fibroblast proliferation and collagen deposition in the tumour niche. Genetic Fn14 ablation significantly reduced inflammatory, fibrogenic and ductular responses during carcinogenic TAA-mediated injury. Conclusion: These novel data provide evidence for the action of TWEAK/Fn14 on macrophage recruitment and phenotype, and cancer-associated fibroblast proliferation in CCA. Targeting TWEAK/Fn14 and its downstream signals may provide a means to inhibit CCA niche development and tumour growth. Lay summary: Cholangiocarcinoma is an aggressive, chemotherapy-resistant liver cancer. Interactions between tumour cells and cells that form a supportive environment for the tumour to grow are a source of this aggressiveness and resistance to chemotherapy. Herein, we describe interactions between tumour cells and their supportive environment via a chemical messenger, TWEAK and its receptor Fn14. TWEAK/Fn14 alters the recruitment and type of immune cells in tumours, increases the growth of cancer-associated fibroblasts in the tumour environment, and is a potential target to reduce tumour formation

    Safety profile of autologous macrophage therapy for liver cirrhosis

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    This work was supported by a Medical Research Council UK grant (Biomedical Catalyst Major Awards Committee; reference MR/M007588/1) to S.J. Forbes. We thank Z.M. Younossi (Center for Outcomes Research in Liver Diseases, Washington, DC, USA) for academic use of the CLDQ instrument and L.J. Fallowfield (Sussex Health Outcomes Research & Education in Cancer (SHORE-C), University of Sussex, UK) for advice about health-related quality of life assessment.Peer reviewedPostprintPostprintPostprintPostprin

    Senolytic treatment preserves biliary regenerative capacity lost through cellular senescence during cold storage

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    Liver transplantation is the only curative option for patients with end-stage liver disease. Despite improvements in surgical techniques, nonanastomotic strictures (characterized by the progressive loss of biliary tract architecture) continue to occur after liver transplantation, negatively affecting liver function and frequently leading to graft loss and retransplantation. To study the biological effects of organ preservation before liver transplantation, we generated murine models that recapitulate liver procurement and static cold storage. In these models, we explored the response of cholangiocytes and hepatocytes to cold storage, focusing on responses that affect liver regeneration, including DNA damage, apoptosis, and cellular senescence. We show that biliary senescence was induced during organ retrieval and exacerbated during static cold storage, resulting in impaired biliary regeneration. We identified decoy receptor 2 (DCR2)–dependent responses in cholangiocytes and hepatocytes, which differentially affected the outcome of those populations during cold storage. Moreover, CRISPR-mediated DCR2 knockdown in vitro increased cholangiocyte proliferation and decreased cellular senescence but had the opposite effect in hepatocytes. Using the p21KO model to inhibit senescence onset, we showed that biliary tract architecture was better preserved during cold storage. Similar results were achieved by administering senolytic ABT737 to mice before procurement. Last, we perfused senolytics into discarded human donor livers and showed that biliary architecture and regenerative capacities were better preserved. Our results indicate that cholangiocytes are susceptible to senescence and identify the use of senolytics and the combination of senotherapies and machine-perfusion preservation to prevent this phenotype and reduce the incidence of biliary injury after transplantation.This work was supported by the UK Medical Research MRC (MR/K017047/1) (to S.J.F.), the Computational and Chemical Biology of Stem Cell Niche (MR/L012766/1) (to S.J.F.), the UK Regenerative Medicine Platform (MR/K026666/1) (to S.J.F.), and the Wellcome Trust Institutional Translational Partnership Award (WT iTPA) (to S.F.-G.). J.M.B. was supported by the Spanish Carlos III Health Institute (ISCIII) (PI15/01132, PI18/01075, and Miguel Servet Program CON14/00129 and CPII19/00008) cofinanced by “Fondo Europeo de Desarrollo Regional” (FEDER); “Instituto de Salud Carlos III” (CIBERehd), Spain; “Euskadi RIS3” (2019222054 and 2020333010); and the Department of Industry of the Basque Country (Elkartek: KK-2020/00008). This research was funded in whole or in part by The Wellcome Trust (grant number 209710/Z/17/Z), a cOAlition S organization

    A Trait‐Based Framework for Assessing the Vulnerability of Marine Species to Human Impacts

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    Marine species and ecosystems are widely affected by anthropogenic stressors, ranging from pollution and fishing to climate change. Comprehensive assessments of how species and ecosystems are impacted by anthropogenic stressors are critical for guiding conservation and management investments. Previous global risk or vulnerability assessments have focused on marine habitats, or on limited taxa or specific regions. However, information about the susceptibility of marine species across a range of taxa to different stressors everywhere is required to predict how marine biodiversity will respond to human pressures. We present a novel framework that uses life-history traits to assess species’ vulnerability to a stressor, which we compare across more than 44,000 species from 12 taxonomic groups (classes). Using expert elicitation and literature review, we assessed every combination of each of 42 traits and 22 anthropogenic stressors to calculate each species’ or representative species group’s sensitivity and adaptive capacity to stressors, and then used these assessments to derive their overall relative vulnerability. The stressors with the greatest potential impact were related to biomass removal (e.g., fisheries), pollution, and climate change. The taxa with the highest vulnerabilities across the range of stressors were mollusks, corals, and echinoderms, while elasmobranchs had the highest vulnerability to fishing-related stressors. Traits likely to confer vulnerability to climate change stressors were related to the presence of calcium carbonate structures, and whether a species exists across the interface of marine, terrestrial, and atmospheric realms. Traits likely to confer vulnerability to pollution stressors were related to planktonic state, organism size, and respiration. Such a replicable, broadly applicable method is useful for informing ocean conservation and management decisions at a range of scales, and the framework is amenable to further testing and improvement. Our framework for assessing the vulnerability of marine species is the first critical step toward generating cumulative human impact maps based on comprehensive assessments of species, rather than habitats
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