77 research outputs found
PARP14 and PARP9/DTX3L regulate interferon-induced ADP-ribosylation
PARP-catalysed ADP-ribosylation (ADPr) is important in regulating various cellular pathways. Until recently, PARP-dependent mono-ADP-ribosylation has been poorly understood due to the lack of sensitive detection methods. Here, we utilised an improved antibody to detect mono-ADP-ribosylation. We visualised endogenous interferon (IFN)-induced ADP-ribosylation and show that PARP14 is a major enzyme responsible for this modification. Fittingly, this signalling is reversed by the macrodomain from SARS-CoV-2 (Mac1), providing a possible mechanism by which Mac1 counteracts the activity of antiviral PARPs. Our data also elucidate a major role of PARP9 and its binding partner, the E3 ubiquitin ligase DTX3L, in regulating PARP14 activity through protein-protein interactions and by the hydrolytic activity of PARP9 macrodomain 1. Finally, we also present the first visualisation of ADPr-dependent ubiquitylation in the IFN response. These approaches should further advance our understanding of IFN-induced ADPr and ubiquitin signalling processes and could shed light on how different pathogens avoid such defence pathways
Bigraphical Refinement
We propose a mechanism for the vertical refinement of bigraphical reactive
systems, based upon a mechanism for limiting observations and utilising the
underlying categorical structure of bigraphs. We present a motivating example
to demonstrate that the proposed notion of refinement is sensible with respect
to the theory of bigraphical reactive systems; and we propose a sufficient
condition for guaranteeing the existence of a safety-preserving vertical
refinement. We postulate the existence of a complimentary notion of horizontal
refinement for bigraphical agents, and finally we discuss the connection of
this work to the general refinement of Reeves and Streader.Comment: In Proceedings Refine 2011, arXiv:1106.348
Potential role of endocrine gastrin in the colonic adenoma carcinoma sequence
The role of hyper-gastrinaemia in the incidence of colonic cancer remains to be clarified. The aim of this study was to determine whether cholecystokinin-2 (CCK-2) receptor expression predicts the sensitivity of human colonic adenomas to the proliferative effects of serum hyper-gastrinaemia. Gene expression of the classical (74âkDa) CCK-2 receptor in human colonic adenoma specimens and cell lines, was quantified by real-time PCR. Western blotting, using a CCK-2 receptor antiserum, confirmed protein expression. A transformed human colonic adenoma was grown in SCID mice, with hyper-gastrinaemia induced by protein pump inhibitors. CCK-2 receptor blockade was achieved by using neutralising antiserum. Both human colonic adenoma cell lines and biopsies expressed CCK-2 receptor mRNA at levels comparable with CCK-2 receptor transfected fibroblasts and oxyntic mucosa. Western blotting confirmed immunoreactive CCK-2 receptor bands localised to 45, 74 and 82.5âkDa. Omeprazole and lansoprazole-induced hyper-gastrinaemia (resulting in serum gastrin levels of 34.0 and 153.0 pM, respectively) significantly increased the weight of the human adenoma grafts (43% (P=0.016) and 70% (P=0.014), respectively). The effect of hypergastrinaemia on tumour growth was reversed by use of antiserum directed against the CCK-2 receptor. Hyper-gastrinaemia may promote proliferation of human colonic adenomas that express CCK-2 receptor isoforms
PARP14 is a PARP with both ADP-ribosyl transferase and hydrolase activities
This is the final version. Available on open access from the American Association for the Advancement of Science via the DOI in this recordData availability:
The MS proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE (92) partner repository with the dataset identifier PXD043452.PARP14 is a mono-ADP-ribosyl transferase involved in the control of immunity, transcription, and DNA replication stress management. However, little is known about the ADP-ribosylation activity of PARP14, including its substrate specificity or how PARP14-dependent ADP-ribosylation is reversed. We show that PARP14 is a dual-function enzyme with both ADP-ribosyl transferase and hydrolase activity acting on both protein and nucleic acid substrates. In particular, we show that the PARP14 macrodomain 1 is an active ADP-ribosyl hydrolase. We also demonstrate hydrolytic activity for the first macrodomain of PARP9. We reveal that expression of a PARP14 mutant with the inactivated macrodomain 1 results in a marked increase in mono(ADP-ribosyl)ation of proteins in human cells, including PARP14 itself and antiviral PARP13, and displays specific cellular phenotypes. Moreover, we demonstrate that the closely related hydrolytically active macrodomain of SARS2 Nsp3, Mac1, efficiently reverses PARP14 ADP-ribosylation in vitro and in cells, supporting the evolution of viral macrodomains to counteract PARP14-mediated antiviral response.Biotechnology and Biological Sciences Research Council (BBSRC)Wellcome TrustOxford University Challenge Seed FundEdward Penley Abraham Research FundOvarian Cancer Research AllianceResearch Council of NorwaySwedish Research CouncilMedical Research Council (MRC)Novo Nordisk Foundation Center for Protein ResearchDanish Council of Independent ResearchDanish Cancer Societ
Setting a baseline for global urban virome surveillance in sewage
The rapid development of megacities, and their growing connectedness across the world is becoming a distinct driver for emerging disease outbreaks. Early detection of unusual disease emergence and spread should therefore include such cities as part of risk-based surveillance. A catch-all metagenomic sequencing approach of urban sewage could potentially provide an unbiased insight into the dynamics of viral pathogens circulating in a community irrespective of access to care, a potential which already has been proven for the surveillance of poliovirus. Here, we present a detailed characterization of sewage viromes from a snapshot of 81 high density urban areas across the globe, including in-depth assessment of potential biases, as a proof of concept for catch-all viral pathogen surveillance. We show the ability to detect a wide range of viruses and geographical and seasonal differences for specific viral groups. Our findings offer a cross-sectional baseline for further research in viral surveillance from urban sewage samples and place previous studies in a global perspective
Multi-agent Systems Design and Prototyping with Bigraphical Reactive Systems
International audienceSeveral frameworks and methodologies have been proposed to ease the design of Multi Agent Systems (MAS), but the vast majority of them is tightly tied to specific implementation platforms. In this paper, we outline a methodology for MAS design and prototyping in the more abstract framework of Bigraphical Reactive Systems (BRS). In our approach, components and elements of the application domain are modelled as bigraphs, and their dynamics as graph rewriting rules. Desiderata can be encoded by means of type systems or logical formulae. Then, the BDI agents (i.e., their beliefs, desires and intentions) are identified and extracted from the BRS. This yield a prototype which can be run as distributed bigraphical system, evolving by means of distributed transactional rewritings triggered by cooperating agents depending on their internal intentions and beliefs.This methodology allows the designer to benefit from the results and tools from the theory of BRS, especially in the requirement analysis and validation phases. Among other results, we mention behavioural equivalences, temporal/spatial logics, visual tools for editing, for simulation and for model checking, etc. Moreover, bigraphs can be naturally composed, thus allowing for modular design of MAS
Establishing a method for analysing metaphors in higher education teaching: a case from business management teaching
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