Post translational modifications regulate the function of E4bp4

The basic leucine zipper transcription factor E4bp4 is essential for various immunological processes, most notably the development of natural killer (NK) cells. E4bp4 is required at the point of lineage commitment when NK cell progenitors develop from common lymphoid progenitors. E4bp4 promotes NK cell development by directly regulating the expression of other transcription factors, including Eomes and Id2. Despite its critical role, little is known about how the functions of the E4bp4 protein are regulated within the cellular environment. This study demonstrates that E4bp4 is post translationally modified by phosphorylation and SUMOylation and that these modifications directly regulate the protein’s function. In the absence of either modification, E4bp4 is both a more potent transcriptional activator and transcriptional repressor. In NK cells, the absence of post translational modifications on E4bp4 promotes the expression of target genes Notch1 and E2A. Most strikingly, when expressed in hematopoietic progenitor cells, versions of E4bp4 lacking phosphorylation or SUMOylation sites, promote the development of up to three times more NK cells than the wild type form of E4bp4. This work has implications for the production of NK cells for use in immunotherapy and provides the first evidence that SUMOylation of an individual transcription factor protein can regulate a highly complex cellular process.Open Acces

Towards More Predictive, Physiological and Animal-free In Vitro Models: Advances in Cell and Tissue Culture 2020 Conference Proceedings

Experimental systems that faithfully replicate human physiology at cellular, tissue and organ level are crucial to the development of efficacious and safe therapies with high success rates and low cost. The development of such systems is challenging and requires skills, expertise and inputs from a diverse range of experts, such as biologists, physicists, engineers, clinicians and regulatory bodies. Kirkstall Limited, a biotechnology company based in York, UK, organised the annual conference, Advances in Cell and Tissue Culture (ACTC), which brought together people having a variety of expertise and interests, to present and discuss the latest developments in the field of cell and tissue culture and in vitro modelling. The conference has also been influential in engaging animal welfare organisations in the promotion of research, collaborative projects and funding opportunities. This report describes the proceedings of the latest ACTC conference, which was held virtually on 30th September and 1st October 2020, and included sessions on in vitro models in the following areas: advanced skin and respiratory models, neurological disease, cancer research, advanced models including 3-D, fluid flow and co-cultures, diabetes and other age-related disorders, and animal-free research. The roundtable session on the second day was very interactive and drew huge interest, with intriguing discussion taking place among all participants on the theme of replacement of animal models of disease

GIS w polskiej edukacji wyższej – dyskusja

The idea for this publication was barn in June 2015, during a meeting of Polish teachers involved with Geographic lnformation Systems. The meeting was initiated by the Department of Geoinformation, Faculty of Geographical Sciences, University of Łódź, which received a grant to organize it. The discussion and presentations from academic teachers representing various universities in Poland were very interesting and sometimes heated. it would be advisable for other educators to familiarise themselves with the aspects of GIS education among Polish geographers, foresters, surveyors and other users. The experience of Geoinformation education in Poland is still modest, so the views of people who have been involved at Polish universities with it since the 1990s should be interesting to readers. Geographic lnformation Systems (GIS) – the integration of environmental and climate issues as an important factor for economic development and quality of life – an innovative second-degree studies. Akronim GIS-E-QL: GIS for environment and quality of life. Project objectives: The main aim of the project is to start-up attractive and innovative second­ degree studies – geoinformation in mutual cooperation of the FGS and the FMCS, students education, improving the competence of academic teachers, conference organization, publishing, cooperation with practitioners and establishing contacts with partners from Norway. This aim is consistent with the “Ana lysis of the economy's demand for graduates in key field of strategy in the context of the Europe 2020” 2012 and “Strategy for development of higher education in Poland 2020”, in the field of promoting innovative courses, formed collectively with practitioners, raising awareness of the environment. Joint actions of educators and practitioners, supported the by the strengthening of university's hardware, software and spatial data, will ensure a high quality project. The existing cooperation with practitioners indicate that further training is necessary and they would like to see postgraduates in their institutions. The final beneficiaries of the project will be the students and the academical teaching staff and indirectly the economy of the region. Students who graduate will be the main recipient of the project, the next will be teaching staff who will have contact with the practices and Norwegian partners with similar interests. In broad terms the project will benefit Polish and European economy and environment.The experience of Polish scientists and educators in the GIS has not been as long as mentioned by Michael F. Goodchild who jointly with Ross Newkirk (Goodchild 2006) started the fi rst GIS training course at the University of Western Ontario in Canada in 1975. Discussions on the scope of knowledge included in the GIS have continued at most universities that have offered such classes. In 1988/89, owing to the National Centre for Geographic Information and Analysis (NCGIA), the 3-volume document of over 1000 pages was put together to include curriculums, student materials and other teaching aids. We have good models and we can use them. Meetings and discussions about the GIS education have been and still are regularly held all over the world (Forer P., Unwin D. 1999). When employees of Polish universities were starting to learn the GIS software and possibilities, Morgan J. M., Fleury B., Becker R. A. (1996) had already identifi ed over 800 higher education institutions all over the world that had offered at least one GIS course. The rapid development of new technologies, methods, the creation of new labour markets has arisen discussions on the contents GIS training in various centres of higher education, e.g. in the Netherlands, the US, and those have been similar to the ones presented in this article (Toppen F. J. 1992) and some issues needed to be resolved in court (DiBiase, D. 2008). You can see how important these meetings of educators are for exchanging opinions and experience. They have allowed to meed people representing various fi elds involved in the geoinformation, which may result in co-operation and new educational initiatives, and sometimes, competition. Finally, we should agree with prof. J. Gaździcki (2009 p. 12) that “It is obvious that the success of any measures to modernise education in the area under consideration depends on the interest of academic communities, involvement of research and academic staff in these endeavours, their will, ambition and willingness to co-operate”.This book has been prepared within the project „Geographic Information Systems (GIS) – the integration of environmental and climate issues as an important factor of economic development and quality of life – an innovative second-degree studies” supported by a grant from Norway through the Norway Grants and co-financed by the Polish funds. (Agreement No FSS/2014/HEI/W/0114/U/0013)

The transcription factor E4bp4/Nfil3 controls commitment to the NK lineage and directly regulates Eomes and Id2 expression

The transcription factor E4bp4 (Nfil3) is essential for natural killer (NK) cell production. Here, we show that E4bp4 is required at the NK lineage commitment point when NK progenitors develop from common lymphoid progenitors (CLPs) and that E4bp4 must be expressed at the CLP stage for differentiation toward the NK lineage to occur. To elucidate the mechanism by which E4bp4 promotes NK development, we identified a central core of transcription factors that can rescue NK production from E4bp4(−/−) progenitors, suggesting that they act downstream of E4bp4. Among these were Eomes and Id2, which are expressed later in development than E4bp4. E4bp4 binds directly to the regulatory regions of both Eomes and Id2, promoting their transcription. We propose that E4bp4 is required for commitment to the NK lineage and promotes NK development by directly regulating the expression of the downstream transcription factors Eomes and Id2

Bone morphogenetic protein 8B promotes the progression of non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is characterized by lipotoxicity, inflammation and fibrosis, ultimately leading to end-stage liver disease. The molecular mechanisms promoting NASH are poorly understood, and treatment options are limited. Here, we demonstrate that hepatic expression of bone morphogenetic protein 8B (BMP8B), a member of the transforming growth factor beta (TGFβ)-BMP superfamily, increases proportionally to disease stage in people and animal models with NASH. BMP8B signals via both SMAD2/3 and SMAD1/5/9 branches of the TGFβ-BMP pathway in hepatic stellate cells (HSCs), promoting their proinflammatory phenotype. In vivo, the absence of BMP8B prevents HSC activation, reduces inflammation and affects the wound-healing responses, thereby limiting NASH progression. Evidence is featured in primary human 3D microtissues modelling NASH, when challenged with recombinant BMP8. Our data show that BMP8B is a major contributor to NASH progression. Owing to the near absence of BMP8B in healthy livers, inhibition of BMP8B may represent a promising new therapeutic avenue for NASH treatment.MV, JLG, AVP are supported by MRC programs (MRC MDU Programme Grant. PO 4050281695 “Lipotoxicity and the Metabolic Syndrome” and MRC DMC MC UU 12012/2 to AVP; Lipid Profiling and Signalling, MC UP A90 1006 to JLG) and MRC adjunct funding as part of the Cambridge Initiative in Metabolic Diseases (Lipid Dynamics and Regulation: MC_PC_13030). MV, MA and AVP are also supported by the Cambridge NIHR Biomedical Research Center (Gastroenterology); MV is recipient of the BRC Gastroenterology Pump-Priming award 2018/2019 that founded part of this study. FO is supported by MRC program Grants MR/K0019494/1 and MR/R023026/1. JL is supported by Medical Research Council PhD studentship and a CRUK program grant (C18342/A23390). QMA, MV, AVP, VR, MA and DT are contributing members of the European NAFLD Registry. QMA is supported by the Newcastle NIHR Biomedical Research Centre (BRC). MV has been fellow of the Fondazione Umberto Veronesi in 2014. MA, AVP, and JLG received funding from the Evelyn Trust. MV, OG, DT, MA, FO, QMA, MJN DJL, and AVP are members of the EPoS (Elucidating Pathways of Steatohepatitis) consortium, which is funded by the Horizon 2020 Framework Program of the European Union under Grant Agreement 634413

Bone morphogenetic protein 8B promotes the progression of non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is characterized by lipotoxicity, inflammation and fibrosis, ultimately leading to end-stage liver disease. The molecular mechanisms promoting NASH are poorly understood, and treatment options are limited. Here, we demonstrate that hepatic expression of bone morphogenetic protein 8B (BMP8B), a member of the transforming growth factor beta (TGFβ)-BMP superfamily, increases proportionally to disease stage in people and animal models with NASH. BMP8B signals via both SMAD2/3 and SMAD1/5/9 branches of the TGFβ-BMP pathway in hepatic stellate cells (HSCs), promoting their proinflammatory phenotype. In vivo, the absence of BMP8B prevents HSC activation, reduces inflammation and affects the wound-healing responses, thereby limiting NASH progression. Evidence is featured in primary human 3D microtissues modelling NASH, when challenged with recombinant BMP8. Our data show that BMP8B is a major contributor to NASH progression. Owing to the near absence of BMP8B in healthy livers, inhibition of BMP8B may represent a promising new therapeutic avenue for NASH treatment.MV, JLG, AVP are supported by MRC programs (MRC MDU Programme Grant. PO 4050281695 “Lipotoxicity and the Metabolic Syndrome” and MRC DMC MC UU 12012/2 to AVP; Lipid Profiling and Signalling, MC UP A90 1006 to JLG) and MRC adjunct funding as part of the Cambridge Initiative in Metabolic Diseases (Lipid Dynamics and Regulation: MC_PC_13030). MV, MA and AVP are also supported by the Cambridge NIHR Biomedical Research Center (Gastroenterology); MV is recipient of the BRC Gastroenterology Pump-Priming award 2018/2019 that founded part of this study. FO is supported by MRC program Grants MR/K0019494/1 and MR/R023026/1. JL is supported by Medical Research Council PhD studentship and a CRUK program grant (C18342/A23390). QMA, MV, AVP, VR, MA and DT are contributing members of the European NAFLD Registry. QMA is supported by the Newcastle NIHR Biomedical Research Centre (BRC). MV has been fellow of the Fondazione Umberto Veronesi in 2014. MA, AVP, and JLG received funding from the Evelyn Trust. MV, OG, DT, MA, FO, QMA, MJN DJL, and AVP are members of the EPoS (Elucidating Pathways of Steatohepatitis) consortium, which is funded by the Horizon 2020 Framework Program of the European Union under Grant Agreement 634413