1,326 research outputs found
The Central Role of Menin and Wild-Type MLL in MLL-AF9-Induced Leukemia
Get PDFChromosomal translocations involving the Mixed Lineage Leukemia (MLL) gene lead to the expression of MLL fusion proteins and acute leukemia. MLL fusion protein-induced leukemia is aggressive, and often refractory to therapy, highlighting the importance of studying the pathogenesis of this disease. MLL fusion proteins upregulate wild-type MLL target genes, including HOX genes, and block hematopoietic differentiation, promoting leukemogenesis. However, the precise mechanism by which MLL fusion proteins upregulate HOX genes and block differentiation has been unclear. My thesis
research shows that leukemia cells expressing the MLL fusion protein MLL-AF9 also express wild-type MLL from the non-translocated MLL allele. Wild-type MLL is required for MLL-AF9-mediated HOX gene upregulation and leukemogenesis. Menin, a
nuclear DNA-binding protein, recruits both wild-type MLL and MLL-AF9 to HOX genes to activate their transcription, highlighting the central role of menin in this disease. We also found that menin blocks MLL-AF9 leukemia cell differentiation by promoting the
expression of the polycomb group protein EZH2. EZH2 represses target genes of the pro-differentiation transcription factor C/EBP&alpha, a previously unknown mechanism for blocking differentiation. The cooperation between EZH2 and trithorax-associated menin is counter to the classical opposing roles of polycomb and trithorax proteins. These findings have uncovered novel insights into how menin and MLL-AF9 upregulate target genes and block leukemia cell differentiation, highlighting novel potential therapeutic targets for this disease
Quantifying the factors influencing people’s car type choices in Europe: Results of a stated preference survey
Get PDFThis study aims at tracking the evolution of the attitude of car drivers towards electro-mobility. The results of a new survey conducted in six European countries are shown. The purchase price continues to represent the major hurdle to widespread adoption of zero tailpipe emission cars.JRC.C.4-Sustainable Transpor
Scalable Generation of Universal Platelets from Human Induced Pluripotent Stem Cells
Get PDFSummary Human induced pluripotent stem cells (iPSCs) provide a potentially replenishable source for the production of transfusable platelets. Here, we describe a method to generate megakaryocytes (MKs) and functional platelets from iPSCs in a scalable manner under serum/feeder-free conditions. The method also permits the cryopreservation of MK progenitors, enabling a rapid “surge” capacity when large numbers of platelets are needed. Ultrastructural/morphological analyses show no major differences between iPSC platelets and human blood platelets. iPSC platelets form aggregates, lamellipodia, and filopodia after activation and circulate in macrophage-depleted animals and incorporate into developing mouse thrombi in a manner identical to human platelets. By knocking out the β2-microglobulin gene, we have generated platelets that are negative for the major histocompatibility antigens. The scalable generation of HLA-ABC-negative platelets from a renewable cell source represents an important step toward generating universal platelets for transfusion as well as a potential strategy for the management of platelet refractoriness
Modelling storm hydrodynamics on gravel beaches with XBeach-G
Get PDFThe research in this study was funded by the Engineering and Physical Sciences Research Council (EPSRC; EP/H040056/1). The full text is under embargo until 01.09.1
Wave farm impact on the beach profile: A case study
Get PDFIf wave energy is to become a fully-fledged renewable, its environmental impacts must be fully understood. The objective of the present work is to examine the impact of a wave farm on the beach profile through a case study. The methodology is based on two coupled numerical models: a nearshore wave propagation model and a morphodynamic model, which are run in two scenarios, both with and without the wave farm. Wave data from a nearby coastal buoy are used to prescribe the boundary conditions. A positive effect on the wave climate, the cross-shore sediment transport and, consequently, the evolution of the beach profile itself due to the presence of the wave farm was found. The wave farm leads to a reduction in the erosion of the beach face. This work constitutes the first stage of the investigation of the effectiveness of a wave farm as a coastal defence measure, and the accuracy of the quantification of the erosion reduction will be enhanced in future research. In any case, the overarching picture that emerges is that wave farms, in addition to providing carbon-free energy, can be used as elements of a coastal defence scheme.If wave energy is to become a fully-fledged renewable, its environmental impacts must be fully understood. The objective of the present work is to examine the impact of a wave farm on the beach profile through a case study. The methodology is based on two coupled numerical models: a nearshore wave propagation model and a morphodynamic model, which are run in two scenarios, both with and without the wave farm. Wave data from a nearby coastal buoy are used to prescribe the boundary conditions. A positive effect on the wave climate, the cross-shore sediment transport and, consequently, the evolution of the beach profile itself due to the presence of the wave farm was found. The wave farm leads to a reduction in the erosion of the beach face. This work constitutes the first stage of the investigation of the effectiveness of a wave farm as a coastal defence measure, and the accuracy of the quantification of the erosion reduction will be enhanced in future research. In any case, the overarching picture that emerges is that wave farms, in addition to providing carbon-free energy, can be used as elements of a coastal defence scheme
Towards a contemporary social care ‘prevention narrative’ of principled complexity: An integrative literature review
Get PDFPrevention has become increasingly central in social care policy and commissioning strategies within the United Kingdom (UK). Commonly there is reliance on understandings borrowed from the sphere of public health, leaning on a prevention discourse characterised by the 'upstream and downstream' metaphor. Whilst framing both structural factors and responses to individual circumstances, the public health approach nonetheless suggests linearity in a cause and effect relationship. Social care and illness follow many trajectories and this conceptualisation of prevention may limit its effectiveness and scope in social care. Undertaken as part of a commissioned evaluation of the Social Services and Wellbeing Act (2014) Wales, a systematic integrative review was conducted to establish the key current debates within prevention work, and how prevention is conceptually framed, implemented and evaluated within the social care context. The databases Scopus, ASSIA, CINAHL and Social Care Online were initially searched in September 2019 resulting in 52 documents being incorporated for analysis. A further re-run of searches was run in March 2021, identifying a further 14 documents, thereby creating a total of 66. Predominantly, these were journal articles or research reports (n = 53), with the remainder guidance or strategy documents, briefings or process evaluations (n = 13). These were categorised by their primary theme and focus, as well as document format and research method before undergoing thematic analysis. This highlighted the continued prominence of three-tiered, linear public health narratives in the framing of prevention for social care, with prevention work often categorised and enacted with inconsistency. Common drivers for prevention activity continue to be cost reduction and reduced dependence on the care system in the future. Through exploring prevention for older people and caregivers, we argue for an approach to prevention aligning with the complexities of the social world surrounding it. Building on developments in complexity theory in social science and healthcare, we offer an alternative view of social care prevention guided by principles rooted in the everyday realities of communities, service users and caregivers
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