The pioneer transcription factors Foxa1 and Foxa2 regulate alternative RNA splicing during thymocyte positive selection.

During positive selection at the transition from CD4+CD8+ double-positive (DP) to single positive (SP) thymocyte, TCR signalling results in appropriate MHC-restriction and signals for survival and progression. We show that the pioneer transcription factors Foxa1 and Foxa2 are required to regulate RNA splicing during positive selection. Foxa1 and Foxa2 had overlapping/compensatory roles. Conditional deletion of both Foxa1 and Foxa2 from DP thymocytes reduced positive selection and development of CD4SP, CD8SP and peripheral naïve CD4+T-cells. Foxa1 and Foxa2 regulated expression of many genes encoding splicing-factors and regulators, including Mbnl1, H1f0, Sf3b1, Hnrnpa1, Rnpc3, Prpf4b, Prf40b and Snrpd3. Within the positively selecting CD69+DP cells, alternative RNA splicing was dysregulated in the double Foxa1/Foxa2 conditional knockout, leading to >850 differentially used exons (DEU). Many genes important for this stage of T-cell development (Ikzf1-3, Ptprc, Stat5a, Stat5b, Cd28, Tcf7) and splicing-factors (Hnrnpab, Hnrnpa2b1, Hnrnpu, Hnrnpul1, Prpf8) showed multiple DEU. Thus Foxa1 and Foxa2 are required during positive selection to regulate alternative splicing of genes essential for T-cell development, and that by also regulating splicing of splicing-factors, they exert widespread control of alternative splicing

In the fetal thymus, Gli3 in thymic epithelial cells promotes thymocyte positive selection and differentiation by repression of Shh

Gli3 is a Hedgehog (Hh) responsive transcription factor that can function as a transcriptional repressor or activator. We show that Gli3 activity in thymic epithelial cells (TEC) promotes positive selection and differentiation from CD4+CD8+ to CD4+CD8- single positive (SP4) cell in the fetal thymus and that Gli3 represses Shh Constitutive deletion of Gli3, and conditional deletion of Gli3 from TEC, reduced differentiation to SP4, whereas conditional deletion of Gli3 from thymocytes did not. Conditional deletion of Shh from TEC increased differentiation to SP4, and expression of Shh was upregulated in the Gli3-deficient thymus. Use of a transgenic Hh-reporter showed that the Hh pathway was active in thymocytes, and increased in the Gli3-deficient fetal thymus. Neutralisation of endogenous Hh proteins in the Gli3-/- thymus restored SP4 differentiation, indicating that Gli3 in TEC promotes SP4 differentiation by repression of Shh Transcriptome analysis showed that Hh-mediated transcription was increased but TCR-mediated transcription decreased in Gli3-/- thymocytes compared to WT

The transcriptional repressor Bcl6 promotes pre-TCR induced differentiation to CD4+CD8+ thymocyte and attenuates Notch1 activation

Pre-TCR signal transduction is required for developing thymocytes to differentiate from CD4-CD8- double negative (DN) to CD4+CD8+ double positive (DP) cell. Notch signalling is required for T-cell fate specification and must be maintained throughout β-selection, but inappropriate Notch activation in DN4 and DP cells is oncogenic. Here, we show that pre-TCR signalling leads to increased expression of the transcriptional repressor Bcl6 and that Bcl6 is required for differentiation to DP. Conditional deletion of Bcl6 from thymocytes reduced pre-TCR-induced differentiation to DP cell, disrupted expansion and enrichment of icTCRβ+ cells within the DN population and increased DN4 cell death. It also increased Notch1 activation and Notch-mediated transcription in the DP population. Thus, Bcl6 is required in thymocyte development for efficient differentiation from DN3 to DP cell and to attenuate Notch1 activation in DP cells. Given the importance of inappropriate NOTCH1 signalling in T-ALL, and the involvement of Bcl6 in other types of leukaemia, this study is important to our understanding of T-ALL

Sport in the city: measuring economic significance at the local level

In many cities throughout Europe, sport is increasingly being used as a tool for economic revitalisation. While there has been a growth in literature relating to the specific economic impacts of sports-led development, including professional sport facilities, teams, and sport events, limited research has been undertaken on the contribution of the whole sport sector to output and employment. In the United Kingdom (UK), studies have focused on evaluating sport-related economic activity at the national level, yet despite the increasing use of sport for local economic development little research has been undertaken at the city level. To address this situation, this article uses the National Income Accounting framework to measure the economic importance of sport in Sheffield, UK. It shows that the value-added in 1996/97 was 165.61m or 4.11% of Gross Domestic Product (GDP), approximately twice the amount predicted from current national estimates. It is argued that this can primarily be explained by previous studies under-estimating the economic importance of sport, largely due to methodological differences. It goes on to suggest that future research on the significance of sport should be undertaken at the local level to provide policymakers with information at the spatial level where regeneration programmes are being implemented.</p

Prospects for radical emissions reduction through behaviour and lifestyle change

Over the past two decades, scholars and practitioners across the social sciences, in policy and beyond have proposed, trialled and developed a wide range of theoretical and practical approaches designed to bring about changes in behaviours and lifestyles that contribute to climate change. With the exception of the establishment of a small number of iconic behaviours such as recycling, it has however proved extremely difficult to bring about meaningful transformations in personal greenhouse gas emissions at either the individual or societal level, with multiple reviews now pointing to the limited efficacy of current approaches. We argue that the majority of approaches designed to achieve mitigation have been constrained by the need to operate within prevailing social scientific, economic and political orthodoxies which have precluded the possibility of non-marginal change. In this paper we ask what a truly radical approach to reducing personal emissions would look like from social science perspectives which challenge the unstated assumptions severely limiting action to date, and which explore new alternatives for change. We emphasise the difficulties likely to impede the instituting of genuinely radical societal change regarding climate change mitigation, whilst proposing ways that the ground could be prepared for such a transformation to take place

Experience of clinical services shapes attitudes to mental health data sharing: findings from a UK-wide survey

BACKGROUND: Routinely-collected mental health data could deliver novel insights for mental health research. However, patients’ willingness to share their mental health data remains largely unknown. We investigated factors influencing likelihood of sharing these data for research purposes amongst people with and without experience of mental illness. METHODS: We collected responses from a diverse sample of UK National Health Service (NHS) users (n = 2187) of which about half (n = 1087) had lifetime experience of mental illness. Ordinal logistic regression was used to examine the influence of demographic factors, clinical service experience, and primary mental illness on willingness to share mental health data, contrasted against physical health data. RESULTS: There was a high level of willingness to share mental (89.7%) and physical (92.8%) health data for research purposes. Higher levels of satisfaction with the NHS were associated with greater willingness to share mental health data. Furthermore, people with personal experience of mental illness were more willing than those without to share mental health data, once the variable of NHS satisfaction had been controlled for. Of the mental illnesses recorded, people with depression, obsessive-compulsive disorder (OCD), personality disorder or bipolar disorder were significantly more likely to share their mental health data than people without mental illness. CONCLUSIONS: These findings suggest that positive experiences of health services and personal experience of mental illness are associated with greater willingness to share mental health data. NHS satisfaction is a potentially modifiable factor that could foster public support for increased use of NHS mental health data in research. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12889-022-12694-z

Work restructuring and changing craft identity: the Tale of the Disaffected Weavers (or what happens when the rug is pulled from under your feet)

This article explores the changes in worker identity that can occur during manufacturing restructuring – specifically those linked to the declining status of craft work – through an in-depth case study of Weaveco, a UK carpet manufacturer. An analysis of changes in the labour process is followed by employee reactions centred on the demise of the traditional craft identity of male carpet weavers. The voices of the weavers dramatize the tensions involved in reconstructing their masculine identity, and we consider the implications this has for understanding gendered work relations

PD-1 Co-inhibitory and OX40 Co-stimulatory Crosstalk Regulates Helper T Cell Differentiation and Anti-Plasmodium Humoral Immunity

SummaryThe differentiation and protective capacity of Plasmodium-specific T cells are regulated by both positive and negative signals during malaria, but the molecular and cellular details remain poorly defined. Here we show that malaria patients and Plasmodium-infected rodents exhibit atypical expression of the co-stimulatory receptor OX40 on CD4 T cells and that therapeutic enhancement of OX40 signaling enhances helper CD4 T cell activity, humoral immunity, and parasite clearance in rodents. However, these beneficial effects of OX40 signaling are abrogated following coordinate blockade of PD-1 co-inhibitory pathways, which are also upregulated during malaria and associated with elevated parasitemia. Co-administration of biologics blocking PD-1 and promoting OX40 signaling induces excessive interferon-gamma that directly limits helper T cell-mediated support of humoral immunity and decreases parasite control. Our results show that targeting OX40 can enhance Plasmodium control and that crosstalk between co-inhibitory and co-stimulatory pathways in pathogen-specific CD4 T cells can impact pathogen clearance

Malaria-associated atypical memory B cells exhibit markedly reduced B cell receptor signaling and effector function

Protective antibodies in Plasmodium falciparum malaria are only acquired after years of repeated infections. Chronic malaria exposure is associated with a large increase in atypical memory B cells (MBCs) that resemble B cells expanded in a variety of persistent viral infections. Understanding the function of atypical MBCs and their relationship to classical MBCs will be critical to developing effective vaccines for malaria and other chronic infections. We show that VH gene repertoires and somatic hypermutation rates of atypical and classical MBCs are indistinguishable indicating a common developmental history. Atypical MBCs express an array of inhibitory receptors and B cell receptor (BCR) signaling is stunted in atypical MBCs resulting in impaired B cell responses including proliferation, cytokine production and antibody secretion. Thus, in response to chronic malaria exposure, atypical MBCs appear to differentiate from classical MBCs becoming refractory to BCR-mediated activation and potentially interfering with the acquisition of malaria immunity. DOI: http://dx.doi.org/10.7554/eLife.07218.00

Artificial Intelligence for Sustainable Development: Synthesis Report, Mobile Learning Week 2019

(First paragraph) 2019’s Mobile Learning Week (MLW), UNESCO’s flagship event for information and communication technology (ICT) in education, focused on the theme ‘Artificial Intelligence for Sustainable Development’. Held over five days in Paris, it comprised a sequence of high-profile events (a global conference, a policy forum and workshops, a symposium and strategy labs), and involved more than 1,500 participants from 140 countries (including Ministers of Education and ICT, other representatives from Member States, the private sector, academia and international organizations)