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

On the possibility to supercool molecular hydrogen down to superfluid transition

Recent calculations by Vorobev and Malyshenko (JETP Letters, 71, 39, 2000) show that molecular hydrogen may stay liquid and superfluid in strong electric fields of the order of $4\times 10^7 V/cm$. I demonstrate that strong local electric fields of similar magnitude exist beneath a two-dimensional layer of electrons localized in the image potential above the surface of solid hydrogen. Even stronger local fields exist around charged particles (ions or electrons) if surface or bulk of a solid hydrogen crystal is statically charged. Measurements of the frequency shift of the $1 \to 2$ photoresonance transition in the spectrum of two-dimensional layer of electrons above positively or negatively charged solid hydrogen surface performed in the temperature range 7 - 13.8 K support the prediction of electric field induced surface melting. The range of surface charge density necessary to stabilize the liquid phase of molecular hydrogen at the temperature of superfluid transition is estimated.Comment: 5 pages, 2 figure

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

Foxa1 and Foxa2 in thymic epithelial cells (TEC) regulate medullary TEC and regulatory T-cell maturation

The Foxa1 and Foxa2 transcription factors are essential for mouse development. Here we show that they are expressed in thymic epithelial cells (TEC) where they regulate TEC development and function, with important consequences for T-cell development. TEC are essential for T-cell differentiation, lineage decisions and repertoire selection. Conditional deletion of Foxa1 and Foxa2 from murine TEC led to a smaller thymus with a greater proportion of TEC and a greater ratio of medullary to cortical TEC. Cell-surface MHCI expression was increased on cortical TEC in the conditional Foxa1Foxa2 knockout thymus, and MHCII expression was reduced on both cortical and medullary TEC populations. These changes in TEC differentiation and MHC expression led to a significant reduction in thymocyte numbers, reduced positive selection of CD4+CD8+ cells to the CD4 lineage, and increased CD8 cell differentiation. Conditional deletion of Foxa1 and Foxa2 from TEC also caused an increase in the medullary TEC population, and increased expression of Aire, but lower cell surface MHCII expression on Aire-expressing mTEC, and increased production of regulatory T-cells. Thus, Foxa1 and Foxa2 in TEC promote positive selection of CD4SP T-cells and modulate regulatory T-cell production and activity, of importance to autoimmunity

T cell phenotype in paediatric heart transplant recipients

Paediatric heart transplantation recipients suffer an increased incidence of infectious, autoimmune and allergic problems. The relative roles of thymus excision and immunosuppressive treatments in contributing to these sequelae are not clear. We compared the immunological phenotypes of 25 heart transplant recipients (Tx), 10 children who underwent thymus excision during non-transplantation cardiac surgery (TE) and 25 age range–matched controls, in two age bands: 1-9 and 10-16 years. Significant differences from controls were seen mainly in the younger age band with Tx showing lower CD3 and CD4 cell counts whilst TE showed lower CD8 cell counts. Naïve T cell and recent thymic emigrant proportions and counts were significantly lower than controls in both groups in the lower age band. T cell recombination excision circle (TREC) levels were lower than controls in both groups in both age bands. There were no differences in regulatory T cells, but in those undergoing thymus excision in infancy, their proportions were higher in TE than Tx, a possible direct effect of immunosuppression. T cell receptor V beta spectratyping showed fewer peaks in both groups than in controls (predominantly in the older age band). Thymus excision in infancy was associated with lower CD8 cell counts and higher proportions of Tregs in TE compared to Tx. These data are consistent with thymus excision, particularly in infancy, being the most important influence on immunological phenotype after heart transplantation

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

Guiding equitable prioritisation of COVID-19 vaccine distribution and strategic deployment in South Africa to enhance effectiveness and access to vulnerable communities and prevent waste

BACKGROUND. In South Africa (SA), >2.4 million cases of COVID 19 and >72 000 deaths were recorded between March 2020 and 1 August 2021, affecting the country’s 52 districts to various extents. SA has committed to a COVID 19 vaccine roll-out in three phases, prioritising frontline workers, the elderly, people with comorbidities and essential workers. However, additional actions will be necessary to support efficient allocation and equitable access for vulnerable, access-constrained communities. OBJECTIVES. To explore various determinants of disease severity, resurgence risk and accessibility in order to aid an equitable, effective vaccine roll-out for SA that would maximise COVID 19 epidemic control by reducing the number of COVID 19 transmissions and resultant deaths, while at the same time reducing the risk of vaccine wastage. METHODS. For the 52 districts of SA, 26 COVID 19 indicators such as hospital admissions, deaths in hospital and mobility were ranked and hierarchically clustered with cases to identify which indicators can be used as indicators for severity or resurgence risk. Districts were then ranked using the estimated COVID 19 severity and resurgence risk to assist with prioritisation of vaccine roll-out. Urban and rural accessibility were also explored as factors that could limit vaccine roll-out in hard-to-reach communities. RESULTS. Highly populated urban districts showed the most cases. Districts such as Buffalo City, City of Cape Town and Nelson Mandela Bay experienced very severe first and second waves of the pandemic. Districts with high mobility, population size and density were found to be at highest risk of resurgence. In terms of accessibility, we found that 47.2% of the population are within 5 km of a hospital with ≥50 beds, and this percentage ranged from 87.0% in City of Cape Town to 0% in Namakwa district. CONCLUSIONS. The end goal is to provide equal distribution of vaccines proportional to district populations, which will provide fair protection. Districts with a high risk of resurgence and severity should be prioritised for vaccine roll-out, particularly the major metropolitan areas. We provide recommendations for allocations of different vaccine types for each district that consider levels of access, numbers of doses and cold-chain storage capability.The American people through the United States Agency for International Development (USAID).http://www.samj.org.zadm2022Human Nutritio

Building common cause towards sustainable consumption: A cross-generational perspective

The notion of sustainable consumption has gained significant traction in recent decades, in parallel with unprecedented growth in global consumption and recognition of its catastrophic environmental impacts. In this context, there is a predominant generational narrative of frugality versus excess, with younger generations often negatively stereotyped as increasingly consumer-driven and environmentally destructive. We argue that it is important to develop a more nuanced understanding of generational difference, drawing on findings from a cross-generational study in Sheffield, UK, involving participants from the ages of 16–96. The aim of this research was to explore how citizens relate to the idea of sustainable consumption across generations, acknowledging but also seeking to look beyond the common tropes of thrift and the throwaway society. We draw on theories of intergenerational value change and consider how insights from the Common Cause framework, which encourages pro-environmental campaigners to make broad appeals to engage a range of intrinsic values, may be applied to sustainable consumption. In doing so, we reflect on the merits of adopting an expansive definition of sustainable consumption that encompasses the three pillars of sustainability – economic stability, environmental protection and human wellbeing – and identify insights from our research for campaigners and policy makers interested in working with intrinsic values to build common cause across generations

The Mitochondrial Ca(2+) Uniporter: Structure, Function, and Pharmacology.

Mitochondrial Ca(2+) uptake is crucial for an array of cellular functions while an imbalance can elicit cell death. In this chapter, we briefly reviewed the various modes of mitochondrial Ca(2+) uptake and our current understanding of mitochondrial Ca(2+) homeostasis in regards to cell physiology and pathophysiology. Further, this chapter focuses on the molecular identities, intracellular regulators as well as the pharmacology of mitochondrial Ca(2+) uniporter complex