Quality control in oocytes by p63 is based on a spring-loaded activation mechanism on the molecular and cellular level.

Mammalian oocytes are arrested in the dictyate stage of meiotic prophase I for long periods of time, during which the high concentration of the p53 family member TAp63α sensitizes them to DNA damage-induced apoptosis. TAp63α is kept in an inactive and exclusively dimeric state but undergoes rapid phosphorylation-induced tetramerization and concomitant activation upon detection of DNA damage. Here we show that the TAp63α dimer is a kinetically trapped state. Activation follows a spring-loaded mechanism not requiring further translation of other cellular factors in oocytes and is associated with unfolding of the inhibitory structure that blocks the tetramerization interface. Using a combination of biophysical methods as well as cell and ovary culture experiments we explain how TAp63α is kept inactive in the absence of DNA damage but causes rapid oocyte elimination in response to a few DNA double strand breaks thereby acting as the key quality control factor in maternal reproduction

Bonding and the agency risk premium: An analysis of migrations between the AIM and the Official List of the London Stock Exchange

Firms that change their listing from the less regulated AIM to the more regulated main section of the London Stock Exchange exhibit positive abnormal returns on the announcement day. For firms moving in the opposite direction, both announcement and implementation day abnormal returns are negative. Following implementation, the pattern is reversed for both categories of firm. We show that differences in liquidity, conventional risk factors and in medium to long term firm survival rates between the two listing regimes do not explain the observed patterns of returns, suggesting that the answer lies in the different bonding requirements of the two market segments and an agency risk premium.JEL Codes: G12, G14, G15, G30, G32, G3

Building Support for Taxation in Developing Countries: Experimental Evidence from Mexico

In spite of the importance of taxation for political and economic development, we know relatively little about the conditions under which citizens might not exact a political cost on leaders for adopting a particular tax. Drawing on insights from the literature on institutional design, this article examines how certain features of taxes – such as allowing for civil society oversight, sunset provisions that make the duration of taxes finite, and earmark mechanisms that direct tax revenue for a specific purpose – affect political support behind them. It also evaluates the role of three important aspects of the fiscal exchange, namely trust in government, perceptions of the public good, and level of income. Based on an original survey experiment focusing on the provision of public safety in Mexico, I find that these design features increase political support for taxation, especially among those with low trust in government, perceptions of high quality of the public good, and low income. These findings have important implications for Mexico, as well as a number of other countries that have both low levels of extraction and increased public spending imperatives

Introducing the Complexity of Educational Diversification

Peer reviewe

Mirroring Opposition Threats

Hugo Chávez and his Bolivarian Movement came to power in 1999 promising to refound the Venezuelan state and restructure the polity in ways that would build “popular power” through the promotion of grassroots participation, organization, and mobilization. Once in office, the Bolivarian forces launched a series of initiatives to sponsor organization and mobilization among supporters, which ranged widely in their functions and strategic purpose. State-mobilized organizations can be seen as operating in three different arenas of politics: the local governance arena; the electoral arena; and the protest arena. From an ideological standpoint, the Bolivarian Movement was oriented toward sponsoring organizations that could operate in the first of these arenas, helping realize Chávez’s vision of constructing a “protagonistic democracy” by establishing vehicles for citizen participation in local governance. In the terminology of this volume, these activities are best seen as a form of “infrastructural mobilization,” working to solidify political support and achieve the government’s longer-term aims

Measuring the Social Return on Investment of community sport and leisure facilities

Rationale/Purpose: There is a growing demand from managers and policy makers for evidence on the wider impacts of sport and physical activity. This is driven by the need to demonstrate accountability for public expenditure and effectiveness in relation to public policy. The research presented in this paper addresses a gap in knowledge relating to the social impact of local sport and leisure facilities. Design/methodology/approach: A Social Return on Investment (SROI) framework was used to measure the impact of sport and physical activity across 12 community sport and leisure facilities in Sheffield. A range of methods were used to measure general participation by regular visitors and a targeted therapeutic exercise programme for specific participants. Findings: The research found the social value of outcomes related to general and targeted participation were £21.67 m and £0.26 m, respectively, and that for every £1 spent a SROI of between £1.20 and £3.42 was generated. Practical implications: The research enables managers to identify the value of facilities beyond the financial indicators commonly used in performance management. Contribution: It contributes to knowledge on valuing the non-market benefits of sport. The research provides a methodological example of using SROI to measure the value of local sport and leisure facilities

Shop stewards’ leadership, left-wing activism and collective workplace union organisation

Providing an account of the dynamic interrelationship between shop steward leadership and membership interaction, Ralph Darlington focuses particular attention on the much-neglected crucial role that left-wing political activists can play in shaping the nature of collective workplace relations

T cell Allorecognition Pathways in Solid Organ Transplantation.

Transplantation is unusual in that T cells can recognize alloantigen by at least two distinct pathways: as intact MHC alloantigen on the surface of donor cells via the direct pathway; and as self-restricted processed alloantigen via the indirect pathway. Direct pathway responses are viewed as strong but short-lived and hence responsible for acute rejection, whereas indirect pathway responses are typically thought to be much longer lasting and mediate the progression of chronic rejection. However, this is based on surprisingly scant experimental evidence, and the recent demonstration that MHC alloantigen can be re-presented intact on recipient dendritic cells-the semi-direct pathway-suggests that the conventional view may be an oversimplification. We review recent advances in our understanding of how the different T cell allorecognition pathways are triggered, consider how this generates effector alloantibody and cytotoxic CD8 T cell alloresponses and assess how these responses contribute to early and late allograft rejection. We further discuss how this knowledge may inform development of cellular and pharmacological therapies that aim to improve transplant outcomes, with focus on the use of induced regulatory T cells with indirect allospecificity and on the development of immunometabolic strategies. KEY POINTS Acute allograft rejection is likely mediated by indirect and direct pathway CD4 T cell alloresponses.Chronic allograft rejection is largely mediated by indirect pathway CD4 T cell responses. Direct pathway recognition of cross-dressed endothelial derived MHC class II alloantigen may also contribute to chronic rejection, but the extent of this contribution is unknown.Late indirect pathway CD4 T cell responses will be composed of heterogeneous populations of allopeptide specific T helper cell subsets that recognize different alloantigens and are at various stages of effector and memory differentiation.Knowledge of the precise indirect pathway CD4 T cell responses active at late time points in a particular individual will likely inform the development of alloantigen-specific cellular therapies and will guide immunometabolic modulation

SARS-CoV-2 spike N-terminal domain modulates TMPRSS2-dependent viral entry and fusogenicity

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike N-terminal domain (NTD) remains poorly characterized despite enrichment of mutations in this region across variants of concern (VOCs). Here, we examine the contribution of the NTD to infection and cell-cell fusion by constructing chimeric spikes bearing B.1.617 lineage (Delta and Kappa variants) NTDs and generating spike pseudotyped lentivirus. We find that the Delta NTD on a Kappa or wild-type (WT) background increases S1/S2 cleavage efficiency and virus entry, specifically in lung cells and airway organoids, through use of TMPRSS2. Delta exhibits increased cell-cell fusogenicity that could be conferred to WT and Kappa spikes by Delta NTD transfer. However, chimeras of Omicron BA.1 and BA.2 spikes with a Delta NTD do not show more efficient TMPRSS2 use or fusogenicity. We conclude that the NTD allosterically modulates S1/S2 cleavage and spike-mediated functions in a spike context-dependent manner, and allosteric interactions may be lost when combining regions from more distantly related VOCs

Combined Point-of-Care Nucleic Acid and Antibody Testing for SARS-CoV-2 following Emergence of D614G Spike Variant

Rapid COVID-19 diagnosis in the hospital is essential, although this is complicated by 30%–50% of nose/throat swabs being negative by SARS-CoV-2 nucleic acid amplification testing (NAAT). Furthermore, the D614G spike mutant dominates the pandemic and it is unclear how serological tests designed to detect anti-spike antibodies perform against this variant. We assess the diagnostic accuracy of combined rapid antibody point of care (POC) and nucleic acid assays for suspected COVID-19 disease due to either wild-type or the D614G spike mutant SARS-CoV-2. The overall detection rate for COVID-19 is 79.2% (95% CI 57.8–92.9) by rapid NAAT alone. The combined point of care antibody test and rapid NAAT is not affected by D614G and results in very high sensitivity for COVID-19 diagnosis with very high specificity