MED12 regulates a transcriptional network of calcium-handling genes in the heart

The Mediator complex regulates gene transcription by linking basal transcriptional machinery with DNA-bound transcription factors. The activity of the Mediator complex is mainly controlled by a kinase submodule that is composed of 4 proteins, including MED12. Although ubiquitously expressed, Mediator subunits can differentially regulate gene expression in a tissue-specific manner. Here, we report that MED12 is required for normal cardiac function, such that mice with conditional cardiac-specific deletion of MED12 display progressive dilated cardiomyopathy. Loss of MED12 perturbs expression of calcium-handling genes in the heart, consequently altering calcium cycling in cardiomyocytes and disrupting cardiac electrical activity. We identified transcription factors that regulate expression of calcium-handling genes that are downregulated in the heart in the absence of MED12, and we found that MED12 localizes to transcription factor consensus sequences within calcium-handling genes. We showed that MED12 interacts with one such transcription factor, MEF2, in cardiomyocytes and that MED12 and MEF2 co-occupy promoters of calcium-handling genes. Furthermore, we demonstrated that MED12 enhances MEF2 transcriptional activity and that overexpression of both increases expression of calcium-handling genes in cardiomyocytes. Our data support a role for MED12 as a coordinator of transcription through MEF2 and other transcription factors. We conclude that MED12 is a regulator of a network of calcium-handling genes, consequently mediating contractility in the mammalian heart

Navigating education in the context of COVID-19 lockdowns and school closures : challenges and resilience among adolescent girls and young women in South Africa

Gender related vulnerabilities and inequalities place female learners at high risk of school disengagement due to COVID-19 disruptions. Understanding the impacts of school closures and educational disruptions on female learners in South Africa is critical to inform appropriate, gender-sensitive policies, and programs, to mitigate further exacerbation of educational inequalities. We examined the effects that COVID-19 and lockdowns have had on the educational experiences of adolescent girls and young women (AGYW) aged 15–24, in six districts of South Africa characterized by high rates of HIV, teenage pregnancy and socio-economic hardship. Following a concurrent triangulation mixed-methods approach, we conducted a cross-sectional survey with 515 AGYW, and qualitative interviews with 50 AGYW. More than half of survey participants enrolled in education had been unable to continue with their studies. Factors associated with educational disruption included low socio-economic status, lack of cell phone access and household food insecurity. Qualitative narratives included challenges with online learning and studying at home in resource restricted settings, and insufficient support from schools and teachers. However, despite multiple barriers to continuing education, some AGYW demonstrated educational resilience, enabled by psychosocial and structural support, and resource access. Our findings lend support to an emerging evidence base showing that the closure of schools and tertiary institutions, combined with challenging home environments, and a lack of access to appropriate technology, has disproportionately impacted the most vulnerable AGYW, exacerbating pre-existing educational inequalities within the South African education system. Addressing structural barriers to educational equity, particularly in the pandemic context, including access of technology and the internet, is urgent

Adaptation and resilience : lessons learned from implementing a combination health and education intervention for adolescent girls and young women in South Africa during the COVID-19 pandemic

The COVID-19 pandemic has been associated with reduced access to health services and worsening health outcomes for HIV and sexual and reproductive health (SRH). Through the analysis of data from an evaluation study of a combination intervention for adolescent girls and young women (AGYW) in South Africa, we sought to examine the way in which implementation and service provision were impacted by the COVID-19 pandemic and related restrictions, describing the adaptation implementers made to respond to this context. The intervention was implemented from 2019 in South African districts identified as high priority, given the high rates of HIV and teenage pregnancy amongst AGYW. The South African government introduced the first COVID-19 lockdown in March 2020. We conducted in-depth interviews with 38 intervention implementers in the period from November 2020 to March 2021. Respondents described various ways in which the COVID-19 pandemic and related restrictions had limited their ability to implement the intervention and provide services as planned. As a result, AGYW intervention beneficiary access to SRH and psychosocial services was disrupted. Implementers described several ways in which they attempted to adapt to the pandemic context, such as offering services remotely or door-to-door. Despite attempts to respond to the context and adapt services, overall COVID-19 negatively affected implementation and service provision, and heightened issues around community acceptability of the programs. Our findings can help to inform efforts to reduce health service disruption, increase health system resilience, and ensure continuous SRH service provision to AGYW in times of pandemics and other crises

A Simple and Practical Approach to Unit Testing: The JML and JUnit Way

Writing unit test code is labor-intensive, hence it is often not done as an integral part of programming. However, unit testing is a practical approach to increasing the correctness and quality of software; for example, the Extreme Programming approach relies on frequent unit testing. In this paper we present a new approach that makes writing unit tests easier. It uses a formal specification language\u27s runtime assertion checker to decide whether methods are working correctly, thus automating the writing of unit test oracles. These oracles can be easily combined with hand-written test data. Instead of writing testing code, the programmer writes formal specifications (e.g., pre- and postconditions). This makes the programmer\u27s task easier, because specifications are more concise and abstract than the equivalent test code, and hence more readable and maintainable. Furthermore, by using specifications in testing, specification errors are quickly discovered, so the specifications are more likely to provide useful documentation and inputs to other tools. We have implemented this idea using the Java Modeling Language (JML) and the JUnit testing framework, but the approach could be easily implemented with other combinations of formal specification languages and unit test tools

A Simple and Practical Approach to Unit Testing: The JML and JUnit Way

Writing unit test code is labor-intensive, hence it is often not done as an integral part of programming. However, unit testing is a practical approach to increasing the correctness and quality of software; for example, the Extreme Programming approach relies on frequent unit testing. In this paper we present a new approach that makes writing unit tests easier. It uses a formal specification language\u27s runtime assertion checker to decide whether methods are working correctly, thus automating the writing of unit test oracles. These oracles can be easily combined with hand-written test data. Instead of writing testing code, the programmer writes formal specifications (e.g., pre- and postconditions). This makes the programmer\u27s task easier, because specifications are more concise and abstract than the equivalent test code, and hence more readable and maintainable. Furthermore, by using specifications in testing, specification errors are quickly discovered, so the specifications are more likely to provide useful documentation and inputs to other tools. We have implemented this idea using the Java Modeling Language (JML) and the JUnit testing framework, but the approach could be easily implemented with other combinations of formal specification languages and unit test tools

Autobiography as unconventional history: Constructing the author

The experience of historians as autobiographers has led them to reconsider the nature of historical knowledge and the function of the historian as an intermediary between the past and present. In the new theoretical context of the social sciences and historiography, we can take this proposal further and consider autobiography as a valid form of history—or, at least, as ‘unconventional history’, understood as negotiations with history that transcend or subvert traditional chronological monographs, posit the ‘subjective’ as a useful form of knowledge, and engage the constructed nature of the text. Taking this hypothesis as a starting point, this article reads historians' autobiographical texts to explore if we can/should continue to defend the classic distinction between subject and object, historian scientist and historian author. In this article I compare the work of several historian autobiographers that permit us to identify different methodologies in approaching the story of the self that also reflects different theoretical conceptions of history. I argue that historians that may be considered ‘constructionist’, such as Fernand Braudel, Annie Kriegel, George Duby, and Eric Hobsbawm, design their autobiographies in the same way they articulate their historical texts: by foregrounding objectivity and establishing critical distance between the subject—the historian who narrates the story—and the object—one's own life. Unconventional or experimental approaches, such as those espoused by Robert Rosenstone, Dominick LaCapra, or Clifford Geertz, result in more self-conscious autobiographies, which are, paradoxically, often more realistic and more revealing of the epistemological nature of life writing. ----------------- La experiencia de los historiadores como autobiógrafos les ha llevado a reconsiderar la naturaleza del conocimiento histórico y la función del historiador como un intermediario entre el pasado y el presente. En el nuevo contexto teórico de las ciencias sociales y la historiografía podemos tomar esta propuesta más allá y considerar la autobiografía como una forma válida de historia-o, al menos, de historia ‘poco convencional’-, entendida como negociaciones con la historia que trascienden o subvierten las tradicionales monografías cronológicas, plantean lo "subjetivo" como una forma útil de conocimiento y participan de la naturaleza construida del texto. Tomando esta hipótesis como punto de partida, este artículo lee los textos autobiográficos de los historiadores para explorar si se puede / debe seguir defendiendo la clásica distinción entre sujeto y objeto, historiador científico e historiador escritor. En este artículo comparo el trabajo de varios historiadores autobiógrafos que nos permiten identificar las diferentes metodologías para acercarse a la historia del yo y que también reflejan las diferentes concepciones teóricas de la historia. Sostengo que los historiadores que pueden considerarse "constructivistas", como Fernand Braudel, Annie Kriegel, George Duby y Eric Hobsbawm, diseñan sus autobiografías de la misma forma que articulan sus textos históricos: poniendo en primer plano la objetividad y estableciendo una distancia crítica entre el sujeto -el historiador que narra la historia-y el objeto- la vida de cada uno. Enfoques no convencionales o experimentales, como los expuestos por Robert Rosenstone, Dominick LaCapra, o Clifford Geertz, resultan autobiografías más autoconscientes, que son, paradójicamente, a menudo más realistas y más reveladoras de la naturaleza epistemológica de la escritura de la vida

The Hin recombinase assembles a tetrameric protein swivel that exchanges DNA strands

Most site-specific recombinases can be grouped into two structurally and mechanistically different classes. Whereas recombination by tyrosine recombinases proceeds with little movements by the proteins, serine recombinases exchange DNA strands by a mechanism requiring large quaternary rearrangements. Here we use site-directed crosslinking to investigate the conformational changes that accompany the formation of the synaptic complex and the exchange of DNA strands by the Hin serine recombinase. Efficient crosslinking between residues corresponding to the ‘D-helix’ region provides the first experimental evidence for interactions between synapsed subunits within this region and distinguishes between different tetrameric conformers that have been observed in crystal structures of related serine recombinases. Crosslinking profiles between cysteines introduced over the 35 residue E-helix region that constitutes most of the proposed rotating interface both support the long helical structure of the region and provide strong experimental support for a subunit rotation mechanism that mediates DNA exchange