Expression of Human Frataxin Is Regulated by Transcription Factors SRF and TFAP2

Friedreich ataxia is an autosomal recessive neurodegenerative disease caused by reduced expression levels of the frataxin gene (FXN) due to expansion of triplet nucleotide GAA repeats in the first intron of FXN. Augmentation of frataxin expression levels in affected Friedreich ataxia patient tissues might substantially slow disease progression.We utilized bioinformatic tools in conjunction with chromatin immunoprecipitation and electrophoretic mobility shift assays to identify transcription factors that influence transcription of the FXN gene. We found that the transcription factors SRF and TFAP2 bind directly to FXN promoter sequences. SRF and TFAP2 binding sequences in the FXN promoter enhanced transcription from luciferase constructs, while mutagenesis of the predicted SRF or TFAP2 binding sites significantly decreased FXN promoter activity. Further analysis demonstrated that robust SRF- and TFAP2-mediated transcriptional activity was dependent on a regulatory element, located immediately downstream of the first FXN exon. Finally, over-expression of either SRF or TFAP2 significantly increased frataxin mRNA and protein levels in HEK293 cells, and frataxin mRNA levels were also elevated in SH-SY5Y cells and in Friedreich ataxia patient lymphoblasts transfected with SRF or TFAP2.We identified two transcription factors, SRF and TFAP2, as well as an intronic element encompassing EGR3-like sequence, that work together to regulate expression of the FXN gene. By providing new mechanistic insights into the molecular factors influencing frataxin expression, our results should aid in the discovery of new therapeutic targets for the treatment of Friedreich ataxia

Cogena, a novel tool for co-expressed gene-set enrichment analysis, applied to drug repositioning and drug mode of action discovery

This work was supported by the portfolio of translational research of the National Institutes for Health Research Cardiovascular Biomedical Research Unit at Barts, the UK Medical Research Council (JID-2015-0339), Major Research Plan of The National Natural Science Foundation of China [grant number U1435222], Plan for Innovative Graduate Student at NUDT [grant number B140202], Plan for interdisciplinary joint PhD students at NUDT and China Scholarship Council [to ZJ]

Christopher Hitchens' Public dying: Toward a Secular-Humanist Ars Moriendi?

This article explores the public dying of journalist, writer, provocateur, public intellectual, and renowned atheist, Christopher Hitchens. It does so primarily through an analysis of television interviews given by Hitchens following his diagnosis with esophageal cancer in June 2010. Four key themes are identified as emerging from analysis of the interviews: (a) Hitchens’ explicit sense of mission in challenging myths and superstitions surrounding cancer, dying, and death; (b) the personal experience of terminal illness and dying and the particular way (or style of dying) by which it is approached; (c) issues of regret and a life well lived; and (d) questions surrounding religion, the afterlife, and possibility of deathbed conversion. In light of the claim that ours is a culture in search of an ars moriendi, the article examines what we can learn from Hitchens’ auto/pathographic interviews (and writings) and the extent to which this rational-humanist, atheistic, and stoical style of dying provides a useable “template” for others nearing the end of life

Current Neuroethical Perspectives on Deep Brain Stimulation and Neuromodulation for Neuropsychiatric Disorders: A Scoping Review of the Past 10 Years

Background: The use of neuromodulation for the treatment of psychiatric disorders has become increasingly common, but this emerging treatment modality comes with ethical concerns. This scoping review aims to synthesize the neuroethical discourse from the past 10 years on the use of neurotechnologies for psychiatric conditions. Methods: A total of 4496 references were imported from PubMed, Embase, and Scopus. The inclusion criteria required a discussion of the neuroethics of neuromodulation and studies published between 2014 and 2024. Results: Of the 77 references, a majority discussed ethical concerns of patient autonomy and informed consent for neuromodulation, with neurotechnologies being increasingly seen as autonomy enablers. Concepts of changes in patient identity and personality, especially after deep brain stimulation, were also discussed extensively. The risks and benefits of neurotechnologies were also compared, with deep brain stimulation being seen as the riskiest but also possessing the highest efficacy. Concerns about equitable access and justice were raised regarding the rise of private transcranial magnetic stimulation clinics and the current experimental status of deep brain stimulation. Conclusions: Neuroethics discourse, particularly for deep brain stimulation, has continued to focus on how post-intervention changes in personality and behavior influence patient identity. Multiple conceptual frameworks have been proposed, though each faces critiques for addressing only parts of this complex phenomenon, prompting calls for pluralistic models. Emerging technologies, especially those involving artificial intelligence through brain computer interfaces, add new dimensions to this debate by raising concerns about neuroprivacy and legal responsibility for actions, further blurring the lines for defining personal identity