Gooding, K. | bioRxiv Science

bioRxiv2025

The apoptosis gene BCL-X splice isoforms have opposing effects in diabetic kidney disease: potential treatment target and prognostic value

In recent years, the importance of alternative splicing (AS) of certain genes in the nature and progression of diabetic nephropathy (DN) has been studied. We report a novel AS event observed in the diabetic kidney - AS of the apoptosis gene BCL-X to increase the pro-apoptotic BCL-XS and decrease the anti-apoptotic BCL-XL. This study aimed to further investigate the role of this novel AS event in the pathogenesis of DN. To characterize important splicing events in progression of DN, human glomerular endothelial cells (GEnCs) were exposed to a diabetic environment for 1 week and RNAseq was performed. While several splicing changes have been discovered we have focused further on the apoptosis gene BCL-X isoforms. In GEnCs, an upregulation of the BCL-XS/BCL-XL ratio was observed which resulted in an increase in GEnC apoptosis. An upregulation of IL-6 was also observed; treatment with IL-6 alone induced a dose-dependent shift in BCL-X splicing to promote expression of the pro-apoptotic BCL-XS. Furthermore, we identified certain splicing factors, SF3B1 and PTBP1, involved in the BCL-X splicing regulation. A switch in expression of the anti-apoptotic BCL-XL isoform rescues apoptosis, suggesting a possible therapeutic avenue. In patients, an increase in the pro-apoptotic BCL-XS in urinary RNA correlated with a decline in the GFR, while in blood it correlated with the level of albuminuria. There is an increase in the pro-apoptotic BCL-XS isoform in the diabetic glomerular endothelium, resulting in increased GEnC apoptosis. Increased BCL-XS expression correlates with a markers of renal function decline, implicating this AS event as a potential biomarker for DN severity and suggesting that the switch of isoforms from BCL-XS to BCL-XL may for a novel therapeutic strategy.

molecular biology↗

bioRxiv2018

Dust or disease? Perceptions of influenza in rural Southern Malawi

BackgroundInfluenza virus infections cause between 291 243 and 645 832 deaths annually, with the highest burden in low-income settings. Research in high-income countries has examined public understanding of influenza, but there is little information on views and behaviours about influenza in low-income countries. We explored communities ideas about the severity, causes, prevention and treatment of influenza in Chikwawa district, Malawi.\n\nMethodsWe conducted 64 in-depth interviews with parents of children aged <5 years, and 7 focus groups with community health workers, parents, and traditional healers. Data were analysed thematically and using a framework matrix to compare views between groups.\n\nResultsRespondents held varied ideas about influenza, and many were uncertain about its causes and treatment. Some parents, traditional healers and health workers thought influenza was not severe because they felt it did not cause death or limit activities, but others disagreed. Many saw influenza as a symptom of other conditions, especially malaria and pneumonia, rather than as a disease of its own. Most mentioned dust as the main cause of influenza and believed influenza could be prevented by cleaning the home thoroughly. Treatment seeking for influenza followed different stages, usually starting with home remedies followed by purchasing drugs from groceries and then visiting a health centre. Seeking a clinician tended to be triggered by severe symptoms like high fever or difficulty breathing, and suspicions of malaria or pneumonia. Community health workers provide health education for communities, but some lacked understanding of influenza.\n\nConclusionOur findings suggest uncertainty about the causes and control of influenza among parents and varied levels of understanding among health providers. Strengthening the capacity of community health workers to provide relevant information about influenza prevention and treatment could address parents interest in further information and support informed health seeking and engagement with future influenza interventions.

pathology↗