Medical Biology - Research Publications
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ItemEndothelial Caspase-8 prevents fatal necroptotic hemorrhage caused by commensal bacteria(SPRINGERNATURE, 2023-01)Caspase-8 transduces signals from death receptor ligands, such as tumor necrosis factor, to drive potent responses including inflammation, cell proliferation or cell death. This is a developmentally essential function because in utero deletion of endothelial Caspase-8 causes systemic circulatory collapse during embryogenesis. Whether endothelial Caspase-8 is also required for cardiovascular patency during adulthood was unknown. To address this question, we used an inducible Cre recombinase system to delete endothelial Casp8 in 6-week-old conditionally gene-targeted mice. Extensive whole body vascular gene targeting was confirmed, yet the dominant phenotype was fatal hemorrhagic lesions exclusively within the small intestine. The emergence of these intestinal lesions was not a maladaptive immune response to endothelial Caspase-8-deficiency, but instead relied upon aberrant Toll-like receptor sensing of microbial commensals and tumor necrosis factor receptor signaling. This lethal phenotype was prevented in compound mutant mice that lacked the necroptotic cell death effector, MLKL. Thus, distinct from its systemic role during embryogenesis, our data show that dysregulated microbial- and death receptor-signaling uniquely culminate in the adult mouse small intestine to unleash MLKL-dependent necroptotic hemorrhage after loss of endothelial Caspase-8. These data support a critical role for Caspase-8 in preserving gut vascular integrity in the face of microbial commensals.
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ItemImmediate impact of stay-at-home orders to control COVID-19 transmission on socioeconomic conditions, food insecurity, mental health, and intimate partner violence in Bangladeshi women and their families: an interrupted time series(ELSEVIER SCI LTD, 2020-11)BACKGROUND: Stay-at-home orders (lockdowns) have been deployed globally to control COVID-19 transmission, and might impair economic conditions and mental health, and exacerbate risk of food insecurity and intimate partner violence. The effect of lockdowns in low-income and middle-income countries must be understood to ensure safe deployment of these interventions in less affluent settings. We aimed to determine the immediate impact of COVID-19 lockdown orders on women and their families in rural Bangladesh. METHODS: An interrupted time series was used to compare data collected from families in Rupganj upazila, rural Bangladesh (randomly selected from participants in a randomised controlled trial), on income, food security, and mental health a median of 1 year and 2 years before the COVID-19 pandemic to data collected during the lockdown. We also assessed women's experiences of intimate partner violence during the pandemic. RESULTS: Between May 19 and June 18, 2020, we randomly selected and invited the mothers of 3016 children to participate in the study, 2424 of whom provided consent. 2414 (99·9%, 95% CI 99·6-99·9) of 2417 mothers were aware of, and adhering to, the stay-at-home advice. 2321 (96·0%, 95·2-96·7) of 2417 mothers reported a reduction in paid work for the family. Median monthly family income fell from US$212 at baseline to $59 during lockdown, and the proportion of families earning less than $1·90 per day rose from five (0·2%, 0·0-0·5) of 2422 to 992 (47·3%, 45·2-49·5) of 2096 (p<0·0001 comparing baseline with lockdown period). Before the pandemic, 136 (5·6%, 4·7-6·6) of 2420 and 65 (2·7%, 2·1-3·4) of 2420 families experienced moderate and severe food insecurity, respectively. This increased to 881 (36·5%, 34·5-38·4) of 2417 and 371 (15·3%, 13·9-16·8) of 2417 during the lockdown; the number of families experiencing any level of food insecurity increased by 51·7% (48·1-55·4; p<0·0001). Mothers' depression and anxiety symptoms increased during the lockdown. Among women experiencing emotional or moderate physical violence, over half reported it had increased since the lockdown. INTERPRETATION: COVID-19 lockdowns present significant economic, psychosocial, and physical risks to the wellbeing of women and their families across economic strata in rural Bangladesh. Beyond supporting only the most socioeconomically deprived, support is needed for all affected families. FUNDING: National Health and Medical Research Council, Australia.