From a genome-wide screen of RNAi molecules against SARS-CoV-2 to a validated broad-spectrum and potent prophylaxis.

Expanding the arsenal of prophylactic approaches against SARS-CoV-2 is of utmost importance, specifically those strategies that are resistant to antigenic drift in Spike. Here, we conducted a screen of over 16,000 RNAi triggers against the SARS-CoV-2 genome, using a massively parallel assay to identify hyper-potent siRNAs. We selected Ten candidates for in vitro validation and found five siRNAs that exhibited hyper-potent activity (IC50 < 20 pM) and strong blockade of infectivity in live-virus experiments. We further enhanced this activity by combinatorial pairing of the siRNA candidates and identified cocktails that were active against multiple types of variants of concern (VOC). We then examined over 2,000 possible mutations in the siRNA target sites by using saturation mutagenesis and confirmed broad protection of the leading cocktail against future variants. Finally, we demonstrated that intranasal administration of this siRNA cocktail effectively attenuates clinical signs and viral measures of disease in the gold-standard Syrian hamster model. Our results pave the way for the development of an additional layer of antiviral prophylaxis that is orthogonal to vaccines and monoclonal antibodies.

The socioeconomic gradient in mortality from ovarian, cervical, and endometrial cancer in Australian women, 2001-2018: A population-based study.

BACKGROUND: Socio-economic (SE) status is closely linked to health status and the mechanisms of this association are complex. One important adverse effect of SE disadvantage is vulnerability to cancer and cancer is a major cause of morbidity and mortality in Australia. AIMS: We aimed to estimate the effect of SE status on mortality rates from ovarian, cervical, and endometrial cancer. MATERIALS AND METHODS: National mortality data were obtained from the Australian Bureau of Statistics (ABS) for the calendar years from 2001 to 2018, inclusive. Individual deaths were grouped by the ABS Index of Relative Socio-economic Advantage and Disadvantage. Population data were obtained to provided denominators allowing calculation of mortality rates (deaths per 100 000 women aged 30-79 years). Statistical analyses performed included tabulating point-estimates of mortality rates and their changes over time and modelling the trends of rates using maximum likelihood method. RESULTS: Age-standardised mortality rates for ovarian and cervical cancer fell over the study period but increased for endometrial cancer. There was clear evidence of a SE gradient in the mortality rate for all three cancers. This SE gradient increased over the study period for ovarian and cervical cancer but remained unchanged for endometrial cancer. CONCLUSIONS: Women at greater SE disadvantage have higher rates of death from the commonest gynaecological cancers and this gradient has not reduced over the last two decades. After the COVID-19 pandemic efforts must be redoubled to ensure that Australians already at risk of ill health do not face even greater risks because of their circumstances.

SARS-CoV-2 binding to ACE2 triggers pericyte-mediated angiotensin-evoked cerebral capillary constriction (preprint)

The SARS-CoV-2 receptor, ACE2, is found on pericytes, contractile cells enwrapping capillaries that regulate brain, heart and kidney blood flow. ACE2 converts vasoconstricting angiotensin II into vasodilating angiotensin-(1-7). In brain slices from hamster, which has an ACE2 sequence similar to human ACE2, angiotensin II alone evoked only a small capillary constriction, but evoked a large pericyte-mediated capillary constriction generated by AT1 receptors in the presence of the SARS-CoV-2 receptor binding domain (RBD). The effect of the RBD was mimicked by blocking ACE2. A mutated non-binding RBD did not potentiate constriction. A similar RBD-potentiated capillary constriction occurred in human cortical slices. This constriction reflects an RBD-induced decrease in the conversion of angiotensin II to angiotensin-(1-7). The clinically-used drug losartan inhibited the RBD-potentiated constriction. Thus AT1 receptor blockers could be protective in SARS-CoV-2 infection by reducing pericyte-mediated blood flow reductions in the brain, and perhaps the heart and kidney.