Pre-miRNA Hsa-Let-7a-2: a Novel Intracellular Partner of Angiotensin II Type 2 Receptor Negatively Regulating its Signals

G protein-coupled receptors (GPCRs) are the largest family of druggable targets, and their biological functions depend on different ligands and intracellular interactomes. Some microRNAs (miRNAs) bind as ligands to RNA-sensitive toll-like receptor 7 to regulate the inflammatory response, thereby contributing to the pathogenesis of cancer or neurodegeneration. It is unknown whether miRNAs bind to angiotensin II (Ang II) type 2 receptor (AGTR2), a critical protective GPCR in cardiovascular diseases, as ligands or intracellular interactomes. Here, screening for miRNAs that bind to AGTR2, we identified and confirmed that the pre-miRNA hsa-let-7a-2 non-competitively binds to the intracellular third loop of AGTR2. Functionally, intracellular hsa-let-7a-2 overexpression suppressed the Ang II-induced AGTR2 effects such as cAMP lowering, RhoA inhibition, and activation of Src homology 2 domain-containing protein-tyrosine phosphatase 1, whereas hsa-let-7a-2 knockdown enhanced these effects. Consistently, overexpressed hsa-let-7a-2 restrained the AGTR2-induced antiproliferation, antimigration, and proapoptosis of cells, and vasodilation of mesenteric arteries. Our findings demonstrated that hsa-let-7a-2 is a novel intracellular partner of AGTR2 that negatively regulates AGTR2-activated signals.

Seasonality and reduced nitric oxide titration dominated ozone increase during COVID-19 lockdown in eastern China

With improving PM2.5 air quality, the tropospheric ozone (O3) has become the top issue of China’s air pollution control. Here, we combine comprehensive observational data analysis with models to unveil the contributions of different processes and precursors to the change of O3 during COVID-19 lockdown in the Yangtze River Delta (YRD), one of the most urbanized megacity regions of eastern China. Despite a 44 to 47% reduction in volatile organic compounds (VOCs) and nitrogen oxides (NOx) emissions, maximum daily 8-h average (MDA8) ozone concentrations increase from 28 ppbv in pre-lockdown to 43 ppbv in lockdown period. We reproduce this transition with the WRF-Chem model, which shows that ~80% of the increase in MDA8 is due to meteorological factors (seasonal variation and radiation), and ~20% is due to emission reduction. We find that daytime photochemistry does not lead to an increase but rather a decrease of daytime O3 production during the lockdown. However, the reduced O3 production is overwhelmed by the weakened nitric oxide (NO) titration resulting in a net increase of O3 concentration. Although the emission reduction increases O3 concentration, it leads to a decrease in the Ox (O3 + NO2) concentration, suggesting reduced atmospheric oxidation capacity on a regional scale. The dominant effect of NO titration demonstrates the importance of prioritizing VOCs reduction, especially from solvent usage and the petrochemical industry with high emission ratios of VOCs/NOx.

SARS Cov-2 vaccination induces de novo donor-specific HLA antibodies in a renal transplant patient on waiting list: A case report.

The ability of COVID-19 vaccination to induce anti-HLA antibodies (Abs) formation in renal transplant candidates is not well studied. A 42-year-old man on a renal transplant waitlist, with no sensitization history, was tested for DSA before and after COVID-19 vaccination. Patient has consistently tested negative for COVID-19 virus. Eighteen days after receiving first dose of mRNA-based vaccine, flow cytometry crossmatch (FCXM) was strongly positive with de novo donor-specific Ab (dnDSA) against B57 and de novo non-DSA against B58. Before vaccination, preliminary FCXM was negative with no anti-HLA Abs. This event prompted the transplant team to cancel the surgery. COVID-19 vaccination could be associated with anti-HLA Abs formation in renal patients on waitlists that could affect future transplantability.

An observation approach in evaluation of ozone production to precursor changes during the COVID-19 lockdown.

The increase of surface ozone during the Corona Virus Disease 2019 (COVID-19) lockdown in China has aroused great concern. In this study, we combine 1.5 years of measurements for ozone, volatile organic compounds (VOCs), and nitrogen oxide (NOX) at four sites to investigate the effect of COVID-19 lockdown on surface ozone in Dongguan, an industrial city in southern China. We show that the average concentrations of NOX and VOCs decreased by 70%-77% and 54%-68% during the lockdown compared to pre-lockdown, respectively. Based on the source apportionment of VOCs, the contribution of industrial solvent use reduced significantly (86%-94%) during the lockdown, and climbed back slowly along with the re-opening of the industry after lockdown. A slight increase in mean ozone concentration (3%-14%) was observed during the lockdown. The rise of ozone was the combined effect of substantial increase at night (58%-91%) and small reduction in the daytime (1%-17%). These conflicting observations in ozone response between day and night to emission change call for a more detailed approach to diagnostic ozone production response with precursor changes, rather than directly comparing absolute concentrations. We propose that the ratio of daily Ox (i.e. ozone + NO2) enhancement to solar radiation can provide a diagnostic parameter for ozone production response during the lockdown period. Smaller ratio of daily OX (ozone + NO2) enhancement to solar radiation during the lockdown were observed from the long-term measurements in Dongguan, suggesting significantly weakened photochemistry during the lockdown successfully reduces local ozone production. Our proposed approach can provide an evaluation of ozone production response to precursor changes from restrictions of social activities during COVID-19 epidemic and also other regional air quality abatement measures (e.g. public mega-events) around the globe.

Efficacy and Safety of Triazavirin Therapy for Coronavirus Disease 2019: A Pilot Randomized Controlled Trial.

No therapeutics have been proven effective yet for the treatment of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To assess the efficacy and safety of Triazavirin therapy for COVID-19, we conducted a randomized, double-blinded controlled trial involving hospitalized adult patients with COVID-19. Participants were enrolled from ten sites, and were randomized into two arms of the study with a ratio of 1:1. Patients were treated with Triazavirin 250 mg versus a placebo three or four times a day for 7 d. The primary outcome was set as the time to clinical improvement, defined as normalization of body temperature, respiratory rate, oxygen saturation, cough, and absorption of pulmonary infection by chest computed tomography (CT) until 28 d after randomization. Secondary outcomes included individual components of the primary outcome, the mean time and proportion of inflammatory absorption in the lung, and the conversion rate to a repeated negative SARS-CoV-2 nucleic acid test of throat swab sampling. Concomitant therapeutic treatments, adverse events, and serious adverse events were recorded. Our study was halted after the recruitment of 52 patients, since the number of new infections in the participating hospitals decreased greatly. We randomized 52 patients for treatment with Triazavirin (n = 26) or a placebo (n = 26). We found no differences in the time to clinical improvement (median, 7 d versus 12 d; risk ratio (RR), 2.0; 95% confidence interval (CI), 0.7-5.6; p = 0.2), with clinical improvement occurring in ten patients in the Triazavirin group and six patients in the placebo group (38.5% versus 23.1%; RR, 2.1; 95% CI, 0.6-7.0; p = 0.2). All components of the primary outcome normalized within 28 d, with the exception of absorption of pulmonary infection (Triazavirin 50.0%, placebo 26.1%). Patients in the Triazavirin group used less frequent concomitant therapies for respiratory, cardiac, renal, hepatic, or coagulation supports. Although no statistically significant evidence was found to indicate that Triazavirin benefits COVID-19 patients, our observations indicated possible benefits from its use to treat COVID-19 due to its antiviral effects. Further study is required for confirmation.