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Aging is a major risk factor for cardiovascular disease. It has previously been shown that protein levels of cathepsin K, a lysosomal cysteine protease, are elevated in the failing heart and that genetic ablation of cathepsin K protects against pressure overload-induced cardiac hypertrophy and contractile dysfunction. Here we test the hypothesis that cathepsin K knockout alleviates age-dependent decline in cardiac function. Cardiac geometry, contractile function, intracellular Ca2+ properties, and cardiomyocyte apoptosis were evaluated using echocardiography, fura-2 technique, immunohistochemistry, Western blot and TUNEL staining, respectively. Aged (24-month-old) mice exhibited significant cardiac remodeling (enlarged chamber size, wall thickness, myocyte cross-sectional area, and fibrosis), decreased cardiac contractility, prolonged relengthening along with compromised intracellular Ca2+ release compared to young (6-month-old) mice, which were attenuated in the cathepsin K knockout mice. Cellular markers of senescence, including cardiac lipofuscin, p21 and p16, were lower in the aged-cathepsin K knockout mice compared to their wild-type counterpart. Mechanistically, cathepsin K knockout mice attenuated an age-induced increase in cardiomyocyte apoptosis and nuclear translocation of mitochondrial apoptosis-inducing factor (AIF). In cultured H9c2 cells, doxorubicin stimulated premature senescence and apoptosis. Silencing of cathepsin K blocked the doxorubicin-induced translocation of AIF from the mitochondria to the nuclei. Collectively, these results suggest that cathepsin K knockout attenuates age-related decline in cardiac function via suppressing caspase-dependent and caspase-independent apoptosis.

The building of an effective wastewater-based epidemiological model that can translate SARS-CoV-2 concentrations in wastewater to the prevalence of virus shedders within a community is a significant challenge for wastewater surveillance. The objectives of this study were to investigate the association between SARS-CoV-2 wastewater concentrations and the COVID-19 cases at the community-level and to assess how SARS-CoV-2 wastewater concentrations should be integrated into a wastewater-based epidemiological statistical model that can provide reliable forecasts for the number of COVID-19 infections and the evolution over time as well. Weekly variations on the SARS-CoV-2 wastewater concentrations and COVID-19 cases from April 29, 2020 through February 17, 2021 were obtained in Borough of Indiana, PA. Vector autoregression (VAR) model with different data forms were fitted on this data from April 29, 2020 through January 27, 2021, and the performance in three weeks ahead forecasting (February 3, 10, and 17) were compared with measures of Mean Absolute Error (MAE) and Mean Absolute Percentage Error (MAPE). A stationary block bootstrapping VAR method was also presented to reduce the variability in the forecasting values. Our results demonstrate that VAR(1) estimated with the logged data has the best interpretation of the data, but a VAR(1) estimated with the original data has a stronger forecasting ability. The forecast accuracy, measured by MAPE, for 1 week, 2 weeks, and 3 weeks in the future can be as low as 11.85%, 8.97% and 21.57%. The forecasting performance of the model on a short time span is unfortunately not very impressive. Also, a single increase in the SARS-CoV-2 concentration can impact the COVID-19 cases in an inverted-U shape pattern with the maximum impact occur in the third week after. The flexibility of this approach and easy-to-follow explanations are suitable for many different locations where the wastewater surveillance system has been implemented.

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