Extracellular pH is usually maintained around 7.4 in multicellular organisms, and cells are optimized to proliferate under this condition. Here, we find cells can adapt to a more acidic pH of 6.5 and become addicted to this acidic microenvironment by expressing phosphatase of regenerating liver (PRL), a driver of cancer malignancy. Genome-scale CRISPR-Cas9 knockout screening and subsequent analyses revealed that PRL promotes H+ extrusion and acid addiction by stimulating lysosomal exocytosis. Further experiments using cultured cells and Caenorhabditis elegans clarified the molecular link between PRL and lysosomal exocytosis across species, involving activation of lysosomal Ca2+ channel TRPML by ROS. MIRA-1 Indeed, disruption of TRPML in cancer cells abolished PRL-stimulated lysosomal exocytosis, acid addiction, and metastasis. Thus, PRL is the molecular switch turning cells addicted to an acidic condition, which should benefit cancer cells to thrive in an acidic tumor microenvironment.Ca2+/calmodulin-dependent protein kinase II δ (CaMKIIδ) has been shown to play a vital role in pathological events in myocardial ischemia/reperfusion (IR) injury. Dysregulation of autophagy in cardiomyocytes is implicated in myocardial IR injury. Here, we examined whether CaMKIIδ inhibition could protect against myocardial IR injury through alleviating autophagy dysfunction and evaluated the potential role of CaMKIIδ in Beclin-1-dependent autophagy in ischemia/reperfused hearts. This study was performed using isolated perfused rat hearts and H9c2 cardiac myoblasts. KN-93, but not KN-92, inhibited the phosphorylation of CaMKIIδ at Thr286 and its substrate phospholamban at Thr17 besides the CaMKIIδ activity in myocardial IR. KN-93, but not KN-92 significantly improved post-ischemic cardiac function and reduced cell death. In cultured H9c2 cardiac myoblasts, KN-93 or CaMKIIδ siRNA, but not KN-92, attenuated simulated IR (SIR)-induced cell death. Moreover, CaMKIIδ inhibition could alleviate IR-induced autophagic dysfunction as evidenced in reduced levels of Atg5, p62, and LC3BII in isolated rat hearts and H9c2 cardiac myoblasts. Furthermore, co-treatment with bafilomycin A1, a lysosomal inhibitor, in CaMKII inhibition-treated cells suggested that CaMKII inhibition alleviated autophagic flux. CaMKIIδ inhibition mitigated the phosphorylation of Beclin-1 at Ser90. As expected, Beclin-1 siRNA significantly decreased the levels of Beclin-1 and Beclin-1 phosphorylation accompanied by partial reductions in Atg5, LC3BII, p62, cleaved caspase-3 and cytochrome c. However, Beclin-1 siRNA had little effect on CaMKIIδ phosphorylation. Taken together, these results demonstrated that CaMKIIδ inhibition reduced myocardial IR injury by improving autophagy dysfunction, and that CaMKIIδ-induced autophagy dysfunction partially depended on the phosphorylation of Beclin-1.The increased prevalence of neurodevelopmental disorders during the last half-century led us to investigate the potential for intergenerational detrimental neurodevelopmental effects of synthetic female gonadal hormones, typically used in contraceptive pills. We examined 3 separate cohorts of mice over the span of 2 years, a total of 150 female F0 mice and over 300 male and female rodents from their F1 progeny. We demonstrate that F1 male offsprings of female mice previously exposed to the synthetic estrogen 17α-ethinylestradiol (EE2) in combination with the synthetic progestin Norethindrone, exhibit neurodevelopmental and behavioral differences compared to control mice. Because the EE2 + Norethindrone administration resulted in gene expression changes in the exposed F0 mice ovaries persisting after the end of treatment, it is likely that the synthetic hormone treatment caused changes in the germline cells and that led to altered neurodevelopment in the offsprings. An altered gene expression pattern was discovered in the frontal cortex of male mice from the first offspring (F1.1) at infancy and an ADHD-like hyperactive locomotor behavior was exhibited in young male mice from the second offspring (F1.2) of female mice treated with contraceptive pill doses of EE2 + Norethindrone prior to pregnancy. The intergenerational neurodevelopmental effects of EE2 + Norethindrone treatment were sex specific, predominantly affecting males. Our observations in mice support the hypothesis that the use of synthetic contraceptive hormones is a potential environmental factor impacting the prevalence of human neurodevelopmental disorders. Additionally, our results indicate that contraceptive hormone drug safety assessments may need to be extended to F1 offspring. Since WHO declared the COVID-19 pandemic a Public Health Emergency of International Concern, more than 20 million cases have been reported, as of Aug 24, 2020. This study aimed to identify what the additional health-care costs of a strategic preparedness and response plan (SPRP) would be if current transmission levels are maintained in a status quo scenario, or under scenarios where transmission is increased or decreased by 50%. The number of COVID-19 cases was projected for 73 low-income and middle-income countries for each of the three scenarios for both 4-week and 12-week timeframes, starting from June 26, 2020. An input-based approach was used to estimate the additional health-care costs associated with human resources, commodities, and capital inputs that would be accrued in implementing the SPRP. The total cost estimate for the COVID-19 response in the status quo scenario was US$52·45 billion over 4 weeks, at $8·60 per capita. For the decreased or increased transmission scenarios, the totals were $33·08 billion and $61·92 billion, respectively. Costs would triple under the status quo and increased transmission scenarios at 12 weeks. The costs of the decreased transmission scenario over 12 weeks was equivalent to the cost of the status quo scenario at 4 weeks. By percentage of the overall cost, case management (54%), maintaining essential services (21%), rapid response and case investigation (14%), and infection prevention and control (9%) were the main cost drivers. The sizeable costs of a COVID-19 response in the health sector will escalate, particularly if transmission increases. Instituting early and comprehensive measures to limit the further spread of the virus will conserve resources and sustain the response. WHO, and UK Foreign Commonwealth and Development Office.WHO, and UK Foreign Commonwealth and Development Office.