Maternal diet during early gestation influences postnatal taste activity-dependent pruning by microglia

A key process in central sensory circuit development involves activity-dependent pruning of exuberant terminals. Here, we studied gustatory terminal field maturation in the postnatal mouse nucleus of the solitary tract (NST) during normal development and in mice where their mothers were fed a low NaCl diet for a limited period soon after conception. Pruning of terminal fields of gustatory nerves in controls involved the complement system and is likely driven by NaCl-elicited taste activity. In contrast, offspring of mothers with an early dietary manipulation failed to prune gustatory terminal fields even though peripheral taste activity developed normally. The ability to prune in these mice was rescued by activating myeloid cells postnatally, and conversely, pruning was arrested in controls with the loss of myeloid cell function. The altered pruning and myeloid cell function appear to be programmed before the peripheral gustatory system is assembled and corresponds to the embryonic period when microglia progenitors derived from the yolk sac migrate to and colonize the brain

Mortality in Four Waves of COVID-19 Is Differently Associated with Healthcare Capacities Affected by Economic Disparities

Background: The greatest challenges are imposed on the overall capacity of disease management when the cases reach the maximum in each wave of the pandemic. Methods: The cases and deaths for the four waves of COVID-19 in 119 countries and regions (CRs) were collected. We compared the mortality across CRs where populations experience different economic and healthcare disparities. Findings: Among 119 CRs, 117, 112, 111, and 55 have experienced 1, 2, 3, and 4 waves of COVID-19 disease, respectively. The average mortality rates at the disease turning point were 0.036, 0.019. 0.017, and 0.015 for the waves 1, 2, 3, and 4, respectively. Among 49 potential factors, income level, gross national income (GNI) per capita, and school enrollment are positively correlated with the mortality rates in the first wave, but negatively correlated with the rates of the rest of the waves. Their values for the first wave are 0.253, 0.346 and 0.385, respectively. The r value for waves 2, 3, and 4 are −0.310, −0.293, −0.234; −0.263, −0.284, −0.282; and −0.330, −0.394, −0.048, respectively. In high-income CRs, the mortality rates in waves 2 and 3 were 29% and 28% of that in wave 1; while in upper-middle-income CRs, the rates for waves 2 and 3 were 76% and 79% of that in wave 1. The rates in waves 2 and 3 for lower-middle-income countries were 88% and 89% of that in wave 1, and for low-income countries were 135% and 135%. Furthermore, comparison among the largest case numbers through all waves indicated that the mortalities in upper- and lower-middle-income countries is 65% more than that of the high-income countries. Interpretation: Conclusions from the first wave of the COVID-19 pandemic do not apply to the following waves. The clinical outcomes in developing countries become worse along with the expansion of the pandemic

DRD4 alleviates acute kidney injury by suppressing ISG15/NOX4 axis-associated oxidative stress

Acute kidney injury (AKI) is a life-threatening health condition associated with increasing morbidity and mortality. Despite extensive research on the mechanisms underlying AKI, effective clinical tools for prediction and treatment remain scarce. Oxidative stress and mitochondrial damage play a critical role in AKI and dopamine D4 receptor (DRD4) has been confirmed to be associated with oxidative stress. In this study, we hypothesized that DRD4 could attenuate AKI through its antioxidative and antiapoptotic effects. In vivo, DRD4 was remarkably decreased in the kidneys of mice subjected to ischemia/reperfusion injury (IRI) or cisplatin treatment. Notably, DRD4 significantly attenuated nephrotoxicity by suppressing oxidative stress and enhancing mitochondrial bioenergetics through the downregulation of reactive oxygen species (ROS) generation and NADPH oxidase 4 (NOX4) expression. In vitro, DRD4 demonstrated the ability to ameliorate oxidative stress-induced apoptosis in HK-2 cells subjected to hypoxia/reoxygenation- or cisplatin treatment. Transcriptome sequencing revealed that, mechanistically, DRD4 reduced the expression of its downstream target, interferon-stimulated gene 15 (ISG15), suppressing NOX4 ISGylation, enhancing the ubiquitination of NOX4, leading to its degradation, and ultimately counteracting oxidative stress-induced AKI. Altogether, these findings underscore the significance of DRD4 in AKI and elucidate DRD4 as a potential protectant against IRI or cisplatin-induced nephrotoxicity