SIRT4 loss reprograms intestinal nucleotide metabolism to support proliferation following perturbation of homeostasis.

The intestine is a highly metabolic tissue, but the metabolic programs that influence intestinal crypt proliferation, differentiation, and regeneration are still emerging. Here, we investigate how mitochondrial sirtuin 4 (SIRT4) affects intestinal homeostasis. Intestinal SIRT4 loss promotes cell proliferation in the intestine following ionizing radiation (IR). SIRT4 functions as a tumor suppressor in a mouse model of intestinal cancer, and SIRT4 loss drives dysregulated glutamine and nucleotide metabolism in intestinal adenomas. Intestinal organoids lacking SIRT4 display increased proliferation after IR stress, along with increased glutamine uptake and a shift toward de novo nucleotide biosynthesis over salvage pathways. Inhibition of de novo nucleotide biosynthesis diminishes the growth advantage of SIRT4-deficient organoids after IR stress. This work establishes SIRT4 as a modulator of intestinal metabolism and homeostasis in the setting of DNA-damaging stress.

Ketogenic diet-produced ß-hydroxybutyric acid accumulates brain GABA and increases GABA/glutamate ratio to inhibit epilepsy.

Ketogenic diet (KD) alleviates refractory epilepsy and reduces seizures in children. However, the metabolic/cell biologic mechanisms by which the KD exerts its antiepileptic efficacy remain elusive. Herein, we report that KD-produced ß-hydroxybutyric acid (BHB) augments brain gamma-aminobutyric acid (GABA) and the GABA/glutamate ratio to inhibit epilepsy. The KD ameliorated pentetrazol-induced epilepsy in mice. Mechanistically, KD-produced BHB, but not other ketone bodies, inhibited HDAC1/HDAC2, increased H3K27 acetylation, and transcriptionally upregulated SIRT4 and glutamate decarboxylase 1 (GAD1). BHB-induced SIRT4 de-carbamylated and inactivated glutamate dehydrogenase to preserve glutamate for GABA synthesis, and GAD1 upregulation increased mouse brain GABA/glutamate ratio to inhibit neuron excitation. BHB administration in mice inhibited epilepsy induced by pentetrazol. BHB-mediated relief of epilepsy required high GABA level and GABA/glutamate ratio. These results identified BHB as the major antiepileptic metabolite of the KD and suggested that BHB may serve as an alternative and less toxic antiepileptic agent than KD.

Tryptophanylation of insulin receptor by WARS attenuates insulin signaling.

Increased circulating amino acid levels have been linked to insulin resistance and development of type 2 diabetes (T2D), but the underlying mechanism remains largely unknown. Herein, we show that tryptophan modifies insulin receptor (IR) to attenuate insulin signaling and impair glucose uptake. Mice fed with tryptophan-rich chow developed insulin resistance. Excessive tryptophan promoted tryptophanyl-tRNA synthetase (WARS) to tryptophanylate lysine 1209 of IR (W-K1209), which induced insulin resistance by inhibiting the insulin-stimulated phosphorylation of IR, AKT, and AS160. SIRT1, but not other sirtuins, detryptophanylated IRW-K1209 to increase the insulin sensitivity. Collectively, we unveiled the mechanisms of how tryptophan impaired insulin signaling, and our data suggested that WARS might be a target to attenuate insulin resistance in T2D patients.

Long-term exposure to ambient ozone at workplace is positively and non-linearly associated with incident hypertension and blood pressure: longitudinal evidence from the Beijing-Tianjin-Hebei medical examination cohort.

BACKGROUND: There is limited longitudinal evidence on the hypertensive effects of long-term exposure to ambient O3. We investigated the association between long-term O3 exposure at workplace and incident hypertension, diastolic blood pressure (DBP), systolic blood pressure (SBP), pulse pressure (PP), and mean arterial pressure (MAP) in general working adults. METHODS: We conducted a cohort study by recruiting over 30,000 medical examination attendees through multistage stratified cluster sampling. Participants completed a standard questionnaire and comprehensive medical examination. Three-year ambient O3 concentrations at each employed participant's workplace were estimated using a two-stage machine learning model. Mixed-effects Cox proportional hazards models and linear mixed-effects models were used to examine the effect of O3 concentrations on incident hypertension and blood pressure parameters, respectively. Generalized additive mixed models were used to explore non-linear concentration-response relationships. RESULTS: A total of 16,630 hypertension-free working participants at baseline finished the follow-up. The mean (SD) O3 exposure was 45.26 (2.70) ppb. The cumulative incidence of hypertension was 7.11 (95% CI: 6.76, 7.47) per 100 person-years. Long-term O3 exposure was independently, positively and non-linearly associated with incident hypertension (Hazard ratios (95% CI) for Q2, Q3, and Q4 were 1.77 (1.34, 2.36), 2.06 (1.42, 3.00) and 3.43 (2.46, 4.79), respectively, as compared with the first quartile (Q1)), DBP (ß (95% CI) was 0.65 (0.01, 1.30) for Q2, as compared to Q1), SBP (ß (95% CI) was 2.88 (2.00, 3.77), 2.49 (1.36, 3.61) and 2.61 (1.64, 3.58) for Q2, Q3, and Q4, respectively), PP (ß (95% CI) was 2.12 (1.36, 2.87), 2.03 (1.18, 2.87) and 2.14 (1.38, 2.90) for Q2, Q3, and Q4, respectively), and MAP (ß (95% CI) was 1.39 (0.76, 2.02), 1.04 (0.24, 1.84) and 1.12 (0.43, 1.82) for Q2, Q3, and Q4, respectively). The associations were robust across sex, age, BMI, and when considering PM2.5 and NO2. CONCLUSIONS: To our knowledge, this is the first cohort study in the general population that demonstrates the non-linear hypertensive effects of long-term O3 exposure. The findings are particularly relevant for policymakers and researchers involved in ambient pollution and public health, supporting the integration of reduction of ambient O3 into public health interventions.

Metabolic modulation of mitochondrial mass during CD4+ T cell activation.

Mitochondrial biogenesis initiates within hours of T cell receptor (TCR) engagement and is critical for T cell activation, function, and survival; yet, how metabolic programs support mitochondrial biogenesis during TCR signaling is not fully understood. Here, we performed a multiplexed metabolic chemical screen in CD4+ T lymphocytes to identify modulators of metabolism that impact mitochondrial mass during early T cell activation. Treatment of T cells with pyrvinium pamoate early during their activation blocks an increase in mitochondrial mass and results in reduced proliferation, skewed CD4+ T cell differentiation, and reduced cytokine production. Furthermore, administration of pyrvinium pamoate at the time of induction of experimental autoimmune encephalomyelitis, an experimental model of multiple sclerosis in mice, prevented the onset of clinical disease. Thus, modulation of mitochondrial biogenesis may provide a therapeutic strategy for modulating T cell immune responses.

Vaccination, human mobility, and COVID-19 health outcomes: Empirical comparison before and during the outbreak of SARS-Cov-2 B.1.1.529 (Omicron) variant.

The B.1.1.529 (Omicron) variant surge has raised concerns about the effectiveness of vaccines and the impact of imprudent reopening. Leveraging over two years of county-level COVID-19 data in the US, this study aims to investigate relationships among vaccination, human mobility, and COVID-19 health outcomes (assessed via case rate and case-fatality rate), controlling for socioeconomic, demographic, racial/ethnic, and partisan factors. A set of cross-sectional models was first fitted to empirically compare disparities in COVID-19 health outcomes before and during the Omicron surge. Then, time-varying mediation analyses were employed to delineate how the effects of vaccine and mobility on COVID-19 health outcomes vary over time. Results showed that vaccine effectiveness against case rate lost significance during the Omicron surge, while its effectiveness against case-fatality rate remained significant throughout the pandemic. We also documented salient structural inequalities in COVID-19-related outcomes, with disadvantaged populations consistently bearing a larger brunt of case and death tolls, regardless of high vaccination rates. Last, findings revealed that mobility presented a significantly positive relationship with case rates during each wave of variant outbreak. Mobility substantially mediated the direct effect from vaccination to case rate, leading to a 10.276 % (95 % CI: 6.257, 14.294) decrease in vaccine effectiveness on average. Altogether, our study implies that sole reliance on vaccination to halt COVID-19 needs to be re-examined. Well-resourced and coordinated efforts to enhance vaccine effectiveness, mitigate health disparity and selectively loosen non-pharmaceutical interventions are essential to bringing the pandemic to an end.

Interactive COVID-19 Mobility Impact and Social Distancing Analysis Platform.

The research team has utilized privacy-protected mobile device location data, integrated with COVID-19 case data and census population data, to produce a COVID-19 impact analysis platform that can inform users about the effects of COVID-19 spread and government orders on mobility and social distancing. The platform is being updated daily, to continuously inform decision-makers about the impacts of COVID-19 on their communities, using an interactive analytical tool. The research team has processed anonymized mobile device location data to identify trips and produced a set of variables, including social distancing index, percentage of people staying at home, visits to work and non-work locations, out-of-town trips, and trip distance. The results are aggregated to county and state levels to protect privacy, and scaled to the entire population of each county and state. The research team is making their data and findings, which are updated daily and go back to January 1, 2020, for benchmarking, available to the public to help public officials make informed decisions. This paper presents a summary of the platform and describes the methodology used to process data and produce the platform metrics.

Asymptomatic Broncholithiasis and Aspergillus Infection: A Case Report and Literature Review.

Broncholithiasis coupled with Aspergillus infection is a rare disease of the respiratory system with complex pathogenesis and non-specific clinical manifestations that can be easily confused with other types of infectious diseases of the respiratory system. The lack of pertinent clinical manifestations in patients increases the risk of clinical misdiagnosis, omission, and incorrect treatment plan selection, which can result in permanent lung structural alterations and lung function decompensation and ultimately harm the lung. We report a rare case of asymptomatic broncholithiasis coupled with Aspergillus infection that was treated at our hospital and discuss the pathophysiology, diagnosis, differential diagnosis, and prognostic follow-up course. Furthermore, relevant studies from China and other countries, including this case, were reviewed. We gathered eight reports, summarized their significant diagnoses and treatments for broncholithiasis and broncholithiasis coupled with Aspergillus infection, and discussed their clinical features. Our study may help improve physicians' awareness of these types of diseases and serve as a resource for future diagnosis and treatment.

Amino acids downregulate SIRT4 to detoxify ammonia through the urea cycle.

Ammonia production via glutamate dehydrogenase is inhibited by SIRT4, a sirtuin that displays both amidase and non-amidase activities. The processes underlying the regulation of ammonia removal by amino acids remain unclear. Here, we report that SIRT4 acts as a decarbamylase that responds to amino acid sufficiency and regulates ammonia removal. Amino acids promote lysine 307 carbamylation (OTCCP-K307) of ornithine transcarbamylase (OTC), which activates OTC and the urea cycle. Proteomic and interactome screening identified OTC as a substrate of SIRT4. SIRT4 decarbamylates OTCCP-K307 and inactivates OTC in an NAD+-dependent manner. SIRT4 expression was transcriptionally upregulated by the amino acid insufficiency-activated GCN2-eIF2α-ATF4 axis. SIRT4 knockout in cultured cells caused higher OTCCP-K307 levels, activated OTC, elevated urea cycle intermediates and urea production via amino acid catabolism. Sirt4 ablation decreased male mouse blood ammonia levels and ameliorated CCl4-induced hepatic encephalopathy phenotypes. We reveal that SIRT4 safeguards cellular ammonia toxicity during amino acid catabolism.

Health disparity in the spread of COVID-19: Evidence from social distancing, risk of interactions, and access to testing.

OBJECTIVE: - To identify and assess whether three major risk factors that due to differential access to flexible resources might help explain disparities in the spread of COVID-19 across communities with different socioeconomic status, including socioeconomic inequalities in social distancing, the potential risk of interpersonal interactions, and access to testing. METHODS: Analysis uses ZIP code level weekly COVID-19 new cases, weekly population movement flows, weekly close-contact index, and weekly COVID-19 testing sites in Southern California from March 2020 to April 2021, merged with the U.S. census data to measure ZIP code level socioeconomic status and cofounders. This study first develops the measures for social distancing, the potential risk of interactions, and access to testing. Then we employ a spatial lag regression model to quantify the contributions of those factors to weekly COVID-19 case growth. RESULTS: Results identify that, during the first COVID-19 wave, new case growth of the low-income group is two times higher than that of the high-income group. The COVID-19 case disparity widens to four times in the second COVID-19 wave. We also observed significant disparities in social distancing, the potential risk of interactions, and access to testing among communities with different socioeconomic status. In addition, all of them contribute to the disparities of COVID-19 incidences. Among them, the potential risk of interactions is the most important contributor, whereas testing accessibility contributes least. We also found that close-contact is a more effective measure of social distancing than population movements in examining the spread of COVID-19. CONCLUSION: - This study answers critically unaddressed questions about health disparities in the spread of COVID-19 by assessing factors that might explain why the spread is different in different groups.

Uncoupled glycerol-3-phosphate shuttle in kidney cancer reveals that cytosolic GPD is essential to support lipid synthesis.

The glycerol-3-phosphate shuttle (G3PS) is a major NADH shuttle that regenerates reducing equivalents in the cytosol and produces energy in the mitochondria. Here, we demonstrate that G3PS is uncoupled in kidney cancer cells where the cytosolic reaction is ∼4.5 times faster than the mitochondrial reaction. The high flux through cytosolic glycerol-3-phosphate dehydrogenase (GPD) is required to maintain redox balance and support lipid synthesis. Interestingly, inhibition of G3PS by knocking down mitochondrial GPD (GPD2) has no effect on mitochondrial respiration. Instead, loss of GPD2 upregulates cytosolic GPD on a transcriptional level and promotes cancer cell proliferation by increasing glycerol-3-phosphate supply. The proliferative advantage of GPD2 knockdown tumor can be abolished by pharmacologic inhibition of lipid synthesis. Taken together, our results suggest that G3PS is not required to run as an intact NADH shuttle but is instead truncated to support complex lipid synthesis in kidney cancer.

Perspectives of PDE inhibitor on treating idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease (ILD) without an identifiable cause. If not treated after diagnosis, the average life expectancy is 3-5 years. Currently approved drugs for the treatment of IPF are Pirfenidone and Nintedanib, as antifibrotic drugs, which can reduce the decline rate of forced vital capacity (FVC) and reduce the risk of acute exacerbation of IPF. However these drugs can not relieve the symptoms associated with IPF, nor improve the overall survival rate of IPF patients. We need to develop new, safe and effective drugs to treat pulmonary fibrosis. Previous studies have shown that cyclic nucleotides participate in the pathway and play an essential role in the process of pulmonary fibrosis. Phosphodiesterase (PDEs) is involved in cyclic nucleotide metabolism, so PDE inhibitors are candidates for pulmonary fibrosis. This paper reviews the research progress of PDE inhibitors related to pulmonary fibrosis, so as to provide ideas for the development of anti-pulmonary fibrosis drugs.

COVID-19 vaccine hesitancy cannot fully explain disparities in vaccination coverage across the contiguous United States.

Vaccine hesitancy has been identified as a major obstacle preventing comprehensive coverage against the COVID-19 pandemic. However, few studies have analyzed the association between ex-ante vaccine hesitancy and ex-post vaccination coverage. This study leveraged one-year county-level data across the contiguous United States to examine whether the prospective vaccine hesitancy eventually translates into differential vaccination rates, and whether vaccine hesitancy can explain socioeconomic, racial, and partisan disparities in vaccine uptake. A set of structural equation modeling was fitted with vaccine hesitancy and vaccination rate as endogenous variables, controlling for various potential confounders. The results demonstrated a significant negative link between vaccine hesitancy and vaccination rate, with the difference between the two continuously widening over time. Counties with higher socioeconomic statuses, more Asian and Hispanic populations, more elderly residents, greater health insurance coverage, and more Democrats presented lower vaccine hesitancy and higher vaccination rates. However, underlying determinants of vaccination coverage and vaccine hesitancy were divergent regarding their different associations with exogenous variables. Mediation analysis further demonstrated that indirect effects from exogenous variables to vaccination coverage via vaccine hesitancy only partially explained corresponding total effects, challenging the popular narrative that portrays vaccine hesitancy as a root cause of disparities in vaccination. Our study highlights the need of well-funded, targeted, and ongoing initiatives to reduce persisting vaccination inequities.

Association of long-term exposure to PM2.5 in workplace with fasting plasma glucose among asymptomatic adults: A multicenter study in North China.

BACKGROUND: The impacts of long-term high exposure to PM2.5 in workplace on glucose metabolism in asymptomatic working adults (AWAs) have rarely been explored. OBJECTIVES: To assess the relationship between long-term exposure to workplace PM2.5 and glucose metabolism in asymptomatic general working adults in heavily polluted regions. METHODS: We used the baseline data of the asymptomatic working participants from the Beijing-Tianjin-Hebei Medical Examination Cohort, which recruited adults undergoing medical examinations. A machine learning-based spatial-temporal model was used to estimate daily average PM2.5 concentrations in the participants' workplaces. We assessed the association of long-term PM2.5 concentrations (three years prior to the interview) and fasting plasma glucose (FPG) using generalized linear mixed-effects models (GLMM) with inclusion of potential confounders. Stratified analyses by sex, age, BMI and smoking status, and two pollutant models were further performed. RESULTS: A total of 37,619 individuals were interviewed and 28,865 were included in the analyses. The mean FPG was 5.20 (0.96) mmol/L, and the estimated three-year average concentration of PM2.5 exposure was 69.51 (6.92) µg/m3. We detected a significant association of long-term exposure to workplace PM2.5 and FPG, a 10 µg/m3 increase in the long-term workplace PM2.5 exposure was associated with 0.075 (95%CI: 0.050-0.100) mmol/L elevated FPG and 25% (OR = 1.25, 95%CI: 1.05-1.50) elevated odds of abnormal fasting glucose metabolism with control of the potential confounding. The detected association between workplace PM2.5 and FPG metabolism remained significant in males, individuals aged > 44 years, overweight and/or obese people, both smokers and non-smokers, and when NO2, SO2, O3, and CO were included in the model. CONCLUSIONS: Long-term exposure to workplace PM2.5 was associated with elevated FPG and/or odds of abnormal glucose metabolism among AWAs. Male, middle-aged, overweight and/or obese AWAs were more susceptible to workplace PM2.5 regardless of smoking status.

Peucedanum praeruptorum Dunn polysaccharides regulate macrophage inflammatory response through TLR2/TLR4-mediated MAPK and NF-κB pathways.

The present study was to investigate the molecular mechanisms underlying macrophage inflammatory response to polysaccharides from Peucedanum praeruptorum Dunn (PPDs) and elucidate the receptors and signaling pathways associated with PPDs-mediated macrophage activation. MTT and Griess method were performed to investigate the effects of PPDs on cell viability and NO production. Neutral red and FITC-dextran were used to determine the pinocytic and phagocytic activity. RT-qPCR and ELISA were employed to analyze the mRNA expression of inflammatory factors and production of cytokines and chemokines. RNA-seq and bioinformatics analysis were conducted to determine the underlying molecules, regulators and pathways, which were further validated by pathway inhibition and neutralization assays. The results indicated that PPDs significantly enhanced pinocytic and phagocytic activity, promoted the expression and secretion of inflammatory factors and chemokines, and boosted the expression of accessory and costimulatory molecules. RNA-Seq analysis identified 1343 DEGs, 405 GO terms and 91 KEGG pathways. IL6 and TNF were identified as hubs of connectivity in PPDs-mediated macrophage activation. "Cytokine-cytokine receptor interaction", "TNF signaling pathway", "NF-kappa B signaling pathway", "JAK-STAT signaling pathway" and "MAPK signaling pathway" were the most significant pathways. The pathway inhibition assay revealed that MAPK and NF-κB pathways were essential to macrophage activation by PPDs. TLR2 and TLR4 were uncovered to be the functional receptors and involved in recognition of PPDs. These results indicated that PPDs modulated macrophage inflammatory response mainly through TLR2/TLR4-dependent MAPK and NF-κB pathways.

Methylene-bridge tryptophan fatty acylation regulates PI3K-AKT signaling and glucose uptake.

Protein fatty acylation regulates numerous cell signaling pathways. Polyunsaturated fatty acids (PUFAs) exert a plethora of physiological effects, including cell signaling regulation, with underlying mechanisms to be fully understood. Herein, we report that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) regulate PI3K-AKT signaling by modifying PDK1 and AKT2. DHA-administered mice exhibit altered phosphorylation of proteins in signaling pathways. Methylene bridge-containing DHA/EPA acylate δ1 carbon of tryptophan 448/543 in PDK1 and tryptophan 414 in AKT2 via free radical pathway, recruit both the proteins to the cytoplasmic membrane, and activate PI3K signaling and glucose uptake in a tryptophan acylation-dependent but insulin-independent manner in cultured cells and in mice. DHA/EPA deplete cytosolic PDK1 and AKT2 and induce insulin resistance. Akt2 knockout in mice abrogates DHA/EPA-induced PI3K-AKT signaling. Our results identify PUFA's methylene bridge tryptophan acylation, a protein fatty acylation that regulates cell signaling and may underlie multifaceted effects of methylene-bridge-containing PUFAs.

Examining spatiotemporal evolution of racial/ethnic disparities in human mobility and COVID-19 health outcomes: Evidence from the contiguous United States.

Social distancing has become a key countermeasure to contain the dissemination of COVID-19. This study examined county-level racial/ethnic disparities in human mobility and COVID-19 health outcomes during the year 2020 by leveraging geo-tracking data across the contiguous US. Sets of generalized additive models were fitted under cross-sectional and time-varying settings, with percentage of mobility change, percentage of staying home, COVID-19 infection rate, and case-fatality ratio as dependent variables, respectively. After adjusting for spatial effects, built environment, socioeconomics, demographics, and partisanship, we found counties with higher Asian populations decreased most in travel, counties with higher White and Asian populations experienced the least infection rate, and counties with higher African American populations presented the highest case-fatality ratio. Control variables, particularly partisanship and education attainment, significantly influenced modeling results. Time-varying analyses further suggested racial differences in human mobility varied dramatically at the beginning but remained stable during the pandemic, while racial differences in COVID-19 outcomes broadly decreased over time. All conclusions hold robust with different aggregation units or model specifications. Altogether, our analyses shine a spotlight on the entrenched racial segregation in the US as well as how it may influence the mobility patterns, urban forms, and health disparities during the COVID-19.

COVID-19 and income profile: How communities in the United States responded to mobility restrictions in the pandemic's early stages.

Mobility interventions in communities play a critical role in containing a pandemic at an early stage. The real-world practice of social distancing can enlighten policymakers and help them implement more efficient and effective control measures. A lack of such research using real-world observations initiates this article. We analyzed the social distancing performance of 66,149 census tracts from 3,142 counties in the United States with a specific focus on income profile. Six daily mobility metrics, including a social distancing index, stay-at-home percentage, miles traveled per person, trip rate, work trip rate, and non-work trip rate, were produced for each census tract using the location data from over 100 million anonymous devices on a monthly basis. Each mobility metric was further tabulated by three perspectives of social distancing performance: "best performance," "effort," and "consistency." We found that for all 18 indicators, high-income communities demonstrated better social distancing performance. Such disparities between communities of different income levels are presented in detail in this article. The comparisons across scenarios also raise other concerns for low-income communities, such as employment status, working conditions, and accessibility to basic needs. This article lays out a series of facts extracted from real-world data and offers compelling perspectives for future discussions.

Do racial and ethnic disparities in following stay-at-home orders influence COVID-19 health outcomes? A mediation analysis approach.

Racial/ethnic disparities are among the top-selective underlying determinants associated with the disproportional impact of the COVID-19 pandemic on human mobility and health outcomes. This study jointly examined county-level racial/ethnic differences in compliance with stay-at-home orders and COVID-19 health outcomes during 2020, leveraging two-year geo-tracking data of mobile devices across ~4.4 million point-of-interests (POIs) in the contiguous United States. Through a set of structural equation modeling, this study quantified how racial/ethnic differences in following stay-at-home orders could mediate COVID-19 health outcomes, controlling for state effects, socioeconomics, demographics, occupation, and partisanship. Results showed that counties with higher Asian populations decreased most in their travel, both in terms of reducing their overall POIs' visiting and increasing their staying home percentage. Moreover, counties with higher White populations experienced the lowest infection rate, while counties with higher African American populations presented the highest case-fatality ratio. Additionally, control variables, particularly partisanship, median household income, percentage of elders, and urbanization, significantly accounted for the county differences in human mobility and COVID-19 health outcomes. Mediation analyses further revealed that human mobility only statistically influenced infection rate but not case-fatality ratio, and such mediation effects varied substantially among racial/ethnic compositions. Last, robustness check of racial gradient at census block group level documented consistent associations but greater magnitude. Taken together, these findings suggest that US residents' responses to COVID-19 are subject to an entrenched and consequential racial/ethnic divide.