Myeloid NCOA4 sequesters KEAP1 to reduce ferroptosis for protection against salmonellosis in mice.

Salmonellosis, caused by Salmonella enterica serovar Typhimurium, is a significant global threat. Host immunity limits bacterial replication by inducing hepcidin, which degrades ferroportin, reducing iron transfer. However, this boosts macrophage iron storage, aiding intracellular pathogens like Salmonella. Mice lacking ferritin heavy chain (FTH1) in myeloid cells suffer worsened Salmonella infection. Nuclear receptor co-activator 4 (NCOA4) regulates iron release via FTH1 degradation during low iron, but its role in salmonellosis is unclear. Here, we reveal that myeloid NCOA4 deficiency augments spleen iron levels and increases cellular iron accumulation, oxidative stress, and ferroptosis in bone marrow-derived macrophages. This deficiency also increases susceptibility to Salmonella-induced colitis in mice. Mechanistically, NCOA4 suppresses oxidative stress by directly binding to the E3 ubiquitin ligase Kelch-like ECH-associated protein 1 (KEAP1) and stabilizing the antioxidant transcription factor nuclear factor-erythroid 2-related factor 2 (NRF2). Activation of NRF2 protects myeloid NCOA4 knockout mice from Salmonella-induced colitis. Antioxidant Tempol and myeloid cell-targeted curcumin offer protection against colitis in myeloid NCOA4-deficient mice. A low iron diet and ferroptosis inhibition also mitigate the heightened colitis in these mice. Overexpression of myeloid cell-specific NCOA4 confers protection against Salmonella-induced colitis via upregulating NRF2 signaling. Serum iron was reduced in myeloid NCOA4-overexpressing mice, but not in NCOA4-deficient mice. Targeted serum metabolomics analysis revealed that many lipids were decreased in myeloid NCOA4-deficient mice, while several of them were increased in myeloid NCOA4-overexpressing mice. Together, this study not only advances our understanding of NCOA4/KEAP1/NRF2/ferroptosis axis but also paves the way for novel myeloid cell-targeted therapies to combat salmonellosis.

Tuning Electron Delocalization of Redox-Active Porous Aromatic Framework for Low-Temperature Aqueous Zn-K Hybrid Batteries with Air Self-Chargeability.

Air self-charging aqueous batteries promise to integrate energy harvesting technology and battery systems, potentially overcoming a heavy reliance on energy and the spatiotemporal environment. However, the exploitation of multifunctional air self-charging battery systems using promising cathode materials and suitable charge carriers remains challenging. Herein, for the first time, we developed low-temperature self-charging aqueous Zn-K hybrid ion batteries (AZKHBs) using a fully conjugated hexaazanonaphthalene (HATN)-based porous aromatic framework as the cathode material, exhibiting redox chemistry using K+ as charge carriers, and regulating Zn-ion solvation chemistry to guide uniform Zn plating/stripping. The unique AZKHBs exhibit the exceptional electrochemical properties in all-climate conditions. Most importantly, the large potential difference causes the AZKHBs discharged cathode to be oxidized using oxygen, thereby initiating a self-charging process in the absence of an external power source. Impressively, the air self-charging AZKHBs can achieve a maximum voltage of 1.15 V, an impressive discharge capacity (466.3 mAh g-1), and exceptional self-charging performance even at -40 °C. Therefore, the development of self-charging AZKHBs offers a solution to the limitations imposed by the absence of a power grid in harsh environments or remote areas.

Combination of facial and nose features of Amur tigers to determine age.

We found that the area of black round or irregular-shaped spots on the tiger's nose increased with age, indicating a positive relationship between age and nose features. We used the deep learning model to train the facial and nose image features to identify the age of Amur tigers, using a combination of classification and prediction methods to achieve age determination with an accuracy of 87.81%.

Association between triglyceride-glucose index and endothelial dysfunction.

BACKGROUND: Triglyceride-glucose (TyG) index, a simple surrogate marker for insulin resistance (IR), has been reported as an independent predictor of arterial structural damage and future cardiovascular events. The association between TyG index and endothelial dysfunction remains uncertain. OBJECTIVE: The purpose of this study was to investigate the association between TyG index and endothelial dysfunction. METHODS: Endothelial dysfunction was measured using flow-mediated dilation (FMD). A total of 840 subjects, who voluntarily accepted FMD measurement at the Health Management Department of Xuanwu Hospital from October 2016 to January 2020, were included in this study. TyG index was calculated as Ln [fasting triglyceride (TG)(mg/dL) × fasting plasma glucose (FPG) (mg/dL)/2]. RESULTS: The mean age was 59.92 ± 10.28 years and 559 (66.55%) participants were male. The TyG index was correlated with FMD values (P = 0.022). Each unit increment in TyG index was associated with lower FMD values (ß = -0.330, 95%CI -0.609 to -0.052, P = 0.020) after adjusting for covariates. Age (ß = -0.069, 95%CI -0.088 to -0.051, P < 0.001), female (ß = 0.592, 95%CI 0.172 to1.012, P = 0.006), smoking (ß = -0.430, 95%CI -0.859 to -0.002, P = 0.049) and hypertension (ß = -0.741, 95%CI -1.117 to -0.365, P < 0.001) were also independent predictors for endothelial dysfunction. A significant association between the TyG index and endothelial dysfunction was found only in populations younger than 60 years (ß = -0.843, 95%CI -1.371 to -0.316, P = 0.002), females (ß = -0.612, 95%CI -1.147 to -0.077, P = 0.025), and populations without diabetes mellitus (DM) (ß = -0.594, 95%CI -1.042 to -0.147, P = 0.009). CONCLUSIONS: Subjects with an elevated TyG index are more likely to have endothelial dysfunction, particularly in populations without DM.

Associations of online health information seeking with health behaviors of cancer survivors.

Objective: To examine the effects of online health information seeking (OHIS) behavior on five health behaviors (regular physical activity, less sedentary, calorie checking, no alcohol consumption, and no smoking) among adult cancer survivors in the United States. Methods: A cross-sectional analysis was conducted with adult cancer survivors (≥18 years old) from Cycles 2, 3, and 4 of the Health Information National Trends Survey (HINTS). The respondents self-reported OHIS, and the data on the five health behaviors were pooled to perform descriptive and multivariable logistic regression analyses using Stata 17.0. Results: Of the 1245 adult cancer survivors, approximately 74% reported OHIS behavior for themselves within the previous year of the survey. We found that OHIS was significantly and positively associated with the level of physical activity (odds ratio [OR] = 1.53, p = .002) and calorie checking (OR = 1.64, p = .001), but not with sedentary behavior, smoking, and alcohol consumption after adjusting for age, sex, race/ethnicity, education, income, body mass index (BMI), marital status, depression, and general health. Conclusions: Findings from this study suggest that most cancer survivors used various forms of digital tools and platforms to seek health information. The study also demonstrated an independent impact of OHIS behavior on physical activity and calorie checking. Healthcare professionals may need to encourage and guide cancer survivors to seek credible eHealth information and further utilize digital health tools as a platform for care delivery, promoting health behaviors and preventing adverse health outcomes among cancer survivors.

Regulation of SOCS3-STAT3 in urate-induced cytokine production in human myeloid cells.

OBJECTIVE: Hyperuricaemia is necessary for gout. High urate concentrations have been linked to inflammation in mononuclear cells. Here, we explore the role of the suppressor of cytokine signaling 3 (SOCS3) in urate-induced inflammation. METHODS: Peripheral blood mononuclear cells (PBMCs) from gout patients, hyperuricemic and normouricemic individuals were cultured for 24h with varying concentrations of soluble urate, followed by 24h restimulation with lipopolysaccharides (LPS)±monosodium urate (MSU) crystals. Transcriptomic profiling was performed using RNA-Sequencing. DNA methylation was assessed using Illumina Infinium® MethylationEPIC BeadChip system (EPIC array). Phosphorylation of signal transducer and activator of transcription 3 (STAT3) was determined by flow cytometry. Cytokine responses were also assessed in PBMCs from patients with JAK2 V617F tyrosine kinase mutation. RESULTS: PBMCs pre-treated with urate produced more interleukin-1beta (IL-1ß) and interleukin-6 (IL-6) and less interleukin-1 receptor anatagonist (IL-1Ra) after LPS simulation. In vitro, urate treatment enhanced SOCS3 expression in control monocytes but no DNA methylation changes were observed at the SOCS3 gene. A dose-dependent reduction in phosphorylated STAT3 concomitant with a decrease in IL-1Ra was observed with increasing concentrations of urate. PBMCs with constitutively activated STAT3 (JAK2 V617F mutation) could not be primed by urate. CONCLUSION: In vitro, urate exposure increased SOCS3 expression, while urate priming, and subsequent stimulation resulted in decreased STAT3 phosphorylation and IL-1Ra production. There was no evidence that DNA methylation constitutes a regulatory mechanism of SOCS3. Elevated SOCS3 and reduced pSTAT3 could play a role in urate-induced hyperinflammation since urate priming had no effect in PBMCs from patients with constitutively activated STAT3.

Glutathione peroxidase 4 suppresses manganese-dependent oxidative stress to reduce colorectal tumorigenesis.

The role of glutathione peroxidase 4 (GPX4) in ferroptosis and various cancers is well-established; however, its specific contribution to colorectal cancer has been unclear. Surprisingly, in a genetic mouse model of colon tumors, the deletion of GPX4 specifically in colon epithelial cells increased tumor burden but decreased oxidized glutathione. Notably, this specific GPX4 deletion did not enhance susceptibility to dextran sodium sulfate (DSS)-induced colitis in mice with varied iron diets but showed vulnerability in mice with a vitamin E-deficient diet. Additionally, a high manganese diet heightened susceptibility, while a low manganese diet reduced DSS-induced colitis in colon epithelial-specific GPX4-deficient mice. Strikingly, the low manganese diet also significantly reduced colorectal cancer formation in both colon epithelial-specific GPX4-deficient and wildtype mice. Mechanistically, antioxidant proteins, especially manganese-dependent superoxide dismutase (MnSOD or SOD2), correlated with disease severity. Treatment with tempol, a superoxide dismutase mimetic radical scavenger, suppressed GPX4 deficiency-induced colorectal tumors. In conclusion, the study elucidates the critical role of GPX4 in inhibiting colorectal cancer progression by regulating oxidative stress in a manganese-dependent manner. The findings underscore the intricate interactions between GPX4, dietary factors, and their collective influence on colorectal cancer development, providing potential insights for personalized therapeutic strategies.

Anchoring π-d Conjugated Metal-Organic Frameworks with Dual-Active Centers on Carbon Nanotubes for Advanced Potassium-Ion Batteries.

Potassium-ion batteries (PIBs) are gradually gaining attention owing to their natural abundance, excellent security, and high energy density. However, developing excellent organic cathode materials for PIBs to overcome the poor cycling stability and slow kinetics caused by the large radii of K+ ions is challenging. This study demonstrates for the first time the application of a hexaazanonaphthalene (HATN)-based 2D π-d conjugated metal-organic framework (2D c-MOF) with dual-active centers (Cu-HATNH) and integrates Cu-HATNH with carbon nanotubes (Cu-HATNH@CNT) as the cathode material for PIBs. Owing to this systematic module integration and more exposed active sites with high utilization, Cu-HATNH@CNT exhibits a high initial capacity (317.5 mA h g-1 at 0.1 A g-1 ), excellent long-term cycling stability (capacity retention of 96.8% at 5 A g-1 after 2200 cycles), and outstanding rate capacity (147.1 mA h g-1 at 10 A g-1 ). The reaction mechanism and performance are determined by combining experimental characterization and density functional theory calculations. This contribution provides new opportunities for designing high-performance 2D c-MOF cathodes with multiple active sites for PIBs.

Rural racial disparities and barriers in mammography utilization among Medicare beneficiaries in Texas: A longitudinal study.

This study examined rural racial/ethnic disparities in long-term mammography screening practices among Medicare beneficiaries. A retrospective longitudinal study was conducted using 100% Texas Medicare data for women aged 65-74 who enrolled in Medicare between 2010-2013. Of the 114,939 eligible women, 21.2% of Hispanics, 33.3% of non-Hispanic Blacks (NHB), and 38.4% non-Hispanic Whites (NHW) in rural areas were regular users of mammography, compared to 33.5%, 44.9%, and 45.3% of their counterparts in urban areas, respectively. Stratification analyses showed rural Hispanics and NHB were 33% (95% CI, 25% - 40%) and 22% (95% CI, 6% - 36%) less likely to be regular users of mammography compared to their urban counterparts. Major barriers to routine mammography screening included the lack of a primary care provider, frequent hospitalization, and comorbidity. The findings of this study highlight the importance of addressing rural racial disparities in mammography utilization among older women to ensure equitable screening practices for all populations.

Boosting H+ Storage in Aqueous Zinc Ion Batteries via Integrating Redox-Active Sites into Hydrogen-Bonded Organic Frameworks with Strong π-π Stacking.

In the emerging aqueous zinc ion batteries (AZIBs), proton (H+ ) with the smallest molar mass and fast (de)coordination kinetics is considered as the most ideal charge carrier compared with Zn2+ counterpart, however, searching for new hosting materials for H+ storage is still at its infancy. Herein, redox-active hydrogen-bonded organic frameworks (HOFs) assembled from diaminotriazine moiety decorated hexaazatrinnphthalene (HOF-HATN) are for the first time developed as the stable cathode hosting material for boosting H+ storage in AZIBs. The unique integration of hydrogen-bonding networks and strong π-π stacking endow it rapid Grotthuss proton conduction, stable supramolecular structure and inclined H+ storage. As a consequence, HOF-HATN displays a high capacity (320 mAh g-1 at 0.05 A g-1 ) and robust cyclability of (>10000 cycles at 5 A g-1 ) based on three-step cation coordination storage. These findings get insight into the proton transport and storage behavior in HOFs and provide the molecular engineering strategy for constructing well-defined cathode hosting materials for rechargeable aqueous batteries.

Twistedly hydrophobic basis with suitable aromatic metrics in covalent organic networks govern micropollutant decontamination.

The pre-designable structure and unique architectures of covalent organic frameworks (COFs) render them attractive as active and porous medium for water crisis. However, the effect of functional basis with different metrics on the regulation of interfacial behavior in advanced oxidation decontamination remains a significant challenge. In this study, we pre-design and fabricate different molecular interfaces by creating ordered π skeletons, incorporating different pore sizes, and engineering hydrophilic or hydrophobic channels. These synergically break through the adsorption energy barrier and promote inner-surface renewal, achieving a high removal rate for typical antibiotic contaminants (like levofloxacin) by BTT-DATP-COF, compared with BTT-DADP-COF and BTT-DAB-COF. The experimental and theoretical calculations reveal that such functional basis engineering enable the hole-driven levofloxacin oxidation at the interface of BTT fragments to occur, accompanying with electron-mediated oxygen reduction on terphenyl motif to active radicals, endowing it facilitate the balanced extraction of holes and electrons.

The impact of BNT162b2 mRNA vaccine on adaptive and innate immune responses.

The mRNA-based BNT162b2 protects against severe disease and mortality caused by SARS-CoV-2 via induction of specific antibody and T-cell responses. Much less is known about its broad effects on immune responses against other pathogens. Here, we investigated the adaptive immune responses induced by BNT162b2 vaccination against various SARS-CoV-2 variants and its effects on the responsiveness of immune cells upon stimulation with heterologous stimuli. BNT162b2 vaccination induced effective humoral and cellular immunity against SARS-CoV-2 that started to wane after six months. We also observed long-term transcriptional changes in immune cells after vaccination. Additionally, vaccination with BNT162b2 modulated innate immune responses as measured by inflammatory cytokine production after stimulation - higher IL-1/IL-6 release and decreased IFN-α production. Altogether, these data expand our knowledge regarding the overall immunological effects of this new class of vaccines and underline the need for additional studies to elucidate their effects on both innate and adaptive immune responses.

Hypoxia-inducible factor upregulation by roxadustat attenuates drug reward by altering brain iron homoeostasis.

Substance use disorder remains a major challenge, with an enduring need to identify and evaluate new, translational targets for effective treatment. Here, we report the upregulation of Hypoxia-inducible factor-1α (HIF-1α) expression by roxadustat (Rox), a drug developed for renal anemia that inhibits HIF prolyl hydroxylase to prevent degradation of HIF-1α, administered either systemically or locally into selected brain regions, suppressed morphine (Mor)-induced conditioned place preference (CPP). A similar effect was observed with methamphetamine (METH). Moreover, Rox also inhibited the expression of both established and reinstated Mor-CPP and promoted the extinction of Mor-CPP. Additionally, the elevation of HIF-1α enhanced hepcidin/ferroportin 1 (FPN1)-mediated iron efflux and resulted in cellular iron deficiency, which led to the functional accumulation of the dopamine transporter (DAT) in plasma membranes due to iron deficiency-impaired ubiquitin degradation. Notably, iron-deficient mice generated via a low iron diet mimicked the effect of Rox on the prevention of Mor- or METH-CPP formation, without affecting other types of memory. These data reveal a novel mechanism for HIF-1α and iron involvement in substance use disorder, which may represent a potential novel therapeutic strategy for the treatment of drug abuse. The findings also repurpose Rox by suggesting a potential new indication for the treatment of substance use disorder.

Iron promotes glycolysis to drive colon tumorigenesis.

Colorectal cancer (CRC) is the third most common cancer and is also the third leading cause of cancer-related death in the USA. Understanding the mechanisms of growth and progression of CRC is essential to improve treatment. Macronutrients such as glucose are energy source for a cell. Many tumor cells exhibit increased aerobic glycolysis. Increased tissue micronutrient iron levels in both mice and humans are also associated with increased colon tumorigenesis. However, if iron drives colon carcinogenesis via affecting glucose metabolism is still not clear. Here we found the intracellular glucose levels in tumor colonoids were significantly increased after iron treatment. 13C-labeled glucose flux analysis indicated that the levels of several labeled glycolytic products were significantly increased, whereas several tricarboxylic acid cycle intermediates were significantly decreased in colonoids after iron treatment. Mechanistic studies showed that iron upregulated the expression of glucose transporter 1 (GLUT1) and mediated an inhibition of the pyruvate dehydrogenase (PDH) complex function via directly binding with tankyrase and/or pyruvate dehydrogenase kinase (PDHK) 3. Pharmacological inhibition of GLUT1 or PDHK reactivated PDH complex function and reduced high iron diet-enhanced tumor formation. In conclusion, excess iron promotes glycolysis and colon tumor growth at least partly through the inhibition of the PDH complex function.

Controlled Attenuation Parameter Is Associated with a Distinct Systemic Inflammatory Milieu after Clearance of HCV Infection.

Hepatitis C virus (HCV) infection is closely associated with lipid metabolism defects along with a high prevalence of hepatic steatosis. After HCV clearance, steatosis persists in many patients. However, the reasons behind this phenomenon are not completely clear. To investigate the association between 92 soluble inflammatory mediators (SIMs) and the steatosis grade, we made use of a cohort of 94 patients with chronic HCV infection who cleared HCV after direct-acting antiviral agent (DAA) treatment. Patients were classified into three groups according to their controlled attenuation parameter (CAP). CAP is associated with ALT, γ-GT and liver stiffness after HCV clearance. While stem cell factor (SCF) and tumor necrosis factor ligand superfamily member 12 (TWEAK) levels were significantly reduced in patients with CAP > 299 dB/m, the levels of fibroblast growth factor (FGF)-21 and interleukin-18 receptor 1 (IL-18R1) were higher in those patients at week 96 after virus clearance. These four markers also showed a linear correlation with CAP values. FGF-21 levels correlated with CAP only after HCV clearance. Taken together, these four biomarkers, namely SCF, TWEAK, FGF-21 and IL-18R1, are associated with CAP status after virus clearance. A potential role of these proteins in the pathogenesis of post-sustained viral response (SVR) nonalcoholic steatohepatitis requires further investigation.

Disparities in screening mammography utilization among Hispanic women in rural Texas from 2002 to 2018.

PURPOSE: To examine the trends of racial/ethnic and urban-rural disparities in screening mammography use with a focus on Hispanic women in rural Texas, as well as to further investigate barriers to mammography screening practices. METHODS: A serial cross-sectional study was conducted on screening mammography including eligible female respondents (≥ 40 years) from the Texas Behavioral Risk Factor Surveillance System survey from 2002 to 2018. FINDINGS: Weighted descriptive analyses showed persistent racial/ethnic and urban-rural disparities in mammography screening rates among eligible women (≥ 40 years) in Texas. Overall, the mammography screening rates for women in rural areas were significantly lower than women in urban areas with a mean rate of 64.09% versus 70.89% (p < 0.001). Rural Hispanic women had the lowest mean mammography screening rate (55.98%) among all eligible women which is 16.27% below the mean mammography screening rate of non-Hispanic white women in urban areas. Weighted logistic regression model revealed that women with no health insurance or primary care providers were 52% (95% Confidence Interval [CI] 0.36-0.63, p < 0.001) or 54% (95% CI 0.35-0.6, p < 0.001) less likely having an up-to-date mammography screening compared with women with health insurance or primary care providers, respectively. CONCLUSIONS: Our study demonstrated significant and persistent racial and urban-rural disparities in screening mammography utilization among Hispanic women compared with non-Hispanic white women from 2002 to 2018. Healthcare access is a major contributor to these disparities. It highlights the need for wide-scale interventions from public health and policymakers targeting under screened racial minorities and rural regions population to promote screening mammography services among disadvantaged population.

Myeloid FTH1 Deficiency Protects Mice From Colitis and Colitis-associated Colorectal Cancer via Reducing DMT1-Imported Iron and STAT3 Activation.

BACKGROUND: Myeloid cells are critical for iron and immune homeostasis. Ferritin heavy chain (FTH1) is essential for intracellular iron storage. Myeloid FTH1 is important in the pathogenesis of many inflammatory diseases. However, the role of myeloid FTH1 in colitis and colitis-associated cancer has not been determined. METHODS: Myeloid FTH1 deficient and wild-type mice were treated with dextran sodium sulfate (DSS) or azoxymethane (AOM)-DSS to compare their susceptibility to acute colitis or colitis-associated cancer. RESULTS: Myeloid FTH1-deficient mice fed with a high-iron diet were less susceptible to DSS-induced acute colitis than wild type mice. Mechanistic studies showed that myeloid FTH1 deficiency resulted in lower expression of an iron uptake protein divalent metal transporter 1 (DMT1) and active phosphorylated signal transducer and activator of transcription 3 (STAT3) in the colon tissues. Our studies also showed that pharmacological STAT3 reactivation restored the susceptibility of myeloid FTH1-deficient mice to DSS-induced acute colitis. Consistently, myeloid FTH1-deficient mice fed with a high-iron diet had reduced DMT1, phosphorylated STAT3 and inflammation in their colon tissues, and were less susceptible to colitis-associated colorectal cancer. CONCLUSIONS: Our study demonstrated that myeloid FTH1 is required for colitis and colitis-associated colorectal cancer via maintaining of DMT1-iron-STAT3 signaling activation under excess iron condition.

Transferrin Receptor-Mediated Iron Uptake Promotes Colon Tumorigenesis.

Transferrin receptor (TFRC) is the major mediator for iron entry into a cell. Under excessive iron conditions, TFRC is expected to be reduced to lower iron uptake and toxicity. However, the mechanism whereby TFRC expression is maintained at high levels in iron-enriched cancer cells and the contribution of TFRC to cancer development are enigmatic. Here the work shows TFRC is induced by adenomatous polyposis coli (APC) gene loss-driven ß-catenin activation in colorectal cancer, whereas TFRC-mediated intratumoral iron accumulation potentiates ß-catenin signaling by directly enhancing the activity of tankyrase. Disruption of TFRC leads to a reduction of colonic iron levels and iron-dependent tankyrase activity, which caused stabilization of axis inhibition protein 2 (AXIN2) and subsequent repression of the ß-catenin/c-Myc/E2F Transcription Factor 1/DNA polymerase delta1 (POLD1) axis. POLD1 knockdown, iron chelation, and TFRC disruption increase DNA replication stress, DNA damage response, apoptosis, and reduce colon tumor growth. Importantly, a combination of iron chelators and DNA damaging agents increases DNA damage response and reduces colon tumor cell growth. TFRC-mediated iron import is at the center of a novel feed-forward loop that facilitates colonic epithelial cell survival. This discovery may provide novel strategies for colorectal cancer therapy.

A time-dependent survival analysis for early prognosis of chronic wounds by monitoring wound alkalinity.

The objective is to determine whether monitoring wound alkalinity between visits may help prognosticate chronic wound healing. The alkalinity of 167 wounds during the first 3 visits was assessed using disposable DETEC® pH. Wounds grouped by frequency of alkaline results were compared by % wound size reduction during each visit and 120-day healing probability. The Cox proportional hazards model for time-dependent variables was used to generate non-healing probability curves, where variables are binary (alkaline/non-alkaline, infection/no infection), categorical (wound type), and continuous (wound area); the response is time to complete wound healing; and the event of interest is complete wound healing in 120 days. Results show that wounds with frequent alkaline results have significantly smaller % size reduction per visit. Logistic regression shows an increase in 120-day healing probability with fewer alkaline results. Survival analysis shows that the instantaneous healing rate of non-alkaline or non-alkaline transitioning wounds is 1.785, 2.925, and 5.908 times that of alkaline or alkaline-transitioning wounds for 1, 2, and 3 alkalinity measurements, respectively. Furthermore, the concordance statistic of each survival model shows that goodness of fit increases with more alkalinity measurements. Overall, frequent wound alkalinity assessments may serve as a novel way to prognosticate wound healing outcomes.

Altered and allele-specific open chromatin landscape reveals epigenetic and genetic regulators of innate immunity in COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes severe COVID-19 in some patients and mild COVID-19 in others. Dysfunctional innate immune responses have been identified to contribute to COVID-19 severity, but the key regulators are still unknown. Here, we present an integrative single-cell multi-omics analysis of peripheral blood mononuclear cells from hospitalized and convalescent COVID-19 patients. In classical monocytes, we identified genes that were potentially regulated by differential chromatin accessibility. Then, sub-clustering and motif-enrichment analyses revealed disease condition-specific regulation by transcription factors and their targets, including an interaction between C/EBPs and a long-noncoding RNA LUCAT1, which we validated through loss-of-function experiments. Finally, we investigated genetic risk variants that exhibit allele-specific open chromatin (ASoC) in COVID-19 patients and identified a SNP rs6800484-C, which is associated with lower expression of CCR2 and may contribute to higher viral loads and higher risk of COVID-19 hospitalization. Altogether, our study highlights the diverse genetic and epigenetic regulators that contribute to COVID-19.