Biology subjects

Wang, X. X.

Publications and source records attributed to Wang, X. X..

7 recordsLinked to original sources

bioRxiv2026

Mathematical AI Predicts 40% and 57% Influenza Vaccine Effectiveness Against H1N1 and H3N2, Respectively, for the 2026--2027 U.S. Season

Background: Clinical influenza vaccine effectiveness (VE) has often been low over the past two decades, highlighting the need for preseason VE forecasting. Timely forecasts could help health authorities plan prevention strategies and allocate healthcare resources. However, preseason forecasting of clinical influenza VE remains relatively uncommon. Methods: We obtained hemagglutinin (HA) sequences from GISAID for U.S. specimens collected in August--September before each influenza season from 2010--2011 through 2024--2025. After quality screening, we compared each virus with the corresponding vaccine target strain for the same season and subtype or lineage using two mathematical distances based on amino acid patterns in the HA protein. We calculated mean distances for each season and subtype or lineage and paired them with published clinical VE estimates, yielding 26 observations across 13 seasons. Using a mathematical AI approach, we fitted linear regression models of VE against each distance and evaluated their predictive performance by forecasting later seasons using data from earlier seasons, with the historical mean VE for each subtype or lineage as a reference. We then applied the same approach to 87 HA sequences collected in August--September 2026 to forecast VE for the 2026--2027 season. Results: We generated component-specific forecasts of influenza VE for the upcoming 2026--2027 U.S. season. Both mathematical distances were negatively associated with historical VE, indicating that greater differences between circulating viruses and vaccine strains were associated with lower VE. The topological model forecast VE of 40.3%, 56.9%, and 47.1% against A(H1N1)pdm09, A(H3N2), and B/Victoria, respectively, whereas the geometric model forecast corresponding VE values of 34.0%, 56.8%, and 51.1%.

bioinformatics↗

bioRxiv2025

The non-steroidal mineralocorticoid receptor (MR) antagonist (FINERENONE) reverses Western diet-induced kidney disease by enhancing mitochondrial metabolism and decreasing lipid accumulation and inflammation

Mineralocorticoid receptor (MR) overactivation plays a crucial role in the pathogenesis of chronic kidney disease, as well as several cardiovascular and arterial diseases. Current studies determined the mechanisms of the beneficial kidney effects of the non-steroidal MR antagonist Finerenone (FN) in a mouse model of western diet-induced obesity and insulin resistance. 10-week-old male C57BL/6J mice were fed a low fat (LF) or a western diet (WD) for 12 weeks followed by treatment with either vehicle or finerenone (FN) for another 14 weeks (intervention studies) until they were 36 weeks old. Finerenone treatment prevented a) the increased albuminuria and kidney injury molecule 1 (KIM1), b) the expanded extracellular mesangial matrix, and podocyte injury, c) fibronectin, collagen IV, CD45 and CD68 immunostaining, d) glomerular basement membrane disruption, podocyte foot process loss, and mitochondrial structural abnormalities, e) the pro-inflammatory cytokines (MCP1), innate immunity pathways (TLR2, STING, STAT3), and fibrosis markers fibronectin, TGF{beta} and Pai1, and f) the increased kidney cholesterol levels. There was also reduced expression of nuclear receptor ERR{gamma} without changes in ERR in WD-fed mice whereas both ERR and ERR{gamma} expression levels increased after Finerenone treatment. NADH lifetime analysis showed decreased bound NADH, compatible with decreased mitochondrial OXPHOS in the kidneys of WD-fed mice compared to controls, which was prevented by finerenone treatment. In conclusion, Finerenone treatment exhibits a renal protective role and prevents the progression of kidney disease by regulating mitochondrial function, most likely via ERR{gamma}, and reducing lipid accumulation and inflammation.

pharmacology and toxicology↗

bioRxiv2023

Farnesoid X receptor agonism prevents neutrophil extracellular traps via reduced sphingosine-1-phosphate in chronic kidney disease

BackgroundActivation of the farnesoid X receptor (FXR) reduces renal inflammation, but the underlying mechanisms remain elusive. Neutrophil extracellular traps (NETs) are webs of DNA formed when neutrophils undergo specialized programmed cell death (NETosis). Sphingosine-1-phosphate (S1P) is a signaling lipid that stimulates NETosis via its receptor on neutrophils. Here, we identify FXR as a negative regulator of kidney NETosis via repressing S1P signaling in male but not female mice. MethodsWe determined the effects of the FXR agonist obeticholic acid (OCA) in mouse models of adenosine phosphoribosyltransferase deficiency and Alport syndrome. We assessed renal NETosis by immunofluorescence in these models and in biopsies from patients with Alport syndrome (6 male, 9 female). We also inhibited de novo sphingosine production in Alport mice to show a causal relationship between S1P signaling and renal NETosis. ResultsRenal FXR activity is greatly reduced in both models, and OCA prevents kidney fibrosis, inflammation, and lipotoxicity. OCA reduces renal neutrophilic inflammation and NETosis in male adenine and Alport mice, but not in female adenine mice. Extensive NETosis was also identified in human Alport kidney biopsies. Kidney sphingosine kinase 1 (Sphk1) expression is increased in mice with kidney disease and reduced by OCA in male but not female mice. Also, Sphk1 expression correlates with NETosis in male but not female mice. Short-term inhibition of sphingosine synthesis reduces neutrophilic inflammation and NETosis. ConclusionFXR agonism represses kidney Sphk1 expression in male but not female mice. This inhibits renal S1P signaling, thereby reducing neutrophilic inflammation and NETosis in a sex-dependent manner.

pharmacology and toxicology↗

bioRxiv2021

PodoCount: A robust, fully automated whole-slide podocyte quantification tool

BackgroundPodocyte depletion is an established indicator of glomerular injury and predicts clinical outcomes. The semi-quantitative nature of existing podocyte estimation methods or podometrics hinders incorporation of such analysis into experimental and clinical pathologic workflows. Computational image analysis offers a robust approach to automate podometrics through objective quantification of cell and tissue structure. Toward this goal, we developed PodoCount, a computational tool for quantitative analysis of podocytes, and validated the generalizability of the tool across a diverse dataset. MethodsPodocyte nuclei and glomerular boundaries were labeled in murine whole kidney sections, n = 135, from six disease models and human kidney biopsies, n = 45, from diabetic nephropathy (DN) patients. Digital whole slide images (WSIs) of tissues were then acquired. Classical image analysis was applied to obtain podocyte nuclear and glomerular morphometrics. Statistically significant morphometric features, which correlated with each murine disease, were identified. Engineered features were also assessed for their ability to predict outcomes in human DN. PodoCount has been disbursed for other researchers as an open-source, cloud-based computational tool. ResultsPodoCount offers highly accurate quantification of podocytes. Engineered podometric features were benchmarked against routine glomerular histopathology and were found to be significant predictors of disease diagnosis, proteinuria level, and clinical outcomes. ConclusionsPodoCount offers high quantification performance in diverse murine disease models as well as in human DN. Resultant podometric features offers significant correlation with associated metadata as well as outcome. Our cloud-based end-user tool will provide a standardized approach for podometric analysis from gigapixel size WSIs in basic research and clinical practice.

pathology↗

bioRxiv2019

An in situ atlas of mitochondrial DNA in mammalian tissues reveals high content in stem/progenitor cells

Mitochondria regulate ATP production, metabolism and cell death. Alterations in mitochondrial DNA (mtDNA) sequence and copy number are implicated in aging and organ dysfunction in diverse inherited and sporadic diseases. Since most measurements of mtDNA use homogenates of complex tissues, little is known about cell type-specific mtDNA copy number heterogeneity in normal physiology, aging and disease. Thus, the precise cell types whose loss of mitochondrial activity and altered mtDNA copy number that result in organ dysfunction in aging and disease have often not been clarified. Here, we validated an in situ hybridization approach to generate a single cell resolution atlas of mtDNA content in mammalian tissues. In hierarchically organized self-renewing tissues, higher levels of mtDNA were observed in stem/proliferative compartments compared to differentiated compartments. Striking zonal patterns of mtDNA levels in the liver reflected the known oxygen tension gradient. In the kidney, proximal and distal tubules had markedly higher mtDNA levels compared to cells within glomeruli and collecting duct epithelial cells. Decreased mtDNA levels were visualized in renal tubules as a function of aging, which was prevented by calorie restriction. We provide a novel approach for quantifying species- and cell type-specific mtDNA copy number and dynamics in any normal or diseased tissue and can be used for monitoring the effects of interventions in animal and human studies.

pathology↗

bioRxiv2019

ERR agonism reverses mitochondrial dysfunction and inflammation in aging

BackgroundA gradual decline in renal function occurs even in healthy aging individuals. In addition to aging per se, concurrent metabolic syndrome and hypertension, which are common in the aging population, can induce mitochondrial dysfunction and inflammation, which collectively contribute to age-related kidney dysfunction and disease. Here we studied the role of the nuclear hormone receptors, the estrogen-related receptors (ERRs) in regulation of age-related mitochondrial dysfunction and inflammation. ERRs were decreased in aging human and mouse kidneys and were preserved in aging mice with lifelong caloric restriction (CR). MethodsA pan-ERR agonist was used to treat 21-month-old mice for 8-weeks. In addition, 21-month-old mice were treated with a STING inhibitor for 3 weeks. ResultsRemarkably, only an 8-week treatment with a pan-ERR agonist reversed the age-related increases in albuminuria, podocyte loss, mitochondrial dysfunction and inflammatory cytokines, including the cGAS-STING and STAT3 signaling pathways. A 3-week treatment of 21-month-old mice with a STING inhibitor reversed the increases in inflammatory cytokines and the senescence marker p21 but also unexpectedly reversed the age-related decreases in PGC-1, ERR, mitochondrial complexes and MCAD expression. ConclusionsOur studies identified ERRs as important modulators of age-related mitochondrial dysfunction and inflammation. These findings highlight novel druggable pathways that can be further evaluated to prevent progression of age-related kidney disease. Significance StatementThere is an increasing need for prevention and treatment strategies for age-related kidney disease. The hallmarks of aging kidneys are decreased mitochondrial function and increased inflammation. The expression of the nuclear hormone receptors estrogen-related receptors (ERRs) are decreased in aging human and mouse kidneys. This paper investigates the role of ERRs in the aging kidney. Treatment of aging mice with a pan-ERR agonist reversed the age-related increases in albuminuria and podocyte loss, mitochondrial dysfunction and inflammatory cytokines, including the cGAS-STING signaling pathways. Treatment of aging mice with a STING inhibitor decreased inflammation and increased mitochondrial gene expression. These findings identify ERRs as important modulators of age-related mitochondrial dysfunction and inflammation.

pathology↗

bioRxiv2019

Natural Amelioration of Mn-induced Chlorosis Facilitated by Mn Down-regulation, Ammonium and Rainwater in Sugarcane Seedlings

We had previously reported that manganese (Mn)-induced chlorosis is a serious problem in ratoon sugarcane seedlings grown in acidic soils. To further monitor the progression of chlorosis and elucidate the corresponding mechanism, both plant growth and nutrient status of sugarcane plants and soils were investigated in the growth seasons of ratoon cane seedlings in 2016 and 2018. The impacts of rainfall and ammonium on chlorosis were also investigated hydroponically. The results showed that the chlorotic seedlings could green in mid-summer; Mn content in the first expanded leaf decreased significantly, whereas iron (Fe) content increased significantly during the progression of greening. The leaf Mn content in the greened seedlings decreased by up to 78.1% when compared with that in the initial chlorotic seedlings. The seedlings also showed a significant increase in seedling height and weight of the expanded leaves, accompanied by a decrease in plant Mn content during the progression of greening. Moreover, young seedlings with less Mn content showed earlier greening than older seedlings with more Mn content. The exchangeable ammonium content in the soils increased significantly during the progression of greening, and the addition of 1 mM ammonium to the chlorotic seedlings resulted in a decrease in leaf Mn content by up to 80%. Furthermore, leaf SPAD value and Fe content increased by 2.0-fold and 1.4-fold, respectively, after rainwater was applied to the chlorotic seedling. These results indicate Mn-induced chlorotic seedlings can turn naturally green, and downregulation of plant Mn content, rainfall in summer, and soil ammonium contribute to the greening of chlorotic seedlings.

plant biology↗