Biology subjects

Price, N. L.

Publications and source records attributed to Price, N. L..

6 recordsLinked to original sources

bioRxiv2026

MSMICA: computational metabolite identification in untargeted metabolomics by integrating MS, retention time, and biological evidence

Mass Spectrometry Metabolomics Identification Connection Algorithm (MSMICA) is an algorithm for automated metabolite identification in untargeted liquid chromatography-high-resolution mass spectrometry (LC-HRMS) analyses. Limitations in metabolite identification can occur due to the availability and cost of standards and prevent recognition of metabolic factors impacting human health and disease. MSMICA performs mass-to-charge-ratio matching with chemical structures and clusters of LC-HRMS features for adduct and isotope forms. A local optimization is then used to integrate retention time prediction, metabolite precursor-product and transporter correlations, and biospecimen-specific abundance information for metabolite identification. Applying MSMICA to various internal and external mammalian datasets, validation results showed a 96.2 +- 5.1% correct rate of metabolite identification. When multiple LC-HRMS datasets were used, MSMICA enabled greater metabolite identifications, expanded metabolic pathway coverage, and data harmonization. Thus, MSMICA applies multiple pieces of evidence to substantially improve metabolite identification coverage and accuracy for known metabolites.

bioinformatics↗

bioRxiv2025

Antibiotic-induced microbiota depletion impairs the pro-regenerative response to a biological scaffold in mice

Therapeutic biological scaffolds promote tissue repair primarily through the induction of type 2 immunity. However, systemic immunological factors-including aging, sex, and previous infections-can modulate this response. The gut microbiota is a well-established modulator of immune function across organ systems, yet its influence on type 2-mediated repair remains underexplored. Here, we establish a bidirectional relationship between the gut microbiota and biological scaffold-mediated tissue repair. Utilizing a conventionalized germ-free mouse, we demonstrate that scaffold implantation induces compositional and functional changes in the gut microbiome, particularly affecting amino acid biosynthesis. Additionally, in a model of antibiotic-induced microbiota depletion (AIMD), we show that dysbiosis disrupts key immune regulators of type 2 immunity, including reductions in eosinophils, pro-regenerative macrophages, and IL-4-producing CD4+ T cells. At 6 weeks post-scaffold implantation, we observed a significant decrease in myocytes with centrally located nuclei alongside an upregulation in pro-fibrotic gene expression with antibiotic treatment. These findings provide insights into the influence of the gut microbiota on type 2-mediated tissue repair. Significance StatementAntibiotics are routinely administered perioperatively to prevent infection during surgeries and biomaterial implantation. Here, we demonstrate that antibiotic-induced microbiota depletion disrupts the type 2 immune response critical for biomaterial-mediated tissue repair. Our findings highlight the gut microbiota as a determinant of constructive healing and a potential contributor to inter-individual variability in responses to biologic scaffolds.

immunology↗

bioRxiv2025

Deep and Quantitative Proteomic Profiling of Low Volume Mouse Serum Across the Lifespan

Assessing and validating circulating biomarkers is essential for the development of pre-clinical biomarkers that predict biological aging and aging-phenotypes in mice. However, comprehensive proteomics of serum, especially in longitudinal mouse studies, are limited by low volumes of samples. In this study, we develop a workflow for comprehensive and quantitative proteomic analysis of low volume mouse serum and demonstrate its utility and performance in identifying and evaluating key associations with aging phenotypes. Notably, a nanoparticle (NP)-based serum processing workflow coupled to mass spectrometry (MS) increases proteomic coverage by 3 to 6-fold across a range of volumes and provides a quantitative and reproducible (CV < 10%) pipeline for NP-based studies. In a study of 30 mice (aged 12, 24, and 30 months), we uncovered 3992 protein groups across all samples (2235 on average) in 20 {micro}L of serum and highlight novel insights into aging-associated changes in serum and associations with glucose and body composition. With 1 {micro}L additional serum, a 48-cytokine assay quantified 39 additional proteins not identified by MS. This study establishes a powerful workflow that enables deep quantitative proteomics of biologically relevant proteins in volumes feasibly obtained from mice (21 {micro}L of serum) and presents fundamental insights into the aging serum proteome.

biochemistry↗

bioRxiv2023

Gene body DNA hydroxymethylation restricts the magnitude of transcriptional changes during aging

DNA hydroxymethylation (5hmC), the most abundant oxidative derivative of DNA methylation, is typically enriched at enhancers and gene bodies of transcriptionally active and tissue-specific genes. Although aberrant genomic 5hmC has been implicated in age-related diseases, its functional role in aging remains unknown. Here, using mouse liver and cerebellum as model organs, we show that 5hmC accumulates in gene bodies associated with tissue-specific function and restricts the magnitude of gene expression changes with age. Mechanistically, 5hmC decreases the binding of splicing associated factors and correlates with age-related alternative splicing events. We found that various age-related contexts, such as prolonged quiescence and senescence, drive the accumulation of 5hmC with age. We provide evidence that this age-related transcriptionally restrictive function is conserved in mouse and human tissues. Our findings reveal that 5hmC regulates tissue-specific function and may play a role in longevity.

genomics↗

bioRxiv2023

Hepatocyte-specific miR-33 deletion attenuates NAFLD-NASH-HCC progression

The complexity of the multiple mechanisms underlying non-alcoholic fatty liver disease (NAFLD) progression remains a significant challenge for the development of effective therapeutics. miRNAs have shown great promise as regulators of biological processes and as therapeutic targets for complex diseases. Here, we study the role of hepatic miR-33, an important regulator of lipid metabolism, during the progression of NAFLD. We report that miR-33 is overexpressed in hepatocytes isolated from mice with NAFLD and demonstrate that its specific suppression in hepatocytes (miR-33 HKO) improves multiple aspects of the disease, including insulin resistance, steatosis, and inflammation and limits the progression to non-alcoholic steatohepatitis (NASH), fibrosis and hepatocellular carcinoma (HCC). Mechanistically, we find that hepatic miR-33 deficiency reduces lipid biosynthesis and promotes mitochondrial fatty acid oxidation to reduce lipid burden in hepatocytes. Additionally, miR-33 deficiency improves mitochondrial function, reducing oxidative stress. In miR-33 deficient hepatocytes, we found an increase in AMPK activation, which regulates several pathways resulting in the attenuation of liver disease. The reduction in lipid accumulation and liver injury resulted in decreased transcriptional activity of the YAP/TAZ pathway, which may be involved in the reduced progression to HCC in the HKO livers. Together, these results suggest suppressing hepatic miR-33 may be an effective therapeutic approach at different stages of NAFLD/NASH/HCC disease progression.

physiology↗

bioRxiv2020

Liver-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice

ABSTRACTAngiopoietin-like 4 (ANGPTL4) is a major regulator of lipoprotein lipase (LPL) activity, which is responsible for maintaining optimal levels of circulating triacylglycerol (TAG) for distribution to different tissues including the adipose tissues (ATs), heart, muscle and liver. Dysregulation of trafficking and portioning of fatty acids (FA) can promote ectopic lipid accumulation in metabolic tissues such as the liver, ultimately leading to systemic metabolic dysfunction. To investigate how ANGPTL4 regulates hepatic lipid and glucose metabolism, we generated liver-specific ANGPTL4 knockout mice (LKO). Using metabolic turnover studies, we demonstrate that hepatic ANGPTL4 deficiency facilitates catabolism of TAG-rich lipoprotein (TRL) remnants in the liver via increased hepatic lipase (HL) activity, which results in a significant reduction in circulating TAG and cholesterol levels. Deletion of hepatocyte ANGPTL4 protects against diet-induce obesity, glucose intolerance, liver steatosis, and atherogenesis. Mechanistically, we demonstrate that absence of ANGPTL4 in hepatocytes promotes FA uptake which results in increased FA oxidation, ROS production, and AMPK activation. Finally, we demonstrate the utility of a targeted pharmacologic therapy that specifically inhibits ANGPTL4 in the liver and protects against diet-induced obesity, dyslipidemia, glucose intolerance, and liver damage without causing any of the deleterious effects previously observed with neutralizing antibodies.Competing Interest StatementThe authors have declared no competing interest.View Full Text

physiology↗