Biology subjects

Guzior, D. V.

Publications and source records attributed to Guzior, D. V..

3 recordsLinked to original sources

bioRxiv2026

MassID provides near complete annotation of metabolomics data with identification probabilities

Liquid chromatography coupled to mass spectrometry (LC/MS) is a powerful tool in metabolomics research, generating tens-of-thousands of signals from a single biological sample. However, current software solutions for unbiased assessment of metabolomics data analysis are limited by complex sources of noise and non-quantitative metabolite identifications that make results difficult to interpret. Here, we present MassID, a cloud-based untargeted metabolomics pipeline that aims to overcome the innate challenges of unbiased metabolite analysis and perform end-to-end data processing, transforming raw spectra to normalized and identified metabolite profiles. MassID incorporates a suite of software functionalities, including deep learning-based peak detection and comprehensive noise filtering. In addition, with MassID we introduce a novel software module: DecoID2 that enables probabilistic metabolite identification for false discovery rate (FDR)-controlled metabolomics. When applied to a human plasma dataset, MassID results in near-complete signal annotation, identification of >4,000 metabolites (including >1,200 compounds at an FDR <5%) across four complementary LC/MS runs, and enables integrated downstream analyses to understand biochemical dysregulation at both the molecular and pathway level. When compared to the Metabolomics Standards Initiative (MSI) confidence levels, identification probability generally correlated with MSI levels. However, only 356/418 of MSI Level 1 compounds were identified with <5% FDR and the remaining 884 FDR < 5% compounds were identified from MSI L2-L3 compounds, highlighting the enhanced specificity and discovery potential achieved by MassID.

bioinformatics↗

bioRxiv2026

Evexomostat (SDX-7320), a Methionine Aminopeptidase Type 2 (METAP2) Inhibitor, Stimulates Weight Loss and Inhibits Obesity-Accelerated Tumor Growth

Obesity and diabetes are associated with worse prognosis for numerous malignancies. Both insulin resistance and altered levels of adipokines may explain the link between obesity and tumor progression. In preclinical models, METAP2 inhibitors induce weight loss and possess anti-tumor activity, but their effects on obesity-accelerated tumor growth are unknown. Here, we investigated the effects of SDX-7320, a novel polymer-conjugated METAP2 inhibitor, on obesity and obesity-accelerated tumor growth. The anti-obesity and metabolic effects of SDX-7320 were evaluated in diet-induced obese (DIO) mice. Pharmacokinetic-pharmacodynamic relationships for SDX-7320 and the active moiety SDX-7539, a fumagillin class METAP2 inhibitor, were assessed in DIO rats. Anti-tumor efficacy of SDX-7320 was assessed in syngeneic models of obesity-accelerated tumor growth. The anti-tumor efficacy of SDX-7320 and tirzepatide, a weight loss agent, were compared in DIO mice with MC38 tumors. Treatment with SDX-7320 stimulated weight loss in obese mice, increased insulin sensitivity, decreased plasma leptin, and increased plasma adiponectin. Pharmacokinetic-pharmacodynamic analysis showed greater anti-obesity efficacy in response to SDX-7320 than SDX-7539. SDX-7320 significantly attenuated obesity-accelerated tumor growth in three different models (B16F10, EO771, MC38). RNA-Seq analysis of MC38 tumors indicated that SDX-7320 suppressed expression of cell cycle genes (decreased G2M checkpoint and E2F target pathways) and increased expression of host immune response genes (elevated interferon alpha- and gamma-response pathways). In obese mice, SDX-7320 led to significantly greater MC38 tumor growth inhibition than tirzepatide, but caused less weight loss. Plasma metabolomics revealed non-overlapping effects of SDX-7320 and tirzepatide, consistent with different mechanisms of action. Taken together, we have shown for the first time that a METAP2 inhibitor attenuates obesity-accelerated tumor growth. Mechanistically, SDX-7320-mediated tumor growth inhibition likely results from both direct anti-tumor effects (given the observed intratumoral changes in the expression of cell cycle and immune response genes), and indirect effects on the host including weight loss, decreased adipose mass, improved insulin sensitivity and normalization of plasma leptin and adiponectin levels. The fact that SDX-7320 caused greater tumor growth inhibition than tirzepatide, yet caused less weight loss, suggests that direct anti-tumor effects significantly contribute to the anti-tumor activity of SDX-7320.

cancer biology↗

bioRxiv2022

Bile acid-CoA:amino acid N-acyltransferase gene knockout alters early life development, the gut microbiome and reveals unusual bile acid conjugates in mice

Bile acids are steroid detergents in bile that contribute to fat absorption, cell signaling and microbiome interactions in mammals. The final step in their synthesis is amino acid conjugation with either glycine or taurine to a cholic acid or chenodeoxycholic acid backbone in the liver by the enzyme bile acid-CoA:amino acid N-acyltransferase (BAAT). Here, we describe the microbial, chemical, and physiological consequences of BAAT gene deletion in mice. BAAT-/- mice were underweight after weaning but quickly exhibited catch-up growth. At 3-weeks-of-age, KO animals had increased phospholipid excretion and decreased subcutaneous fat pad mass, glycogen staining in hepatocytes and vitamin A stores in the liver, but these phenotypes were less marked in adulthood. Their bile acid (BA) pool was highly altered throughout the 8-weeks of life but was not completely devoid of conjugated BAs. These animals had 27-fold lower amounts of taurine-conjugated BAs than wildtype in their liver, but similar concentrations of glycine-conjugated BAs and higher microbially-conjugated BAs. The BA pool in BAAT-/- was enriched in a variety of unusual bile acids that were putatively sourced from cysteamine conjugation with subsequent oxidation and methylation of the sulfur group to mimic taurine. KO mice also had an altered microbiome, but most strongly in the first 3-weeks, indicating bile acid conjugation is important for proper microbiome development during the postnatal period. Finally, antibiotic treatment increased taurine, glycine, and the unusually conjugated BAs in BAAT-/- animals, indicating the microbiome was not the likely source of the conjugation. Instead, BA conjugation in KO animals was likely derived from the peroxisomal acyltransferases ACNAT1 and ACNAT2, which are duplications of BAAT in the mouse genome, but inactivated in humans. This study demonstrates that BA conjugation is important for early life development in mice and is facilitated by other host or microbial enzymes besides BAAT in a manner that results in molecular mimics of taurine that may rescue pathological phenotypes.

microbiology↗