Biology subjects

Wetzel, L.

Publications and source records attributed to Wetzel, L..

5 recordsLinked to original sources

bioRxiv2026

Mechanisms regulating combination effect of antibody-drug conjugates and cancer immunotherapy

Antibody-drug conjugates (ADCs) have emerged as a transformative class of cancer therapeutics with important challenges still to be addressed. Combination of ADC with immunotherapy is a promising strategy but mechanisms and effective application remain to be determined. We evaluated ADC combinations with T cell engagers (TCEs) and checkpoint inhibitors (CPI). ADC-TCE combinations produced robust antitumor activity independent of antigen and payload and persisted despite ADC-related T cell loss. Efficacy was dominated by a direct effect of ADC on tumor cells. ADCs induced autophagy that upregulated TNF receptors (TNFRs) and mannose-6-phosphate receptors (M6PR). When ADCs were combined with TCEs TNF released by T cells was primarily responsible for potent antitumor effect of combination. In contrast, M6PR was dispensable for ADC-TCE activity but critical for combinations with CPI expanded antigen-specific T cells via enhanced granzyme B uptake. These data reveal a unifying, target- and payload-agnostic mechanism enabling rational ADC-immunotherapy combinations. SignificanceThis is first evidence that ADC-induced tumor cell autophagy via up-regulation of TNFR and M6PR could be responsible for potent antitumor effect of combination of ADC with TCE. TCEs exploit a TNF-TNFR axis, whereas antigen-specific T cells leverage granzyme B-M6PR uptake. This mechanistic framework explains broad ADC-TCE synergy and guides rational selection of ADC-immunotherapy combinations beyond checkpoint blockade.

immunology↗

bioRxiv2026

Brain Functional Connectivity Signatures of Craving Across Substance Use Disorders: A Transdiagnostic Approach

Craving is a hallmark feature of substance use disorders (SUDs) and a major risk factor for relapse, yet reliable biomarkers that enable individual-level prediction remain scarce. Here, we applied connectome-based predictive modeling (CPM) to resting-state functional magnetic resonance imaging (fMRI) data in a transdiagnostic sample of individuals with cannabis, opioid, or tobacco use disorder (n = 78). Using CPM, we identified a distributed functional brain network that reliably predicted self-reported craving. Computational lesion analyses revealed key contributions from the right medial orbitofrontal cortex, right dorsal posterior cingulate cortex, and left lateral medial frontal gyrus. Importantly, the craving network generalized across two independent datasets. In alcohol-dependent patients (n = 41), the identified craving network, along with its positive and negative subnetworks, predicted distinct cognitive and motivational components of craving. In a second external dataset of smokers (n = 28), the craving network predicted both nicotine craving after abstinence as well as intra-individual changes in craving between sated and craving states. Together, these findings provide evidence for a robust, transdiagnostic craving signature in SUDs. Future work should assess the networks predictive utility for longitudinal outcomes such as relapse risk and treatment response.

neuroscience↗

bioRxiv2025

The in vitro bacterial viability and microbial composition of commercially available canine and feline fecal microbial transplantation products

Fecal microbial transplantation (FMT) is the transfer of feces from a healthy donor into the gastrointestinal tract of a diseased recipient to confer a health benefit. FMT is increasingly utilized in veterinary medicine and is offered commercially by AnimalBiomeTM. This study aims to quantitate the colony forming units per gram (CFU/g) in lyophilized AnimalBiomeTM FMT products compared to fresh and lyophilized in-house FMT; and to evaluate microbial compositions across multiple FMT products. FMT products were cultured in aerobic and anaerobic environments. 16s rRNA amplicon sequencing (V4 region) was performed on FMT products and colonies taken from FMT cultures. Three lots each of AnimalBiomeTM DoggyBiomeTM (DB), DoggyBiomeTM from raw fed dogs (DBR), and KittyBiomeTM (KB) were evaluated. Freshly processed stool from screened donors enrolled in The Ohio State University Companion Animal Fecal Bank (CAFB) were used as controls. Freshly processed feces yielded significantly greater total CFU/g compared to all lyophilized products (dogs, P<0.01; cats, P<0.01). KB and feline CAFB lyophilized products exhibited comparable viability (P=0.14). Canine CAFB lyophilized FMT yielded significantly greater CFU/g than DB (P=0.17) and DBR (P=0.018). Each donor has a unique microbial profile (PERMANOVA; dogs, P=0.001; cats, P=0.03). DBR FMT products have a significantly greater abundance of Enterobacteriaceae compared to other canine products (P<0.01); however, no AnimalBiomeTM product showed detectable growth of Gram-negative microbes. These findings will provide evidence for practitioners when choosing FMT products for their patients. Further research is needed to determine the impact of FMT processing on engraftment and clinical outcome.

microbiology↗

bioRxiv2025

Cell type-specific master metabolic regulators of Alzheimer's disease

Alzheimers disease (AD) exhibits metabolic heterogeneity; yet, the consequences on metabolic dynamics in a cell-type-specific manner and the underlying metabolite-sensor network basis remain unclear. Here, we show that neurons exhibit a striking decrease in energy and lipid-related metabolic activity, contrasted by an increase in microglial metabolism associated with neuroinflammation. To identify cell-type specific master metabolic regulators of AD underlying the metabolic alterations in AD, we introduce scFUMES (single cell FUnctional MEtabolite-Sensor), an algorithm integrating single-cell RNA sequencing, interactomics, genomics, transcriptomics, and metabolomics from human brain biobanks. Applied to two AD-vulnerable regions (middle temporal gyrus and dorsolateral prefrontal cortex), scFUMES uncovers hundreds of AD-associated regulators, with neurons and microglia showing the most interactions. Particularly, scFUMES pinpoints genetics-informed master metabolic regulators across AD severity, sex and APOE genotype (e.g., PPARD-glycerol in microglia). Experimental testing reveals that two interaction pairs predicted by scFUMES, neuronal palmitic acid bound fatty acid binding protein 3 and gut metabolite indole-3-propionic acid binding to kynurenine aminotransferase 1, both lower pathological tau species in AD. Collectively, scFUMES systematically maps AD master metabolic regulators, offering insights into cellular metabolic heterogeneity and therapeutic strategies for AD and other AD-related dementia if broadly applied.

systems biology↗

bioRxiv2018

Glycosyltransferase homologs prevent promiscuous cell aggregation and promote multicellular development in the choanoflagellate S. rosetta

The mechanisms underlying multicellular development in the animal stem lineage may be reconstructed through the study of choanoflagellates, the closest living relatives of animals. To determine the genetic underpinnings of multicellularity in the emerging model choanoflagellate S. rosetta, we performed a screen for mutants with defects in multicellular rosette development. In two of the mutants, Jumble and Couscous, single cells failed to develop into orderly rosettes but instead aggregated promiscuously into amorphous clumps of cells. Both mutants mapped to lesions in genes encoding glycosyltransferases and the mutations perturbed glycosylation patterns in the extracellular matrix (ECM). In animals, glycosyltransferases transfer activated sugars to donor molecules and thereby sculpt the polysaccharide-rich ECM, regulate integrin and cadherin activity, and, when disrupted, contribute to tumorigenesis. The finding that glycosyltransferases promote proper rosette development and prevent cell aggregation in S. rosetta suggests a pre-metazoan role for glycosyltransferases in regulating development and preventing abnormal tumor-like multicellularity.\n\nIMPACT STATEMENTA genetic screen reveals that glycosyltransferases are required for proper rosette development and the prevention of cell clumping in one of the closest living relatives of animals, the choanoflagellate S. rosetta.

genetics↗