Biology subjects

Gershteyn, I. M.

Publications and source records attributed to Gershteyn, I. M..

5 recordsLinked to original sources

bioRxiv2026

Decoherence via Demyelination Hypothesis (DDH): A Mechanism of Cognitive Decline During Aging

Progressive cognitive decline and loss of white matter integrity are observed during aging, but whether these two processes are connected remains unclear. We propose the Decoherence via Demyelination Hypothesis (DDH) as a mechanism linking non-uniform, tract-specific myelin loss during aging, which results in the degradation of conduction timing that is required to coordinate long-range neuronal assemblies. This impairs the dynamic assembly of task-dependent functional networks and promotes age-associated cognitive change. Axonal myelination determines conduction velocity as well as signal transmission fidelity, properties essential for phase-locked integration of long-distance inputs with local oscillations and for the assembly of mesoscale functional brain networks. If myelin loss is heterogeneous across tracts, the resulting timing perturbations should be heterogeneous as well, with disproportionate impact on networks supporting higher-order cognition. To test this, we analyzed structural and microstructural MRI in 638 individuals aged 40-99, quantifying fasciculation in different white matter pathways as well as neurite orientation dispersion and density imaging (NODDI) to the gray-white matter interface beneath cortical regions. We observed tract-specific, non-uniform myelin decline, with significant nonlinear losses in tracts serving high order cognition and memory (uncinate fasciculus, fornix, corpus callosum), consistent with accelerated late-life vulnerability in pathways implicated in cognitive aging and increased risk for neurodegenerative diseases. Tract-level degeneration tracked with age-related shifts in network organization and cognition. These findings may support DDH as a framework for age-associated cognitive change. Particularly, tract-specific timing perturbations drive the breakdown of coordinated network activity in aging.

neuroscience↗

bioRxiv2026

Integrated Cytotoxic and Safety Mechanism of IMV-M (TM), a MUC16 x DR5 Bispecific Antibody

BackgroundIMV-M is a MUC16xDR5 bispecific antibody has demonstrated MUC16-selective anti-tumor activity. However, it remained unclear whether multiple binding of IMV-M on a single MUC16 molecule was required for IMV-M cytotoxicity, whether circulating CA125 could attenuate its efficacy or cause off-target toxicity, and whether anti-drug antibodies might induce IMV-M aggregation and related adverse effects. MethodsA comparative analysis of three bispecific antibodies, IMV-M (sofituzumabxDR5), 11D10xDR5, and fluorxDR5, sharing an identical IgG1-anti-DR5 scFv architecture, was performed. Sofituzumab binds to multiple epitopes on a single MUC16 molecule, whereas 11D10 binds a single MUC16 epitope, and fluor does not bind any human antigen. Antibody binding to shed and cell-surface MUC16 was evaluated by ELISA and flow cytometry. Cytotoxicity was assessed in a MUC16+/DR5+ tumor cell line and MUC16-/DR5+ hepatic cell lines. Additional studies examined the effects of soluble CA125 and Fc-directed polyclonal antibodies on IMV-M activity. ResultsIMV-M bound MUC16 to a markedly higher extent than the 11D10xDR5 comparator, consistent with its multivalent engagement, while binding of fluorxDR5 to MUC16 was negligent. Only IMV-M induced potent cytotoxicity in MUC16+ tumor cells, whereas 11D10xDR5 and fluorxDR5 control antibodies were inactive, demonstrating that multivalent clustering on MUC16 is required for apoptosis. IMV-M showed no significant cytotoxicity toward hepatic cell lines, even in the presence of Fc-directed polyclonal antibodies or clinically relevant concentrations of soluble CA125. ConclusionsThese findings indicate that IMV-M cytotoxic activity requires clustering on MUC16, that CA125 at clinically relevant concentrations does not mediate IMV-M neutralization, and that aggregate formation with secondary antibodies or soluble MUC16 does not induce off-target toxicity.

cancer biology↗

bioRxiv2025

A bispecific antibody overcomes limitations of prior strategies to achieve effective and tumor-selective Death Receptor 5 (DR5) clustering

The bispecific antibody IMV-M was designed to bind and cluster Death Receptor 5 (DR5) specifically upon engaging the tumor antigen MUC16. This dual-binding mechanism induces apoptosis in MUC16-positive tumor cells through a novel enhancement process. IMV-M exhibited potent, MUC16-selective anti-tumor activity in vitro and in xenograft models, achieving efficacy at safe therapeutic doses without requiring secondary crosslinking. In contrast, earlier DR5-targeting tumor-selective bispecific antibodies either demonstrated limited anti-tumor activity or relied on secondary crosslinking, highlighting that binding of a bispecific antibody to a tumor antigen and DR5 alone is insufficient for effective DR5 clustering. Our findings reveal that an additional crowding mechanism for efficient DR5 clustering by bispecific antibodies is required. In contrast to the targeted delivery approach with antibody-drug conjugates (ADCs), our approach offers a pathway for developing more effective and safer cancer therapies. Importantly, the MUC16 antigen is overexpressed in substantial subsets of ovarian, pancreatic, and lung cancers while being almost completely absent in normal tissues, with highly limited expression in certain epithelial cells, indicating broad applicability of this bispecific antibody.

molecular biology↗

bioRxiv2020

Immunodietica: interrogating the role of diet in autoimmune disease

Diet is an environmental factor in autoimmune disorders, where the immune system erroneously destroys ones own tissues. Yet, interactions between diet and autoimmunity remain largely unexplored, particularly the impact of immunogenetics, ones human leukocyte antigen (HLA) allele make-up, in this interplay. Here, we interrogated animals and plants for the presence of epitopes implicated in human autoimmune diseases. We mapped autoimmune epitope distribution across organisms and determined their tissue expression pattern. Interestingly, diet-derived epitopes implicated in a disease were more likely to bind to HLA alleles associated with that disease than to protective alleles, with visible differences between organisms with similar autoimmune epitope content. We then analyzed an individuals HLA haplotype, generating a personalized heatmap of potential dietary autoimmune triggers. Our work uncovered differences in autoimmunogenic potential across food sources and revealed differential binding of diet-derived epitopes to autoimmune disease-associated HLA alleles, shedding light on the impact of diet on autoimmunity.

immunology↗

bioRxiv2019

Immunodietica: A data-driven approach to investigate interactions between diet and autoimmune disorders

Autoimmunity is on the rise around the globe. Diet has been proposed as a risk factor for autoimmunity and shown to modulate the severity of several autoimmune disorders. Yet, the interaction between diet and autoimmunity in humans remains largely unstudied. Here, we systematically interrogated commonly consumed animals and plants for peptide epitopes previously implicated in human autoimmune disease. A total of fourteen species investigated could be divided into three broad categories regarding their content in human autoimmune epitopes, which we represented using a new metric, the Gershteyn-Ferreira index (GF index). Strikingly, pig contains a disproportionately high number of unique autoimmune epitopes compared to all other species analyzed. This work uncovers a potential new link between pork consumption and autoimmunity in humans and lays the foundation for future studies on the impact of diet on the pathogenesis and progression of autoimmune disorders.

immunology↗