Meyers, E. C. | bioRxiv Science

bioRxiv2026

Progressive neurodegeneration in human dorsal root ganglion from diabetes to painful neuropathy

Diabetic painful neuropathy (DPN) is characterized by neuropathic pain accompanied by loss of sensory function. We hypothesized that neurodegeneration in the dorsal root ganglion (DRG) could underlie DPN progression. To address this question, we performed multi-omic evaluation on DRGs from otherwise healthy organ donors, donors with diabetes but no neuropathy, and donors with clinically diagnosed DPN. We discovered that the first stages of neurodegeneration begin early in diabetes before the onset of DPN, with Nageotte nodule formation accompanied by apoptotic gene expression and decreased proportion of specific populations of A-fibers in DPN with remodeling of non-neuronal cells. Our findings define DPN as a neurodegenerative disorder of the DRG, identify molecular markers of disease stage, and highlight the need for early intervention to prevent irreversible neurodegeneration.

neuroscience↗

bioRxiv2026

Small RNA sequencing of human sural nerves identifies widespread microRNA dysregulation and Schwann cell-localized miR-21-5p in diabetic peripheral neuropathy

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes with no disease modifying treatments. Despite the prevalence, the molecular mechanisms of DPN are not fully characterized. Among the various molecular regulators, microRNAs (miRNAs) control protein synthesis and are essential for normal development and homeostasis, with dysregulation implicated in cancer and neurodegenerative diseases. In this study, we performed small RNA-sequencing to profile the miRNA landscape of human sural nerves from individuals with and without DPN. Our analysis revealed that nearly 10% of all miRNAs detected are dysregulated and among those 74% are significantly downregulated in DPN. Target gene enrichment analysis of the differentially expressed miRNAs yielded pathways significantly associated with nerve regeneration, metabolic dysfunction, and immune cell activity. In particular, miR-21-5p is significantly upregulated in DPN, showed a positive association with axonal loss severity, and localizes to Schwann cells, consistent with its broader role as an injury- and inflammation-responsive miRNA that shifts from early pro-regenerative functions to maladaptive, inflammation-amplifying effects that impair Schwann cell mediated nerve repair. These results suggest that miRNAs may contribute to peripheral nerve degeneration by promoting inflammation, apoptosis, oxidative stress, and impaired nerve regeneration, while also opening potential avenues for biomarker discovery and therapeutic intervention. Article highlightsO_LIWe undertook this study to address the limited understanding of molecular changes contributing to diabetic peripheral neuropathy (DPN) in humans. C_LIO_LIWe sought to profile microRNAs (miRNAs), key post-transcriptional regulators of gene expression, in human sural nerves and developed a dedicated computational pipeline for robust miRNA quantification, differential expression, and target enrichment analysis. C_LIO_LIOur analyses revealed widespread miRNA dysregulation in DPN, with most altered miRNAs downregulated and miR-21-5p significantly upregulated in DPN, highly correlated with axonal loss severity and localized to Schwann cells. C_LIO_LIThese findings suggest that miRNA imbalance, including elevated Schwann cell miR-21-5p, may contribute to nerve dysfunction in DPN and provide new opportunities for biomarker development and therapeutic targeting. C_LI

neuroscience↗

bioRxiv2021

Dynamic Detection and Reversal of Myocardial Ischemia Using an Artificially Intelligent Bioelectronic Medicine

SummaryMyocardial ischemia is spontaneous, usually asymptomatic, and contributes to fatal cardiovascular consequences. Importantly, biological neural networks cannot reliably detect and correct myocardial ischemia on their own. In this study, we demonstrate an artificially intelligent and responsive bioelectronic medicine, where an artificial neural network (ANN) supplements biological neural networks enabling reliable detection and correction of myocardial ischemia. ANNs were first trained to decode spontaneous cardiovascular stress and myocardial ischemia with an overall accuracy of [~]92%. ANN-controlled vagus nerve stimulation (VNS) reversed the major biomarkers of myocardial ischemia with no side effects. In contrast, open-loop VNS or ANN-controlled VNS following a caudal vagotomy essentially failed to reverse correlates of myocardial ischemia. Lastly, variants of ANNs were used to meet clinically relevant needs, including interpretable visualizations and unsupervised detection of emerging cardiovascular stress states. Overall, these results demonstrate that ANNs can supplement deficient biological neural networks via an artificially intelligent bioelectronic medicine system.

bioengineering↗