Biology subjects

Nelson, J. B.

Publications and source records attributed to Nelson, J. B..

3 recordsLinked to original sources

bioRxiv2025

Perceptual learning mechanisms with single-stimulus exposure

The present manuscript briefly reviews associative and non-associative theories of perceptual learning and presents two experiments (1a & 1b) examining the extent to which retrospective revaluation (RR) and a restoration in perceptual effectiveness (RPE) can account for the enhanced discriminability that experience with a single stimulus produces. In both experiments participants were exposed to compound visual stimuli BX, CY, and DZ in an online video-game method followed by conditioning with compound stimuli AX and AY. In Experiment 1a generalization to compounds BX, DX, BY, and DY was assessed. Generalization to compounds involving B, either BX or BY, was less than to DX or DY, possibly reflecting enhanced salience of B, or that B had become inhibitory for the outcome through RR. Experiment 1b used a retardation test comparing compound stimuli BW and DW. Acquisition was more effective with BW than DW, suggesting that B had become more perceptually effective, resulting in it producing more external inhibition than D in Experiment 1a, and allowing it to condition more rapidly in Experiment 1b. Results are discussed with respect to current theories of perceptual learning and are consistent with that offered by Hall [17].

animal behavior and cognition↗

bioRxiv2024

12-Lipoxygenase Inhibition Suppresses Islet Immune and Inflammatory Responses and Delays Autoimmune Diabetes in Human Gene Replacement Mice

Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing {beta} cells and involves an interplay between {beta} cells and cells of the innate and adaptive immune systems. We investigated the therapeutic potential of targeting 12-lipoxygenase (12-LOX), an enzyme implicated in inflammatory pathways in {beta} cells and macrophages, using a mouse model in which the endogenous mouse Alox15 gene is replaced by the human ALOX12 gene. Our finding demonstrated that VLX-1005, a potent 12-LOX inhibitor, effectively delayed the onset of autoimmune diabetes in human gene replacement non-obese diabetic mice. By spatial proteomics analysis, VLX-1005 treatment resulted in marked reductions in infiltrating T and B cells and macrophages with accompanying increases in immune checkpoint molecule PD-L1, suggesting a shift towards an immune-suppressive microenvironment. RNA sequencing analysis of isolated islets and polarized proinflammatory macrophages revealed significant alteration of cytokine-responsive pathways and a reduction in interferon response after VLX-1005 treatment. Our studies demonstrated that the ALOX12 human replacement gene mouse provides a platform for the preclinical evaluation of LOX inhibitors and supports VLX-1005 as an inhibitor of human 12-LOX that engages the enzymatic target and alters the inflammatory phenotypes of islets and macrophages to promote the delay of autoimmune diabetes.

molecular biology↗

bioRxiv2023

Suppression of the Integrated Stress Response in Islet β Cells Decreases Risk of Autoimmune Diabetes

Preventing the onset of autoimmune type 1 diabetes (T1D) is feasible through pharmacological interventions that target molecular stress-responsive mechanisms. Cellular stresses, such as nutrient deficiency, viral infection, or unfolded proteins, trigger the integrated stress response (ISR), which curtails protein synthesis by phosphorylating eIF2. In T1D, maladaptive unfolded protein response (UPR) in insulin-producing {beta} cells renders these cells susceptible to autoimmunity. We show that inhibition of the eIF2 kinase PERK, a common component of the UPR and ISR, reverses the mRNA translation block in stressed human islets and delays the onset of diabetes, reduces islet inflammation, and preserves {beta} cell mass in T1D-susceptible mice. Single-cell RNA sequencing of islets from PERK-inhibited mice shows reductions in the UPR and PERK signaling pathways and alterations in antigen processing and presentation pathways in {beta} cells. Spatial proteomics of islets from these mice shows an increase in the immune checkpoint protein PD-L1 in {beta} cells. Golgi membrane protein 1, whose levels increase following PERK inhibition in human islets and EndoC-{beta}H1 human {beta} cells, interacts with and stabilizes PD-L1. Collectively, our studies show that PERK activity enhances {beta} cell immunogenicity, and inhibition of PERK may offer a strategy to prevent or delay the development of T1D.

cell biology↗