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UGT2B10 Variant Effects on Dexmedetomidine Metabolism Using Nicotine Studies
No full textBackground:
Dexmedetomidine is a procedural sedative primarily metabolized by the UDP-glucuronosyltransferase (UGT) 2B10. UGT2B10 also contributes to nicotine metabolism. Most research on the effect of gene variants on UGT2B10’s glucuronidation efficacy has focused on nicotine. This study outlines current data on the relationship between UGT2B10 pharmacogenomics, nicotine pharmacokinetics, and race, then extrapolates that information to dexmedetomidine.
Methods:
A literature review was conducted on UGT2B10 variants and dexmedetomidine or nicotine in PubMed. Due to lack of studies on dexmedetomidine glucuronidation, studies using nicotine were used to classify variants as poor, intermediate, or extensive metabolizers; characterize their expression in African/African Americans (AA) and Europeans (C), and establish their respective activity based on nicotine metabolite percentages.
Results:
UGT2B10 accounts for about 20% of nicotine metabolism. The UGT2B10 variants rs61750900 (AA= 37.62%; C=0.18%) and rs2942857 (AA=4.42%; C=9.28%) are nonfunctional. Poor metabolizers (PM) are homozygous for one of these variants and see a 97% decrease in UGT2B10 metabolites. Intermediate metabolizers (IM) have one variant allele and one wild-type allele, with a 32% decrease in UGT2B10 metabolites. Extensive metabolizers (EM), have two wild-type alleles. Metabolites from other pathways increase as UGT2B10 metabolites decrease. These results were superimposed onto dexmedetomidine metabolism to predict metabolite percentages in UGT2B10 IM and PM. In PM, only 1.02% of dexmedetomidine metabolites were predicted to be from UGT2B10.
Conclusion:
Nicotine metabolism data suggests variants of UGT2B10 significantly impact dexmedetomidine metabolism. PMs have 97% decreased nicotine UGT2B10 metabolism and a compensatory increase in nicotine’s other metabolites. UGT2B10 accounts for the largest portion of dexmedetomidine metabolism. Thus, UGT2B10 PMs may have decreased glucuronide metabolites, with increased proportion of other pathways.
Giving the same dose of dexmedetomidine to PM or ultrarapid metabolizers (UM) may result in toxicity or undersedation, respectively. More research needs to be done on UGT2B10 variants to optimize patient care
IFN-α Induces Heterogenous ROS Production in Human β-Cells
No full textType 1 diabetes (T1D) is a multifactorial disease involving genetic and environmental factors, including viral infection. We investigated the impact of interferon alpha (IFN-α), a cytokine produced during the immune response to viral infection or the presence of un-edited endogenous double-stranded RNAs, on human β-cell physiology. Intravital microscopy on transplanted human islets using a β-cell-selective reactive oxygen species (ROS) biosensor (RIP1-GRX1-roGFP2), revealed a subset of human β-cells that acutely produce ROS in response to IFN-α. Comparison to Integrated Islet Distribution Program (IIDP) phenotypic data revealed that healthier donors had more ROS accumulating cells. In vitro IFN-α treatment of human islets similarly elicited a heterogenous increase in superoxide production that originated in the mitochondria. To determine the unique molecular signature predisposing cells to IFN-α stimulated ROS production, we flow sorted human islets treated with IFN-α. RNA sequencing identified genes involved in inflammatory and immune response in the ROS-producing cells. Comparison with single cell RNA-Seq datasets available through the Human Pancreas Analysis Program (HPAP) showed that genes upregulated in ROS-producing cells are enriched in control β-cells rather than T1D donors. Combined, these data suggest that IFN-α stimulates mitochondrial ROS production in healthy human β-cells, potentially predicting a more efficient antiviral response
Subthreshold Effects of Low-Frequency Alternating Current on Nerve Conduction Delay
No full textBackground/Objectives: Low-frequency alternating current (LFAC) has been shown to induce nerve conduction block (LFACb). However, the effects of LFAC on conduction delay prior to block remain unclear. This study investigates the impact of LFACb on conduction velocity and blocking thresholds in myelinated and unmyelinated fibers using experimental and computational models. Methods: Four models were employed to analyze LFACb effects: (1) in-vivo experiments in earthworms examined conduction delays across nerve bundles with distinct conduction velocities; (2) ex-vivo experiments in canine vagus nerves assessed the upstream and downstream effects of LFAC waveforms ranging from 50 mHz to 500 mHz; (3) in-silico simulations using the Horn, Yoshida, and Schild (HYS) model for unmyelinated fibers explored size-dependent conduction delays and blocking thresholds; and (4) in-silico simulations using the McIntyre, Richardson, and Grill (MRG) model extended to 504 Nodes of Ranvier characterized myelination effects, localized nodal interactions, and diameter-dependent thresholds. Results: LFAC-induced conduction delays were independent of LFAC frequency but strongly influenced by fiber diameter and conduction velocity. Larger fibers exhibited lower block thresholds and shorter delays before block onset. In contrast, smaller fibers demonstrated prolonged subthreshold conduction delays before achieving full block. Conclusions: These findings suggest that LFACb could serve as a neuromodulation tool for selectively blocking larger fibers while preserving smaller fiber function. This has potential applications in functional electrical stimulation (FES) and temporary, non-destructive nerve blocks for clinical and research applications
A Bayesian Design For Platform Trials With Temporal Changes
No full textIUIThe platform trial, which aims to find the best treatment for a disease by sequentially investigating multiple treatments in a single trial, has become increasingly popular in recent decades. An inherent problem for a platform trial is how to borrow information from the non-current controls to improve the efficiency of the statistical inference. The practical solution of directly combining all the control patients does not work due to the population heterogeneity between the concurrent and non-current controls. The temporal changes are the significant resources for that heterogeneity, which will affect patients’ responses over time. In this paper, we develop a Bayesian design to evaluate treatment effects of platform trials accounting for temporal changes. We treat each cohort of patients as a matching set and develop a conditional likelihood method to eliminate the impact of temporal changes. The performance of the proposed method is evaluated through simulation studies
Regulatory T Cells Kinetics in Immune Reconstitution Inflammatory Syndrome in HIV-Tuberculosis Co-Infected Individuals
No full textBackground: Combination antiretroviral therapy (cART) can suppress human immunodeficiency virus (HIV-1) replication, but some patients develop worsening of co-infections, termed immune reconstitution inflammatory syndrome. Regulatory T cells (Tregs) are a population of CD4+ T cells that modulate immune responses. We hypothesized that immune reconstitution inflammatory syndrome (IRIS) is associated with Tregs dysfunction.
Methods: We prospectively enrolled antiretroviral naive HIV patients with co-infection with Mycobacterium tuberculosis (MTB; N = 26) or controls with no prior opportunistic infection (N = 10). We prospectively measured HIV viral load, CD4+ T cell count, regulatory T cell (CD4high, CD127low-neg, Foxp3+) proportion, and Interferon-γ (IFN-γ) response to MTB peptides before and after initiation of combination antiretroviral therapy.
Results: Eleven of the MTB patients developed IRIS; 15 did not. IRIS patients had a lower proportion of Tregs at baseline compared to no-IRIS patients (HIV/no-OI and HIV/MTB no-IRIS), but the difference did not reach statistical significance (IRIS: 9.6 [5.3-11.2]; no-IRIS: 13.9 [7.6-22.5] p = 0.066). After 2 weeks of cART the proportion of Tregs was significantly lower in HIV/MTB IRIS patients (HIV/MTB IRIS: 9.8 [6.6-13.6], HIV/MTB no-IRIS: 15.8 [11.1-18.8]. The antigen-specific IFN-γ production was greater in the patients who developed IRIS compared with those who did not develop IRIS.
Conclusion: IRIS patients had a lower proportion of Tregs and more marked IFN-γ production, suggesting that Tregs may be responsible for suppressing the antigen-specific inflammatory response
Mental Health Matters and Faculty Make the Difference: Chancellor's Student Mental Health Council Research Project 2025
No full textThe Chancellor's Student Mental Health Council at Indiana University Indianapolis has conducted an in-depth study to explore the role of faculty in supporting student mental health. This presentation examines the challenges faculty face in recognizing and addressing student mental health concerns. Through surveys and focus groups, the research identifies trends in faculty perceptions. The findings and recommendations highlight the need for enhanced faculty training, clearer guidelines, and standardized tools to improve faculty confidence and effectiveness in referring students to appropriate resources. The study ultimately advocates for a more unified vision across IU Indianapolis, ensuring faculty are well-equipped to support the diverse mental health needs of their students