Molecular and Physiological Factors of Neuroprotection in Hypoxia-Tolerant Models: Pharmacological Clues for the Treatment of Stroke

The naked mole-rat possesses several unique physiological and molecular features that underlie their remarkably and exceptional resistance to tissue hypoxia. Elevated pattern of Epo, an erythropoietin (Epo) factor; c-fos; vascular endothelial growth factor (VEGF); and hypoxia-inducible factors (HIF-1α) contribute to the adaptive strategy to cope with hypoxic stress. Moreover, the naked mole-rat has a lower metabolic rate than any other eutherian mammal of comparable size that has been studied. The ability to actively reduce metabolic rate represents a strategy widely used in the face of decreased tissue oxygen availability. Understanding the different molecular and physiological factors that induce metabolic suppression could guide the development of pharmacological agents for the clinical management of stroke patient

Human Machine Interfaces for Teleoperators and Virtual Environments

In Mar. 1990, a meeting organized around the general theme of teleoperation research into virtual environment display technology was conducted. This is a collection of conference-related fragments that will give a glimpse of the potential of the following fields and how they interplay: sensorimotor performance; human-machine interfaces; teleoperation; virtual environments; performance measurement and evaluation methods; and design principles and predictive models

In Acute Ischemic Stroke Patients With Smoking Incidence, Are More Women Than Men More Likely to Be Included or Excluded From Thrombolysis Therapy?

Background: Clinical factors associated with exclusion from recombinant tissue plasminogen activator in both men and women are not completely understood. The aim of this study is to determine whether there is a gender difference in clinical risk factors that excluded ischemic stroke patients with a history of smoking from recombinant tissue plasminogen activator. Methods: Retrospective data from a stroke registry were analyzed, and multivariable linear regression models were used to determine gender differences. Logistic regression models determined exclusion clinical risk factors for thrombolysis in male and female acute ischemic stroke patients with a history of smoking, while sequentially adjusting for sociodemographic, clinical, and stroke-related variables. The Kaplan–Meier survival analysis was used to determine the exclusion probabilities of men and women with a history of smoking within the stroke population. Results: Of the 1,446 acute ischemic stroke patients eligible for recombinant tissue plasminogen activator, 379 patients with a history of smoking were examined, of which 181 received recombinant tissue plasminogen activator while 198 were excluded from receiving recombinant tissue plasminogen activator. Of the 198 patients, 75 females and 123 males were excluded from receiving recombinant tissue plasminogen activator. After multivariable adjustment for age, National Institutes of Health scores, and stroke-related factors, females who present with weakness/paresis on initial examination (OR = 0.117, 95% CI, 0.025–0.548) and men who present with a history of previous transient ischemic attack (OR = 0.169, 95% CI, 0.044–0.655), antiplatelet medication use (OR = 0.456, 95% CI, 0.230–0.906), and weakness/paresis on initial examination (OR = 0.171, 95% CI, 0.056–0.521) were less likely to be excluded from recombinant tissue plasminogen activator (thrombolysis therapy). Conclusions: In an ischemic stroke population with a history of smoking, female smokers are more likely to be excluded from thrombolysis therapy in comparison to men, even after adjustment for confounding variables

PRINCIPAL COMPONENTS ANALYSIS CORRECTS COLLIDER BIAS IN POLYGENIC RISK SCORE EFFECT SIZE ESTIMATION

BACKGROUND: Genome-wide polygenic scoring has emerged as a way to predict psychiatric and behavioral outcomes and identify environments that promote the expression of genetic risks. An increasing number of studies demonstrate that the effects of polygenic risk scores (PRS) may be biased by the inclusion of heritable environments as covariates when the environment is influenced by unmeasured confounding variables, an example of collider bias. Inclusion of the principal components of observed confounders as covariates may correct for the effect of unmeasured confounders. METHODS: A simulation study was conducted to test principal components analysis (PCA) as a correction for collider bias. Data were sampled from a model which tested different values for the effect of the polygenic risk score on the heritable environment, the correlation structure of the unmeasured confounding data, and the proportion of the confounding data that is used to construct the principal components. Other model parameters were fixed across all simulation iterations. RESULTS: Modeling the first PC of observed confounders as a covariate recovers the PRS effect size estimate under reasonable assumptions about the proportion of the confounding data that is measured or the correlation structure of the confounding data. Required assumptions become stricter as the effect of PRS on environment (and the magnitude of bias) increases. CONCLUSION: Inclusion of the first PC of observed confounders as a covariate may improve the accuracy of PRS effect size estimation when heritable environments are included in the model as covariates. Future directions include application of this method in observed data.https://scholarscompass.vcu.edu/gradposters/1130/thumbnail.jp

Simulation and Analyses of Stage Separation Two-Stage Reusable Launch Vehicles

NASA has initiated the development of methodologies, techniques and tools needed for analysis and simulation of stage separation of next generation reusable launch vehicles. As a part of this activity, ConSep simulation tool is being developed which is a MATLAB-based front-and-back-end to the commercially available ADAMS(registered Trademark) solver, an industry standard package for solving multi-body dynamic problems. This paper discusses the application of ConSep to the simulation and analysis of staging maneuvers of two-stage-to-orbit (TSTO) Bimese reusable launch vehicles, one staging at Mach 3 and the other at Mach 6. The proximity and isolated aerodynamic database were assembled using the data from wind tunnel tests conducted at NASA Langley Research Center. The effects of parametric variations in mass, inertia, flight path angle, altitude from their nominal values at staging were evaluated. Monte Carlo runs were performed for Mach 3 staging to evaluate the sensitivity to uncertainties in aerodynamic coefficients

Simulation and Analyses of Stage Separation of Two-Stage Reusable Launch Vehicles

NASA has initiated the development of methodologies, techniques and tools needed for analysis and simulation of stage separation of next generation reusable launch vehicles. As a part of this activity, ConSep simulation tool is being developed which is a MATLAB-based front-and-back-end to the commercially available ADAMS(Registerd TradeMark) solver, an industry standard package for solving multi-body dynamic problems. This paper discusses the application of ConSep to the simulation and analysis of staging maneuvers of two-stage-to-orbit (TSTO) Bimese reusable launch vehicles, one staging at Mach 3 and the other at Mach 6. The proximity and isolated aerodynamic database were assembled using the data from wind tunnel tests conducted at NASA Langley Research Center. The effects of parametric variations in mass, inertia, flight path angle, altitude from their nominal values at staging were evaluated. Monte Carlo runs were performed for Mach 3 staging to evaluate the sensitivity to uncertainties in aerodynamic coefficients

Nicotinamide N-methyltransferase catalyses the N-methylation of the endogenous ß-carboline norharman: evidence for a novel detoxification pathway

Nicotinamide N-methyltransferase (NNMT) is responsible for the N-methylation of nicotinamide to 1-methylnicotinamide. Our recent studies have demonstrated that NNMT regulates cellular processes fundamental to the correct functioning and survival of the cell. It has been proposed that NNMT may possess β-carboline (BC) N-methyltransferase activity, endogenously and exogenously produced pyridine-containing compounds which, when N-methylated, are potent inhibitors of Complex I and have been proposed to have a role in the pathogenesis of Parkinson's disease. We have investigated the ability of recombinant NNMT to N-methylate norharman (NH) to 2-N-methylnorharman (MeNH). In addition, we have investigated the toxicity of the BC NH, its precursor 1,2,3,4-tetrahydronorharman (THNH) and its N-methylated metabolite MeNH, using our in vitro SH-SY5Y NNMT expression model. Recombinant NNMT demonstrated NH 2N-methyltransferase activity, with a Km of 90 ± 20 µM, a kcat of 3 × 10(-4) ± 2 × 10(-5) s(-1) and a specificity constant (kcat/Km) of 3 ± 1 s(-1) M(-1) THNH was the least toxic of all three compounds investigated, whereas NH demonstrated the greatest, with no difference observed in terms of cell viability and cell death between NNMT-expressing and non-expressing cells. In NNMT-expressing cells, MeNH increased cell viability and cellular ATP concentration in a dose-dependent manner after 72 and 120 h incubation, an effect that was not observed after 24 h incubation or in non-NNNT-expressing cells at any time point. Taken together, these results suggest that NNMT may be a detoxification pathway for BCs such as NH