The Adenovirus E3 RID Complex Protects Some Cultured Human T and B Lymphocytes from Fas-Induced Apoptosis

Human group C adenoviruses cause an acute infection in respiratory epithelia and establish a long-term or persistent infection, possibly in lymphocytes. The mechanism by which this persistence is maintained is unknown; however, it would require that persistently infected lymphocytes not be deleted. The adenovirus genome encodes proteins that prevent the immune system from eliminating the virus-infected cell, including the E3 receptor internalization and degradation (RID) complex. The RID complex prevents death of infected cells by blocking apoptosis initiated through death domain-containing receptors of the tumor necrosis factor receptor (TNFR) superfamily, including TNFR1 (L. R. Gooding, T. S. Ranheim, A. E. Tollefson, L. Aquino, P. Duerksen-Hughes, T. M. Horton, and W. S. Wold, J. Virol. 65:4114-4123, 1991), TNF-related apoptosis-inducing ligand receptors (TRAIL-R1 and -R2) (C. A. Benedict, P. S. Norris, T. I. Prigozy, J. L. Bodmer, J. A. Mahr, C. T. Garnett, F. Martinon, J. Tschopp, L. R. Gooding, and C. F. Ware, J. Biol. Chem. 276:3270-3278, 2001; A. E. Tollefson, K. Toth, K. Doronin, M. Kuppuswamy, O. A. Doronina, D. L. Lichtenstein, T. W. Hermiston, C. A. Smith, and W. S. Wold, J. Virol. 75:8875-8887, 2001), and Fas (J. Shisler, C. Yang, B. Walter, C. F. Ware, and L. R. Gooding, J. Virol. 71:8299-8306, 1997). Here, we test the ability of RID to protect human lymphocytes from apoptosis induced by ligation of Fas, a mechanism important for regulating lymphocyte populations. Using a retrovirus expressing RID to infect six human lymphocyte cell lines, we found that RID functions in the absence of other viral proteins to downregulate surface Fas on some, but not all, cell lines. Total cellular levels of Fas decrease as measured by Western blotting, and this loss of Fas correlates with protection from apoptosis induced by ligation of Fas in every cell line tested. Although in some cases, RID causes loss of only a fraction of surface Fas, the presence of RID completely blocks the immediate events downstream of Fas ligation (i.e., Fas-FADD association and caspase-8 cleavage) in susceptible cell lines. Nonetheless, the ability of RID to block Fas signaling is independent of the Fas signaling pathway used (type I or type II). Interestingly, among the four T-cell lines tested, RID caused loss of Fas in the two T-cell lines bearing a relatively immature phenotype, while having no activity in T cells with mature phenotypes. Collectively, these data suggest that RID functions to prevent apoptosis of some human lymphocytes by internalizing surface Fas receptors. It is possible that the expression of RID facilitates long-term infection by preventing Fas-mediated deletion of persistently infected lymphocytes

Impacts of low concentration surfactant on red blood cell dielectrophoretic responses.

Cell dielectrophoretic responses have been extensively studied for biomarker expression, blood typing, sepsis, circulating tumor cell separations, and others. Surfactants are often added to the analytical buffer in electrokinetic cellular microfluidic systems to lower surface/interfacial tensions. In nonelectrokinetic systems, surfactants influence cell size, shape, and agglomeration; this has not been systematically documented in electrokinetic systems. In the present work, the impacts of the Triton X-100 surfactant on human red blood cells (RBCs) were explored via ultraviolet-visible spectroscopy (UV-Vis) and dielectrophoresis (DEP) to compare nonelectrokinetic and electrokinetic responses, respectively. The UV-Vis spectra of Triton X-100 treated RBCs were dramatically different from that of native RBCs. DEP responses of RBCs were compared to RBCs treated with low concentrations of Triton X-100 (0.07-0.17 mM) to ascertain surfactant effects on dielectric properties. A star-shaped electrode design was used to quantify RBC dielectric properties by fitting a single-shell oblate cell model to experimentally-derived DEP spectra. The presence of 0.07 and 0.11 mM of Triton X-100 shifted the RBC\u27s DEP spectra yielding lower crossover frequencie

Racial Differences in Associations of Cognitive Health Status With Happiness, Helplessness, and Hopelessness Among Older Adults: An Exploratory Study

BackgroundThe relationship between healthy and positive aging and dementia and cognitive impairment has received limited attention in the field of aging. Affect impacts cognitive changes and processes, and cognitive impairment is associated with affective comorbidities. The purpose of the study was to examine (a) whether happiness, helplessness, and hopelessness are linked to cognitive health status, and (b) whether these associations differ by race.MethodsParticipants were enrollees in the Wisconsin Alzheimer’s Disease Research Center’s Clinical Core (ADRC). Average age at baseline was 60.85 (SD = 8.65), 73.70 (SD = 8.02), and 73.80 (SD = 9.59) years for cognitively normal individuals, individuals with MCI, and individuals with dementia, respectively.ResultsIn the full sample, chi-square test results revealed associations between Cognitive Health Status (CHS) and (a) happiness, χ2(2) = 6.06, p &amp;lt; 0.05, (b) helplessness, χ2(2) = 6.44, p &amp;lt; 0.05, and (c) hopelessness, χ2(2) = 14.11, p &amp;lt; 0.01.ConclusionThis study provides support for the association of both positive and negative affect with cognitive health status in middle- to older-aged adults.</jats:sec

Alzheimer's disease biomarkers in Black and non-Hispanic White cohorts: A contextualized review of the evidence

Black Americans are disproportionately affected by dementia. To expand our understanding of mechanisms of this disparity, we look to Alzheimer's disease (AD) biomarkers. In this review, we summarize current data, comparing the few studies presenting these findings. Further, we contextualize the data using two influential frameworks: the National Institute on Aging-Alzheimer's Association (NIA-AA) Research Framework and NIA's Health Disparities Research Framework. The NIA-AA Research Framework provides a biological definition of AD that can be measured in vivo. However, current cut-points for determining pathological versus non-pathological status were developed using predominantly White cohorts-a serious limitation. The NIA's Health Disparities Research Framework is used to contextualize findings from studies identifying racial differences in biomarker levels, because studying biomakers in isolation cannot explain or reduce inequities. We offer recommendations to expand study beyond initial reports of racial differences. Specifically, life course experiences associated with racialization and commonly used study enrollment practices may better account for observations than exclusively biological explanations

Plasma Aβ42/40 and cognitive variability are associated with cognitive function in Black Americans: Findings from the AA‐FAIM cohort

Abstract Introduction It is critical to develop more inclusive Alzheimer's disease (AD) research protocols to ensure that historically excluded groups are included in preclinical research and have access to timely diagnosis and treatment. If validated in racialized groups, plasma AD biomarkers and measures of subtle cognitive dysfunction could provide avenues to expand diversity in preclinical AD research. We sought to evaluate the utility of two easily obtained, low‐burden disease markers, plasma amyloid beta (Aβ)42/40, and intra‐individual cognitive variability (IICV), to predict concurrent and longitudinal cognitive performance in a sample of Black adults. Methods Two hundred fifty‐seven Black participants enrolled in the African Americans Fighting Alzheimer's in Midlife (AA‐FAIM) study underwent at least one cognitive assessment visit; a subset of n = 235 had plasma samples. Baseline IICV was calculated as the standard deviation across participants’ z scores on five cognitive measures: Rey Auditory Verbal Learning Test Delayed Recall, Trail Making Test Parts A and B (Trails A and B), and Boston Naming Test. Using mixed effects regression models, we compared concurrent and longitudinal models to baseline plasma Aβ42/40 or IICV by age interactions. PrecivityAD assays quantified baseline plasma Aβ42/40. Results IICV was associated with concurrent/baseline performance on several outcomes but did not modify associations between age and cognitive decline. In contrast, plasma Aβ42/40 was unrelated to baseline cognitive performance, but a pattern emerged in interactions with age in longitudinal models of Trails A and B and Rey Auditory Verbal Learning Test total learning trials. Although not significant after correcting for multiple comparisons, low Aβ42/40 was associated with faster cognitive declines over time. Discussion Our results are promising as they extend existing findings to an Black American sample using low‐cost, low‐burden methods that can be implemented outside of a research center, thus supporting efforts for inclusive AD biomarker research

Regression From Prediabetes to Normal Glucose Regulation and Prevalence of Microvascular Disease in the Diabetes Prevention Program Outcomes Study (DPPOS)

OBJECTIVE Regression from prediabetes to normal glucose regulation (NGR) was associated with reduced incidence of diabetes by 56% over 10 years in participants in the Diabetes Prevention Program Outcomes Study (DPPOS). In an observational analysis, we examined whether regression to NGR also reduced risk for microvascular disease (MVD). RESEARCH DESIGN AND METHODS Generalized estimating equations were used to examine the prevalence of aggregate MVD at DPPOS year 11 in people who regressed to NGR at least once (vs. never) during the Diabetes Prevention Program (DPP). Logistic regression assessed the relationship of NGR with retinopathy, nephropathy, and neuropathy, individually. Generalized additive models fit smoothing splines to describe the relationship between average A1C during follow-up and MVD (and its subtypes) at the end of follow-up. RESULTS Regression to NGR was associated with lower prevalence of aggregate MVD in models adjusted for age, sex, race/ethnicity, baseline A1C, and treatment arm (odds ratio [OR] 0.78, 95% CI 0.65–0.78, P = 0.011). However, this association was lost in models that included average A1C during follow-up (OR 0.95, 95% CI 0.78–1.16, P = 0.63) or diabetes status at the end of follow-up (OR 0.92, 95% CI 0.75–1.12, P = 0.40). Similar results were observed in examination of the association between regression to NGR and prevalence of nephropathy and retinopathy, individually. Risk for aggregate MVD, nephropathy, and retinopathy increased across the A1C range. CONCLUSIONS Regression to NGR is associated with a lower prevalence of aggregate MVD, nephropathy, and retinopathy, primarily due to lower glycemic exposure over time. Differential risk for the MVD subtypes begins in the prediabetes A1C range. </jats:sec

Metabolite Profiles of Incident Diabetes and Heterogeneity of Treatment Effect in the Diabetes Prevention Program

Novel biomarkers of type 2 diabetes (T2D) and response to preventative treatment in individuals with similar clinical risk may highlight metabolic pathways that are important in disease development. We profiled 331 metabolites in 2,015 baseline plasma samples from the Diabetes Prevention Program (DPP). Cox models were used to determine associations between metabolites and incident T2D, as well as whether associations differed by treatment group (i.e., lifestyle [ILS], metformin [MET], or placebo [PLA]), over an average of 3.2 years of follow-up. We found 69 metabolites associated with incident T2D regardless of treatment randomization. In particular, cytosine was novel and associated with the lowest risk. In an exploratory analysis, 35 baseline metabolite associations with incident T2D differed across the treatment groups. Stratification by baseline levels of several of these metabolites, including specific phospholipids and AMP, modified the effect that ILS or MET had on diabetes development. Our findings highlight novel markers of diabetes risk and preventative treatment effect in individuals who are clinically at high risk and motivate further studies to validate these interactions.</jats:p