Intracellular proteins with long lifespans have recently been linked to age-dependent defects, ranging from decreased fertility to the functional decline of neurons. Why long-lived proteins exist in ...metabolically active cellular environments and how they are maintained over time remains poorly understood. Here, we provide a system-wide identification of proteins with exceptional lifespans in the rat brain. These proteins are inefficiently replenished despite being translated robustly throughout adulthood. Using nucleoporins as a paradigm for long-term protein persistence, we found that nuclear pore complexes (NPCs) are maintained over a cell’s life through slow but finite exchange of even its most stable subcomplexes. This maintenance is limited, however, as some nucleoporin levels decrease during aging, providing a rationale for the previously observed age-dependent deterioration of NPC function. Our identification of a long-lived proteome reveals cellular components that are at increased risk for damage accumulation, linking long-term protein persistence to the cellular aging process.
Display omitted
Display omitted
•Metabolic pulse-chase labeling of rats identified long-lived proteins in rats•Long-lived proteins include nucleoporins, histone variants, and enzymes•Long-lived proteins cannot be replaced despite their robust translation•Nuclear pores are maintained over the lifespan of the organism
A system-wide identification of proteins with exceptional lifespans in the rat brain suggests that these have a higher propensity for damage. Cells utilize specific mechanisms to ensure that such proteins are maintained in a functional state through aging.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Bayesian parameter estimation and Bayesian hypothesis testing present attractive alternatives to classical inference using confidence intervals and
p
values. In part I of this series we outline ten ...prominent advantages of the Bayesian approach. Many of these advantages translate to concrete opportunities for pragmatic researchers. For instance, Bayesian hypothesis testing allows researchers to quantify evidence and monitor its progression as data come in, without needing to know the intention with which the data were collected. We end by countering several objections to Bayesian hypothesis testing. Part II of this series discusses JASP, a free and open source software program that makes it easy to conduct Bayesian estimation and testing for a range of popular statistical scenarios (Wagenmakers et al.
this issue
).
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Tutorial on directed acyclic graphs Digitale, Jean C.; Martin, Jeffrey N.; Glymour, Medellena Maria
Journal of clinical epidemiology,
02/2022, Volume:
142
Journal Article
Peer reviewed
Open access
Directed acyclic graphs (DAGs) are an intuitive yet rigorous tool to communicate about causal questions in clinical and epidemiologic research and inform study design and statistical analysis. DAGs ...are constructed to depict prior knowledge about biological and behavioral systems related to specific causal research questions. DAG components portray who receives treatment or experiences exposures; mechanisms by which treatments and exposures operate; and other factors that influence the outcome of interest or which persons are included in an analysis. Once assembled, DAGs — via a few simple rules — guide the researcher in identifying whether the causal effect of interest can be identified without bias and, if so, what must be done either in study design or data analysis to achieve this. Specifically, DAGs can identify variables that, if controlled for in the design or analysis phase, are sufficient to eliminate confounding and some forms of selection bias. DAGs also help recognize variables that, if controlled for, bias the analysis (e.g., mediators or factors influenced by both exposure and outcome). Finally, DAGs help researchers recognize insidious sources of bias introduced by selection of individuals into studies or failure to completely observe all individuals until study outcomes are reached. DAGs, however, are not infallible, largely owing to limitations in prior knowledge about the system in question. In such instances, several alternative DAGs are plausible, and researchers should assess whether results differ meaningfully across analyses guided by different DAGs and be forthright about uncertainty. DAGs are powerful tools to guide the conduct of clinical research.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This paper introduces JASP, a free graphical software package for basic statistical procedures such as t tests, ANOVAs, linear regression models, and analyses of contingency tables. JASP is ...open-source and differentiates itself from existing open-source solutions in two ways. First, JASP provides several innovations in user interface design; specifically, results are provided immediately as the user makes changes to options, output is attractive, minimalist, and designed around the principle of progressive disclosure, and analyses can be peer reviewed without requiring a "syntax". Second, JASP provides some of the recent developments in Bayesian hypothesis testing and Bayesian parameter estimation. The ease with which these relatively complex Bayesian techniques are available in JASP encourages their broader adoption and furthers a more inclusive statistical reporting practice. The JASP analyses are implemented in R and a series of R packages.
While considerable knowledge has been gained through the use of established cognitive and motor assessment tools, there is a considerable interest and need for the development of a battery of ...reliable and validated assessment tools that provide real-time and remote analysis of cognitive and motor function in the elderly. Smartphones appear to be an obvious choice for the development of these "next-generation" assessment tools for geriatric research, although to date no studies have reported on the use of smartphone-based applications for the study of cognition in the elderly. The primary focus of the current study was to assess the feasibility, reliability, and validity of a smartphone-based application for the assessment of cognitive function in the elderly. A total of 57 non-demented elderly individuals were administered a newly developed smartphone application-based Color-Shape Test (CST) in order to determine its utility in measuring cognitive processing speed in the elderly. Validity of this novel cognitive task was assessed by correlating performance on the CST with scores on widely accepted assessments of cognitive function. Scores on the CST were significantly correlated with global cognition (Mini-Mental State Exam: r = 0.515, p<0.0001) and multiple measures of processing speed and attention (Digit Span: r = 0.427, p<0.0001; Trail Making Test: r = -0.651, p<0.00001; Digit Symbol Test: r = 0.508, p<0.0001). The CST was not correlated with naming and verbal fluency tasks (Boston Naming Test, Vegetable/Animal Naming) or memory tasks (Logical Memory Test). Test re-test reliability was observed to be significant (r = 0.726; p = 0.02). Together, these data are the first to demonstrate the feasibility, reliability, and validity of using a smartphone-based application for the purpose of assessing cognitive function in the elderly. The importance of these findings for the establishment of smartphone-based assessment batteries of cognitive and motor function in the elderly is discussed.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The repetition-induced truth effect refers to a phenomenon where people rate repeated statements as more likely true than novel statements. In this paper, we document
qualitative
individual ...differences in the effect. While the overwhelming majority of participants display the usual
positive
truth effect, a minority are the opposite—they reliably discount the validity of repeated statements, what we refer to as
negative
truth effect. We examine eight truth-effect data sets where individual-level data are curated. These sets are composed of 1105 individuals performing 38,904 judgments. Through Bayes factor model comparison, we show that reliable negative truth effects occur in five of the eight data sets. The negative truth effect is informative because it seems unreasonable that the mechanisms mediating the positive truth effect are the same that lead to a discounting of repeated statements’ validity. Moreover, the presence of qualitative differences motivates a different type of analysis of individual differences based on ordinal (i.e., Which sign does the effect have?) rather than metric measures. To our knowledge, this paper reports the first such reliable qualitative differences in a cognitive task.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To address the role of translationally active HIV reservoir in chronic inflammation and non-AIDS related disorders, we first need a simple and accurate assay to evaluate viral protein expression in ...virally suppressed subjects.
We optimized an HIV Nef enzyme-linked immunosorbent assay (ELISA) and used it to quantify plasma Nef levels as an indicator of the leaky HIV reservoir in an HIV-infected cohort.
This study accessed 134 plasma samples from a well-characterized cohort study of HIV-infected and uninfected adults in San Francisco (the SCOPE cohort). We optimized an ELISA for detection of plasma Nef in HIV-negative subjects and HIV-infected non-controllers, and evaluated its utility to quantify plasma Nef levels in a cross-sectional study of ART-suppressed and elite controller HIV-infected subjects.
Here, we describe the performance of an optimized HIV Nef ELISA. When we applied this assay to the study cohort we found that plasma Nef levels were correlated with plasma HIV RNA levels in untreated disease. However, we were able to detect Nef in plasma of approximately half of subjects on ART or with elite control, despite the lack of detectable plasma HIV RNA levels using standard assays. Plasma Nef levels were not consistently associated with CD4+ T-cell count, CD8+ T-cell count, self-reported nadir CD4+ T-cell count or the CD4+/CD8+ T-cell ratio in HIV-infected subjects.
Since plasma HIV RNA levels are undetectable in virally suppressed subjects, it is reasonable to assume that viral protein expression in leaky reservoir, and not plasma virions, is the source of Nef accumulating in plasma. To examine this further, improvements of the assay sensitivity, by lowering the background through improvements in the quality of Nef antibodies, and detailed characterization of the HIV reservoirs are needed.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background.Although antiretroviral therapy has the ability to fully restore a normal CD4+ cell count (>500 cells/mm3) in most patients, it is not yet clear whether all patients can achieve ...normalization of their CD4+ cell count, in part because no study has followed up patients for >7 years. Methods.Three hundred sixty-six patients from 5 clinical cohorts who maintained a plasma human immunodeficiency virus (HIV) RNA level <1000 copies/mL for at least 4 years after initiation of antiretroviral therapy were included. Changes in CD4+ cell count were evaluated using mixed-effects modeling, spline-smoothing regression, and Kaplan-Meier techniques. Results.The majority (83%) of the patients were men. The median CD4+ cell count at the time of therapy initiation was 201 cells/mm3 (interquartile range, 72–344 cells/mm3), and the median age was 47 years. The median follow-up period was 7.5 years (interquartile range, 5.5–9.7 years). CD4+ cell counts continued to increase throughout the follow-up period, albeit slowly after year 4. Although almost all patients (95%) who started therapy with a CD4+ cell count ⩾300 cells/mm3 were able to attain a CD4+ cell count ⩾500 cells/mm3, 44% of patients who started therapy with a CD4+ cell count <100 cells/mm3 and 25% of patients who started therapy with a CD4+ cell count of 100–200 cells/mm3 were unable to achieve a CD4+ cell count >500 cells/mm3 over a mean duration of follow-up of 7.5 years; many did not reach this threshold by year 10. Twenty-four percent of individuals with a CD4+ cell count <500 cells/mm3 at year 4 had evidence of a CD4+ cell count plateau after year 4. The frequency of detectable viremia (“blips”) after year 4 was not associated with the magnitude of the CD4+ cell count change. Conclusions.A substantial proportion of patients who delay therapy until their CD4+ cell count decreases to <200 cells/mm3 do not achieve a normal CD4+ cell count, even after a decade of otherwise effective antiretroviral therapy. Although the majority of patients have evidence of slow increases in their CD4+ cell count over time, many do not. These individuals may have an elevated risk of non–AIDS-related morbidity and mortality.
Full text
Available for:
BFBNIB, NUK, PNG, UL, UM, UPUK
To combat the functional decline of the proteome, cells use the process of protein turnover to replace potentially impaired polypeptides with new functional copies. We found that extremely long-lived ...proteins (ELLPs) did not turn over in postmitotic cells of the rat central nervous system. These ELLPs were associated with chromatin and the nuclear pore complex, the central transport channels that mediate all molecular trafficking in and out of the nucleus. The longevity of these proteins would be expected to expose them to potentially harmful metabolites, putting them at risk of accumulating damage over extended periods of time. Thus, it is possible that failure to maintain proper levels and functional integrity of ELLPs in nonproliferative cells might contribute to age-related deterioration in cell and tissue function.
Full text
Available for:
BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Mucosal-associated invariant T (MAIT) cells are an evolutionarily conserved antimicrobial MR1-restricted T-cell subset. MAIT cells are CD161+, express a Vα7.2 TCR, are primarily CD8+ and numerous in ...blood and mucosal tissues. However, their role in HIV-1 infection is unknown. In this study, we found levels of MAIT cells to be severely reduced in circulation in patients with chronic HIV-1 infection. Residual MAIT cells were highly activated and functionally exhausted. Their decline was associated with time since diagnosis, activation levels, and the concomitant expansion of a subset of functionally impaired CD161− Vα7.2+ T cells. Such cells were generated in vitro by exposure of MAIT cells to Escherichia coli. Notably, whereas the function of residual MAIT cells was at least partly restored by effective antiretroviral therapy, levels of MAIT cells in peripheral blood were not restored. Interestingly, MAIT cells in rectal mucosa were relatively preserved, although some of the changes seen in blood were recapitulated in the mucosa. These findings are consistent with a model in which the MAIT-cell compartment, possibly as a result of persistent exposure to microbial material, is engaged, activated, exhausted, and progressively and persistently depleted during chronic HIV-1 infection.
•Antimicrobial CD8+ MAIT cells are activated, exhausted, and progressively and persistently depleted during chronic HIV-1 infection.•This decline in MAIT cell level and function may seriously impair the ability to mount immune responses to bacterial and fungal pathogens.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PDF
