Although the field of genetics has grown by leaps and bounds within the last decade due to the completion and availability of the human genome sequence, transcriptional regulation still cannot be ...explained solely by an individual's DNA sequence. Complex coordination and communication between a plethora of well-conserved chromatin modifying factors are essential for all organisms. Regulation of gene expression depends on histone post translational modifications (HPTMs), DNA methylation, histone variants, remodeling enzymes, and effector proteins that influence the structure and function of chromatin, which affects a broad spectrum of cellular processes such as DNA repair, DNA replication, growth, and proliferation. If mutated or deleted, many of these factors can result in human disease at the level of transcriptional regulation. The common goal of recent studies is to understand disease states at the stage of altered gene expression. Utilizing information gained from new high-throughput techniques and analyses will aid biomedical research in the development of treatments that work at one of the most basic levels of gene expression, chromatin. This chapter will discuss the effects of and mechanism by which histone modifications and DNA methylation affect transcriptional regulation.
Although maternal age has been associated with a number of birth defects in several reports, the literature on the association of maternal age with isolated congenital heart defect (CHD) phenotypes ...has been limited. We evaluated CHD prevalence based on a cohort of 5,289 infants and fetuses with isolated CHDs born during the period 1968-2005 and ascertained by the Metropolitan Atlanta Congenital Defects Program (MACDP) among residents of five central counties in Atlanta. For our denominator, we obtained information on births to residents of the same counties from vital records (n = 1,301,143). We calculated prevalence ratios for 23 CHD phenotypes by several maternal age categories, using the group 25-29 years of age as a reference group. We used Poisson regression models to estimate adjusted prevalence ratios (aPRs) and 95% confidence intervals (CIs), controlling for maternal race, infant sex, and birth cohort. A maternal age of 35 years or older was associated with an increased prevalence for several CHD phenotypes: laterality defects (aPR = 2.06; CI 1.22-3.48), all conotruncal defects (aPR = 1.30; CI 1.03-1.65), and specifically for dextro-transposition of the great arteries (aPR = 1.65; CI 1.10-2.48), coarctation of the aorta (aPR = 1.54; CI 1.10-2.16), ventricular septal defects (aPR = 1.20; CI 1.06-1.36), and atrial septal defects (aPR = 1.36; CI 1.05-1.77). Our findings suggest that the birth prevalence of specific isolated CHDs varies with maternal age. Further studies are warranted to corroborate these observations, taking into account potential confounding by known modifiable risk factors.
Metformin and exercise independently improve insulin sensitivity and decrease the risk of diabetes. Metformin was also recently proposed as a potential therapy to slow aging. However, recent evidence ...indicates that adding metformin to exercise antagonizes the exercise‐induced improvement in insulin sensitivity and cardiorespiratory fitness. The purpose of this study was to test the hypothesis that metformin diminishes the improvement in insulin sensitivity and cardiorespiratory fitness after aerobic exercise training (AET) by inhibiting skeletal muscle mitochondrial respiration and protein synthesis in older adults (62 ± 1 years). In a double‐blinded fashion, participants were randomized to placebo (n = 26) or metformin (n = 27) treatment during 12 weeks of AET. Independent of treatment, AET decreased fat mass, HbA1c, fasting plasma insulin, 24‐hr ambulant mean glucose, and glycemic variability. However, metformin attenuated the increase in whole‐body insulin sensitivity and VO2max after AET. In the metformin group, there was no overall change in whole‐body insulin sensitivity after AET due to positive and negative responders. Metformin also abrogated the exercise‐mediated increase in skeletal muscle mitochondrial respiration. The change in whole‐body insulin sensitivity was correlated to the change in mitochondrial respiration. Mitochondrial protein synthesis rates assessed during AET were not different between treatments. The influence of metformin on AET‐induced improvements in physiological function was highly variable and associated with the effect of metformin on the mitochondria. These data suggest that prior to prescribing metformin to slow aging, additional studies are needed to understand the mechanisms that elicit positive and negative responses to metformin with and without exercise.
Objective To identify the proportion of major structural noncardiac anomalies identified with congenital heart defects (CHDs). Study design Records of infants with CHDs in the Metropolitan Atlanta ...Congenital Defects Program who were born during the period 1968 through 2005 were classified as having isolated, syndromic, multiple CHD (ie, having an unrecognized pattern of multiple congenital anomalies or a recognized pattern of multiple congenital anomalies of unknown etiology), or laterality defects. Frequencies of associated noncardiac anomalies were obtained. Results We identified 7984 live-born and stillborn infants and fetuses with CHDs. Among them, 5695 (71.3%) had isolated, 1080 (13.5%) had multiple, 1048 (13.1%) had syndromic, and 161 (2.0%) had laterality defects. The percentage of multiple congenital anomalies was highest for case with atrial septal defects (18.5%), cardiac looping defects (17.2%), and conotruncal defects (16.0%), and cases with atrioventricular septal defects represented the highest percentages of those with syndromic CHDs (66.7%). Conclusions Including those with syndromes and laterality defects, 28.7% of case infants with CHDs had associated major noncardiac malformations. Thus, infants with CHDs warrant careful examination for the presence of noncardiac anomalies.
Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized by a classic triad of hypertelorism, bifid uvula and/or cleft palate, and generalized arterial tortuosity. ...There are limited data on the prevalence and rupture risk of intracranial aneurysms (IAs) in the setting of LDS, with no established guidelines.
To analyze the prevalence and rupture risk of IA in LDS.
Electronic medical records of patients with a confirmed diagnosis of LDS and available cerebrovascular imaging were reviewed. Patients were divided into 2 groups based on the presence of IA. Unmatched and propensity-matched analyses were used to identify potential risk factors for aneurysm formation.
Records of 1111 patients were screened yielding a total of 60 patients with a diagnosis of LDS. Eighteen (30%) patients had IA, 4 (22.2%) of whom had multiple aneurysms for a total of 24 IAs. Twenty-three (95.8%) aneurysms were located in the anterior circulation; none of them were ruptured. On unmatched analysis, age ( P = .015), smoking history ( P = .034), hypertension ( P = .035), and number of extracranial aneurysms ( P < .001) were significantly higher in patients with IA. After matching for age, sex, race, stroke history, family history, and extracranial aneurysms, smoking history ( P = .009) remained significant.
Patients with LDS have an increased risk of IAs, especially with a history of smoking. The prevalence rate of IAs in our series was 30%. Screening imaging should be considered at diagnosis, and patients should be encouraged to abstain from smoking. Further studies are needed to elucidate the risk of IA rupture and treatment considerations in this unique population.
Background
COVID-19 introduced new barriers to health care including cancer screenings. This study evaluated the role of pandemic- and copay-related barriers to colonoscopy and the extent to which ...home-based testing methods were utilized.
Methods
A cross-sectional survey assessed colorectal cancer (CRC) attitudes and screening early in the COVID-19 pandemic.
Results
Respondents (342; 50.37% female) were 62.32 (SD = 6.87) years old. Roughly half were White/Caucasian (329; 48.45%); 29.75% were Black/African American (202); and 21.80% were another race (148). Roughly two-thirds were up-to-date with CRC screening (459; 67.59%). In an adjusted model, those with a higher agreement that concerns about COVID-19 delayed scheduling their colonoscopy (OR = .79; 95% CI: .08, .63; P = .045) and concerns about copays delayed scheduling their colonoscopy (OR = .73; 95% CI: .73, .57; P = .02) were less likely to be up-to-date on screening. In another adjusted model, those screened during the pandemic were significantly more likely to be screened via an at-home test (OR = 10.93; 95% CI: 5.95, 20.27; P < .001).
Discussion
During the COVID-19 pandemic, screening copay-related concerns persisted and were significantly higher among those not up-to-date with CRC screening. Increased at-home testing and addressing copay barriers may increase CRC screening adherence now and in future infectious disease outbreaks.
The 2016 Colorado Trail Race (CTR) was an ultra-endurance mountain bike race in which competitors cycled for up to 24 h/day between altitudes of 1,675 and 4,025 m to complete 800 km and 21,000 m of ...elevation gain. In one athlete, we had the unique opportunity to characterize skeletal muscle protein synthesis and mitochondrial respiration in response to a normal activity control period (CON) and the CTR. We hypothesized that mitochondrial protein synthesis would be elevated and mitochondrial respiration would be maintained during the extreme stresses of the CTR. Titrated and bolus doses of ADP were provided to determine substrate-specific oxidative phosphorylation (OXPHOS) and electron transport system (ETS) capacities in permeabilized muscle fibers via high-resolution respirometry. Protein synthetic rates were determined by daily oral consumption of deuterium oxide (
H
O). The endurance athlete had OXPHOS (226 pmol·s
·mg tissue
) and ETS (231 pmol·s
·mg tissue
) capacities that rank among the highest published to date in humans. Mitochondrial (3.2-fold), cytoplasmic (2.3-fold), and myofibrillar (1.5-fold) protein synthesis rates were greater during CTR compared with CON. With titrated ADP doses, the apparent K
of ADP, OXPHOS, and ETS increased after the CTR. With provision of ADP boluses after the CTR, the addition of fatty acids (-12 and -14%) mitigated the decline in OXPHOS and ETS capacity during carbohydrate-supported respiration (-26 and -31%). In the face of extreme stresses during the CTR, elevated rates of mitochondrial protein synthesis may contribute to rapid adaptations in mitochondrial bioenergetics. NEW & NOTEWORTHY The mechanisms that maintain skeletal muscle function during extreme stresses remain incompletely understood. In the current study, greater rates of mitochondrial protein synthesis during the energetic demands of ultra-endurance exercise may contribute to rapid adaptations in mitochondrial bioenergetics. The endurance athlete herein achieved mitochondrial respiratory capacities among the highest published for humans. Greater mitochondrial protein synthesis during ultra-endurance exercise may contribute to improved mitochondrial respiration and serve as a mechanism to resist cellular energetic stresses.
Abstract
Background
Mobility limitation in older adults is common and associated with poor health outcomes and loss of independence. Identification of at-risk individuals remains challenging because ...of time-consuming clinical assessments and limitations of statistical models for dynamic outcomes over time. Therefore, we aimed to develop machine learning models for predicting future mobility limitation in older adults using repeated measures data.
Methods
We used annual assessments over 9 years of follow-up from the Health, Aging, and Body Composition study to model mobility limitation, defined as self-report of any difficulty walking a quarter mile or climbing 10 steps. We considered 46 predictors, including demographics, lifestyle, chronic conditions, and physical function. With a split sample approach, we developed mixed models (generalized linear and Binary Mixed Model forest) using (a) all 46 predictors, (b) a variable selection algorithm, and (c) the top 5 most important predictors. Age was included in all models. Performance was evaluated using area under the receiver operating curve in 2 internal validation data sets.
Results
Area under the receiver operating curve ranged from 0.80 to 0.84 for the models. The most important predictors of mobility limitation were ease of getting up from a chair, gait speed, self-reported health status, body mass index, and depression.
Conclusions
Machine learning models using repeated measures had good performance for identifying older adults at risk of developing mobility limitation. Future studies should evaluate the utility and efficiency of the prediction models as a tool in clinical settings for identifying at-risk older adults who may benefit from interventions aimed to prevent or delay mobility limitation.
The T cell repertoire of healthy mice and humans harbors self-reactive CD4
conventional T (T
) cells capable of inducing autoimmunity. Using T cell receptor profiling paired with in vivo clonal ...analysis of T cell differentiation, we identified T
cell clones that are recurrently enriched in non-lymphoid organs following ablation of Foxp3
regulatory T (T
) cells. A subset of these clones was highly proliferative in the lymphoid organs at steady state and exhibited overt reactivity to self-ligands displayed by dendritic cells, yet were not purged by clonal deletion. These clones spontaneously adopted numerous hallmarks of follicular helper T (T
) cells, including expression of Bcl6 and PD-1, exhibited an elevated propensity to localize within B cell follicles at steady state, and produced interferon-γ in non-lymphoid organs following sustained T
cell depletion. Our work identifies a naturally occurring population of self-reactive T
-like cells and delineates a previously unappreciated fate for self-specific T
cells.
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