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Adenosine-to-inosine RNA editing is essential to prevent undesired immune activation. This diverse process alters the genetic content of the RNA and may recode proteins, change splice sites and miRNA targets, and mimic genomic mutations. Recent studies have associated or implicated aberrant editing with pathological conditions, including cancer, autoimmune diseases, and neurological and psychiatric conditions. RNA editing patterns in cardiovascular tissues have not been investigated systematically so far, and little is known about its potential role in cardiac diseases. Some hints suggest robust editing in this system, including the fact that ADARB1 (ADAR2), the main coding-sequence editor, is most highly expressed in these tissues. Here we characterized RNA editing in the heart and arteries and examined a contributory role to the development of atherosclerosis and two structural heart diseases -Ischemic and Dilated Cardiomyopathies. Analyzing hundreds of RNA-seq samples taken from the heart and arteries of cardiac patients and controls, we find that global editing, alongside inflammatory gene expression, is increased in patients with atherosclerosis, cardiomyopathies, and heart failure. We describe a single recoding editing site and suggest it as a target for focused research. This recoding editing site in the IGFBP7 gene is one of the only evolutionary conserved sites between mammals, and we found it exhibits consistently increased levels of editing in these patients. Our findings reveal that RNA editing is abundant in arteries and is elevated in several key cardiovascular conditions. They thus provide a roadmap for basic and translational research of RNA as a mediator of atherosclerosis and non-genetic cardiomyopathies.

RNA editing by adenosine deaminases changes the information encoded in the mRNA from its genomic blueprint. Editing of protein-coding sequences can introduce novel, functionally distinct, protein isoforms and diversify the proteome. The functional importance of a few recoding sites has been appreciated for decades. However, systematic methods to uncover these sites perform poorly, and the full repertoire of recoding in human and other mammals is unknown. Here we present a new detection approach, and analyze 9125 GTEx RNA-seq samples, to produce a highly-accurate atlas of 1517 editing sites within the coding region and their editing levels across human tissues. Single-cell RNA-seq data shows protein recoding contributes to the variability across cell subpopulations. Most highly edited sites are evolutionary conserved in non-primate mammals, attesting for adaptation. This comprehensive set can facilitate understanding of the role of recoding in human physiology and diseases. Gabay et al. provide a highly-accurate atlas of recoding by A-to-I RNA editing in human, profiled across tissues and cell subpopulations. Most highly edited sites are evolutionary conserved in non-primate mammals, attesting for adaptation.

Background Most evidence about what works in transitional care comes from small studies in single clinical specialties. We tested the hypothesis that exposures to nine recommended features of transitional healthcare were associated with better outcomes for young people with long-term conditions during transition from child-centred to adult-oriented health services. Methods This is a longitudinal, observational cohort study in UK secondary care including 374 young people, aged 14–18.9 years at recruitment, with type 1 diabetes ( n = 150), cerebral palsy ( n = 106) or autism spectrum disorder with an associated mental health problem ( n = 118). All were pre-transfer and without significant learning disability. We approached all young people attending five paediatric diabetes centres, all young people with autism spectrum disorder attending four mental health centres, and randomly selected young people from two population-based cerebral palsy registers. Participants received four home research visits, 1 year apart and 274 participants (73%) completed follow-up. Outcome measures were Warwick Edinburgh Mental Wellbeing Scale, Mind the Gap Scale (satisfaction with services), Rotterdam Transition Profile (Participation) and Autonomy in Appointments. Results Exposure to recommended features was 61% for ‘coordinated team’, 53% for ‘age-banded clinic’, 48% for ‘holistic life-skills training’, 42% for ‘promotion of health self-efficacy’, 40% for ‘meeting the adult team before transfer’, 34% for ‘appropriate parent involvement’ and less than 30% for ‘written transition plan’, ‘key worker’ and ‘transition manager for clinical team’. Three features were strongly associated with improved outcomes. (1) ‘Appropriate parent involvement’, example association with Wellbeing (b = 4.5, 95% CI 2.0–7.0, p  = 0.001); (2) ‘Promotion of health self-efficacy’, example association with Satisfaction with Services (b = − 0.5, 95% CI – 0.9 to – 0.2, p  = 0.006); (3) ‘Meeting the adult team before transfer’, example associations with Participation (arranging services and aids) (odds ratio 5.2, 95% CI 2.1–12.8, p  < 0.001) and with Autonomy in Appointments (average 1.7 points higher, 95% CI 0.8–2.6, p  < 0.001). There was slightly less recruitment of participants from areas with greater socioeconomic deprivation, though not with respect to family composition. Conclusions Three features of transitional care were associated with improved outcomes. Results are likely to be generalisable because participants had three very different conditions, attending services at many UK sites. Results are relevant for clinicians as well as for commissioners and managers of health services. The challenge of introducing these three features across child and adult healthcare services, and the effects of doing so, should be assessed.

Measurement of aging is critical to understanding its causes and developing interventions, but little consensus exists on what components such measurements should include or how they perform in predicting mortality. The aim of this study was to identify factors of aging among a comprehensive set of indicators, and to evaluate their relative performance in predicting mortality. Measurements on 34 clinical, survey, and neuroimaging variables, along with epigenetic age markers, were obtained from two waves (2004–2021) of the Midlife in the United States (MIDUS) study. Mortality data was also available on 11875 participants, including 1908 twins. Factor analyses were used to identify aging factors, and these were used to predict mortality as of 2022. Twin data were used to model predictors of mortality within families. Factor analyses identified 9 major dimensions of aging: frailty, cognition, adiposity, glucose, blood pressure, inflammation, lipids, adaptive functioning, and neurological functioning. The strongest predictors of survival among the aging dimensions were cognition, adaptive functioning, and inflammation, and among the epigenetic markers, the decline-predictive markers (GrimAge and DunedinPACE). When entered in joint prediction models, cognition remained a significant predictor of mortality, but the epigenetic markers did not. Cognition, adaptive functioning, and inflammation remained significant predictors of mortality within twin pairs as well. Aging is a multidimensional construct, with cognition, adaptive functioning, and inflammation being the strongest predictors of survival among the aging dimensions examined. Their association with mortality is observed within families, suggesting that early developmental factors cannot entirely account for their association with survival. Interventions and assessments should prioritize cognition in measures of aging quality, along with adaptive functioning and inflammation.

Hepatocellular carcinoma (HCC) develops on the background of chronic hepatitis. Leukocytes found within the HCC microenvironment are implicated as regulators of tumour growth. We show that diethylnitrosamine (DEN)-induced murine HCC is attenuated by antibody-mediated depletion of hepatic neutrophils, the latter stimulating hepatocellular ROS and telomere DNA damage. We additionally report a previously unappreciated tumour suppressor function for hepatocellular nfkb1 operating via p50:p50 dimers and the co-repressor HDAC1. These anti-inflammatory proteins combine to transcriptionally repress hepatic expression of a S100A8/9, CXCL1 and CXCL2 neutrophil chemokine network. Loss of nfkb1 promotes ageing-associated chronic liver disease (CLD), characterized by steatosis, neutrophillia, fibrosis, hepatocyte telomere damage and HCC. Nfkb1 S340A/S340A mice carrying a mutation designed to selectively disrupt p50:p50:HDAC1 complexes are more susceptible to HCC; by contrast, mice lacking S100A9 express reduced neutrophil chemokines and are protected from HCC. Inhibiting neutrophil accumulation in CLD or targeting their tumour-promoting activities may offer therapeutic opportunities in HCC. The role of neutrophils in cancer development is not widely appreciated. Here, the authors show that NF-κB-deficient hepatocytes overproduce chemokines, leading to hepatocellular carcinoma due to excessive neutrophil recruitment, and that neutrophil depletion prevents liver cancer in these mice.

Myofibroblasts are critical cellular elements of wound healing generated at sites of injury by transdifferentiation of resident cells. A paradigm for this process is conversion of hepatic stellate cells (HSC) into hepatic myofibroblasts. Treatment of HSC with DNA methylation inhibitor 5-aza-2′-deoxycytidine (5-azadC) blocked transdifferentiation. 5-azadC also prevented loss of I κ B α and PPAR γ expression that occurs during transdifferentiation to allow acquisition of proinflammatory and profibrogenic characteristics. ChIP analysis revealed I κ B α promoter is associated with transcriptionally repressed chromatin that converts to an active state with 5-azadC treatment. The methyl-CpG-binding protein MeCP2 which promotes repressed chromatin structure is selectively detected in myofibroblasts of diseased liver. siRNA knockdown of MeCP2 elevated I κ B α promoter activity, mRNA and protein expression in myofibroblasts. MeCP2 interacts with I κ B α promoter via a methyl-CpG-dependent mechanism and recruitment into a CBF1 corepression complex. We conclude that MeCP2 and DNA methylation exert epigenetic control over hepatic wound healing and fibrogenesis

How forests respond to accelerated climate change will affect the terrestrial carbon cycle. To better understand these responses, more examples are needed to assess how tree growth rates react to abrupt changes in growing‐season temperatures. Here we use a natural experiment in which a glacier's fluctuations exposed a temperate rainforest to changes in summer temperatures of similar magnitude to those predicted to occur by 2050. We hypothesized that the onset of glacier‐accentuated temperature trends would act to increase the variance in stand‐level tree growth rates, a proxy for forest net primary productivity. Instead, dendrochronological records reveal that the growth rates of five, co‐occurring conifer species became less synchronous, and this diversification of species responses acted to reduce the variance and to increase the stability of community‐wide growth rates. These results warrant further inquiry into how climate‐induced changes in tree‐growth diversity may help stabilize future ecosystem services like forest carbon storage. Plain Language Summary Knowing how ecosystems responded to rapid climate changes in the past can help society prepare for the unprecedented rates of change expected in the future. Here, we take advantage of a natural experiment in which a fluctuating glacier caused a temperate rainforest to experience accentuated climate trends similar to those predicted to occur globally over the coming century. As climate changes became accentuated, tree species that once grew in unison shifted to more diversified growth patterns, which unexpectedly caused less variance and greater stability in community‐wide growth rates. Similar diversified growth responses may become important in stabilizing rates of forest carbon sequestration elsewhere. Key Points A glacier‐adjacent forest in Southeast Alaska serves as a natural climate change experiment Dendrochronology reveals that asynchronous species growth rates enhanced the forest‐wide growth stability during accelerated climate trends

Background: Early warning tools identify patients at risk of deterioration in hospitals. Electronic medical records in hospitals offer real-time data and the opportunity to automate early warning tools and provide real-time, dynamic risk estimates. Objective: This review describes published studies on the development, validation, and implementation of tools for predicting patient deterioration in general wards in hospitals. Methods: An electronic database search of peer reviewed journal papers from 2008-2020 identified studies reporting the use of tools and algorithms for predicting patient deterioration, defined by unplanned transfer to the intensive care unit, cardiac arrest, or death. Studies conducted solely in intensive care units, emergency departments, or single diagnosis patient groups were excluded. Results: A total of 46 publications were eligible for inclusion. These publications were heterogeneous in design, setting, and outcome measures. Most studies were retrospective studies using cohort data to develop, validate, or statistically evaluate prediction tools. The tools consisted of early warning, screening, or scoring systems based on physiologic data, as well as more complex algorithms developed to better represent real-time data, deal with complexities of longitudinal data, and warn of deterioration risk earlier. Only a few studies detailed the results of the implementation of deterioration warning tools. Conclusions: Despite relative progress in the development of algorithms to predict patient deterioration, the literature has not shown that the deployment or implementation of such algorithms is reproducibly associated with improvements in patient outcomes. Further work is needed to realize the potential of automated predictions and update dynamic risk estimates as part of an operational early warning system for inpatient deterioration.

Individual differences in children's executive functions (EFs) are relevant for a wide range of normal and atypical psychological outcomes across the life span, but the origins of variation in children's EFs are not well understood. We used data from a racially and socioeconomically diverse sample of 505 third- through eighth-grade twins and triplets from the Texas Twin Project to estimate genetic and environmental influences on a Common EF factor and on variance unique to four core EF domains: inhibition, switching, working memory, and updating. As has been previously demonstrated in young adults, the Common EF factor was 100% heritable, which indicates that correlations among the four EF domains are entirely attributable to shared genetic etiology. Nonshared environmental influences were evident for variance unique to individual domains. General EF may thus serve as an early life marker of genetic propensity for a range of functions and pathologies later in life.