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Physiology is regulated by interconnected cell and tissue circadian clocks. Disruption of the rhythms generated by the concerted activity of these clocks is associated with metabolic disease. Here we tested the interactions between clocks in two critical components of organismal metabolism, liver and skeletal muscle, by rescuing clock function either in each organ separately or in both organs simultaneously in otherwise clock-less mice. Experiments showed that individual clocks are partially sufficient for tissue glucose metabolism, yet the connections between both tissue clocks coupled to daily feeding rhythms support systemic glucose tolerance. This synergy relies in part on local transcriptional control of the glucose machinery, feeding-responsive signals such as insulin, and metabolic cycles that connect the muscle and liver. We posit that spatiotemporal mechanisms of muscle and liver play an essential role in the maintenance of systemic glucose homeostasis and that disrupting this diurnal coordination can contribute to metabolic disease.

Somatic mutations in blood indicative of clonal hematopoiesis of indeterminate potential (CHIP) are associated with an increased risk of hematologic malignancy, coronary artery disease, and all-cause mortality. Here we analyze the relation between CHIP status and incident peripheral artery disease (PAD) and atherosclerosis, using whole-exome sequencing and clinical data from the UK Biobank and Mass General Brigham Biobank. CHIP associated with incident PAD and atherosclerotic disease across multiple beds, with increased risk among individuals with CHIP driven by mutation in DNA Damage Repair (DDR) genes such as TP53 and PPM1D. To model the effects of DDR-induced CHIP on atherosclerosis, we used a competitive bone marrow transplantation strategy, and generated atherosclerosis-prone Ldlr-/- chimeric mice carrying 20% p53-deficient hematopoietic cells. The chimeric mice were analyzed 13-weeks post-grafting and showed increased aortic plaque size and accumulation of macrophages within the plaque, driven by increased proliferation of p53-deficient plaque macrophages. In summary, our findings highlight the role of CHIP as a broad driver of atherosclerosis across the entire arterial system beyond the coronary arteries, and provide genetic and experimental support for a direct causal contribution of TP53-mutant CHIP to atherosclerosis.

The goal of this study was to evaluate the measurement invariance of an adapted assessment of motivations for social withdrawal ("Social Preference Scale--Revised"; SPS-R) across cultural contexts and explore associations with loneliness. Participants were a large sample of university students (N = 4,397; M[subscript age] = 20.08 years, SD = 2.96; 66% females) from 10 countries (Argentina, Australia, Canada, China, India, Italy, South Korea, Norway, Turkey, and the United States). With this cross-cultural focus, we illustrate the "multiple-group factor analysis alignment method," an approach developed to assess measurement invariance when there are several groups. Results indicated approximate measurement invariance across the 10 country groups. Additional analyses indicated that overall, shyness, avoidance, and unsociability are three related, but distinct factors, with some notable country differences evident (e.g., in China, India, and Turkey). Shyness and avoidance were related positively to loneliness in all countries, but the strength of the association between shyness and loneliness differed in Italy and India relative to the other countries. Results also indicated that unsociability was related positively to loneliness in the United States only. Theoretical and assessment implications are discussed.

Life on Earth anticipates recurring 24-hour environmental cycles via genetically encoded molecular clocks active in all mammalian organs. Communication between these clocks controls circadian homeostasis. Intertissue communication is mediated, in part, by temporal coordination of metabolism. Here, we characterize the extent to which clocks in different organs control systemic metabolic rhythms, an area that remains largely unexplored. We analyzed the metabolome of serum from mice with tissue-specific expression of the clock gene Bmal1. Having functional hepatic and muscle clocks can only drive a minority (13%) of systemic metabolic rhythms. Conversely, limiting Bmal1 expression to the central pacemaker in the brain restores rhythms to 57% of circulatory metabolites. Rhythmic feeding imposed on clockless mice resulted in a similar rescue, indicating that the central clock mainly regulates metabolic rhythms via behavior. These findings explicate the circadian communication between tissues and highlight the importance of the central clock in governing those signals.

Executive Functions (EFs) describe a set of cognitive control abilities that help children to develop self-regulated behavior and do well in their schooling. The promotion of EFs in children at social risk is an area of relevance for neurosciences and education. On this basis, the present study set out to analyze a school-based intervention targeted to strengthening EFs in Argentine children at social risk. Participants were 69 children from 8 to 10 years old, from an urban-marginalized federal school in Mendoza. A quasi-experimental pre-test post-test design was used, with a control group. The cognitive intervention was embedded in the school curriculum and was carried out for a month and a half. The schoolchildren were evaluated before and after the intervention with EFs' neuropsychological tests. The main results showed that the group cognitive intervention was associated with gains in the schoolchildren's attention processes, although it did not favor other EFs, which could indicate moderate effectiveness. These data provide evidence in favor of ecological interventions as a way to promote attention development trajectories in children at social risk, and in turn, draw up guidelines to reflect on the design and the modalities of school-based interventions.

The mammalian circadian clock, expressed throughout the brain and body, controls daily metabolic homeostasis. Clock function in peripheral tissues is required, but not sufficient, for this task. Because of the lack of specialized animal models, it is unclear how tissue clocks interact with extrinsic signals to drive molecular oscillations. Here, we isolated the interaction between feeding and the liver clock by reconstituting Bmal1 exclusively in hepatocytes (Liver-RE), in otherwise clock-less mice, and controlling timing of food intake. We found that the cooperative action of BMAL1 and the transcription factor CEBPB regulates daily liver metabolic transcriptional programs. Functionally, the liver clock and feeding rhythm are sufficient to drive temporal carbohydrate homeostasis. By contrast, liver rhythms tied to redox and lipid metabolism required communication with the skeletal muscle clock, demonstrating peripheral clock cross-talk. Our results highlight how the inner workings of the clock system rely on communicating signals to maintain daily metabolism.

Ketone bodies are bioactive metabolites that function as energy substrates, signaling molecules, and regulators of histone modifications. β-hydroxybutyrate (β-OHB) is utilized in lysine β-hydroxybutyrylation (Kbhb) of histones, and associates with starvation-responsive genes, effectively coupling ketogenic metabolism with gene expression. The emerging diversity of the lysine acylation landscape prompted us to investigate the full proteomic impact of Kbhb. Global protein Kbhb is induced in a tissue-specific manner by a variety of interventions that evoke β-OHB. Mass spectrometry analysis of the β-hydroxybutyrylome in mouse liver revealed 891 sites of Kbhb within 267 proteins enriched for fatty acid, amino acid, detoxification, and one-carbon metabolic pathways. Kbhb inhibits S-adenosyl-L-homocysteine hydrolase (AHCY), a rate-limiting enzyme of the methionine cycle, in parallel with altered metabolite levels. Our results illuminate the role of Kbhb in hepatic metabolism under ketogenic conditions and demonstrate a functional consequence of this modification on a central metabolic enzyme.

Circadian gene expression driven by transcription activators CLOCK and BMAL1 is intimately associated with dynamic chromatin remodeling. However, how cellular metabolism directs circadian chromatin remodeling is virtually unexplored. We report that the S-adenosylhomocysteine (SAH) hydrolyzing enzyme adenosylhomocysteinase (AHCY) cyclically associates to CLOCK-BMAL1 at chromatin sites and promotes circadian transcriptional activity. SAH is a potent feedback inhibitor of S-adenosylmethionine (SAM)-dependent methyltransferases, and timely hydrolysis of SAH by AHCY is critical to sustain methylation reactions. We show that AHCY is essential for cyclic H3K4 trimethylation, genome-wide recruitment of BMAL1 to chromatin, and subsequent circadian transcription. Depletion or targeted pharmacological inhibition of AHCY in mammalian cells markedly decreases the amplitude of circadian gene expression. In mice, pharmacological inhibition of AHCY in the hypothalamus alters circadian locomotor activity and rhythmic transcription within the suprachiasmatic nucleus. These results reveal a previously unappreciated connection between cellular metabolism, chromatin dynamics, and circadian regulation.

Circadian rhythms govern physiology and metabolism, leading to controlled homeostasis. We discuss the impact of circadian rhythms on society and the challenges for the imminent future of personalized medicine.

Metabolic syndrome has increased at a worrisome level. Lifestyle changes are not sufficient to prevent and improve the adverse effects of obesity, thus novel interventions are necessary. The aim of this study was to investigate the use and metabolic outcomes of a non-pharmacological intervention in a high-fat diet (HFD) fed mouse model, capable of recapitulating key aspects of metabolic syndrome. We show that Policaptil Gel Retard has remarkable, beneficial effects on metabolic dysfunction caused by consumption of HFD. We describe the mechanism by which such effects are obtained, highlighting the fact that the amelioration of metabolic function observed upon Policaptil Gel Retard administration is profound and of systemic nature, despite being originated by sequestering, therefore non-pharmacological events elicited in the gut lumen.

Binge drinking and chronic exposure to ethanol contribute to alcoholic liver diseases (ALDs). A potential link between ALDs and circadian disruption has been observed, though how different patterns of alcohol consumption differentially impact hepatic circadian metabolism remains virtually unexplored. Using acute versus chronic ethanol feeding, we reveal differential reprogramming of the circadian transcriptome in the liver. Specifically, rewiring of diurnal SREBP transcriptional pathway leads to distinct hepatic signatures in acetyl-CoA metabolism that are translated into the subcellular patterns of protein acetylation. Thus, distinct drinking patterns of alcohol dictate differential adaptation of hepatic circadian metabolism.

The circadian clock is an endogenous, time-tracking system that directs multiple metabolic and physiological functions required for homeostasis. The master or central clock located within the suprachiasmatic nucleus in the hypothalamus governs peripheral clocks present in all systemic tissues, contributing to their alignment and ultimately to temporal coordination of physiology. Accumulating evidence reveals the presence of additional clocks in the brain and suggests the possibility that circadian circuits may feed back to these from the periphery. Here, we highlight recent advances in the communications between clocks and discuss how they relate to circadian physiology and metabolism.

Fatty acid uptake and altered metabolism constitute hallmarks of metastasis.sup.1,2, yet evidence of the underlying biology, as well as whether all dietary fatty acids are prometastatic, is lacking. Here we show that dietary palmitic acid (PA), but not oleic acid or linoleic acid, promotes metastasis in oral carcinomas and melanoma in mice. Tumours from mice that were fed a short-term palm-oil-rich diet (PA), or tumour cells that were briefly exposed to PA in vitro, remained highly metastatic even after being serially transplanted (without further exposure to high levels of PA). This PA-induced prometastatic memory requires the fatty acid transporter CD36 and is associated with the stable deposition of histone H3 lysine 4 trimethylation by the methyltransferase Set1A (as part of the COMPASS complex (Set1A/COMPASS)). Bulk, single-cell and positional RNA-sequencing analyses indicate that genes with this prometastatic memory predominantly relate to a neural signature that stimulates intratumoural Schwann cells and innervation, two parameters that are strongly correlated with metastasis but are aetiologically poorly understood.sup.3,4. Mechanistically, tumour-associated Schwann cells secrete a specialized proregenerative extracellular matrix, the ablation of which inhibits metastasis initiation. Both the PA-induced memory of this proneural signature and its long-term boost in metastasis require the transcription factor EGR2 and the glial-cell-stimulating peptide galanin. In summary, we provide evidence that a dietary metabolite induces stable transcriptional and chromatin changes that lead to a long-term stimulation of metastasis, and that this is related to a proregenerative state of tumour-activated Schwann cells. Palmitic acid induces stable transcriptional and chromatin changes that lead to long-term stimulation of metastasis in orthotopic models of cancer through the secretion by tumour-associated Schwann cells of a specialized proregenerative extracellular matrix, the ablation of which inhibits metastasis initiation., Author(s): Gloria Pascual [sup.1] , Diana Domínguez [sup.1] , Marc Elosúa-Bayes [sup.2] , Felipe Beckedorff [sup.3] , Carmelo Laudanna [sup.1] , Claudia Bigas [sup.1] , Delphine Douillet [sup.4] , Carolina [...]

Cardiac hypertrophy, initially an adaptive response of the myocardium to stress, can progress to heart failure. The epigenetic signature underlying this phenomenon is poorly understood. Here, we report on the genome-wide distribution of seven histone modifications in adult mouse cardiomyocytes subjected to a prohypertrophy stimulus in vivo. We found a set of promoters with an epigenetic pattern that distinguishes specific functional classes of genes regulated in hypertrophy and identified 9,207 candidate active enhancers whose activity was modulated. We also analyzed the transcriptional network within which these genetic elements act to orchestrate hypertrophy gene expression, finding a role for myocyte enhancer factor (MEF)2C and MEF2A in regulating enhancers. We propose that the epigenetic landscape is a key determinant of gene expression reprogramming in cardiac hypertrophy and provide a basis for understanding the role of chromatin in regulating this phenomenon.

Introduction: Attentional Efficiency (AE) is defined as the accuracy with which a child discriminates, from a group of similar stimuli, those which are identical to a model, within a certain time period. Various factors may be associated with a higher or lower AE, among which is socioeconomic context. The goals of this study were: 1) To describe argentine students' attentional efficiency according to the type of school (private-public), according to the students' age and gender and according to the educational and occupational level of the students' mothers; 2) To compare attentional efficiency according to the type of school (private-public), students' age and gender and educational and occupational level of their mothers. Method: A comparative cross-sectional study was used. Two groups of 10-to-13-year-old students were formed: 74 from public schools (Mean 11.26; S.D. 0.93; 53% boys and 47% girls) and 67 students (Mean 11.49; S.D. 1.05; 54% boys and 46% girls) from a private schools. Type of school is categorized by Mendoza general Board of Education. Private schools are located in urban areas. Public schools are situated in peripheral areas in contexts of social vulnerability. Social vulnerability is a condition of social risk that hinders, either immediately or in the long term, the satisfaction of welfare needs, both in terms of survival and quality of life. In this kind of contexts there are lower levels of education in the families, poor working conditions and/or unemployment, families dysfunction and poor mother and child health services. All of these situations lead to unequal social conditions and decreasing opportunities for children's development. There are 10 public schools in peripheral areas and 25 private schools in urban areas at Guaymallen, Mendoza. The participants were from two schools, one from public and other from private school. Results: The results revealed lower attentional efficiency in school children attending public schools than in those attending a private schools. No statistically-significant differences were observed in attentional efficiency in relation to the gender or age of the participating children. The students whose mothers had attained a university level of education showed a significantly higher attentional performance, in contrast with those students whose mothers had only attended primary school. In addition, the students whose mothers were employed showed a significantly higher attentional performance in contrast with those children whose mothers were unemployed. Nevertheless, no statistically-significant differences were observed in attentional efficiency in relation to occupational level of qualification of students' mothers. Conclusion: This study concurs with research showing the influence of socioeconomic context on children's attentional performance, contributing evidence on the need to adjust educational practices and cognitive interventions to boost children's academic achievements.

A growing body of research has documented factors that predict happiness in adults; however, studies on children's happiness have just begun. The aim of this study was to explore Argentine children's reasons for happiness. The sample included 120 children between the ages of 7 and 9 years (M = 8.03; SD = 0.72) who attended Argentine public schools. The Face Scale was used to evaluate how children assess happiness and a focused interview was conducted to obtain their spontaneous verbal descriptions of what made them happy. A content analysis was then conducted was after the interviews. Most of the children reckoned that family and friendships were the main sources of happiness. They also mentioned different kinds of activities as sources of happiness, like school, recreation and leisure activities, and owning and playing with pets. These findings may be useful for designing mental health programs aimed at promoting positive socio-emotional development during childhood. Keywords: Happiness, Children, Socio-emotional developmental, Well-being, Poverty, How do Argentine children assess their happiness? What makes them happy? What are the self-reported reasons they feel happy? These are recurrent inquiries in the field of psychology and a [...]