Méthylation de gènes liés au stress à travers différents tissus périphériques humains, et la pertinence pour le fonctionnement cérébral

Différents facteurs environnementaux peuvent influencer l'expression génétique via des modifications épigénétiques telles que la méthylation de l'ADN. Un nombre grandissant d’études épigénétiques psychiatriques font usage de mesures périphériques de méthylation de l'ADN pour la compréhension de la fonction cérébrale et du comportement humain. La méthylation périphérique au niveau de gènes liés au stress a été associée à l’adversité précoce et à la vulnérabilité au développement de troubles de santé mentale. Les échantillons périphériques couramment utilisés sont dérivés du sang, de la salive ou des cellules buccales. Toutefois, nous ne savons toujours pas à quel point les niveaux de méthylation à travers différents tissus périphériques intra-individuels, ainsi que leurs associations respectives avec le fonctionnement cérébral et le comportement, sont comparables. L'objectif de cette étude était d'examiner les associations entre la méthylation périphérique de deux gènes liés au stress, NR3C1 et FKBP5, la connectivité cérébrale au repos et la fonction cérébrale en réponse à des stimuli émotionnels chez 44 adultes en santé. De plus, la force de ces associations a été comparée entre les échantillons de salive et de cellules buccales. Finalement, la stabilité de la méthylation de ces deux gènes à travers différents tissus périphériques, et à travers le temps, a été vérifiée. Les résultats de cette étude démontrent une association positive entre la méthylation salivaire de NR3C1 et la connectivité fronto-limbique au repos, et entre la méthylation de FKBP5 dérivée des cellules buccales et la réponse fronto-médiane bilatérale et parahippocampique gauche à des stimuli de tristesse. Les niveaux de méthylation de FKBP5 dérivés des cellules buccales et de la salive étaient significativement corrélés, des résultats qui n’ont pas été répliqués pour le gène NR3C1. Finalement, les niveaux de méthylation des deux gènes sont demeurés stables pour une période de 2 ans. Nos résultats ouvrent à la possibilité que la stabilité de la méthylation à travers différents tissus périphériques, ainsi que les associations entre la méthylation périphérique et différents processus mentaux, pourraient être spécifiques aux gènes étudiés et aux types de cellules périphériques utilisés.Early environmental factors influence gene expression via epigenetic modifications such as DNA methylation. Peripheral DNA methylation of stress-related genes has been associated with early adversity and vulnerability to different mental health outcomes. Commonly used peripheral samples are derived from blood, saliva or buccal cells. However, it is still not known whether peripherally derived DNA methylation in a specific cell type is most strongly associated with human brain processes and behavior. The aim of the present study was to investigate the association between peripherally derived NR3C1 and FKBP5 methylation, frontal-limbic brain function and resting-state functional connectivity in healthy adults, and to compare the strength of these associations across different peripheral tissue samples. Additionally, cross-tissue convergence and two-year stability of DNA methylation were assessed for both genes. Saliva derived NR3C1 methylation was associated with greater fronto-limbic resting-state connectivity, whereas buccal cell-derived FKBP5 methylation was positively associated with bilateral middle frontal and left parahippocampal response to sad emotional stimuli. Saliva- and buccal cellderived FKBP5 methylation levels were significantly correlated to one another, and methylation in both genes remained stable for two years. Results regarding cross-tissue convergence and were not replicated for NR3C1. These findings suggest that methylation in different genes and in different peripheral tissues might differently capture brain processes, and that DNA methylation tissue specificity and time stability might in turn be gene specific

Associations between daily mood states and brain gray matter volume, resting-state functional connectivity and task-based activity in healthy adults

Numerous studies have shown differences in the functioning in the areas of the frontal-limbic circuitry between depressed patients and controls. However, current knowledge on frontal-limbic neural substrates of individual differences in mood states in everyday life in healthy individuals is scarce. The present study investigates anatomical, resting-state, and functional neural correlates of daily mood states in healthy individuals. We expected to observe associations between mood and the frontal-limbic circuitry and the default-mode network (DMN). A total of 42 healthy adults (19 men, 23 women; 34 ± 1.2 years) regularly followed for behavior and psychosocial functioning since age of 6, underwent a functional magnetic resonance imaging scan, and completed a daily diary of mood states and related cognitions for 5 consecutive days. Results showed that individuals with smaller left hippocampal gray matter volumes experienced more negative mood and rumination in their daily life. Greater resting-state functional connectivity (rsFC) within the DMN, namely between posterior cingulate cortex (PCC) and medial prefrontal cortex regions as well as between PCC and precuneus, was associated with both greater negative and positive mood states in daily life. These rsFC results could be indicative of the role of the DMN regional functioning in emotional arousal, irrespective of valence. Lastly, greater daily positive mood was associated with greater activation in response to negative emotional stimuli in the precentral gyri, previously linked to emotional interference on cognitive control. Altogether, present findings might reflect neural mechanisms underlying daily affect and cognition among healthy individuals

A high-resolution map of human evolutionary constraint using 29 mammals.

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease

Analysis of the African coelacanth genome sheds light on tetrapod evolution

It was a zoological sensation when a living specimen of the coelacanth was first discovered in 1938, as this lineage of lobe-finned fish was thought to have gone extinct 70 million years ago. The modern coelacanth looks remarkably similar to many of its ancient relatives, and its evolutionary proximity to our own fish ancestors provides a glimpse of the fish that first walked on land. Here we report the genome sequence of the African coelacanth, Latimeria chalumnae. Through a phylogenomic analysis, we conclude that the lungfish, and not the coelacanth, is the closest living relative of tetrapods. Coelacanth protein-coding genes are significantly more slowly evolving than those of tetrapods, unlike other genomic features . Analyses of changes in genes and regulatory elements during the vertebrate adaptation to land highlight genes involved in immunity, nitrogen excretion and the development of fins, tail, ear, eye, brain, and olfaction. Functional assays of enhancers involved in the fin-to-limb transition and in the emergence of extra-embryonic tissues demonstrate the importance of the coelacanth genome as a blueprint for understanding tetrapod evolution

A High-Resolution Map of Human Evolutionary Constraint Using 29 Mammals

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ~4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ~60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease.National Human Genome Research Institute (U.S.)National Institute of General Medical Sciences (U.S.) (Grant number GM82901)National Science Foundation (U.S.). Postdoctural Fellowship (Award 0905968)National Science Foundation (U.S.). Career (0644282)National Institutes of Health (U.S.) (R01-HG004037)Alfred P. Sloan Foundation.Austrian Science Fund. Erwin Schrodinger Fellowshi

Global disparities in surgeons’ workloads, academic engagement and rest periods: the on-calL shIft fOr geNEral SurgeonS (LIONESS) study

: The workload of general surgeons is multifaceted, encompassing not only surgical procedures but also a myriad of other responsibilities. From April to May 2023, we conducted a CHERRIES-compliant internet-based survey analyzing clinical practice, academic engagement, and post-on-call rest. The questionnaire featured six sections with 35 questions. Statistical analysis used Chi-square tests, ANOVA, and logistic regression (SPSS® v. 28). The survey received a total of 1.046 responses (65.4%). Over 78.0% of responders came from Europe, 65.1% came from a general surgery unit; 92.8% of European and 87.5% of North American respondents were involved in research, compared to 71.7% in Africa. Europe led in publishing research studies (6.6 ± 8.6 yearly). Teaching involvement was high in North America (100%) and Africa (91.7%). Surgeons reported an average of 6.7 ± 4.9 on-call shifts per month, with European and North American surgeons experiencing 6.5 ± 4.9 and 7.8 ± 4.1 on-calls monthly, respectively. African surgeons had the highest on-call frequency (8.7 ± 6.1). Post-on-call, only 35.1% of respondents received a day off. Europeans were most likely (40%) to have a day off, while African surgeons were least likely (6.7%). On the adjusted multivariable analysis HDI (Human Development Index) (aOR 1.993) hospital capacity > 400 beds (aOR 2.423), working in a specialty surgery unit (aOR 2.087), and making the on-call in-house (aOR 5.446), significantly predicted the likelihood of having a day off after an on-call shift. Our study revealed critical insights into the disparities in workload, access to research, and professional opportunities for surgeons across different continents, underscored by the HDI

The genomic substrate for adaptive radiation in African cichlid fish

Cichlid fishes are famous for large, diverse and replicated adaptive radiations in the Great Lakes of East Africa. To understand the molecular mechanisms underlying cichlid phenotypic diversity, we sequenced the genomes and transcriptomes of five lineages of African cichlids: the Nile tilapia (Oreochromis niloticus), an ancestral lineage with low diversity; and four members of the East African lineage: Neolamprologus brichardi/pulcher (older radiation, Lake Tanganyika), Metriaclima zebra (recent radiation, Lake Malawi), Pundamilia nyererei (very recent radiation, Lake Victoria), and Astatotilapia burtoni (riverine species around Lake Tanganyika). We found an excess of gene duplications in the East African lineage compared to tilapia and other teleosts, an abundance of non-coding element divergence, accelerated coding sequence evolution, expression divergence associated with transposable element insertions, and regulation by novel microRNAs. In addition, we analysed sequence data from sixty individuals representing six closely related species from Lake Victoria, and show genome-wide diversifying selection on coding and regulatory variants, some of which were recruited from ancient polymorphisms. We conclude that a number of molecular mechanisms shaped East African cichlid genomes, and that amassing of standing variation during periods of relaxed purifying selection may have been important in facilitating subsequent evolutionary diversification

Body Shame, Psychological Flexibility, and Binge Eating

A cross-sectional study exploring the effects of body image shame on binge eating and the moderating role of body image psychological flexibilit

Associations Between Daily Mood States and Brain Gray Matter Volume, Resting-State Functional Connectivity and Task-Based Activity in Healthy Adults

Numerous studies have shown differences in the functioning in the areas of the frontal-limbic circuitry between depressed patients and controls. However, current knowledge on frontal-limbic neural substrates of individual differences in mood states in everyday life in healthy individuals is scarce. The present study investigates anatomical, resting-state, and functional neural correlates of daily mood states in healthy individuals. We expected to observe associations between mood and the frontal-limbic circuitry and the default-mode network (DMN). A total of 42 healthy adults (19 men, 23 women; 34 ± 1.2 years) regularly followed for behavior and psychosocial functioning since age of 6, underwent a functional magnetic resonance imaging scan, and completed a daily diary of mood states and related cognitions for 5 consecutive days. Results showed that individuals with smaller left hippocampal gray matter volumes experienced more negative mood and rumination in their daily life. Greater resting-state functional connectivity (rsFC) within the DMN, namely between posterior cingulate cortex (PCC) and medial prefrontal cortex regions as well as between PCC and precuneus, was associated with both greater negative and positive mood states in daily life. These rsFC results could be indicative of the role of the DMN regional functioning in emotional arousal, irrespective of valence. Lastly, greater daily positive mood was associated with greater activation in response to negative emotional stimuli in the precentral gyri, previously linked to emotional interference on cognitive control. Altogether, present findings might reflect neural mechanisms underlying daily affect and cognition among healthy individuals