Prospective Association of Morning Salivary Cortisol with Depressive Symptoms in Mid-Life: A Life-Course Study

Objective Associations of cortisol and depression vary at different life-stages, yet population-based, prospective studies are scarce. We aimed to assess associations of morning cortisol with depressive symptoms in mid-life taking account of lifetime psychological health. Methods Participants were 5,403 men and women from the 1958 British Birth Cohort whose salivary cortisol was assessed at 45y (45min after waking (T1) and 3h later (T2)) and who completed the 5-item Mental-Health Index (MHI-5) about depressive symptoms at age 50y. Lifetime psychological health was identified from child and adult measures. Results For women, higher T2 cortisol at 45y predicted depression (MHI-5 scores ≤52) at 50y (odds ratio [OR]=1.17; 95% confidence intervals [CI] 1.05,1.30 per standard deviation increase in T2 cortisol), attenuating when adjusted for current (45y) and previous (7-42y) psychological health (OR=1.11; 95% CI 0.98, 1.24). Similarly, an association in women of flatter cortisol delta (T2-T1) with depressive symptoms at 50y weakened after adjustment for current (45y) and previous (7-42y) psychological health. For men, lower T2 cortisol at 45y predicted greater depressive symptoms at 50y and the association strengthened when adjusted for lifetime psychological health. Likewise, lower cortisol AUC predicted higher risk of depression for men after adjusting for prior psychological health (OR=0.85; CI 0.72, 1.00). Associations were largely unaltered by control for covariates. Conclusions In women, higher cortisol in late morning at 45y is prospectively associated with depressive symptoms at 50y through a link with lifetime psychological health. In men, lower cortisol predicts subsequent symptoms, independent of depressive history

Child Neglect and Maltreatment and Childhood-to-Adulthood Cognition and Mental Health in a Prospective Birth Cohort

OBJECTIVE: Life-long adverse effects of childhood maltreatment on mental health are well established, but effects on child-to-adulthood cognition and related educational attainment have yet to be examined in the general population. We aimed to establish whether different forms of child maltreatment are associated with poorer cognition and educational qualifications in childhood/adolescence and whether associations persist to midlife, parallel to associations for mental health. METHOD: Cognitive abilities at ages 7, 11, and 16 years (math, reading, and general intellectual ability) and 50 years (immediate/delayed memory, verbal fluency, processing speed) were assessed using standardized tests, and qualifications by age 42 were self-reported. Information on childhood maltreatment (neglect and abuse: sexual, physical, psychological, witnessed), cognition, and mental health was available for 8,928 participants in the 1958 British Birth Cohort. RESULTS: We found a strong association of child neglect with cognitive deficits from childhood to adulthood. To illustrate, the most neglected 6% of the population (score ≥4) had a 0.60 (95% CI = 0.56-0.68) SD lower cognitive score at age 16 and a 0.28 (95% CI = 0.20-0.36) SD deficit at age 50 years relative to the non-neglected participants (score = 0) after adjustment for confounding factors and mental health, and they also had increased risk of poor qualifications (i.e., none/low versus degree-level). Childhood neglect and all forms of abuse were associated with poorer child-to-adulthood mental health, but abuse was mostly unrelated to cognitive abilities. CONCLUSION: The study provides novel data that child neglect is associated with cognitive deficits in childhood/adolescence and decades later in adulthood, independent of mental health, and highlights the lifelong burden of child neglect on cognitive abilities and mental health

Diurnal cortisol and mental well-being in middle and older age: Evidence from four cohort studies

© 2017 Article author(s). Objectives We conducted an individual participant meta-analysis to test the hypothesis that cortisol patterns indicative of dysregulated hypothalamic-pituitary-adrenal axis functioning would be prospectively associated with poorer well-being at follow-up. Setting Four large UK-based cohort studies. Participants Those providing valid salivary or serum cortisol samples (n=7515 for morning cortisol; n=1612 for cortisol awakening response) at baseline (age 44-82) and well-being data on the Warwick Edinburgh Mental Wellbeing Scale at follow-up (0-8 years) were included. Results Well-being was not associated with morning cortisol, diurnal slope or awakening response though a borderline association with evening cortisol was found. Adjusting for sex and follow-up time, each 1 SD increase in evening cortisol was associated with a â'0.47 (95% CI â'1.00 to 0.05) point lower well-being. This was attenuated by adjustment for body mass index, smoking and socioeconomic position. Between-study heterogeneity was low. Conclusions This study does not support the hypothesis that diurnal cortisol is prospectively associated with well-being up to 8 years later. However, replication in prospective studies with cortisol samples over multiple days is required

Slx8 removes Pli1-dependent protein-SUMO conjugates including SUMOylated Topoisomerase I to promote genome stability

Peer reviewedPublisher PD

Dysregulation of the hypothalamic pituitary adrenal (HPA) axis and cognitive capability at older ages: individual participant meta-analysis of five cohorts

Evidence on the association between functioning of the hypothalamic pituitary adrenal (HPA) axis and cognitive capability at older ages is mixed. We undertook a systematic review (until October 2016) and individual participant data (IPD) meta-analysis to test if dysregulation of the HPA axis is associated with worse cognitive capability. Five cohort studies were included in the IPD meta-analysis of diurnal cortisol patterns with crystallised and fluid cognitive ability. Higher night time cortisol was associated with worse fluid ability (standardised coefficient per SD increase −0.063, 95% CI −0.124, −0.002, P = 0.04; I 2 = 79.9%; age and gender adjusted). A larger diurnal drop was associated with better fluid ability (standardised coefficient per SD increase 0.037, 95% CI 0.008, 0.065, P = 0.01; I 2 = 49.2%; age and gender adjusted). A bigger cortisol awakening response (CAR) was weakly associated with better fluid (P = 0.09; I 2 = 0.0%; age and gender adjusted) and crystallised (P = 0.10; I 2 = 0.0%; age and gender adjusted) ability. There is weak evidence that a greater diurnal decline of the HPA axis and a larger CAR are associated with improvements in cognition at older ages. As associations are cross-sectional, we cannot rule out reverse causation

Mutations in the latent TGF-beta binding protein 3 (LTBP3) gene cause brachyolmia with amelogenesis imperfecta

Inherited dental malformations constitute a clinically and genetically heterogeneous group of disorders. Here, we report on four families, three of them consanguineous, with an identical phenotype, characterized by significant short stature with brachyolmia and hypoplastic amelogenesis imperfecta (AI) with almost absent enamel. This phenotype was first described in 1996 by Verloes et al. as an autosomal recessive form of brachyolmia associated with AI. Whole-exome sequencing resulted in the identification of recessive hypomorphic mutations including deletion, nonsense and splice mutations, in the LTBP3 gene, which is involved in the TGF-beta signaling pathway. We further investigated gene expression during mouse development and tooth formation. Differentiated ameloblasts synthesizing enamel matrix proteins and odontoblasts expressed the gene. Study of an available knockout mouse model showed that the mutant mice displayed very thin to absent enamel in both incisors and molars, hereby recapitulating the AI phenotype in the human disorder

Loss of ubiquitin E2 Ube2w rescues hypersensitivity of Rnf4 mutant cells to DNA damage

SUMO and ubiquitin play important roles in the response of cells to DNA damage. These pathways are linked by the SUMO Targeted ubiquitin Ligase Rnf4 that catalyses transfer of ubiquitin from a ubiquitin loaded E2 conjugating enzyme to a polySUMO modified substrate. Rnf4 can functionally interact with multiple E2s, including Ube2w, in vitro. Chicken cells lacking Rnf4 are hypersensitive to hyroxyurea, DNA alkylating drugs and DNA crosslinking agents, but this sensitivity is suppressed by simultaneous depletion of Ube2w. Cells depleted of Ube2w alone are not hypersensitive to the same DNA damaging agents. Similar results were also obtained in human cells. These data indicate that Ube2w does not have an essential role in the DNA damage response, but is deleterious in the absence of Rnf4. Thus, although Rnf4 and Ube2w functionally interact in vitro, our genetic experiments indicate that in response to DNA damage Ube2w and Rnf4 function in distinct pathways

Transcriptional Activation of the Adenoviral Genome Is Mediated by Capsid Protein VI

Gene expression of DNA viruses requires nuclear import of the viral genome. Human Adenoviruses (Ads), like most DNA viruses, encode factors within early transcription units promoting their own gene expression and counteracting cellular antiviral defense mechanisms. The cellular transcriptional repressor Daxx prevents viral gene expression through the assembly of repressive chromatin remodeling complexes targeting incoming viral genomes. However, it has remained unclear how initial transcriptional activation of the adenoviral genome is achieved. Here we show that Daxx mediated repression of the immediate early Ad E1A promoter is efficiently counteracted by the capsid protein VI. This requires a conserved PPxY motif in protein VI. Capsid proteins from other DNA viruses were also shown to activate the Ad E1A promoter independent of Ad gene expression and support virus replication. Our results show how Ad entry is connected to transcriptional activation of their genome in the nucleus. Our data further suggest a common principle for genome activation of DNA viruses by counteracting Daxx related repressive mechanisms through virion proteins

SUMO-Targeted Ubiquitin Ligase, Rad60, and Nse2 SUMO Ligase Suppress Spontaneous Top1–Mediated DNA Damage and Genome Instability

Through as yet undefined proteins and pathways, the SUMO-targeted ubiquitin ligase (STUbL) suppresses genomic instability by ubiquitinating SUMO conjugated proteins and driving their proteasomal destruction. Here, we identify a critical function for fission yeast STUbL in suppressing spontaneous and chemically induced topoisomerase I (Top1)–mediated DNA damage. Strikingly, cells with reduced STUbL activity are dependent on tyrosyl–DNA phosphodiesterase 1 (Tdp1). This is notable, as cells lacking Tdp1 are largely aphenotypic in the vegetative cell cycle due to the existence of alternative pathways for the removal of covalent Top1–DNA adducts (Top1cc). We further identify Rad60, a SUMO mimetic and STUbL-interacting protein, and the SUMO E3 ligase Nse2 as critical Top1cc repair factors in cells lacking Tdp1. Detection of Top1ccs using chromatin immunoprecipitation and quantitative PCR shows that they are elevated in cells lacking Tdp1 and STUbL, Rad60, or Nse2 SUMO ligase activity. These unrepaired Top1ccs are shown to cause DNA damage, hyper-recombination, and checkpoint-mediated cell cycle arrest. We further determine that Tdp1 and the nucleotide excision repair endonuclease Rad16-Swi10 initiate the major Top1cc repair pathways of fission yeast. Tdp1-based repair is the predominant activity outside S phase, likely acting on transcription-coupled Top1cc. Epistasis analyses suggest that STUbL, Rad60, and Nse2 facilitate the Rad16-Swi10 pathway, parallel to Tdp1. Collectively, these results reveal a unified role for STUbL, Rad60, and Nse2 in protecting genome stability against spontaneous Top1-mediated DNA damage