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Early life stress (ELS) is a risk factor for the development of depression in adolescence; the mediating neurobiological mechanisms, however, are unknown. In this study, we examined in early pubertal youth the associations among ELS, cortisol stress responsivity, and white matter microstructure of the uncinate fasciculus and the fornix, two key frontolimbic tracts; we also tested whether and how these variables predicted depressive symptoms in later puberty. A total of 208 participants (117 females; M age = 11.37 years; M Tanner stage = 2.03) provided data across two or more assessment modalities: ELS; salivary cortisol levels during a psychosocial stress task; diffusion magnetic resonance imaging; and depressive symptoms. In early puberty there were significant associations between higher ELS and decreased cortisol production, and between decreased cortisol production and increased fractional anisotropy in the uncinate fasciculus. Further, increased fractional anisotropy in the uncinate fasciculus predicted higher depressive symptoms in later puberty, above and beyond earlier symptoms. In post hoc analyses, we found that sex moderated several additional associations. We discuss these findings within a broader conceptual model linking ELS, emotion dysregulation, and depression across the transition through puberty, and contend that brain circuits implicated in the control of hypothalamic-pituitary-adrenal axis function should be a focus of continued research.
Control of DNA copy number is essential to maintain genome stability and ensure proper cell and tissue function. In polyploid cells, the SNF2-domain-containing SUUR protein inhibits replication fork progression within specific regions of the genome to promote DNA underreplication. While dissecting the function of SUUR's SNF2 domain, we identified an interaction between SUUR and Rif1. Rif1 has many roles in DNA metabolism and regulates the replication timing program. We demonstrate that repression of DNA replication is dependent on Rif1. Rif1 localizes to active replication forks in a partially SUUR-dependent manner and directly regulates replication fork progression. Importantly, SUUR associates with replication forks in the absence of Rif1, indicating that Rif1 acts downstream of SUUR to inhibit fork progression. Our findings uncover an unrecognized function of the Rif1 protein as a regulator of replication fork progression.
© 2018, Munden et al.
One of the major concerns in oncology lies in the ability to detect recurrences at their earliest stage to increase the likelihood of cure following second line, or salvage, therapy. Although human papillomavirus (HPV)-driven oropharyngeal cancers have a good prognosis, 20-25% of patients will recur within 5 years of treatment and a significant portion will die from their disease. In recent years, great effort has been put toward evaluating the potential clinical utility of HPV-related biomarkers for early diagnosis of recurrent disease. Indeed, following completion of treatment, detection of HPV-DNA in oral rinses or blood and serologic assays against HPV oncoproteins could be helpful to track residual disease or recurrence. Several recent studies have reported promising findings, thus potentially paving the way for the use of biomarkers in the management of HPV-OPC. In this review, we evaluate and discuss the current knowledge on this topic and provide some directions for future research.
Copyright © 2018 Elsevier Ltd. All rights reserved.
We recently reported the case of a young patient with multisystem failure carrying a de novo mutation in SLC12A2, the gene encoding the Na-K-2Cl cotransporter-1 (NKCC1). Heterologous expression studies in nonepithelial cells failed to demonstrate dominant-negative effects. In this study, we examined expression of the mutant cotransporter in epithelial cells. Using Madin-Darby canine kidney (MDCK) cells grown on glass coverslips, permeabilized support, and Matrigel, we show that the fluorescently tagged mutant cotransporter is expressed in cytoplasm and at the apical membrane and affects epithelium integrity. Expression of the mutant transporter at the apical membrane also results in the mislocalization of some of the wild-type transporter to the apical membrane. This mistargeting is specific to NKCC1 as the Na-K-ATPase remains localized on the basolateral membrane. To assess transporter localization in vivo, we created a mouse model using CRISPR/cas9 that reproduces the 11 bp deletion in exon 22 of Slc12a2. Although the mice do not display an overt phenotype, we show that the colon and salivary gland expresses wild-type NKCC1 abundantly at the apical pole, confirming the data obtained in cultured epithelial cells. Enough cotransporter must remain, however, on the basolateral membrane to participate in saliva secretion, as no significant decrease in saliva production was observed in the mutant mice.
Numerous studies have linked exposure to stress to adverse health outcomes through the effects of cortisol, a product of the stress response system, on cellular aging processes. Accelerated DNA methylation age is a promising epigenetic marker associated with stress and disease risk that may constitute a link from stress response to changes in neural structures. Specifically, elevated glucocorticoid signaling likely contributes to accelerating DNA methylation age, which may signify a maladaptive stress-related cascade that leads to hippocampal atrophy. We examined the relations among diurnal cortisol levels, DNA methylation age and hippocampal volume in a longitudinal study of 46 adolescent girls. We computed area under the curve from two daily cortisol collection periods, and calculated DNA methylation age using previously established methods based on a set of CpG sites associated with chronological age. We computed a residual score by partialling out chronological age; higher discrepancies reflect relatively accelerated DNA methylation age. We assessed hippocampal volume via T1-weighted images and automated volumetric segmentation. We found that greater diurnal cortisol production was associated with accelerated DNA methylation age, which in turn was associated with reduced left hippocampal volume. Finally, accelerated DNA methylation age significantly mediated the association between diurnal cortisol and left hippocampal volume. Thus, accelerated DNA methylation age may be an epigenetic marker linking hypothalamic-pituitary-adrenal axis dysregulation with neural structure. If these findings are replicated, the current study provides a method for advancing our understanding of mechanisms by which glucocorticoid signaling is associated with cellular aging and brain development.
Several studies have shown that young children who have experienced early caregiving adversity (e.g. previously institutionalization (PI)) exhibit flattened diurnal cortisol slopes; however, less is known about how these patterns might differ between children and adolescents, since the transition between childhood and adolescence is a time of purported plasticity in the hypothalamic-pituitary-adrenal (HPA) axis. PI youth experience a massive improvement in caregiving environment once adopted into families; therefore we anticipated that a developmental increase in HPA axis plasticity during adolescence might additionally allow for an enhanced enrichment effect by the adoptive family. In a cross-sectional sample of 197 youths (PI and Comparison; 4-15 years old) we observed age-related group differences in diurnal slope. First replicating previous findings, PI children exhibited flattened diurnal slope. This group difference, however, was not observed in adolescents. Moderation analyses showed that pubertal development, increased time with family, and early adoption contributed to the steeper diurnal cortisol slope in PI adolescents. These findings add support to existing theories positing that the transition between middle childhood and adolescence may mark an additional sensitive period for diurnal cortisol patterning, allowing PI youth to benefit from the enriched environment provided by adoptive parents during this period of development.
Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.
Researchers have documented dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in children and adolescents who experienced early life stress (ELS). The precise nature of this dysregulation, however, has been difficult to discern. In fact, both elevated and blunted patterns of diurnal cortisol regulation have been reported in children and adolescents exposed to greater ELS, including both reduced and heightened cortisol levels and change in cortisol across the day. These divergent findings may be due to developmental changes in the relation between ELS and HPA-axis functioning. The present study was designed to examine the role of puberty in the impact of the severity of ELS on the regulation of diurnal cortisol. Boys and girls (N=145) ages 9-13 years recruited from lower-risk communities completed an interview about their ELS experiences and at-home collection of diurnal cortisol. ELS experiences were objectively coded for severity, and children's level of pubertal development was measured using Tanner Staging. Multi-level piecewise mixed-effects models tested the effects of ELS severity and pubertal stage on cortisol levels at waking, the cortisol awakening response (CAR), and the daytime cortisol slope. While we found no significant interactive effects of pubertal stage and ELS severity on cortisol levels at waking or the daytime cortisol slope, findings indicated that pubertal stage interacted with ELS severity to predict the cortisol awakening response (CAR). Specifically, in earlier puberty, higher ELS was associated with a blunted CAR compared to lower ELS; in contrast, in later puberty, higher ELS was associated with a heightened CAR compared to lower ELS. Differences in the relation between ELS severity and the CAR were uniquely determined by puberty, and not by age. By considering and examining the role of puberty, the current study provides a developmental explanation for previous divergent findings of both blunted and heightened patterns of diurnal cortisol following ELS. These results indicate that careful attention should be given to children's pubertal status before drawing conclusions concerning the nature of diurnal cortisol dysregulation.
Copyright © 2016 Elsevier Ltd. All rights reserved.
OBJECTIVES - Hypothalamic-pituitary-adrenal (HPA) axis dysregulation is associated with chronic pain. Studying pain sensitivity and the HPA axis could elucidate the role of stress in chronic pain development, which might be influenced by familial factors, including genes.
METHODS - Associations between pain sensitivity and salivary cortisol and familial confounding in these associations were examined in 88 female, community-based twin pairs (75% monozygotic, mean age 29 y). Cortisol was assessed after 0.25 mg dexamethasone (DEX), recovery from 0.25 mg DEX, and after 0.5 mg DEX. Cold pressor task (CPT) pain ratings were obtained at threshold and at tolerance. Conditioned pain modulation (CPM) was examined using thermal heat as the testing stimulus and hot water as the conditioning stimulus. Generalized estimating equation models were used and adjusted for baseline pain rating, age, and other relevant covariates.
RESULTS - After controlling for baseline cortisol, greater cortisol suppression following DEX administration and lower recovery cortisol levels were associated with higher pain ratings at tolerance during the CPT (Bs=-2.42 to -17.82; Ps=0.031 to<0.001) as well as with reduced CPM (Bs=-0.92 to -1.68; Ps=0.003 to 0.046). Interestingly, familial confounding was evident in the CPT and CPM during recovery from DEX administration, but not immediately following DEX administration.
DISCUSSION - These findings contribute to understanding possible mechanisms underlying chronic pain by demonstrating that HPA axis response to negative feedback is related to pain sensitivity.
Although ovarian hormones are thought to have a potential role in the well-known sex difference in mood and anxiety disorders, the mechanisms through which ovarian hormone changes contribute to stress regulation are not well understood. One mechanism by which ovarian hormones might impact mood regulation is by mediating the effect of psychosocial stress, which often precedes depressive episodes and may have mood consequences that are particularly relevant in women. In the current study, brain activity and mood response to psychosocial stress was examined in healthy, normally cycling women at either the high or low estradiol phase of the menstrual cycle. Twenty eight women were exposed to the Montreal Imaging Stress Task (MIST), with brain activity determined through functional magnetic resonance imaging, and behavioral response assessed with subjective mood and stress measures. Brain activity responses to psychosocial stress differed between women in the low versus high estrogen phase of the menstrual cycle: women with high estradiol levels showed significantly less deactivation in limbic regions during psychosocial stress compared to women with low estradiol levels. Additionally, women with higher estradiol levels also had less subjective distress in response to the MIST than women with lower estradiol levels. The results of this study suggest that, in normally cycling premenopausal women, high estradiol levels attenuate the brain activation changes and negative mood response to psychosocial stress. Normal ovarian hormone fluctuations may alter the impact of psychosocially stressful events by presenting periods of increased vulnerability to psychosocial stress during low estradiol phases of the menstrual cycle. This menstrual cycle-related fluctuation in stress vulnerability may be relevant to the greater risk for affective disorder or post-traumatic stress disorder in women.
Copyright © 2015 Elsevier Ltd. All rights reserved.
A variety of evidence suggests that, among humans, the individual tendency to choose immediate rewards ("Now") over larger, delayed rewards ("Later"), or Now bias, varies with frontal dopamine (DA) levels. As cyclic elevations in estradiol (E+) modulate other frontal DA-dependent behaviors, we tested ovarian cycle effects on Now bias, and whether any such effects are E+ mediated. To do so, we quantified Now/Later choice behavior in naturally cycling adult females (n = 87; ages 18-40 years) during both the menstrual phase (MP; cycle day 1-2; low E+), and the follicular phase (FP; cycle day 11-12; high E+). Now bias decreased an average of 3.6% from MP to FP (p = 0.006). Measures of salivary E+ levels at each visit were available in a subsample of participants (n = 34). Participants with a verified E+ rise from MP to FP showed significantly greater decreases in Now bias at mid-cycle (n = 23) than those without a rise (n = 11; p = 0.03); Now bias decreased an average of 10.2% in the E+ rise group but increased an average of 7.9% in the no E+ rise group. The change in Now bias from MP to FP inversely correlated with the change in E+ (ρ = -0.39; p = 0.023), an effect driven by individuals with putatively lower frontal DA based on genotype at the Val(158)Met polymorphism in the COMT gene. This is the first demonstration that intertemporal choice varies across the ovarian cycle, with Now bias declining at mid-cycle, when fertility peaks. Moreover, our data suggest that the interacting effects of estradiol and frontal DA mediate this cycle effect on decision making.