A Latent Profile Analysis of Social Support, Online Contacts, and Preference for Online Communication Among Same- and Both-Sex Attracted and Other-Sex Attracted Adolescents.

This study aimed to assess differences between other-sex attracted and same- and both-sex attracted adolescents in profiles of peer and family social support, online contacts, and preferences for online communication. Data stem from the 2017 Dutch "Health and Behavior in School-Aged Children" (HBSC) survey (N = 6,823; 4.0% same- and both-sex attracted; M age=14.73, SD = 1.59, range = 12-18). We conducted latent profile analyses to estimate profiles in peer and family social support, online contacts, and preferences for online communication. Then we assessed the association between sexual attraction and profile membership. A five-profile solution fitted the data best. Profiles were characterized as high support, online contact, and average online communication preference (35.6%); high support, low online contact, and weak online communication preference (42.9%); average support, high online contact, and strong online communication preference (9.9%); low support, low online contact, and average online communication preference (6.9%); and low support, average online contact, and average online communication preference (5.0%). Same- and both-sex attracted adolescents had higher odds than other-sex attracted adolescents of being in the latter three profiles than in the first profile. Thus, same- and both-sex attracted adolescents were more likely to report average to low rates of peer and family social support, high to low frequency of online contact, and an average to strong preference for online communication than other-sex attracted adolescents. The average to low levels of support especially influenced these sexual orientation-based differences in profile membership.

Bi-allelic ATG4D variants are associated with a neurodevelopmental disorder characterized by speech and motor impairment.

Autophagy regulates the degradation of damaged organelles and protein aggregates, and is critical for neuronal development, homeostasis, and maintenance, yet few neurodevelopmental disorders have been associated with pathogenic variants in genes encoding autophagy-related proteins. We report three individuals from two unrelated families with a neurodevelopmental disorder characterized by speech and motor impairment, and similar facial characteristics. Rare, conserved, bi-allelic variants were identified in ATG4D, encoding one of four ATG4 cysteine proteases important for autophagosome biogenesis, a hallmark of autophagy. Autophagosome biogenesis and induction of autophagy were intact in cells from affected individuals. However, studies evaluating the predominant substrate of ATG4D, GABARAPL1, demonstrated that three of the four ATG4D patient variants functionally impair ATG4D activity. GABARAPL1 is cleaved or "primed" by ATG4D and an in vitro GABARAPL1 priming assay revealed decreased priming activity for three of the four ATG4D variants. Furthermore, a rescue experiment performed in an ATG4 tetra knockout cell line, in which all four ATG4 isoforms were knocked out by gene editing, showed decreased GABARAPL1 priming activity for the two ATG4D missense variants located in the cysteine protease domain required for priming, suggesting that these variants impair the function of ATG4D. The clinical, bioinformatic, and functional data suggest that bi-allelic loss-of-function variants in ATG4D contribute to the pathogenesis of this syndromic neurodevelopmental disorder.

Moderating role of coping in the association between minority stress and suicidal ideation and suicide attempts among sexual and gender minority young adults.

OBJECTIVE: This study examined associations of minority stressors (i.e., victimization, internalized homonegativity, and stigma consciousness), and coping styles (i.e., active, avoidant, and passive) with suicidal ideation and suicide attempts (suicidality) among sexual and gender minority (SGM) young adults, and whether coping style moderated these associations. METHODS: Logistic regression analyses examined these associations among 1432 SGM young adults (ages 18-29). RESULTS: Minority stressors and passive coping were associated with a higher likelihood of suicidality. Avoidant coping was associated with a lower likelihood of lifetime suicidal ideation and attempts among sexual minority participants, and active coping with a lower likelihood of past-year suicidal ideation among sexual minority participants. Moderation analyses among sexual minority participants showed that when avoidant coping was high, associations between low victimization (compared with no victimization) and lifetime suicide attempts, and stigma consciousness and lifetime suicide attempts became non-significant, and the association between internalized homonegativity and lifetime suicide attempts became significant. Among gender minority participants, when passive coping was high the association between low victimization and lifetime suicidal ideation became significant. CONCLUSION: This study underlines the importance of minority stress and coping for suicidality among SGM young adults and the need for more research regarding the role of coping.

Minority Stress and Suicidal Ideation and Suicide Attempts Among LGBT Adolescents and Young Adults: A Meta-Analysis.

Purpose: This meta-analytic study examined associations between minority stressors and suicidal ideation and suicide attempts among LGBT adolescents and young adults (aged 12-25 years). Methods: Identified studies were screened using the inclusion and exclusion criteria. Studies had to include an association between a minority stressor and a suicidality outcome and were categorized into 10 meta-analyses. Overall effect sizes were calculated using three-level meta-analyses. In addition, moderation by sampling strategy was examined. Results: A total of 44 studies were included. Overall, LGBT bias-based victimization, general victimization, bullying, and negative family treatment were significantly associated with suicidal ideation and/or suicide attempts. Associations of discrimination and internalized homophobia and transphobia with suicidal ideation and/or suicide attempts were not significant. No moderation effects were found for sampling strategy. Conclusion: Although overall effect sizes were small, our meta-analytic study shows a clear link between various types of minority stressors and suicidal ideation and suicide attempts among LGBT adolescents and young adults.

DNA-methylation dynamics across short-term, exposure-containing CBT in patients with panic disorder.

Interaction of genetic predispositions and environmental factors via epigenetic mechanisms have been hypothesized to play a central role in Panic Disorder (PD) aetiology and therapy. Cognitive Behavioral Therapy (CBT), including exposure interventions, belong to the most efficient treatments of PD although its biological mechanism of action remains unknown. For the first time, we explored the dynamics and magnitude of DNA-methylation and immune cell-type composition during CBT (n = 38) and the therapeutic exposure intervention (n = 21) to unravel their biological correlates and identify possible biomarkers of therapy success. We report transient regulation of the CD4 + T-Cells, Natural Killers cells, Granulocytes during exposure and a significant change in the proportions of CD4 + T cells, CD8 + T cells and B-Cells and Granulocytes during therapy. In an epigenome-wide association study we identified cg01586609 located in a CpG island and annotated to the serotonin receptor 3 A (HTR3A) to be differentially methylated during fear exposure and regulated at gene expression level with significant differences between remitters and non-remitters (p = 0.028). We moreover report cg01699630 annotated to ARG1 to undergo long lasting methylation changes during therapy (paired t test, genome-wide adj.p value = 0.02). This study reports the first data-driven biological candidates for epigenetically mediated effects of acute fear exposure and CBT in PD patients. Our results provide evidence of changes in the serotonin receptor 3 A methylation and expression during fear exposure associated with different long-term CBT trajectories and outcome, making it a possible candidate in the search of markers for therapy success. Finally, our results add to a growing body of evidence showing immune system changes associated with PD.

Attachment style change and working alliance in panic disorder patients treated with cognitive behavioral therapy.

An insecure attachment style (AS), described as being highly anxious and/or avoidant, is often assumed to be stable over time, yet some studies show that AS can change. To the extent that AS may be malleable over shorter time periods, it potentially impacts key therapy processes and outcomes. In the present study, we first investigated the stability of AS in patients with panic disorder (N = 49) treated with short-term cognitive behavioral therapy (CBT) including follow-up. Second, we tested whether time-specific change of AS predicted subsequent symptom severity, interpersonal distress (ID), and alliance, or vice versa. Third, we investigated if anxious attachment and ID average levels impact the alliance-outcome relation. Analyses were conducted at within- and between-patient levels with 5 measurements (baseline, intermediate, end, and follow-up after 4 and 8 months) over the course of CBT (12 sessions/8 weeks, 2 booster sessions) using linear mixed-effects models. A strong decrease in anxious attachment was found that was stable until 8 months after therapy. At the within-patient level, a reciprocal relationship of reduction in anxious attachment with less symptom severity, stronger alliance, and a prediction of less ID was found. ID decrease preceded less avoidance. At the between-patient level, anxious attachment and ID moderated the relation of alliance change and subsequent depressive symptoms. The prolonged improvement in interpersonal patterns suggests that short-term CBT positively modifies attachment working models in panic disorder patients. Effects on therapy process indicate that anxiously attached and interpersonally distressed patients seem to benefit more from alliance increase. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Exposure-induced changes of plasma metabolome and gene expression in patients with panic disorder.

BACKGROUND: Anxiety disorders including panic disorder (PD) are the most prevalent psychiatric diseases leading to high disability and burden in the general population. Acute panic attacks are distinctive for PD but also frequent in other anxiety disorders. The neurobiology or specific molecular changes leading to and present during panic attacks are insufficiently known so far. METHODS: In the present pilot study, we investigated dynamic metabolomic and gene expression changes in peripheral blood of patients with PD (n = 25) during two exposure-induced acute panic attacks. RESULTS: The results show that the metabolite glyoxylate was dynamically regulated in peripheral blood. Additionally, glyoxylate levels were associated with basal anxiety levels and showed gender-related differences at baseline. As glyoxylate is part of the degradation circuit of cholecystokinin, this suggests that this neuropeptide might be directly involved in exposure-induced panic attacks. Only gene expression changes of very small magnitude were observed in this experimental setting. CONCLUSIONS: From this first metabolome and gene expression study in exposure-induced acute panic attacks in PD we conclude that metabolites can potentially serve as dynamic markers for different anxiety states. However, these findings have to be replicated in cohorts with greater sample sizes.

Correction to: Lifetime stress accelerates epigenetic aging in an urban, African American cohort: relevance of glucocorticoid signaling.

Upon publication of the original article [1] it was highlighted by the authors that a transposition error affected Additional file 1, causing the misplacement of several columns and rendering the table difficult to read. This transposition does not influence any of the results nor analyses presented in the paper and has since been formally noted in this correction article; the corrected file is available here as an Additional File. The publisher apologizes for this error.

"DNA Methylation signatures in panic disorder".

Panic disorder (PD) affects about four million Europeans, with women affected twice as likely as men, causing substantial suffering and high economic costs. The etiopathogenesis of PD remains largely unknown, but both genetic and environmental factors contribute to risk. An epigenome-wide association study (EWAS) was conducted to compare medication-free PD patients (n = 89) with healthy controls (n = 76) stratified by gender. Replication was sought in an independent sample (131 cases, 169 controls) and functional analyses were conducted in a third sample (N = 71). DNA methylation was assessed in whole blood using the Infinium HumanMethylation450 BeadChip. One genome-wide association surviving FDR of 5% (cg07308824, P = 1.094 × 10-7, P-adj = 0.046) was identified in female PD patients (N = 49) compared to controls (N = 48). The same locus, located in an enhancer region of the HECA gene, was also hypermethylated in female PD patients in the replication sample (P = 0.035) and the significance of the association improved in the meta-analysis (P-adj = 0.004). Methylation at this CpG site was associated with HECA mRNA expression in another independent female sample (N = 71) both at baseline (P = 0.046) and after induction by dexamethasone (P = 0.029). Of 15 candidates, 5 previously reported as associated with PD or anxiety traits also showed differences in DNA methylation after gene-wise correction and included SGK1, FHIT, ADCYAP1, HTR1A, HTR2A. Our study examines epigenome-wide differences in peripheral blood for PD patients. Our results point to possible sex-specific methylation changes in the HECA gene for PD but overall highlight that this disorder is not associated with extensive changes in DNA methylation in peripheral blood.

Dietary beta-carotene and lutein metabolism is modulated by the APOE genotype.

The human apolipoprotein E (APOE) genotype has been suggested to interact with nutrient metabolism particularly with lipid soluble vitamins. Plasma carotenoid levels are determined by numerous dietary and genetic factors with high inter-individual variation; however, the APOE genotype has not been systematically examined so far. Our aim was to investigate the effect of the APOE genotype on dietary carotenoid metabolism with special regard to transcriptional regulation of carotenoid absorption, cleavage and adipocyte fat storage. We supplemented targeted replacement mice expressing human APOE3 and APOE4 isoforms with dietary beta-carotene (BC) and lutein (LUT) for 8 weeks. Plasma BC and adipose tissue BC and LUT levels were in trend lower in APOE4 than APOE3 mice, while hepatic expression of the beta-carotene oxygenases BCO1 and BCO2 was significantly higher. In contrast to the liver, mRNA levels of proteins involved in carotenoid absorption and cleavage in the small intestinal mucosa as well as of adipogenic markers in the adipose tissue were not different between APOE3 and APOE4 mice. Our data suggest that the hepatic carotenoid cleavage activity is higher in APOE4 mice partially reducing the circulation and extra-hepatic accumulation of intact carotenoids as compared to APOE3. Therefore we suggest considering the APOE genotype as modulator of carotenoid status in the future. © 2016 BioFactors, 42(4):388-396, 2016.

Off-Target drug effects resulting in altered gene expression events with epigenetic and "Quasi-Epigenetic" origins.

This review synthesizes examples of pharmacological agents who have off-target effects of an epigenetic nature. We expand upon the paradigm of epigenetics to include "quasi-epigenetic" mechanisms. Quasi-epigenetics includes mechanisms of drugs acting upstream of epigenetic machinery or may themselves impact transcription factor regulation on a more global scale. We explore these avenues with four examples of conventional pharmaceuticals and their unintended, but not necessarily adverse, biological effects. The quasi-epigenetic drugs identified in this review include the use of beta-lactam antibiotics to alter glutamate receptor activity and the action of cyclosporine on multiple transcription factors. In addition, we report on more canonical epigenome changes associated with pharmacological agents such as lithium impacting autophagy of aberrant proteins, and opioid drugs whose chronic use increases the expression of genes associated with addictive phenotypes. By expanding our appreciation of transcriptomic regulation and the effects these drugs have on the epigenome, it is possible to enhance therapeutic applications by exploiting off-target effects and even repurposing established pharmaceuticals. That is, exploration of "pharmacoepigenetic" mechanisms can expand the breadth of the useful activity of a drug beyond the traditional drug targets such as receptors and enzymes.

Lifetime stress accelerates epigenetic aging in an urban, African American cohort: relevance of glucocorticoid signaling.

BACKGROUND: Chronic psychological stress is associated with accelerated aging and increased risk for aging-related diseases, but the underlying molecular mechanisms are unclear. RESULTS: We examined the effect of lifetime stressors on a DNA methylation-based age predictor, epigenetic clock. After controlling for blood cell-type composition and lifestyle parameters, cumulative lifetime stress, but not childhood maltreatment or current stress alone, predicted accelerated epigenetic aging in an urban, African American cohort (n = 392). This effect was primarily driven by personal life stressors, was more pronounced with advancing age, and was blunted in individuals with higher childhood abuse exposure. Hypothesizing that these epigenetic effects could be mediated by glucocorticoid signaling, we found that a high number (n = 85) of epigenetic clock CpG sites were located within glucocorticoid response elements. We further examined the functional effects of glucocorticoids on epigenetic clock CpGs in an independent sample with genome-wide DNA methylation (n = 124) and gene expression data (n = 297) before and after exposure to the glucocorticoid receptor agonist dexamethasone. Dexamethasone induced dynamic changes in methylation in 31.2 % (110/353) of these CpGs and transcription in 81.7 % (139/170) of genes neighboring epigenetic clock CpGs. Disease enrichment analysis of these dexamethasone-regulated genes showed enriched association for aging-related diseases, including coronary artery disease, arteriosclerosis, and leukemias. CONCLUSIONS: Cumulative lifetime stress may accelerate epigenetic aging, an effect that could be driven by glucocorticoid-induced epigenetic changes. These findings contribute to our understanding of mechanisms linking chronic stress with accelerated aging and heightened disease risk.

Genetic diseases conferring resistance to infectious diseases.

This review considers available evidence for mechanisms of conferred adaptive advantages in the face of specific infectious diseases. In short, we explore a number of genetic conditions, which carry some benefits in adverse circumstances including exposure to infectious agents. The examples discussed are conditions known to result in resistance to a specific infectious disease, or have been proposed as being associated with resistance to various infectious diseases. These infectious disease-genetic disorder pairings include malaria and hemoglobinopathies, cholera and cystic fibrosis, tuberculosis and Tay-Sachs disease, mycotic abortions and phenylketonuria, infection by enveloped viruses and disorders of glycosylation, infection by filoviruses and Niemann-Pick C1 disease, as well as rabies and myasthenia gravis. We also discuss two genetic conditions that lead to infectious disease hypersusceptibility, although we did not cover the large number of immunologic defects leading to infectious disease hypersusceptibilities. Four of the resistance-associated pairings (malaria/hemogloginopathies, cholera/cystic fibrosis, tuberculosis/Tay-Sachs, and mycotic abortions/phenylketonuria) appear to be a result of selection pressures in geographic regions in which the specific infectious agent is endemic. The other pairings do not appear to be based on selection pressure and instead may be serendipitous. Nonetheless, research investigating these relationships may lead to treatment options for the aforementioned diseases by exploiting established mechanisms between genetically affected cells and infectious organisms. This may prove invaluable as a starting point for research in the case of diseases that currently have no reliably curative treatments, e.g., HIV, rabies, and Ebola.

Salmonella as a biological "Trojan horse" for neoplasia: future possibilities including brain cancer.

This manuscript considers available evidence that a specific Salmonella strain could be used as an effective orally-administered option for cancer therapy involving the brain. It has been established that Salmonella preferentially colonizes neoplastic tissue and thrives as a facultative anaerobe in the intra-tumor environment. Although Salmonella accumulates in tumors by passive processes, it is still possible for lipopolysaccharide to cause sepsis and endotoxic shock during the migration of bacteria to the tumor site. An LPS-free version of a recently identified Salmonella isolate may have the capability to circumvent the blood brain barrier and provide a safer method of reaching brain tumors. This isolate merits further research as a "Trojan horse" for future oral biotherapy of brain cancer.

Antibiotics acting as neuroprotectants via mechanisms independent of their anti-infective activities.

This review considers available evidence that some antibiotics have ancillary neuroprotective effects. Notably, ß-lactam antibiotics are believed to increase the expression of glutamate transporter GLT1, potentially relieving the neurological excitotoxicity that characterizes disorders like amyotrophic lateral sclerosis. Minocycline has shown promise in reducing the severity of a number of neurological diseases, including multiple sclerosis, most likely by reducing apoptosis and the expression of inflammatory mediators in the brain. Rapamycin inhibits the activity of a serine/threonine protein kinase that has a role in the pathogenesis of numerous neurologic diseases. Herein we examine the unique neuroprotective aspects of these drugs originally developed as anti-infective agents.

Bioactive tetrapeptide GEKG boosts extracellular matrix formation: in vitro and in vivo molecular and clinical proof.

The 'matrikine' concept claims that processing of the precursors for collagen results in the formation of peptides such as KTTKS which in turn augments extracellular matrix (ECM) production. In the present study, we show the development of an anti-ageing active from an in silico approach by molecular design resulting in the tetrapeptide GEKG derived from ECM proteins. The efficacy of the peptide to significantly induce collagen production of the protein level and mRNA level has been demonstrated in vitro in human dermal fibroblasts and in vivo in a double-blind, randomized, placebo-controlled study enroling 10 volunteers with an average age of 48.2 years. The effect of GEKG on facial wrinkles was studied in 30 volunteers using state of the art fringe projection, which allows determination of surface roughness in three-dimensions. Here, only GEKG but not the placebo was able to significantly decrease skin roughness as a measure for wrinkles.

Molecular and dietary regulation of beta,beta-carotene 15,15'-monooxygenase 1 (BCMO1).

beta,beta-Carotene 15,15'-monooxygenase-1 (BCMO1) is a key enzyme in vitamin A metabolism in mammals. Various dietary components such as non-pro-vitamin A carotenoids, fat, and polyphenols have been shown to influence the intestinal absorption and conversion of pro-vitamin A carotenoids. Furthermore, vitamin A deficiency has been shown to induce BCMO1 expression, whereas supplementation with vitamin A or its active metabolites, all-trans and 9-cis retinoic acid, dose-dependently reverse these effects. A diet-responsive regulatory network involving the intestine specific homeodomain transcription factor ISX has been shown to regulate the intestinal vitamin A uptake and production via a negative feedback control. Furthermore, non-synonymous single nucleotide polymorphisms in the human BCMO1 gene have been discovered causing observably reduced BCMO1 activity. Detailed knowledge about BCMO1 regulation as well as genetic variations causing variable cleavage activities may provide a background, on which individual and/or population based dietary recommendations for beta-carotene and vitamin A intake could be established.

The effect of state anxiety on paranoid ideation and jumping to conclusions. An experimental investigation.

Theoretical models of persecutory delusions have emphasized the impact of reasoning biases and negative emotion at the early stages of symptom formation. However, the causal mechanisms remain unclear. This study tests the hypothesis that state anxiety will increase paranoid ideation and that this increase will be moderated by the level of individual vulnerability and mediated by the tendency to jump to conclusions. Healthy participants (n = 90) with varying levels of vulnerability (psychosis symptoms assessed by the Community Assessment of Psychic Experiences) were randomly assigned to either an anxiety or a nonanxiety condition. Anxiety was induced by pictures from the International Affective Picture System and by in sensu exposure to individual anxiety-provoking situations. During each condition, symptoms of paranoia were assessed by a state-adapted version of the Paranoia Checklist. Jumping to conclusions (JTC) was assessed using a modified version of the beads task. Overall, participants in the anxiety condition reported significantly more paranoid thoughts and showed more JTC than participants in the neutral condition. Participants with higher baseline vulnerability were more likely to show an increase in paranoia as reaction to the anxiety manipulation. Moreover, the association of anxiety and paranoia was mediated by the increased tendency to jump to conclusions in the beads task. The results are in line with a threat anticipation conceptualization of paranoia and provide evidence for an interaction of anxiety and reasoning biases in the development of paranoid beliefs. A combination of meta-cognitive training directed at reasoning biases and promoting emotion regulation skills might prove beneficial in preventing symptoms.

The heparan sulfate proteoglycan GPC3 is a potential lung tumor suppressor.

Recently, we used gene expression profiling of lung adenocarcinoma and paired normal tissue from smokers and nonsmokers to identify genes and molecular pathways associated with cigarette smoking and lung carcinogenesis. The gene encoding Glypican 3, a glycosylphosphatidylinositol-linked heparan sulfate proteoglycan, was decreased in lung adenocarcinoma. Within nonmalignant lung, GPC3 expression was decreased in smokers compared with nonsmokers; indicating that expression is associated with cigarette smoking. Microarray results were confirmed using an independent cohort of tumors and nonmalignant lung tissues. Immunohistochemical studies localized Glypican 3 protein expression to the apical surface of lung bronchiolar epithelial cells, potential cells of origin for adenocarcinoma. Northern blot analysis demonstrated expression was absent in all tested non-small cell lung carcinoma lines. Pharmacologic treatment of lung cell lines indicated that GPC3 expression was epigenetically silenced by promoter hypermethylation. Human lung carcinoma tumor cells ectopically expressing GPC3 demonstrated increased apoptosis response when exposed to etoposide and growth inhibition when implanted in nude mice. These findings suggest that GPC3 is a candidate lung tumor suppressor gene whose expression may be regulated by exposure to cigarette smoke and functions to modulate cellular response to exogenous damage.