Transcription dosage compensation does not occur in Down syndrome.

BACKGROUND: The increase in DNA copy number in Down syndrome (DS; caused by trisomy 21) has led to the DNA dosage hypothesis, which posits that the level of gene expression is proportional to the gene's DNA copy number. Yet many reports have suggested that a proportion of chromosome 21 genes are dosage compensated back towards typical expression levels (1.0×). In contrast, other reports suggest that dosage compensation is not a common mechanism of gene regulation in trisomy 21, providing support to the DNA dosage hypothesis. RESULTS: In our work, we use both simulated and real data to dissect the elements of differential expression analysis that can lead to the appearance of dosage compensation, even when compensation is demonstrably absent. Using lymphoblastoid cell lines derived from a family with an individual with Down syndrome, we demonstrate that dosage compensation is nearly absent at both nascent transcription (GRO-seq) and steady-state RNA (RNA-seq) levels. Furthermore, we link the limited apparent dosage compensation to expected allelic variation in transcription levels. CONCLUSIONS: Transcription dosage compensation does not occur in Down syndrome. Simulated data containing no dosage compensation can appear to have dosage compensation when analyzed via standard methods. Moreover, some chromosome 21 genes that appear to be dosage compensated are consistent with allele specific expression.

Transcription dosage compensation does not occur in Down syndrome.

Background: Trisomy 21, also known as Down syndrome, describes the genetic condition of having an extra copy of chromosome 21. The increase in DNA copy number has led to the "DNA dosage hypothesis", which claims that the level of gene transcription is proportional to the gene's DNA copy number. Yet many reports have suggested that a proportion of chromosome 21 genes are dosage compensated back towards typical expression levels (1.0x). In contrast, other reports suggest that dosage compensation is not a common mechanism of gene regulation in Trisomy 21, providing support to the DNA dosage hypothesis. Results: In our work, we use both simulated and real data to dissect the elements of differential expression analysis that can lead to the appearance of dosage compensation even when compensation is demonstrably absent. Using lymphoblastoid cell lines derived from a family of an individual with Down syndrome, we demonstrate that dosage compensation is nearly absent at both nascent transcription (GRO-seq) and steady-state RNA (RNA-seq) levels. Conclusions: Transcriptional dosage compensation does not occur in Down syndrome. Simulated data containing no dosage compensation can appear to have dosage compensation when analyzed via standard methods. Moreover, some chromosome 21 genes that appear to be dosage compensated are consistent with allele specific expression.

Molecular Resolution Nanostructure and Dynamics of the Deep Eutectic Solvent-Graphite Interface as a Function of Potential.

Interest in deep eutectic solvents (DESs), particularly for electrochemical applications, has boomed in the past decade because they are more versatile than conventional electrolyte solutions and are low cost, renewable, and non-toxic. The molecular scale lateral nanostructures as a function of potential at the solid-liquid interface-critical design parameters for the use of DESs as electrochemical solvents-are yet to be revealed. In this work, in situ amplitude modulated atomic force microscopy complemented by molecular dynamics simulations is used to probe the Stern and near-surface layers of the archetypal and by far most studied DES, 1:2 choline chloride:urea (reline), at the highly orientated pyrolytic graphite surface as a function of potential, to reveal highly ordered lateral nanostructures with unprecedented molecular resolution. This detail allows identification of choline, chloride, and urea in the Stern layer on graphite, and in some cases their orientations. Images obtained after the potential is switched from negative to positive show the dynamics of the Stern layer response, revealing that several minutes are required to reach equilibrium. These results provide valuable insight into the nanostructure and dynamics of DESs at the solid-liquid interface, with implications for the rational design of DESs for interfacial applications.

Examining the Prospective Bidirectional Associations between Subjective and Objective Attractiveness and Adolescent Internalizing Symptoms and Life Satisfaction.

Research has consistently shown that more physically attractive individuals are perceived by others to be happier and better psychologically adjusted than those perceived as less attractive. However, due to the lack of longitudinal research in adolescents, it is still unclear whether poor mental health predicts or is predicted by either objective or subjective attractiveness during this critical developmental period. The purpose of the current study was to examine prospective bidirectional associations between both subjective and objective ratings of attractiveness, life satisfaction and symptoms of social anxiety, depression and eating disorders (i.e., internalizing symptoms) from early to mid-adolescence. Participants (T1: N = 528, 49.9% girls; Mage = 11.19; SD = 0.55) were followed annually over four time points. The cross-lagged panel model results revealed evidence of prospective associations between both forms of attractiveness and life satisfaction and internalizing symptoms, which were driven more by changes in the mental health outcomes than by changes in the subjective and objective attractiveness ratings. The results also indicated that the pattern, strength, and direction of the associations tested were robust across boys and girls, and white and non-white ethnic groups. Overall, the findings suggest that it is important to find effective ways of educating adolescents who are unhappy with their appearance that making changes to improve their mental health, rather than focusing on their physical appearance, will have benefits not only for how they perceive themselves but also for how they are perceived by others.

A longitudinal investigation of sleep hygiene as a mediator linking parental warmth with adolescent sleep.

STUDY OBJECTIVES: Parental warmth in adolescence protects sleep in early adulthood, yet the nature, directions, and mechanisms of this association across adolescence are unknown. This study examined parental warmth, adolescent sleep hygiene and sleep outcomes (morning/eveningness, school night sleep duration, and daytime sleepiness) across five annual waves, spanning four years, using a cross-lagged panel design. METHODS: Adolescents and one primary caregiver (96% mothers) completed questionnaires assessing parental warmth (child- and parent-report) and adolescent sleep hygiene and sleep (child-report), across five annual waves: Wave 1 (N = 531, Mage = 11.18, SD = 0.56, 51% male), Wave 2 (N = 504, Mage = 12.19, SD = 0.53, 52% male), Wave 3 (N = 478, Mage = 13.19, SD = 0.53, 52% male), Wave 4 (N = 440, Mage = 14.76, SD = 0.47, 51% male), and Wave 5 (N = 422, Mage = 15.75, SD = 0.49, 51% male). RESULTS: Greater child-reported parental warmth was indirectly associated with better adolescent sleep (greater morningness, longer school night sleep duration, less sleepiness) through healthier sleep hygiene. The inverse was also often observed. Warmth had a direct relationship with sleep duration and sleepiness, independent of sleep hygiene. Parent-reported parental warmth did not predict, nor was predicted by child-reported adolescent sleep. CONCLUSIONS: Parental warmth may protect against developmental changes in adolescent sleep, partially by improving sleep hygiene practices. Similarly, inadequate adolescent sleep may negatively impact parental warmth via deteriorating sleep hygiene. Sleep hygiene emerged as a key mechanism for protecting adolescent sleep and parent-child relationships.

Risk and Protective Factors for Prospective Changes in Adolescent Mental Health during the COVID-19 Pandemic.

The restrictions put in place to contain the COVID-19 virus have led to widespread social isolation, impacting mental health worldwide. These restrictions may be particularly difficult for adolescents, who rely heavily on their peer connections for emotional support. However, there has been no longitudinal research examining the psychological impact of the COVID-19 pandemic among adolescents. This study addresses this gap by investigating the impact of the COVID-19 pandemic on adolescents' mental health, and moderators of change, as well as assessing the factors perceived as causing the most distress. Two hundred and forty eight adolescents (Mage = 14.4; 51% girls; 81.8% Caucasian) were surveyed over two time points; in the 12 months leading up to the COVID-19 outbreak (T1), and again two months following the implementation of government restrictions and online learning (T2). Online surveys assessed depressive symptoms, anxiety, and life satisfaction at T1 and T2, and participants' schooling, peer and family relationships, social connection, media exposure, COVID-19 related stress, and adherence to government stay-at-home directives at T2 only. In line with predictions, adolescents experienced significant increases in depressive symptoms and anxiety, and a significant decrease in life satisfaction from T1 to T2, which was particularly pronounced among girls. Moderation analyses revealed that COVID-19 related worries, online learning difficulties, and increased conflict with parents predicted increases in mental health problems from T1 to T2, whereas adherence to stay-at-home orders and feeling socially connected during the COVID-19 lockdown protected against poor mental health. This study provides initial longitudinal evidence for the decline of adolescent's mental health during the COVID-19 pandemic. The results suggest that adolescents are more concerned about the government restrictions designed to contain the spread of the virus, than the virus itself, and that those concerns are associated with increased anxiety and depressive symptoms, and decreased life satisfaction.

Global analysis of p53-regulated transcription identifies its direct targets and unexpected regulatory mechanisms.

The p53 transcription factor is a potent suppressor of tumor growth. We report here an analysis of its direct transcriptional program using Global Run-On sequencing (GRO-seq). Shortly after MDM2 inhibition by Nutlin-3, low levels of p53 rapidly activate ∼200 genes, most of them not previously established as direct targets. This immediate response involves all canonical p53 effector pathways, including apoptosis. Comparative global analysis of RNA synthesis vs steady state levels revealed that microarray profiling fails to identify low abundance transcripts directly activated by p53. Interestingly, p53 represses a subset of its activation targets before MDM2 inhibition. GRO-seq uncovered a plethora of gene-specific regulatory features affecting key survival and apoptotic genes within the p53 network. p53 regulates hundreds of enhancer-derived RNAs. Strikingly, direct p53 targets harbor pre-activated enhancers highly transcribed in p53 null cells. Altogether, these results enable the study of many uncharacterized p53 target genes and unexpected regulatory mechanisms.DOI: http://dx.doi.org/10.7554/eLife.02200.001.

The impact of post-transcriptional regulation in the p53 network.

The p53 transcription factor regulates the synthesis of mRNAs encoding proteins involved in diverse cellular stress responses such as cell-cycle arrest, apoptosis, autophagy and senescence. In this review, we discuss how these mRNAs are concurrently regulated at the post-transcriptional level by microRNAs (miRNAs) and RNA-binding proteins (RBPs), which consequently modify the p53 transcriptional program in a cell type- and stimulus-specific manner. We also discuss the action of specific miRNAs and RBPs that are direct transcriptional targets of p53 and how they act coordinately with protein-coding p53 target genes to orchestrate p53-dependent cellular responses.

The BPQ: a scale for the assessment of borderline personality based on DSM-IV criteria.

The aim of the study was to develop a self-report measure that assesses borderline personality traits as defined by DSM-IV criteria, including separate subscales for each criterion. A sample of normal subjects from community colleges in the midwestern region of the United States was used to develop the scale. The psychometric properties of the scale were examined using an additional United States sample and student samples from England and Australia. The scale was compared with existing measures of borderline and schizotypal personality. Evidence for the internal consistency and convergent and divergent validity of the new scale is presented. The results of several analyses of variance comparing males and females in the three national groups are reported. A Principal Components Analysis of the subscales suggested either a single factor or two correlated factors. Oblique rotation yielded a structure that distinguished identity/interpersonal and impulsivity borderline personality traits. It is concluded that the new scale provides a useful tool for clinicians and researchers interested in screening for borderline personality traits in both general and clinical populations. Suggestions for further research are indicated.

A long-term outcome study of intersex conditions.

CONTEXT: Clinical management of intersex conditions is controversial because the available evidence is limited and conflicting, with no long-term population based studies comparing matched controls. OBJECTIVE: To assess the long-term psychological, sexual and social outcomes of patients with intersex compared with two matched control populations. DESIGN, SETTING AND PARTICIPANTS: Three different aged-matched (18-32 years) patient groups completed a self-administered questionnaire of established quality of life and well-being inventories measuring physical' health, psychological adjustment and sexuality, following a mail-out to all identified patients. The intersex group (n = 50) and the Hirschsprung disease, a congenital disorder, control group (n = 27), were patients who had attended the Royal Children's Hospital, a tertiary centre, for their clinical care. The insulin dependent diabetes mellitus control group was recruited from an adult tertiary hospital. The study was conducted at the hospital-based Murdoch Childrens Research Institute. MAIN OUTCOME MEASURES: Psychological, sexual and social outcomes. RESULTS: The intersex group did not differ from controls on physical or mental health, depression, state anxiety, neuroticism, psychoticism or stressful life events. Intersex participants were satisfied with their overall body appearance, although intersex males were less satisfied than controls with the size (p <0.05) and appearance (p <0.01) of their sex organs. The intersex group was less likely to experience orgasm (p <0.05), tended to experience more pain during intercourse (p = 0.06), had more difficulties with penetration (p <0.01) and were less likely to have sexual activity several times or more a week (p <0.05) than the combined control groups. Intersex participants did not differ from controls in level of sexual desire or enjoyment of sexual activities. CONCLUSIONS: Most patients with intersex had positive psychosocial and psychosexual outcomes, although some problems were reported with sexual activity. These results overall suggest that a model of care including early genital surgery carried out at a centre of excellence with a multidisciplinary team can minimize long-term complication rates.

Bridging the information and support gap: evaluation of a hospital-based cancer support nurse service.

Health professionals play an important role in meeting the information and support needs of individuals following a diagnosis of cancer. The aim of this study was to evaluate the acceptability and impact of a hospital-based cancer support nurse (CSN) service. A total of 98 patients completed a structured telephone interview after discharge concerning their use, perceptions and satisfaction with the service. The majority of patients perceived service delivery to be appropriate and reported that they had gained both information and support. The service also had a positive impact on behavioural, cognitive and affective outcomes. Overall satisfaction with the service was very high. Results indicate that a hospital-based cancer support nurse service provides a promising model for meeting the early information and support needs of patients, thereby promoting continuity of care.