Glutamine methylation in histone H2A is an RNA-polymerase-I-dedicated modification.

Nucleosomes are decorated with numerous post-translational modifications capable of influencing many DNA processes. Here we describe a new class of histone modification, methylation of glutamine, occurring on yeast histone H2A at position 105 (Q105) and human H2A at Q104. We identify Nop1 as the methyltransferase in yeast and demonstrate that fibrillarin is the orthologue enzyme in human cells. Glutamine methylation of H2A is restricted to the nucleolus. Global analysis in yeast, using an H2AQ105me-specific antibody, shows that this modification is exclusively enriched over the 35S ribosomal DNA transcriptional unit. We show that the Q105 residue is part of the binding site for the histone chaperone FACT (facilitator of chromatin transcription) complex. Methylation of Q105 or its substitution to alanine disrupts binding to FACT in vitro. A yeast strain mutated at Q105 shows reduced histone incorporation and increased transcription at the ribosomal DNA locus. These features are phenocopied by mutations in FACT complex components. Together these data identify glutamine methylation of H2A as the first histone epigenetic mark dedicated to a specific RNA polymerase and define its function as a regulator of FACT interaction with nucleosomes.

The BODY-Q Stretch Marks Scale: A Development and Validation Study.

BACKGROUND: Stretch marks are common permanent dermal lesions that can cause psychosocial distress. A number of treatment modalities are available, with the majority targeted towards collagen production. OBJECTIVES: To develop and field test a new BODY-Q scale to measure appearance of stretch marks in order to provide a means to incorporate the patient perspective into future treatment studies. METHODS: We previously described the development of the BODY-Q conceptual framework, which involved a literature review, 63 patient interviews, 22 cognitive interviews and input from 9 experts, and the international field-test study that involved 403 weight loss and 331 body contouring patients. To develop the Stretch Marks scale, we reexamined appearance codes from the original interviews. The scale was field tested in an international study. Rasch measurement theory (RMT) analysis was used to refine the scale and examine measurement properties. RESULTS: The Stretch Marks scale was completed by 630 participants, who provided 774 assessments. After dropping 3 items, the data fit the Rasch model (P = 0.56). Items (eg, length, width, amount, location, up close) mapped out a well-targeted clinical hierarchy. All items had ordered thresholds and good item fit. There was no evidence of differential item functioning (bias) by gender, age group or language (English vs Danish). The scale evidenced high reliability (ie, person separation index = 0.94, Cronbach's alpha = 0.97). For construct validity, the mean score correlated with the total number of body areas with stretch marks, higher BMI before bariatric surgery, and other BODY-Q scales. CONCLUSIONS: This scale could be used to measure the impact of innovative treatments for stretch marks.

Origins and functional impact of copy number variation in the human genome.

Structural variations of DNA greater than 1 kilobase in size account for most bases that vary among human genomes, but are still relatively under-ascertained. Here we use tiling oligonucleotide microarrays, comprising 42 million probes, to generate a comprehensive map of 11,700 copy number variations (CNVs) greater than 443 base pairs, of which most (8,599) have been validated independently. For 4,978 of these CNVs, we generated reference genotypes from 450 individuals of European, African or East Asian ancestry. The predominant mutational mechanisms differ among CNV size classes. Retrotransposition has duplicated and inserted some coding and non-coding DNA segments randomly around the genome. Furthermore, by correlation with known trait-associated single nucleotide polymorphisms (SNPs), we identified 30 loci with CNVs that are candidates for influencing disease susceptibility. Despite this, having assessed the completeness of our map and the patterns of linkage disequilibrium between CNVs and SNPs, we conclude that, for complex traits, the heritability void left by genome-wide association studies will not be accounted for by common CNVs.

Self-Report Scales to Measure Expectations and Appearance-Related Psychosocial Distress in Patients Seeking Cosmetic Treatments.

BACKGROUND: The use of screening scales in cosmetic practices may help to identify patients who require education to modify inappropriate expectations and/or psychological support. OBJECTIVES: To describe the development and validation of scales that measure expectations (about how one's appearance and quality of life might change with cosmetic treatments) and appearance-related psychosocial distress. METHODS: The scales were field-tested in patients 18 years and older seeking facial aesthetic or body contouring treatments. Recruitment took place in clinics in the United States, United Kingdom, and Canada between February 2010 and January 2015. Rasch Measurement Theory (RMT) analysis was used for psychometric evaluation. Scale scores range from 0 to 100; higher scores indicate more inappropriate expectations and higher psychosocial distress. RESULTS: Facial aesthetic (n = 279) and body contouring (n = 90) patients participated (97% response). In the RMT analysis, all items had ordered thresholds and acceptable item fit. Person Separation Index and Cronbach alpha values were 0.88 and 0.92 for the Expectation scale, and 0.81 and 0.89 for the Psychosocial Distress scale respectively. Higher expectation correlated with higher psychosocial distress (R = 0.40, P < .001). In the facial aesthetic group, lower scores on the FACE-Q Satisfaction with Appearance scale correlated with higher expectations (R = -0.27, P = .001) and psychosocial distress (R = -0.52, P < .001). In the body contouring group, lower scores on the BODY-Q Satisfaction with Body scale correlated with higher psychosocial distress (R = -0.31, P = .003). Type of treatment and marital status were associated with scale scores in multivariate models. CONCLUSIONS: Future research could examine convergent and predictive validity. As research data are accumulated, norms and interpretation guidelines will be established. LEVEL OF EVIDENCE: 2 Risk.

Development and optimisation of a multi-component workplace intervention to increase cycling for the Cycle Nation Project.

The Cycle Nation Project (CNP) aimed to develop, test the feasibility of and optimize a multi-component individual-/social-level workplace-based intervention to increase cycling among office staff at a multinational bank (HSBC UK). To do this, we first explored barriers to cycling in a nationally-representative survey of UK adults, then undertook focus groups with bank employees to understand any context-specific barriers and ways in which these might be overcome. These activities led to identification of 10 individual-level, two social-level, and five organizational-level modifiable factors, which were mapped to candidate intervention components previously identified in a scoping review of cycling initiatives. Interviews with HSBC UK managers then explored the practicality of implementing the candidate intervention components in bank offices. The resultant pilot CNP intervention included 32 core components across six intervention functions (education, persuasion, incentivisation, training, environmental restructuring, enablement). Participants received a loan bike for 12-weeks (or their own bike serviced), and a 9-week cycle training course (condensed to 6 weeks for those already confident in basic cycling skills), including interactive information sharing activities, behavior change techniques (e.g., weekly goal setting), bike maintenance training, practical off-road cycling skill games and on-road group rides. Sessions were delivered by trained bank staff members who were experienced cyclists. The CNP pilot intervention was delivered across three sites with 68 participants. It was completed in two sites (the third site was stopped due to COVID-19) and was feasible and acceptable to both women and men and across different ethnicities. In addition, the CNP intervention was successful (at least in the short term) in increasing cycling by 3 rides/week on average, and improving perceptions of safety, vitality, confidence, and motivation to cycle. Following minor modifications, the long-term effectiveness and cost-effectiveness of the CNP intervention should be tested in a full-scale randomized controlled trial.

Body Contouring and Skin Tightening Using a Unique Novel Multisource Radiofrequency Energy Delivery Method.

Objective: The objective of this study was to examine the efficacy and safety of the latest multisource radiofrequency handpiece, specially designed for body area skin treatments. The new handpiece features six concentric electrodes, each connected to an independently controlled radiofrequency generator. Design and settings: This was an international multicenter study across two sites. Twenty-five patients were enrolled into the study. Patients underwent at least five sessions of body skin tightening and circumference reduction. The first four sessions were held at one-week intervals and the other 1 to 4 remaining sessions, at two-week intervals. Participants: Twenty-five patients (23 women and 2 men). Measurements: Overall change was graded by the physicians using the global aesthetic improvement scale. Patients were asked to complete satisfaction questionnaires at the end of the treatment sessions. Images were taken prior to the treatments, before every treatment session, and at the follow-up visit. Results: No adverse events were reported as a result of the treatment. Measured body weight of the patients, as monitored during the study period, was stable (±2kg). Ninety-two percent of the patients were pleased with the results and finished all the treatment sessions. Twenty-four patients (96%) saw an improvement in body shape. Ninety-two percent of the patients would recommend the treatment to others. Overall change graded by the physician by the global aesthetic improvement scale provided the following results: 44 percent of the patients had more than 75-percent improvement, 32 percent of the patients between 50- to 75-percent improvement, 20 percent of the patients had between 25- to 50-percent improvement and only four percent had less than 25-percent improvement. Conclusion: The authors' data show that the handpiece examined provides high efficacy in skin tightening and body contouring after 5 to 8 painless treatments. Patient subjective questionnaires show very high satisfaction rates.

A lncRNA fine tunes the dynamics of a cell state transition involving Lin28, let-7 and de novo DNA methylation.

Execution of pluripotency requires progression from the naïve status represented by mouse embryonic stem cells (ESCs) to a state capacitated for lineage specification. This transition is coordinated at multiple levels. Non-coding RNAs may contribute to this regulatory orchestra. We identified a rodent-specific long non-coding RNA (lncRNA) linc1281, hereafter Ephemeron (Eprn), that modulates the dynamics of exit from naïve pluripotency. Eprn deletion delays the extinction of ESC identity, an effect associated with perduring Nanog expression. In the absence of Eprn, Lin28a expression is reduced which results in persistence of let-7 microRNAs, and the up-regulation of de novo methyltransferases Dnmt3a/b is delayed. Dnmt3a/b deletion retards ES cell transition, correlating with delayed Nanog promoter methylation and phenocopying loss of Eprn or Lin28a. The connection from lncRNA to miRNA and DNA methylation facilitates the acute extinction of naïve pluripotency, a pre-requisite for rapid progression from preimplantation epiblast to gastrulation in rodents. Eprn illustrates how lncRNAs may introduce species-specific network modulations.

The BODY-Q: A Patient-Reported Outcome Instrument for Weight Loss and Body Contouring Treatments.

BACKGROUND: Body contouring performed for cosmetic purposes, or after weight loss, has the potential to improve body image and health-related quality of life (HRQL). The BODY-Q is a new patient-reported outcome (PRO) instrument designed to measure patient perceptions of weight loss and/or body contouring. In this article, we describe the psychometric properties of the BODY-Q scales after an international field-test. METHODS: Weight loss and body contouring patients from Canada, United States, and United Kingdom were recruited between November 2013 and February 2015. Data were collected using an iPad directly into a web-based application or a questionnaire booklet. Rasch measurement theory analysis was used for item reduction and to examine reliability, validity, and ability to detect change. RESULTS: The sample included 403 weight loss and 331 body contouring patients. Most BODY-Q items had ordered thresholds (134/138) and good item fit. Scale reliability was acceptable, ie, Person separation index >0.70 for 16 scales, Cronbach α ≥0.90 for 18 of 18 scales, and Test-retest ≥0.87 for 17 of 18 scales. Appearance and HRQL scores were lower in participants with more obesity-related symptoms, higher body mass index, and more excess skin and in those pre- versus postoperative body contouring. The 134 weight loss patients who completed the BODY-Q twice, either 6 weeks (weight loss/nonsurgical body contouring program) or 6 months (bariatric program) later, improved significantly on 7 appearance and 4 HRQL scales. CONCLUSION: The BODY-Q is a clinically meaningful and scientifically sound patient-reported outcome instrument that can be used to measure outcomes in patients who undergo weight loss and/or body contouring.

c-Myc and downstream targets in the pathogenesis and treatment of cancer.

The c-Myc oncoprotein is a master regulator of genes involved in diverse cellular processes. Situated upstream of signalling pathways regulating cellular replication/growth as well as apoptosis/growth arrest, c-Myc may help integrate processes determining cell numbers and tissue size in physiology and disease. In cancer, this 'dual potential' allows c-Myc to act as its own tumour suppressor. Evidently, given that deregulated expression of c-Myc is present in most, if not all, human cancers (Table 1) and is associated with a poor prognosis, by implication these in-built 'failsafe' mechanisms have been overcome. To explore the complex activity of c-Myc and its potential as a therapeutic target 'post-genome era' technologies for determining global gene expression alongside advanced new models for the study of tumourigenesis in vivo have proved invaluable. Thus, many recent studies have provided encouragement for the therapeutic targeting of c-Myc in cancer and have revealed new protein targets for manipulating aspects of c-Myc activity. The remarkable regression of even advanced and genetically unstable tumours, seen following deactivation of c-Myc in various models is particularly exciting. This review will discuss what is known about the role of c-Myc in growth deregulation and cancer and will conclude with a discussion of the most promising recent developments in Myc-targeted therapeutics.