Coordinated regulation of Myc trans-activation targets by Polycomb and the Trithorax group protein Ash1

<p>Abstract</p> <p>Background</p> <p>The Myc oncoprotein is a transcriptional regulator whose function is essential for normal development. Myc is capable of binding to 10% of the mammalian genome, and it is unclear how a developing embryo controls the DNA binding of its abundant Myc proteins in order to avoid Myc's potential for inducing tumorigenesis.</p> <p>Results</p> <p>To identify chromatin binding proteins with a potential role in controlling Myc activity, we established a genetic assay for dMyc activity in <it>Drosophila</it>. We conducted a genome-wide screen using this assay, and identified the Trithorax Group protein Ash1 as a modifier of dMyc activity. Ash1 is a histone methyltransferase known for its role in opposing repression by Polycomb. Using RNAi in the embryo and Affymetrix microarrays, we show that <it>ash1 </it>RNAi causes the increased expression of many genes, suggesting that it is directly or indirectly required for repression in the embryo, in contrast to its known role in maintenance of activation. Many of these genes also respond similarly upon depletion of <it>Pc </it>and <it>pho </it>transcripts, as determined by concurrent microarray analysis of <it>Pc </it>and <it>pho </it>RNAi embryos, suggesting that the three are required for low levels of expression of a common set of targets. Further, many of these overlapping targets are also activated by Myc overexpression. We identify a second group of genes whose expression in the embryo requires Ash1, consistent with its previously established role in maintenance of activation. We find that this second group of Ash1 targets overlaps those activated by Myc and that ectopic Myc overcomes their requirement for Ash1.</p> <p>Conclusion</p> <p>Genetic, genomic and chromatin immunoprecipitation data suggest a model in which Pc, Ash1 and Pho are required to maintain a low level of expression of embryonic targets of activation by Myc, and that this occurs, directly or indirectly, by a combination of disparate chromatin modifications.</p

“I’ll look after the kids while you go and have a shower”: An Evaluation of a service to address mild to moderate maternal perinatal mental health problems

Background: Perinatal mental health (PMH) problems are a major public health concern because they may impair parenting ability which potentially has an immediate and long-term impact on the physical, cognitive and emotional health of the child. Aims: We evaluated a Perinatal Support Service (PSS) which supports positive attachment between mothers with PMH problems and their child, to evidence its impact on maternal mental health and maternal-infant interaction. Method: Using a mixed-methods approach, anonymised pre and post service outcomes data from 123 clients, fourteen interviews and a focus group discussion were analysed. Results: We found significant improvement in anxiety (t (55) = 6.96, p<.01, 95% CI [3.15, 5.70]), and depression (t (55) = 6.58, p <.01, 95% CI [3.03, 5.68]) on the HADS, and on the GAD -7 (t (12) = 4.541, p = .001, 95% CI [3.48,9.90]) after the PSS. Anxiety post service (M=9.08, SD = 4.96) was lower than baseline anxiety (M=15.77, SD = 4.68). Receiving emotional and practical support contributed to improvements in mental health and mother-child interaction. Conclusion: Given the paucity of PMH services in the UK, it is imperative that services such as the PSS continue to receive funding to address unmet PMH needs

Synchronous reorientation of the Woodlark Basin spreading center

Abstract A sidescan and multibeam bathymetry survey of the Woodlark Basin reveals that its 500-km-long spreading center reoriented synchronously, without propagation, about 80 ka. There is no evidence of the V-shaped pseudofault geometry typical of spreading center propagation, nor of the progressive fanning of seafloor fabric characteristic of spreading center rotation. The reorientation is recognized by a sharp contact between two seafloor fabric trends, and ruptured off-axis lithosphere formed up to 0.7 m.y. previously. The length of the reoriented spreading segments and the tendency to fault pre-reorientation seafloor fabric are controlled by the strength of the lithosphere, the angle of the reorientation, and the length of preexisting spreading and transform segments. We document the process of synchronous reorientation in the Woodlark Basin and propose that it may occur in other ocean basins

Living with frailty and haemodialysis: a qualitative study

Background: Frailty is highly prevalent in people receiving haemodialysis (HD) and is associated with poor outcomes. Understanding the lived experiences of this group is essential to inform holistic care delivery. / Methods: Semi-structured interviews with N = 25 prevalent adults receiving HD from 3 HD units in the UK. Eligibility criteria included a Clinical Frailty Scale (CFS) score of 4–7 and a history of at least one fall in the last 6 months. Sampling began guided by maximum variation sampling to ensure diversity in frailty status; subsequently theoretical sampling enabled exploration of preliminary themes. Analysis was informed by constructivist grounded theory; later we drew upon the socioecological model. / Results: Participants had a mean age of 69 ± 10 years, 13 were female, and 13 were White British. 14 participants were vulnerable or mildly frail (CFS 4–5), and 11 moderately or severely frail (CFS 6–7). Participants characterised frailty as weight loss, weakness, exhaustion, pain and sleep disturbance arising from multiple long-term conditions. Participants’ accounts revealed: the consequences of frailty (variable function and psychological ill-health at the individual level; increasing reliance upon family at the interpersonal level; burdensome health and social care interactions at the organisational level; reduced participation at the community level; challenges with financial support at the societal level); coping strategies (avoidance, vigilance, and resignation); and unmet needs (overprotection from family and healthcare professionals, transactional health and social care exchanges). / Conclusions: The implementation of a holistic needs assessment, person-centred health and social care systems, greater family support and enhancing opportunities for community participation may all improve outcomes and experience. An approach which encompasses all these strategies, together with wider public health interventions, may have a greater sustained impact. Trial registration: ISRCTN12840463

Exercise for people living with frailty and receiving haemodialysis:a mixed-methods randomised controlled feasibility study

Objectives Frailty is highly prevalent in haemodialysis (HD) patients, leading to poor outcomes. This study aimed to determine whether a randomised controlled trial (RCT) of intradialytic exercise is feasible for frail HD patients, and explore how the intervention may be tailored to their needs.Design Mixed-methods feasibility.Setting and participants Prevalent adult HD patients of the CYCLE-HD trial with a Clinical Frailty Scale Score of 4–7 (vulnerable to severely frail) were eligible for the feasibility study.Interventions Participants in the exercise group undertook 6 months of three times per week, progressive, moderate intensity intradialytic cycling (IDC).Outcomes Primary outcomes were related to feasibility. Secondary outcomes were falls incidence measured from baseline to 1 year following intervention completion, and exercise capacity, physical function, physical activity and patient-reported outcomes measured at baseline and 6 months. Acceptability of trial procedures and the intervention were explored via diaries and interviews with n=25 frail HD patients who both participated in (n=13, 52%), and declined (n=12, 48%), the trial.Results 124 (30%) patients were eligible, and of these 64 (52%) consented with 51 (80%) subsequently completing a baseline assessment. n=24 (71% male; 59±13 years) dialysed during shifts randomly assigned to exercise and n=27 (81% male; 65±11 years) shifts assigned to usual care. n=6 (12%) were lost to follow-up. The exercise group completed 74% of sessions. 27%–89% of secondary outcome data were missing. Frail HD patients outlined several ways to enhance trial procedures. Maintaining ability to undertake activities of daily living and social participation were outcomes of primary importance. Participants desired a varied exercise programme.Conclusions A definitive RCT is feasible, however a comprehensive exercise programme may be more efficacious than IDC in this population.</div

Mundane objects in the city: Laundry practices and the making and remaking of public/private sociality and space in London and New York

The paper considers how shifting laundry practices and technologies associated with dirty washing have over time summoned different spaces, socialities and socio-spatial assemblages in the city, enrolling different actors and multiple publics and constituting different associations, networks and relations in its wake as it travels from the home and back again. It argues that rather than being an inert object of unpleasant matter, whose encounter with humans has been largely restricted to certain categories of person for its transformation to re-use, and thus passed unnoticed, the paper explores how laundry practices have figured in producing and reproducing gendered (and classed) relations of labour, and enacting multiple socio-spatial, and gendered, relations and assemblages in the city, which have largely gone unnoticed in accounts of everyday urban life

Tectonic and magmatic controls on hydrothermal activity in the Woodlark Basin

The Woodlark Basin is one of the rare places on earth where the transition from continental breakup to seafloor spreading can be observed. The potential juxtaposition of continental rocks, a large magmatic heat source, crustal-scale faulting, and hydrothermal circulation has made the Woodlark Basin a prime target for seafloor mineral exploration. However, over the past 20 years, only two locations of active hydrothermalism had been found. In 2009 we surveyed 435 km of the spreading axis for the presence of hydrothermal plumes. Only one additional plume was found, bringing the total number of plumes known over 520 km of ridge axis to only 3, much less than at ridges with similar spreading rates globally. Particularly the western half of the basin (280 km of axis) is apparently devoid of high temperature plumes despite having thick crust and a presumably high magmatic budget. This paucity of hydrothermal activity may be related to the peculiar tectonic setting at Woodlark, where repeated ridge jumps and a re-location of the rotation pole both lead to axial magmatism being more widely distributed than at many other, more mature and stable mid-ocean ridges. These factors could inhibit the development of both a stable magmatic heat source and the deeply penetrating faults needed to create long-lived hydrothermal systems. We conclude that large seafloor massive sulfide deposits, potential targets for seafloor mineral exploration, will probably not be present along the spreading axis of the Woodlark Basin, especially in its younger, western portion

Assessing the Impact and Effectiveness of Hearing Voices Network Self-Help Groups

The Hearing Voices Network (HVN) is an influential service-user led organisation that promotes self-help as an important aspect of recovery. This study presents the first systematic assessment of the impact and effectiveness of HVN self-help groups. A customized 45-item questionnaire, the Hearing Voices Groups Survey, was sent to 62 groups affiliated with the English HVN. 101 responses were received. Group attendance was credited with a range of positive emotional, social and clinical outcomes. Aspects that were particularly valued included: opportunities to meet other voice hearers, provision of support that was unavailable elsewhere, and the group being a safe and confidential place to discuss difficult issues. Participants perceived HVN groups to facilitate recovery processes and to be an important resource for helping them cope with their experiences. Mental health professionals can use their expertise to support the successful running of these groups

A randomised controlled trial of a brief online mindfulness-based intervention on paranoia in a non-clinical sample

Paranoia is common and distressing in the general population and can impact on health, emotional well-being and social functioning, such that effective interventions are needed. Brief online mindfulness-based interventions (MBIs) have been shown to reduce symptoms of anxiety and depression in non-clinical samples, however at present there is no research investigating whether they can reduce paranoia. The current study explored whether a brief online MBI increased levels of mindfulness and reduced levels of paranoia in a non-clinical population. The mediating effect of mindfulness on any changes in paranoia was also investigated. One hundred and ten participants were randomly allocated to either a two week online MBI including 10 minutes of daily guided mindfulness practice or to a waitlist control condition. Measures of mindfulness and paranoia were administered at baseline, post-intervention and one-week follow-up. Participants in the MBI group displayed significantly greater reductions in paranoia compared to the waitlist control group. Mediation analysis demonstrated that change in mindfulness skills (specifically the observe, describe and nonreact facets of the FFMQ) mediated the relationship between intervention type and change in levels of paranoia. This study provides evidence that a brief online MBI can significantly reduce levels of paranoia in a non-clinical population. Furthermore, increases in mindfulness skills from this brief online MBI can mediate reductions in non-clinical paranoia. The limitations of the study are discussed

Gene Regulation and Epigenetic Remodeling in Murine Embryonic Stem Cells by c-Myc

BACKGROUND:The Myc oncoprotein, a transcriptional regulator involved in the etiology of many different tumor types, has been demonstrated to play an important role in the functions of embryonic stem (ES) cells. Nonetheless, it is still unclear as to whether Myc has unique target and functions in ES cells. METHODOLOGY/PRINCIPAL FINDINGS:To elucidate the role of c-Myc in murine ES cells, we mapped its genomic binding sites by chromatin-immunoprecipitation combined with DNA microarrays (ChIP-chip). In addition to previously identified targets we identified genes involved in pluripotency, early development, and chromatin modification/structure that are bound and regulated by c-Myc in murine ES cells. Myc also binds and regulates loci previously identified as Polycomb (PcG) targets, including genes that contain bivalent chromatin domains. To determine whether c-Myc influences the epigenetic state of Myc-bound genes, we assessed the patterns of trimethylation of histone H3-K4 and H3-K27 in mES cells containing normal, increased, and reduced levels of c-Myc. Our analysis reveals widespread and surprisingly diverse changes in repressive and activating histone methylation marks both proximal and distal to Myc binding sites. Furthermore, analysis of bulk chromatin from phenotypically normal c-myc null E7 embryos demonstrates a 70-80% decrease in H3-K4me3, with little change in H3-K27me3, compared to wild-type embryos indicating that Myc is required to maintain normal levels of histone methylation. CONCLUSIONS/SIGNIFICANCE:We show that Myc induces widespread and diverse changes in histone methylation in ES cells. We postulate that these changes are indirect effects of Myc mediated by its regulation of target genes involved in chromatin remodeling. We further show that a subset of PcG-bound genes with bivalent histone methylation patterns are bound and regulated in response to altered c-Myc levels. Our data indicate that in mES cells c-Myc binds, regulates, and influences the histone modification patterns of genes involved in chromatin remodeling, pluripotency, and differentiation