Using a 3D virtual muscle model to link gene expression changes during myogenesis to protein spatial location in muscle

Background: Myogenesis is an ordered process whereby mononucleated muscle precursor cells (myoblasts) fuse into multinucleated myotubes that eventually differentiate into myofibres, involving substantial changes in gene expression and the organisation of structural components of the cells. To gain further insight into the orchestration of these structural changes we have overlaid the spatial organisation of the protein components of a muscle cell with their gene expression changes during differentiation using a new 3D visualisation tool: the Virtual Muscle 3D (VMus3D)

Alcohol, tobacco and illicit drug use amongst same-sex attracted women: results from the Western Australian Lesbian and Bisexual Women's Health and Well-Being Survey

Background: The prevalence of alcohol, tobacco and illicit drug use has been reported to be higheramongst lesbian and bisexual women (LBW) than their heterosexual counterparts. However, few studieshave been conducted with this population in Australia and rates that have been reported vary considerably.Methods: A self-completed questionnaire exploring a range of health issues was administered to 917women aged 15-65 years (median 34 years) living in Western Australia, who identified as lesbian orbisexual, or reported having sex with another woman. Participants were recruited from a range of settings,including Perth Pride Festival events (67.0%, n = 615), online (13.2%, n = 121), at gay bars and nightclubs(12.9%, n = 118), and through community groups (6.9%, n = 63). Results were compared against availablestate and national surveillance data.Results: LBW reported consuming alcohol more frequently and in greater quantities than women in thegeneral population. A quarter of LBW (25.7%, n = 236) exceeded national alcohol guidelines by consumingmore than four standard drinks on a single occasion, once a week or more. However, only 6.8% (n = 62)described themselves as a heavy drinker, suggesting that exceeding national alcohol guidelines may be anormalised behaviour amongst LBW. Of the 876 women who provided data on tobacco use, 28.1% (n =246) were smokers, nearly double the rate in the female population as a whole. One third of the sample(33.6%, n = 308) reported use of an illicit drug in the previous six months. The illicit drugs most commonlyreported were cannabis (26.4%, n = 242), meth/amphetamine (18.6%, n = 171), and ecstasy (17.9%, n =164). Injecting drug use was reported by 3.5% (n = 32) of participants.Conclusion: LBW appear to use alcohol, tobacco and illicit drugs at higher rates than women generally,indicating that mainstream health promotion messages are not reaching this group or are not perceivedas relevant. There is an urgent need for public health practitioners working in the area of substance useto recognise that drug consumption and use patterns of LBW are likely to be different to the widerpopulation and that special considerations and strategies are required to address the unique and complexneeds of this population

The Biochemistry, Ultrastructure, and Subunit Assembly Mechanism of AMPA Receptors

The AMPA-type ionotropic glutamate receptors (AMPA-Rs) are tetrameric ligand-gated ion channels that play crucial roles in synaptic transmission and plasticity. Our knowledge about the ultrastructure and subunit assembly mechanisms of intact AMPA-Rs was very limited. However, the new studies using single particle EM and X-ray crystallography are revealing important insights. For example, the tetrameric crystal structure of the GluA2cryst construct provided the atomic view of the intact receptor. In addition, the single particle EM structures of the subunit assembly intermediates revealed the conformational requirement for the dimer-to-tetramer transition during the maturation of AMPA-Rs. These new data in the field provide new models and interpretations. In the brain, the native AMPA-R complexes contain auxiliary subunits that influence subunit assembly, gating, and trafficking of the AMPA-Rs. Understanding the mechanisms of the auxiliary subunits will become increasingly important to precisely describe the function of AMPA-Rs in the brain. The AMPA-R proteomics studies continuously reveal a previously unexpected degree of molecular heterogeneity of the complex. Because the AMPA-Rs are important drug targets for treating various neurological and psychiatric diseases, it is likely that these new native complexes will require detailed mechanistic analysis in the future. The current ultrastructural data on the receptors and the receptor-expressing stable cell lines that were developed during the course of these studies are useful resources for high throughput drug screening and further drug designing. Moreover, we are getting closer to understanding the precise mechanisms of AMPA-R-mediated synaptic plasticity

Defensive coping and health-related quality of life in chronic kidney disease: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Coping with the stresses of chronic disease is considered as a key factor in the perceived impairment of health related quality of life (HRQL). Little is known though about these associations in chronic kidney disease (CKD). The present study aimed to investigate the relationship of defensive coping and HRQL among patients in different CKD stages, after adjusting for psychological distress, sociodemographic and disease-related variables.</p> <p>Methods</p> <p>The sample consisted of 98 CKD patients, attending a university nephrology department. Seventy-nine (79) pre-dialysis patients of disease stages 3 to 4 and 19 dialysis patients were included. HRQL was assessed by the 36-item Short-Form health survey (SF-36), defensive coping by the Rationality/Emotional Defensiveness (R/ED) scale of the Lifestyle Defense Mechanism Inventory (LDMI) and psychological distress by the depression and anxiety scales of the revised Hopkins Symptom CheckList (SCL-90-R). Regression analyses were carried out to examine the association between SF-36 dimensions and defensive coping style.</p> <p>Results</p> <p>Patients on dialysis had worse scores on SF-36 scales measuring physical aspects of HRQL. In the fully adjusted analysis, a higher defensive coping score was significantly associated with a lower score on the mental component summary (MCS) scale of the SF-36 (worse mental health). In contrast, a higher defensive score showed a small positive association with the physical component summary (PCS) scale of the SF-36 (better health), but this was marginally significant.</p> <p>Conclusions</p> <p>The results provided evidence that emotional defensiveness as a coping style tends to differentially affect the mental and the physical component of HRQL in CKD. Clinicians should be aware of the effects of long-term denial and could examine the possibility of screening for defensive coping and depression in recently diagnosed CKD patients with the aim to improve both physical and mental health.</p

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe