Activation of an Endogenous Retrovirus-Associated Long Non-Coding RNA in Human Adenocarcinoma

Background Long non-coding RNAs (lncRNAs) are emerging as molecules that significantly impact many cellular processes and have been associated with almost every human cancer. Compared to protein-coding genes, lncRNA genes are often associated with transposable elements, particularly with endogenous retroviral elements (ERVs). ERVs can have potentially deleterious effects on genome structure and function, so these elements are typically silenced in normal somatic tissues, albeit with varying efficiency. The aberrant regulation of ERVs associated with lncRNAs (ERV-lncRNAs), coupled with the diverse range of lncRNA functions, creates significant potential for ERV-lncRNAs to impact cancer biology. Methods We used RNA-seq analysis to identify and profile the expression of a novel lncRNA in six large cohorts, including over 7,500 samples from The Cancer Genome Atlas (TCGA). Results We identified the tumor-specific expression of a novel lncRNA that we have named Endogenous retroViral-associated ADenocarcinoma RNA or ‘EVADR’, by analyzing RNA-seq data derived from colorectal tumors and matched normal control tissues. Subsequent analysis of TCGA RNA-seq data revealed the striking association of EVADR with adenocarcinomas, which are tumors of glandular origin. Moderate to high levels of EVADR were detected in 25 to 53% of colon, rectal, lung, pancreas and stomach adenocarcinomas (mean = 30 to 144 FPKM), and EVADR expression correlated with decreased patient survival (Cox regression; hazard ratio = 1.47, 95% confidence interval = 1.06 to 2.04, P = 0.02). In tumor sites of non-glandular origin, EVADR expression was detectable at only very low levels and in less than 10% of patients. For EVADR, a MER48 ERV element provides an active promoter to drive its transcription. Genome-wide, MER48 insertions are associated with nine lncRNAs, but none of the MER48-associated lncRNAs other than EVADR were consistently expressed in adenocarcinomas, demonstrating the specific activation of EVADR. The sequence and structure of the EVADR locus is highly conserved among Old World monkeys and apes but not New World monkeys or prosimians, where the MER48 insertion is absent. Conservation of the EVADR locus suggests a functional role for this novel lncRNA in humans and our closest primate relatives. Conclusions Our results describe the specific activation of a highly conserved ERV-lncRNA in numerous cancers of glandular origin, a finding with diagnostic, prognostic and therapeutic implications

Dysregulated Zn2+ homeostasis impairs cardiac type-2 ryanodine receptor and mitsugumin 23 functions, leading to sarcoplasmic reticulum Ca2+ leakage

SJP is supported by a Royal Society of Edinburgh Biomedical Fellowship. Benedict Reilly-O’Donnell is supported by a University of St Andrews 600th Anniversary Scholarship. This work was supported by the British Heart Foundation (grant no: FS/14/69/31001 to SJP) and the Japan Society for the Promotion of Science (Core-to-Core Program awarded to HT).Aberrant Zn2+ homeostasis is associated with dysregulated intracellular Ca2+ release, resulting in chronic heart failure. In the failing heart a small population of cardiac ryanodine receptors (RyR2) displays sub-conductance-state gating leading to Ca2+ leakage from sarcoplasmic reticulum (SR) stores, which impairs cardiac contractility. Previous evidence suggests contribution of RyR2-independent Ca2+ leakage through an uncharacterized mechanism. We sought to examine the role of Zn2+ in shaping intracellular Ca2+ release in cardiac muscle. Cardiac SR vesicles prepared from sheep or mouse ventricular tissue were incorporated into phospholipid bilayers under voltage-clamp conditions, and the direct action of Zn2+ on RyR2 channel function was examined. Under diastolic conditions, the addition of pathophysiological concentrations of Zn2+ (≥2 nm) caused dysregulated RyR2-channel openings. Our data also revealed that RyR2 channels are not the only SR Ca2+-permeable channels regulated by Zn2+. Elevating the cytosolic Zn2+ concentration to 1 nm increased the activity of the transmembrane protein mitsugumin 23 (MG23). The current amplitude of the MG23 full-open state was consistent with that previously reported for RyR2 sub-conductance gating, suggesting that in heart failure in which Zn2+ levels are elevated, RyR2 channels do not gate in a sub-conductance state, but rather MG23-gating becomes more apparent. We also show that in H9C2 cells exposed to ischemic conditions, intracellular Zn2+ levels are elevated, coinciding with increased MG23 expression. In conclusion, these data suggest that dysregulated Zn2+ homeostasis alters the function of both RyR2 and MG23 and that both ion channels play a key role in diastolic SR Ca2+ leakage.Publisher PDFPeer reviewe

Microlaser-based contractility sensing in single cardiomyocytes and whole hearts

Microscopic whispering gallery mode lasers detect minute changes in cellular refractive index inside individual cardiac cells and in live zebrafish. We show that these signals encode cardiac contractility that can be used for intravital sensing.Postprin

Development of a standard for calculation and measurement of the moderator temperature coefficient of reactivity in water-moderated power reactors

The contents of ANS 19.11, the standard for ``Calculation and Measurement of the Moderator Temperature Coefficient of Reactivity in Water-Moderated Power Reactors,`` are described. The standard addresses the calculation of the moderator temperature coefficient (MTC) both at standby conditions and at power. In addition, it describes several methods for the measurement of the at-power MTC and assesses their relative advantages and disadvantages. Finally, it specifies a minimum set of documentation requirements for compliance with the standard

Association between Hypertension and Retinal Vascular Features in Ultra-Widefield Fundus Imaging

Objective: Changes to the retinal vasculature are known to be associated with hypertension independently of traditional risk factors. We investigated whether measurements of retinal vascular calibre from ultra-widefield fundus imaging were associated with hypertensive status.Methods: We retrospectively collected and semiautomatically measured ultra-widefield retinal fundus images from a subset of participants enrolled in an ongoing population study of ageing, categorised as normotensive or hypertensive according to thresholds on systolic/diastolic blood pressure (140/90 mm Hg) measured in a clinical setting. Vascular calibre in the peripheral retina was measured to calculate the nasal-annular arteriole:venule ratio (NA-AVR), a novel combined parameter.Results: Left and right eyes were analysed from 440 participants (aged 50-59 years, mean age of 54.6±2.9 years, 247, 56.1% women), including 151 (34.3%) categorised as hypertensive. Arterioles were thinner and the NA-AVR was smaller in people with hypertension. The area under the receiver operating characteristic curve of NA-AVR for hypertensive status was 0.73 (95% CI 0.68 to 0.78) using measurements from left eyes, while for right eyes, it was 0.64 (95% CI 0.59 to 0.70), representing evidence of a statistically significant difference between the eyes (p=0.020).Conclusions: Semiautomated measurements of NA-AVR in ultra-widefield fundus imaging were associated with hypertension. With further development, this may help screen people attending routine eye health check-ups for high blood pressure. These individuals may then follow a care pathway for suspected hypertension. Our results showed differences between left and right eyes, highlighting the importance of investigating both eyes of a patient.</p

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Mothers’ accounts of the impact on emotional wellbeing of organised peer support in pregnancy and early parenthood: a qualitative study

Background The transition to parenthood is a potentially vulnerable time for mothers’ mental health and approximately 9–21% of women experience depression and/or anxiety at this time. Many more experience sub-clinical symptoms of depression and anxiety, as well as stress, low self-esteem and a loss of confidence. Women’s emotional wellbeing is more at risk if they have little social support, a low income, are single parents or have a poor relationship with their partner. Peer support can comprise emotional, affirmational, informational and practical support; evidence of its impact on emotional wellbeing during pregnancy and afterwards is mixed. Methods This was a descriptive qualitative study, informed by phenomenological social psychology, exploring women’s experiences of the impact of organised peer support on their emotional wellbeing during pregnancy and in early parenthood. Semi-structured qualitative interviews were undertaken with women who had received peer support provided by ten projects in different parts of England, including both projects offering ‘mental health’ peer support and others offering more broadly-based peer support. The majority of participants were disadvantaged Black and ethnic minority women, including recent migrants. Interviews were audio-recorded and transcripts were analysed using inductive thematic analysis. Results 47 mothers were interviewed. Two key themes emerged: (1) ‘mothers’ self-identified emotional needs’, containing the subthemes ‘emotional distress’, ‘stressful circumstances’, ‘lack of social support’, and ‘unwilling to be open with professionals’; and (2) ‘how peer support affects mothers’, containing the subthemes ‘social connection’, ‘being heard’, ‘building confidence’, ‘empowerment’, ‘feeling valued’, ‘reducing stress through practical support’ and ‘the significance of “mental health” peer experiences’. Women described how peer support contributed to reducing their low mood and anxiety by overcoming feelings of isolation, disempowerment and stress, and increasing feelings of self-esteem, self-efficacy and parenting competence. Conclusion One-to-one peer support during pregnancy and after birth can have a number of interrelated positive impacts on the emotional wellbeing of mothers. Peer support is a promising and valued intervention, and may have particular salience for ethnic minority women, those who are recent migrants and women experiencing multiple disadvantages

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis