Non-coding regulatory elements: potential roles in disease and the case of epilepsy

Non-coding DNA (ncDNA) refers to the portion of the genome that does not code for proteins and accounts for the greatest physical proportion of the human genome. ncDNA includes sequences that are transcribed into RNA molecules, such as ribosomal RNAs (rRNAs), microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and un-transcribed sequences that have regulatory functions, including gene promoters and enhancers. Variation in non-coding regions of the genome have an established role in human disease, with growing evidence from many areas, including several cancers, Parkinson's disease and autism. Here, we review the features and functions of the regulatory elements that are present in the non-coding genome and the role that these regions have in human disease. We then review the existing research in epilepsy and emphasise the potential value of further exploring non-coding regulatory elements in epilepsy. In addition, we outline the most widely used techniques for recognising regulatory elements throughout the genome, current methodologies for investigating variation and the main challenges associated with research in the field of non-coding DNA

The Production and Fate of Volatile Organosulfur Compounds in Sulfidic and Ferruginous Sediment

Volatile organic sulfur compounds (VOSCs) link the atmospheric, marine, and terrestrial sulfur cycles in marine and marginal marine environments. Despite the important role VOSCs play in global biogeochemical sulfur cycling, less is known about how the local geochemical conditions influence production and consumption of VOSCs. We present a study of dimethyl sulfide (DMS), methanethiol (MeSH), and dimethylsulfoniopropionate (DMSP) in sulfide-rich (sulfidic) and iron-rich (ferruginous) salt marsh sediment from north Norfolk, UK. Initial results illustrate the importance of minimizing time between sampling in remote field locations and laboratory analysis, due to rapid degradation of VOSCs. With rapid analysis of sediment from different depths, we observe high concentrations of DMS, MeSH, and DMSP, with concentrations in surface sediment an order of magnitude higher than those in previous studies of surface water. We measure systematic differences in the concentration and depth distribution of MeSH and DMS between sediment environments; DMS concentrations are higher in ferruginous sediment, and MeSH concentrations are higher in sulfidic sediment. With repeated measurements over a short time period, we show that the degradation patterns for DMS and MeSH are different in the ferruginous versus sulfidic sediment. We discuss potential biogeochemical interactions that could be driving the observed differences in VOSC dynamics in ferruginous and sulfidic sediment.This work was supported by a Churchill Scholarship to J. V. W., NERC Grant NE/S001352/1 to A.V.T. and J. D. T., NERC Grant NE/K01546X/1 to K. R. R., and NERC Grants NE/P012671/1, NE/N002385/1, and NE/M004449/1 to J. D. T. Initial analyses were supported by ERCStG307582 (CARBONSINK) to A. V. T

Primary Care Atrial Fibrillation Service: outcomes from consultant-led anticoagulation assessment clinics in the primary care setting in the UK

OBJECTIVE: Stroke-risk in atrial fibrillation (AF) can be significantly reduced by appropriate thromboembolic prophylaxis. However, National Institute for Health and Care Excellence estimates suggest that up to half of eligible patients with AF are not anticoagulated, with severe consequences for stroke prevention. We aimed to determine the outcome of an innovative Primary Care AF (PCAF) service on anticoagulation uptake in a cohort of high-risk patients with AF in the UK. METHODS: The PCAF service is a novel cooperative pathway providing specialist resources within general practitioner (GP) practices. It utilises a four-phase protocol to identify high-risk patients with AF (CHA(2)DS(2)-VASc ≥1) who are suboptimally anticoagulated, and delivers Consultant-led anticoagulation assessment within the local GP practice. We assessed rates of anticoagulation in high-risk patients before and after PCAF service intervention, and determined compliance with newly-initiated anticoagulation at follow-up. RESULTS: The PCAF service was delivered in 56 GP practices (population 386 624; AF prevalence 2.1%) between June 2012 and June 2014. 1579 high-risk patients with AF with suboptimal anticoagulation (either not taking any anticoagulation or taking warfarin but with a low time-in-therapeutic-range) were invited for review, with 86% attending. Of 1063 eligible patients on no anticoagulation, 1020 (96%) agreed to start warfarin (459 (43%)) or a non-vitamin K antagonist oral anticoagulant (NOAC, 561 (53%)). The overall proportion of eligible patients receiving anticoagulation improved from 77% to 95% (p<0.0001). Additionally, 111/121 (92%) patients suboptimally treated with warfarin agreed to switch to a NOAC. Audit of eight practices after 195 (185–606) days showed that 90% of patients started on a new anticoagulant therapy had continued treatment. Based on data extrapolated from previous studies, around 30–35 strokes per year may have been prevented in these previously under-treated high-risk patients. CONCLUSIONS: Systematic identification of patients with AF with high stroke-risk and consultation in PCAF consultant-led clinics effectively delivers oral anticoagulation to high-risk patients with AF in the community

Predictors of severe asthma attack re-attendance in Ecuadorian children: a cohort study.

Asthma is a common cause of emergency care attendance in low- and middle-income countries (LMICs). While few prospective studies of predictors for emergency care attendance have been undertaken in high-income countries, none have been performed in a LMIC.We followed a cohort of 5-15-year-old children treated for asthma attacks in emergency rooms of public health facilities in Esmeraldas City, Ecuador. We collected blood and nasal wash samples, and performed spirometry and exhaled nitric oxide fraction measurements. We explored potential predictors for recurrence of severe asthma attacks requiring emergency care over 6 months' follow-up.We recruited 283 children of whom 264 (93%) were followed-up for ≥6 months or until their next asthma attack. Almost half (46%) had a subsequent severe asthma attack requiring emergency care. Predictors of recurrence in adjusted analyses were (adjusted OR, 95% CI) younger age (0.87, 0.79-0.96 per year), previous asthma diagnosis (2.2, 1.2-3.9), number of parenteral corticosteroid courses in previous year (1.3, 1.1-1.5), food triggers (2.0, 1.1-3.6) and eczema diagnosis (4.2, 1.02-17.6). A parsimonious Cox regression model included the first three predictors plus urban residence as a protective factor (adjusted hazard ratio 0.69, 95% CI 0.50-0.95). Laboratory and lung function tests did not predict recurrence.Factors independently associated with recurrent emergency attendance for asthma attacks were identified in a low-resource LMIC setting. This study suggests that a simple risk-assessment tool could potentially be created for emergency rooms in similar settings to identify higher-risk children on whom limited resources might be better focused

‘Like the stranger at a funeral who cries more than the bereaved’: ethical dilemmas in ethnographic research with children

This article contributes to debates on the practicality and utility of prior ethical review in ethnography and qualitative research using an ethnography of children’s involvement in artisanal gold mining work in Ghana as a case study. Reflecting on dilemmas and obstacles encountered in attempts to employ prescribed institutional ethical guidance modelled for childhood research in the UK during the fieldwork, the discussion brings to attention some of the problems that can arise when ethical guidance is not anchored in the lived realities or value systems of the setting in which fieldwork is conducted. The article seeks to rejuvenate calls for more flexible and socio-culturally responsive ethical review and practice as an alternative to the prescriptive ethical regimes

Adaptive introgression underlies polymorphic seasonal camouflage in snowshoe hares

Snowshoe hares (Lepus americanus) maintain seasonal camouflage by molting to a white winter coat, but some hares remain brown during the winter in regions with low snow cover. We show that cis-regulatory variation controlling seasonal expression of the Agouti gene underlies this adaptive winter camouflage polymorphism. Genetic variation at Agouti clustered by winter coat color across multiple hare and jackrabbit species, revealing a history of recurrent interspecific gene flow. Brown winter coats in snowshoe hares likely originated from an introgressed black-tailed jackrabbit allele that has swept to high frequency in mild winter environments. These discoveries show that introgression of genetic variants that underlie key ecological traits can seed past and ongoing adaptation to rapidly changing environments. (c) The Authors, Some Rights Reserved

Symptoms and patient factors associated with diagnostic intervals for pancreatic cancer (SYMPTOM pancreatic study): a prospective cohort study

This is the final version. Available on open access from Elsevier via the DOI in this recordBackground Pancreatic cancer is the tenth most common cancer in the UK; however, outcomes are poor, in part due to late diagnosis. We aimed to identify symptoms and other clinical and sociodemographic factors associated with pancreatic cancer diagnosis and diagnostic intervals. Methods We did this prospective cohort study at seven hospitals in two regions in England. We recruited participants aged 40 years or older who were referred for suspicion of pancreatic cancer. Data were collected by use of a patient questionnaire and primary care and hospital records. Descriptive and regression analyses were done to examine associations between symptoms and patient factors with the total diagnostic interval (time from onset of the first symptom to the date of diagnosis), comprising patient interval (time from first symptom to first presentation) and health system interval (time from first presentation to diagnosis). Findings We recruited 391 participants between Jan 1, 2011, and Dec 31, 2014 (24% response rate). 119 (30%) participants were diagnosed with pancreatic cancer (41 [34%] had metastatic disease), 47 (12%) with other cancers, and 225 (58%) with no cancer. 212 (54%) patients had multiple first symptoms whereas 161 (41%) patients had a solitary first symptom. In this referred population, no initial symptoms were reported more frequently by patients with cancer than by those with no cancer. Several subsequent symptoms predicted pancreatic cancer: jaundice (51 [49%] of 105 patients with pancreatic cancer vs 25 [12%] of 211 patients with no cancer; p<0·0001), fatigue (48/95 [51%] vs 40/155 [26%]; p=0·0001), change in bowel habit (36/87 [41%] vs 28/175 [16%]; p<0·0001), weight loss (55/100 [55%] vs 41/184 [22%]; p<0·0001), and decreased appetite (41/86 [48%] vs 41/156 [26%]; p=0·0011). There was no difference in any interval between patients with pancreatic cancer and those with no cancer (total diagnostic interval: median 117 days [IQR 57–234] vs 131 days [IQR 66–284]; p=0·32; patient interval 18 days [0–37] vs 15 days [1–62]; p=0·22; health system interval 76 days [28–161] vs 79 days [30–156]; p=0·68). Total diagnostic intervals were shorter when jaundice (hazard ratio [HR] 1·38, 95% CI 1·07–1·78; p=0·013) and decreased appetite (1·42, 1·11–1·82; p=0·0058) were reported as symptoms, and longer in patients presenting with indigestion (0·71, 0·56–0·89; p=0·0033), back pain (0·77, 0·59–0·99; p=0·040), diabetes (0·71, 0·52–0·97; p=0·029), and self-reported anxiety or depression, or both (0·67, 0·49–0·91; p=0·011). Health system intervals were likewise longer with indigestion (0·74, 0·58–0·95; p=0·0018), back pain (0·76, 0·58–0·99; p=0·044), diabetes (0·63, 0·45–0·89; p=0·0082), and self-reported anxiety or depression, or both (0·63, 0·46–0·88; p=0·0064), but were shorter with male sex (1·41, 1·1–1·81; p=0·0072) and decreased appetite (1·56, 1·19–2·06; p=0·0015). Weight loss was associated with longer patient intervals (HR 0·69, 95% CI 0·54–0·89; p=0·0047). Interpretation Although we identified no initial symptoms that differentiated people diagnosed with pancreatic cancer from those without pancreatic cancer, key additional symptoms might signal the disease. Health-care professionals should be vigilant to the possibility of pancreatic cancer in patients with evolving gastrointestinal and systemic symptoms, particularly in those with diabetes or mental health comorbidities. Funding National Institute for Health Research and Pancreatic Cancer Action.National Institute for Health Research (NIHR

Identification of Specific Circular RNA Expression Patterns and MicroRNA Interaction Networks in Mesial Temporal Lobe Epilepsy

Circular RNAs (circRNAs) regulate mRNA translation by binding to microRNAs (miRNAs), and their expression is altered in diverse disorders, including cancer, cardiovascular disease, and Parkinson’s disease. Here, we compare circRNA expression patterns in the temporal cortex and hippocampus of patients with pharmacoresistant mesial temporal lobe epilepsy (MTLE) and healthy controls. Nine circRNAs showed significant differential expression, including circRNA-HOMER1, which is expressed in synapses. Further, we identified miRNA binding sites within the sequences of differentially expressed (DE) circRNAs; expression levels of mRNAs correlated with changes in complementary miRNAs. Gene set enrichment analysis of mRNA targets revealed functions in heterocyclic compound binding, regulation of transcription, and signal transduction, which maintain the structure and function of hippocampal neurons. The circRNA–miRNA–mRNA interaction networks illuminate the molecular changes in MTLE, which may be pathogenic or an effect of the disease or treatments and suggests that DE circRNAs and associated miRNAs may be novel therapeutic targets

Multimodal characterization of the visual network in Huntington's disease gene carriers

Objective A sensorimotor network structural phenotype predicted motor task performance in a previous study in Huntington’s disease (HD) gene carriers. We investigated in the visual network whether structure – function – behaviour relationship patterns, and the effects of the HD mutation, extended beyond the sensorimotor network. Methods We used multimodal visual network MRI structural measures (cortical thickness and white matter connectivity), plus visual evoked potentials and task performance (Map Search; Symbol Digit Modalities Test) in healthy controls and HD gene carriers. Results Using principal component (PC) analysis, we identified a structure – function relationship common to both groups. PC scores differed between groups indicating white matter disorganization (higher RD, lower FA) and slower, and more disperse, VEP signal transmission (higher VEP P100 latency and lower VEP P100 amplitude) in HD than controls while task performance was similar. Conclusions HD may be associated with reduced white matter organization and efficient visual network function but normal task performance. Significance These findings indicate that structure – function relationships in the visual network, and the effects of the HD mutation, share some commonalities with those in the sensorimotor network. However, implications for task performance differ between the two networks suggesting the influence of network specific factors