Comparative analysis and visualization of multiple collinear genomes

Abstract Background Genome browsers are a common tool used by biologists to visualize genomic features including genes, polymorphisms, and many others. However, existing genome browsers and visualization tools are not well-suited to perform meaningful comparative analysis among a large number of genomes. With the increasing quantity and availability of genomic data, there is an increased burden to provide useful visualization and analysis tools for comparison of multiple collinear genomes such as the large panels of model organisms which are the basis for much of the current genetic research. Results We have developed a novel web-based tool for visualizing and analyzing multiple collinear genomes. Our tool illustrates genome-sequence similarity through a mosaic of intervals representing local phylogeny, subspecific origin, and haplotype identity. Comparative analysis is facilitated through reordering and clustering of tracks, which can vary throughout the genome. In addition, we provide local phylogenetic trees as an alternate visualization to assess local variations. Conclusions Unlike previous genome browsers and viewers, ours allows for simultaneous and comparative analysis. Our browser provides intuitive selection and interactive navigation about features of interest. Dynamic visualizations adjust to scale and data content making analysis at variable resolutions and of multiple data sets more informative. We demonstrate our genome browser for an extensive set of genomic data sets composed of almost 200 distinct mouse laboratory strains

Breaking bad habits by improving executive function in individuals with obesity

Background: Two primary factors that contribute to obesity are unhealthy eating and sedentary behavior. These behaviors are particularly difficult to change in the long-term because they are often enacted habitually. Cognitive Remediation Therapy has been modified and applied to the treatment of obesity (CRT-O) with preliminary results of a randomized controlled trial demonstrating significant weight loss and improvements in executive function. The objective of this study was to conduct a secondary data analysis of the CRT-O trial to evaluate whether CRT-O reduces unhealthy habits that contribute to obesity via improvements in executive function. Method: Eighty participants with obesity were randomized to CRT-O or control. Measures of executive function (Wisconsin Card Sort Task and Trail Making Task) and unhealthy eating and sedentary behavior habits were administered at baseline, post-intervention and at 3 month follow-up. Results: Participants receiving CRT-O demonstrated improvements in both measures of executive function and reductions in both unhealthy habit outcomes compared to control. Mediation analyses revealed that change in one element of executive function performance (Wisconsin Card Sort Task perseverance errors) mediated the effect of CRT-O on changes in both habit outcomes. Conclusion: These results suggest that the effectiveness of CRT-O may result from the disruption of unhealthy habits made possible by improvements in executive function. In particular, it appears that cognitive flexibil ity, as measured by the Wisconsin Card Sort task, is a key mechanism in this process. Improving cognitive flexibility may enable individuals to capitalise on interruptions in unhealthy habits by adjusting their behavior in line with their weight loss goals rather than persisting with an unhealthy choice. Trial registration: The RCT was registered with the Australian New Zealand Registry of Clinical Trials (trial id: ACTRN12613000537752)

Weight outcomes audit in 1.3 million adults during their first 3 months' attendance in a commercial weight management programme

Background: Over sixty percent of adults in the UK are now overweight/obese. Weight management on a national scale requires behavioural and lifestyle solutions that are accessible to large numbers of people. Evidence suggests commercial weight management programmes help people manage their weight but there is little research examining those that pay to attend such programmes rather than being referred by primary care. The objective of this analysis was to evaluate the effectiveness of a UK commercial weight management programme in self-referred, fee-paying participants. Methods: Electronic weekly weight records were collated for self-referred, fee-paying participants of Slimming World groups joining between January 2010 and April 2012. This analysis reports weight outcomes in 1,356,105 adult, non-pregnant participants during their first 3 months’ attendance. Data were analysed by regression, ANOVA and for binomial outcomes, chi-squared tests using the R statistical program. Results: Mean (SD) age was 42.3 (13.6) years, height 1.65 m (0.08) and start weight was 88.4 kg (18.8). Mean start BMI was 32.6 kg/m² (6.3 kg/m²) and 5 % of participants were men. Mean weight change of all participants was −3.9 kg (3.6), percent weight change −4.4 (3.8), and BMI change was −1.4 kg/m² (1.3). Mean attendance was 7.8 (4.3) sessions in their first 3 months. For participants attending at least 75 % of possible weekly sessions (n = 478,772), mean BMI change was −2.5 kg/m² (1.3), weight change −6.8 kg (3.7) and percent weight change −7.5 % (3.5). Weight loss was greater in men than women absolutely (−6.5 (5.3) kg vs −3.8 (3.4) kg) and as a percentage (5.7 % (4.4) vs 4.3 % (3.7)), respectively. All comparisons were significant (p < 0.001). Level of attendance and percent weight loss in the first week of attendance together accounted for 55 % of the variability in weight lost during the study period. Conclusions: A large-scale commercial lifestyle-based weight management programme had a significant impact on weight loss outcomes over 3 months. Higher levels of attendance led to levels of weight loss known to be associated with significant clinical benefits, which on this scale may have an impact on public health

Comparative analysis of the ATRX promoter and 5' regulatory region reveals conserved regulatory elements which are linked to roles in neurodevelopment, alpha-globin regulation and testicular function

BACKGROUND ATRX is a tightly-regulated multifunctional protein with crucial roles in mammalian development. Mutations in the ATRX gene cause ATR-X syndrome, an X-linked recessive developmental disorder resulting in severe mental retardation and mild alpha-thalassemia with facial, skeletal and genital abnormalities. Although ubiquitously expressed the clinical features of the syndrome indicate that ATRX is not likely to be a global regulator of gene expression but involved in regulating specific target genes. The regulation of ATRX expression is not well understood and this is reflected by the current lack of identified upstream regulators. The availability of genomic data from a range of species and the very highly conserved 5' regulatory regions of the ATRX gene has allowed us to investigate putative transcription factor binding sites (TFBSs) in evolutionarily conserved regions of the mammalian ATRX promoter. RESULTS We identified 12 highly conserved TFBSs of key gene regulators involved in biologically relevant processes such as neural and testis development and alpha-globin regulation. CONCLUSIONS Our results reveal potentially important regulatory elements in the ATRX gene which may lead to the identification of upstream regulators of ATRX and aid in the understanding of the molecular mechanisms that underlie ATR-X syndrome.This work was supported by Department of Zoology research grants

Parallel Driving and Modulatory Pathways Link the Prefrontal Cortex and Thalamus

Pathways linking the thalamus and cortex mediate our daily shifts from states of attention to quiet rest, or sleep, yet little is known about their architecture in high-order neural systems associated with cognition, emotion and action. We provide novel evidence for neurochemical and synaptic specificity of two complementary circuits linking one such system, the prefrontal cortex with the ventral anterior thalamic nucleus in primates. One circuit originated from the neurochemical group of parvalbumin-positive thalamic neurons and projected focally through large terminals to the middle cortical layers, resembling ‘drivers’ in sensory pathways. Parvalbumin thalamic neurons, in turn, were innervated by small ‘modulatory’ type cortical terminals, forming asymmetric (presumed excitatory) synapses at thalamic sites enriched with the specialized metabotropic glutamate receptors. A second circuit had a complementary organization: it originated from the neurochemical group of calbindin-positive thalamic neurons and terminated through small ‘modulatory’ terminals over long distances in the superficial prefrontal layers. Calbindin thalamic neurons, in turn, were innervated by prefrontal axons through small and large terminals that formed asymmetric synapses preferentially at sites with ionotropic glutamate receptors, consistent with a driving pathway. The largely parallel thalamo-cortical pathways terminated among distinct and laminar-specific neurochemical classes of inhibitory neurons that differ markedly in inhibitory control. The balance of activation of these parallel circuits that link a high-order association cortex with the thalamus may allow shifts to different states of consciousness, in processes that are disrupted in psychiatric diseases

Primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic liver disease with a slowly progressive course. Without treatment, most patients eventually develop fibrosis and cirrhosis of the liver and may need liver transplantation in the late stage of disease. PBC primarily affects women (female preponderance 9–10:1) with a prevalence of up to 1 in 1,000 women over 40 years of age. Common symptoms of the disease are fatigue and pruritus, but most patients are asymptomatic at first presentation. The diagnosis is based on sustained elevation of serum markers of cholestasis, i.e., alkaline phosphatase and gamma-glutamyl transferase, and the presence of serum antimitochondrial antibodies directed against the E2 subunit of the pyruvate dehydrogenase complex. Histologically, PBC is characterized by florid bile duct lesions with damage to biliary epithelial cells, an often dense portal inflammatory infiltrate and progressive loss of small intrahepatic bile ducts. Although the insight into pathogenetic aspects of PBC has grown enormously during the recent decade and numerous genetic, environmental, and infectious factors have been disclosed which may contribute to the development of PBC, the precise pathogenesis remains enigmatic. Ursodeoxycholic acid (UDCA) is currently the only FDA-approved medical treatment for PBC. When administered at adequate doses of 13–15 mg/kg/day, up to two out of three patients with PBC may have a normal life expectancy without additional therapeutic measures. The mode of action of UDCA is still under discussion, but stimulation of impaired hepatocellular and cholangiocellular secretion, detoxification of bile, and antiapoptotic effects may represent key mechanisms. One out of three patients does not adequately respond to UDCA therapy and may need additional medical therapy and/or liver transplantation. This review summarizes current knowledge on the clinical, diagnostic, pathogenetic, and therapeutic aspects of PBC

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402