DNA methylation plays a fundamental role in the regulation of the genome, but the optimal strategy for analysis of genome-wide DNA methylation data remains to be determined. We developed a ...comprehensive analysis pipeline for epigenome-wide association studies (EWAS) using the Illumina Infinium HumanMethylation450 BeadChip, based on 2,687 individuals, with 36 samples measured in duplicate. We propose new approaches to quality control, data normalisation and batch correction through control-probe adjustment and establish a null hypothesis for EWAS using permutation testing. Our analysis pipeline outperforms existing approaches, enabling accurate identification of methylation quantitative trait loci for hypothesis driven follow-up experiments.
Engaged Research and Practice Betty Overton, Penny A. Pasque, John C. Burkhardt / Betty Overton, Penny A. Pasque, John C. Burkhardt
2017, 2016, 2023-07-03, 2016-11-09
eBook
Engaged Research and Practice is about the intersection of two prevailing and complementary ideas that are commanding attention in higher education: engaged research and higher education for the ...public good.
Engaged, actionable, or participatory research and scholarship offers a process for identifying and addressing the complex issues facing our communities and society. This handbook offers important insights and tangible examples of how higher education professionals and educators can work directly with communities and in policy settings to understand the deeper meanings often lost in conversations about educational opportunity. Each chapter addresses the ways in which faculty, community, and administrative leaders can connect research and practice through unique research projects. The authors offer clear explanations of "how" their engaged research was conducted to illustrate explicit pathways for practitioners. This book also includes short narratives where authors involved with this research reflect on their experiences and the lessons they learned while immersed in community- and policy-related work.
Liver dysfunction and type 2 diabetes (T2D) are consistently associated. However, it is currently unknown whether liver dysfunction contributes to, results from, or is merely correlated with T2D due ...to confounding. We used Mendelian randomization to investigate the presence and direction of any causal relation between liver function and T2D risk including up to 64,094 T2D case and 607,012 control subjects. Several biomarkers were used as proxies of liver function (i.e., alanine aminotransferase ALT, aspartate aminotransferase AST, alkaline phosphatase ALP, and γ-glutamyl transferase GGT). Genetic variants strongly associated with each liver function marker were used to investigate the effect of liver function on T2D risk. In addition, genetic variants strongly associated with T2D risk and with fasting insulin were used to investigate the effect of predisposition to T2D and insulin resistance, respectively, on liver function. Genetically predicted higher circulating ALT and AST were related to increased risk of T2D. There was a modest negative association of genetically predicted ALP with T2D risk and no evidence of association between GGT and T2D risk. Genetic predisposition to higher fasting insulin, but not to T2D, was related to increased circulating ALT. Since circulating ALT and AST are markers of nonalcoholic fatty liver disease (NAFLD), these findings provide some support for insulin resistance resulting in NAFLD, which in turn increases T2D risk.
Accurate monitoring of changes in dietary patterns in response to food policy implementation is challenging. Metabolic profiling allows simultaneous measurement of hundreds of metabolites in urine, ...the concentrations of which can be affected by food intake. We hypothesised that metabolic profiles of urine samples developed under controlled feeding conditions reflect dietary intake and can be used to model and classify dietary patterns of free-living populations.
In this randomised, controlled, crossover trial, we recruited healthy volunteers (aged 21–65 years, BMI 20–35 kg/m2) from a database of a clinical research unit in the UK. We developed four dietary interventions with a stepwise variance in concordance with the WHO healthy eating guidelines that aim to prevent non-communicable diseases (increase fruits, vegetables, whole grains, and dietary fibre; decrease fats, sugars, and salt). Participants attended four inpatient stays (72 h each, separated by at least 5 days), during which they were given one dietary intervention. The order of diets was randomly assigned across study visits. Randomisation was done by an independent investigator, with the use of opaque, sealed, sequentially numbered envelopes that each contained one of the four dietary interventions in a random order. Participants and investigators were not masked from the dietary intervention, but investigators analysing the data were masked from the randomisation order. During each inpatient period, urine was collected daily over three timed periods: morning (0900–1300 h), afternoon (1300–1800 h), and evening and overnight (1800–0900 h); 24 h urine samples were obtained by pooling these samples. Urine samples were assessed by proton nuclear magnetic resonance (1H-NMR) spectroscopy, and diet-discriminatory metabolites were identified. We developed urinary metabolite models for each diet and identified the associated metabolic profiles, and then validated the models using data and samples from the INTERMAP UK cohort (n=225) and a healthy-eating Danish cohort (n=66). This study is registered with ISRCTN, number ISRCTN43087333.
Between Aug 13, 2013, and May 18, 2014, we contacted 300 people with a letter of invitation. 78 responded, of whom 26 were eligible and invited to attend a health screening. Of 20 eligible participants who were randomised, 19 completed all four 72 h study stays between Oct 2, 2013, and July 29, 2014, and consumed all the food provided. Analysis of 1H-NMR spectroscopy data indicated that urinary metabolic profiles of the four diets were distinct. Significant stepwise differences in metabolite concentrations were seen between diets with the lowest and highest metabolic risks. Application of the derived metabolite models to the validation datasets confirmed the association between urinary metabolic and dietary profiles in the INTERMAP UK cohort (p<0·0001) and the Danish cohort (p<0·0001).
Urinary metabolite models developed in a highly controlled environment can classify groups of free-living people into consumers of diets associated with lower or higher non-communicable disease risk on the basis of multivariate metabolite patterns. This approach enables objective monitoring of dietary patterns in population settings and enhances the validity of dietary reporting.
UK National Institute for Health Research and UK Medical Research Council.
Abstract
Aims
To characterize serum metabolic signatures associated with atherosclerosis in the coronary or carotid arteries and subsequently their association with incident cardiovascular disease ...(CVD).
Methods and results
We used untargeted one-dimensional (1D) serum metabolic profiling by proton nuclear magnetic resonance spectroscopy (1H NMR) among 3867 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), with replication among 3569 participants from the Rotterdam and LOLIPOP studies. Atherosclerosis was assessed by coronary artery calcium (CAC) and carotid intima-media thickness (IMT). We used multivariable linear regression to evaluate associations between NMR features and atherosclerosis accounting for multiplicity of comparisons. We then examined associations between metabolites associated with atherosclerosis and incident CVD available in MESA and Rotterdam and explored molecular networks through bioinformatics analyses. Overall, 30 1H NMR measured metabolites were associated with CAC and/or IMT, P = 1.3 × 10−14 to 1.0 × 10−6 (discovery) and P = 5.6 × 10−10 to 1.1 × 10−2 (replication). These associations were substantially attenuated after adjustment for conventional cardiovascular risk factors. Metabolites associated with atherosclerosis revealed disturbances in lipid and carbohydrate metabolism, branched chain, and aromatic amino acid metabolism, as well as oxidative stress and inflammatory pathways. Analyses of incident CVD events showed inverse associations with creatine, creatinine, and phenylalanine, and direct associations with mannose, acetaminophen-glucuronide, and lactate as well as apolipoprotein B (P < 0.05).
Conclusion
Metabolites associated with atherosclerosis were largely consistent between the two vascular beds (coronary and carotid arteries) and predominantly tag pathways that overlap with the known cardiovascular risk factors. We present an integrated systems network that highlights a series of inter-connected pathways underlying atherosclerosis.
This study identifies 38 cases of windthrows in the Amazonia to explore the relationship between windthrows and the characteristics (storm passing time, cloud top temperature, and maximum ...precipitation) of mesoscale convective systems (MCSs) that produced them. Most of windthrow cases in this study occurred in August and September. The storm passing time is positively correlated with the size of windthrows. MCSs with colder cloud top temperature (with a mean at 206 K)—indicating deeper convection—resulted in large windthrows, while those with warm cloud top (with a mean above 230 K) resulted in relatively small windthrows except for windthrows in the western Amazonia. No significant relationship is found between maximum precipitation intensity and the area of windthrows.
Plain Language Summary
Fan‐shaped dead forest patches were found over the entire Amazonia. These patches affect the role the Amazon forests played in the world's carbon cycle. Scientists found that frequent thunderstorms result in these dead forest patches, but how does the process happen? In this study, we explored the three characteristics of thunderstorms, including their passing over time, cloud top temperature, and associated precipitation, to identify their relationship with the size of the dead forests. We found that long‐lived thunderstorms with thicker and tall clouds, providing more power to the mesoscale convective systems, result in bigger sizes of dead forest patches. Moreover, forests in the western Amazonia are more vulnerable to thunderstorms than forests on the other parts of the Amazonia.
Key Points
The storm passing time of mesoscale convective systems (MCSs) is positively correlated with the size of windthrows
MCSs with colder cloud top temperature are associated with larger size of windthrows
No significant relationship is found between maximum precipitation intensity and the area of windthrows
Arrhythmogenic right ventricular cardiomyopathy (ARVC) has a prevalence of at least 1 in 1000, is a leading cause of sudden cardiac death in people aged < or =35 years, and accounts for up to 10% of ...deaths from undiagnosed cardiac disease in the <65 age group. The classic form of the disease has an early predilection for the right ventricle, but recognition of left-dominant and biventricular subtypes has prompted proposal of the broader term arrhythmogenic cardiomyopathy. The clinical profile of the disease bridges the gap between the cardiomyopathies and inherited arrhythmia syndromes. The early "concealed" phase is characterized by propensity toward ventricular tachyarrhythmia in the setting of well-preserved morphology, histology, and ventricular function. As the disease progresses, however, myocyte loss, inflammation, and fibroadiposis become evident. Up to 40% of cases harbor rare variants in genes encoding components of the desmosome, specialized intercellular junctions that confer mechanical strength to cardiac and epithelial tissue, and may also participate in signaling networks. Phenotypic heterogeneity and the nonspecific nature of associated features complicate clinical diagnosis, which requires multipronged cardiovascular investigation rather than a single test. Development of a prospectively validated risk-stratification algorithm for the full disease spectrum remains the foremost clinical challenge.
A plethora of environmental and behavioral factors interact, resulting in changes in gene expression and providing a basis for the development and progression of cardiovascular diseases. ...Heterogeneity in gene expression responses among cells and individuals involves epigenetic mechanisms. Advancing technology allowing genome-scale interrogation of epigenetic marks provides a rapidly expanding view of the complexity and diversity of the epigenome. In this review, the authors discuss the expanding landscape of epigenetic modifications and highlight their importance for future understanding of disease. The epigenome provides a mechanistic link between environmental exposures and gene expression profiles ultimately leading to disease. The authors discuss the current evidence for transgenerational epigenetic inheritance and summarize the data linking epigenetics to cardiovascular disease. Furthermore, the potential targets provided by the epigenome for the development of future diagnostics, preventive strategies, and therapy for cardiovascular disease are reviewed. Finally, the authors provide some suggestions for future directions.
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The mechanisms that predispose to hypertension, coronary artery disease (CAD), and type 2 diabetes (T2D) in individuals of normal weight are poorly understood. In contrast, in monogenic primary ...lipodystrophy-a reduction in subcutaneous adipose tissue-it is clear that it is adipose dysfunction that causes severe insulin resistance (IR), hypertension, CAD, and T2D. We aimed to test the hypothesis that common alleles associated with IR also influence the wider clinical and biochemical profile of monogenic IR. We selected 19 common genetic variants associated with fasting insulin-based measures of IR. We used hierarchical clustering and results from genome-wide association studies of eight nondisease outcomes of monogenic IR to group these variants. We analyzed genetic risk scores against disease outcomes, including 12,171 T2D cases, 40,365 CAD cases, and 69,828 individuals with blood pressure measurements. Hierarchical clustering identified 11 variants associated with a metabolic profile consistent with a common, subtle form of lipodystrophy. A genetic risk score consisting of these 11 IR risk alleles was associated with higher triglycerides (β = 0.018; P = 4 × 10(-29)), lower HDL cholesterol (β = -0.020; P = 7 × 10(-37)), greater hepatic steatosis (β = 0.021; P = 3 × 10(-4)), higher alanine transaminase (β = 0.002; P = 3 × 10(-5)), lower sex-hormone-binding globulin (β = -0.010; P = 9 × 10(-13)), and lower adiponectin (β = -0.015; P = 2 × 10(-26)). The same risk alleles were associated with lower BMI (per-allele β = -0.008; P = 7 × 10(-8)) and increased visceral-to-subcutaneous adipose tissue ratio (β = -0.015; P = 6 × 10(-7)). Individuals carrying ≥17 fasting insulin-raising alleles (5.5% population) were slimmer (0.30 kg/m(2)) but at increased risk of T2D (odds ratio OR 1.46; per-allele P = 5 × 10(-13)), CAD (OR 1.12; per-allele P = 1 × 10(-5)), and increased blood pressure (systolic and diastolic blood pressure of 1.21 mmHg per-allele P = 2 × 10(-5) and 0.67 mmHg per-allele P = 2 × 10(-4), respectively) compared with individuals carrying ≤9 risk alleles (5.5% population). Our results provide genetic evidence for a link between the three diseases of the "metabolic syndrome" and point to reduced subcutaneous adiposity as a central mechanism.
Insulin resistance and related metabolic disturbances are major risk factors for the higher T2D risk and associated morbidity and mortality amongst South Asians. The contribution of physical activity ...to the increased prevalence of insulin resistance and related disturbances amongst South Asians is unknown.
We recruited 902 South Asian and European men and women, aged 35-85 years from the ongoing LOLIPOP study. Clinical characterisation comprised standardised questionnaire and measurement of height, weight, waist and hip circumference and blood pressure. Fasting bloods were taken for assessment of glucose, insulin, lipids and HbA1c. Physical activity was quantified using a validated accelerometer, Actigraph GT3X+, worn for 7 days. Univariate and multivariate approaches were used to investigate the relationship between ethnicity, physical activity, insulin resistance and related metabolic disturbances.
Total physical activity was ~31% (P = 0.01) lower amongst South Asians compared to Europeans (Mean MET.minutes SD: 1505.2 52 vs. 2050.9 86.6, P<0.001). After adjusting for age and sex, total physical activity had a negative association with HOMA-IR (B SE: -0.18 0.08, P = 0.04) and fasting glucose levels (BSE: -0.11 0.04, P = 0.02). There was no association between physical activity and other glycemic and lipid parameters. Total physical activity per week contributed towards the differences in insulin resistance and associated metabolic disturbances between South Asians and Europeans.
Lower levels of physical activity may contribute to the increased insulin resistance in South Asians compared to Europeans. Our results suggest that lifestyle modification through increased physical activity may help to improve glucose metabolism and reduce the burden of excess T2D and related complications amongst South Asians.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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