DNA methylation is a defining feature of mammalian cellular identity and is essential for normal development. Most cell types, except germ cells and pre-implantation embryos, display relatively ...stable DNA methylation patterns, with 70-80% of all CpGs being methylated. Despite recent advances, we still have a limited understanding of when, where and how many CpGs participate in genomic regulation. Here we report the in-depth analysis of 42 whole-genome bisulphite sequencing data sets across 30 diverse human cell and tissue types. We observe dynamic regulation for only 21.8% of autosomal CpGs within a normal developmental context, most of which are distal to transcription start sites. These dynamic CpGs co-localize with gene regulatory elements, particularly enhancers and transcription-factor-binding sites, which allow identification of key lineage-specific regulators. In addition, differentially methylated regions (DMRs) often contain single nucleotide polymorphisms associated with cell-type-related diseases as determined by genome-wide association studies. The results also highlight the general inefficiency of whole-genome bisulphite sequencing, as 70-80% of the sequencing reads across these data sets provided little or no relevant information about CpG methylation. To demonstrate further the utility of our DMR set, we use it to classify unknown samples and identify representative signature regions that recapitulate major DNA methylation dynamics. In summary, although in theory every CpG can change its methylation state, our results suggest that only a fraction does so as part of coordinated regulatory programs. Therefore, our selected DMRs can serve as a starting point to guide new, more effective reduced representation approaches to capture the most informative fraction of CpGs, as well as further pinpoint putative regulatory elements.
Summary
Purpose
Whether patients with inflammatory bowel disease (IBD) exhibit a high risk of developing varicella zoster virus (VZV) infection in Asian populations remains inconclusive. We ...investigated the causal relationship between two diseases by analysing the Taiwan National Health Insurance Research Database.
Patients and methods
Based on a universal insurance claims database, we enrolled 7055 IBD patients and 28,220 age‐ and sex‐matched controls. We calculated the hazard ratios (HRs) and 95% confidence intervals (CIs) of the herpes zoster virus (HZV) in the IBD and comparison cohorts, using the Cox proportional hazards regression model.
Results
Patients with IBD exhibited significantly higher risk of the HZV compared with the controls (adjusted HRs, 1.42; 95% CI, 1.27–1.60). Further analysis indicated that male patients (adjusted HRs, 1.61; 95% CI, 1.35–1.92), aged 35–44 (adjusted HRs, 1.47; 95% CI, 1.08–2.01) and aged 65 years and older (adjusted HRs, 1.47; 95% CI, 1.19–1.80), and patients without comorbidities (adjusted HRs, 1.44; 95% CI, 1.26–1.66), exhibited excessive risks of VZV infection. Moreover, our findings show that the overall risk of developing VZV infection increased risk from 1.03 (95% CI, 0.90–1.18) (≤ 2 visits) to 9.76 (95% CI, 7.60–12.5) (> 4 visits), which correlates positively with the frequency of medical visits (trend test p < 0.0001).
Conclusion
Patients with IBD, particularly men aged 35–44/65 years and over, and patients without comorbidities, are associated with a long‐term risk of VZV infection. The excessive risk of VZV infection should be considered for administering vaccines to IBD patients.
We apply a heterogeneous graph convolution network (GCN) combined with a multi-layer perceptron (MLP) denoted by GCNMLP to explore the potential side effects of drugs. Here the SIDER, OFFSIDERS, and ...FAERS are used as the datasets. We integrate the drug information with similar characteristics from the datasets of known drugs and side effect networks. The heterogeneous graph networks explore the potential side effects of drugs by inferring the relationship between similar drugs and related side effects. This novel in silico method will shorten the time spent in uncovering the unseen side effects within routine drug prescriptions while highlighting the relevance of exploring drug mechanisms from well-documented drugs. In our experiments, we inquire about the drugs Vancomycin, Amlodipine, Cisplatin, and Glimepiride from a trained model, where the parameters are acquired from the dataset SIDER after training. Our results show that the performance of the GCNMLP on these three datasets is superior to the non-negative matrix factorization method (NMF) and some well-known machine learning methods with respect to various evaluation scales. Moreover, new side effects of drugs can be obtained using the GCNMLP.
Beige and brown adipocytes generate heat in response to reductions in ambient temperature. When warmed, both beige and brown adipocytes exhibit morphological “whitening,” but it is unknown whether or ...to what extent this represents a true shift in cellular identity. Using cell-type-specific profiling in vivo, we uncover a unique paradigm of temperature-dependent epigenomic plasticity of beige, but not brown, adipocytes, with conversion from a brown to a white chromatin state. Despite this profound shift in cellular identity, warm whitened beige adipocytes retain an epigenomic memory of prior cold exposure defined by an array of poised enhancers that prime thermogenic genes for rapid response during a second bout of cold exposure. We further show that a transcriptional cascade involving glucocorticoid receptor and Zfp423 can drive warm-induced whitening of beige adipocytes. These studies identify the epigenomic and transcriptional bases of an extraordinary example of cellular plasticity in response to environmental signals.
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•Cell-type-specific RNA-seq identify markers for white, brown, and beige adipocytes•Beige adipocytes exhibit reprogramming between white and brown chromatin states•Warmed beige adipocytes retain an epigenomic memory of prior cold exposure•A GR-Zfp423 pathway mediates beige adipocyte whitening during warming
Both beige and brown adipocytes “whiten” upon warming. Roh et al. elegantly show that beige, but not brown, adipocytes undergo temperature-dependent reprogramming between brown- and white-like states, while retaining epigenomic memory of prior cold exposure. A transcriptional cascade underlies this plasticity response to environmental signals.
Background and Aims
Mutations in the disheveled, Egl‐10 and pleckstrin domain‐containing protein 5 (DEPDC5) gene have emerged as an important cause of various familial focal epilepsy syndromes. ...However, the significance of DEPDC5 mutations in patients with sporadic focal epilepsy has yet to be characterized.
Materials and Methods
We studied a kindred of familial focal epilepsy with variable foci using whole‐exome sequencing. We subsequently studied a cohort of 293 patients with focal epilepsy and sequenced all exons of DEPDC5 using targeted resequencing.
Results
We reported a Taiwanese family with a novel splice site mutation which affected mRNA splicing and activated the downstream mammalian target of rapamycin (mTOR) pathway. Among patients with focal epilepsies, the majority (220/293) of these patients had sporadic focal epilepsy without malformation of cortical development. Two (0.9%) of these patients had probably pathogenic mutations in the
DEPDC5 gene.
Discussion and Conclusions
Our finding suggests that DEPDC5 is not only the most common gene for familial focal epilepsy but also could be a significant gene for sporadic focal epilepsy. Since focal epilepsies account for more than 60% of all epilepsies, the effect of mTORC1 inhibitor on patients with focal epilepsy due to DEPDC5 mutations will be an important future direction of research.
Background
Vitamin D has antineoplastic effects, but the synthesis of vitamin D requires ultraviolet radiation, a known risk factor for melanoma.
Objective
To investigate the correlations between ...serum vitamin D levels and risk and prognosis of melanoma.
Methods
A systematic review and meta‐analysis were conducted. Online databases were searched on 31 Oct 2018.
Results
Twenty‐five studies with a total of 11166 patients with melanoma were included. There was no significant difference in serum vitamin D levels between patients with melanoma and controls standardized mean difference (SMD), −0.185; 95% confidence interval (CI), −0.533 to 0.162. However, the prevalence of vitamin D deficiency was significantly higher in patients with melanoma than that in controls (odds ratio, 2.115; 95% CI, 1.151–3.885). In terms of prognosis, serum vitamin D levels were significantly higher in melanoma patients with lower Breslow thickness (≦1 vs. >1 mm: SMD, 0.243; 95% CI, 0.160–0.327). Moreover, melanoma patients with lower vitamin D levels had a significantly higher mortality rate (hazard ratio, 1.558; 95% CI, 1.258–1.931).
Conclusions
Vitamin D deficiency is associated with higher Breslow thickness and mortality in melanoma patients.
Background
Childhood asthma comprises different phenotypes with complex pathophysiology. Different asthma phenotypes evoke various clinical symptoms and vary in their responses to treatments.
Methods
...We applied k‐means clustering algorithm of twelve objective laboratory tests among 351 asthmatic children enrolled in the Taiwanese Consortium of Childhood Asthma Study (TCCAS). We constructed gene expression profiles of peripheral blood mononuclear cells (PBMC) from children with different asthma phenotypes.
Results
Five distinct phenotypes of childhood asthma were identified and can be characterized by either eosinophil‐predominant or neutrophil‐predominant inflammatory characteristics. In the gene expression profile analysis, significant differences were noted for neutrophil‐predominant asthma, compared with samples from all the other asthma phenotypes. The vast majority of the differentially expressed genes in neutrophil‐predominant asthma was associated with corticosteroid response. From an independent inhaled corticosteroid (ICS) response cohort, we also found neutrophils could be activated in this severe asthma phenotype and neutrophil‐predominant asthma may be associated with corticosteroid nonresponsiveness.
Conclusion
Phenotype clustering of childhood asthma can be helpful to identify clinically relevant patients and reveal different inflammatory characteristics in asthmatic children. Neutrophil‐predominant asthma is the most severe asthma phenotype with poor corticosteroid response. Gene expression profile of different asthma phenotypes not only improve our knowledge of childhood asthma, but also can guide asthma precision medicine.
Neutrophil‐predominant asthma is the most severe asthma phenotype with poor corticosteroid response. Five distinct phenotypes of childhood asthma identified in this study with differences in lung function, symptom frequency, healthcare utilization, percentages of eosinophils and neutrophils in peripheral blood, and serum IgE. Gene expression signature in PBMC constitutes an easier way to objectively identify corticosteroid‐resistant asthma in clinical settings.
We have fabricated surface-enhanced Raman scattering (SERS) substrates based on arrays of silver nanoparticles grown on porous anodic alumina templates. Using this nanotechnology platform, label-free ...and high-speed detection of bacteria are achieved. SERS spectra of various bacteria including Staphylococcus Aureus (Gram-positive bacterium), Klebsiella Pneumoniae (Gram-negative bacterium), and Mycobacterium Smegmatis (Mycobacterium) were recorded. The highly reproducible SERS-based technological platform is capable of differentiating different kinds of bacteria by PCA, LDA, clustering analysis, and SVM methods, which provides promising opportunity for biosensing of clinical microbes.
Summary
Background
Aspirin increases the risk of gastrointestinal bleeding.
Aim
To investigate the risk of lower gastrointestinal bleeding (LGIB) in aspirin users.
Methods
Low‐dose (75‐325 mg daily) ...aspirin users and controls matched by age, gender and enrollment time in a 1:5 ratio were selected from 1 million randomly sampled subjects in the National Health Insurance Research Database of Taiwan. Cox proportional hazard regression models were developed to evaluate the predictors of LGIB with adjustments for age, gender, comorbidities including coronary artery disease, ischaemic stroke, diabetes, hypertension, chronic kidney disease, liver cirrhosis, chronic obstructive pulmonary disease, dyslipidemia, uncomplicated peptic ulcer disease, history of peptic ulcer bleeding, and concomitant use of clopidogrel, ticlopidine, warfarin, nonsteroidal anti‐inflammatory drugs (NSAIDs), cyclooxygenase‐2 inhibitors, steroids, proton pump inhibitors (PPIs), histamine‐2 receptor antagonists (H2RAs), nitrates, alendronate, selective serotonin reuptake inhibitors (SSRIs) and calcium channel blockers.
Results
A total of 53 805 aspirin users and 269 025 controls were included. Aspirin group had a higher incidence of LGIB within 1 year than control group (0.20% vs 0.06%, P<.0001). Aspirin (hazard ratio HR: 2.75, 95% confidence interval CI: 2.06‐3.65), NSAIDs (HR: 8.61, 95% CI: 3.28‐22.58), steroids (HR: 10.50, 95% CI: 1.98‐55.57), SSRIs (HR: 11.71, 95% CI: 1.40‐97.94), PPIs (HR: 8.47, 95% CI: 2.26‐31.71), and H2RAs (HR: 10.83, 95% CI: 2.98‐39.33) were significantly associated with LGIB.
Conclusions
The risk of LGIB was higher in low‐dose aspirin users than in aspirin nonusers in this nationwide cohort. Low‐dose aspirin, NSAIDs, steroids, SSRIs, PPIs and H2RAs were independent risk factors for LGIB.
Linked ContentThis article is linked to Taha and Chen et al papers. To view these articles visit https://doi.org/10.1111/apt.14114 and https://doi.org/10.1111/apt.14138.
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