Multi-dimensional histone methylations for coordinated regulation of gene expression under hypoxia

Hypoxia increases both active and repressive histone methylation levels via decreased activity of histone demethylases. However, how such increases coordinately regulate induction or repression of hypoxia-responsive genes is largely unknown. Here, we profiled active and repressive histone tri-methylations (H3K4me3, H3K9me3, and H3K27me3) and analyzed gene expression profiles in human adipocyte-derived stem cells under hypoxia. We identified differentially expressed genes (DEGs) and differentially methylated genes (DMGs) by hypoxia and clustered the DEGs and DMGs into four major groups. We found that each group of DEGs was predominantly associated with alterations in only one type among the three histone tri-methylations. Moreover, the four groups of DEGs were associated with different TFs and localization patterns of their predominant types of H3K4me3, H3K9me3 and H3K27me3. Our results suggest that the association of altered gene expression with prominent single-type histone tri-methylations characterized by different localization patterns and with different sets of TFs contributes to regulation of particular sets of genes, which can serve as a model for coordinated epigenetic regulation of gene expression under hypoxia.111Ysciescopu

Generation of T Follicular Helper Cells Is Mediated by Interleukin-21 but Independent of T Helper 1, 2, or 17 Cell Lineages

SummaryAfter activation, CD4+ helper T (Th) cells differentiate into distinct effector subsets. Although chemokine (C-X-C motif) receptor 5-expressing T follicular helper (Tfh) cells are important in humoral immunity, their developmental regulation is unclear. Here we show that Tfh cells had a distinct gene expression profile and developed in vivo independently of the Th1 or Th2 cell lineages. Tfh cell generation was regulated by ICOS ligand (ICOSL) expressed on B cells and was dependent on interleukin-21 (IL-21), IL-6, and signal transducer and activator of transcription 3 (STAT3). However, unlike Th17 cells, differentiation of Tfh cells did not require transforming growth factor β (TGF-β) or Th17-specific orphan nuclear receptors RORα and RORγ in vivo. Finally, naive T cells activated in vitro in the presence of IL-21 but not TGF-β signaling preferentially acquired Tfh gene expression and promoted germinal-center reactions in vivo. This study thus demonstrates that Tfh is a distinct Th cell lineage

The Spectrum of Benign Esophageal Lesions: Imaging Findings

Benign esophageal lesions occur in various diseases. Barium studies are useful for the evaluation of mucosal surface lesions but provide little information about the extramucosal extent of disease. Computed tomography and magnetic resonance imaging, on the other hand, permit the assessment of wall thickness, mediastinal involvement, adjacent lymphadenopathy, and distant spread. In diseases such as fibrovascular polyps, duplication cysts, scleroderma, trauma, caustic esophagitis, hiatal hernia, esophageal diverticulum, achalasia, and paraesophageal varices, the findings of imaging studies are specific, obviating the need for further invasive diagnostic work-up. The advent of helical computed tomography and its volume data set allows the acquisition of multiplanar images, and magnetic resonance imaging is useful both for this and for tissue characterization. Thus, multiplanar cross-sectional imaging further extends the role of imaging modalities to the evaluation of benign esophageal lesions. Through an awareness of the multiplanar cross-sectional appearances of various benign esophageal lesions, the radiologist can play an important role in the detection, diagnosis, further diagnostic planning, and treatment of the diseases in which they occur

Acetylation changes tau interactome to degrade tau in Alzheimer’s disease animal and organoid models

© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.Alzheimer's disease (AD) is an age-related neurodegenerative disease. The most common pathological hallmarks are amyloid plaques and neurofibrillary tangles in the brain. In the brains of patients with AD, pathological tau is abnormally accumulated causing neuronal loss, synaptic dysfunction, and cognitive decline. We found a histone deacetylase 6 (HDAC6) inhibitor, CKD-504, changed the tau interactome dramatically to degrade pathological tau not only in AD animal model (ADLPAPT) brains containing both amyloid plaques and neurofibrillary tangles but also in AD patient-derived brain organoids. Acetylated tau recruited chaperone proteins such as Hsp40, Hsp70, and Hsp110, and this complex bound to novel tau E3 ligases including UBE2O and RNF14. This complex degraded pathological tau through proteasomal pathway. We also identified the responsible acetylation sites on tau. These dramatic tau-interactome changes may result in tau degradation, leading to the recovery of synaptic pathology and cognitive decline in the ADLPAPT mice11Nsciescopu

Segmented tomographic evaluation of structural degradation of carbon support in proton exchange membrane fuel cells

The variation of the three-dimensional (3D) structure of the membrane electrode of a fuel cell during proton exchange cycling involves the corrosion/compaction of the carbon support. The increasing degradation of the carbon structure continuously reduces the electrocatalytic performance of proton exchange membrane fuel cells (PEM-FCs). This phenomenon can be explained by performing 3D tomographic analysis at the nanoscale. However, conventional tomographic approaches which present limited experimental feasibility, cannot perform such evaluation and have not provided sufficient structural information with statistical significance thus far. Therefore, a reliable methodology is required for the 3D geometrical evaluation of the carbon structure. Here, we propose a segmented tomographic approach which employs pore network analysis that enables the visualization of the geometrical parameters corresponding to the porous carbon structure at a high resolution. This approach can be utilized to evaluate the 3D structural degradation of the porous carbon structure after cycling in terms of local surface area, pore size distribution, and their 3D networking. These geometrical parameters of the carbon body were demonstrated to be substantially reduced owing to the cycling-induced degradation. This information enables a deeper understanding of the degradation phenomenon of carbon supports and can contribute to the development of stable PEM-FC electrodes. (C) 2022 Science Press and Dalian Institute of Chemical Physics, Chinese Academy of Sciences. Published by ELSEVIER B.V. and Science Press

Oncogenic CagA Promotes Gastric Cancer Risk via Activating ERK Signaling Pathways: A Nested Case-Control Study

Background: CagA cellular interaction via activation of the ERK signaling pathway may be a starting point in the development of gastric cancer. This study aimed to evaluate whether genes involved in ERK downstream signaling pathways activated by CagA are susceptible genetic markers for gastric cancer. Methods: In the discovery phase, a total of 580 SNPs within +/-5 kbp of 30 candidate genes were genotyped to examine an association with gastric cancer risk in the Korean Multi-center Cancer Cohort (100 incident gastric cancer case-control sets). The most significant SNPs (raw or permutated p value??0.02) identified in the discovery analysis were re-evaluated in the extension phase using unconditional logistic regression model (400 gastric cancer case-control sets). Combined analyses including pooled-and meta-analysis were conducted to summarize all the results. Results: 24 SNPs in eight genes (ERK, Dock180, C3G, Rap1, Src, CrkL, Mek and Crk) were significantly associated with gastric cancer risk in the individual SNP analyses in the discovery phase (p??0.05). In the extension analyses, ERK rs5999749, Dock180 rs4635002 and C3G rs7853122 showed marginally significant gene-dose effects for gastric cancer. Consistently, final combined analysis presented the SNPs as significantly associated with gastric cancer risk (OR = 1.56, [95% CI: 1.19-2.06], OR = 0.61, [95% CI: 0.43-0.87], OR = 0.59, [95% CI: 0.54-0.76], respectively). Conclusions: Our findings suggest that ERK rs5999749, Dock180 rs4635002 and C3G rs7853122 are genetic determinants in gastric carcinogenesis

Association between body mass index and cardiovascular disease mortality in east Asians and south Asians: pooled analysis of prospective data from the Asia Cohort Consortium

Objective: To evaluate the association between body mass index and mortality from overall cardiovascular disease and specific subtypes of cardiovascular disease in east and south Asians. Design: Pooled analyses of 20 prospective cohorts in Asia, including data from 835 082 east Asians and 289 815 south Asians. Cohorts were identified through a systematic search of the literature in early 2008, followed by a survey that was sent to each cohort to assess data availability. Setting: General populations in east Asia (China, Taiwan, Singapore, Japan, and Korea) and south Asia (India and Bangladesh). Participants: 1 124 897 men and women (mean age 53.4 years at baseline). Main outcome measures: Risk of death from overall cardiovascular disease, coronary heart disease, stroke, and (in east Asians only) stroke subtypes. Results: 49 184 cardiovascular deaths (40 791 in east Asians and 8393 in south Asians) were identified during a mean follow-up of 9.7 years. East Asians with a body mass index of 25 or above had a raised risk of death from overall cardiovascular disease, compared with the reference range of body mass index (values 22.5-24.9; hazard ratio 1.09 (95% confidence interval 1.03 to 1.15), 1.27 (1.20 to 1.35), 1.59 (1.43 to 1.76), 1.74 (1.47 to 2.06), and 1.97 (1.44 to 2.71) for body mass index ranges 25.0-27.4, 27.5-29.9, 30.0-32.4, 32.5-34.9, and 35.0-50.0, respectively). This association was similar for risk of death from coronary heart disease and ischaemic stroke; for haemorrhagic stroke, the risk of death was higher at body mass index values of 27.5 and above. Elevated risk of death from cardiovascular disease was also observed at lower categories of body mass index (hazard ratio 1.19 (95% confidence interval 1.02 to 1.39) and 2.16 (1.37 to 3.40) for body mass index ranges 15.0-17.4 and less than 15.0, respectively), compared with the reference range. In south Asians, the association between body mass index and mortality from cardiovascular disease was less pronounced than that in east Asians. South Asians had an increased risk of death observed for coronary heart disease only in individuals with a body mass index greater than 35 (hazard ratio 1.90, 95% confidence interval 1.15 to 3.12). Conclusions: Body mass index shows a U shaped association with death from overall cardiovascular disease among east Asians: increased risk of death from cardiovascular disease is observed at lower and higher ranges of body mass index. A high body mass index is a risk factor for mortality from overall cardiovascular disease and for specific diseases, including coronary heart disease, ischaemic stroke, and haemorrhagic stroke in east Asians. Higher body mass index is a weak risk factor for mortality from cardiovascular disease in south Asians

Identification of Serum MicroRNAs as Novel Non-Invasive Biomarkers for Early Detection of Gastric Cancer

BACKGROUND: To investigate the potential of serum miRNAs as biomarkers for early detection of gastric cancer (GC), a population-based study was conducted in Linqu, a high-risk area of GC in China. METHODOLOGY/PRINCIPAL FINDINGS: All subjects were selected from two large cohort studies. Differential miRNAs were identified in serum pools of GC and control using TaqMan low density array, and validated in individual from 82 pairs of GC and control, and 46 pairs of dysplasia and control by real-time quantitative reverse transcription-polymerase chain reaction. The temporal trends of identified serum miRNA expression were further explored in a retrospective study on 58 GC patients who had at least one pre-GC diagnosis serum sample based on the long-term follow-up population. The miRNA profiling results demonstrated that 16 miRNAs were markedly upregulated in GC patients compared to controls. Further validation identified a panel of three serum miRNAs (miR-221, miR-744, and miR-376c) as potential biomarkers for GC detection, and receiver operating characteristic (ROC) curve-based risk assessment analysis revealed that this panel could distinguish GCs from controls with 82.4% sensitivity and 58.8% specificity. MiR-221 and miR-376c demonstrated significantly positive correlation with poor differentiation of GC, and miR-221 displayed higher level in dysplasia than in control. Furthermore, the retrospective study revealed an increasing trend of these three miRNA levels during GC development (P for trend<0.05), and this panel could classify serum samples collected up to 5 years ahead of clinical GC diagnosis with 79.3% overall accuracy. CONCLUSIONS/SIGNIFICANCE: These data suggest that serum miR-221, miR-376c and miR-744 have strong potential as novel non-invasive biomarkers for early detection of GC