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Genome topology provides a structural basis for epigenome-mediated transcriptional regulation in eukaryotes. Here the authors characterized the 3D genome of stratified squamous epithelia. They generated a Hi-C map of human limbal stem/progenitor cells (LSCs) and integrated these data with epigenomics, transcription factor binding maps, and transcriptome data.

Background Excessive delivery of free fatty acids (FFAs) to the liver promotes steatosis and insulin resistance (IR), with IR defined as reduced glucose uptake, glycogen synthesis and anti-lipolysis stimulated by normal insulin levels. Whether the associations between FFAs and diabetes development differ between patients with and without nonalcoholic fatty liver disease (NAFLD) remains unclear. Methods Consecutive subjects (2,220 NAFLD subjects and 1,790 non-NAFLD subjects according to ultrasound imaging) were enrolled from the First Affiliated Hospital of Sun Yat-sen University between 2009 and 2019. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Results There was an approximate J-shaped relationship between FFA levels and HOMA-IR in the NAFLD group. Higher FFA concentration quartiles were associated with higher risks of IR (odds ratio [OR], 9.24; 95% confidence interval [CI], 6.43 to 13.36), prediabetes (OR, 10.48; 95% CI, 5.66 to 19.39), and type 2 diabetes mellitus (T2DM; OR, 19.43; 95% CI, 12.75 to 29.81) in the NAFLD group but not in the non-NAFLD group. The cut-off points for the FFA levels increased in a stepwise manner in discriminating IR, prediabetes and T2DM (573, 697, and 715 μmol/L) in the NAFLD group but not in non-NAFLD individuals. Conclusion A distinct dose-dependent relationship of FFA levels was found with IR, prediabetes and T2DM in NAFLD patients. Screening serum FFA levels in NAFLD patients would be valuable in preventing diabetes development.

Abstract Background Although imbalanced intestinal flora contributes to the pathogenesis of nonalcoholic fatty liver disease (NAFLD), conflicting results have been obtained for patient-derived microbiome composition analyses. A meta-analysis was performed to summarize the characteristics of intestinal microbiota at the species level in NAFLD patients. Methods Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement, a completed search (last update: December 30, 2020) of databases was performed to identify eligible case-control studies detecting gut microbiota in NAFLD patients. The meta-analysis results are presented as the standard mean difference (SMD) and 95% confidence interval (CI). Bias controls were evaluated with the Newcastle-Ottawa Scale (NOS), funnel plot analysis, and Egger’s and Begg’s tests. Results Fifteen studies (NOS score range: 6–8) that detected the gut microbiota in the stools of 1265 individuals (577 NAFLD patients and 688 controls) were included. It was found that Escherichia, Prevotella and Streptococcus (SMD = 1.55 [95% CI: 0.57, 2.54], 1.89 [95% CI: 0.02, 3.76] and 1.33 [95% CI: 0.62, 2.05], respectively) exhibited increased abundance while Coprococcus, Faecalibacterium and Ruminococcus (SMD = − 1.75 [95% CI: − 3.13, − 0.37], − 9.84 [95% CI: − 13.21, − 6.47] and − 1.84 [95% CI, − 2.41, − 1.27], respectively) exhibited decreased abundance in the NAFLD patients compared with healthy controls. No differences in the abundance of Bacteroides, Bifidobacterium, Blautia, Clostridium, Dorea, Lactobacillus, Parabacteroides or Roseburia were confirmed between the NAFLD patients and healthy controls. Conclusions This meta-analysis revealed that changes in the abundance of Escherichia, Prevotella, Streptococcus, Coprococcus, Faecalibacterium and Ruminococcus were the universal intestinal bacterial signature of NAFLD.

BackgroundProgressive overloads of intrahepatic triglycerides are related to metabolic dysregulation of multiple lipid and lipoprotein profiles, but whether similar dose effects are found in each subtype of metabolic associated fatty liver disease (MAFLD) remains unclear. We aimed to characterize the lipid profiles associated with liver fat content (LFC) in MAFLD patients who were overweight, lean/normal weight, or had diabetes.MethodsWe conducted a cross-sectional study enrolling 1,182 consecutive participants (144 non-MAFLD and 1,038 MAFLD) who underwent MRI proton density fat fraction measurement (MRI-PDFF) from 2011 to 2020. Lipid and apolipoprotein profiles, free fatty acid (FFA), liver and metabolism parameters, and anthropometric measurements were also assessed.ResultsMAFLD patients with type 2 diabetes or overweight/obesity had a higher proportion of abnormal lipid and lipoprotein profiles than those who were lean/normal weight. The degree of LFC had a positive correlation with total cholesterol, triglyceride, ApoB, and ApoE in patients with overweight/obesity and type 2 diabetes. In those with overweight/obesity, there were dose–response relationships between moderate-to-severe steatosis and total cholesterol, triglyceride, HDL-c, LDL-c, ApoB, ApoE, and Lp(a). A similar trend was observed for triglyceride in those with type 2 diabetes and for HDL-c in patients who were lean/normal weight (all p for trend

Abstract Background Insulin resistance (IR) related metabolic disorders are associated with a worse prognosis of chronic hepatitis B virus (CHB) infection or nonalcoholic fatty liver disease (NAFLD). However, the relationships among CHB, steatosis, IR and metabolic factors remain controversial. The study aims to evaluate the impact of insulin resistance severity on metabolic profiles in patients with CHB, NAFLD and the coincidence of the two. Methods We conducted a cross-sectional study between January 2011 and December 2018 that included 2768 consecutive Chinese subjects (healthy controls: 667, CHB: 970, NAFLD: 878, CHB with NAFLD: 253). IR was determined with the homeostasis model assessment for insulin resistance (HOMA-IR). Metabolic measures included fasting serum insulin, glucose, lipid profiles and uric acid. Results The prevalence of IR was increased in CHB with NAFLD subjects compared with that in control subjects or subjects with CHB or NAFLD alone (41.5% vs 2.9%/11.9%/36.9%, respectively; P

Abstract Background Despite the development of new treatment protocols for glioblastoma (GBM), temozolomide (TMZ) resistance remains a primary hindrance. Previous studies, including our study, have shown that aberrant N6‐methyladenosine (m6A) modification is implicated in GBM pathobiology. However, the roles and precise mechanisms of m6A modification in the regulation of TMZ resistance in GBM remain unclear. Methods m6A individual‐nucleotide‐resolution cross‐linking and immunoprecipitation sequencing (miCLIP‐seq) was performed to identify m6A modification of transcripts in TMZ‐resistant and ‐sensitive tumors. To explore the role of METTL3 in TMZ resistance, TMZ‐resistant GBM cells were transfected with METTL3 shRNA or overexpression lentivirus and then assessed by cell viability, tumor sphere formation, and apoptosis assays. An intracranial GBM xenograft model was developed to verify the effect of METTL3 depletion during TMZ treatment in vivo. ATAC‐seq, ChIP‐qPCR, and dual‐luciferase reporter assays were carried out to verify the role of SOX4/EZH2 in the modulation of METTL3 expression upon TMZ treatment. Results We demonstrated that TMZ treatment upregulated the expression of the m6A methyltransferase METTL3, thereby increasing m6A modification of histone modification‐related gene transcripts. METTL3 is required to maintain the features of GBM stem cells. When combined with TMZ, METTL3 silencing suppressed orthotopic TMZ‐resistant xenograft growth in a cooperative manner. Mechanistically, TMZ induced a SOX4‐mediated increase in chromatin accessibility at the METTL3 locus by promoting H3K27ac levels and recruiting RNA polymerase II. Moreover, METTL3 depletion affected the deposition of m6A on histone modification‐related gene transcripts, such as EZH2, leading to nonsense‐mediated mRNA decay. We revealed an important role of EZH2 in the regulation of METTL3 expression, which was via an H3K27me3 modification‐independent manner. Conclusions Our findings uncover the fundamental mechanisms underlying the interplay of m6A RNA modification and histone modification in TMZ resistance and emphasize the therapeutic potential of targeting the SOX4/EZH2/METTL3 axis in the treatment of TMZ‐resistant GBM.

Background: The consistency in steatosis grading between magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) and controlled attenuation parameter (CAP) before and after treatment remains unclear. This study aimed to compare the diagnostic accuracy of steatosis grading between MRI-PDFF and CAP using liver biopsy as standard and to evaluate the value of monitoring changes in steatosis grading with CAP during follow-up utilizing MRI-PDFF as a reference. Methods: Consecutive patients from a biopsy cohort and a randomized controlled trial were included in this study and classified into 3 groups (the biopsy, orlistat treatment, and routine treatment subgroups). Hepatic steatosis was measured via MRI-PDFF and CAP at baseline and at the 6th month; the accuracy and cutoffs were assessed in the liver biopsy cohort at baseline. Results: A total of 209 consecutive patients were enrolled. MRI-PDFF and CAP showed comparable diagnostic accuracy for detecting pathological steatosis [⩾S1, area under the receiver operating characteristic curve (AUC) = 0.984 and 0.972, respectively]; in contrast, CAP presented significantly lower AUCs in grades S2–3 and S3 (0.820 and 0.815, respectively). The CAP values correlated well with the MRI-PDFF values at baseline and at the 6th month ( r = 0.809 and 0.762, respectively, both p

Background: The clinical burden and natural history of non-alcoholic fatty liver disease (NAFLD) vary globally. We aimed to investigate NAFLD-related mortality profiles in hospitalized patients in southern China.Methods: A multicenter retrospective investigation with a 10-year study period (2009–2018) analyzed 10,071 deaths during hospitalization (NAFLD: 2,015; other liver diseases: 1,140; without liver diseases: 6,916) was performed using a multiple cause of death analysis. Medical histories and biochemistry and imaging findings were extracted from the electronic medical record system. The underlying causes of death were classified by 10th Revision of the International Classification of Diseases (ICD-10) codes.Results: The distribution of death causes in patients with NAFLD has stabilized over time, with cardio- and cerebral vascular disease (CVD) ranked first (35.6%), followed by extrahepatic malignancies (22.6%), infection (11.0%), kidney disease (7.5%), liver-related diseases (5.2%), respiratory diseases (3.9%), digestive diseases (3.5%), endocrine diseases (3.5%), and other diseases (7.2%). NAFLD patients had more deaths attributable to CVD, extrahepatic malignancies, liver-related diseases (all P < 0.001) and multiorgan failure than the deceased controls. The severity of steatosis was independently associated with these relationships (liver-related diseases: OR = 1.37, 95% CI: 1.20–1.59, cardio- and cerebrovascular diseases: OR = 1.23, 95% CI: 1.19–1.31, infectious diseases: OR = 1.14, 95% CI: 1.04–1.26, and renal diseases: OR = 1.21, 95% CI: 1.02–1.47, all P < 0.05) after adjustment for sex, body mass index (BMI), fasting blood glucose, low-density lipoprotein cholesterol, uric acid, metabolic syndromes and fibrosis index based on the 4 factors.Conclusion : NAFLD patients had higher proportions of death due to underlying CVD and liver-related diseases than the general population in China; these proportions positively correlated with steatosis degree.

Myeloid ecotropic viral integration site 1 (MEIS1) plays an essential role in the development of several embryonic organs, such as the central nervous system and eyes. To further investigate the role of MEIS1 in embryonic development, herein, we generated a MEIS1 homozygous knockout human embryonic stem cell (hESC) line using the CRISPR/Cas9 genome-editing technology. We believe that this cell line will be a good resource for exploring the function of the MEIS1 gene in embryonic development in vitro. Furthermore, the gene-knockout method reported in this study is efficient and labor-saving, which may provide an effective strategy for hESC gene deletion.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignant cancer with complex genomic variations, and no targetable genomic lesions have been found yet. Super‐enhancers (SEs) have been found to contribute to the continuous and robust oncogenic transcription. Here, histone H3 lysine 27 acetylation (H3K27ac) is profiled in PDAC cell lines to establish SE landscapes. Concurrently, it is also shown that PDAC is vulnerable to the perturbation of the SE complex using bromodomain‐containing protein 4 (BRD4) inhibitor, JQ1, synergized with cyclin‐dependent kinase 7 (CDK7) inhibitor, THZ1. Formulations of hydrophobic l‐phenylalanine‐poly (ester amide) nanoparticles (NPs) with high drug loading of JQ1 and THZ1 (J/T@8P4s) are further designed and developed. J/T@8P4s is assessed for size, encapsulation efficiency, morphology, drug release profiles, and drug uptake in vitro. Compared to conventional free drug formulation, the nanodelivery system dramatically reduces the hepatotoxicity while significantly enhancing the tumor inhibition effects and the bioavailability of incorporated JQ1 and THZ1 at equal doses in a Gemcitabine‐resistant PDAC patient‐derived xenograft (PDX) model. Overall, the present study demonstrates that the J/T@8P4s can be a promising therapeutic treatment against the PDAC via suppression of SE‐associated oncogenic transcription, and provides a strategy utilizing NPs to assist the drug delivery targeting SEs.

Background: The liver effect of orlistat as a weight control treatment in patients with nonalcoholic fatty liver disease (NAFLD) with obesity remains undetermined. This study quantified liver fat improvement by orlistat in a Chinese cohort with NAFLD accompanied by obesity, diagnosed by a lower body mass index threshold than that for White patients. Materials and methods: We conducted a parallel-group, open-label, 24-week, randomized clinical trial registered at the Chinese Clinical Trial Registry (ChiCTR-IPR-17012258). Obese participants with NAFLD were randomized 1:1.5 to the intervention group with orlistat or conventional care. Liver fat quantification was assessed by magnetic resonance imaging-based proton density fat fraction with Dixon sequence. Results: Overall, 170 ( n = 68, orlistat 120 mg three times/day and n = 102, conventional therapy) and 130 patients with NAFLD ( n = 56, orlistat and n = 74, conventional therapy) were included for intention-to-treat (ITT) and per-protocol (PP) analysis, respectively. Orlistat reduced liver fat content to a greater degree than conventional care [−5.45% versus −1.96%, p

This paper studies the effect of the dimple cross-sectional profile on the behavior of gas parallel slider bearings using the numerical method. The numerical method is performed in MATLAB software. The influence of geometrical parameters of dimples on the dimensionless average pressure is studied for different dimple cross-sectional profiles. The geometrical parameters of dimples include dimple depth, dimple area density, transversal textured ratio, and longitudinal textured ratio. It is found that the hydrodynamic lubrication of dimple-textured gas parallel slider bearings is controlled by the dimple depth, dimple area density, transversal textured ratio, longitudinal textured ratio, and dimple cross-sectional profile. Furthermore, the impact of sliding speed on the hydrodynamic lubrication is studied for different dimple cross-sectional profiles. The results indicate that the optimum sliding speed for maximizing the hydrodynamic pressure is controlled by the dimple cross-sectional profile.

The aim of this paper is to investigate the effect of micro grooves on the lubrication performance of gas-lubricated inclined slider bearing. This paper is based on numerical analysis. The detailed numerical investigation is carried out in matlab software. The grooving parameters are optimized to obtain the maximum average pressure for various inclination angles of gas-lubricated inclined slider bearing. The results show that the inclination angle of the micro-grooves, depth of the micro-grooves, width of the micro-grooves, and spacing of the micro-grooves have an important influence on the hydrodynamic pressure of gas-lubricated inclined slider bearing with micro-grooves. Besides, the influence of the sliding speed on average pressure increment for various inclination angles of gas-lubricated inclined slider bearing is investigated. It is observed that the sliding speed generating the maximum average pressure increment is dependent on the inclination angle of gas-lubricated inclined slider bearing.

Real estate majorly contributes to the national gross domestic product (GDP) growth, occupying an important position in the national economy. It is the largest fixed asset for households. The real estate market is associated with a wide range of economic aspects with more upstream and downstream enterprises. Simultaneously, the factors affecting the real estate market are complex and variable. Fluctuations in the real estate market affect the entire economic system. This requires the government to formulate relevant housing policies to stabilize the operation of the real estate market. Therefore, it is meaningful to study the impact of housing policies on the real estate market and provide reasonable opinions for the housing sector in formulating policies. This study adopts a systematic quantitative literature review to examine the impact of housing policies on the real estate market. This study finds that housing policies affecting the real estate market can be divided into the following three categories: monetary, tax, and macro-prudential policies. Changes in supply and demand in the real estate market primarily reflect the effectiveness of policies, with housing price factors as the transmission mechanism. Furthermore, the influence of housing policies from different countries and regions on real estate market factors is compared to provide a reference for scholars to pursue further study.

Abstract Nanosheet (NS) vertical‐stacked complementary field‐effect transistors (CFETs), where the NS n‐FET and NS p‐FET are vertically stacked and controlled using a common gate, would result in maximum device footprint reduction. However, silicon‐based transistor will become invalid due to mobility degradation and leakage current rising when scaling the thickness of channel and dielectric. Here, it is experimentally demonstrated that CFET can scaling down to 1 nm channel thickness with excellent performance, where chemical vapor deposition (CVD) one layer (1L) WSe2 p‐type NS FET is vertically stacked on top of CVD 1L MoS2 n‐type NS FET. Bottom MoS2 NS FET achieves high on‐state current of ION = 3.3 × 10−5 A µm µm−1 and low off‐state current of IOFF = 3.3 × 10−13 A µm µm−1 at VDS = 0.7 V, with the subthreshold swing reaching 80 mV dec−1. Top WSe2 NS FET achieves high on‐state current of ION = 1.2 × 10−5 A µm µm−1 and IOFF = 4 × 10−11 A µm µm−1 at VDS = −0.7 V, while the subthreshold swing reaching 150 mV dec−1. Statistical data of 22 CFET devices demonstrate excellent uniformity toward large‐area applications. The CFET based on large‐scale 2D materials breaks the limit of channel scaling and provides a technological base for future high‐performance and low‐power electronics.

The existing numerous adaptive variants of differential evolution (DE) have been improved the search ability of classic DE to certain extent. Nevertheless, those variants of DE do not obtain the promising performance in solving black box problems with unknown features, which is mainly because the adaptive rules of those variants are designed according to their designers’ cognition on the problem features. To enhance the optimization ability of DE in optimizing black box problems with unknown features, a differential evolution with autonomous selection of mutation strategies and control parameters (ASDE) is proposed in this paper, inspired by autonomous decision-making mechanism of reinforcement learning. In ASDE, a historical experience archive with population features is utilized to preserve accumulated historical experience of the combination of mutation strategies and control parameters. Furthermore, the accumulated historical experience can be autonomously mapped into rules repository, and the individuals can choose the combination of mutation strategies and control parameters according to those rules. Additionally, an updating and utilization mechanism of the historical experience is designed to assure that the historical experience can be effectively accumulated and utilized efficiently. Compared with some state-of-the-art intelligence algorithms on 15 functions of CEC2015, 28 functions of CEC2017, and parameter extraction problems of the photovoltaic model, ASDE has the advantages of solution accuracy, convergence speed, and robustness in solving black box problems with unknown features.