Search

ObjectiveTo verify the role of aldehyde dehydrogenase 2 (ALDH2) in wound healing and to explore the underlying mechanisms. MethodsA murine excisional wound model was developed and mice were randomly assigned to control group and Alda-1 (ALDH2 agonist) group. Wound healing rate and activity of ALDH2 were measured. Masson staining was used to observe the collagen fiber content, and immunohistochemistry was used to detect the expression of ALDH2 and α-smooth muscle actin (α-SMA). The expression of collagen type Ⅰ and Ⅲ (Col-Ⅰ, Col-Ⅲ), and the number of F4/80, inducible nitric oxide synthase (iNOS) and CD206 positive (F4/80+, iNOS+, CD206+) cells were analyzed using immunofluorescences. Furthermore, interleukin (IL)-4-stimulated RAW264.7 cells were treated with Alda-1 or CVT-10216 (an ALDH2 inhibitor) in vitro. The proportion of F4/80+CD206+ cells were analyzed using flow cytometry. Anti-inflammatory and pro-inflammatory cytokines were examined using ELISA. The expression of protein associated with the AKT/mTOR pathway were detected via western blotting. ResultsCompared with control group, the wound healing rate of mice in the Alda-1 group was significantly improved, and the expression of Col-Ⅰ, Col-Ⅲ, and α-SMA in the wound surface increased. Although the number of F4/80+ cells in wounds did not significantly differ, there was a decrease in iNOS+ cells and an increase in CD206+ cells. In vitro, compared to IL-4 group, IL-4+Alda-1 group exhibited an increased proportion of F4/80+CD206+ macrophages and higher levels of anti-inflammatory factors, alongside a reduction in levels of pro-inflammatory factors. Conversely, IL-4+CVT-10216 group demonstrated a decreased proportion of F4/80+CD206+ macrophages, lower levels of anti-inflammatory factors with a concomitant increase in pro-inflammatory factors. Additionally, the protein expressions of p-AKT and p-mTOR were significantly elevated in IL-4+Alda-1 group and diminished in IL-4+CVT-10216 group. ConclusionALDH2 induces M2 macrophage polarization via AKT/mTOR pathway to promote wound healing in mice.

Abstract Background Lipids are associated with atherosclerosis, and novel lipid indices have been recently identified to be closely linked to cardiovascular diseases. This study explored the association between four novel lipid indices and the white matter hyperintensities (WMHs) in patients diagnosed with cerebral small vessel disease (CSVD). Methods Between January 2023 and February 2024, 219 patients were recruited, including 165 patients with CSVD WMHs and 54 healthy controls. Based on WMHs severity, patients with CSVD were categorised into mild and moderate-to-severe cohorts using the Fazekas rating scale. The plasma levels of four novel lipid indices (low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio [LDL-C/HDL-C], triglyceride/high-density lipoprotein cholesterol ratio [TG/HDL-C], total cholesterol/high-density lipoprotein cholesterol ratio [TC/HDL-C], and non-high-density lipoprotein cholesterol [Non-HDL-C]), were rigorously monitored in the enrolled patients. Results A total of 165 patients with CSVD WMHs were enrolled, including 94 with mild WMHs and 71 with moderate-to-severe WMHs. Multivariable logistic regression analysis revealed that LDL-C/HDL-C, TG/HDL-C, TC/HDL-C, and Non-HDL-C levels were significantly associated with WMHs (all P ≤ 0.001). Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance of plasma lipid levels for WMHs in patients with CSVD. The novel lipid indicators outperformed traditional lipid indicators in assessing the diagnostic capability of WMHs. The combined index of the four blood lipid indices had an optimal cutoff point (OCP) of 0.489, with 88.3% sensitivity and 60.6% specificity. The area under the curve (AUC) is 0.800 (95% confidence interval [CI], 0.731–0.869; P

Abstract Background Mild fetal ventriculomegaly (VM) is a nonspecific finding common to several pathologies with varying prognosis and is, therefore, a challenge in fetal consultation. We aimed to perform a constant, detailed analysis of prenatal findings and postnatal outcomes in fetuses with early-onset and late-onset mild ventriculomegaly, and provide a new evidence basis and new perspective for prenatal counseling. Methods This is a retrospective cohort study of women with a diagnosis of mild fetal VM between January 2018 and October 2020. The population was divided into two groups according to the gestational ages (GAs) at initial diagnosis: the early-onset group (diagnosed at/before 24+6 weeks) and the late-onset group (diagnosed after 24+6 weeks). Clinical data and pregnancy outcomes were obtained from hospital records. The children’s neurodevelopment status was assessed using the Ages and Stages Questionnaire, Third Edition (ASQ-3) and telephone interviews. Results Our study cohort comprised 324 fetuses, out of which 94 (29%) were classified as early-onset group and 230 (71%) late-onset group. Early-onset group was more likely to have concurrent additional abnormalities, whereas in the late-onset group, isolated enlargement was more common (P = 0.01). Unilateral enlargement was more common in the late-onset group (P = 0.05), and symmetrical enlargement in the early-onset group (P

BackgroundBilateral ductus arteriosus (BDA) is a relatively rare vascular malformation. According to the double arch theory, BDA is formed when the distal ends of the sixth pairs of primitive arches on the left and right sides have not regressed. We describe a fetus with prenatal echocardiographic findings of BDA and right aortic arch mirror-image branching (RAA-MIB) combined with congenital heart disease. Furthermore, to gain a deeper understanding of the embryological mechanism of BDA, we review the literature on all combinations of BDA present in 40 fetuses/infants.Case summaryA 22-year-old female patient underwent fetal echocardiography at 23 weeks of gestation. Both the two-dimensional (2D) grayscale image and color Doppler flow imaging (CDFI) revealed dextro-transposition of the great arteries combined with a ventricular septal defect and RAA-MIB. The following scan revealed a rare vascular ring, which was identified as BDA extending from the confluent of the left pulmonary artery and right pulmonary artery, completely encircling the trachea to form an “O”-shaped vascular ring before finally converging into the descending aorta. A persistent left superior vena cava was also observed. We subsequently used four-dimensional (4D) color Doppler imaging with the spatiotemporal image correlation (STIC) HD live flow and STIC HD live flow silhouette mode to clearly display ventricular arterial connectivity and the direction of vessel travel. Adjusting the image quality and display angle is very important when applying STIC. The 4D images confirmed our diagnosis. After multidisciplinary counseling and discussion with her family, this female patient decided to terminate the pregnancy.ConclusionOur review of the literature summarized nine combinations classified into three types of BDA and aortic arch pathology. However, our case differs because it is a novel combination of intracardiac structural abnormalities and vascular rings in a fetus. Prenatal ultrasound diagnosis of BDA is important and requires a combination of 2D grayscale, CDFI, and STIC images to assist in scanning.

Objectives Little study has reported the association of maternal weight gain in early pregnancy with fetal congenital heart disease (CHD). We aimed to explore the potential relationship based on a China birth cohort while adjusting by multiple factors.Design Cohort study.Setting China birth cohort study conducted from 2017 to 2021.Participants The study finally included 114 672 singleton pregnancies in the 6–14 weeks of gestation, without missing data or outliers, loss to follow-up or abnormal conditions other than CHD. The proportion of CHD was 0.65% (749 cases).Primary and secondary outcome measures Association between maternal pre-pregnancy weight gain and CHD in the offspring were analysed by multivariate logistic regression, with the unadjusted, minimally adjusted and maximally adjusted methods, respectively.Results The first-trimester weight gain showed similar discrimination of fetal CHD to that period of maternal body mass index (BMI) change (DeLong tests: p=0.091). Compared with weight gain in the lowest quartile (the weight gain less than 0.0 kg), the highest quartile (over 2.0 kg) was associated with a higher risk of fetal CHD in unadjusted (OR 1.36, 95% CI: 1.08 to 1.72), minimally adjusted (adjusted OR (aOR) 1.29, 95% CI: 1.02 to 1.62) and maximally adjusted (aOR 1.29, 95% CI: 1.02 to 1.63) models. The association remains robust in pregnant women with morning sickness, normal pre-pregnancy BMI, moderate physical activity, college/university level, natural conception or with folic acid (FA) and/or multivitamin supplementation.Conclusions and relevance Although the association of maternal pre-pregnancy weight gain on fetal CHD is weak, the excessive weight gain may be a potential predictor of CHD in the offspring, especially in those with morning sickness and other conditions that are routine in the cohort, such as normal pre-pregnancy BMI, moderate physical activity, college/university level, natural conception or with FA and/or multivitamin supplementation.

Abstract Radiotherapy (RT) can induce tumor regression outside the irradiation field, known as the abscopal effect. However, the detailed underlying mechanisms remain largely unknown. A tumor‐bearing mouse model is successfully constructed by inducing both subcutaneous tumors and lung metastases. Single‐cell RNA sequencing, immunofluorescence, and flow cytometry are performed to explore the regulation of tumor microenvironment (TME) by RT. A series of in vitro assays, including luciferase reporter, RNA Pulldown, and fluorescent in situ hybridization (FISH) assays, are performed to evaluate the detailed mechanism of the abscopal effect. In addition, in vivo assays are performed to investigate combination therapy strategies for enhancing the abscopal effect. The results showed that RT significantly inhibited localized tumor and lung metastasis progression and improved the TME. Mechanistically, RT promoted the release of tumor‐derived exosomes carrying circPIK3R3, which is taken up by macrophages. circPIK3R3 promoted Type I interferon (I‐IFN) secretion and M1 polarization via the miR‐872‐3p/IRF7 axis. Secreted I‐IFN activated the JAK/STAT signaling pathway in CD8+ T cells, and promoted IFN‐γ and GZMB secretion. Together, the study shows that tumor‐derived exosomes promote I‐IFN secretion via the circPIK3R3/miR‐872‐3p/IRF7 axis in macrophages and enhance the anti‐tumor immune response of CD8+ T cells.

Satellite-derived bathymetry plays a significant role in characterizing river systems, furnishing invaluable insights for applications such as flood risk management. In this paper, we introduce a bathymetry inversion framework, namely reflectance transformation - convolutional neural network (RT-CNN), geared towards long river segments, exemplified by a 210-kilometer stretch of the Bei River's in South China. The framework hinges on a neural network driven by a reflectance transformation model, an optical construct that harnesses radiance data from visible, near-infrared, and shortwave infrared bands. This modified input undergoes spatial–temporal fusion and convolutional neural network processing, culminating in high-resolution (10-meter) bathymetric estimations. The RT-CNN approach adeptly blends Landsat and Sentinel imagery with a substantial dataset of over 18,000 SONAR measurements, integrating convolutional neural network regressions for bathymetric inference. Comparative analysis against established machine learning methodologies, including random forest, gradient boosting decision tree, support vector machines, and multiple linear regression, underscores the supremacy of the proposed RT-CNN framework. Despite the Bei River's changing hydrodynamic attributes along its length, the RT-CNN delivers accurate bathymetric estimates. Specifically, across 2012, 2016, and 2019, the convolutional neural network consistently outperforms other algorithms, achieving an accuracy range of 0.43 to 1.63 m (with a 18% accuracy improvement compared to the existing methods) within an approximate elevation difference of 60 m from upstream to downstream. Temporal trend analyses indicate that heightened precipitation volumes and vegetation loss correlate with downstream shallowing in the Bei River during recent years.

Abstract Femtosecond-laser-assisted material restructuring employs extreme optical intensities to localize the ablation regions. To overcome the minimum feature size limit set by the wave nature of photons, there is a need for new approaches to tailored material processing at the nanoscale. Here, we report the formation of deeply-subwavelength features in silicon, enabled by localized laser-induced phase explosions in prefabricated silicon resonators. Using short trains of mid-infrared laser pulses, we demonstrate the controllable formation of high aspect ratio (>10:1) nanotrenches as narrow as $${\sim }{{{{{\boldsymbol{\lambda }}}}}}{{{{{\boldsymbol{/}}}}}}{{{{{\boldsymbol{80}}}}}}$$ ~ λ / 80 . The trench geometry is shown to be scalable with wavelength, and controlled by multiple parameters of the laser pulse train, such as the intensity and polarization of each laser pulse and their total number. Particle-in-cell simulations reveal localized heating of silicon beyond its boiling point and suggest its subsequent phase explosion on the nanoscale commensurate with the experimental data. The observed femtosecond-laser assisted nanostructuring of engineered microstructures (FLANEM) expands the nanofabrication toolbox and opens exciting opportunities for high-throughput optical methods of nanoscale structuring of solid materials.

The effects of three different types of modified starch additives, hydroxypropyl starch phosphate (FMS 117), acetylated distarch adipate (FMS 121), and pregelatinized acetylated distarch adipate (FMS 1820), on the gel property and product quality of surimi gel were researched. FMS 117, FMS 121, and FMS 1820 were added to Spanish Mackerel surimi in 0.5%, 1%, 1.5%, and 2%, respectively, and chroma, water holding capacity, gel strength, textural properties, rheological properties, water molecule relaxation times were measured. The results showed that the addition of FMS 117 and FMS 121 could increase the water holding capacity of Spanish mackerel surimi gel significantly (P˂0.05), increase the proportion of immobilized water (r=0.35, P

Background: Research on maternal weight gain in early pregnancy with healthy live offspring is lacking for Chinese women. Based on the China birth cohort study (CBCS), we aimed to explore maternal weight gain in different groups. Methods: Singleton pregnancies of 6 + 0~13 + 6 weeks of gestation from the CBCS were considered, not including missing data or outliers, those lost at follow-up, or those with non-typical conditions of the offspring. Maternal first-trimester weight and body mass index (BMI) gain was considered as the early pregnancy weight minus the pre-pregnancy weight. Using Pearson’s or Spearman’s correlation and linear regression models to explore the relationship between maternal weight and BMI gain and gestational age (GA), stratified and sensitivity analyses were carried out to identify the study’s robustness. Results: There were 25,292 singleton pregnancies with healthy live offspring who were ultimately enrolled, and there was a linear correlation between GA and maternal weight gain (=0.55 + 0.05 × GA (weeks), p < 0.001, r2 = 0.002) and BMI change (=0.21 + 0.02 × GA (weeks), p < 0.001, r2 = 0.002). The association remained robust in the stratified and sensitivity analyses of the subgroups. Conclusions: Although the association between GA and maternal pre-pregnancy weight and BMI gain is weak, a slight correlation was shown, especially in pregnant women with a typical or low pre-pregnancy BMI, Han ethnicity, moderate levels of physical activity, natural conception, and folic acid (FA) and/or multivitamin supplementation.

Abstract Diabetes is one of the most common phenotypes of Wolfram syndrome owing to the presence of the variants of the WFS1 gene and is often misdiagnosed as other types of diabetes. We aimed to explore the prevalence of WFS1-related diabetes (WFS1-DM) and its clinical characteristics in a Chinese population with early-onset type 2 diabetes (EOD). We sequenced all exons of the WFS1 gene in 690 patients with EOD (age at diagnosis ≤ 40 years) for rare variants. Pathogenicity was defined according to the standards and guidelines of the American College of Medical Genetics and Genomics. We identified 33 rare variants predicted to be deleterious in 39 patients. The fasting [1.57(1.06–2.22) ng/ml] and postprandial C-peptide levels [2.8(1.75–4.46) ng/ml] of the patients with such WFS1 variations were lower than those of the patients without WFS1 variation [2.09(1.43–3.05) and 4.29(2.76–6.07) respectively, ng/ml]. Six (0.9%) patients carried pathogenic or likely pathogenic variants; they met the diagnostic criteria for WFS1-DM according to the latest guidelines, but typical phenotypes of Wolfram syndrome were seldom observed. They were diagnosed at an earlier age and usually presented with an absence of obesity, impaired beta cell function, and the need for insulin treatment. WFS1-DM is usually mistakenly diagnosed as type 2 diabetes, and genetic testing is helpful for individualized treatment.

BackgroundInflammatory cytokines have long been considered closely related to the development of oral lichen planus (OLP), and we further explored the causal relationship between the two by Mendelian randomization (MR) method.MethodsWe performed bidirectional MR analyses by large genome-wide association studies (GWAS). The data included a large-scale OLP dataset, as well as datasets of 41 inflammatory cytokines. All data were obtained from the University of Bristol database, which includes 41 inflammatory cytokines, and the GWAS Catalog database, which includes 91 inflammatory cytokines. OLP data were obtained from the Finngen database, which includes 6411 cases and 405770 healthy controls. We used the inverse variance weighted (IVW) method, MR-Egger method, weighted median method, simple mode method and weighted mode method to analyze the causal relationship between inflammatory cytokines and OLP, and we also combined with sensitivity analysis to further verify the robustness of the results. We performed a meta-analysis of positive or potentially positive results for the same genes to confirm the reliability of the final results.ResultsWe primarily used the IVW analysis method, corrected using the Benjamin Hochberg (BH) method. When p

The advancement of computer technology has led to an overwhelming amount of textual information, hindering the efficiency of knowledge intake. To address this issue, various text summarization techniques have been developed, including statistics, graph sorting, machine learning, and deep learning. However, the rich semantic features of text often interfere with the abstract effects and lack effective processing of redundant information. In this paper, we propose the Multi-Features Maximal Marginal Relevance BERT (MFMMR-BertSum) model for Extractive Summarization, which utilizes the pre-trained model BERT to tackle the text summarization task. The model incorporates a classification layer for extractive summarization. Additionally, the Maximal Marginal Relevance (MMR) component is utilized to remove information redundancy and optimize the summary results. The proposed method outperforms other sentence-level extractive summarization baseline methods on the CNN/DailyMail dataset, thus verifying its effectiveness.

Abstract Objective Capsular characteristics of pleomorphic adenoma (PA) has various forms. Patients without complete capsule has a higher risk of recurrence than patients with complete capsule. We aimed to develop and validate CT-based intratumoral and peritumoral radiomics models to make a differential diagnosis between parotid PA with and without complete capsule. Methods Data of 260 patients (166 patients with PA from institution 1 (training set) and 94 patients (test set) from institution 2) were retrospectively analyzed. Three Volume of interest (VOIs) were defined in the CT images of each patient: tumor volume of interest (VOItumor), VOIperitumor, and VOIintra-plus peritumor. Radiomics features were extracted from each VOI and used to train nine different machine learning algorithms. Model performance was evaluated using receiver operating characteristic (ROC) curves and the area under the curve (AUC). Results The results showed that the radiomics models based on features from VOIintra-plus peritumor achieved higher AUCs compared to models based on features from VOItumor. The best performing model was Linear discriminant analysis, which achieved an AUC of 0.86 in the tenfold cross-validation and 0.869 in the test set. The model was based on 15 features, including shape-based features and texture features. Conclusions We demonstrated the feasibility of combining artificial intelligence with CT-based peritumoral radiomics features can be used to accurately predict capsular characteristics of parotid PA. This may assist in clinical decision-making by preoperative identification of capsular characteristics of parotid PA.

Abstract Central to homologous recombination (HR) is the assembly of Rad51 recombinase on single-strand DNA (ssDNA), forming the Rad51-ssDNA filament. How the Rad51 filament is efficiently established and sustained remains partially understood. Here, we find that the yeast ubiquitin ligase Bre1 and its human homolog RNF20, a tumor suppressor, function as recombination mediators, promoting Rad51 filament formation and subsequent reactions via multiple mechanisms independent of their ligase activities. We show that Bre1/RNF20 interacts with Rad51, directs Rad51 to ssDNA, and facilitates Rad51-ssDNA filament assembly and strand exchange in vitro. In parallel, Bre1/RNF20 interacts with the Srs2 or FBH1 helicase to counteract their disrupting effect on the Rad51 filament. We demonstrate that the above functions of Bre1/RNF20 contribute to HR repair in cells in a manner additive to the mediator protein Rad52 in yeast or BRCA2 in human. Thus, Bre1/RNF20 provides an additional layer of mechanism to directly control Rad51 filament dynamics.

The sulfate transporter (SULTR) is responsible for the transport and uptake of sulfate, which plays an indispensable role in the growth cycle of plants and adaptation to plant stress. However, there are few reports on the response and regulation of SULTR gene family members in walnuts (Juglans regia L.) to sodium selenate, low temperatures, high temperatures, and simulated drought stress. In this study, the whole genome of the SULTR genes family in walnuts was identified and analyzed by the bioinformatics method. The results show that the walnut genome contains seventeen JrSULTR genes, which are unevenly distributed on eight chromosomes and can be divided into four subfamilies. Cis-acting elements that respond to stress and participate in the regulation of plant hormones were found in the promoter sequence of the JrSULTR genes. The analysis of transcriptome data showed that the expression of JrSULTR1.2b was significantly upregulated under sodium selenate treatment, and the results of qRT-PCR analysis were basically consistent with the transcriptome data. The expression of JrSULTR3.1a and JrSULTR3.4b increased with the prolongation of simulated drought stress time. The transcription levels of JrSULTR1.2b and JrSULTR3.1a were significantly increased after low-temperature treatment. After 9 h of high-temperature treatment, the expression levels of JrSULTR3.1a and JrSULTR3.3 were significantly increased. JrSULTR1.2b and JrSULTR3.1a showed significant expression specificity under stress treatment. At the same time, we also performed subcellular localization of these two genes, which was consistent with the predicted results and was in the cell membrane, and their regulatory functions need to be further studied. These studies laid the foundation for us to explore the specific function of the JrSULTR genes in alleviating abiotic stress in walnuts.

BackgroundMetabolic diseases during pregnancy result in negative consequences for mothers. Pre-pregnancy body mass index (BMI) and late-pregnancy glycated-hemoglobin (HbA1c) are most important factors independently affecting the risk of gestational diabetes mellitus (GDM). However how both affect the combined risk of other metabolic diseases in women with GDM is unclear. The study aims to investigate the influence of pre-pregnancy BMI and pregnancy glycemic levels on other gestational metabolic diseases in women with GDM.MethodsPregnancies with GDM from January 2015 to December 2018 in the Xi’an longitudinal mother-child cohort study (XAMC) were retrospectively enrolled. Those without other metabolic diseases by the time of oral glucose tolerance test (OGTT) detection were finally recruited and divided into four groups by pre-pregnancy BMI (Underweight

Downscaling Chlorophyll-a (Chl-a) concentration derived from satellite image is crucial for refined applications such as water quality monitoring. However, the precision of downscaling is usually constrained by various environmental factors. In this paper, we develop a downscaling method for Chl-a concentration to improve precision, especially for inland lakes with different surrounding environment. The method downscales the Sentinel-3 Chl-a concentration from 300 m to 30 m, based on the multivariate analysis (MVA) and the gradient boosting decision tree (GBDT) model. Firstly, we analyzed 21 Chl-a concentration related indices to identify optimal factors for Chl-a concentration variability. Secondly, a GBDT model is constructed to convey the non-linear relationship between the optimal factors and Chl-a concentration at coarse resolution. Finally, fine-resolution Chl-a concentrations were produced by employing the model to refine cofactors for 12 distinct lakes. The results indicated that the proposed MVA-GBDT method effectively inferred the variability of Chl-a concentration with a mean RMSE of 4.505 mg/m3, an improvement of 5%–39% over other methods. Furthermore, for lakes with large water quality heterogeneity, the method led to a cross validation RMSE and a difference in accuracy of 5.371 mg/m3 and 0.866 mg/m3, respectively. In addition, this study examined the significance of the auxiliary factors and found that the NDCI and WST were the two most important factors for MVA-GBDT to detect Chl-a concentration distributions, particularly for NDCI in lakes with high nutrient contrasts. These findings contribute to the generation of fine-scale Chl-a concentrations in lakes and support related applications.

ObjectiveThis study aimed to investigate the clinical implications of fasting serum insulin (FINS) levels in subjects with type 2 diabetes who were receiving insulin therapy.MethodsA total of 1,553 subjects with type 2 diabetes [774 subjects who had never received insulin treatment (N-INS) and 779 subjects who were receiving insulin therapy (constant insulin treatment, C-INS)] admitted to the Department of Endocrinology and Metabolism of Peking University People’s Hospital were enrolled in this study. Their FINS levels were measured and those with hyperinsulinemia were identified. The underlying mechanisms of hyperinsulinemia were revealed by measuring insulin antibodies (IAs) and analyzing changes in FINS levels before and after polyethylene glycol (PEG) precipitation. In addition, the clinical characteristics of patients with different types of hyperinsulinemia were compared.ResultsHigher FINS levels and a higher incidence (43.8%, 341/779) of hyperinsulinemia (FINS > 15μIU/mL) were observed in subjects with C-INS than in subjects with N-INS. Among subjects with C-INS and hyperinsulinemia, 66.9% (228/341) were IAs positive, and the incidence of IAs was found to be positively associated with FINS level. By performing PEG precipitation, we found that all subjects without IAs (i.e., those with real hyperinsulinemia) and 31.1% of subjects (71/228) with IAs (i.e., those with both real and IAs-related hyperinsulinemia) still had hyperinsulinemia after PEG precipitation, whereas FINS levels in the other 68.9% of subjects (157/228) with IAs were normal (IAs-related hyperinsulinemia) after PEG precipitation. Comparisons between the groups showed that subjects with real hyperinsulinemia showed more obvious insulin resistance characteristics, including higher lipid levels, BMIs, and homoeostasis model assessment2-estimated insulin resistance (HOMA2-IR) index, and were more likely to have hypertension, obesity, and metabolic syndromes (p

The mono-ubiquitination of the histone protein H2B (H2Bub1) is a highly conserved histone post-translational modification that plays critical roles in many fundamental processes. In yeast, this modification is catalyzed by the conserved Bre1–Rad6 complex. Bre1 contains a unique N-terminal Rad6-binding domain (RBD), how it interacts with Rad6 and contributes to the H2Bub1 catalysis is unclear. Here, we present crystal structure of the Bre1 RBD–Rad6 complex and structure-guided functional studies. Our structure provides a detailed picture of the interaction between the dimeric Bre1 RBD and a single Rad6 molecule. We further found that the interaction stimulates Rad6’s enzymatic activity by allosterically increasing its active site accessibility and likely contribute to the H2Bub1 catalysis through additional mechanisms. In line with these important functions, we found that the interaction is crucial for multiple H2Bub1-regulated processes. Our study provides molecular insights into the H2Bub1 catalysis.

Abstract Background Conventional MR imaging has limited value in identifying H3 K27M mutations. We aimed to investigate the capacity of quantitative MR imaging variables in identifying the H3 K27M mutation status of diffuse midline glioma. Materials and Methods Twenty‐three patients with H3 K27M mutation and thirty‐two wild‐type patients were recruited in this retrospective study, all of whom underwent multimodal MR imaging. Clinical data and quantitative MR imaging variables were explored by subgroup analysis stratified by age (juveniles and adults). Then, a logistic model for all patients was constructed to identify potential variables for predicting K27M mutation status. Besides, a retrospective validation set including 13 patients was recruited. The C‐index and F1 score were used to evaluate the performance of the prediction model. Results It turned out that patients with H3 K27M mutation were younger in the adult subgroup. In the mutation group, some relative apparent diffusion coefficient (rADC) histogram parameters and myo‐inositol/creatine plus phosphocreatine (Ins/tCr) ratio were lower than in the wild‐type group of both juveniles and adults (p

Background: Previous studies on the risk of pertussis exposure to atmospheric pollutants are still inconclusive. Methods: Air pollutant, meteorological data and epidemiological distribution of pertussis cases in China during 2004–2018 were concluded in this study. A distributed lag nonlinear model (DLNM) for a maximum lag of 15 months was developed to evaluate the lag effects of monthly air pollutants and meteorological factors on pertussis incidence. Then a generalized additive model (GAM) was constructed to explore the interaction effect among air pollutants, meteorological factors and pertussis incidence and the stratified effect of selected variables. Results: A total of 74,249 cases of pertussis were included during 2004–2018 in China. Long-term exposure to NO2 was positively associated with the risk of pertussis at 32–94 µg/m3. Interaction and stratified analyses showed that there were certain correlations between 4 air pollutants (PM2.5, SO2, NO2, and O3) and 3 meteorological factors (temperature, sunlight and wind speed). In the high PM2.5 environment, a unit increment in NO2 contributed to a 2.52% (95% CI: 2.13%-2.92%) increase in pertussis incidence risk, while in a low PM2.5 environment, a unit increment of NO2 contributed to a 2.16% (95% CI: 1.64%-2.69%) increase in pertussis incidence risk. Conclusions: Our study indicated that air pollutants and meteorological factors have delayed effects on the occurrence of pertussis in China, and the effect of NO2 can be modified by PM2.5, SO2, and O3. In the prevention and control of pertussis, the additive effect of different factors on pertussis and the variability of weather should be considered.

ObjectivesMitochondrial DNA (mtDNA) plays an important role in the pathogenesis of diabetes. Variants in mtDNA have been reported in diabetes, but studies on the whole mtDNA variants were limited. Our study aims to explore the association of whole mtDNA variants with diabetes and diabetic kidney disease (DKD).MethodsThe whole mitochondrial genome was screened by next-generation sequencing in cohort 1 consisting of 50 early-onset diabetes (EOD) patients with a maternally inherited diabetes (MID) family history. A total of 42 variants possibly associated with mitochondrial diseases were identified according to the filtering strategy. These variants were sequenced in cohort 2 consisting of 90 EOD patients with MID. The association between the clinical phenotype and these variants was analyzed. Then, these variants were genotyped in cohort 3 consisting of 1,571 type 2 diabetes mellitus patients and 496 subjects with normal glucose tolerance (NGT) to analyze the association between variants with diabetes and DKD.ResultsPatients with variants in the non-coding region had a higher percentage of obesity and levels of fasting insulin (62.1% vs. 24.6%, P = 0.001; 80.0% vs. 26.5% P < 0.001). The patients with the variants in rRNA had a higher prevalence of obesity (71.4% vs. 30.3%, P = 0.007), and the patients with the variants in mitochondrial complex I had a higher percentage of the upper tertile of FINS (64.3% vs. 34.3%, P = 0.049). Among 20 homogeneous variants successfully captured, two known variants (m.A3943G, m.A10005G) associated with other mitochondrial diseases were only in the diabetic group, but not in the NGT group, which perhaps indicated its possible association with diabetes. The prevalence of DKD was significantly higher in the group with the 20 variants than those without these variants (18.7% vs. 14.6%, P = 0.049) in the participants with diabetes of cohort 3.ConclusionMtDNA variants are associated with MID and DKD, and our findings advance our understanding of mtDNA in diabetes and DKD. It will have important implications for the individual therapy of mitochondrial diabetes.

Both gallium oxide and gallium nitride have great potential for use as high power transparent conducting oxide materials for a wide range of optoelectronic applications. It is, therefore, important to determine the dynamic optical field breakdown for these materials. Here, we report laser damage thresholds for Ga2O3 and GaN using 9 fs few-cycle pulses with a center wavelength near 760 nm. We determine laser-induced damage thresholds (LIDTs) for both single pulse and multi-pulse exposures, with multi-pulse LIDT showing significant reduction compared to single pulse LIDT (in some cases, >50%), possibly due to laser-induced defects. We show that Ga2O3 and GaN have an ultrafast optical field breakdown of 23 and 18 GV/m when nearly polarized along their [010] and [111] planes, respectively, extending their suitability for high power applications to the ultrashort pulse regime. To accurately characterize the excited carrier density criteria in which apparent laser damage occurs, carrier excitation dynamics for the entire laser pulse interaction were simulated using a modified Keldysh ionization model. For the measured single-shot threshold fluences, the plasma critical density was surpassed by 2 orders of magnitude and 2D finite-difference time-domain simulations were employed to understand the pulse interaction near the surface.

Abstract Tourette syndrome (TS) is a neurobehavioral disorder for which the neurological mechanism has not been elucidated. Voxel-based morphometry (VBM) studies have revealed abnormalities in gray matter volume (GMV) in patients with TS; however, consistent results have not been obtained. The current study attempted to provide a voxel wise meta-analysis of gray matter changes using seed-based d mapping (SDM). We identified ten relevant studies that investigated gray matter alterations in TS patients and performed a meta-analysis using the SDM method to quantitatively estimate regional gray matter abnormalities. Next, we examined the relationships between GMV abnormalities and demographic and clinical characteristics. Our results demonstrated that TS patients had smaller GMV in the bilateral inferior frontal gyri and greater GMV in the cerebellum, right striatum (putamen), and bilateral thalami (pulvinar nucleus) than healthy controls. A meta-regression analysis did not identify correlations between GMV changes and demographic or clinical variables. This meta-analysis confirmed significant and consistent GMV changes in several brain regions of TS patients, primarily in the cortico-striato-thalamo-cortical network.

Abstract Background Pseudohypoaldosteronism type II (PHAII), also called Gordon syndrome, is a rare hereditary disease caused by variants in the WNK1, WNK4, KLHL3 and CUL3 genes. The combination of PHAII with hyperthyroidism and secondary hyperparathyroidism has not been reported previously. Case presentation A 54-year-old female with recently diagnosed Graves’ disease presented hyperkalemia, hypertension, hypercalciuria, elevated levels of parathyroid hormone (PTH) and normal renal function. PHAII was established based on the finding of a homozygous variant (c.328 A > G, T110A) in the KLHL3 gene. Low-dose thiazide diuretics normalized her potassium, calcium and PTH. Conclusions PHAII caused by a KLHL3 variant can affect adults later in life. This diagnosis should be considered in patients with hypertension, consistent hyperkalemia, and normal eGFR and can be corrected by thiazides. The patient also had hyperthyroidism and secondary hyperparathyroidism. The latter was also corrected by thiazide treatment. The hyperthyroidism was assumed to be unrelated to PHAII.

(1) Background: The objective of this study was to investigate the diagnostic value of chromosomal microarray analysis (CMA) for congenital heart defects (CHDs) with different cardiac phenotypes and extracardiac abnormalities (ECAs) and to explore the pathogenic genetic factors of CHDs. (2) Methods: We collected fetuses diagnosed with CHDs by echocardiography at our hospital from January 2012 to December 2021. We analyzed the CMA results of 427 fetuses with CHDs. We then categorized the CHD into different groups according to two dimensions: different cardiac phenotypes and whether it was combined with ECAs. The correlation between the numerical chromosomal abnormalities (NCAs) and copy number variations (CNVs) with CHDs was analyzed. Statistical analyses, including Chi-square tests and t-tests, were performed on the data using IBM SPSS and GraphPad Prism. (3) Results: In general, CHDs with ECAs increased the detection rate for CA, especially the conotruncal defects. CHD combined with the thoracic and abdominal walls and skeletal, thymic and multiple ECAs, were more likely to exhibit CA. Among the CHD phenotypes, VSD and AVSD were associated with NCA, while DORV may be associated with NCA. The cardiac phenotypes associated with pCNVs were IAA (type A and B), RAA, TAPVC, CoA and TOF. In addition, IAA, B, RAA, PS, CoA and TOF were also associated with 22q11.2DS. The length distribution of the CNV was not significantly different between each CHD phenotype. We detected twelve CNV syndromes, of which six syndromes may be related to CHDs. The pregnancy outcome in this study suggests that termination of pregnancy with fetal VSD and vascular abnormality is more dependent on genetic diagnosis, whereas the outcome in other phenotypes of CHDs may be associated with other additional factors. (4) Conclusions: CMA examination for CHDs is still necessary. We should identify the existence of fetal ECAs and specific cardiac phenotypes, which are helpful for genetic counseling and prenatal diagnosis.

Protein-protein docking reveals the process and product in protein interactions. Typically, a protein docking works with a docking model sampling, and then an evaluation method is used to rank the near-native models out from a large pool of generated decoys. In practice, the evaluation stage is the bottleneck to perform accurate protein docking. In this paper, PointNet, a deep learning algorithm based on point cloud, is applied to evaluate protein docking models. The proposed architecture is able to directly learn deep representations carrying the geometrical properties and atomic attributes from the 3D structural data of protein decoys. The experimental results show that the informative representations can benefit our proposed method to outperform other algorithms.

Photoresponsive materials have been widely used in sensing, bioimaging, molecular switches, information storage, and encryption nowadays. Although a large amount of photoresponsive materials have been reported, the construction of these smart materials into precisely prescribed complex 3D geometries is rarely studied. Here we designed a novel photoresponsive material methyl methacrylate containing triphenylethylene (TrPEF2-MA) that can be directly used for digital light processing (DLP) 3D printing. Based on TrPEF2-MA, a series of photoresponsive 3D structures with reversible color switching under ultraviolet/visible light irradiations were fabricated. These complex photoresponsive 3D structures show high resolutions (50 μm), excellent repeatability (25 cycles without fatigue), and tunable saturate color degrees. Multicomponent DLP 3D printing processes were also carried out to demonstrate their great properties in information hiding and information-carrying properties. This design strategy for constructing photoresponsive 3D structures is attractive in the area of adaptive camouflage, information hiding, information storage, and flexible electronics.

Developing renewable energy sources and controlling water pollution are critical but challenging problems. Urea oxidation (UOR) and methanol oxidation (MOR), both of which have high research value, have the potential to effectively address wastewater pollution and energy crisis problems. A three-dimensional neodymium-dioxide/nickel-selenide-modified nitrogen-doped carbon nanosheet (Nd2O3-NiSe-NC) catalyst is prepared in this study by using mixed freeze-drying, salt-template-assisted technology, and high-temperature pyrolysis. The Nd2O3-NiSe-NC electrode showed good catalytic activity for MOR (peak current density ~145.04 mA cm−2 and low oxidation potential ~1.33 V) and UOR (peak current density ~100.68 mA cm−2 and low oxidation potential ~1.32 V); the catalyst has excellent MOR and UOR characteristics. The electrochemical reaction activity and the electron transfer rate increased because of selenide and carbon doping. Moreover, the synergistic action of neodymium oxide doping, nickel selenide, and the oxygen vacancy generated at the interface can adjust the electronic structure. The doping of rare-earth-metal oxides can also effectively adjust the electronic density of nickel selenide, allowing it to act as a cocatalyst, thus improving the catalytic activity in the UOR and MOR processes. The optimal UOR and MOR properties are achieved by adjusting the catalyst ratio and carbonization temperature. This experiment presents a straightforward synthetic method for creating a new rare-earth-based composite catalyst.

Abstract Histone acetylation is a key histone post‐translational modification that shapes chromatin structure, dynamics, and function. Bromodomain (BRD) proteins, the readers of acetyl‐lysines, are located in the center of the histone acetylation‐signaling network. How they regulate DNA repair and genome stability remains poorly understood. Here, a conserved function of the yeast Bromodomain Factor 1 (Bdf1) and its human counterpart TAF1 is reported in promoting DNA double‐stranded break repair by homologous recombination (HR). Depletion of either yeast BDF1 or human TAF1, or disruption of their BRDs impairs DNA end resection, Replication Protein A (RPA) and Rad51 loading, and HR repair, causing genome instability and hypersensitivity to DNA damage. Mechanistically, it is shown that Bdf1 preferentially binds the DNA damage‐induced histone H4 acetylation (H4Ac) via the BRD motifs, leading to its chromatin recruitment. Meanwhile, Bdf1 physically interacts with RPA, and this interaction facilitates RPA loading in the chromatin context and the subsequent HR repair. Similarly, TAF1 also interacts with H4Ac or RPA. Thus, Bdf1 and TAF1 appear to share a conserved mechanism in linking the HR repair to chromatin acetylation in preserving genome integrity.

Objective: The treatment procedures of primary angle-closure glaucoma (PACG) with extensive peripheral anterior synechia (PAS) is a subject of debate. This study is to investigate the clinical features of phacoemulsification (Phaco)-visco dissection in medically controlled PACG patients with PAS > 180° and evaluate the predictability of Ultrasound Biomicroscopy (UBM) parameters on postoperative intraocular pressure (IOP).Methods: 48 eyes (48 patients) with acute angle-closure glaucoma (AACG) and 30 eyes (30 patients) with chronic angle-closure glaucoma (CACG) were prospectively included. All patients underwent phaco-viscogoniolysis and foldable lens implantation and were followed for 1 year after surgery. We analyzed preoperative and postoperative IOP, the numbers of anti-glaucoma medicine, the visual field value, the extent of PAS, and UBM parameters alterations, and evaluated the correlation between preoperative UBM parameters and one-year postoperative IOP.Results: IOP reduced significantly from 16.24 ± 4.33 to 14.49 ± 3.69 mmHg in AACG group and from 16.16 ± 3.69 mmHg to 14.31 ± 4.12 mmHg in CACG group, and PAS decreased significantly from 270 ± 60.33 to 171 ± 56.44° in AACG group and from 285 ± 70.46 to 168 ± 61.32° in CACG group, and the number of anti-glaucoma drugs decreased significantly in both groups. Several UBM parameters, including anterior chamber depth, trabecular iris angle, and peripheral iris thickness 500 increased while iris convex reduced considerably in the two groups, and angle opening distance 500 and trabecular-meshwork ciliary process angle increased significantly only in AACG group. One-year postoperative IOP correlated with preoperative angle opening distance 500 and trabecular iris angle negatively and iris convex positively.Conclusion: Phaco-visco dissection can effectively reduce IOP, the numbers of glaucomatous medications, and PAS in medically controlled PACG patients with extensive PAS. UBM parameters might be valuable for analyzing postoperative anterior segment structure and predicting postoperative IOP of Phaco-visco dissection in PACG patients with extensive PAS.

We report on comprehensive research regarding the potential of phase-conjugate wave (PCW) generation via backward degenerate four-wave mixing process as a pulse cleaner in femtosecond high-power laser systems. We analyzed the performance of this technique by investigating the contrast enhancement capability, gain bandwidth, and energy conversion efficiency. All of these parameters are important in pulse cleaning. The numerical calculations verified that a considerably large efficiency bandwidth product and an excellent contrast enhancement capability can be realized by finding a balance between each physical effect. The simulation results based on this study provide guidance for the application of this technique in laser systems with different bandwidths. The method, which is based on PCW generation, provides new insights for femtosecond petawatt laser systems as pulse cleaners.

The radio-occultation technique can provide vertical profiles of planetary ionospheric and atmospheric parameters, which merit the planetary-climate and space-weather scientific research so far. The Tianwen-1 one-way single-frequency radio-occultation technique was developed to retrieve Mars ionospheric and atmospheric parameters. The first radio-occultation event observation experiment was conducted on 5 August 2021. The retrieved excess Doppler frequency, bending angle, refractivity, electron density, neutral mass density, pressure and temperature profiles are presented. The Mars ionosphere M1 (M2) layer peak height is at 140 km (105 km) with a peak density of about 3.7 × 1010 el/m3 (5.3 × 1010 el/m3) in the retrieved electron-density profile. A planetary boundary layer (−2.35 km~5 km), a troposphere (temperature decreases with height) and a stratosphere (24 km–40 km) clearly appear in the retrieved temperature profile below 50 km. Results show that Tianwen-1 radio occultation data are scientifically reliable and useful for further Mars climate and space-weather studies.

The deterioration of a composite insulator’s mandrel will cause a serious power-grid accident, so it is necessary to find the defect as soon as possible. Infrared imaging is an effective means to detect mandrel-deterioration defects, but sheath-aging defects will cause trouble to screen mandrel deterioration. Therefore, it is urgent to distinguish the two defects. In this paper, two composite insulators that are out of service with different heating characteristics are tested and analyzed, and the temperature-rise characteristics are analyzed by building a simulation model. The results show that the temperature rise of composite insulators with oxidative decomposition of epoxy resin is large, and the range usually extends from the hardware of the high-voltage side to several umbrella skirts. The temperature rise caused by the composite insulator with the fiber completely wrapped by epoxy resin is small, which mainly occurs from the hardware to the first umbrella skirt. The simulation model constructed in this paper is consistent with the experimental results, which verifies the accuracy of the model. The model can distinguish the mandrel-deterioration defect and sheath-aging defect, and has guiding significance and important reference value for the detection rate of the mandrel-deterioration composite insulator and ensuring the safe and stable operation of the power grid.

This study investigates the recovery of oily sludge using ultrasound-assisted rhamnolipids and uses oil recovery yield as an evaluation index. The Box–Behnken response surface method was employed to investigate the individual and interactive effects of four different operating factors: frequency, dosage, liquid–solid ratio, and stirring speed. The model optimization results showed that the order of degree of influence of these four factors is frequency > liquid–solid ratio > dosage > stirring speed. The mathematical model predicted the highest oil recovery yield as 92.27%, which was highly accurate (in the 95% confidence interval) as from the experimental results, the highest oil recovery yield was 89.95% under optimal reaction conditions (frequency = 25.58 kHz, dosage = 150.45 mg/L, liquid–solid ratio = 4.1:1 mL/g, and stirring speed = 407 rpm). Thus, the deviation from the prediction model was only 2.32%, indicating that this method provides a theoretical basis for the treatment of oily sludge and can be implemented for practical application in Huaidong in the Xinjiang Province.

Angiogenesis is considered one of the hallmarks of cancer and plays a critical role in the development of tumor. Fibroblast growth factor 2 (FGF-2) is a member of the FGF family and participates in excessive cancer cell proliferation and tumor angiogenesis. Thus, targeting FGF-2 was considered to be a promising anti-tumor strategy. A disulfide-stabilized diabody (ds-Diabody) against FGF-2 was produced in Pichia pastoris (GS115) by fermentation and the anti-tumor activity was analyzed. The novel 10-L fed batch fermentation with newly designed media was established, and the maximum production of the ds-Diabody against FGF-2 reached 210.4 mg/L. The ds-Diabody against FGF-2 was purified by Ni2+ affinity chromatography and DEAE anion exchange chromatography. The recombinant ds-Diabody against FGF-2 could effectively inhibit proliferation, migration, and invasion of melanoma and glioma tumor cells stimulated by FGF-2. Furthermore, xenograft tumor model assays showed that the ds-Diabody against FGF-2 had potent antitumor activity in nude mice by inhibiting tumor growth and angiogenesis. The tumor growth inhibition rate of melanoma and glioma was about 70 and 45%, respectively. The tumor angiogenesis inhibition rate of melanoma and glioma was about 64 and 51%, respectively. The results revealed that the recombinant ds-Diabody against FGF-2 may be a promising anti-tumor drug for cancer therapy.

ObjectiveGraves’ disease (GD) and autoimmune thyroiditis (AIT) are two major causes of thyrotoxicosis that require correct diagnosis to plan appropriate treatment. The objectives of this study were to evaluate the usefulness of thyroid-related parameters for distinguishing GD from AIT and identify a novel index for differential diagnosis of thyrotoxicosis.DesignThis retrospective study was performed using electronic medical records in Peking University People’s Hospital (Beijing, China).MethodsIn total, 650 patients with GD and 155 patients with AIT from December 2015 to October 2019 were included in cohort 1. Furthermore, 133 patients with GD and 14 patients with AIT from December 2019 to August 2020 were included in cohort 2 for validation of the novel index identified in cohort 1. All patients were of Chinese ethnicity and were newly diagnosed with either GD or AIT. Thyroid-related clinical information was collected before intervention by reviewing the patients’ electronic medical records. Receiver operating characteristic curve analysis was used to identify the optimal cutoff for distinguishing GD from AIT.ResultsIn cohort 1, thyroid-stimulating hormone (TSH) receptor antibody was identified as the best indicator for distinguishing GD from AIT. The area under the receiver operating characteristic curve was 0.99(95% confidence interval: 0.98–0.99, p

Photodeformable materials are a class of molecules that can convert photon energy into mechanical energy, which have attracted tremendous attention in the last few decades. Owing to their unique photoinduced deformable properties, including fast light-response and diverse mechanical behaviors, photodeformable materials have exhibited great potential in many practical applications such as actuators, photoswitches, artificial muscles, and bioimaging. In this review, we sort out the current state of photodeformable crystals and classify them into six categories by molecular structures: diarylethenes, azobenzenes, anthracenes, olefins, triarylethylenes, and other systems. Three distinct light-responsive mechanisms, photocyclization, trans-cis isomerization, and photodimerization, are revealed to play significant roles in the molecular photodeformation. Their corresponding photodeformable behaviors such as twisting, bending, hopping, bursting, and curling, as well as the potential applications, are also discussed. Furthermore, the challenges and prospective development directions of photodeformable crystals are highlighted.

The chirped pulse amplification technique has enabled the generation of pulses of a few femtosecond duration with peak powers multi-Tera and Peta–Watt in the near infrared. Its implementation to realize even shorter pulse duration, higher energy, and higher repetition rate laser systems relies on overcoming the limitations imposed by laser damage of critical components. In particular, the laser damage of coatings in the amplifiers and in post-compression optics have become a bottleneck. The robustness of optical coatings is typically evaluated numerically through steady-state simulations of electric field enhancement in multilayer stacks. However, this approach cannot capture crucial characteristics of femtosecond laser induced damage (LID), as it only considers the geometry of the multilayer stack and the optical properties of the materials composing the stack. This approach neglects that in the interaction of an ultrashort pulse and the materials there is plasma generation and associated material modifications. Here, we present a numerical approach to estimate the LID threshold of dielectric multilayer coatings based on strong field electronic dynamics. In this dynamic scheme, the electric field propagation, photoionization, impact ionization, and electron heating are incorporated through a finite-difference time-domain algorithm. We applied our method to simulate the LID threshold of bulk fused silica, and of multilayer dielectric mirrors and gratings. The results are then compared with experimental measurements. The salient aspects of our model, such as the implementation of the Keldysh photoionization model, the impact ionization model, the electron collision model for ‘low’-temperature, dense plasma, and the LID threshold criterion for few-cycle pulses are discussed.

Ovarian cancer is the leading cancer-related cause of death in women worldwide. It is of great relevance to understand the mechanism responsible for tumor progression and identify unique oncogenesis markers for a higher chance of preventing this malignant disease. The high-expression OC-2 gene has been shown to be a potential candidate for regulating oncogenesis and angiogenesis in ovarian cancer. Hence, we wished to investigate the impact of OC-2 gene on ovarian cancer aggressiveness. CRISPR/Cas9, a gene editing tool, allows for direct ablation of OC-2 at the genomic level, and we successfully generated OC-2 KO cell lines from SKOV3 and CAOV3 cells. In an apoptosis assay, OC-2 KO induced the apoptosis activation of tumor cells, with the up-regulation of Bax/Caspase-8 and the down-regulation of Bcl-2. Consequently, the proliferation, migration, and invasion of OC-2 KO cell lines were significantly inhibited. Assays of qRT-PCR and Western blotting showed that the expression levels of pro-angiogenic growth factors VEGFA, FGF2, HGF, and HIF-1α and the activation of Akt/ERK pathways were significantly down-regulated at the loss of OC-2. In the xenograft model, OC-2 KO potently suppressed the subcutaneous tumor growth, with the inhibition exceeding 56%. The down-regulation of CD31 and relevant pro-angiogenic growth factors were observed in OC-2 KO tumor tissues. Taken together, OC-2 depletion negatively regulated the ovarian cancer progression possibly by apoptosis activation and angiogenesis inhibition. This work revealed a pivotal regulator of apoptosis and angiogenesis networks in ovarian cancer, and we applied the CRISPR/Cas9 system to the transcription factor pathway for developing a broad-acting anti-tumor gene therapy.

Tumor angiogenesis plays an important role in the progression and metastasis of ovarian cancer. EGFL6 protein is highly expressed in ovarian cancer and has been proposed to play an important role in promoting tumor angiogenesis. Here, a CRISPR/Cas9 system was used to knockout the EGFL6 gene in the ovarian cancer cell line SKOV3, using specific guide RNA targeting the exons of EGFL6. The knockout of EGFL6 markedly inhibited the proliferation, migration, and invasion of SKOV3 cells, as well as promoted apoptosis of tumor cells. In the nude mouse model of ovarian cancer, knockout of EGFL6 remarkably inhibited tumor growth and angiogenesis. The transcript profile assays detected 4,220 differentially expressed genes in the knockout cells, including 87 genes that were correlated to proliferation, migration, invasion, and angiogenesis. Moreover, Western blotting confirmed that EGFL6 knockout downregulated the FGF-2/PDGFB signaling pathway. Thus, the results of this study indicated that EGFL6 could regulate cell proliferation, migration, and angiogenesis in ovarian cancer cells by regulating the FGF-2/PDGFB signaling pathway.

Tumor angiogenesis is dependent on growth factors, and inhibition of their pathways is one of the promising strategies in cancer therapy. However, resistance to single pathway has been a great concern in clinical trials so that it necessitates multiple targetable factors for developing tumor angiogenesis inhibitors. Moreover, the strategy of Fc fusion protein is an attractive platform for novel peptide agents, which gains increasing importance with FDA approval because of better immunogenicity and stability. Here, we applied the Fc fusion protein concept to bFGF/VEGFA pathways and designed a multi-epitope Peptibody with immunogenic peptides derived from human bFGF and VEGFA sequences. Immunization with Peptibody could elicit high-titer anti-bFGF and anti-VEGFA antibodies, activate T cells, and induce Th1/Th2-type cytokines. In in vitro experiments, the isolated anti-Peptibody antibody inhibited the proliferation and migration of A549 cells and human umbilical vein endothelial cells (HUVECs) by decreasing the MAPK/Akt/mTOR signal pathways. In the murine tumor model, pre-immunization with Peptibody suppressed the tumor growth and neovascularization of lung cancer by decreasing the production of bFGF/VEGFA/PDGF, the MAPK/Akt/mTOR signal pathways, and the activation of suppressive cells in tumor sites. Further, the biological characterizations of the recombinant Peptibody were investigated systematically, including protein primary structure, secondary structure, stability, and toxicity. Collectively, the results highlighted the strategy of bFGF/VEGFA pathways and Fc fusion protein in suppressing tumor progression and angiogenesis, which emphasized the potential of multiple targetable factors for producing enduring clinical responses in tumor patients.

ObjectiveMaturity-onset diabetes of the young caused by hepatocyte nuclear factor-1 alpha (HNF1A) variants (HNF1A-MODY) is a common form of monogenetic diabetes. Although patients with HNF1A-MODY might specifically benefit from sulfonylurea treatment, available methods for screening this specific type of diabetes are not cost-effective. This study was designed to establish an optimized clinical strategy based on multiple biomarkers to distinguish patients with HNF1A-MODY from clinically diagnosed early-onset type 2 diabetes (EOD) for genetic testing in a Chinese population.Research design and methodsA case–control study including 125 non-related young patients with EOD and 15 probands with HNF1A-MODY (cohort 1) was conducted to evaluate reported biomarkers for HNF1A-MODY. A cut-off for the fasting insulin (Fins) level, the 97.5 percentile of 150 healthy subjects with normal components of metabolic syndrome (cohort 2), was used to filter out individuals with obvious insulin resistance (Fins 1.12 mmol/L), the sensitivity and specificity of HNF1A-CSS were 100% and 69.3%, respectively. In the pooled analysis of all young patients, HNF1A-CSS displayed 90.5% sensitivity and 73.6% specificity for identifying patients with HNF1A-MODY among those with clinically diagnosed EOD.ConclusionOur HNF1A-CSS is useful for distinguishing patients with HNF1A-MODY from patients with EOD in a young Chinese population.

Background Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and sodium‐glucose cotransporter‐2 inhibitors (SGLT2is) have shown their beneficial effects on cardiovascular outcomes and multiple cardiovascular risk factors, including hypertension. However, the mechanism of blood pressure (BP)–lowering effects of these agents has not been elucidated. This study aims to evaluate the effect of hemoglobin A1c reduction or body weight reduction with GLP‐1RA treatment and SGLT2i treatment on BP changes in patients with type 2 diabetes mellitus. Methods and Results Studies were identified by a search of MEDLINE, EMBASE, and the Cochrane Central Register until June 2019. Meta‐regression analysis was performed to evaluate the association between hemoglobin A1c reduction or body weight reduction and changes of BP. A total of 184 trials were included. Both GLP‐1RA and SGLT2i led to significant reductions in systolic BP (weighted mean difference, −2.856 and −4.331 mm Hg, respectively; P

Background: Anorexia nervosa (AN) is a debilitating illness whose neural basis remains unclear. Studies using tract-based spatial statistics (TBSS) with diffusion tensor imaging (DTI) have demonstrated differences in white matter (WM) microarchitecture in AN, but the findings are inconclusive and controversial.Objectives: To identify the most consistent WM abnormalities among previous TBSS studies of differences in WM microarchitecture in AN.Methods: By systematically searching online databases, a total of 11 datasets were identified, including 245 patients with AN and 246 healthy controls (HC). We used Seed-based d Mapping to analyze fractional anisotropy (FA) differences between AN patients and HC, and performed meta-regression analysis to explore the effects of clinical characteristics on WM abnormalities in AN.Results: The pooled results of all AN patients showed robustly lower FA in the corpus callosum (CC) and the cingulum compared to HC. These two regions preserved significance in the sensitivity analysis as well as in all subgroup analyses. Fiber tracking showed that the WM tracts primarily involved were the body of the CC and the cingulum bundle. Meta-regression analysis revealed that the body mass index and mean age were not linearly correlated with the lower FA.Conclusions: The most consistent WM microstructural differences in AN were in the interhemispheric connections and limbic association fibers. These common “targets” advance our understanding of the complex neural mechanisms underlying the puzzling symptoms of AN, and may help in developing early treatment approaches.

As the first line defensive mediators against Mycobacterium tuberculosis (M.tb) infection, macrophages can be modulated by M.tb to influence innate and adaptive immunity. Recently, we have identified several potential immunodominant T-cell antigens from the region of deletion (RD) of M.tb H37Rv, including Rv1768 from RD14. In this study, we further determined that Rv1768 was highly conserved among virulent M.tb strains and mainly distributed as a secreted protein. Exposure to recombinant purified Rv1768 (rRv1768) induced apoptosis of bone marrow derived macrophages (BMDMs) but showed no dose-dependent manner. Regarding macrophage activation, significant higher levels of iNOS and pro-inflammatory cytokines (like IL-6 and TNF-α) were detected in rRv1768-challenged BMDMs, whereas arginase 1 (Arg1) expression was markedly decreased. Meanwhile, MHC-II expression and antigen presentation activity of BMDMs were also enhanced by rRv1768 stimulation, leading to significantly increased IFN-γ expression of CD4+ T cells isolated from H37Rv-infected mice. It is worthy to note that Rv1768-induced IFN-γ production of peripheral blood mononuclear cells (PBMCs) and Rv1768-specific immunoglobulins was specifically observed in H37Rv-infected mice, but not BCG-infected or normal mice. Analysis of clinical blood samples further revealed that Rv1768 had a higher sensitivity and specificity (91.38 and 96.83%) for tuberculosis diagnosis than the results obtained from clinical CFP10 and ESAT6 peptides (CE)-based enzyme-linked immunospot (ELISPOT) assay. The area under ROC curve of Rv1768 was 0.9618 (95% CI: 0.919–1.000) when cutoff value set as 7 spots. In addition, Rv1768-specific IgG and IgM also exhibited moderate diagnostic performance for tuberculosis compared with CE specific antibodies. Our data suggest that Rv1768 is an antigen that strongly activates macrophages and has potential to serve as a novel ELISPOT-based TB diagnostic agent.

In this study, we investigated the effects of different frying conditions on the quality characteristics of fried Spanish mackerel (Scaberulous niphonius) to address the food quality degradation of self-heating fish products after frying, sterilization, and reheating. Furthermore, the effect of different moisture contents (65%, 60%, 55%, and 50%) of fried Spanish mackerel on texture, color, and microstructure after sterilization and self-heating were examined. The flavor fingerprints of different frying temperatures (140 °C, 160 °C, 180 °C, and 200 °C) coupled with the optimal moisture content were identified; furthermore, volatile organic compounds (VOCs) were studied using headspace-gas chromatography-ion mobility spectrometry (HS-GC-IMS) with principal component analysis (PCA). The results indicated that the shear force value significantly increased, while the hardness and chewiness significantly decreased simultaneously with decreasing moisture content. Samples containing 65% moisture content showed the highest L*, a*, and W values, while their b* value was the lowest, and the most clearly visible fibrous veins with tiny cracks could be observed in them. Samples fried at 160 °C and 65% moisture content exhibited the richest VOCs, with a greasy or fried aroma. Based on the PCA, there were significant differences in the sample VOCs under different frying conditions. In summary, among all treatments, frying at 160 °C with 65% moisture content resulted in the highest food quality of fish filets. The results of this study could provide a theoretical basis for improving the food quality of self-heated fish products.

The goal of the present study was to explore the relations between social avoidance, peer preference, loneliness, and social sensitivity among urban Chinese children. Participants were 951 children attending primary and middle schools from grade 3 to grade 7. Cross-sectional data were collected using self-report assessments and peer nominations. Results indicated that: (1) social avoidance positively predicted loneliness; (2) peer preference partially mediated the relation between social avoidance and loneliness; (3) social sensitivity moderated the mediating path through peer preference. The findings not only explain the mental health problems of avoidant children from the standpoint of social sensitivity and peer preference, but also have illuminating implications for guiding individual adaptation and mental health intervention.

miR-122, the expression of which is regulated by several transcription factors, such as HNF1A, was recently reported to be associated with type 2 diabetes (T2DM) and hepatocellular carcinoma. HNF1A variants can cause diabetes and might be involved in the development of primary liver neoplasm. Differences in miR-122 expression among different types of diabetes have not been studied. This study aimed to investigate differences in serum miR-122 levels in Chinese patients with different forms of diabetes, including T2DM, type 1 diabetes (T1DM), HNF1A variant-induced diabetes (HNF1A-DM), glucokinase variant-induced diabetes (GCK-DM), and mitochondrial A3243G mutation-induced diabetes (MDM). In total, 12 HNF1A-DM patients, 24 gender-, age-, and body mass index-matched (1 : 2) T2DM patients and 24 healthy subjects were included in this study. In addition, 30 monogenic diabetes (11 GCK-DM and 19 MDM) and 17 T1DM patients were included. Fasted blood biochemistry and miR-122 were measured. The results showed that the HNF1A-DM patients had lower miR-122 levels [0.046 (0.023, 0.121)] than T2DM patients [0.165 (0.036, 0.939), P=0.02] and healthy controls [0.249 (0.049, 1.234), P=0.019]. The area under the curve of the receiver operating characteristic curve for miR-122 to discriminate HNF1A-DM and T2DM was 0.687 (95% CI: 0.52–0.86, P=0.07). There was no difference in serum miR-122 among HNF1A-DM, GCK-DM, MDM, and T1DM patients. Lower serum miR-122 is a unique feature of HNF1A-DM patients and might partially explain the increased risk for liver neoplasm and abnormal lipid metabolism in HNF1A-DM patients.