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Drug-induced interstitial lung disease (DILD) is the most common pulmonary adverse event of anticancer drugs. In recent years, the incidence of anticancer DILD has gradually increased with the rapid development of novel anticancer agents. Due to the diverse clinical manifestations and the lack of specific diagnostic criteria, DILD is difficult to diagnose and may even become fatal if not treated properly. Herein, a multidisciplinary group of experts from oncology, respiratory, imaging, pharmacology, pathology, and radiology departments in China has reached the “expert consensus on the diagnosis and treatment of anticancer DILD” after several rounds of a comprehensive investigation. This consensus aims to improve the awareness of clinicians and provide recommendations for the early screening, diagnosis, and treatment of anticancer DILD. This consensus also emphasizes the importance of multidisciplinary collaboration while managing DILD.

Proliferation of embryonic fibroblasts under the same cell culture conditions, hinny embryonic fibroblasts (HiEFs) was slower than horse embryonic fibroblast (HEFs), donkey embryonic fibroblasts (DEFs) and mule embryonic fibroblasts (MuEFs). The imprinted genes IGF2 and IGF2R are important for cell proliferation. Therefore, we investigated whether the slower proliferation of HiEFs is related to an aberrant gene expression of IGF2 or its receptors or genes influencing the expression of the IGF2 system.Real-time polymerase chain reaction, immunofluorescence and cell starving experiment in HEFs, DEFs, MuEFs and HiEFs revealed that the slower proliferation of HiEF in vitro was related to its lower expression of IGF2R (P 0.001). Moreover, quantification of allele-specific expression and bisulfate assay confirmed that in both MuEFs and HiEFs, IGF2R had normal maternal imprinting, implying that the imprint aberrant was not involved in the lower IGF2R expression in HiEFs.The reduction of IGF2R expression in HiEFs is associated with its slower proliferation in vitro.

This paper describes a pedestrian re-identification algorithm, which was developed by integrating semi-supervised learning and similarity-preserving generative adversarial networks (SPGAN). The pedestrian re-identification task aimed to rapidly capture the same target using different cameras. Importantly, this process can be applied in the field of security. Because real-life environments are complex, the number of detected identities is uncertain, and the cost of manual labeling is high; therefore, it is difficult to apply the re-identification model based on supervised learning in real-life scenarios. To use the existing labeled dataset and a large amount of unlabeled data in the application environment, this report proposes a semi-supervised pedestrian re-identification model, which combines a teacher–student model with SPGAN. SPGAN was used to reduce the difference between the target domain and the source domain by transferring the style of the labeled dataset from the source domain. Additionally, the dataset from the source domain was used after the style transfer to pre-train the model; this enabled the model to adapt more rapidly to the target domain. The teacher–student model and the transformer model were then employed to generate soft pseudo-labels and hard pseudo-labels (via iterative training) and to update the parameters through distillation learning. Thus, it retained the learned features while adapting to the target domain. Experimental results indicated that the maps of the applied method on the Market-to-Duke, Duke-to-Market, Market-to-MSMT, and Duke-to-MSMT domains were 70.2, 79.3, 30.2, and 33.4, respectively.

This study aimed to evaluate the efficacy and safety of mycophenolate mofetil (MMF) or tacrolimus (TAC) compared with azathioprine (AZA) as maintenance therapy for active lupus nephritis (ALN). Patients with ALN who responded to 24 weeks of induction treatment were enrolled. Patients who received MMF or TAC as induction therapy continued MMF or TAC treatment during the maintenance period, whereas those who received intravenous cyclophosphamide were subjected to AZA treatment. The primary endpoint was the incidence of renal relapse. Secondary endpoints included extrarenal flares and composite endpoints (deaths, end-stage renal disease, or doubling of serum creatinine levels). A total of 123 ALN patients (47 in the MMF group, 37 in the TAC group, and 39 in the AZA group) were enrolled. The median follow-up time was 60 months. Ten MMF-treated patients, ten TAC-treated patients, and eight AZA-treated patients experienced renal relapses (P = 0.844). The cumulative renal relapse rates in the MMF group (P = 0.934) and TAC group (P = 0.673) were similar to the renal relapse rate in the AZA group. No significant difference in the incidence of severe adverse event was observed among the groups. Long-term maintenance therapies with MMF or TAC might have similarly low rates of renal relapse and similar safety profiles compared with AZA.

Background To evaluate the predictive effect of TCED-HFV grading and imaging biomarkers on anti-vascular endothelial growth factor (anti-VEGF) treatment in diabetic macular edema (DME). Methods 81 eyes of 81 DME patients who were treated with anti-VEGF were included in this retrospective cohort study. All patients underwent a comprehensive ophthalmic examination at baseline and follow-up, including best-corrected visual acuity (BCVA), fundus photography, and spectral domain–optical coherence tomography (SD-OCT). Baseline imaging biomarkers were qualitatively and quantitatively graded according to the TCED-HFV classification protocol, and DME was divided into early stage, advanced stage, severe stage, and atrophy stage. Results Six months post treatment, central subfield thickness (CST) in 49 eyes (60.5%) had decreased by 10% from baseline, 30 eyes (37.0%) had achieved CST P P P P P = 0.049) and negatively correlated with the reduction of CST (Kendall’s tau-b=-0.32, P Conclusion The TCED-HFV grading protocol facilitates a comprehensive assessment of DME severity, standardizes the grading of multiple imaging biomarkers, and predicts the anatomical and functional outcomes of anti-VEGF treatment.

Immune and inflammatory responses have an important function in the pathophysiology of pulmonary hypertension (PH). However, little is known about the immune landscape in peripheral circulation in patients with high-altitude pulmonary hypertension (HAPH). We apply single-cell transcriptomics to characterize the monocytes that are significantly enriched in the peripheral blood mononuclear cells (PBMC) of HAPH patients. We discover an increase in C1 (non-classical) and C2 (intermediate) monocytes in PBMCs and a decrease in hypoxia-inducible transcription factor-1α (HIF-1α) in all monocyte subsets associated with HAPH. In addition, we demonstrate that similar immune adaptations may exist in HAPH and PH. Overall, we characterize an immune cell atlas of the peripheral blood in HAPH patients. Our data provide evidence that specific monocyte subsets and HIF-1α downregulation might be implicated in the pathogenesis of HAPH.

Background Patients with type 2 diabetes mellitus (T2DM) have been reported to be more susceptible to 2019 novel coronavirus (2019-nCoV) and more likely to develop severe pneumonia. However, the safety and immunological responses of T2DM patients after receiving the inactivated vaccines are not quite definite. Therefore, we aimed to explore the safety, antibody responses, and B-cell immunity of T2DM patients who were vaccinated with inactivated coronavirus disease 2019 (COVID-19) vaccines. Methods Eighty-nine patients with T2DM and 100 healthy controls (HCs) were enrolled, all of whom had received two doses of full-course inactivated vaccines. At 21–105 days after full-course vaccines: first, the safety of the vaccines was assessed by questionnaires; second, the titers of anti-receptor binding domain IgG (anti-RBD-IgG) and neutralizing antibodies (NAbs) were measured; third, we detected the frequency of RBD-specific memory B cells (RBD-specific MBCs) to explore the cellular immunity of T2DM patients. Results The overall incidence of adverse events was similar between T2DM patients and HCs, and no serious adverse events were recorded in either group. Compared with HCs, significantly lower titers of anti-RBD-IgG (p = 0.004) and NAbs (p = 0.013) were observed in T2DM patients. Moreover, the frequency of RBD-specific MBCs was lower in T2DM patients than in HCs (p = 0.027). Among the 89 T2DM patients, individuals with lower body mass index (BMI) had higher antibody titers (anti-RBD-IgG: p = 0.009; NAbs: p = 0.084). Furthermore, we found that sex, BMI, and days after vaccination were correlated with antibody titers. Conclusions Inactivated COVID-19 vaccines were safe in patients with T2DM, but the antibody responses and memory B-cell responses were significantly decreased compared to HCs. Trial registration number and date NCT05043246. September 14, 2021. (Clinical Trials.gov)

Background Focal and segmental glomerulosclerosis (FSGS) is a histological pathology that characterizes a wide spectrum of diseases. Many genes associated with FSGS have been studied previously, but there are still some FSGS families reported in the literature without the identification of known gene mutations. The aim of this study was to investigate the new genetic cause of adult-onset FSGS. Methods This study included 40 FSGS families, 77 sporadic FSGS cases, 157 non-FSGS chronic kidney disease (CKD) families and 195 healthy controls for analyses. Whole-exome sequencing (WES) and Sanger sequencing were performed on probands and family members of all recruited families and sporadic FSGS cases. Results Using WES, we have identified a novel heterozygous missense variant (c.T1655C:p.V552A) in exportin 5 gene (XPO5) in two families (FS-133 and CKD-05) affected with FSGS and CKD. Sanger sequencing has confirmed the co-segregation of this identified variant in an autosomal dominant pattern within two families, while this variant was absent in healthy controls. Furthermore, the identified mutation was absent in 195 ethnically matched healthy controls by Sanger sequencing. Subsequently, in silico analysis demonstrated that the identified variant was highly conservative in evolution and likely to be pathogenic. Conclusions Our study reports an adult-onset autosomal dominant inheritance of the XPO5 variant in familial FSGS for the first time. Our study expanded the understanding of the genotypic, phenotypic and ethnical spectrum of mutation in this gene.

Background We aimed to evaluate the value of using preoperative magnetic resonance imaging (MRI) features and clinical indicators to predict the early response of hepatocellular carcinoma (HCC) to transcatheter arterial chemoembolization (TACE). We also aimed to establish a preoperative prediction model. Methods We retrospectively reviewed data of 111 patients with HCC who underwent magnetic resonance imaging (MRI) before the first TACE and underwent MRI or computed tomography between 30 and 60 days after TACE. We used the modified response evaluation criteria in solid tumors for evaluating the TACE response. We used univariate and multivariate logistic regression analyses to identify independent predictors based on MRI features and clinical indicators. Moreover, receiver operating characteristic (ROC) curve analyses were performed to assess the diagnostic performance of the prediction model and each independent predictor. Results Among the 111 included patients, 85 were men (76.6%). Patient age was 31–86 years (average age, 61.08 ± 11.50 years). After the first treatment session, 56/111 (50.5%) patients showed an objective response (complete response + partial response), whereas the remaining showed non-response (stable disease + local progressive disease). In the univariate analysis, we identified irregular margins, number of nodules, and satellite nodules as predictors of early objective response. However, in the multivariate logistic regression analysis, irregular margins, number of nodules and pretreatment platelet were identified as the independent predictors of early objective response. A combined prediction model was then established, which factored in irregular margins, the number of nodules, and the pretreatment platelet count. This model showed good diagnostic performance (area under the ROC curve = 0.755), with the sensitivity, specificity, positive predictive value, and negative predictive value being 78.6%, 69.1%, 72.1%, and 76.0%, respectively. Conclusions Irregular margins, the number of nodules and the pretreatment platelet count are independent predictors of the early response of HCC to TACE. Our clinical combined model can provide a superior predictive power to a single indicator.

Introduction: Type I cryoglobulinemia is a rare disease which affects the skin, central nervous system and kidneys. It is usually associated with lymphoproliferative disorders such as multiple myeloma, lymphoma and monoclonal gammopathy of renal significance. Proteinuria and membranoproliferative glomerulonephritis are the most common renal manifestations; Case presentation: Here we report the case of a female patient in her late 40 s who had proteinuria accompanied by Raynaud’s phenomenon, high blood and plasma viscosity, hearing loss, and cardiac and central nervous system involvement. Monoclonal immunoglobulin G-λ protein was detected and serum was positive for cryoglobulin. Renal biopsy revealed massive cryo-plugs with unique ultrastructural appearance in the glomerular and peritubular capillary lumina. Immunofluorescence showed predominant IgG3/λ deposition in cryo-plugs. As reported, the clinical manifestations of this patient resulted from cryoprecipitate and hyperviscosity syndrome; Conclusion: Cryoglobulinemia should be considered as a possible diagnosis in patients with Raynaud’s phenomenon, hyperviscosity syndrome and monoclonal immunoglobulin.

As S-donor metalloligands, the dithiolato [NiN2S2] complexes are employed to synthesize the bimetallic model of the active site of [NiFe]-Hydrogenases ([NiFe]-H2ases). In this work, three [NiN2S2] complexes were used to react with [NiCl2(PNP)] (PNP = (Ph2PCH2)2NCH3), respectively, to find out the influences of [NiN2S2] ligands on the structure and property of model complexes. It’s interesting to find dianion [Ni(phma)]2− (H4phma = N,N'-1,2-phenylenebis(2-mercaptoacetamide)) and [Ni(ema)]2− (H4ema = N,N'-1,2-ethylenebis(2-mercaptoacetamide)) could afford the desired dinuclear models [Ni(phma)(μ-S,S′)Ni(PNP)] (1) and [Ni(ema)(μ-S,S′)Ni(PNP)] (2), while the reaction of neutral [Ni(bme-dach)] (bme-dach = N,N′-bis-2-methyl-mercaptopropyl-1,4-diazacycloheptane) only yielded a trinuclear complex [Ni{Ni(bme-dach)(μ-S,S′)}2][BF4]2 (3). The structures of these complexes have been carefully characterized by NMR, high resolution mass spectrometry, elemental analysis, and X-ray diffraction structure analysis. As the model of [NiFe]-H2ases, complex 1 could electrocatalyze H2 evolution with a rate constant of 9.35 × 103 M−1 s−1 in the presence of CH3COOH.

The optimal coronary revascularization strategy for patients with unprotected left main coronary artery (ULMCA) disease and left ventricular systolic dysfunction (LVSD) remains uncertain. The purpose of this study was to evaluate the clinical outcomes after percutaneous coronary intervention (PCI) with a drug-eluting stent (DES) versus coronary artery bypass grafting (CABG) in patients with ULMCA disease with or without LVSD.A total of 984 patients with ULMCA disease who received a DES (n = 511) or underwent CABG (n = 473) were included in this study. We retrospectively analyzed the clinical parameters and outcomes of ULMCA disease patients with different left ventricular ejection fraction levels.There were no significant differences in major adverse cardiac and cerebral events, all-cause death, cardiac death, myocardial infarction, or stroke between the CABG and DES groups with or without LVSD. The rate of target vessel revascularization was significantly higher with DES compared with CABG in patients without LVSD; however, the difference was not significant between the mild LVSD and severe LVSD groups.For patients with ULMCA disease and LVSD, there was no significant difference between DES and CABG in terms of efficacy and safety. Treatment with DES was an acceptable alternative to CABG.HINTERGRUND: Die optimale Strategie zu Koronargefäßrevaskularisierung bei Patienten mit koronarer Herzkrankheit (KHK) des ungeschützten linken Hauptstamms (ULMCA) und linksventrikulärer systolischer Dysfunktion (LVSC) bleibt ungewiss. Ziel der vorliegenden Studie war es, die klinischen Ergebnisse nach perkutaner Koronarintervention (PCI) mit einem medikamentenfreisetzenden Stent (DES) vs. Koronararterien-Bypass-Operation (CABG) bei Patienten mit ULMCA-KHK mit oder ohne LVSD zu untersuchen.In die Studie wurden 984 Patienten mit ULMCA-KHK aufgenommen, die mittels DES (n = 511) oder CABG (n = 473) versorgt wurden. Retrospektiv wurden die klinischen Parameter und Ergebnisse der Patienten mit ULMCA-KHK mit verschiedenen linksventrikulären Ejektionsfraktionswerten analysiert.Es gab keine signifikanten Unterschiede zwischen der CABG- und DES-Gruppe mit oder ohne LVSD bei schweren unerwünschten kardialen und zerebralen Ereignissen, Tod jeglicher Ursache, Herztod, Myokardinfarkt oder Schlaganfall. Die Rate an Zielgefäßrevaskularisierungen war für Patienten ohne LVSD bei Behandlung mit einem DES signifikant höher als bei CABG-Therapie; allerdings war der Unterschied zwischen der Gruppe mit leichtgradiger LVSD und der Gruppe mit schwerer LVSD nicht signifikant.Für Patienten mit ULMCA-KHK und LVSD bestand kein signifikanter Unterschied zwischen der Therapie mit DES und CABG hinsichtlich der Wirksamkeit und Sicherheit. Die Behandlung mit einem DES stellte eine akzeptable Alternative zur CABG-Therapie dar.

Colorectal cancer (CRC) is the third most common malignant tumor. DNA damage played a crucial role on tumorigenesis, and abnormal DNA repair pathways affected the occurrence and progress of CRC. In current study, we aimed to construct a DNA repair-related genes (DRG) signature to predict the overall survival (OS) of CRC patients. Differentially expressed DRGs (DE-DRGs) were analyzed using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The prognostic gene signature was identified by univariate Cox regression and Least Absolute Shrinkage and Selection Operator (LASSO)-penalized Cox proportional hazards regression analysis. The predictive ability of the model was evaluated by utilizing Kaplan-Meier curves and Time-dependent receiver operating characteristic (ROC) curves. Gene set enrichment analysis (GSEA) was performed to explore the underlying biological processes and signaling pathways. Single sample gene set enrichment analysis (ssGSEA) was implemented to estimate the immune status between the different risk group. A total of 118 DE-DRGs were identified between 42 normal samples and 488 CRC samples in TCGA cohort, and 36 DE-DRGs were associated with OS in the univariate Cox regression. A 9 DE-DRGs (ESCO2, AXIN2, PLK1, CDC25C, IGF1, TREX2, ALKBH2, ESR1 and MC1R) signature was constructed to classify patients into high-risk and low-risk group. The risk score was an independent prognostic indicator for OS (HR>1, P

Background Cancer cells have an imbalance in oxidation-reduction (redox) homeostasis. Understanding the precise mechanisms and the impact of the altered redox microenvironment on the immunologic reaction to tumors is limited. Methods We isolated exosomes from ovarian cancer cells through ultracentrifuge and characterized by Western-blots and Nanoparticle Tracking Analysis. 2D, 3D-coculture tumor model, and 3D live cell imaging were used to study the interactions between tumor cells, macrophages and CD3 T cells in vitro. The role of exosomal miR-155-5p in tumor growth was evaluated in xenograft nude mice models and immune-competent mice models. Flow cytometry and flow sorting were used to determine the expression levels of miR-155-5p and PD-L1 in ascites and splenic macrophages, and the percentages of CD3 T cells subpopulations. Results The elevation of reactive oxygen species (ROS) greatly downregulated exosomal miR-155-5p expression in tumor cells. Neutralization of ROS with N-acetyl-L-cysteine (NAC) increased the levels of miR-155-5p in tumor exosomes that were taken up by macrophages, leading to reduction of macrophage migration and tumor spheroid infiltration. We further found that programmed death ligand 1 (PD-L1) is a functional target of miR-155-5p. Co-culture of macrophages pre-treated with NAC-derived tumor exosomes or exosomal miR-155-5p with T-lymphocytes leading to an increased percentage of CD8+ T-lymphocyte and a decreased CD3+ T cell apoptosis through PD-L1 downregulation. Tumor growth in nude mice was delayed by treatment with NAC-derived tumor exosomes. Delivery of tumor exo-miR-155-5p in immune-intact mice suppressed ovarian cancer progression and macrophage infiltration, and activated CD8+ T cell function. It is of note that exo-miR-155-5p inhibited tumor growth more potently than the PD-L1 antibody, suggesting that in addition to PD-L1, other pathways may also be targeted by this approach. Conclusions Our findings demonstrate a novel mechanism, ROS-induced down-regulation of miR-155-5p, by which tumors modulate the microenvironment that favors tumor growth. Understanding of the negative impact of ROS on the tumor immune response will improve current therapeutic strategies. Targeting miR-155-5p can be an alternative approach to prevent formation of an immunosuppressive TME through downregulation of PD-L1 and other immunosuppressive factors. Graphical Abstract

BackgroundSETD1A, a member of SET1/MLL family H3K4 methyltransferases, is involved in the tumorigenesis of numerous cancers. However, the biological role and mechanism of SETD1A in non-small cell lung cancer (NSCLC) remain to be elucidated.MethodsThe expression of SETD1A, NEAT1, EZH2, and β-catenin in NSCLC tissues and cell lines was detected by qRT-PCR, immunohistochemistry and western blotting. The regulatory mechanisms were validated by chromatin immunoprecipitation, co-immunoprepitation and luciferase reporter assay. The self-renewal, cisplatin sensitivity and tumorigenesis of NSCLC cells were analyzed using sphere formation, CCK-8, colony formation assays and xenograft tumor models.ResultsSETD1A expression was significantly increased in NSCLC and its overexpression predicted a poor prognosis of patients with NSCLC. Functional experiments showed that SETD1A positively regulated cancer stem cell property and negatively regulated cisplatin sensitivity in NSCLC cells via the Wnt/β-catenin pathway. Next, we found that SETD1A positively regulated the Wnt/β-catenin pathway via interacting with and stabilizing β-catenin. The SET domain is dispensable for the interaction between SETD1A and β-catenin. Furthermore, we identified that SETD1A bound to the promoters of NEAT1 and EZH2 to activate gene transcription by inducing H3K4me3 enrichment. Rescue experiments showed that SETD1A promoted the Wnt/β-catenin pathway and exerted its oncogenic functions in NSCLC, at least, partly through NEAT1 and EZH2 upregulation. In addition, SETD1A was proven to be a direct target of the Wnt/β-catenin pathway, thus forming a positive feedback loop in NSCLC cells.ConclusionSETD1A and Wnt/β-catenin pathway form a positive feedback loop and coordinately contribute to NSCLC progression.

Background The deleterious effect of maternal high-fat diet (HFD) on the fetal rat liver may cause later development of non-alcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate the effect of maternal HFD-induced maternal hepatic steatosis and dysbiosis on the fetal liver and intestines, and the effect of prenatal metformin in a rat model. Methods Sprague–Dawley rats were assigned to three groups (N = 6 in each group). Before mating, the rats were randomly assigned to HFD or normal-chow diet (NCD) group for 7 weeks. After mating, the HFD group rats were continued with high-fat diet during pregnancy and some of the HFD group rats were co-treated with metformin (HFMf) via drinking water during pregnancy. All maternal rats and their fetuses were sacrificed on gestational day 21. The liver and intestinal tissues of both maternal and fetal rats were analyzed. In addition, microbial deoxyribonucleic acid extracted from the maternal fecal samples was analyzed. Results HFD resulted in maternal weight gain during pregnancy, intrahepatic lipid accumulation, and change in the serum short-chain fatty acid profile, intestinal tight junctions, and dysbiosis in maternal rats. The effect of HFD on maternal rats was alleviated by prenatal metformin, which also ameliorated inflammation and apoptosis in the fetal liver and intestines. Conclusions This study demonstrated the beneficial effects of prenatal metformin on maternal liver steatosis, focusing on the gut-liver axis. In addition, the present study indicates that prenatal metformin could ameliorate maternal HFD-induced inflammation and apoptosis in the fetal liver and intestines. This beneficial effect of in-utero exposure of metformin on fetal liver and intestines has not been reported. This study supports the use of prenatal metformin for pregnant obese women.

Biological aerosol particles play a crucial role in the Earth system, particularly in the land/ocean-atmosphere interactions. This paper aims to summarize the up-to-date research progresses on the characteristics, biomarkers as well as the health-related, climatic and ecological effects of biological aerosol particles in polluted regions, especially in East Asia and South Asia. The atmospheric abundance, size distribution, and community structure of microorganisms show differences during haze and non-haze conditions. The long-distance transportation of dust-associated microorganisms influences the abundance and community structure of airborne microbes in downwind areas. Wildfire smoke or biomass burning potentially impacts the release, transport and dispersal of microorganisms in the atmosphere. Meteorological conditions and air pollutants likely interact with airborne microorganisms, pollen, and fluorescent biological aerosol particles. Molecular biomarkers including proteins and amino acids, sugars, and lipid compounds have been used to fingerprint the sources of biological aerosols and give important biogeochemical information of atmospheric aerosols. In addition to pathogenic and allergenic microorganisms and pollen, biological aerosol particles indicated by abundant endotoxins and antibiotic resistance genes could have significant impacts on public health. In polluted regions, the potential influences of biological aerosol particles on climate and ecosystems could be more complex. We comprehensively summarize the recent research progresses on the characteristics, biomarkers, influencing factors, and effects of biological aerosol particles in polluted regions, mostly in East Asia and South Asia. To further understand the complicated effects of biological aerosol particles in polluted regions, the development and application of novel approaches and techniques as well as in-depth investigations on the roles of biological aerosol particles in atmospheric chemistry, cloud formation, and public health need to be implemented.

In this study, we designed geometry learning activities so that students could apply newly learned knowledge to solve real-life problems, such as estimating the distance to real objects they find in their local community, measuring objects’ length, width, and height, and calculating objects’ surface area. Our participating students were divided into three groups, and each group used different tools in different contexts for the measurements and calculations: the students in control group A used traditional tools, such as rulers, paper, and pencil, and their learning activities took place in the local community; the students in control group B used traditional tools as well, but their learning activities took place in classroom; the students in the experimental group learned geometry in a local community setting using a tablet PC-based ubiquitous geometry (UG) system that we developed for this study. We tested the difference in geometry learning performance, such as geometry reasoning and spatial estimation abilities, among the three groups. We also investigated the perceptions of students in the experimental group toward the UG system. Furthermore, student behaviors toward measuring objects using the UG system and their relationship with geometry reasoning and spatial estimation abilities were explored. Our results showed that the geometry learning performance of the students in the experimental group was significantly better than that of the students in the other two groups. Our results also showed that the students in the experimental group had high learning motivation and intention to use the UG system. Further analysis revealed that the students who measured more objects in the real world using our system had better geometry reasoning and spatial estimation abilities. However, only the students who measured objects correctly had high learning gains. The results suggest that the learning activities supported by the UG system were beneficial for enhancing geometry reasoning and spatial estimation abilities because the students were able to apply newly learned knowledge to the real world. Based on the results, we give some advice on the design of learning activities.

Increased epicardial adipose tissue (EAT) has been proposed as a risk factor for non-alcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the association of EAT with NAFLD. The PubMed, EMBASE, and Cochrane databases were systematically reviewed by two independent investigators to identify relevant studies assessing the association of EAT thickness (EAT-t) and volume (EAT-v) with NAFLD. Comparisons between NAFLD subjects and controls were performed with meta-analysis and trial sequential analysis (TSA). A total of thirteen case–control studies (n = 2260 patients) were included in the final analysis. The EAT was significantly increased in NAFLD patients compared with the controls (EAT, SMD: 0.73, 95% CI 0.51–0.94, p

Background and aim Long-term treatment with tenofovir disoproxil fumarate (TDF) has demonstrated suppression of viral replication outside of China. This study aims to assess efficacy, resistance and safety of TDF for up to 240 weeks in Chinese patients with chronic hepatitis B virus (HBV) infection. Methods Patients (HBeAg-positive or HBeAg-negative) who were randomised to receive TDF 300 mg or adefovir dipivoxil (ADV) 10 mg once daily in the 48-week double-blind phase (N = 498) were eligible to enter the open-label TDF phase (TDF–TDF and ADV–TDF groups) for additional 192 weeks. Results Overall, 457/512 (89.3%) randomised patients completed 240 weeks of treatment. Virological suppression was achieved in 84.5% and 87.9% in HBeAg-positive patients and 89.6% and 89.5% in HBeAg-negative patients in TDF–TDF and ADV–TDF groups, respectively, at week 240. The majority of patients from both groups had normalized alanine transaminase levels. More patients had HBeAg loss (41.7% vs. 36.4%) and HBeAg seroconversion (32.0% vs. 28.3%) in TDF–TDF than in ADV–TDF group, respectively. Only one HBeAg-positive patient in TDF–TDF group had HBsAg loss at week 240. No evidence of resistance to TDF was observed. The incidence of adverse events was similar in both groups (TDF–TDF, 56.4% vs. ADV–TDF, 51.6%). One patient had serum creatinine elevation ≥ 0.5 mg/dL above baseline, and three patients had confirmed grade 3/4 phosphorus abnormalities ( Conclusion In Chinese patients with chronic HBV, long-term treatment with TDF showed sustained viral suppression without development of resistance up to 240 weeks. No new safety concerns were found with TDF in this patient population. Clinical Trial Registration ClinicalTrial.gov Identifier NCT01300234; GSK Clinical Study Register 114648.

Expansin (EXP) plays an important role in plant root formation. The EXP genes associated with chrysanthemum roots have not yet been reported. Here we isolated a root-specific EXP gene in chrysanthemum (Chrysanthemum morifolium), namely CmEXPA4. Bioinformatics analysis showed that CmEXPA4-encoded protein has a conserved DPPB (Double-Psi Beta-Barrel) domain in the N-terminal with a series of Cys residues, an HFD (His-Phe-Asp) motif in the central region, and a pollen allergen domain in the C-terminal. The protein also has a specific α-insertion of WCNP (Trp-Cys-Asn-Pro), which suggests that it belongs to the A-subgroup of the EXP family. In the present study, we cloned the 1,129 bp promoter region upstream of CmEXPA4, and the analysis revealed an abundance of cis-acting elements associated with hormones, light and stress-related responses, and some root-specific regulatory elements in particular. Subcellular localization results indicated that CmEXPA4 locates in the cell wall. Exogenous indole butyric acid induced the up-regulation of CmEXPA4 expression, whereas exogenous abscisic acid inhibited its expression. Tissue expression analysis showed that CmEXPA4 was preferentially expressed in the roots and was synchronized with the rapid emergence of the root. These results suggested that CmEXPA4 may act on the growth and development of chrysanthemum roots. The function of CmEXPA4 was further tested by virus-induced gene silencing, and the results showed that CmEXPA4 silencing inhibited the normal development of the chrysanthemum root system. The roots appeared thinner and shorter, and several important root parameters, including total length, average diameter, surface area, total volume, and root tip number, decreased significantly. The cortical cells of the transgenic plant roots were significantly smaller and shorter than those of the control. Collectively, our results demonstrated that CmEXPA4 gene plays a key role in the growth and development of chrysanthemum roots and affects the root system by acting on the individual cells.

Purpose Higher alcohol is a by-product of the fermentation of wine, and its content is one of the most important parameters that affect and are used to appraise the final quality of Chinese rice wine. Ammonium compensation is an efficient and convenient method to reduce the content of higher alcohols, but the molecule mechanism is poorly understood. Therefore, an iTRAQ-based proteomic analysis was designed to reveal the proteomic changes of Saccharomyces cerevisiae to elucidate the molecular mechanism of ammonium compensation in reducing the content of higher alcohols. Methods The iTRAQ proteomic analysis method was used to analyze a blank group and an experimental group with an exogenous addition of 200 mg/L (NH4)2HPO4 during inoculation. The extracted intracellular proteins were processed by liquid chromatography-mass spectrometry and identified using bioinformatics tools. Real-time quantitative polymerase chain reaction was used to verify the gene expression of differentially expressed proteins. Results About 4062 proteins, including 123 upregulated and 88 downregulated proteins, were identified by iTRAQ-based proteomic analysis. GO and KEGG analysis uncovered that significant proteins were concentrated during carbohydrate metabolism, such as carbon metabolism, glyoxylate, and dicarboxylate metabolism, pyruvate metabolism, and the nitrogen metabolism, such as amino acid synthesis and catabolism pathway. In accordance with the trend of differential protein regulation in the central carbon metabolism pathway and the analysis of carbon metabolic flux, a possible regulatory model was proposed and verified, in which ammonium compensation facilitated glucose consumption, regulated metabolic flow direction into tricarboxylic acid, and further led to a decrease in higher alcohols. The results of RT-qPCR confirmed the authenticity of the proteomic analysis results at the level of gene. Conclusion Ammonium assimilation promoted by ammonium compensation regulated the intracellular carbon metabolism of S. cerevisiae and affected the distribution of metabolic flux. The carbon flow that should have gone to the synthesis pathway of higher alcohols was reversed to the TCA cycle, thereby decreasing the content of higher alcohols. These findings may contribute to an improved understanding of the molecular mechanism for the decrease in higher alcohol content through ammonium compensation.

Background Glucocorticosteroid is used for patients with primary nephrotic syndrome. This study aims to identify and validate that biomarkers can be used to predict steroid resistance. Methods Our study contained two stages, discovery and validation stage. In discovery stage, we enrolled 51 minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS) patients treated with full dose steroid. Five urinary biomarkers including β2-microglobulin (β2-MG) and α1-microglobulin (α1-MG) were tested and candidates’ biomarkers were selected based on their associations with steroid response. In validation stage, candidates’ biomarkers were validated in two prospectively enrolled cohorts. Validation cohort A included 157 FSGS/MCD patients. Validation cohort B included 59 membranous nephropathy (MN) patients. Patients were classified into response group (RG) or non-response group (NRG) based on their responses to steroid treatment. Results In discovery stage, higher urinary β2-MG was independently associated with response to corticosteroid treatment in MCD/FSGS patients [OR = 1.89, 95% CI 1.02–3.53] after adjusted by age and gender. In validation cohort A, patients in NRG had a significant higher urinary β2-MG [Ln (β2-MG/uCr): 4.6 ± 1.7 vs 3.2 ± 1.5] compared to patients in RG. We then developed a 3-variable risk score in predicting steroid resistance in FSGS/MCD patients based on the best predictive model including Ln(β2-MG/uCr) [OR = 1.76, 95% CI 1.30–2.37], age [OR = 1.005, 95% CI 0.98–1.03] and pathology [MCD vs FSGS, OR = 0.20, 95% CI 0.09–0.46]. The area under the ROC curves of the risk score in predicting steroid response was 0.80 (95% CI 0.65–0.85). However, no such association was found in MN patients. Conclusions Our study identified a 3-variable risk score in predicting steroid resistance in patients with FSGS or MCD.

Background Fat accumulation in the liver contributes to the development of non-alcoholic fatty liver disease (NAFLD). N-acetylcysteine (NAC) is an antioxidant, acting both directly and indirectly via upregulation of cellular antioxidants. We examined the mechanisms of liver steatosis after 12 months high fat (HF) diet and tested the ability of NAC to rescue liver steatosis. Methods Seven-week-old C57BL/6 (B6) male mice were administered HF diet for 12 months (HF group). Two other groups received HF diet for 12 months accompanied by NAC for 12 months (HFD + NAC(1–12)) or 6 months (HFD + NAC(1–6)). The control group was fed regular diet for 12 months (CD group). Results Liver steatosis was more pronounced in the HF group than in the CD group after 12 month feeding. NAC intake for 6 or 12 months decreased liver steatosis in comparison with HF diet (p p Conclusion HF diet for 12 months induces significant liver steatosis via altered ER stress and UPR pathway activity, as well as liver apoptosis. NAC treatment rescues the liver steatosis and apoptosis induced by HF diet.

Jasmonates (JAs) play an important role in many developmental processes, such as root growth, leaf senescence, male fertility, and defense responses against insects and pathogens. The F-box protein COI1, which plays a central role in JA signal transduction, perceives the JA signal and is required for all the JA-mediated defense responses against biotic and abiotic stresses. JA signaling elements including COI1 have been extensively investigated in Arabidopsise. However, the elements of the JA signaling pathway in maize are largely unknown. In this study, we identified four F-box protein genes from the maize genome, which share high homology with AtCOI1, designated as ZmCOI1a, ZmCOI1b, ZmCOI1c, and ZmCOI2, collectively ZmCOIs. To test whether or not the homologous genes of maize are functionally conservative in JA signaling, we over-expressed ZmCOIs in the Arabidopsis coi1-1 mutant. The results showed that over-expression of ZmCOI1a, ZmCOI1b or ZmCOI1c in the coi1-1 mutant resulted in the restoration of male fertility, indicating successful complementation of coi1-1 sterility by ZmCOI1a, ZmCOI1b, and ZmCOI1c. However, ZmCOI2 was not able to restore male fertility of the mutant, indicating that ZmCOI2 has a function diverged from JA signaling. Furthermore, over-expression of the ZmCOI1a, ZmCOI1b, and ZmCOI1c genes, except ZmCOI2, which, in the coi1-1 mutant, caused restoration of resistance to the leaf pathogen Botrytis cinerea and the soil-borne pathogen Pythium aristosporum. In addition, a set of JA-dependent genes are highly induced by wounding in the transformants of ZmCOIa, ZmCOI1b, and ZmCOI1c, but not inducible in transformants of ZmCOI2 or in the coi1-1 mutant, indicating that ZmCOIa, ZmCOI1b, and ZmCOI1c, except ZmCOI2, which can compensate coi1-1 mutation of Arabidopsis for the stress defense response. Putting all the data together, our results suggested that ZmCOIa, ZmCOI1b, and ZmCOI1c, but not ZmCOI2, act as AtCOI1 orthologues in maize for JA signal transduction.

Japanese encephalitis is a zoonotic, mosquito-borne, infectious disease caused by Japanese encephalitis virus (JEV), which is prevalent in China. At present, there are no specific drugs or therapies for JEV infection, which can only be treated symptomatically. Lentivirus-mediated RNA interference (RNAi) is a highly efficient method to silence target genes. In this study, two lentiviral shRNA, LV-C and LV-NS5, targeting the conserved viral gene sequences were used to inhibit different JEV genotypes strains in BHK21 cells and mice. The results showed that LV-C significantly inhibited JEV genotype I and genotype III strains in cells and mice. Quantitative RT-PCR analysis showed that JEV mRNA were reduced by 83.2-90.9% in cells by LV-C and that flow cytometry analysis confirmed the inhibitory activity of LV-C. The viral titers were reduced by about 1000-fold in cells and the brains of suckling mice by LV-C, and the pretreatment of LV-C protected 60-80% of mice against JEV-induced lethality. The inhibitory activities of LV-NS5 in cells and mice were weaker than those of LV-C. These results indicate that RNAi targeting of the two conserved viral gene sequences had significantly suppressed the replication of different JEV genotypes strains in vitro and in vivo, highlighting the feasibility of RNAi targeting of conserved viral gene sequences for controlling JEV infection.

To compare the efficacy of glucocorticoids in primary focal segmental glomerulosclerosis (pFSGS) patients with moderate proteinuria. Registered at http://www.chictr.org.cn/ , study No. ChiCTR-OPN-17012789. pFSGS patients with urine protein between 1.0 and 3.5 g/24 h were recruited from 2006 to 2016. No decline in urine protein > 50% was observed after 2 months of run-in angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (ACEI/ARB) treatment. Patients were assigned to study group (glucocorticoids with ACEI/ARB) or control group (ACEI/ARB without glucocorticoids). Variables including 24-h urinary protein, serum albumin and serum creatinine during the trial were recorded. Remission was defined as proteinuria 50%, and our composite end point as > 30% decrease of eGFR or eGFR

This study uses the total-factor energy productivity change index (TFEPCH) to investigate the changes in energy productivity of construction industry for 30 provincial regions in China from 2006 to 2015, adopting the improved Luenberger productivity index combined with the directional distance function. In addition to traditional economic output indicator, this study introduces building floor space under construction as a physical output indicator for energy productivity evaluation. The TFEPCH was decomposed into energy technical efficiency change and energy technical progress shift. Results indicate that, first, energy productivity of China’s construction industry decreased by 7.1% annually during 2006–2015. Energy technical regress, rather than energy technical efficiency, contributed most to the overall decline in energy productivity of China’s construction industry. Second, energy productivity in the central region of China decreased dramatically, by a cumulative sum of approximately 77.1%, since 2006, while energy productivity in the eastern and western regions decreased by over 54.3 and 65.3%, respectively. Only two of the 30 provinces considered—Hebei and Shandong—improved their energy productivity during 2006–2015. The findings presented here provide a basis for decision-making and references for administrative departments to set differentiated energy efficiency goals and develop relevant measures. Additionally, the findings are highly significant for energy and resource allocation of Chinese construction industry in different regions.

Cathelicidin-BF (BF-30), a peptide isolated from the snake venom of Bungarus fasciatus, exhibits multiple biological functions, including antimicrobial, anticancer and anti-inflammatory. However, the effect of BF-30 on platelet and thrombus formation was reported rarely. In this study, we investigated the antiplatelet and antithrombotic effects of BF-30 and its underlying mechanism. Our results showed that BF-30 potently inhibited thrombin-induced platelet aggregation, and further specifically blocked protease-activated receptor 4 (PAR4). It also reduced P-selectin expression, AktSer473 phosphorylation and platelet spreading on fibrinogen. Furthermore, BF-30 exhibited potent inhibitory activity on thrombus formation in vivo: it decreased death of mice with acute pulmonary thrombosis and attenuated thrombosis weight in arterio-venous shunt model. Additionally, a tail cutting bleeding time assay revealed that BF-30 did not prolong bleeding time in mice at efficient dosage. Taken together, BF-30 is a PAR4 antagonist, and inhibits thrombus formation without obvious bleeding risk in vivo. We believe that this study may provide a source for the development of PAR4 antagonist for the treatment of thrombotic disorders.

D-type cyclins (D1, D2 and D3) and their associated cyclin-dependent kinases (CDK4 and CDK6) are components of the core cell cycle machinery that drives cell proliferation. Inhibitors of CDK4 and CDK6 are currently being tested in clinical trials for patients with several cancer types, with promising results. Here, using human cancer cells and patient-derived xenografts in mice, we show that the cyclin D3-CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2. This re-directs the glycolytic intermediates into the pentose phosphate (PPP) and serine pathways. Inhibition of cyclin D3-CDK6 in tumour cells reduces flow through the PPP and serine pathways, thereby depleting the antioxidants NADPH and glutathione. This, in turn, increases the levels of reactive oxygen species and causes apoptosis of tumour cells. The pro-survival function of cyclin D-associated kinase operates in tumours expressing high levels of cyclin D3-CDK6 complexes. We propose that measuring the levels of cyclin D3-CDK6 in human cancers might help to identify tumour subsets that undergo cell death and tumour regression upon inhibition of CDK4 and CDK6. Cyclin D3-CDK6, through its ability to link cell cycle and cell metabolism, represents a particularly powerful oncoprotein that affects cancer cells at several levels, and this property can be exploited for anti-cancer therapy.

Drug-induced liver injury (DILI) is an important clinical problem, which has received more attention in recent decades. It can be induced by small chemical molecules, biological agents, traditional Chinese medicines (TCM), natural medicines (NM), health products (HP), and dietary supplements (DS). Idiosyncratic DILI is far more common than intrinsic DILI clinically and can be classified into hepatocellular injury, cholestatic injury, hepatocellular-cholestatic mixed injury, and vascular injury based on the types of injured target cells. The CSH guidelines summarized the epidemiology, pathogenesis, pathology, and clinical manifestation and gives 16 evidence-based recommendations on diagnosis, differential diagnosis, treatment, and prevention of DILI.

The optimal coronary revascularization strategy for patients with unprotected left main coronary artery (ULMCA) disease and left ventricular systolic dysfunction (LVSD) remains uncertain. The purpose of this study was to evaluate the clinical outcomes after percutaneous coronary intervention (PCI) with a drug-eluting stent (DES) versus coronary artery bypass grafting (CABG) in patients with ULMCA disease with or without LVSD. A total of 984 patients with ULMCA disease who received a DES (n = 511) or underwent CABG (n = 473) were included in this study. We retrospectively analyzed the clinical parameters and outcomes of ULMCA disease patients with different left ventricular ejection fraction levels. There were no significant differences in major adverse cardiac and cerebral events, all-cause death, cardiac death, myocardial infarction, or stroke between the CABG and DES groups with or without LVSD. The rate of target vessel revascularization was significantly higher with DES compared with CABG in patients without LVSD; however, the difference was not significant between the mild LVSD and severe LVSD groups. For patients with ULMCA disease and LVSD, there was no significant difference between DES and CABG in terms of efficacy and safety. Treatment with DES was an acceptable alternative to CABG.

Adenotonsillectomy is recommended for children who need surgery for obstructive sleep apnea syndrome (OSAS). Overnight, polysomnography (PSG) is suggested for post-surgery follow-up, but this diagnostic technique is time consuming and inconvenient. Desaturation index (DI) has been reported as a good tool for predicting both the presence and severity of OSAS in children. The purpose of this study was to determine the usefulness of the DI for post-surgery follow-up of children with OSAS. This retrospective study enrolled 42 children, aged 3–12 years, who were snorers diagnosed with OSAS by overnight PSG and who underwent an adenotonsillectomy. Pre- and postoperative PSG parameters, nocturnal pulse oximetry data, and modified Epworth sleepiness scale scores were assessed. Previously determined cut-off DI values (2.05, 3.50, and 4.15 for mild, moderate, and severe OSAS, respectively) were used to predict residual OSAS. Of the 42 children, obvious improvements were observed in apnea-hypopnea index (AHI, decreased 45.5 %), arousal index (decreased 30.5 %), DI (decreased 40.4 %), and snore index (decreased 100.3 %) compared with the preoperative measurements. Among these objective PSG measures, DI had the strongest correlation with AHI both pre- and post-surgeries (r = 0.947 and r = 0.954, respectively; p all

This paper investigates the temporal pumping artifact (TPA) induced by digital video coding using H.264/AVC and H.265/HEVC standards and proposes a visual-masking-based method to estimate regions with perceptible TPA, referred to as VM-TPA-PRE, for head-and-shoulder video sequences which are common in video messaging, video conferencing and video telephony applications. In digitally coded head-and-shoulder video sequences, the TPA manifests itself as a stumbling effect caused by severe quality fluctuations from frame to frame among adjacent pictures which are most likely to be perceived in regions that the human visual system (HVS) is sensitive to. Considering the object-based or region-of-interest-based video coding theory, accurately estimating regions of the TPA perceivable to the HVS is the key to effective assessment and processing of the TPA and to improve visual quality of videos impaired by the TPA. Experimental results clearly show that the estimation by the VM-TPA-PRE is accurate and in line with human perception.

Natural killer (NK) cells have a vital role in killing hepatocellular carcinoma (HCC) cells; however, the mechanism underlying tumor-infiltrating NK (TINK)-cell dysfunction remains poorly understood. Using flow cytometry staining, we precisely characterized the frequency, phenotype and function of NK subsets distinguished by CD27 and CD11b in 30 patients with HCC in comparison to 30 healthy controls. Interestingly, we found a substantial proportion of liver-infiltrating CD11b−CD27− (DN) NK subsets in tumor tissue from HCC patients. Remarkably, these relatively expanded DN NK subsets exhibited an inactive and immature phenotype. By detecting the expression of CD107a and interferon-gamma (IFN-γ) on NK subsets and NK cells, we demonstrated that DN NK subsets exhibited a poor cytotoxic capacity and deficient potential to produce IFN-γ in comparison to the other three subsets, which contributed to the dysfunction of TINK cells in HCC patients. In addition, we found that the presence of DN NK cells was closely associated with the clinical outcomes of HCC patients, as the frequency of DN NK cells among TINK cells was positively correlated with tumor stage and size. A large percentage of DN NK cells among TINK cells was an independent prognostic factor for lower survival in the 60-month follow-up period. In conclusion, a substantial proportion of CD11b−CD27−NK subsets among TINK cells accounts for NK-cell dysfunction in patients with HCC and is associated with tumor progression. Our study may provide a novel therapeutic target for the treatment of patients with HCC.

The objective of this study was to investigate the protective effects of rhein lysinate (RHL) on the liver. Mice were divided into four groups: C57BL/J control, the KK/HlJ diabetic model, and 25 and 50 mg/kg/day RHL-treated KK/HlJ groups. The KK/HlJ diabetic mouse model was made by injecting STZ and feeding mice diabetic food. At 16 weeks, mice were sacrificed and their livers were harvested. The results indicated that compared with the C57BL/J control group, the body weights, liver weights and liver weight-to-body weight ratio were increased in KK/HlJ diabetic mice; however, these values were decreased following treatment with RHL. Compared with the C57BL/J control, KK/HlJ diabetic mice had a significantly lower level of SOD and GSH-px in their livers, but had a significantly higher level of MDA. However, these effects were ameliorated by RHL. Hepatic adipose infiltration was observed in KK/HlJ mice, but not in C57BL/J mice. RHL decreased the incidence of hepatic adipose infiltration and significantly decreased the expression of TNF-α, IL-6, NF-κB, SREBP-1c, and Fas, as well as the phosphorylation of NF-κB in the liver. In conclusion, RHL can improve hepatic function by decreasing hepatic adipose infiltration and the expression of inflammatory factors.