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Candida albicans (C. albicans) is an opportunistic pathogenic fungus that often causes mucosal and systemic infections. Several pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and C-type lectin receptors (CLRs), have been implicated in the host recognition of C. albicans. These PRRs recognize the pathogen-associated molecular patterns (PAMPs) of C. albicans to activate innate immune cells, thereby rapidly inducing various inflammatory responses by activating intracellular signaling cascades. Herbal medicine and its active components deserve priority development due to their low toxicity and high antibacterial, antiviral and antifungal activities. This review discussed the activities of herbal compounds against C. albicans and their related mechanisms, especially their regulatory role on innate immune cells such as neutrophils, macrophages, and dendritic cells (DCs) implicated in C. albicans infections. Our work aims to find new therapeutic drugs and targets to prevent and treat diseases caused by C. albicans infection with the mechanisms by which this fungus interacts with the innate immune response.

Summary: Background: Affordability to novel anticancer drugs has become a major health issue in China. It is encouraging to note that China initiated its drug regulatory reform and national price negotiation policies since 2015. As a growing number of domestic within-class targeted anticancer drugs are approved in China, it is expected that this may reduce the price of novel anticancer drugs and improve the affordability of anticancer drugs. This study aimed to evaluate the price, efficacy, and safety of the within-class anticancer drugs between domestic and imported drugs approved in China from 2010 to 2022. Methods: The domestic and imported within-class targeted drugs for solid cancers approved in China between 2010 and 2022 were extracted. We classified it as a class of anticancer drugs based on the same indication and similar biological mechanism. The published literature derived from pivotal clinical trials of these domestic and imported drugs was identified based on the review report and the latest labels issued by the China National Medical Products Administration. We evaluated the monthly treatment price at launch and the latest (2022), primary efficacy endpoint and safety between domestic and imported anticancer drugs. Meta-analyses were further employed to evaluate the efficacy and safety of the domestic and imported anticancer drugs, including pooled hazard ratios (HR) for progression-free survival (PFS), overall survival (OS), objective response rates (ORR) for solid cancers, and relative risk for serious adverse events (SAE) and Grade ≥3 adverse events (AEs). Findings: In our cohort study, 12 within-class anticancer drugs with 7 cancer diseases were analyzed, including 18 domestic (21 indications; 21 pivotal trials) and 18 imported (21 indications; 27 pivotal trials) novel anticancer drugs, respectively. The median monthly treatment price of domestic and imported drugs from the years of launch to 2022 had significantly decreased by 71% and 62%, respectively. Moreover, the median monthly treatment price of domestic targeted anticancer drugs on the market at launch ($3786 vs. $5393, P = 0.007) and the latest ($1222 vs. $2077, P = 0.011) was significantly lower than that of imported drugs. No significant differences in median PFS gains (9.0 vs. 11.0 months; P = 0.24), OS gains (9.3 vs 10.6 months; P = 0.66), and ORR (57% vs 62%, P = 0.77) of targeted anticancer drugs in their pivotal trials were observed between the domestic and imported drugs. Additionally, there was no significant difference between domestic and imported drugs in the incidence of SAE (23% vs. 24%; P = 0.41) and Grade ≥3 AEs (59% vs. 57%; P = 0.45). These findings were also further confirmed in the meta-analyses for primary efficacy endpoints and safety outcomes. Interpretation: The prices of both domestic and imported anticancer drugs significantly decreased after market entry mainly due to the role of national price negotiations. The median monthly treatment price of domestic within-class targeted anticancer drugs was significantly lower than that of imported drugs. Furthermore, the efficacy and safety of domestic anticancer drugs were comparable to that of imported drugs. This evidence implicated that the development of within-class anticancer drugs with national price negotiations in China significantly improved the affordability for patients. Funding: This study was supported by postdoctoral fellowship from Tsinghua-Peking Joint Centers for Life Sciences (CLS).

Osteoarthritis (OA) is a degenerative disease that is difficult to cure owing to its complicated pathogenesis. Exercise therapy has been endorsed as a primary treatment option. However, it remains controversial how exercise intensity regulates OA progression. Here, a declining propensity for TGF-β1 was predicted via bioinformatics analysis of microarray GSE57218 and validated in cartilage samples obtained from arthroplasty. Based on this, cyclic tensile strain or TGF-β1 intervention was performed on human OA chondrocytes, and we found that moderate-intensity mechanical loads protected chondrocytes against pyroptosis. During this process, the elevation of TGF-β1 is mechanically stimuli-dependent and exerts an inhibitory effect on chondrocyte pyroptosis. Moreover, we elucidated that TGF-β1 activated Smad2/3 and inhibited the NF-κB signaling pathway to suppress chondrocyte pyroptosis. Furthermore, we established a rat knee OA model by intra-articular injection of monosodium iodoacetate and performed treadmill exercises of different intensities. Similar to the in vitro results, we demonstrated that moderate-intensity treadmill exercise had an outstanding chondroprotective effect. An inappropriate intensity of mechanical stimulation may aggravate OA both in vivo and in vitro. Overall, our findings demonstrated that activation of the TGF-β1/Smad2/Smad3 axis and inhibition of NF-κB coordinately inhibit chondrocyte pyroptosis under mechanical loads. This study sheds light on the future development of safe and effective exercise therapies for OA.

Introduction: Achieving a successful reconstruction of alveolar bone morphology still remains a challenge because of the irregularity and complex microenvironment of tooth sockets. Biological materials including hydroxyapatite and collagen, are used for alveolar ridge preservation. However, the healing effect is often unsatisfactory.Methods: Inspired by superwetting biomimetic materials, we constructed a 3D actively-spreading bone repair material. It consisted of photocurable polyether F127 diacrylate hydrogel loaded with mixed spheroids of mesenchymal stem cells (MSCs) and vascular endothelial cells (ECs).Results: Biologically, cells in the spheroids were able to spread and migrate outwards, and possessed both osteogenic and angiogenic potential. Meanwhile, ECs also enhanced osteogenic differentiation of MSCs. Mechanically, the excellent physical properties of F127DA hydrogel ensured that it was able to be injected directly into the tooth socket and stabilized after light curing. In vivo experiments showed that MSC-EC-F127DA system promoted bone repair and preserved the shape of alveolar ridge within a short time duration.Discussion: In conclusion, the novel photocurable injectable MSC-EC-F127DA hydrogel system was able to achieve three-dimensional tissue infiltration, and exhibited much therapeutic potential for complex oral bone defects in the future.

Many carbon-related physiological questions in plants such as carbon (C) limitation or starvation have not yet been resolved thoroughly due to the lack of suitable experimental methodology. As a first step towards resolving these problems, we conducted infusion experiments with bonsai trees (Ficus microcarpa) and young maple trees (Acer pseudoplatanus) in greenhouse, and with adult Scots pine trees (Pinus sylvestris) in the field, that were “fed” with 13C-labelled glucose either through the phloem or the xylem. We then traced the 13C-signal in plant organic matter and respiration to test whether trees can take up and metabolize exogenous sugars infused. Ten weeks after infusion started, xylem but not phloem infusion significantly increased the δ13C values in both aboveground and belowground tissues of the bonsai trees in the greenhouse, whereas xylem infusion significantly increased xylem δ13C values and phloem infusion significantly increased phloem δ13C values of the adult pines in the field experiment, compared to the corresponding controls. The respiration measurement experiment with young maple trees showed significantly increased δ13C-values in shoot respired CO2 at the time of four weeks after xylem infusion started. Our results clearly indicate that trees do translocate and metabolize exogenous sugars infused, and because the phloem layer is too thin, and thus xylem infusion can be better operated than phloem infusion. This tree infusion method developed here opens up new avenues and has great potential to be used for research on the whole plant C balance and its regulation in response to environmental factors and extreme stress conditions.

The uncertainty caused by the growing use of renewable energy sources, such as wind and solar energy, makes it difficult to forecast the operation costs of micro-energy systems, particularly those in remote rural areas. Motivated by this point, this paper analyzes the possible operational risks and then introduces Condition Value at Risk (CVaR) to quantify the cost of the operational risk. On this basis, stochastic programming based on a multi-energy microgrid planning model that minimizes the investment cost, the operating cost, and the cost of operational risk, while considering the physical limitations of the multi-energy microgrid, is presented. Especially, scenarios of wind and solar energy output are generated using the Latin hypercube sampling method and reduced using the crowding measure-based scenario reduction method. After piecewise linearization and second-order cone relaxation, the model proposed in this paper is processed as a mixed integer linear model and solved by CPLEX. According to the achieved typical scenarios processed by the reduction method, the simulation shows that the presented configuration model can balance the investment cost and the cost of the operational risk, which effectively enhances the system’s ability to cope with uncertainties and fluctuations. Moreover, by adjusting the risk preference coefficient, the conservativeness of the planning scheme can be correspondingly adjusted.

Osteoarthritis (OA) is one of the most common refractory degenerative joint diseases worldwide. Synovitis is believed to drive joint cartilage destruction during OA pathogenesis. Cuproptosis is a novel form of copper-induced cell death. However, few studies have examined the correlations between cuproptosis-related genes (CRGs), immune infiltration, and synovitis. Therefore, we analyzed CRGs in synovitis during OA. Microarray datasets (GSE55235, GSE55457, GSE12021, GSE82107 and GSE176308) were downloaded from the Gene Expression Omnibus database. Next, we conducted differential and subtype analyses of CRGs across synovitis. Immune infiltration and correlation analyses were performed to explore the association between CRGs and immune cell abundance in synovitis. Finally, single-cell RNA-seq profiling was performed using the GSE176308 dataset to investigate the expression of CRGs in the various cell clusters. We found that the expression of five CRGs (FDX1, LIPT1, PDHA1, PDHB, and CDKN2A) was significantly increased in the OA synovium. Moreover, abundant and various types of immune cells infiltrated the synovium during OA, which was correlated with the expression of CRGs. Additionally, single-cell RNA-seq profiling revealed that the cellular composition of the synovium was complex and that their proportions varied greatly as OA progressed. The expression of CRGs differed across various cell types in the OA synovium. The current study predicted that cuproptosis may be involved in the pathogenesis of synovitis. The five screened CRGs (FDX1, LIPT1, PDHA1, PDHB, and CDKN2A) could be explored as candidate biomarkers or therapeutic targets for OA synovitis.

The production of metrnl, a novel adipomyokine, is induced upon exercise in adipose tissue and skeletal muscle. In this study, we investigated the anti-inflammatory and antipyroptotic effects of exercise-induced metrnl producted in rats in vitro and in vivo. Forty Sprague-Dawley rats were divided randomly into five groups: control (CG), osteoarthritis (OA) with sedentary lifestyle (OAG), OA with low intensity exercise (OAL), OA with moderate intensity exercise (OAM), and OA with high intensity exercise (OAH). The correlation between the level of metrnl and OA degree was detected using ELISA, X-ray imaging, histology, and immunohistochemistry in vivo. Primary chondrocytes were preincubated with recombinant metrnl before interleukin-1β administration to verify the anti-inflammatory and antipyroptotic effects of metrnl. Western blotting and quantitative reverse transcription (qRT)-PCR were used to evaluate the differences in protein and mRNA expression between groups, respectively. Reactive oxygen species (ROS) assay, immunofluorescence, transmission electron microscopy (TEM), and flow cytometry were used to evaluate morphological changes and pyroptosis in chondrocytes. In the moderate-intensity treadmill exercise group, the severity of OA showed maximum relief and the metrnl levels had the most significant increase. Metrnl exerted its anti-inflammatory effect through the suppression of the PI3K/Akt/NF-κB pathway in IL-1β-induced OA chondrocytes, which was accompanied with the recovery of collagen II expression and the attenuation of MMP13 and ADAMTS5. Moreover, metrnl ameliorated chondrocyte pyroptosis by inhibiting the activation of the nod-like receptor protein-3/caspase-1/gasdermin D cascade. In conclusion, moderate-intensity exercise improves inflammation and pyroptosis by increasing metrnl release, which inhibits the PI3K/Akt/NF-κB and further NLRP3/caspase-1/GSDMD signaling pathways.

Abstract Gastric cancer (GC) is the second cause of cancer-related death and metastasis is an important cause of death. Considering difficulties in searching for metastatic driver mutations, we tried a novel strategy here. We conducted an integrative genomic analysis on GC and identified early drivers lead to metastasis. Whole-exome sequencing (WES), transcriptomes sequencing and targeted-exome sequencing (TES) were performed on tumors and matched normal tissues from 432 Chinese GC patients, especially the comparative analysis between higher metastatic-potential (HMP) group with T1 stage and lymph-node metastasis, and lower metastatic-potential (LMP) group without lymph-nodes or distant metastasis. HMP group presented higher mutation load and heterogeneity, enrichment in immunosuppressive signaling, more immune cell infiltration than LMP group. An integrated mRNA-lncRNA signature based on differentially expressed genes was constructed and its prognostic value was better than traditional TNM stage. We identified 176 candidate prometastatic mutations by WES and selected 8 genes for following TES. Mutated TP53 and MADCAM1 were significantly associated with poor metastasis-free survival. We further demonstrated that mutated MADCAM1 could not only directly promote cancer cells migration, but also could trigger tumor metastasis by establishing immunosuppressive microenvironment, including promoting PD-L1-mediated immune escape and reprogramming tumor-associated macrophages by regulating CCL2 through Akt/mTOR axis. In conclusion, GCs with different metastatic-potential are distinguishable at the genetic level and we revealed a number of potential metastatic driver mutations. Driver mutations in early-onset metastatic GC could promote metastasis by establishing an immunosuppressive microenvironment. This study provided possibility for future target therapy of GC.

Abstract Objective To describe the clinical outcome and physical condition of patients with locally advanced breast cancer (LABC) who received neoadjuvant chemotherapy followed by mastectomy and latissimus dorsi myocutaneous flap repair. Methods A retrospective review of 142 patients with locally advanced breast cancer was selected from 1156 breast cancer patients in the South and North areas of The Affiliated Calmette Hospital of Kunming Medical University between May 2008 and December 2018. Results All participants (n = 142) were women aged 40–55 years (average age 47.35 ± 0.43 years) who received neoadjuvant chemotherapy followed by mastectomy and latissimus dorsi flap repair. The median follow-up period was 16 months (range 12–24 months). For stage of disease, there were 19 cases (13%) in stage IIB, 31 cases (22%) in stage IIIA, 39 cases (28%) in stage IIIB, and 53 cases (37%) in stage IIIC, which were statistically significant with the physical condition of patients (≤ 0.001). Neoadjuvant chemotherapy was administered to shrink the tumors, and an average tumor size decrease from 10.05 ± 1.59 cm × (8.07 ± 1.54) cm to 6.11 ± 1.72 cm × (3.91 ± 1.52) cm (P < 0.001) was considered statistically significant. A t test was used for the ECOG score statistics, and the results showed that the scores were statistically significant (≤ 0.001) before and after neoadjuvant chemotherapy and after surgery. Conclusions Neoadjuvant chemotherapy is an accepted treatment option for patients with locally advanced breast cancer, and the use of a latissimus dorsi musculocutaneous flap for post-mastectomy reconstruction may improve the patients’ physical condition. Our results indicated that this strategy was safe and feasible.

Coronavirus disease 2019, responsible for a global pandemic, is caused by the severe acute respiratory syndrome coronavirus 2. Several vaccines have been developed and approved worldwide, particularly in China. As of Oct 17, 2021, four new coronavirus vaccines in China have been conditionally approved for marketing by the National Medical Products Administration, two of which have been authorized for emergency use in the Emergency Use Listing of the World Health Organization. Domestic vaccine R&D in China has relied on legal and regulatory support. This article summarizes the regulatory policy for vaccine development, review and approval. Vaccine approval laws have been continually improved, and regulations for special approval have been used to shorten the review time. China has coordinated pandemic-related needs, both domestically and with other countries, and made substantial progress in cooperative international anti-pandemic efforts.

Measurement(s) building rooftop area Technology Type(s) computational modeling technique Sample Characteristic - Environment city Sample Characteristic - Location China

Abstract Rheumatoid arthritis (RA) is an aggressive autoimmune arthritis, and current therapies remain unsatisfactory due to low remission rate and substantially adverse effects. Low-dose interleukin-2 (Ld-IL2) is potentially a therapeutic approach to further improve the disease. This randomized, double-blind, placebo-controlled trial was undertaken to evaluate the efficacy and safety of Ld-IL2 in patients with active RA. Patients were randomly assigned (1:1) to receive Ld-IL2, defined as a dose of 1 million IU, or placebo in a 12-week trial with a 12-week follow-up. Three cycles of Ld-IL2 or placebo were administered subcutaneously every other day for 2 weeks (a total of 7 doses), followed by a 2-week break. All patients received a stable dose of methotrexate (MTX). The primary outcomes were the proportion of patients achieving the ACR20, DAS28-ESR

The near-surface energy budget closure has always been a scientific hot topic in the land-surface processes research， especially over the underlying surface of heterogeneous wetlands.In this investigation， the horizontal thermal advection caused by thermal inhomogeneity of the underlying surface over the wetland is calculated based on the data of the Flower-lake observation field in the Zoige alpine wetland.With considering the horizontal thermal advection， its contribution to the near-surface energy closure is analyzed.The results show that the mean horizontal thermal advection of the Zoige wetland is 22.9 W·m-2， and the maximum value can reach 58.7 W·m-2 in the daytime of summer 2017.After introducing the horizontal thermal advection and soil heat storage into the near-surface energy balance equation， the near-surface energy closure ratio increased from 41.8% to 67.9% in summer.The contribution of horizontal thermal advection was 5.8%， that of soil thermal storage was 20.1%， and that of plant photosynthetic thermal storage was 1.0%.The diurnal variation of the near-surface horizontal thermal advective is equivalent to the sensible heat flux in Zoige wetland， and the maximum diurnal variation is about one third of the thermal storage of the wetland soil.

Abstract Background A single‐agent of anti programmed cell death 1/programmed cell death ligand 1 (anti‐PD‐1/PD‐L1) therapy has been explored for resectable lung cancer before surgery. However, the effectiveness and safety of neoadjuvant programmed cell death 1 (PD‐1) blockade combined with chemotherapy have not been published. Methods Twenty‐one consecutive patients with potentially resectable squamous cell carcinoma of the lung who received neoadjuvant therapy followed by surgery in Beijing Cancer Hospital were included in this study. Eight patients received two cycles of neoadjuvant platinum‐based doublet chemotherapy combined with anti‐programmed cell death 1 (anti‐PD‐1) therapy, while 13 patients received two cycles of neoadjuvant platinum‐based doublet chemotherapy only. Chest computed tomography was repeated before neoadjuvant treatment and surgery. Adverse events were monitored. The major pathological response (MPR) rate was determined after surgery. Selected specimens were sent for immunohistochemical and multiplex immunofluorescence analyses, and T‐cell receptor DNA sequencing. Results Compared with neoadjuvant chemotherapy alone, the combination of PD‐1 blockade and chemotherapy increased the pathological complete response rate (37.5% vs. 7.69%) and MPR rate (50% vs. 38.46%). The pathological and radiological evaluations are not consistent. No unknown adverse effects were reported for all the patients. More tumor infiltrating lymphocytes were observed in patients who received PD‐1 blockade. No unknown pathological features associated with PD‐1 blockade were found. Immune suppression in the peritumoral spaces around the residual tumor cells was observed. The amino acid sequences of the T‐cell receptors are not significantly shared among the patients. Conclusions The combination of neoadjuvant chemotherapy and PD‐1 blockade is safe and feasible, and might indicate an increased MPR and pathological complete response rate. More investigations are needed for the best combination of the neoadjuvant therapy.

Abstract We propose criteria of tracking vortex surfaces in complex flows based on the vortex-surface field (VSF). The criteria characterize the accuracy and Lagrangian tracking performance of the numerical VSF solution, and determine the time period when the vortex surface tracking is satisfactory. Moreover, we develop a turbulent-like flow combining large-scale coherent structures in the Taylor–Green flow and small-scale turbulent structures in homogeneous isotropic turbulence (HIT). From tracking of vortex surfaces during the effective tracking period, we find that the imposed HIT disturbance significantly wrinkles vortex surfaces. Subsequently, the wrinkled vortex tube with large vorticity magnitude tends to be further twisted, contributing to energy cascade, while the wrinkling is mitigated in the region with small vorticity magnitude.

Abstract Background Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism caused by ATP7B (encoding a copper-transporting P-type ATPase) variants that shows various characteristics according to race and geographical region. This study was aimed to provide a comprehensive analysis of ATP7B variants in China and to investigate a plausible role of common variants in WD manifestations. Methods A total of 1366 patients (1302 index patients and 64 siblings) clinically diagnosed with WD (Leipzig score ≥ 4) were recruited. They underwent ATP7B gene sequencing and information of age and symptoms at onset was collected. The genotype–phenotype correlation was assessed in the index patients who were examined with two pathogenic variants and onset with hepatic (n = 276) or neurologic (n = 665) symptoms. Results We identified 294 potentially pathogenic ATP7B variants (112 truncating, 174 missense, 8 in-frame) in the 1302 index patients, including 116 novel variants. The most frequent variant was c.2333G>T (R778L, allele frequency: 28.96%), followed by c.2975C>T (P992L, 13.82%), c.2621C>T (A874V, 5.99%), c.2755C>G (R919G, 2.46%), and c.3646G>A (V1216M, 1.92%). In 1167 patients, both pathogentic variants were identified, of which 532 different variant combinations were found. By binary logistic regression analysis, the factor associated with neurological presentation was high age-at-onset, but not sex, protein-truncating variant (PTV), or the common missense variants (R778L, P992L, and A874V). In the neurological group, low age-at-onset was a factor associated with dystonia, gait abnormality, and salivation; high age-at-onset was a factor associated with tremor; and the sex, low age-at-onset and A874V were independent factors associated with dysarthria. In addition, PTV, R778L, and P992L were predominant in early-onset patients, whereas A874V was predominant in late-onset patients, and patients with R778L/A874V genotype displayed a higher age-at-onset than patients with R778L/R778L or R778L/P992L genotype. Conclusions Our work expanded the ATP7B variant spectrum and highlighted the differences among patients with WD in age-at-onset and ATP7B variants, which may provide some valuable insights into the diagnosis, counseling, and treatment of patients with WD.

Influenza vaccines faced significant challenges in achieving sufficient protective efficacy and production efficiency in the past. In recent decades, novel influenza vaccines, characterized by efficient and scalable production, advanced platforms, and new adjuvant technologies, have overcome some of these weaknesses and have been widely licensed. Furthermore, researchers are actively pursuing the development of next-generation and universal influenza vaccines to provide comprehensive protection against potential pandemic subtypes or strains. However, new challenges have emerged as these novel vaccines undergo evaluation and authorization. In this review, we primarily outline the critical challenges and advancements in research and development (R&D) and highlight the improvements in regulatory responses for influenza vaccines.

Simulating fluid dynamics on a quantum computer is intrinsically difficult due to the nonlinear and non-Hamiltonian nature of the Navier-Stokes equation (NSE). We propose a framework for quantum computing of fluid dynamics based on the hydrodynamic Schrödinger equation (HSE), which can be promising in simulating three-dimensional turbulent flows in various engineering applications. The HSE is derived by generalizing the Madelung transform to compressible or incompressible flows with finite vorticity and dissipation. Since the HSE is expressed as a unitary operator on a two-component wave function, it is more suitable than the NSE for quantum computing. The flow governed by the HSE can resemble a turbulent flow consisting of tangled vortex tubes with the five-thirds scaling of energy spectrum. We develop a prediction-correction quantum algorithm to solve the HSE. This algorithm is implemented for simple flows on the quantum simulator Qiskit with partial exponential speedup.

The class imbalance problem in finance fraud datasets often leads to biased prediction towards the nonfraud class, resulting in poor performance in the fraud class. This study explores the effects of utilizing the Synthetic Minority Oversampling TEchnique (SMOTE), a Generative Adversarial Network (GAN), and their combinations to address the class imbalance issue. Their effectiveness was evaluated using a Feed-forward Neural Network (FNN), Convolutional Neural Network (CNN), and their hybrid (FNN+CNN). This study found that regardless of the data generation techniques applied, the classifier’s hyperparameters can affect classification performance. The comparisons of various data generation techniques demonstrated the effectiveness of the hybrid SMOTE and GAN, including SMOTified-GAN, SMOTE+GAN, and GANified-SMOTE, compared with SMOTE and GAN. The SMOTified-GAN and the proposed GANified-SMOTE were able to perform equally well across different amounts of generated fraud samples.

Previous studies have primarily concentrated on the hepatotoxicity of MC-LR, whereas its gastric toxicity effects and mechanisms of long-term exposure under low dosage remain unknown. Herein, the gastric tissue from C57BL/6 mice fed with drinking water contaminated by low-dose MC-LR (including 1, 60, and 120 μg/L) was investigated. The results obtained showed that exposure to different concentrations of MC-LR resulted in significant shedding and necrosis of gastric epithelial cells in mice, and a down-regulation of tight junction markers, including ZO-1, Claudin1, and Occludin in the stomach, which might lead to increased permeability of the gastric mucosa. Moreover, the protein expression levels of p-RAF/RAF, p-ERK1/2/ERK1/2, Pink1, Parkin, and LC3-II/LC-3-I were increased in the gastric tissue of mice exposed to 120 μg/L of MC-LR, while the protein expression level of P62 was significantly decreased. Furthermore, we found that pro-inflammatory factors, including IL-6 and TNF-ɑ, were dramatically increased, while the anti-inflammatory factor IL-10 was significantly decreased in the gastric tissue of MC-LR-exposed mice. The activation of the MAPK signaling pathway and mitophagy might contribute to the development of gastric damage by promoting inflammation. We first reported that long-term exposure to MC-LR induced gastric toxicity by activating the MAPK signaling pathway, providing a new insight into the gastric toxic mechanisms caused by MC-LR.

Microcystin-LR (MC-LR) contamination is a worldwide environmental problem that poses a grave threat to the water ecosystem and public health. Exposure to MC-LR has been associated with the development of intestinal injury, but there are no effective treatments for MC-LR-induced intestinal disease. Probiotics are “live microorganisms that are beneficial to the health of the host when administered in sufficient quantities”. It has been demonstrated that probiotics can prevent or treat a variety of human diseases; however, their ability to mitigate MC-LR-induced intestinal harm has not yet been investigated. The objective of this study was to determine whether probiotics can mitigate MC-LR-induced intestinal toxicity and its underlying mechanisms. We first evaluated the pathological changes in colorectal tissues using an animal model with sub-chronic exposure to low-dose MC-LR, HE staining to assess colorectal histopathologic changes, qPCR to detect the expression levels of inflammatory factors in colorectal tissues, and WB to detect the alterations on CSF1R signaling pathway proteins in colorectal tissues. Microbial sequencing analysis and screening of fecal microorganisms differential to MC-LR treatment in mice. To investigate the role of microorganisms in MC-LR-induced colorectal injury, an in vitro model of MC-LR co-treatment with microorganisms was developed. Our findings demonstrated that MC-LR treatment induced an inflammatory response in mouse colorectal tissues, promoted the expression of inflammatory factors, activated the CSF1R signaling pathway, and significantly decreased the abundance of Lactobacillus. In a model of co-treatment with MC-LR and Lactobacillus fermentum (L. fermentum), it was discovered that L. fermentum substantially reduced the incidence of the colorectal inflammatory response induced by MC-LR and inhibited the protein expression of the CSF1R signaling pathway. This is the first study to suggest that L. fermentum inhibits the CSF1R signaling pathway to reduce the incidence of MC-LR-induced colorectal inflammation. This research may provide an excellent experimental foundation for the development of strategies for the prevention and treatment of intestinal diseases in MC-LR.

(1) Background: Heart failure (HF) is the final stage of multiple cardiac diseases, which have now become a severe public health problem worldwide. β-Adrenergic receptor (β-AR) overactivation is a major pathological factor associated with multiple cardiac diseases and mediates cardiac fibrosis and inflammation. Previous research has demonstrated that Bruton’s tyrosine kinase (BTK) mediated cardiac fibrosis by TGF-β related signal pathways, indicating that BTK was a potential drug target for cardiac fibrosis. Zanubrutinib, a second-generation BTK inhibitor, has shown anti-fibrosis effects in previous research. However, it is unclear whether Zanubrutinib can alleviate cardiac fibrosis induced by β-AR overactivation; (2) Methods: In vivo: Male C57BL/6J mice were treated with or without the β-AR agonist isoproterenol (ISO) to establish a cardiac fibrosis animal model; (3) Results: In vivo: Results showed that the BTK inhibitor Zanubrutinib (ZB) had a great effect on cardiac fibrosis and inflammation induced by β-AR. In vitro: Results showed that ZB alleviated β-AR-induced cardiac fibroblast activation and macrophage pro-inflammatory cytokine production. Further mechanism studies demonstrated that ZB inhibited β-AR-induced cardiac fibrosis and inflammation by the BTK, STAT3, NF-κB, and PI3K/Akt signal pathways both in vivo and in vitro; (4) Conclusions: our research provides evidence that ZB ameliorates β-AR-induced cardiac fibrosis and inflammation.

After years of more rigid and conventional production processes, the traditional manufacturing industry has been moving toward flexible manufacturing and intelligent manufacturing in recent years. After more than half a century of development, robotics has penetrated into all aspects of human production and life, bringing significant changes to the development of human society. At the same time, the key technology of human–machine cooperative operation has become a research hotspot, and how to realize a human–machine integrated safety system has attracted attention. Human–machine integration means that humans and robots can work in the same natural space, coordinating closely and interacting naturally. To realize real human–robot integration under human–robot cooperative operation, the good judgment of intentional interaction and accidental collision and the detection of collision joints and collision points when accidental collision occurs are the key points. In this paper, we propose a method to identify the collision joints by detecting real-time current changes in each joint of the robot and solve the collision point location information of the collision joints through the principle of virtual displacement and the principle of force method using the force sensor data installed at the base of the robot as the known condition. The results show that the proposed method of identifying the collision joints using changes in joint current and then establishing a collision detection algorithm to solve the collision point location is correct and reliable.

In order to evaluate the influence of the strength of base material, root welding material and filler material on the strain capacity of girth welds in X80 pipeline, the passivation behavior of crack tips during cracking was accurately simulated with the Key Hole model by the nonlinear finite element method based on the China–Russia Eastern Gas Pipeline with a diameter of 1 422 mm and a wall thickness of 21.4 mm. Here, consideration was given to the complete geometrical morphology of welded joints and the partition of four materials with different properties. In addition, the crack initiation behavior of circumferential cracks in the root inner surface under the action of tensile load was researched. According to the results, the strength of root welding material has little impact on the overall strain capacity of double V-groove welded joint, which can be ignored. The overmatching of filler material with the base material is the most important to guarantee the strain capacity in the weld zone. Moreover, in the case that it is difficult to enhance the strength of filler material, limiting the strength indicator of base material is an effective way to improve the strain capacity of welded joints in high-grade steel pipelines.

Melatonin regulates lily bulblet development; however, the key interactions have not yet been determined. In this study, we found that adding 20 μM melatonin to the growth medium increased the bulblet circumference and the trehalose and starch content. Moreover, the expression of numerous genes involved in cell proliferation and carbohydrate accumulation were upregulated. Further analysis showed that melatonin downregulated the expression of LoRAV and upregulated the expression of LoBPM3 at an early stage. Cloning and bioinformatics analysis showed that LoRAV is 1056 bp in length and encodes a protein with two structural domains, namely, AP2 and B3; the encoded protein is localized to the nucleus and has no self-activation activity, and this protein interacts with LoBPM3. The expression of LoTCP4 and LoAMY was upregulated, while the expression of LoAGPase, LoCYCB2-1, and LoPCNA was inhibited when LoRAV was transiently overexpressed. However, the trends in the expression of the genes mentioned above, except LoAGPase and LoAMY, were reversed when LoRAV-OE was treated with melatonin. Interestingly, the expression of LoRAV, LoTCP4 and LoAMY was inhibited, and the expression of LoCYCB2-1 was upregulated by transient overexpression of LoBPM3, but the expression of LoBPM3 was not regulated by LoRAV overexpression. Based on these data, we suggest that melatonin promoted bulb development, which was partly associated with regulation of the LoBPM3-LoRAV module; thus, LoRAV negatively regulates cell proliferation of bulblets, and LoBPM3 is located upstream of LoRAV and attenuates its expression.

Abstract Background Resistance to gefitinib remains a major obstacle for the successful treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. In this paper, we studied the precise actions of circular RNA (circRNA) microtubule actin crosslinking factor 1 (circ_MACF1) in gefitinib resistance. Methods We established gefitinib-resistant NSCLC cells (PC9/GR and A549/GR). The levels of circ_MACF1, microRNA (miR)-942-5p, and transforming growth factor beta receptor 2 (TGFBR2) were gauged by quantitative real-time PCR (qRT-PCR) or western blot. Subcellular fractionation and Ribonuclease R (RNase R) assays were done to characterize circ_MACF1. Cell survival, proliferation, colony formation, apoptosis, migration, and invasion were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), 5-Ethynyl-2’-Deoxyuridine (EdU), colony formation, flow cytometry, and transwell assays, respectively. Dual-luciferase reporter assays were used to verify the direct relationship between miR-942-5p and circ_MACF1 or TGFBR2. The xenograft assays were used to assess the role of circ_MACF1 in vivo. Results Circ_MACF1 was down-regulated in A549/GR and PC9/GR cells. Overexpression of circ_MACF1 repressed proliferation, migration, invasion, and promoted apoptosis and gefitinib sensitivity of A549/GR and PC9/GR cells in vitro, as well as inhibited tumor growth under gefitinib in vivo. Circ_MACF1 directly targeted miR-942-5p, and miR-942-5p mediated the regulatory effects of circ_MACF1. TGFBR2 was identified as a direct and functional target of miR-942-5p. Circ_MACF1 modulated TGFBR2 expression through miR-942-5p. Conclusion Our findings demonstrated that circ_MACF1 regulated cell functional behaviors and gefitinib sensitivity of A549/GR and PC9/GR cells at least partially by targeting miR-942-5p to induce TGFBR2 expression.

Regional cross-border electricity trading is popular in price and cooperation. It is a reliable path to alleviate the shortage of power supply during rapid economic growth. As an important export commodity, the pricing options for hydropower directly relate to the cooperation intention of business parties. This study demonstrates the price formation methods and internal relationships of cascade hydropower stations in CBET. To simulate the decision-making of a bilateral forward contract, a bi-level optimization model was constructed, and the objectives of each layer represent the interests of both parties. The BOM was linearized with Karush-Kuhn-Tucker conditions and strong duality, and finally solved using mixed-integer linear programming. The prices of CHSs in southwestern China were calculated under different pricing options and the results were absorbed in an actual transaction case. Consequently, the complementarity between different exporting countries was verified. The most suitable pricing option for CBET was determined, that is the unified electricity price based on the marginal cost, to be $481~\textrm {CNY/MW}\cdot \textrm {h}$ , which is 20% to 60% higher than the thermal and photovoltaic from other countries. Furthermore, national policy support and economic subsidies are key guarantees for the sustainable development of CBET, which can reduce the discount electricity price to below that of thermal generation by 30%.

Remote sensing image change detection (RSICD) is a technique that explores the change of surface coverage in a certain time series by studying the difference between multiple remote sensing images (RSIs) collected over the same area. Traditional RSICD algorithms exhibit poor performance on complex change detection (CD) tasks. In recent years, deep learning (DL) techniques have achieved outstanding results in the fields of RSI segmentation and target recognition. In CD research, most of the methods treat multitemporal remote sensing data as one input and directly apply DL-based image segmentation theory on it while ignoring the spatio-temporal information in these images. In this article, a new siamese neural network is designed by combing an attention mechanism (Siamese_AUNet) with UNet to solve the problems of RSICD algorithms. SiameseNet encodes the feature extraction of RSIs by two branches in the siamese network, respectively. The weights are shared between these two branches in siamese networks. Subsequently, an attention mechanism is added to the model in order to improve its detection ability for changed objects. The models are then compared with conventional neural networks using three benchmark datasets. The results show that the Siamese_AUNet newly proposed in this article exhibits better performance than other standard methods when solving problems related to weak CD and noise suppression.

As shale gas reservoirs have low porosity and low permeability, hydraulic fracturing is a necessary means for industrial exploitation of shale gas. In this study, aiming at the problem of reservoir damage in the process of hydraulic fracturing of shale gas reservoir, a physical simulation method of slickwater fracturing fluid flow in shale core has been established. The change laws of physical parameters of the shale were quantified after slickwater fracturing fluid filtrating into it. The main factors affecting physical parameters of shale matrix around fractures were found out in the process of fracturing, shut-in, and flowback of slickwater fracturing fluid. The results show that after treated by slickwater fracturing fluid, the wettability of shale becomes more uniform in distribution (the water contact angles from 43° to 48°). In the fracturing filtration zone, the damage rate of fracturing fluid to shale porosity is 6.4%-42.0%. Low differential pressure flowback can reduce the damage of the shale, and prolonging the time of shut-in has no obvious effect on the damage to porosity. After 0.3 d (imbibition stability time), the damage of fracturing fluid to shale permeability is basically stable (55.9%). Permeability damage is mainly caused by residue of the fracturing fluid in large pores and bound water in small pores. Analysis of weights of all fracturing parameters shows that flowback differential pressure has the largest influence weight on shale porosity (51.4%), and well shut-in time has the largest influence weight on shale permeability (62.7%). Therefore, in the production process, it is suggested to properly reduce the backflow differential pressure and moderately shorten the well shut-in time.

We review the progress on the applications of the vortex-surface field (VSF). The VSF isosurface is a vortex surface consisting of vortex lines. Based on the generalized Helmholtz theorem, the VSF isosurfaces of the same threshold at different times have strong coherence. As a general flow diagnostic tool for studying vortex evolution, the numerical VSF solution is first constructed in a given flow field by solving a pseudo-transport equation driven by the instantaneous frozen vorticity, and then the VSF evolution is calculated by the two-time method. From the database of numerical simulations or experiments, the VSF can elucidate mechanisms in the flows with essential vortex dynamics, such as isotropic turbulence, wall flow transition, flow past a flapping plate and turbulence–flame interaction. The characterization of VSFs reveals the correlation between robust statistical features and the critical quantities needed to be predicted in engineering applications, such as the friction coefficient in transition, thrust in bio-propulsion and growth rate in interface instability. Since the VSF evolution captures the essential Lagrangian-based dynamics of vortical flows, it inspires novel numerical methods on cutting-edge hardware, e.g. graphic and quantum processors.

Landslide-induced impulse waves in alpine valleys are a significant risk to large-scale dam and reservoir engineering projects in the surrounding area. In this study, a 1 : 200-scale physical model of landslide-induced impulse waves in a V-shaped river channel was established, and 18 groups of tests were conducted to evaluate the influence of different parameters, such as the volume and shape of the landslide body, water entry velocity, and water depth of the reservoir. Based on the test results, a dimensionless formula was established for the first wave height of impulse waves caused by a deep-water landslide in a V-shaped channel. An energy conversion law was determined for the impact of landslide-induced impulse waves on the reservoir bank. Finally, a distribution law was obtained for the initial maximum pressure caused by landslide-induced impulse waves along the water depth on the opposite bank. The theoretical predictions of the dimensionless formula showed good agreement with the experimental results, and the energy conversion rate of the landslide-induced impulse waves initially increased and then decreased with an increasing Froude number. The maximum dynamic water pressure showed a triangular distribution with increasing water depth below the surface of the still water body. The impact pressure of the impulse waves on the slope on the opposite bank increased with the water entry velocity. This study provides a scientific basis for the risk prevention and control of landslide-induced impulse waves in river channels feeding into reservoirs.

PurposeTuberculosis is common infectious diseases, characterized by infectivity, concealment and chronicity, and the early diagnosis is helpful to block the spread of tuberculosis and reduce the resistance of Mycobacterium tuberculosis to anti-tuberculosis drugs. At present, there are obvious limitations in the application of clinical detection methods used for the early diagnosis of tuberculosis. RNA sequencing (RNA-Seq) has become an economical and accurate gene sequencing method for quantifying transcripts and detecting unknown RNA species.MethodsA peripheral blood mRNA sequencing was used to screen the differentially expressed genes between healthy people and tuberculosis patients. A protein-protein interaction (PPI) network of differentially expressed genes was constructed through Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. The potential diagnostic targets of tuberculosis were screened by the calculation of degree, betweenness and closeness in Cytoscape 3.9.1 software. Finally, the functional pathways and the molecular mechanism of tuberculosis were clarified in combination of the prediction results of key gene miRNAs, and by Gene Ontology (GO) enrichment analysis and the Kyoto Encyclopedia Genes and Genomes (KEGG) pathway annotation analysis.Results556 Differential genes of tuberculosis were screened out by mRNA sequencing. Six key genes (AKT1, TP53, EGF, ARF1, CD274 and PRKCZ) were screened as the potential diagnostic targets for tuberculosis by analyzing the PPI regulatory network and using three algorithms. Three pathways related to the pathogenesis of tuberculosis were identified by KEGG pathway analysis, and two key miRNAs (has-miR-150-5p and has-miR-25-3p) that might participate in the pathogenesis of tuberculosis were screened out by constructing a miRNA-mRNA pathway regulatory network.ConclusionSix key genes and two important miRNAs that could regulate them were screened out by mRNA sequencing. The 6 key genes and 2 important miRNAs may participate in the pathogenesis of infection and invasion of Mycobacterium tuberculosis through herpes simplex virus 1 infection, endocytosis and B cell receptor signaling pathways.

The combined usage of phasor measurement units and machine learning algorithms provides the opportunity for developing response-based wide-area system integrity protection scheme against transient instability in power systems. However, only the transient stability status is usually predicted in the literature, which is not enough for real-time decision-making for response-based emergency control. In this paper, an integrated approach is proposed. The GRU-based predictor is firstly proposed for post-disturbance transient stability prediction. On this basis, a multi-task learning framework is proposed for the identification of unstable machines and also the estimation of generation shedding. Case study on the IEEE 39-bus system demonstrates that, apart from the basic task of transient stability prediction, the proposed GRU-based multi-task predictor can predict the grouping of unstable machines correctly. Moreover, based on the estimated amount of generation shedding, the generated remedial control actions can retain the synchronism of the power system.

1,5-Pentanediamine hydrochloride (PDAH) was an important raw material for the preparation of bio-based pentamethylene diisocyanate (PDI). PDI has shown excellent properties in the application of adhesives and thermosetting polyurethane. In this study, PDAH was recovered from 1,5-pentanediamine (PDA) fermentation broth using a cation exchange resin and purified by crystallization. D152 was selected as the most suitable resin for purifying PDAH. The effects of solution pH, initial temperature, concentration of PDA, and adsorption time were studied by the static adsorption method. The equilibrium adsorption data were well fitted to Langmiur, Freundlich, and Temkin-Pyzhev adsorption isotherms. The adsorption free energy, enthalpy, and entropy were calculated. The experimental data were well described by the pseudo first-order kinetics model. The dynamic experiment in the fixed bed column showed that under optimal conditions, the adsorption capacity reached 96.45 mg g−1, and the recovery proportion of the effective section reached 80.16%. In addition, the crystallization of the PDAH solution obtained by elution proved that the crystal product quality of resin eluting solution was highest. Thus, our research will contribute to the industrial scale-up of the separation of PDAH.

As one of the top ten environmental problems to be solved in the world, marine plastic waste and microplastic pollution seriously affect the health of marine ecosystems and the sustainable development of Marine economies. It is necessary to promote the establishment of a scientific and systematic Marine plastic waste and microplastic pollution control system and take strong measures to fundamentally curb and reverse the trend of marine pollution intensification in China. This paper first explains the practical significance of marine plastic waste and microplastic pollution control from three aspects: the sustainable development of the blue economy, the structural upgrading of the pan-plastic industry, and the improvement of public health awareness. Secondly, the particularity of marine plastic waste and microplastic pollution control system is summarized from three aspects of formation mechanism, migration path and damage performance. Then, it identifies domestic and international governance strategies and action plans from the perspectives of mechanism, subject, object, and measures, summarizes existing problems in the existing marine plastic waste and microplastic pollution control system, and gives directions for future improvement. Finally, some countermeasures and suggestions are put forward to accelerate the construction of China’s marine plastic waste and microplastic pollution control system, including the formation of a cross sectoral integrated land and sea control system, a full life cycle waste management process, a multi-participation model for marine ecological and environmental governance, and a global marine pollution prevention and control system.

Although epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) show efficacy in lung adenocarcinoma (LUAD) patients, TKI resistance inevitably develops, limiting long-term results. Thus, there is an urgent need to address drug resistance in LUAD. Long non-coding RNA (lncRNA) HIF1A-AS2 could be a critical mediator in the progression of various tumor types. We examined the function of HIF1A-AS2 in modifying tumor aggravation and osimertinib resistance in lung adenocarcinoma. Using clinical samples, we showed that HIF1A-AS2 was upregulated in LUAD specimens, predicting poorer overall survival and disease-free survival. HIF1A-AS2 silencing inhibited the proliferation, migration, and tumorigenesis of LUAD cells and therapeutic efficacy of osimertinib against tumor cells in vitro and in vivo. RNA precipitation assays, western blotting, luciferase assays, and rescue experiments demonstrated that HIF1A-AS2 sponged microRNA-146b-5p (miR-146b-5p), promoting interleukin-6 (IL-6) expression, activating the IL-6/STAT3 pathway, and leading to LUAD progression. miR-146b-5p and IL-6 levels were correlated with the prognosis of LUAD patients. Our results indicated that HIF1A-AS2 functions as an oncogenic factor in adenocarcinoma cells by targeting the miR-146b-5p/IL-6/STAT3 axis and may be a prognostic indicator of survival. Moreover, it can be a potential therapeutic target to enhance the efficacy of osimertinib in LUAD patients.

The core-shell 2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane/2,4,6-Trinitrotoluene (CL-20/TNT) composite was prepared by spray-drying method in which sensitive high energy explosive (CL-20) was coated with insensitive explosive (TNT). The structure and properties of different formulations of CL-20/TNT composite and CL-20/TNT mixture were characterized by scanning electron microscopy (SEM), Transmission electron microscopy (TEM), Laser particle size analyzer, X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), differential scanning calorimetry (DSC), impact sensitivity test and detonation performance. The results of SEM, TEM, XPS and XRD show that ϵ-CL-20 particles are coated by TNT. When the ratio of CL-20/TNT is 75/25, core-shell structure is well formed, and thickness of the shell is about 20–30 nm. And the analysis of heat and impact show that with the increase of TNT content, the TNT coating on the core-shell composite material can not only catalyze the thermal decomposition of core material (CL-20), but also greatly reduce the impact sensitivity. Compared with the CL-20/TNT mixture (75/25) at the same ratio, the characteristic drop height of core-shell CL-20/TNT composite (75/25) increased by 47.6% and the TNT coating can accelerate the nuclear decomposition in the CL-20/TNT composites. Therefore, the preparation of the core-shell composites can be regarded as a unique means, by which the composites are characterized by controllable decomposition rate, high energy and excellent mechanical sensitivity and could be applied to propellants and other fields.

Abstract Rare, yet biologically critical, lipids that contain very long chain fatty acids (VLCFA-lipids) are synthesized in the brain by the enzyme ELOVL4. High levels of VLCFA-lipids are toxic to cells and excess VLCFA-lipids are actively removed by ABCD1 in an ATP-dependent manner. Virtually nothing is known about the impact of VLCFA-lipids in neurodegenerative diseases. Here, we investigated the possible role of VLCFA-lipids in frontotemporal dementia (FTD), which is a leading cause of younger-onset dementia. Using quantitative discovery lipidomics, we identified three VLCFA-lipid species that were significantly increased in FTD brain compared to controls, with strong correlations with ELOVL4. Increases in ELOVL4 expression correlated with significant decreases in the membrane-bound synaptophysin in FTD brain. Furthermore, increases in ABCD1 expression correlated with increases in VLCFA-lipids. We uncovered a new pathomechanism that is pertinent to understanding the pathogenesis of FTD.

Muntjac deer underwent rapid species radiation and dramatic chromosome fusions within a short period of time. Here the authors reveal that repeat sequences likely mediated illegitimate recombination to result in chromosome fusions and that 3D chromatin architecture around fusion sites have no significant change, while significant interactions across fusion sites were gradually established after speciation.

Objective: DNA damage response (DDR) genes have low mutation rates, which may restrict their clinical applications in predicting the outcomes of immune checkpoint inhibitor (ICI) treatment. Thus, a systemic analysis of multiple DDR genes is needed to identify potential biomarkers of ICI efficacy. Methods: A total of 39,631 patients with mutation data were selected from the cBioPortal database. A total of 155 patients with mutation data were obtained from the Fudan University Shanghai Cancer Center (FUSCC). A total of 1,660 patients from the MSK-IMPACT cohort who underwent ICI treatment were selected for survival analysis. A total of 249 patients who underwent ICI treatment from the Dana-Farber Cancer Institute (DFCI) cohort were obtained from a published dataset. The Cancer Genome Atlas (TCGA) level 3 RNA-Seq version 2 RSEM data for gastric cancer were downloaded from cBioPortal. Results: Six MMR and 30 DDR genes were included in this study. Six MMR and 20 DDR gene mutations were found to predict the therapeutic efficacy of ICI, and most of them predicted the therapeutic efficacy of ICI, in a manner dependent on TMB, except for 4 combined DDR gene mutations, which were associated with the therapeutic efficacy of ICI independently of the TMB. Single MMR/DDR genes showed low mutation rates; however, the mutation rate of all the MMR/DDR genes associated with the therapeutic efficacy of ICI was relatively high, reaching 10%–30% in several cancer types. Conclusions: Coanalysis of multiple MMR/DDR mutations aids in selecting patients who are potential candidates for immunotherapy.

Abstract Background Anthocyanins, which belong to flavonoids, are widely colored among red-purple pigments in the Asiatic hybrid lilies (Lilium spp.). Transcription factor (TF) LhMYBSPLATTER (formerly known as LhMYB12-Lat), identified as the major kernel protein, regulating the anthocyanin biosynthesis pathway in ‘Tiny Padhye’ of Tango Series cultivars, which the pigmentation density is high in the lower half of tepals and this patterning is of exceptional ornamental value. However, the research on mechanism of regulating the spatial and temporal expression differences of LhMYBSPLATTER, which belongs to the R2R3-MYB subfamily, is still not well established. To explore the molecular mechanism of directly related regulatory proteins of LhMYBSPLATTER in the anthocyanin pigmentation, the yeast one-hybrid (Y1H) cDNA library was constructed and characterized. Results In this study, we describe a yeast one-hybrid library to screen transcription factors that regulate LhMYBSPLATTER gene expression in Lilium, with the library recombinant efficiency of over 98%. The lengths of inserted fragments ranged from 400 to 2000 bp, and the library capacity reached 1.6 × 106 CFU of cDNA insert, which is suitable to fulfill subsequent screening. Finally, seven prey proteins, including BTF3, MYB4, IAA6-like, ERF4, ARR1, ERF WIN1-like, and ERF061 were screened by the recombinant bait plasmid and verified by interaction with the LhMYBSPLATTER promoter. Among them, ERFs, AUX/IAA, and BTF3 may participate in the negative regulation of the anthocyanin biosynthesis pathway in Lilium. Conclusion A yeast one-hybrid library of lily was successfully constructed in the tepals for the first time. Seven candidate TFs of LhMYBSPLATTER were screened, which may provide a theoretical basis for the study of floral pigmentation.

In this study, we report the effects of hydroxypropyl methylcellulose (HPMC) and KH2PO4 on the water resistance of magnesium oxychloride cement (MOC), a novel bone cement composite. Different MOC samples were soaked in simulated body fluid (SBF). After soaking for 7–56 d, the surfaces of the experimental group (1 wt.% HPMC/2 wt.% KH2PO4-MOC) and control group (2 wt.% KH2PO4-MOC) appeared pores, which grew with increasing immersion time. Compared with the control group, the experimental group had smaller pore sizes and a denser surface. Furthermore, the compressive strength in the experimental group increased from 35.1 ± 1.9 MPa to 41.8 ± 2.3 MPa, and the softening coefficient increased from 0.34 to 0.45. Thus, HPMC could improve the water erosion resistance of the MOC. The implantation study of the femoral defects in rats showed that the sample modified by 1 wt.% HPMC/2 wt.% KH2PO4 had good biocompatibility and biodegradability. The results indicate that the modification of MOC with HPMC and KH2PO4 is a promising technique to form biodegradable bone repair materials and has good application prospects in the field of biomedical materials.

BackgroundConventionally, serum ceruloplasmin levels below the lower reference limit (0. 20 g/L) is considered a diagnostic cutoff point for Wilson's disease (WD). However, the lower reference limit varies with assay methodologies and the individuals in the included studies. The objective of this study was to determine the optimal cutoff value of serum ceruloplasmin levels for the diagnosis of WD in a large Chinese cohort and to identify factors associated with serum ceruloplasmin.MethodsThe cutoff value of ceruloplasmin levels was developed based on a retrospective derivation cohort of 3,548 subjects (1,278 patients with WD and 2,270 controls) and was validated in a separate validation cohort of 313 subjects (203 patients with WD and 110 controls). The performance of immunoassay was tested by receiver operating characteristic curve (ROC) analysis, and differences among the groups were analyzed by using the Mann–Whitney U-test and the Kruskal–Wallis test.ResultsThe conventional cutoff of serum ceruloplasmin levels of

In this study, we investigated the effects of Ganoderma lucidum aqueous extract (GLW) on improving learning and memory impairment (LMI) and analyzed the key genes and pathways involved. GLW can improve LMI in mice by increasing the activities of SOD and GSH-Px, increasing the contents of GLU and ACH, and reducing the contents of MDA and GABA. 644 differential expressed genes were screened by mRNA sequencing technology, and KEGG pathway analysis showed that Cholinergic synapse pathway was an important pathway for GLW to improve LMI in mice. Gnb1 and Adcy2 genes are the key genes in GLW pathway to improve LMI in mice. Gnb1 gene is positively regulated by M2 protein, which inhibits Cav-1 protein and promotes MAPK pathway. Adcy2 gene is promoted by nAChR protein and inhibited by Gnb1 gene, but it itself plays a positive regulatory role in CAMP pathway.

Laser wakefield acceleration, a highly nonlinear process, can provide high-quality electron beams and betatron radiation. However, it has always been a challenge to optimize the photon number of betatron radiation because X-ray production is the secondary process followed by electron generation and many influential parameters are highly coupled with each other. To balance these parameters and optimize target value, we use a machine-learning algorithm called Bayesian optimization that ignores the complicated middle process and so is suitable to solve this kind of problems. Without designed initialization, we optimize betatron radiation in experiments by changing plasma density and laser focal position. The X-ray photon number doubles compared with initial condition within 10 iterations, which shows the rapidity of this algorithm. PIC simulation also illustrates the complexity of the optimization and reveals the reason why X-ray photon number increases.

ObjectivesIgA nephropathy (IgAN) is the most common primary glomerular disease, and is the leading cause of chronic renal failure. Because mesangial lesions are the main pathological changes seen in IgAN, we investigated factors associated with the progression of mesangial lesions in IgAN.MethodsWe enrolled participants with IgAN who underwent repeat renal biopsies. Based on the progression of mesangial proliferative lesions, the participants were divided into progressive and stable groups. The progression group included participants with a ratio of mesangial cell proliferation score ≥ 1.1 (i.e., proliferation of > 10%) in the second biopsy specimen compared to the first biopsy specimen. The stable group included participants who did not fulfill the aforementioned criteria. We recorded the laboratory parameters, expression of renin-angiotensin system (RAS) receptors (angiotensin II type 1 receptor [AT1R], angiotensin II type 2 receptor [AT2R], Mas receptor [MasR], and the Mas-related G protein-coupled receptor, member D [MrgD]) and mesangial matrix proteins (collagen [Col] IV, fibronectin [FN] and laminin) at the first and second renal biopsies, and the use of immunosuppressive therapy and/or RAS blockers after the first biopsy.ResultsWe enrolled 24 patients with IgAN who underwent repeat renal biopsies. Half of patients showed progression of mesangial lesions on repeat renal biopsy after a median of 4.3 (1–6) years. The progression group had significantly higher expression levels of AT1R and mesangial matrix proteins (Col IV and FN), and significantly lower expression of AT2R and MasR, compared to the stable group. Multivariate analysis showed that the use of RAS blockers (hazard ratio [HR], 0.27; 95% CI, 0.08–0.97; p < 0.05) and the level of proteinuria (HR, 1.8; 95% CI, 1.04–3.12; p < 0.05) were associated with progression of mesangial lesions. Additionally, the progression group exhibited a more rapid decline of renal function compared to the stable group (0.38 and 0.012 ml/min/1.73 m2/month, respectively; p = 0.004).ConclusionsContinuous activation of the intrarenal RAS and massive proteinuria correlate with histological progression of mesangial lesions in IgAN patients, which may further accelerate the deterioration of renal function.

It is still unknown whether the previous summer season drought and fertilization will affect the winter non-structural carbohydrate (NSC) reserves, spring leaf development, and mortality of trees in the next year. We, therefore, conducted an experiment with Quercus pubescens (downy oaks) saplings grown under four drought levels from field capacity (well-watered; ~25% volumetric water content) to wilting point (extreme drought; ~6%), in combination with two fertilizer treatments (0 vs. 50 kg/ha/year blended) for one growing season to answer this question. We measured the pre- and post-winter NSC, and calculated the over-winter NSC consumption in storage tissues (i.e. shoots and roots) following drought and fertilization treatment, and recorded the spring leaf phenology, leaf biomass, and mortality next year. The results showed that, irrespective of drought intensity, carbon reserves were abundant in storage tissues, especially in roots. Extreme drought did not significantly alter NSC levels in tissues, but delayed the spring leaf expansion and reduced the leaf biomass. Previous season fertilization promoted shoot NSC use in extreme drought-stressed saplings over winter (showing reduced carbon reserves in shoots after winter), but it also showed positive effects on survival next year. We conclude that: (1) drought-stressed downy oak saplings seem to be able to maintain sufficient mobile carbohydrates for survival, (2) fertilization can alleviate the negative effects of extreme drought on survival and recovery growth of tree saplings.

Abstract Background The treatment for intertrochanteric femoral fractures (IFF) among the elderly has been a controversial topic. Hemiarthroplasty (HA) and proximal femoral nail antirotation (PFNA) have their own advantages in the management of IFF. Hence, this study aims to compare and analyze differences in the effectiveness of both procedures on IFF among the elderly. Methods Overall, 99 patients (81.09 ± 8.29 years; 68 women) underwent HA or PFNA from January 2016 to May 2020. IFF were classified according to the Arbeitsgemeins für Osteosynthesefragen (AO) classification. The difference in underlying diseases, the American Society of Anesthesiologists (ASA) grade, Singh index, Harris scores, surgical time, intraoperative bleeding, postoperative blood test results, postoperative number of days to partially bearing weight, and survival outcomes were analyzed. Postoperative follow-ups were performed every 3 months. Results There was no significant difference in the AO classification, underlying diseases, ASA grade, Singh index, surgical time, and survival outcomes of the HA (45 patients) group and PFNA group (54 patients). The HA group was associated with earlier partial weight-bearing (HA: 4 [2 ~ 4.5] days, PFNA: 10 [8~14] days). It also had a higher total Harris score than the PFNA group at the 6-month follow-up visit (HA: 86.8 [81.90 ~ 90.23], PFNA: 83.48 [75.13 ~ 88.23]). Harris scores decreased more in patients aged ≥90 years in the PFNA group than in the HA group. The postoperative stress recovery rate in the HA group was faster based on postoperative blood test results. Conclusions PFNA and HA have good therapeutic effects in the treatment of IFF. The advantages of HA were reflected in short-term weight bearing, faster recovery from stress, and better joint function in the long term. This advantage is more obvious in the patient population aged over 90 years. Therefore, we suggest that surgeons should consider the benefit of HA in the treatment of IFF among the elderly. Trial registration Chinese Clinical Trial Registry, ChiCTR2000035814. Registered 17 August 2020, https://www.chictr.org.cn/showproj.aspx?proj=57083