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Abstract The present study was undertaken to investigate the therapeutic effect and underlying mechanisms of lumbrokinase (LK) on diabetic kidney disease (DKD). Kidney tissue samples from DKD patients and normal controls were collected from hospitals. The type 2 diabetic nephropathy model was induced in db/db mice. The mice were then randomly divided into a model group (DM group) and an LK group. db/m mice were used as the control group (Con group). After 12 weeks of treatment with LK (234 KU/kg/day), biochemical parameters were tested, and pathological changes in the kidney were observed under a light microscope. The epithelial-to-mesenchymal transition (EMT), mRNA m6A methylation proteins, and activated TGF-β1/Smad pathway components were assessed by western blot or immunofluorescence in DKD patients, model mice, and high glucose-stimulated HK-2 cells. We found that the m6A eraser METTL3 was expressed at low levels in DKD patients, model mice, and high glucose-stimulated HK-2 cells. METTL3 overexpression reversed the high glucose-induced activation of the TGF-β1/Smad pathway and EMT through snail in vitro. However, LK can restore the expression of the m6A-modifying enzyme METTL3 in vivo and in vitro, suppressed EMT, and alleviated renal interstitial fibrosis by downregulating snail. Overall, LK ameliorated renal fibrosis through the regulation of Snail via m6A RNA METTL3.

Abstract Cyanidin‐3‐O‐glucoside (C3G), an abundant and widely utilized anthocyanin monomer, has been shown to significantly inhibit cholesterol absorption. Building on our previous research demonstrating the role of Lactobacillus as a specific intestinal microflora associated with C3G‐mediated cholesterol absorption inhibition, the present study aimed to evaluate the inhibitory effects of C3G on high‐fat diet–induced cholesterol absorption. Results indicate that C3G significantly reduced total cholesterol and triglyceride levels while suppressing red grease formation in Caco‐2 cells. In vivo, C3G ameliorated blood lipid levels and mitigated small intestinal damage, as evidenced by restored villus length and basal thickness. Additionally, C3G upregulated intestinal farnesoid X receptor (FXR) mRNA expression and inhibited the expression of key cholesterol absorption proteins, Niemann‐Pick C1‐Like 1 and acetyl‐CoA acetyltransferase 2. Furthermore, C3G increased short‐chain fatty acid content and activated ileal bile acid‐binding protein expression. C3G also inhibited intestinal bile acid (BA) reabsorption, promoted fecal BA excretion, and obstructed cholesterol emulsification. Moreover, C3G modulated gut microbiota abundance and diversity, increasing the abundance of Akkermansia, Bifidobacterium, Coprococcus, Ruminococcus, and Butyricicoccus. In conclusion, our findings suggest that C3G inhibits cholesterol absorption by reshaping intestinal flora composition and regulating the FXR‐BAs axis. This study provides a theoretical foundation for the use of C3G as a raw material for inhibiting cholesterol absorption.

To address the issues of low bioavailability, degradation during processing, and limited use in precision nutrition of anthocyanins (ACNs). ACNs nanoparticles using ACNs as the core, soybean lecithin constructed-Liposome (Lipo), and Gum Arabic (GA) as the carrier were prepared in this study, namely Liposome/Gum Arabic-anthocyanins (Lipo/GA-ACNs) nanoparticles. In this study, nanoparticles of ACNs with ACNs as the core and liposomes (Lipo) constructed using soy lecithin and gum arabic (GA) as carriers, namely liposome/gum arabic-anthocyanins (Lipo/GA-ACNs) nanoparticles, were prepared. Environmental factors and in vitro simulated digestion on the stability of Lipo/GA-ACNs nanoparticles with various formulations were investigated. Additionally, the in vitro lipid-lowering activity of Lipo/GA-ACNs nanoparticles after digestion was examined. Results showed that Lipo/GA-ACNs nanoparticles had good stability under simulated thermal processing and different ion environments. When the ACNs to GA mass ratio was 1:10, the Lipo/GA-ACNs nanoparticles inhibited lipid droplet accumulation and reactive oxygen species accumulation in HepG-2 cells 3.8% and 1.99% more effectively than ACNs after simulated digestion. This study concluded that Lipo/1.0GA was a promising oral delivery system to deliver ACNs and achieve liver lipid-lowering, with the potential to be developed into functional foods with precision nutritional properties.

The colonic mucosal barrier is an important component of the intestinal barrier, and its integrity is crucial for maintaining digestive tract homeostasis and normal metabolism in the body. This study aimed to elucidate the mechanisms by which malvidin-3-O-galactoside (M3G) might ameliorate colonic mucosal barrier function, from the perspective of physical barrier function and immune barrier function. Male C57BL/6J mice were given dextran sulfate sodium (DSS) to establish a mice model for colitis and then administrated with or without M3G for one week. The results showed that M3G supplementation significantly improved the disease activity index (DAI) score and colon tissue injury in mice with DSS-induced colitis. M3G improved the colonic physical barrier function by modulating the expression of mucin2 (MUC2), claudin-1, occludin, zona occludens 1 (ZO-1), and intestinal fatty acid binding protein (iFABP) in the colonic mucosa. Additionally, M3G also relieved the colonic immune barrier of mice by increasing the level of secretory immunoglobulin A (SIgA) in colon tissue and the percentages of CD4+T (CD3+CD4+) and CD8+T (CD3+CD8+) cells in colon lamina propria monocytes in mice. Furthermore, M3G down-regulated Notch signaling pathway-related proteins such as Notch1, notch intracellular domain (NICD), delta-like ligand 4 (DLL4), delta-like ligand 1 (DLL1), and hairy/enhancer of split 1 (Hes1) of colon tissue. The present results demonstrated that M3G can improve colonic mucosal barrier function by inhibiting the Notch signaling pathway.

Abstract Background Cetaceans, having experienced prolonged adaptation to aquatic environments, have undergone evolutionary changes in their respiratory systems. This process of evolution has resulted in the emergence of distinctive phenotypic traits, notably the abundance of elastic fibers and thickened alveolar walls in their lungs, which may facilitate alveolar collapse during diving. This structure helps selective exchange of oxygen and carbon dioxide, while minimizing nitrogen exchange, thereby reducing the risk of DCS. Nevertheless, the scientific inquiry into the mechanisms through which these unique phenotypic characteristics govern the diving behavior of marine mammals, including cetaceans, remains unresolved. Results This study entails an evolutionary analysis of 42 genes associated with pulmonary fibrosis across 45 mammalian species. Twenty-one genes in cetaceans exhibited accelerated evolution, featuring specific amino acid substitutions in 14 of them. Primarily linked to the development of the respiratory system and lung morphological construction, these genes play a crucial role. Moreover, among marine mammals, we identified eight genes undergoing positive selection, and the evolutionary rates of three genes significantly correlated with diving depth. Specifically, the SFTPC gene exhibited convergent amino acid substitutions. Through in vitro cellular experiments, we illustrated that convergent amino acid site mutations in SFTPC contribute positively to pulmonary fibrosis in marine mammals, and the presence of this phenotype can induce deep alveolar collapse during diving, thereby reducing the risk of DCS during diving. Conclusions The study unveils pivotal genetic signals in cetaceans and other marine mammals, arising through evolution. These genetic signals may influence lung characteristics in marine mammals and have been linked to a reduced risk of developing DCS. Moreover, the research serves as a valuable reference for delving deeper into human diving physiology.

Introduction Patients with clinically significant portal hypertension (CSPH) are recommended to be treated with non-selective beta-blockers (ie, carvedilol) to prevent the first hepatic decompensation event by the renewing Baveno VII consensus. CSPH is defined by hepatic venous pressure gradient (HVPG)≥10 mm Hg; however, the HVPG measurement is not widely adopted due to its invasiveness. Liver stiffness (LS)≥25 kPa can be used as a surrogate of HVPG≥10 mm Hg to rule in CSPH with 90% of the positive predicting value in majority aetiologies of patients. A compelling argument is existing for using LS≥25 kPa to diagnose CSPH and then to initiate carvedilol in patients with compensated cirrhosis, and about 5%–6% of patients under this diagnosis criteria may not be benefited from carvedilol and are at risk of lower heart rate and mean arterial pressure. Randomised controlled trial on the use of carvedilol to prevent liver decompensation in CSPH diagnosed by LS remains to elucidate. Therefore, we aimed to investigate if compensated cirrhosis patients with LS≥25 kPa may benefit from carvedilol therapy.Methods and analysis This study is a randomised, double-blind, placebo-controlled, multicentre trial. We will randomly assign 446 adult compensated cirrhosis patients with LS≥25 kPa and without any previous decompensated event and without high-risk gastro-oesophageal varices. Patients are randomly divided into two groups, with 223 subjects in group A and 223 subjects in group B. Group A is a carvedilol intervention group, while group B is a placebo group. All patients in both groups will receive aetiology therapies and are followed up at an interval of 6 months. The 3-year incidences of decompensated events of cirrhosis-related and liver-related death are the primary outcome. The secondary outcomes include development of each complication of portal hypertension individually (ascites, variceal bleeding or overt hepatic encephalopathy), development of spontaneous bacterial peritonitis and other bacterial infections, development of new varices, growth of small varices to large varices, delta changes in LS and spleen stiffness, change in hepatic dysfunction assessed by Child-Pugh and model for end-stage liver disease score, change in platelet count, development of hepatocellular carcinoma, development of portal vein thrombosis and adverse events with a 3-year follow-up. A predefined interim analysis will be performed to ensure that the calculation is reasonable.Ethics and dissemination The study protocol has been approved by the ethics committees of the Sixth People’s Hospital of Shenyang (2023-05-003-01) and independent ethics committee for clinical research of Zhongda Hospital, affiliated to Southeast University (2023ZDSYLL433-P01). The results from this trial will be submitted for publication in peer-reviewed journals and will be presented at international conferences.Trial registration number ChiCTR2300073864.

Vaccinium uliginosum L. (VU), rich in polyphenols, is an important wild berry resource primarily distributed in extremely cold regions. However, the detailed composition of Vaccinium uliginosum L. polyphenols (VUPs) has not been reported, which limits the development and utilization of VU. In this study, VU-free polyphenols (VUFPs) and VU-bound polyphenols (VUBPs) were, respectively, extracted using an ultrasonic, complex enzyme and alkali extraction method; the compositions were identified using ultra-performance liquid chromatography–electrospray ionization mass spectrometry, and lipid-lowering activity in vitro was evaluated. The results showed that 885 polyphenols and 47 anthocyanins were detected in the VUFPs and VUBPs, and 30 anthocyanin monomers were firstly detected in VU. Compared with the model group, the accumulation of lipid droplets and the total cholesterol and triglyceride contents in the high-concentration VUP group reduced by 36.95%, 65.82%, and 62.43%, respectively, and liver damage was also alleviated. It was also found that VUP can regulate the level of Asialoglycoprotein receptor 1, a new target for lipid lowering. In summary, this study provides a detailed report on VUP for the first time, confirming that VUP has lipid-lowering potential in vitro. These findings suggest new strategies and theoretical support for the development and utilization of VU, especially in the field of functional foods.

ABSTRACT Plants rely on strigolactones (SLs) to regulate their development and form symbiotic relationships with microbes as part of the adaptive phosphorus (P) efficiency strategies. However, the impact of SLs on root-associated microbial communities in response to P availability remains unknown. Here, root microbiota of SL biosynthesis (max3-11) and perception (d14-1) were compared to wild-type Col-0 plants under different P concentrations. Using high-throughput sequencing, the relationship between SLs, P concentrations, and the root-associated microbiota was investigated to reveal the variation in microbial diversity, composition, and interaction. Plant genotypes and P availability played important but different roles in shaping the root-associated microbial community. Importantly, SLs were found to attract Acinetobacter in low P conditions, which included an isolated CP-2 (Acinetobacter soli) that could promote plant growth in cocultivation experiments. Moreover, SLs could change the topologic structure within co-occurrence networks and increase the number of keystone taxa (e.g., Rhizobiaceae and Acidobacteriaceae) to enhance microbial community stability. This study reveals the key role of SLs in mediating root-associated microbiota interactions.IMPORTANCEStrigolactones (SLs) play a crucial role in plant development and their symbiotic relationships with microbes, particularly in adapting to phosphorus levels. Using high-throughput sequencing, we compared the root microbiota of plants with SL biosynthesis and perception mutants to wild-type plants under different phosphorus concentrations. These results found that SLs can attract beneficial microbes in low phosphorus conditions to enhance plant growth. Additionally, SLs affect microbial network structures, increasing the stability of microbial communities. This study highlights the key role of SLs in shaping root-associated microbial interactions, especially in response to phosphorus availability.

Abstract Background Mesenchymal stromal cells (MSCs) have broad potential as a cell therapy including for the treatment of drug-resistant inflammatory conditions with abnormal T cell proliferation such as graft-versus-host disease (GVHD). Clinical success, however, has been complicated by the heterogeneity of culture-expanded MSCs as well as donor variability. Here, we devise culture conditions that promote expansion of MSCs with enhanced immunomodulatory functions both in vitro and in animal models of GVHD. Methods Human bone marrow-derived MSCs were expanded at high-confluency (MSCHC) and low-confluency state (MSCLC). Their immunomodulatory properties were evaluated with in vitro co-culture assays based on suppression of activated T cell proliferation and secretion of pro-inflammatory cytokines from activated T cells. Metabolic state of these cells was determined, while RNA sequencing was performed to explore transcriptome of these MSCs. Ex vivo expanded MSCHC or MSCLC was injected into human peripheral blood mononuclear cells (PBMC)-induced GVHD mouse model to determine their in vivo therapeutic efficacy based on clinical grade scoring, human CD45+ blood count and histopathological examination. Results As compared to MSCLC, MSCHC significantly reduced both the proliferation of anti-CD3/CD28-activated T cells and secretion of pro-inflammatory cytokines upon MSCHC co-culture across several donors even in the absence of cytokine priming. Mechanistically, metabolic analysis of MSCHC prior to co-culture with activated T cells showed increased glycolytic metabolism and lactate secretion compared to MSCLC, consistent with their ability to inhibit T cell proliferation. Transcriptome analysis further revealed differential expression of immunomodulatory genes including TRIM29, BPIFB4, MMP3 and SPP1 in MSCHC as well as enriched pathways including cytokine–cytokine receptor interactions, cell adhesion and PI3K-AKT signalling. Lastly, we demonstrate in a human PBMC-induced GVHD mouse model that delivery of MSCHC showed greater suppression of inflammation and improved outcomes compared to MSCLC and saline controls. Conclusion Our study provides evidence that ex vivo expansion of MSCs at high confluency alters the metabolic and transcriptomic states of these cells. Importantly, this approach maximizes the production of MSCs with enhanced immunomodulatory functions without priming, thus providing a non-invasive and generalizable strategy for improving the use of MSCs for the treatment of inflammatory diseases.

Abundant polyphenols make chokeberry have beneficial antioxidant and antiproliferative activity. In order to explore the contribution of different polyphenols in chokeberry to these activities, this study was conducted to determine polyphenol composition from 7 chokeberry varieties produced in China. Totally, 11 kinds of main polyphenol monomers were identified and quantified by UPLC-Q-TOF-MS and UPLC-PDA. HepG2 cells were used to evaluate their cellular antioxidant and antiproliferative activities. Partial least squares method was utilized to analyze multivariate correlations between proportion of different composition and monomers in total polyphenols with these activities. The results showed that the highest proportion in chokeberry polyphenols was proanthocyanidins. In comparing the bioactivities of 7 varieties of chokeberry, ‘Viking’ and purple chokeberry had the strongest antioxidant activity, while ‘Fukangyuan 1#’ had the strongest antiproliferative activity. In terms of the contribution sources of these bioactivities, the total antioxidant activity of chokeberry mainly depended on the contribution of free polyphenols. As the main source of cellular antioxidant activity, anthocyanins and neochlorogenic acid can provide more contribution. The antiproliferative activity mainly depended on the proportion of free polyphenols and proanthocyanidins in total polyphenols. The results may provide some new possibilities for the comprehensive utilization of polyphenols from chokeberry.

Abstract Background Dendrobium officinale Kimura et Migo (D. officinale) is a well-known traditional Chinese medicine with high content polysaccharides in stems. The SWEET (Sugars Will Eventually be Exported Transporters) family is a novel class of sugar transporters mediating sugar translocation among adjacent cells of plants. The expression patterns of SWEETs and whether they are associated with stress response in D. officinale remains uncovered. Results Here, 25 SWEET genes were screened out from D. officinale genome, most of which typically contained seven transmembrane domains (TMs) and harbored two conserved MtN3/saliva domains. Using multi-omics data and bioinformatic approaches, the evolutionary relationship, conserved motifs, chromosomal location, expression patterns, correlationship and interaction network were further analyzed. DoSWEETs were intensively located in nine chromosomes. Phylogenetic analysis revealed that DoSWEETs were divided into four clades, and conserved motif 3 specifically existed in DoSWEETs from clade II. Different tissue-specific expression patterns of DoSWEETs suggested the division of their roles in sugar transport. In particular, DoSWEET5b, 5c, and 7d displayed relatively high expression levels in stems. DoSWEET2b and 16 were significantly regulated under cold, drought, and MeJA treatment, which were further verified using RT-qPCR. Correlation analysis and interaction network prediction discovered the internal relationship of DoSWEET family. Conclusions Taken together, the identification and analysis of the 25 DoSWEETs in this study provide basic information for further functional verification in D. officinale.

Scope: High-fat diet (HFD) induces imbalance in the small intestine environment, where fat digestion and absorption mainly take place. This study aimed to elucidate the mechanisms by which Lonicera caerulea polyphenols (LCP) might inhibit fat absorption, from the perspective of small intestine microbiota and epithelial barrier integrity. Methods and results: Male Sprague-Dawley rats were given HFD with or without co-administration of LCP for 8 weeks. The results showed that LCP supplementation significantly decreased the levels of serum triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C), and increased the contents of fecal sterols, in HFD rats. LCP also inhibited the dysfunction of the small intestine epithelial barrier, via alleviating the oxidative stress activated by Nrf2-ARE pathway, and by modulating the expressions of pro-inflammatory factors such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), nuclear factor kappa-B p65 (NF-κB p65) and inducible nitric oxide synthase (iNOS) in the small intestine. Additionally, LCP administration restored the balance in small intestine microbiota and increased the abundance of the specific bacteria, such as Lactobacillus, involved in fat absorption. Conclusion: Our results demonstrated that LCP may be beneficial to inhibit fat absorption. The mechanism seems to be associated with the protection of the epithelial barrier integrity and the modulation of specific bacteria in the small intestine.

Clinical sorafenib treatment could activate C-X-C receptor type 4 (CXCR4)/stromal source factor-1α (SDF-1α) axis to aggravate intra-tumoral hypoxia of hepatocellular carcinoma (HCC), which further leads to progression, invasion, metastasis, and immunosuppression of tumors and in return causes resistance to sorafenib therapy. Therefore, a multi-functional oxygen delivery nanoplatform was rationally constructed based on an oxygen-saturated perfluorohexane (PFH)-cored liposome, with the CXCR4 antagonist LFC131 peptides modifying on the surface to simultaneously deliver sorafenib and the CSF1/CSF1R inhibitor PLX3397 (named PFH@LSLP) for sorafenib-resistant HCC treatment. The PFH@LSLP was developed to overcome sorafenib resistance by synergistic effects of the following 3 roles: 1) the O2-saturated PFH core could alleviate the tumor hypoxia by O2 supply; 2) the LFC131 peptide recognized the hypoxia-related overexpressed CXCR4 and then blocked SDF-1α/CXCR4 axis to re-sensitize the HCC cells to sorafenib; 3) PLX3397 activated the immune responses via inhibiting the CSF1/CSF1R pathway in TAMs, further enhanced CD8+ T cell infiltration to reverse immunosuppression in tumors. Antitumor performance on H22 tumor-bearing mice and HCC patient-derived tumor xenograft (PDX) model showed that PFH@LSLP could overcome sorafenib resistance by synergistic effect of hypoxia attenuation, resistance-related gene regulation, and immune-microenvironment modification.

Acanthamoeba is an opportunistic protozoa, which exists widely in nature and is mainly distributed in soil and water. Acanthamoeba usually exists in two forms, trophozoites and cysts. The trophozoite stage is one of growth and reproduction while the cyst stage is characterized by cellular quiescence, commonly resulting in human infection, and the lack of effective monotherapy after initial infection leads to chronic disease. Acanthamoeba can infect several human body tissues such as the skin, cornea, conjunctiva, respiratory tract, and reproductive tract, especially when the tissue barriers are damaged. Furthermore, serious infections can cause Acanthamoeba keratitis, granulomatous amoebic encephalitis, skin, and lung infections. With an increasing number of Acanthamoeba infections in recent years, the pathogenicity of Acanthamoeba is becoming more relevant to mainstream clinical care. This review article will describe the etiological characteristics of Acanthamoeba infection in detail from the aspects of biological characteristic, classification, disease, and pathogenic mechanism in order to provide scientific basis for the diagnosis, treatment, and prevention of Acanthamoeba infection.

Abstract Background As a skeletal malignancy, osteosarcoma has high incidence among primary malignant bone tumors. With increasing researches on molecules which mediate cancer progression, molecular mechanism has gradually become the pivot of osteosarcoma research and treatment. Aim Our study aimed at investigating the function of G3BP stress granule assembly factor 2 (G3BP2), which is an oncogene for breast cancer (BC) and prostate cancer but remains unknown in osteosarcoma cells. Methods Related gene expression was confirmed by RT-qPCR. Functional assays including immunofluorescence (IF), colony formation, transferase-mediated dUTP nick-end labeling (TUNEL) as well as transwell assays were utilized to test the cell biological process caused by the genes. Meanwhile, RNA pull-down assay, along with luciferase reporter and RNA immunoprecipitation (RIP) assays, was utilized to detect the interaction G3BP2, miR-124-3p and FGD5 antisense RNA 1 (FGD5-AS1) may exert on the regulation of osteosarcoma cells. Results G3BP2 was with high expression in osteosarcoma cells, and it aggravated the malignant cell behaviors in osteosarcoma. Additionally, miR-124-3p was verified to negatively regulate G3BP2 expression in osteosarcoma cells. Moreover, lncRNA FGD5-AS1 was predicted and testified to be the sponge of miR-124-3p and modulated G3BP2 expression positively. Subsequently, FGA5-AS1 accelerated osteosarcoma cell proliferation through up-regulating G3BP2. Furthermore, we identified EBF transcription factor 1 (EBF1) as the transcription factor for FGA5-AS1, and EBF1 served as a tumor facilitator in osteosarcoma cells. Conclusion EBF1 induced-FGA5-AS1 aggravated osteosarcoma cell malignancy by targeting miR-124-3p and G3BP2.

Breast cancer and colorectal cancer are two of the most common malignant tumors worldwide. They cause the leading causes of cancer mortality. Many researches have demonstrated that long noncoding RNAs (lncRNAs) have close linkages with the occurrence and development of the two cancers. Therefore, it is essential to design an effective way to identify potential lncRNA biomarkers for them. In this study, we developed a computational method (LDA-RWLMF) by integrating random walk with restart and Logistic Matrix Factorization to investigate the roles of lncRNA biomarkers in the prognosis and diagnosis of the two cancers. We first fuse disease semantic and Gaussian association profile similarities and lncRNA functional and Gaussian association profile similarities. Second, we design a negative selection algorithm to extract negative LncRNA-Disease Associations (LDA) based on random walk. Third, we develop a logistic matrix factorization model to predict possible LDAs. We compare our proposed LDA-RWLMF method with four classical LDA prediction methods, that is, LNCSIM1, LNCSIM2, ILNCSIM, and IDSSIM. The results from 5-fold cross validation on the MNDR dataset show that LDA-RWLMF computes the best AUC value of 0.9312, outperforming the above four LDA prediction methods. Finally, we rank all lncRNA biomarkers for the two cancers after determining the performance of LDA-RWLMF, respectively. We find that 48 and 50 lncRNAs have the highest association scores with breast cancer and colorectal cancer among all lncRNAs known to associate with them on the MNDR dataset, respectively. We predict that lncRNAs HULC and HAR1A could be separately potential biomarkers for breast cancer and colorectal cancer and need to biomedical experimental validation.

Summary: Background: There are currently limited systemic treatment options for patients with advanced neuroendocrine tumours (NETS) and the efficacy of existing treatments is sub-optimal. We evaluated the efficacy and safety of Tegafur/gimeracil/oteracil/potassium capsules (S-1)/Temozolomide with or without thalidomide for the treatment of NETS (STEM trial). Methods: A randomised, controlled, open-label, phase 2 trial conducted at eight hospitals in China. Adults (≥18 years) with unresectable/metastatic, pancreatic or non-pancreatic NETS, with an Eastern Cooperative Oncology Group (ECOG) PS of 0–1, and progression on ≤2 previous therapies were randomised (1:1, using hierarchical block randomization with block length 4, stratified by pancreatic/non-pancreatic disease to receive S-1 40–60 mg orally twice daily on days 1–14 plus temozolomide 200 mg orally daily on days 10–14 in a 21-day cycle OR S-1 and temozolomide plus thalidomide orally nightly (100 mg on days 1–7, 200 mg on days 8–14, and 300 mg from day 15), until disease progression, death, intolerable toxicity, withdrawal of informed consent or at the investigator's discretion. The primary endpoint was objective response rate (ORR) by RECIST 1.1 in an intention-to-treat population. Safety was assessed in all patients who received treatment. The study was registered at ClinicalTrials.gov: NCT03204019 (pancreatic group) and NCT03204032 (non-pancreatic group). Findings: Between March 23, 2017 and November 16, 2020, 187 patients were screened and 140 were randomly assigned to S-1/temozolomide plus thalidomide (n = 69) or S-1/temozolomide (n =71). After a median follow-up of 12·1 months (IQR: 8·4–16·6), the ORR was comparable in the S-1/temozolomide plus thalidomide and S-1/temozolomide groups 26·1% [95% CI 17·2–37·5] versus 25·4% [95% CI 16·7–36·6]; odds ratio: 1·03 [95% CI 0·48–2·22]; P = 0·9381). In the S-1/temozolomide plus thalidomide group, the most common grade 3–4 treatment-related adverse event was fatigue (2/68, 3%), and in the control group were thrombocytopenia and diarrhea (both 1/71, 2%). There were no treatment-related deaths in either group. Interpretation: S-1/temozolomide with or without thalidomide leads to a comparable treatment response in patients with advanced/metastatic NETS. Funding: This work was supported by CAMS Innovation Fund for Medical Sciences (CIFMS,2021-I2M-1-066, 2017-I2M-4-002, 2021-I2M-1-019, 2017-I2M-1-001), the National Natural Science Foundation of China (81972311, 82141127, 31970794,), the State Key Project on Infection Diseases of China (2017ZX10201021-007-003), the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2019PT310026), Sanming Project of Medicine in Shenzhen (SZSM202011010), and the State Key Laboratory Special fund from the Ministry of Science (2060204).

BackgroundEmotional disturbance is an important risk factor of suicidal behaviors. To ensure speech emotion recognition (SER), a novel technique to evaluate emotional characteristics of speech, precision in labeling emotional words is a prerequisite. Currently, a list of suicide-related emotional word is absent. The aims of this study were to establish an Emotional Words List for Suicidal Risk Assessment (EWLSRA) and test the reliability and validity of the list in a suicide-related SER task.MethodsSuicide-related emotion words were nominated and discussed by 10 suicide prevention professionals. Sixty-five tape-recordings of calls to a large psychological support hotline in China were selected to test psychometric characteristics of the EWLSRA.ResultsThe results shows that the EWLSRA consists of 11 emotion words which were highly associated with suicide risk scores and suicide attempts. Results of exploratory factor analysis support one-factor model of this list. The Fleiss’ Kappa value of 0.42 indicated good inter-rater reliability of the list. In terms of criteria validities, indices of despair (Spearman ρ = 0.54, P < 0.001), sadness (ρ = 0.37, P = 0.006), helplessness (ρ = 0.45, P = 0.001), and numbness (ρ = 0.35, P = 0.009) were significantly associated with suicidal risk scores. The index of the emotional word of numbness in callers with suicide attempt during the 12-month follow-up was significantly higher than that in callers without suicide attempt during the follow-up (P = 0.049).ConclusionThis study demonstrated that the EWLSRA has adequate psychometric performance in identifying suicide-related emotional words of recording of hotline callers to a national wide suicide prevention line. This list can be useful for SER in future studies on suicide prevention.

Smartphone addiction is widespread among college students. Physical exercise and core self-evaluation are two potential factors that may influence smartphone addiction. This study aimed to investigate the relationship between physical exercise and college students’ smartphone addiction, as well as the mediating effect of core self-evaluation. Here, 643 undergraduate university students are surveyed via questionnaire using the Physical Activity Rating Scale, the Smartphone Addiction Scale for College Students, and the Core Self-Evaluations Scale. The participants include 363 males (56.5%) and 280 females (43.5%), with ages ranging from 17 to 25 years old (mean = 19.68, SD = 1.40). The obtained data are analyzed using SPSS26.0 and the PROCESS plugins. The main findings of the study are as follows: (1) There is a significant negative correlation between physical exercise and smartphone addiction (r = −0.30, p < 0.01), a significant positive correlation between physical exercise and core self-evaluation (r = 0.25, p < 0.01), and a significant negative correlation between core self-evaluation and smartphone addiction (r = −0.52, p < 0.01). (2) There is a mediating effect of core self-evaluation between physical exercise and smartphone addiction. The current study can provide new evidence for the impact of physical exercise on smartphone addiction and highlights the importance of core self-evaluation. Moreover, research ideas and methodological guidance are provided for the following interventions and treatments targeting college students’ smartphone addiction.

In this study, LiNi0.8Co0.15Al0.05O2@x%Al2O3-coated cathode materials were regeneratively compounded by the solid-phase sintering method, and their structural characterization and electrochemical performance were systematically analyzed. The regenerated ternary cathode material precursor synthesized by the co-precipitation method was roasted with lithium carbonate at a molar ratio of 1:1.1, and then completely mixed with different contents of aluminum hydroxide. The combined materials were then sintered at 800 °C for 15 h to obtain the regenerated coated cathode material, LiNi0.8Co0.15Al0.05O2@x%Al2O3. The thermogravimetry analysis, phase composition, morphological characteristics, and other tests show that when the added content of aluminum hydroxide is 3%, the regenerated cathode material, LiNi0.8Co0.15Al0.05O2@1.5%Al2O3, exhibits the highest-order layered structure with Al2O3 coating. This material can better inhibit the production of Ni2+, and improve material structure and electrochemical properties. The first charge–discharge efficiency of the battery assembled with this regenerated cathode material is 97.4%, a 50-cycle capacity retention is 93.4%, and a 100-cycle capacity retention is 87.6%. The first charge–discharge efficiency is far better than that of the uncoated regenerated battery.

Abstract Purpose To investigate the diversity of the epiphytic bacteria on corn (Zea mays) and alfalfa (Medicago sativa) collected in Hengshui City and Xingtai City, Hebei Province, China, and explore crops suitable for natural silage. Methods The Illumina MiSeq/NovaSeq high-throughput sequencing system was used to conduct paired-end sequencing of the community DNA fragments from the surface of corn and alfalfa collected in Hengshui and Xingtai. QIIME2 and R software were used to sort and calculate the number of sequences and taxonomic units for each sample. Thereafter, the alpha and beta diversity indices at of species level were calculated, and the abundance and distribution of taxa were analyzed and compared between samples. Result At phylum level, the dominant groups were Proteobacteria (70%), Firmicutes (13%), Actinobacteria (9%), and Bacteroidetes (7%). Meanwhile, the dominant genera were Pseudomonas (8%), Acinetobacter (4%), Chryseobacterium (3%), and Hymenobacter (1%). Enterobacteriaceae (24%) were the most predominant bacteria in both the corn and alfalfa samples. Alpha diversity analysis and beta diversity indices revealed that the diversity of epiphytic microbial communities was significantly affected by plant species but not by region. The diversity and richness of the epiphytic bacterial community of alfalfa were significantly higher than those of corn. Conclusion This study contributes to the expanding knowledge on the diversity of epiphytic bacteria in corn and alfalfa silage and provides a basis for the selection of raw materials.

Abstract Background Nitrogen, as a limiting factor for net primary productivity in grassland ecosystems, is an important link in material cycles in grassland ecosystems. However, the nitrogen assimilation efficiency and mechanisms of grassland plants under grazing disturbance are still unclear. This study investigated Stipa breviflora desert steppe which had been grazed for 17 years and sampled the root system and leaf of the constructive species Stipa breviflora during the peak growing season under no grazing, light grazing, moderate grazing and heavy grazing treatments. The activities of enzymes related to nitrogen assimilation in roots and leaves were measured. Results Compared with no grazing, light grazing and moderate grazing significantly increased the activities of nitrate reductase (NR), glutamine synthetase (GS), glutamic oxaloacetic transaminase (GOT) and glutamic pyruvate transaminase (GPT) in leaves, and GS, GOT and GPT in roots of Stipa breviflora, while heavy grazing significantly decreased the activities of GS in leaves and NR in roots of Stipa breviflora. NR, GOT and GPT activities in leaves and roots of Stipa breviflora were positively correlated with nitrogen content, soluble protein, free amino acid and nitrate content. Conclusions Grazing disturbance changed the activities of nitrogen assimilation related enzymes of grassland plants, and emphasized that light grazing and moderate grazing were beneficial for nitrogen assimilation by grassland plants. Therefore, establishing appropriate stocking rates is of great significance for material flows in this grassland ecosystem and for the stability and sustainable utilization of grassland resources.

Abstract Background The coronavirus disease 2019 (COVID-19) pandemic profoundly impacts on mental health, yet it is still unclear whether COVID-19 distress makes people more vulnerable to suicidal behavior. The present study aims to examine the association between COVID-19 related psychological distress and risk for suicide attempt, and moderators of this association, among hotline callers. Methods This case-control study was conducted at the largest psychological support hotline in China. Hotline callers who sought help for psychological distress and reported whether or not they attempted suicide in the last 2 weeks (recent suicide attempt) were analyzed. The primary predictor of recent suicide attempt was the presence or absence of COVID-19 related psychological distress. Demographic variables and common risk and protective factors for suicidal behavior were also studied. Callers with COVID-19 related distress (COVID-19 callers) and those without such distress (non-COVID-19 callers) were compared on these variables. Recent suicide attempt was regressed on COVID-19 related distress and the other variables, and significant interaction terms of aforementioned predictors by COVID-19 related distress, to identify variables that moderate the association of COVID-19 related distress and recent suicide attempt. Results Among 7337 included callers, there were 1252 COVID-19 callers (17.1%) and 6085 non-COVID-19 callers (82.9%). The COVID-19 callers were less likely to report recent suicide attempt (n = 73, 5.8%) than the non-COVID-19 callers (n = 498, 8.2%, P = 0.005). The COVID-19 callers were also less likely to have high scores on depressive symptoms (22.6% vs 26.3%, P

Background: Coronavirus disease 2019 (COVID-19) outbreak is progressing rapidly, and poses significant threats to public health. A number of clinical practice results showed that traditional Chinese medicine (TCM) plays a significant role for COVID-19 treatment. Objective: To explore the active components and molecular mechanism of semen armeniacae amarum treating COVID-19 by network pharmacology and molecular docking technology. Methods: The active components and potential targets of semen armeniacae amarum were retrieved from traditional Chinese medicine systems pharmacology (TCMSP) database. Coronavirus disease 2019-associated targets were collected in the GeneCards, TTD, OMIM and PubChem database. Compound target, compound-target pathway and medicine-ingredient-target disease networks were constructed by Cytoscape 3.8.0. Protein-protein interaction (PPI) networks were drawn using the STRING database and Cytoscape 3.8.0 software. David database was used for gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The main active components were verified by AutoDock Vina 1.1.2 software. A lipopolysaccharide (LPS)-induced lung inflammation model in Institute of Cancer Research (ICR) mice was constructed and treated with amygdalin to confirm effects of amygdalin on lung inflammation and its underlying mechanisms by western blot analyses and immunofluorescence. Results: The network analysis revealed that nine key, active components regulated eight targets (Proto-oncogene tyrosine-protein kinase SRC (SRC), interleukin 6 (IL6), mitogen-activated protein kinase 1 (MAPK1), mitogen-activated protein kinase 3 (MAPK3), vascular endothelial growth factor A (VEGFA), epidermal growth factor receptor (EGFR), HRAS proto-oncogene (HRAS), caspase-3 (CASP3)). Gene ontology and KEGG enrichment analysis suggested that semen armeniacae amarum plays a role in COVID-19 by modulating 94 biological processes, 13 molecular functions, 15 cellular components and 80 potential pathways. Molecular docking indicated that amygdalin had better binding activity to key targets such as IL6, SRC, MAPK3, SARS coronavirus-2 3C-like protease (SARS-CoV-2 3CLpro) and SARS-CoV-2 angiotensin converting enzyme II (ACE2). Experimental validation revealed that the lung pathological injury and inflammatory injury were significantly increased in the model group and were improved in the amygdalin group. Conclusion: Amygdalin is a candidate compound for COVID-19 treatment by regulating IL6, SRC, MAPK1 EGFR and VEGFA to involve in PI3K-Akt signalling pathway, VEGF signalling pathway and MAPK signalling pathway. Meanwhile, amygdalin has a strong affinity for SARS-CoV-2 3CLpro and SARS-CoV-2 ACE2 and therefore prevents the virus transcription and dissemination.

The aim of this study was to evaluate the performance of an assay using dried plasma spot (DPS) and dried blood spot (DBS) samples for the serological detection of anti-hepatitis C virus (HCV) antibodies. Between January and July 2019, plasma, DPS and DBS specimens were collected from individuals at high-risk for HCV infection. Samples were tested for anti-HCV by ELISA, and the performance of DPS and DBS specimens was examined using results from the plasma testing, as the standard. Blood samples were collected from 329 persons, including 129 men who have sex with men and 200 intravenous drug users. Results from the plasma testing indicated that 118 samples (59.0%) were HCV positive. Data from the DPS sample testing showed sensitivity as 99.2% (95% confidence interval [CI]: 0.95–1.00) and specificity as 100% (95% CI: 0.98–1.00) for HCV detection, with Kappa of 99.3% (95% CI: 0.98–1.00) while in DBS sample testing the sensitivity as 98.3% (95% CI: 0.93–1.00) and specificity as 100% (95% CI: 0.98–1.00), with Kappa of 98.7% (95% CI: 0.97–1.00), respectively. Spearman’s correlation coefficients for the comparisons between plasma and DPS specimen, plasma and DBS specimens, DPS and DBS specimens were 0.857, 0.750, and 0.739, respectively. Compared with the results in plasma, 1 sample was not detected using the DPS specimens, and 2 samples were failed for the positive detection, using the DBS specimens. Both DPS and DBS samples were promising alternatives to plasma, for the detection of anti-HCV antibodies.

The current pandemic has significantly impacted educational practices, modifying many aspects of how and when we learn. In particular, remote learning and the use of digital platforms have greatly increased in importance. Online teaching and e-learning provide many benefits for information retention and schedule flexibility in our on-demand world while breaking down barriers caused by geographic location, physical facilities, transportation issues, or physical impediments. However, educators and researchers have noticed that students face a learning and performance decline as a result of this sudden shift to online teaching and e-learning from classrooms around the world. In this paper, we focus on reviewing eye-tracking techniques and systems, data collection and management methods, datasets, and multi-modal learning data analytics for promoting pervasive and proactive learning in educational environments. We then describe and discuss the crucial challenges and open issues of current learning environments and data learning methods. The review and discussion show the potential of transforming traditional ways of teaching and learning in the classroom, and the feasibility of adaptively driving learning processes using eye-tracking, data science, multimodal learning analytics, and artificial intelligence. These findings call for further attention and research on collaborative and intelligent learning systems, plug-and-play devices and software modules, data science, and learning analytics methods for promoting the evolution of face-to-face learning and e-learning environments and enhancing student collaboration, engagement, and success.

This report describes a case of disseminated nocardiosis, caused by Nocardia vulneris, in a 61-year-old man with macroglobulinemia and presenting with repeated fever, cough, shortness of breath, and muscle pain. The isolated Nocardia strain was resistant to ciprofloxacin, but susceptible to amikacin, gentamicin, tobramycin, linezolid, trimethoprim-sulfamethoxazole, amoxicillin/clavulanic, moxifloxacin, ceftriaxone, cefotaxim, and imipenem. The patient was started on combined meropenem and doxycycline treatment, followed by trimethoprim-sulfamethoxazole, which was subsequently switched to a combination treatment of linezolid, amikacin, and trimethoprim-sulfamethoxazole. The patient recovered, and his condition remained stable. Although infection by Nocardia vulneris is rare, and it is easy to miss detection in clinical practice, clinicians should be aware of the possibility of this infection. In addition, the MIC value of the drug sensitivity test should be ascertained when there is a wide choice of medicines. The current case was treated successfully with linezolid, amikacin, and trimethoprim-sulfamethoxazole. In cases of disseminated nocardiosis, the patient should be treated with antimicrobial therapy for at least 12 months. Furthermore, bacteriological examination and antimicrobial susceptibility testing should be performed regularly.

Recently, female breast cancer (BC) has surpassed lung cancer to occupy the first place of the most commonly diagnosed cancer. The unsatisfactory prognosis of endocrine therapy for breast cancer might be attributed to the discordance in estrogen receptor (ER) status between primary tumors and corresponding metastases, as well as temporal and spatial receptor status heterogeneity at point-in-time between biopsy and treatment. The purpose of this study was to evaluate the prognostic and predictive value of ER status in circulating tumor cells (CTCs) in BC patients. We analyzed ER expression on CTCs isolated using the Pep@MNPs method in 2.0 ml of blood samples from 70 patients with BC and 67 female controls. The predictive and prognostic value of ER expression in CTCs and immunohistochemistry results of biopsies for progression-free survival (PFS) and overall survival (OS) of patients in response to therapies were assessed. The detection rate for CTCs was 95.71% (67/70 patients), with a median of 8 CTCs within 2 ml of peripheral venous blood (PVB). A concordance of 76.56% in ER status between CTCs and corresponding primary tumor and 69.23% between CTCs and corresponding metastases was observed. We also found that patients with ER-positive CTCs (CTC ER+) had longer PFS and OS than those without ER-positive CTCs (CTC ER-). Our findings suggested that ER status in CTCs of BC patients may provide valuable predictive and prognostic insights into endocrine therapies, although further evaluation in larger prospective trials is required.

The protective effects of blueberry anthocyanin extracts against damage induced by extremely low-frequency electromagnetic field (ELF-EMF) were investigated in a rat model. Wistar rats were exposed to ELF-EMF with or without the administration of blueberry anthocyanin extracts (50, 100, and 200 mg/kg per day intragastrically once a day) for 30 days. Blueberry anthocyanin extracts supplementation inhibited the decrease in Nissl substance levels, cell membrane integrity, and mitochondrial membrane potential induced by ELF-EMF; prevented the increase in nitric oxide, malondialdehyde, and Ca2+ concentrations; suppressed superoxide dismutase and glutathione depletion; and enhanced the cognitive ability of the rats exposed to ELF-EMF. The protective effects of blueberry anthocyanin extracts against hippocampal neuron injury caused by ELF-EMF were dose-dependent. These results demonstrated that blueberry anthocyanin extracts suppress hippocampal neuron injury caused by ELF-EMF by inhibiting cell membrane damage and oxidative stress pathways, and suggested that blueberry anthocyanin treatment potentially prevents hippocampal neuron injury.

HCC (Hepatocellular Carcinoma) is a critical health issue worldwide. Our previous animal experiment has confirmed that blueberry malvidin-3-galactoside (M3G) can regulate the progression of HCC. In this study, feces samples from the same batch of mice were collected to explore the regulatory mechanism of M3G on intestinal microbiota and microbial TCA cycle metabolism KEGG pathway in HCC mice based on 16S rRNA sequencing and metagenomics. Our results showed that blueberry M3G increased the microbial diversity and regulated the structure of intestinal microbiota in mice, such as increasing the abundance of Clostridia (butyric acid-producing bacteria), Oscillospira and Ruminococcus, and reducing the abundance of pathogenic Erysipelotrichi. Compared with the group of liver cancer (LC) and 5-fluorouracil (5 F), blueberry M3G significantly regulated microbial TCA cycle KEGG pathway via improving the expression of key proteins (porA, DLAT, aceE, PC and OGDH). Additionally, we found which the abundance of Muribaculum intestinale (M.intestinale) increased by blueberry M3G may be an important factor affecting the microbial TCA cycle KEGG pathway via the pearson correlation (R) analysis of protein and microbiota. Taken together, these results demonstrate that the blueberry M3G has the potential to be an intestinal microbiota regulator and an adjuvant to HCC therapy.

Malvidin-3-galactoside (Mv-3-gal) is the major anthocyanin monomer in blueberry anthocyanins. The compound is well-characterized by its anti-oncogenesis function in multiple organs including liver. In the current study, the mechanism driving the anti-hepatocellular carcinoma (HCC) function of Mv-3-gal was further explored by focusing on apoptosis and metastases pathways. HCC cell line Huh-7 was firstly administrated with Mv-3-gal of different concentrations and the effect of Mv-3-gal on cell proliferation, apoptosis, colony formation ability, metastasis potential as well as the activity of Akt/PTEN and MAPK pathways was assessed. The results showed that Mv-3-gal inhibited the cell proliferation and colony formation ability, induced cell cycle arrest and apoptosis in a dose-dependent manner. Regarding the metastasis potential, Mv-3-gal suppressed the migration and invasion potential of Huh-7 cells by regulating MMPs expression. Taken together, the findings highlighted the anti-HCC potent of Mv-3-gal, which was associated with the inhibition of Akt/PTEN, MAPK and MMP pathways.

BackgroundPrevious studies have described the correlation of suicidal ideation (SI) or suicide attempts (SA) in people living with HIV (PLWH), whereas few studies compare the correlation between SI and SA in PLWH. Understanding specific risk factors for SI and SA among PLWH will help with developing tailored and effective suicide prevention strategies among this high-risk group.MethodsA cross-sectional study was conducted from December 2020 to April 2021 in Baoji municipality, Shaanxi Province. The PLWH registered with the Baoji Municipal Center for Disease Control and Prevention (CDC) were recruited and interviewed. Questionnaires and interviews for this study consisted of socio-demographic variables, mental health history, and psychosocial characteristics. The HIV-related clinical features were obtained from CDC medical records. The PLWH included were divided into three groups, i.e., those with a history of suicide attempts (SA group), those with suicidal ideation only (SI group), and those without any suicidal behavior (NSB group). Multinomial logistic regression was used for three-way comparisons among these three groups of PLWH.ResultsIn total, 995 PLWH were interviewed. The prevalence of probable depression, probable anxiety, SI, and SA in PLWH after being diagnosed as HIV+ was 18.6%, 13.5%, 26.7%, and 3.2%, respectively. Compared with the NSB group, the SI or SA groups were more likely to report probable depression [adjusted odds ratio (AOR) = 2.43, 4.44, respectively], probable anxiety (AOR = 2.80, 5.62, respectively), and high HIV-related stigma (AOR = 2.05, 2.65, respectively). The SI group was more likely to experience high HIV-related stress (AOR = 1.91) and lower quality of life (AOR = 0.56) than the NSB group. Social support and HIV-related clinical features were not associated with SI or SA in this sample. The SA group did not differ from the SI group on any of the psychosocial or HIV-related clinical features.ConclusionsMental health problems are serious in community residents identified with having an HIV infection in a Central West China municipality. It is important to deliver low-cost and effective psychological services tailored for PLWH that are focused on reducing mental health problems. Future studies should utilize sensitive screening measures and further clarify factors potentially associated with the transition from SI to SA in PLWH.

Strigolactones (SLs) are a class of important plant hormones mainly regulating plant architecture such as branching, which is crucial for crop yield. It is valuable to study SL signaling pathway and its physiological function in sugarcane, the most important sugar crop, for further molecular breeding. Here, two putative SL receptors SsD14a/b and the interacting F-box protein SsMAX2 were identified in Saccharum spontaneum. SL induced both SsD14a and SsD14b to interact with SsMAX2 in yeast. SsD14a, but not SsD14b, could bind with AtMAX2 and AtSMXL7/SsSMXL7. Overexpression of SsD14a or SsMAX2 rescued the increased branching phenotypes of Arabidopsis thaliana d14-1 or max2-3 mutants, respectively. Moreover, the crystal structure of N-terminal truncated SsD14a was solved, with an overall structure identical to AtD14 and OsD14 in the open state, consistent with its conserved branching suppression capacity in Arabidopsis. In line with the biochemical observations, SsD14b could not completely complement in d14-1 although these two SsD14 proteins have almost identical primary sequences except for very few residues. Complement with the combination of SsD14b and SsMAX2 still failed to rescue the d14-1 max2-3 double mutant multi-branching phenotype, indicating SsD14b–AtSMXL7 complex formation is required for regulating branching. Mutagenesis analyses revealed that residue R310 at α10 helix of SsD14a was crucial for the binding with SsSMXL7/AtSMXL7 but not SsMAX2. The site-equivalent single-residue P304R substitution enabled SsD14b to bind with AtMAX2 and AtSMXL7/SsSMXL7 and to rescue the phenotype of d14-1 max2-3 together with SsMAX2. Moreover, this conserved Arg residue across species including rice and Arabidopsis determined the activity of SL receptors through maintaining their interaction with SMXL repressors. Taken together, our work identified conserved and divergent strigolactone receptors in sugarcane core SL signaling pathway and revealed a key residue crucial for plant branching control.

Objective Cholecystostomy is a palliative treatment for patients unfit to undergo immediate cholecystectomy. Nevertheless, the role of cholecystostomy in the clinical management of such patients remains unclear. The Acute Physiology and Chronic Health Evaluation IV (APACHE IV) scoring system is useful for estimating the hospital mortality of high-risk patients. We evaluated the therapeutic effect of cholecystostomy by the APACHE IV scoring system in patients aged >65 years with acute cholecystitis. Methods In total, 597 patients aged >65 years with acute cholecystitis were retrospectively analyzed using APACHE IV scores. Results The fitness of the APACHE IV score prediction was good, with an area under the receiver operating characteristic curve of 0.894. The chi square independence test indicated that compared with conservative treatment, cholecystostomy may have different effects on mortality for patients whose estimated mortality rate was >10%. Comparison of the estimated mortality of patients before and after cholecystostomy indicated that the estimated mortality was significantly lower after than before puncture, both in the whole patient group and in the group with an estimated mortality of >10%. Conclusion The APACHE IV scoring system showed that cholecystostomy is a safe and effective treatment for elderly high-risk patients with acute cholecystitis.

The wall-associated kinase (WAK) multigene family plays critical roles in various cellular processes and stress responses in plants, however, whether WAKs are involved in salt tolerance is obscure. Herein, we report the functional characterization of a rice WAK, WAK112, whose expression is suppressed by salt. Overexpression of OsWAK112 in rice and heterologous expression of OsWAK112 in Arabidopsis significantly decreased plant survival under conditions of salt stress, while knocking down the OsWAK112 in rice increased plant survival under salt stress. OsWAK112 is universally expressed in plant and associated with cell wall. Meanwhile, in vitro kinase assays and salt tolerance analyses showed that OsWAK112 possesses kinase activity and that it plays a negative role in the response of plants to salt stress. In addition, OsWAK112 interacts with S-adenosyl-L-methionine synthetase (SAMS) 1/2/3, which catalyzes SAM synthesis from ATP and L-methionine, and promotes OsSAMS1 degradation under salt stress. Furthermore, in OsWAK112-overexpressing plants, there is a decreased SAMS content and a decreased ethylene content under salt stress. These results indicate that OsWAK112 negatively regulates plant salt responses by inhibiting ethylene production, possibly via direct binding with OsSAMS1/2/3.

Abstract Background Hypercoagulation and neutrophilia are described in several cancers, however, whether they are involved in lung carcinogenesis is currently unknown. Emodin is the main bioactive component from Rheum palmatum and has many medicinal values, such as anti-inflammation and anticancer. This study is to investigate the contributions of neutrophils to the effects of emodin on hypercoagulation and carcinogenesis. Methods The effects of emodin on neutrophil phenotypes were assessed by cell proliferation, morphological changes, phagocytosis and autophagy in vitro. The anti-coagulation and cancer-preventing actions of emodin were evaluated in the urethane-induced lung carcinogenic model. The expressions of Cit-H3 and PAD4 in lung sections were assessed by immunohistochemistry, CD66b+ neutrophils were distinguished by immunofluorescence, and cytokines and ROS were examined with ELISA. The neutrophils-regulating and hypercoagulation-improving efficacies of emodin were confirmed in a Lewis lung cancer allograft model. The related targets and pathways of emodin were predicted by network pharmacology. Results In vitro, emodin at the dose of 20 µM had no effect on cell viability in HL-60N1 but increased ROS and decreased autophagy and thus induced apoptosis in HL-60N2 with the morphological changes. In the urethane-induced lung carcinogenic model, before lung carcinogenesis, urethane induced obvious hypercoagulation which was positively correlated with lung N2 neutrophils. There were the aggravated hypercoagulation and lung N2 neutrophils after lung carcinoma lesions. Emodin treatment resulted in the ameliorated hypercoagulation and lung carcinogenesis accompanied by the decreased N2 neutrophils (CD66b+) in the alveolar cavity. ELISA showed that there were more IFN-γ, IL-12 and ROS and less IL-6, TNF-α and TGF-β1 in the alveolar cavity in the emodin group than those in the control group. Immunohistochemical analysis showed that emodin treatment decreased Cit-H3 and PAD4 in lung sections. In the Lewis lung cancer allograft model, emodin inhibits tumor growth accompanied by the attenuated coagulation and intratumor N2 neutrophils. Network pharmacology indicated the multi-target roles of emodin in N2 neutrophil activation. Conclusions This study suggests a novel function of emodin, whereby it selectively suppresses N2 neutrophils to prevent hypercoagulation and lung carcinogenesis.

Blue honeysuckles are rich in polyphenol compounds that exert many beneficial effects. Previously, we demonstrated that polyphenol-rich blue honeysuckle extract (BHE) could alleviate silica-induced lung inflammation; however, its role in anti-fibrosis effects remains unknown. Here, we applied polyphenol-rich BHE to silica-injured mice to investigate its anti-fibrosis effect and the underlying mechanism. The results showed that BHE alleviated silica-induced pulmonary fibrosis in mice by altering regulatory T cell activity and mitigating T helper (Th)1/Th17 responses, resulting in reduced Th2 cytokine and transcription-factor mRNA levels. Additionally, cell-signaling detection revealed that p38 and c-Jun N-terminal kinase phosphorylation were effectively blocked by BHE treatment, which also downregulated the expression of inducible nitric oxide synthase and upregulated two antioxidant mediators [nuclear factor (erythroid-derived 2)-like 2 and heme oxygenase-1] in the lung. These findings support the use of BHE as functional food to modulate immune responses and alleviate lung fibrosis.

DNA methyltransferases (MTases) can be regarded as biomarkers, as demonstrated by many studies on genetic diseases. Many researchers have developed biosensors to detect the activity of DNA MTases, and nucleic acid amplification, which need other probe assistance, is often used to improve the sensitivity of DNA MTases. However, there is no integrated probe that incorporates substrates and template and primer for detecting DNA MTases activity. Herein, we first designed a padlock probe (PP) to detect DNA MTases, which combines target detection with rolling circle amplification (RCA) without purification or other probe assistance. As the substrate of MTase, the PP was methylated and defended against HpaII, lambda exonuclease, and ExoI cleavage, as well as digestion, by adding MTase and the undestroyed PP started RCA. Thus, the fluorescent signal was capable of being rapidly detected after adding SYBRTM Gold to the RCA products. This method has a detection limit of approximately 0.0404 U/mL, and the linear range was 0.5–110 U/mL for M.SssI. Moreover, complex biological environment assays present prospects for possible application in intricacy environments. In addition, the designed detection system can also screen drugs or inhibitors for MTases.

Background: To compare the characteristics between hotline callers with and without the Coronavirus Disease 2019 (COVID-19) related psychological problems.Methods: From January 25 to March 31, 2020, 581 callers with COVID-19 related psychological problems (COVID-19 callers) and 695 callers without COVID-19 related psychological problems (non-COVID-19 callers) to the Beijing Psychological Support Hotline were recruited. The demographic characteristics, primary concerns, suicidal ideation, depression and other psychological problems were compared between the two groups of callers.Results: Both groups of the callers were predominantly female and highly educated. The primary concerns reported by the COVID-19 callers were depression (38.4%) and family relationship problems (26.0%). As compared to the non-COVID-19 callers, COVID-19 callers reported more financial (7.4%) and work related problems (4.1%), but revealed lower prevalence of suicidal ideation (47.9% v 71.3%), lower degrees of psychological distress (74.3 v 79.1), intensity of suicidal ideation (0 v 50), severity of depression (57.9 v 65.1), and higher degree of hopefulness (41.1 v 33.6) (all p values < 0.01). Additionally, a lower proportion of COVID-19 callers met the criteria of depressed mood (51.6% v 61.4%) and other 4 symptoms than the non-COVID-19 callers (p values < 0.01).Conclusions: Based on the content of the primary concerns and the relatively low level of depression of the COVID-19 callers, the psychological intervention for them during the pandemic should focus on “psychological supports.” Coping strategies for daily life stressors and promotion of scientific knowledge about the pandemic should also be included in the hotline-related interventions.

IntroductionCandida auris is an emerging multidrug-resistant fungus that may cause infections with a high mortality rate. The first case of C. auris infection was reported in 2009 and infections have been reported in 44 countries. The fungus now represents a major global public health threat. We analyzed cases from the emergence of C. auris infections up until the end of 2020. It is hoped that the results of this analysis will raise awareness in scientists to promote protection and control research pertaining to this pathogen.MethodsPubMed and Web of Science databases were searched for all papers related to C. auris infections up until December 31, 2020. We sorted and organized these data into the following categories: date of publication, patient age and sex, underlying diseases, risk factors for infection, patient mortality information, drug sensitivity information of C. auris isolates, and genetic classification. The χ2 test was used to screen for factors that may affect patient mortality.ResultsA total of 912 patients were included in the analysis. There’s a higher proportion of men and a high proportion of patients were premature babies and elderly people. The proportions of patients with underlying diseases such as diabetes, kidney disease, trauma, and ear disease were also high. More than half of patients had a history of central venous catheter use and a history of broad-spectrum antibiotic use. The χ2 test revealed that only kidney disease (P < 0.05) was an important risk factor for mortality in C. auris-infected patients.ConclusionsA comprehensive understanding of C. auris was achieved following this retrospective analysis, including the characteristics of C. auris-infected patients. In recent years, increasing numbers of multidrug-resistant C. auris isolates have been identified, and the high mortality rates associated with infection merit greater attention from the medical world.

Alzheimer's disease (AD) has become a worldwide disease that is harmful to human health and brings a heavy economic burden to healthcare system. Xiao-Xu-Ming Decoction (XXMD) has been widely used to treat stroke and other neurological diseases for more than 1000 years in China. However, the synergistic mechanism of the constituents in XXMD for the potential treatment of AD is still unclear. Therefore, the present study aimed to predict the potential targets and uncover the material basis of XXMD for the potential treatment of AD. A network pharmacology-based method, which combined data collection, drug-likeness filtering and absorption, distribution, metabolism, excretion and toxicity (ADME/T) properties filtering, target prediction and network analysis, was used to decipher the effect and potential targets of XXMD for the treatment of AD. Then, the acetylcholinesterase (AChE) inhibitory assay was used to screen the potential active constituents in XXMD for the treatment of AD, and the molecular docking was furtherly used to identify the binding ability of active constituents with AD-related target of AChE. Finally, three in vitro cell models were applied to evaluate the neuroprotective effects of potential lead compounds in XXMD. Through the China Natural Products Database, Traditional Chinese Medicine Systems Pharmacology (TCMSP) Database, Traditional Chinese Medicine (TCM)-Database @Taiwan and literature, a total of 1481 compounds in XXMD were finally collected. After ADME/T properties filtering, 908 compounds were used for the further study. Based on the prediction data, the constituents in XXMD formula could interact with 41 AD-related targets. Among them, cyclooxygenase-2 (COX-2), estrogen receptor α (ERα) and AChE were the major targets. The constituents in XXMD were found to have the potential to treat AD through multiple AD-related targets. 62 constituents in it were found to interact with more than or equal to 10 AD-related targets. The prediction results were further validated by in vitro biology experiment, resulting in several potential anti-AD multitarget-directed ligands (MTDLs), including two AChE inhibitors with the IC50 values ranging from 4.83 to 10.22 μM. Moreover, fanchinoline was furtherly found to prevent SH-SY5Y cells from the cytotoxicities induced by sodium nitroprusside, sodium dithionate and potassium chloride. In conclusion, XXMD was found to have the potential to treat AD by targeting multiple AD-related targets and canonical pathways. Fangchinoline and dauricine might be the potential lead compounds in XXMD for the treatment of AD.

Helicobacter pylori (HP) contributes to the development of gastrointestinal disorders. Cyanidin-3-O-glucoside (C3G) is a major anthocyanin in human diets. In the current study, the effects and associated mechanism of C3G on HP lipopolysaccharide (LPS)-induced symptoms on human gastric epithelial cell (HGEC) cells were explored. The cells were exposed to LPS and C3G, and cellular viability, apoptotic rate, inflammation level, and toll-like receptor (TLR)-mediated nuclear factor-kappa B (NF-κB) pathway activity were measured. C3G suppressed the abnormal DNA synthesis and induced apoptosis in LPS-treated HGEC cells. C3G also reduced inflammation in LPS-treated HGEC cells. Although C3G exposure reduced the expressions of TLR2 and TLR4, it had no influence on TLR5. C3G deactivated TLR-mediated NF-κB signaling. The effects of C3G were stronger than anthocyanin extract but weaker than curcumin. The protective effects of C3G against HP LPS-induced injuries in gastric epithelial cells were associated with the deactivation of TLR2- and TLR4-mediated NF-κB signaling.

Cyanidin-3-glucoside (C3G) is an abundant anthocyanin that exhibits antimicrobial, cardioprotective, and hepatoprotective effects. We applied C3G to silica-injured mice to investigate the efficacy of dietary C3G on lung inflammation and the underlying action mechanism as this information is currently unavailable. We found that C3G treatment significantly alleviated lung inflammation and reduced inflammatory cell infiltration into the lungs. It also reduced the pro-inflammatory cytokine levels in bronchoalveolar lavage fluid. Flow cytometry analysis revealed that C3G treatment ameliorated pulmonary helper and cytotoxic T cell immune responses by decreasing cytokine levels. Regulatory T cells and IL-17A producing-regulatory T cells were also decreased by C3G treatment. Furthermore, C3G effectively suppressed SP-induced activation of the STAT1 and STAT3 signaling pathways of lung tissues. These results demonstrated that dietary C3G could alleviate SP induced lung injury in mice and support the use of C3G as functional food to modulate pulmonary immune responses to silica particles.

A high-order bilateral consensus robot formation control protocol for multi-agent systems is proposed in this paper. Considering the relationship between the state of the information exchange topology and derivatives, a third-order bilateral consistency protocol is presented and is extended it to a higher order bilateral consensus protocol. First, sufficient conditions for the third-order multi-agent system are given to achieve the bilateral consensus control protocol, and the system’s asymptotical stability is also achieved by adjusting the feedback system gain parameters. Then, by further studying the cohesive relationship between each state variable of the third-order protocol and the gauge transformation, the sufficient conditions of the higher order system are also provided. Finally, by applying the third-order control protocol to the control of multi-robot formation, the general control scheme of robot formation is given and the control of robot formation is successfully achieved.

Human blood contains cell-free DNA (cfDNA), with circulating tumor-derived DNAs (ctDNAs) widely used in cancer diagnosis and treatment. However, it is still difficult to efficiently and accurately identify and distinguish specific ctDNAs from normal cfDNA in cancer patient blood samples. In this study, ctDNA fragment length distribution analysis showed that ctDNA fragments are frequently shorter than the normal cfDNAs, which is consistent with previous findings. Interestingly, the ctDNA fragment length was found to be partially associated with the mutant allele frequency, with a low mutant allele frequency (< ~0.6%) associated with a longer ctDNA fragment length when compared to normal cfDNAs. The findings of this study contribute to improving the detection of low-frequency tumor mutations.

This study explores the contributions of neutrophils to chemotherapeutic resistance and berberine-regulated cancer cell sensitivity to doxorubicin (DOX). In vitro experiments, continuous DOX treatment led to the shift of HL-60 cells to N2 neutrophils and thus induced chemotherapeutic resistance. The combination treatment with DOX and 2 µM berberine resulted in the differentiation of HL-60 cells toward N1 and therefore stimulated HL-60 cell immune clearance. Berberine increased reactive oxygen species (ROS) and decreased autophagy and therefore induced apoptosis in HL-60-N2 cells with morphological changes, but had no effect on cell viability in HL-60-N1 cells. The neutrophil-regulating efficacy of berberine was confirmed in the urethane-induced lung carcinogenic model and H22 liver cancer allograft model. Furthermore, we found that DOX-derived neutrophils had high levels of CD133 and CD309 surface expression, which prevented both chemotherapeutic sensitivity and immune rejection by self-expression of PD-L1 and surface expression of PD-1 receptor on T cells, whereas berberine could downregulate CD133 and CD309 surface expression. Finally, berberine-relevant targets and pathways were evaluated. This study first suggests an important role of berberine in regulating neutrophil phenotypes to maintain cancer cell sensitivity to DOX.

The blue honeysuckle is a rich source of bioactive compounds. In this study, we obtained a polyphenol-rich blue honeysuckle extract (BHE) and found that cyanidin 3-glucoside and chlorogenic acid accounted for most of its phenolic content. Administration of BHE to mice alleviated silica particle (SP)-induced lung inflammation and reduced the recruitment of macrophages to lungs. BHE also reduced the pro-inflammatory cytokine levels in the bronchoalveolar lavage fluid. In vitro study showed that BHE reduced pro-inflammatory cytokine secretion by macrophages and reduced apoptosis in macrophages. Cell signaling analysis revealed that BHE inhibited p38 and c-Jun N-terminal kinase phosphorylation and decreased the nuclear expression of nuclear factor-κB. BHE treatment also down-regulated the expression of inducible nitric oxide synthase and up-regulated two antioxidant mediators, nuclear factor (erythroid-derived 2)-like 2 and heme oxygenase-1, in macrophages. The findings demonstrated that BHE may serve as a complementary and alternative functional food to prevent SP-induced pulmonary diseases.

Abstract Background Propolis and its major constituent – caffeic acid phenethyl ester (CAPE) have good abilities on antitumor and anti-inflammation. However, little is known about the actions of propolis and CAPE on tumor in inflammatory microenvironment, and inflammatory responses play decisive roles at different stages of tumor development. To understand the effects and mechanisms of ethanol-extracted Chinese propolis (EECP) and its major constituent - CAPE in inflammation-stimulated tumor, we investigated their effects on Toll-like receptor 4 (TLR4) signaling pathway which plays a crucial role in breast cancer MDA-MB-231 cell line. Methods 80% confluent breast cancer MDA-MB-231 cells were stimulated with 1 μg/mL lipopolysaccaride (LPS). Then the cells were divided for treatment by CAPE (25 μg/mL) and EECP (25, 50 and 100 μg/mL), respectively. Cell viability, nitric oxide (NO) production and cell migration were measured by sulforhodamine B assay, chemical method and scratch assay. The levels of TLR4, MyD88, IRAK4, TRIF, caspase 3, PARP, LC3B and p62 were investigated through western blotting. The expression of TLR4, LC3B and nuclear factor-κB p65 (NF-κB p65) were tested by immunofluorescence microscopy assay. Results Treatment of different concentrations of EECP (25, 50 and 100 μg/mL) and CAPE (25 μg/mL) significantly inhibited LPS-stimulated MDA-MB-231 cell line proliferation, migration and NO production. Furthermore, EECP and CAPE activated caspase3 and PARP to induce cell apoptosis, and also upregulated LC3-II and decreased p62 level to induce autophagy during the process. TLR4 signaling pathway molecules such as TLR4, MyD88, IRAK4, TRIF and NF-κB p65 were all down-regulated after EECP and CAPE treatment in LPS-stimulated MDA-MB-231 cells. Conclusions These findings indicated that EECP and its major constituent - CAPE inhibited breast cancer MDA-MB-231 cells proliferation in inflammatory microenvironment through activating apoptosis, autophagy and inhibiting TLR4 signaling pathway. EECP and CAPE may hold promising prospects in treating inflammation-induced tumor.

Lonicera caerulea L. berry extract has antioxidant and anti-inflammatory properties. The mechanism underlying the inhibitory effect of L. caerulea berry extract on lipopolysaccharide (LPS)-induced toxicity in BRL-3A cells was investigated in this study. It was observed that post-treatment with L. caerulea berry extract inhibited LPS-elicited decreases in catalase and superoxide dismutase activities, total antioxidant capacity, acetylcholinesterase activity, the mRNA expression levels of interleukin-10, and the protein expressions of poly (ADP-ribose) polymerase (PARP) and B-cell lymphoma-2. Furthermore, the extract significantly reduced LPS-induced increases in the activities of aspartate aminotransferase and alanine aminotransferase, the mRNA expressions of nuclear factor-kappa B and tumour necrosis factor-alpha, and the protein expressions of caspase-3, cleaved caspase-3, cleaved PARP, and Bax. Moreover, the extract suppressed LPS-induced apoptosis of BRL-3A cells. Taken together, the L. caerulea berry extract attenuates LPS-induced liver toxicity via antioxidant, anti-inflammatory, and anti-apoptotic pathways. Additionally, cyanidin-3-glucoside contributes more to these activities of the extract.

The first complete chloroplast genome (cpDNA) sequence of Lophatherum gracile Brongn. was determined from Illumina HiSeq pair-end sequencing data in this study. The cpDNA is 140,595 bp in length, contains a large single-copy region (LSC) of 82,447 bp, and a small single-copy region (SSC) of 12,626 bp, which were separated by a pair of inverted repeats (IR) regions of 22,761 bp. The genome contains 130 genes, including 83 protein-coding genes, eight ribosomal RNA genes, and 39 transfer RNA genes. The further phylogenomic analysis showed that L. gracile and Zeugites pittieri clustered in a clade in Poaceae family.