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γ-Valerolactone (GVL) is a promising biomass-based platform compound that can be used for the removal of hemicellulose in pulp. In this study, a paper-grade pulp was treated using GVL to generate dissolving pulp for viscose production. The GVL concentration, treatment temperature, and reaction time had significant effect on the hemicellulose dissolution. The dissolving pulp with α-cellulose content of 92.3% and hemicellulose content of 5.45% was achieved with 60% GVL at 120 °C for 2 h. The Fock reactivity and intrinsic viscosity of the obtained dissolving pulp were 54.6% and 595 mL/g, which is comparable with the commercial product. In addition, GVL spent liquor was also recycled and reused to upgrade paper-grade pulp. By using purified recycled GVL to treat original pulp, the Fock reactivity of pulp was improved, and the cellulose content of as-prepared upgraded pulp increased to 92.1%, which was close to the cellulose content of dissolving pulp obtained from fresh GVL solution, while the intrinsic viscosity decreased significantly to 598 mL/g. Therefore, the efficient reuse of GVL not only ensured the high quality of dissolving pulp, but it also saved production costs and reduced environmental pollution.

Abstract mRNA vaccines are regarded as a highly promising avenue for next‐generation cancer therapy. Nevertheless, the intricacy of production, inherent instability, and low expression persistence of linear mRNA significantly restrict their extensive utilization. Circular RNAs (circRNAs) offer a novel solution to these limitations due to their efficient protein expression ability, which can be rapidly generated in vitro without the need for extra modifications. Here, we present a novel neoantigen vaccine based on circRNA that induces a potent anti‐tumor immune response by expressing hepatocellular carcinoma‐specific tumor neoantigens. By cyclizing linearRNA molecules, we were able to enhance the stability of RNA vaccines and form highly stable circRNA molecules with the capacity for sustained protein expression. We confirmed that neoantigen‐encoded circRNA can promote dendritic cell (DC) activation and enhance DC‐induced T‐cell activation in vitro, thereby enhancing T‐cell killing of tumor cells. Encapsulating neoantigen‐encoded circRNA within lipid nanoparticles for in vivo expression has enabled the creation of a novel circRNA vaccine platform. This platform demonstrates superior tumor treatment and prevention in various murine tumor models, eliciting a robust T‐cell immune response. Our circRNA neoantigen vaccine offers new options and application prospects for neoantigen immunotherapy in solid tumors.

ABSTRACT Land-use effectiveness can be ensured by utilizing GIS and geostatistical tools in conjunction with land assessment methods to prevent soil erosion and salinization. This study employs a GIS-based LESA methodology, combined with geostatistics, to evaluate the land’s capacity to produce agricultural crops on calcareous soils. Land Evaluation for Agricultural Uses (LESA) key components are site assessment and land evaluation, with the former being non-soil-dependent and the latter being soil-dependent. Geostatical kriging was used to interpolate and generalize a GIS map of land capability. The study found that 27.88, 47.94, 18.76, and 5.41 % of the study area were unsuitable for crop farming, marginally suitable, moderately suitable, and highly suitable, respectively. Our research demonstrates that a flexible GIS framework can assist decision-makers in more accurately assessing land resources, including unsuitable, marginally-suitable, and reforested lands.

Abstract The Chinese alligator (Alligator sinensis) is currently an endangered species due to a combination of factors, including climate change, anthropogenic activities, and habitat fragmentation. Captivity plays a crucial role in mitigating the decline of the Chinese alligator population. Currently, there is a lack of clarity regarding the influence of host development and captive conditions on the gut microbiota of Chinese alligators. The aim of the study was to investigate the gut bacterial communities of Chinese alligators and their surrounding environmental bacterial communities using 16S rRNA sequencing. The primary gut flora of Chinese alligators consists of Proteobacteria, Bacteroidetes, and Firmicutes. Proteobacteria is the most abundant and efficient settler in the gut, water, and sediment. PCoA and Adonis test revealed significant differences in bacterial communities across these habitats. Venn analysis revealed overlap in OTUs among the gut, water, and sediment, varying with growth stage and density stress. Different growth stages of Chinese alligator guts harbor distinct pathogenic bacteria, requiring attention. Density stress leads to an increase in pathogenic bacteria, a decrease in gut absorption efficiency. PICRUst2 predicts more abundant metabolic pathways related to gut function during high‐density stress, possibly linked to Roseburia. SourceTracker Analysis indicated that water bacteria have a greater impact on Chinese alligator gut bacteria than sediment, and density stress significantly affects the contribution of environmental microorganisms to the gut microbes of Chinese alligator. BugBase analysis identified water body microbes as the main source of “potentially pathogenic” phenotypes in the gut microbiota. RDA analysis found dissolved oxygen (DO) in water to be the most significant factor influencing water microorganisms, positively correlated with certain pathogenic strains. These findings enhance our understanding of the significance of microbial communities in the gut and surrounding aquatic environment of the Chinese alligator. Furthermore, they provide theoretical support for environmental regulation, disease control, and healthy breeding.

Abstract Early diagnosis of hepatocellular carcinoma (HCC) lacks highly sensitive and specific protein biomarkers. Here, we describe a staged mass spectrometry (MS)-based discovery-verification-validation proteomics workflow to explore serum proteomic biomarkers for HCC early diagnosis in 1002 individuals. Machine learning model determined as P4 panel (HABP2, CD163, AFP and PIVKA-II) clearly distinguish HCC from liver cirrhosis (LC, AUC 0.979, sensitivity 0.925, specificity 0.915) and healthy individuals (HC, AUC 0.992, sensitivity 0.975, specificity 1.000) in an independent validation cohort, outperforming existing clinical prediction strategies. Furthermore, the P4 panel can accurately predict LC to HCC conversion (AUC 0.890, sensitivity 0.909, specificity 0.877) with predicting HCC at a median of 11.4 months prior to imaging in prospective external validation cohorts (No.: Keshen 2018_005_02 and NCT03588442). These results suggest that proteomics-driven serum biomarker discovery provides a valuable reference for the liquid biopsy, and has great potential to improve early diagnosis of HCC.

Hepatocellular carcinoma (HCC) is a common malignancy with poor prognosis. In recent years, immune checkpoint inhibitors (ICIs) have enabled breakthroughs in the clinical treatment of patients with HCC, but the overall response rate to ICIs in HCC patients is still low, and no validated biomarker is available to guide clinical decision making. Here, we demonstrated that the long non-coding RNA Lnc-CCNH-8 is highly expressed in HCC and correlates with poor prognosis. Functionally, elevated Lnc-CCNH-8 inactivated co-cultured T cells in vitro and compromised antitumor immunity in an immunocompetent mouse model. Mechanistically, up-regulated Lnc-CCNH-8 can sponge microRNA (miR)-217 to regulate the expression of PD-L1. In addition, Lnc-CCNH-8 can also stabilize PD-L1 through miR-3173/PKP3 axis. Furthermore, mice bearing tumors with high Lnc-CCNH-8 expression had significant therapeutic sensitivity to anti-PD-L1 monoclonal antibody treatment. More important, HCC patients with high levels of plasma exosomal Lnc-CCNH-8 had a better therapeutic response to ICIs. Taken together, our results reveal the function of Lnc-CCNH-8 in inducing immune escape from CD8+ T-cell-mediated killing by up-regulating PD-L1 in a miR-217/miR-3173-dependent manner, which also reveals a novel mechanism of PD-L1 regulation in HCC, and exosomal Lnc-CCNH-8 can serve as a predictive marker for immunotherapy response in HCC.

BackgroundTuberculosis (TB) is a significant public health concern, particularly in China. Long noncoding RNAs (lncRNAs) can provide abundant pathological information regarding etiology and could include candidate biomarkers for diagnosis of TB. However, data regarding lncRNA expression profiles and specific lncRNAs associated with TB are limited.MethodsWe performed ceRNA-microarray analysis to determine the expression profile of lncRNAs in peripheral blood mononuclear cells (PBMCs). Weighted gene co-expression network analysis (WGCNA) was then conducted to identify the critical module and genes associated with TB. Other bioinformatics analyses, including Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and co-expression networks, were conducted to explore the function of the critical module. Finally, real-time quantitative polymerase chain reaction (qPCR) was used to validate the candidate biomarkers, and receiver operating characteristic analysis was used to assess the diagnostic performance of the candidate biomarkers.ResultsBased on 8 TB patients and 9 healthy controls (HCs), a total of 1,372 differentially expressed lncRNAs were identified, including 738 upregulated lncRNAs and 634 downregulated lncRNAs. Among all lncRNAs and mRNAs in the microarray, the top 25% lncRNAs (3729) and top 25% mRNAs (2824), which exhibited higher median expression values, were incorporated into the WGCNA. The analysis generated 16 co-expression modules, among which the blue module was highly correlated with TB. GO and KEGG analyses showed that the blue module was significantly enriched in infection and immunity. Subsequently, considering module membership values (>0.85), gene significance values (>0.90) and fold-change value (>2 or

Summary: Hypoxic microenvironment is clinically associated with metastasis and poor prognosis of numerous cancers. The mechanisms by which intratumoral hypoxia regulates metastasis are not fully understood. Our study identifies a downregulation of Lnc-CSMD1-7 in hepatocellular carcinoma (HCC) and correlated with poor prognosis of HCC patients. Lnc-CSMD1-7 negatively regulated HCC cell migration and invasion in vitro and suppressed lung metastasis in vivo. Mechanistically, Lnc-CSMD1-7 directly binds to RBFOX2, thereby affecting RBFOX2-regulated alternative splicing in epithelial and mesenchymal-specific events. More importantly, hypoxic microenvironment and m6A methylation mediate the downregulation of Lnc-CSMD1-7 expression. Specifically, hypoxia transcriptionally upregulates the expression of the m6A methyltransferase METTL16 via HIF-1α, and METTL16 directly binds to Lnc-CSMD1-7 and downregulates the RNA stability of Lnc-CSMD1-7 via m6A methylation, ultimately promoting HCC metastasis. Our findings highlight the regulatory function of the METTL16/Lnc-CSMD1-7/RBFOX2 axis in modulating hypoxia-induced HCC progression, which may provide potential prognostic and therapeutic targets for HCC treatment.

Abstract The N6-methyladenosine (m6A) RNA methyltransferase METTL16 is an emerging player in RNA modification landscape and responsible for the deposition of m6A in a few transcripts. AURKA (aurora kinase A) has been confirmed as an oncogene in cancer development including hepatocellular carcinoma (HCC). Nevertheless, it remains unclear whether METTL16 mediated m6A modification of lncRNAs can regulate AURKA activation in cancer progression. Here we aimed to investigate the functional links between lncRNAs and the m6A modification in AURKA signaling and HCC progression. Here we show that LncRNA TIALD (transcript that induced AURKA Lysosomal degradation) was down-regulated in HCC tissues by METTL16 mediated m6A methylation to facilitate its RNA degradation, and correlates with poor prognosis. Functional assays reveal that TIALD inhibits HCC metastasis both in vitro and in vivo. Mechanistically, TIALD directly interacts with AURKA and facilitate its degradation through the lysosomal pathway to inhibited EMT and metastasis of HCC. AURKA’s specific inhibitor alisertib exerts effective therapeutic effect on liver cancer with low TIALD expression, which might provide a new insight into HCC therapy. Our study uncovers a negative functional loop of METTL16-TIALD-AURKA axis, and identifies a new mechanism for METTL16 mediated m6A-induced decay of TIALD on AURKA signaling in HCC progression, which may provide potential prognostic and therapeutic targets for HCC.

Two unreported heteropolysaccharides, denoted as YCJP–1 and YCJP–2, were isolated from the herbs of Chloranthus japonicus. YCJP–1 was a heteropolysaccharide composed of glucose, galactose, arabinose, mannose, rhamnose, and a minor proportion of uronic acids, with the molecular weight mainly distributed in the 74,475–228,443 Da range. YCJP–2 was mainly composed of glucose, mannose, and galactose, with the molecular weights ranging from 848 to 5810 Da. To further evaluate the anti-gastric cancer effects of C. japonicus, the inhibitory effects of the crude polysaccharide (YCJP) and the purified polysaccharides (YCJP–1 and YCJP–2) were determined using a CCK-8 assay and colon-forming assay on MGC-803 and AGS gastric cancer cell lines. Our results showed that YCJP, YCJP–1, and YCJP–2 possess prominent inhibitory effects on the proliferation of MGC-803 and AGS cells, and the AGS cell was more sensitive to YCJP, YCJP–1, and YCJP–2. Moreover, YCJP–2 demonstrated superior anti-gastric cancer effects compared to YCJP–1. This could potentially be attributed to YCJP–2’s higher glucose content and narrower molecular weight distribution.

Objective: This study aimed to establish and validate a dynamic online nomograph for predicting the risk of frailty in older patients hospitalized with heart failure in China. Methods: A total of 451 older adults with heart failure hospitalized were selected between December 2021 and November 2022 at the Department of Cardiovascular Medicine in a Class A tertiary hospital in Shandong, China. The data of patients were obtained by using Barthel Index, instrumental activity of daily living scale, mini nutrition assessment-short form, Pittsburgh sleep quality index scale, Morse fall risk assessment scale and general information scale. The brain natriuretic peptide and echocardiographic indexes of patients were collected by electronic medical records. All participants were randomly divided into the training set (n = 319) and the validation set (n = 132) at the ratio of 7:3. The training set is used for model construction, and the validation set is used for internal validation. Using the Least Absolute Shrinkage and Selection Operator (LASSO) regression method to filter modeling variables, while the multivariable logistic regression was used to establish the nomogram based on the screened optimal variables. The performance of the model was evaluated by the area under the curve (AUC) of the receiver operator characteristic (ROC) curve, Hosmer-Lemeshow test, calibration plot, and decision curve analysis (DCA). Results: The prevalence of frailty in 451 patients was 50.6%, 51.4%, and 48.5% in the training and validation sets, respectively. Drinking, grip strength, New York Heart Association (NYHA) class, multimorbidity, hospitalization history of heart failure, Barthel Index, the instrumental activities of daily living, nutritional status, sleep, fall, and left atrial end-diastolic diameter were used for LASSO regression analysis as the significant predictors of frailty. According to internal validation, the AUC of the ROC curve for the nomogram was 0.920, with a sensitivity of 86.8% and specificity of 84.4%. Moreover, in the validation set, the P-values of the H-L test were 0.742, and the calibration curve had good concordance between the estimated frailty risk and actual observation, indicating the model was well-calibrated. The DCA results confirmed that the nomogram had a well-performance in clinical suitability. Conclusions: An online dynamic nomogram predicting frailty for older patients hospitalized for heart failure in China was well-established and identified in this study. This model benefits medical professionals in identifying high-risk frailty in older hospitalized patients with heart failure, which could reduce the medical and disease burden of heart failure to a certain extent. However, further verification is needed in the future.

Specific detection of cellular superoxide is challenging. Here, the authors designed 1,2,4,5-tetrazine based fluorogenic probes for specific and sensitive imaging of superoxide, and applied them in high throughput screening of modulators of oxidative stress.

Abstract Doxorubicin‐induced cardiomyopathy (DIC) brings tough clinical challenges as well as continued demand in developing agents for adjuvant cardioprotective therapies. Here, a zebrafish phenotypic screening with deep‐learning assisted multiplex cardiac functional analysis using motion videos of larval hearts is established. Through training the model on a dataset of 2125 labeled ventricular images, ZVSegNet and HRNet exhibit superior performance over previous methods. As a result of high‐content phenotypic screening, cyanidin chloride (CyCl) is identified as a potent suppressor of DIC. CyCl effectively rescues cardiac cell death and improves heart function in both in vitro and in vivo models of Doxorubicin (Dox) exposure. CyCl shows strong inhibitory effects on lipid peroxidation and mitochondrial damage and prevents ferroptosis and apoptosis‐related cell death. Molecular docking and thermal shift assay further suggest a direct binding between CyCl and Keap1, which may compete for the Keap1‐Nrf2 interaction, promote nuclear accumulation of Nrf2, and subsequentially transactivate Gpx4 and other antioxidant factors. Site‐specific mutation of R415A in Keap1 significantly attenuates the protective effects of CyCl against Dox‐induced cardiotoxicity. Taken together, the capability of deep‐learning‐assisted phenotypic screening in identifying promising lead compounds against DIC is exhibited, and new perspectives into drug discovery in the era of artificial intelligence are provided.

Xuanfeibaidu Formula (XFBD) is a Chinese medicine used in the clinical treatment of coronavirus disease 2019 (COVID-19) patients. Although XFBD has exhibited significant therapeutic efficacy in clinical practice, its underlying pharmacological mechanism remains unclear. Here, we combine a comprehensive research approach that includes network pharmacology, transcriptomics, and bioassays in multiple model systems to investigate the pharmacological mechanism of XFBD and its bioactive substances. High-resolution mass spectrometry was combined with molecular networking to profile the major active substances in XFBD. A total of 104 compounds were identified or tentatively characterized, including flavonoids, terpenes, carboxylic acids, and other types of constituents. Based on the chemical composition of XFBD, a network pharmacology-based analysis identified inflammation-related pathways as primary targets. Thus, we examined the anti-inflammation activity of XFBD in a lipopolysaccharide-induced acute inflammation mice model. XFBD significantly alleviated pulmonary inflammation and decreased the level of serum proinflammatory cytokines. Transcriptomic profiling suggested that genes related to macrophage function were differently expressed after XFBD treatment. Consequently, the effects of XFBD on macrophage activation and mobilization were investigated in a macrophage cell line and a zebrafish wounding model. XFBD exerts strong inhibitory effects on both macrophage activation and migration. Moreover, through multimodal screening, we further identified the major components and compounds from the different herbs of XFBD that mediate its anti-inflammation function. Active components from XFBD, including Polygoni cuspidati Rhizoma, Phragmitis Rhizoma, and Citri grandis Exocarpium rubrum, were then found to strongly downregulate macrophage activation, and polydatin, isoliquiritin, and acteoside were identified as active compounds. Components of Artemisiae annuae Herba and Ephedrae Herba were found to substantially inhibit endogenous macrophage migration, while the presence of ephedrine, atractylenolide I, and kaempferol was attributed to these effects. In summary, our study explores the pharmacological mechanism and effective components of XFBD in inflammation regulation via multimodal approaches, and thereby provides a biological illustration of the clinical efficacy of XFBD.

The reusable launch vehicle (RLV) presents a new avenue for reducing cost of space transportation. The landing mechanism, which provides landing support and impact absorption, is a vital component of the RLV at final stage of recovery. This study proposes a novel legged deployable landing mechanism (LDLM) for RLV. The Watt-II six-bar mechanism is adopted to obtain the preferred configuration via the application of the linkage variation approach. To endow the proposed LDLM with advantages of large landing support region, lightweight, and reasonable linkage internal forces, a multi-objective optimization paradigm is developed. Furthermore, the optimal scale parameters for guiding the LDLM prototype design is obtained numerically using the non-dominated sorting genetic algorithm-II (NSGA-II) evolutionary algorithm. A fully-functional scaled RLV prototype is developed by integrating the gravity-governed deploying scheme to facilitate unfolding action to avoid full-range actuation, a dual-backup locking mechanism to enhance reliability of structure stiffening as fully deployed, and a shock absorber (SA) with multistage honeycomb to offer reliable shock absorbing performance. The experimental results demonstrate that the proposed LDLM is capable of providing rapid and smooth deployment (duration less than 1.5 s) with mild posture disturbance to the cabin (yaw and pitch fluctuations less than 6°). In addition, it provides satisfactory impact attenuation (acceleration peak less than 10g (g is the gravitational acceleration)) in the 0.2 m freefall test, which makes the proposed LDLM a potential alternative for developing future RLV archetype.

Prevention is of paramount importance in tunnel engineering, especially in operation tunnel. In this study, the deformation data of Suzhou Metro Line 1 are used to evaluate the health of shield tunnel during operation. Firstly, the relationship between effective ratio of bending rigidity and tunnel deformation is analyzed, the results show that the effective ratio of bending rigidity has a negative power relationship with the tunnel deformation, and the conversion from deformation data to effective ratio of bending rigidity is realized and the corresponding risk classification criterion are established. Secondly, Grey Relational Analysis and Entropy Weight Method are used to deal with the deformation data, which overcomes the problem that data selection is not representative. Finally, the optimum effective ratio of bending rigidity is obtained successfully to complete the risk assessment of operation tunnel, and the assessment result is highly consistent with actual project. In addition, the corresponding application named Operation Tunnel Deformation Risk Assessment System is developed by using computer technology, which saves time for assessment and increases flexibility. The risk assessment method passes validation in the case tunnel, which can provide a reference for the disaster prevention in operation tunnel.

Water inrush is one of the major disasters during tunnel construction. Due to its characteristics of great harm and difficult prediction, it has always been the focus of research. In order to reveal the mechanism of fault water inrush, a laboratory experiment is adopted to simulate tunnel excavation. The results show, firstly, the pore water pressure and soil pressure of model are unchanged before the fault is exposed; after the fault is exposed, the pore water pressure and soil pressure of vault decrease first, followed by the arch and haunch, and the decline of arch and vault is greater than that of haunch. Secondly, excavation has the greatest impact on the displacement of rock mass directly above the tunnel axis, and the farther away from the axis, the smaller the impact. Thirdly, the seepage channel around vault begins to expand, and clear water begins to seep out after the fault exposure. As the sediment in the crack is carried out by water flow, the clear water gradually becomes turbid, seepage channel changes from pore flow to fissure flow and then to pipe flow. Finally, Comsol is used to analyze the fault water inrush mechanism from the perspective of permeability change, and the correctness of model test is verified by comparing with engineering practice.

The valorization of the black liquor produced during the chemical pulping of wheat straw is the key to the sustainable use of this abundant agricultural waste. However, the silica problem has hampered the recovery process. Herein, nanoprecipitation technology was used to produce lignin nanoparticles (LNPs) from wheat straw black liquor using γ-valerolactone (GVL) as a solvent and water as an anti-solvent. The results showed that a uniform, well-dispersed, and stable LNP was produced. The particle size and Zeta potential of 161 nm and −24 mV of the LNP suspension were obtained at a GVL concentration of 87%. The chemical structure and bonding of the lignin were adequately preserved after nanoprecipitation based on two-dimensional heteronuclear single quantum coherence nuclear magnetic resonance (2D-HSQC NMR) spectroscopy, Fourier transform infrared (FTIR) analysis, and thermal stability was improved based on thermogravimetric analysis. In addition, the abundant phenolic hydroxyl groups of LNP quantified by 31P-NMR analysis are beneficial for chemical cross-linking and modification. This work not only achieved the valorization of wheat straw black liquor but also opened up a new avenue for advanced nanomaterials.

Prostatitis, a prevalent urinary tract disorder in males, has a complex etiology that leads to severe clinical discomfort. Pule’an Tablets, a classic single-component formulation primarily based on rapeseed pollen, have been clinically proven to have a beneficial therapeutic effect on both prostatitis and benign prostatic hyperplasia. However, there is currently a lack of research on the chemical composition and mechanisms of action of Pule’an Tablets in treating prostatitis. In this study, using liquid chromatography–mass spectrometry (LC-MS), a total of 53 compounds in Pule’an Tablets were identified, including flavonoids, phenylpropionamides, lipids, glucosinolates, and nucleic acids. Subsequently, through a network pharmacology analysis, potential target genes and their mechanisms of action were predicted accordingly. The results suggested that genes such as LPAR5, LPAR6, LPAR4, LPAR3, LPAR2, LPAR1, F2, ENPP2, MMP9, and TNF, along with pathways like prostate cancer, endocrine resistance, bladder cancer, and the IL-17 signaling pathway, may represent potential pathways involved in the therapeutic effects of Pule’an Tablets. This study represents the first systematic investigation into the chemical composition of Pule’an Tablets, shedding light on the potential mechanisms underlying their efficacy in treating prostatitis. These findings could serve as a valuable reference for future pharmacological research on Pule’an Tablets.

Aberrant expression of long non-coding RNAs (lncRNAs) is associated with progression of multiple human cancers including hepatocellular carcinoma (HCC). However, the role of lncRNAs in HCC is not been fully understood. Our study aimed to investigate the biological function and potential molecular mechanism of Lnc-PAL2G4A-4 in HCC. In the current study, we show that Lnc-PLA2G4A-4 was significantly up-regulated in HCC tissues and high Lnc-PLA2G4A-4 expression was remarkably associated with tumor size, microvascular invasion and poor prognosis of HCC patients. Functionally, Lnc-PLA2G4A-4 positively regulated cell proliferation, invasion and migration in vitro, and facilitated lung metastasis of HCC in vivo. Mechanistically, Lnc-PLA2G4A-4 functioned as a competing endogenous RNA (ceRNA) to bind to miR-23b-3p and subsequently facilitate miR-23b-3p's target gene versican (VCAN) expression in HCC cells. Over-expression of miR-23b-3p could reverse Lnc-PLA2G4A-4 induced cell phenotypes in HCC and suppress versican expression of by rescue analysis. Collectively, Lnc-PLA2G4A-4 promotes HCC progression by targeting the miR-23b-3p/versican axis, which may be a potential biomarker and therapeutic target for HCC.

Abstract Immune checkpoint blockade based on antibodies has shown great clinical success in patients, but the transitory working manner leads to restricted therapeutic benefits. Herein, a genetically engineered adenovirus is developed as the vector to deliver CRISPR/Cas9 (sgCas9‐AdV) to achieve permanent PD‐L1 gene editing with efficiency up to 78.7% exemplified in Hepa 1‐6 liver cancer cells. Furthermore, the sgCas9‐AdV is loaded into hydrogel made by silk fiber (SgCas9‐AdV/Gel) for in vivo application. The silk‐gel not only promotes local retention of sgCas9‐AdV in tumor tissue, but also masks them from host immune system, thus ensuring effectively gene transduction over 9 days. Bearing these advantages, the sgCas9‐AdV/Gel inhibits Hepa 1‐6 tumor growth with 100% response rate by single‐dose injection, through efficient PD‐L1 disruption to elicit a T cell‐mediated antitumor response. In addition, the sgCas9‐AdV/Gel is also successfully extended into other refractory tumors. In CT26 colon tumor characterized by poor response to anti‐PD‐L1, sgCas9‐AdV/Gel is demonstrated to competent and superior anti‐PD‐L1 antibody to suppress tumor progression. In highly aggressive orthotopic 4T1 mouse breast tumor, such a therapeutic paradigm significantly inhibits primary tumor growth and induces a durable immune response against tumor relapse/metastasis. Thus, this study provides an attractive and universal strategy for immunotherapy.

Supergene hydrous sulfate minerals form through the oxygenation and weathering of primary sulfides. In the Qinghai–Tibet Plateau region, with an alpine and dry environment, hydrous sulfate minerals oxidized from pyrite-bearing ore bodies provide important clues regarding the mineralization and environment. The Tuolugou sedimentary-exhalative (SEDEX) Co-Au deposit is located in the East Kunlun metallogenic belt of the northern Qinghai–Tibet Plateau in China. In the mining district, pyrite is the prevalent Co-hosting sulfide mineral, and is partially exposed on the surface to weathering and oxidation. Herein, we document the mineral assemblages in the supergene oxidation zone in the Tuolugou deposit, probe the genesis of supergene assemblage, and explore the implications for exploration. Three zones can be recognized in the oxidation zone of the Tuolugou deposit, including the outer zone (natrojarosite), intermediate zone (rozenite and aplowite), and inner zone (roemerite and melanterite). The mechanism of oxidation under aerobic and anaerobic conditions, as well as zoning with different oxidation degrees, are described in detail. Hydrous sulfates such as natrojarosite can be used as possible indicators of the exploration of albitite-related SEDEX deposit in this region.

Cardiovascular disease (CVD) remains the leading cause of death worldwide. Natural compounds extracted from medicinal plants characterized by diverse biological activities and low toxicity or side effects, are increasingly taking center stage in the search for new drugs. Currently, preclinical evaluation of natural products relies mainly on the use of immortalized cell lines of human origin or animal models. Increasing evidence indicates that cardiomyopathy models based on immortalized cell lines do not recapitulate pathogenic phenotypes accurately and a substantial physiological discrepancy between animals and humans casts doubt on the clinical relevance of animal models for these studies. The newly developed human induced pluripotent stem cell (hiPSC) technology in combination with highly-efficient cardiomyocyte differentiation methods provides an ideal tool for modeling human cardiomyopathies in vitro. Screening of drugs, especially screening of natural products, based on these models has been widely used and has shown that evaluation in such models can recapitulate important aspects of the physiological properties of drugs. The purpose of this review is to provide information on the latest developments in this area of research and to help researchers perform screening of natural products using the hiPSC-CM platform.

Fusobacterium nucleatum (F. nucleatum) is enriched in colorectal cancer (CRC) tissues and a high amount of F. nucleatum was associated with an immunosuppressive tumor environment. PD-L1 is an important immune checkpoint expressed on tumor cells and promotes tumor immune escape. Whether PD-L1 is regulated by F. nucleatum is still unclear. We demonstrated that F. nucleatum promoted CRC progression and upregulated PD-L1 protein expression in CRC cell lines. Combined m6A-seq and RNA-seq identified m6A-modified IFIT1 mediating F. nucleatum induced PD-L1 upregulation. IFIT1 mRNA was modified with m6A modifications in 3’UTR and the m6A levels were altered by F. nucleatum treatment. Our results also indicated that IFIT1 served as a potential oncogene in CRC and regulated PD-L1 protein levels through altering PD-L1 ubiquitination. Clinical CRC data confirmed the correlation among F. nucleatum abundance, IFIT1 and PD-L1 expressions. Our work highlighted the function of F. nucleatum in stimulating PD-L1 expression through m6A-modified IFIT1 and provided new aspects for understanding F. nucleatum mediated immune escape.

Abstract Background Clinically, prophylactic anti-recurrence treatments for hepatocellular carcinoma (HCC) patients after radical surgery are extremely limited. Neoantigen based vaccine can generate robust anti-tumor immune response in several solid tumors but whether it could induce anti-tumor immune response in HCC and serve as a safe and effective prophylactic strategy for preventing postoperative HCC recurrence still remain largely unclear. Methods Personalized neoantigen vaccine was designed and immunized for 10 HCC patients with high risk of postoperative recurrence in a prime-boost schedule. The safety and immune response were assessed through adverse events, tissue sequencing, ELISpot, TCR sequencing. The clinical response was evaluated by recurrence-free survival (RFS) and personalized circulating tumor DNA (ctDNA) sequencing. Results In the 10 enrolled patients, no obvious adverse events were observed during neoantigen vaccinations. Until the deadline of clinical trial, 8 of 10 patients were confirmed with clinical relapse by imaging, the other 2 patients remained relapse-free. From receiving first neoantigen vaccination, the median RFS of 10 patients were 7.4 months. Among 7 patients received all planned neoantigen vaccinations, 5 of them demonstrated neoantigen-induced T cell responses and have significantly longer RFS after radical surgery than other 5 patients without responsive neoantigens or only with prime vaccination and propensity scores matching control patients (p = 0.035). Moreover, tracking personalized neoantigen mutations in ctDNA could provide real-time evaluation of clinical response in HCC patients during neoantigen vaccination and follow up. Conclusion Personalized neoantigen vaccine is proved as a safe, feasible and effective strategy for HCC anti-recurrence, and its progression could be sensitively monitored by corresponding neoantigen mutations in ctDNA, and thus provided solid information for individualized medicine in HCC. Trial registration This study was registered at Chinese Clinical Trial Registry; Registration number: ChiCTR1900020990 .

In order to investigate the landing process of a vertical landing reusable vehicle, a dynamic model with a complex nonlinear dissipative element is established based on the discrete impulse step approach, which includes a three-dimensional multi-impact model considering friction and material compliance, and a multistage aluminum honeycomb theoretical model. The normal two-stiffness spring model is adopted in the foot–ground impact model, two motion patterns (stick and slip) are considered on the tangential plane and the structural changes caused by buffering behavior are included, and the energy conversion during the impact follows the law of conservation of energy. The state transition method is used to solve the dynamic stability convergence problem of the vehicle under the coupling effect of impact and buffering deformation in the primary impulse space. Landing experiments on a scaled physical reusable vehicle prototype are conducted to demonstrate that the theoretical results exhibit good agreement with the experimental data.

Rock fractures have a significant impact on the stability of geotechnical engineering, and grouting is currently the most commonly used reinforcement method to address this issue. To ensure the stability of grouted rock mass, it is necessary to study its deformation law and mechanical properties. In this study, theoretical analyses and laboratory experiments were conducted, and the fracture width, Weibull model and effective bearing area were introduced to improve the applicability and accuracy of the original damage constitutive model. Moreover, the constitutive model of grouted rock mass was derived by combining it with the mixing law of composite materials. The main conclusions are summarized as follows: (1) Based on macroscopic damage tensor theory, the fracture width parameter was introduced, which effectively described the variation law of macroscopic damage with fracture width to improve the accuracy of the original damage constitutive model. (2) The effective bearing area was used to optimize the original Weibull model to match the stress-strain curve of the rock mass with fractures. (3) The grouting-reinforced rock mass was considered to be a composite material, the original equivalent elastic modulus model was improved by combining macroscopic damage with the Reuss model, and the constitutive damage model of the grouted rock mass was deduced.

Bimsoils are a loose rock and soil system, and the occurrence of geological hazards is closely related to water. To investigate the permeability and seepage characteristics of bimsoils, factors on permeability are discussed in detail considering cementation state, and variable mass seepage is studied tentatively with self-developed apparatus. Results shown that the order of factors on permeability is rock content > cementation degree > rock size > Talbot index (describing the mass percentage for different particle size of sand), and there are significant differences between factors. Besides, permeability generally increases with the increase of rock content and decreases with the increase of cementing agent content, while increases slightly due to agglomeration effect at the clay content of 8%. It is more obvious for reducing the permeability of higher rock content bimsoils by strong cementing agent, however, it tends to be same eventually with cement content increasing. The seepage of bimsoils is dominated by fine particle losses, and the secondary inrush occurs under the larger particle radius ratio. Moreover, particle losses and the time needed for secondary inrush both increase with the increase of particle radius ratio. The results would provide consults for the preparation of similar materials and the prevention of tunnels and underground engineering disasters.

Ischemic stroke is a leading cause of death worldwide, and it remains an urgent task to develop novel and alternative therapeutic strategies for the disease. We previously reported the positive effects of Guhong injection (GHI), composed of safflower extract and aceglutamide, in promoting functional recovery in ischemic stroke mice. However, the active substances and pharmacological mechanism of GHI is still elusive. Aiming to identify the active anti-stroke components in GHI, here we conducted a multi-phenotypic screening in zebrafish models of phenylhydrazine-induced thrombosis and ponatinib-induced cerebral ischemia. Peripheral and cerebral blood flow was quantified endogenously in erythrocytes fluorescence-labeled thrombosis fish, and baicalein and rutin were identified as major anti-thrombotic substances in GHI. Moreover, using a high-throughput video-tracking system, the effects of locomotion promotion of GHI and its main compounds were analyzed in cerebral ischemia model. Chlorogenic acid and gallic acid showed significant effects in preventing locomotor dyfunctions. Finally, GHI treatment greatly decreased the expression levels of coagulation factors F7 and F2, NF-κB and its mediated proinflammatory cytokines in the fish models. Molecular docking suggested strong affinities between baicalein and F7, and between active substances (baicalein, chlorogenic acid, gallic acid, and rutin) and NF-κB p65. In summary, our findings established a novel drug discovery method based on multi-phenotypic screening of zebrafish, provided endogenous evidences of GHI in preventing thrombus formation and promoting behavioral recovery after cerebral ischemia, and identified baicalein, rutin, chlorogenic acid, and gallic acid as active compounds in the management of ischemic stroke.

MOFs (Metal-Organic Framework), as promising crystalline materials of adsorption and separation, has been the subject of many recent investigations. However, the H2O stability of MOFs and the variation of adsorption selectivity in humid environments largely hinder attempts as excellent adsorbents in numerous scenarios. This study employs hydro-thermal synthesis [Cd0.5(DPETA)0.5]n using 2,3′,5,5′-Diphenyl tetracarboxylic acid (DPETA) and Cd(NO3)2·4H2O as ligands and metal ions, respectively. And it is modified by adding auxiliary ligands 4-4′-bipyridyl (bpy) and 1,2-bis (4-pyridyl) ethylene(bpe) to obtain [Cd1.5bpy2(DPETA)]n and [Cd2bpe2(DPETA)]n.The phase purity of the MOFs is examined using PXRD and FT-IR spectrum. The adsorption capacities of three MOFs are tested separately for water, ethanol and methanol using vapor adsorption. Their adsorption conformations and hydrogen bond lengths are also calculated by the GCMC method. The adsorption selection ratios of methanol and ethanol are deduced in combination with the IAST method under three components of water, methanol and ethanol. The results shows a methanol/ethanol adsorption separation ratio of 45 for [Cd1.5bpy2(DPETA)]n at 297 K, which is consistent with the of GCMC demonstrated. These results suggest that the methanol/ethanol adsorption selectivity ratio can be improved by increasing the adsorption force on methanol through by adding of auxiliary pyridyl ethylene. It can be used for efficient methanol/ethanol separation in humid environments.

Hormonal regulation and symbiotic relationships provide benefits for plants to overcome stress conditions. The aim of this study was to elucidate the effects of arbuscular mycorrhizal fungal (AMF) inoculum, methyl jasmonate (MeJA), and saline-alkali effects on the growth and physiology of tall fescue (Festuca elata “Crossfire II”). Treatments included AMF-inoculation, and non-AMF inoculation, four MeJA application concentrations (0, 50, 100, and 200 mg/L), and two saline-alkali levels (0 and 200 mmol/L). The results showed that AMF inoculation significantly enhanced saline-alkali resistance of the plants, and the beneficial effects were increased by MeJA at a concentration of 50 mg/L (50 MeJA) and decreased by MeJA at a concentration both of 100 (100 MeJA) and 200 mg/L (200 MeJA). AMF inoculation plants when treated with 50 MeJA accumulated significantly more biomass, had greater proline and total phenolic concentration, and lower malondialdehyde (MDA) concentration than plants only treated either with AMF or 50 MeJA. However, no significant differences in growth or physiological characteristics were observed between AMF and non-AMF plants when treated either with 100 or 200 MeJA. All of these results suggest that the interaction between a certain concentration of MeJA and AMF can significantly increase saline-alkali resistance of the tall fescue by regulating the biomass, proline, total phenolic, and MDA. Our findings provide new information on the effect of biological and chemical priming treatments on plant performance under saline-alkali stress.

Experience marketing plays an important role in improving the quality and upgrading tourism services in cultural tourism cities and helps guide the planning and development, commodity design, and business management of cultural tourism products. However, the urgent problems that need to be solved are as follows: How does experiential marketing in cultural tourism cities affect tourists' consumption behavior? How to adjust consumption emotion in tourist experience and revisit intention? Starting from the experience needs of tourists, this study selected Jinan city, represented by “Qilu culture,” as the research object; discussed the relationship between experiential marketing, consumption emotion, and revisit intention; and used a structural equation model to verify the relationship between the three. This study divided the perception of experiential marketing into four dimensions—sensory experience, action experience, emotional experience, and thinking experience, and divided tourists' revisit intention into two dimensions— “revisit” and “recommendation”. Totally, 305 tourists were randomly selected to participate in the questionnaire survey, and they came from 34 provinces in China. The results showed that cultural tourism cities can enhance tourists' positive consumption emotion through experiential marketing over time, and high-quality tourist consumption experience directly motivates tourists to revisit intention and then promotes tourists to go to cultural tourism cities for secondary consumption. These results suggest that cultural tourism cities should start from Maslow's hierarchy of needs theory, pay attention to the needs of tourists at different levels, and adopt effective experiential marketing strategies from tourism experience to improve the quality of tourists' travel experience and promote tourists' revisit intention.

Abstract Background Inflammatory bowel diseases (IBD) are chronic relapsing intestinal inflammations with increasing global incidence, and new drug development remains in urgent demand for IBD management. To identify effective traditional Chinese medicine (TCM) formulae and compounds in IBD treatment, we innovatively combined the techniques of knowledge mining, high-content screening and high-resolution mass spectrometry, to conduct a systematic screening in Zhongjing formulae, which is a large collection of TCM prescriptions with most abundant clinical evidences. Methods Using Word2vec-based text learning, the correlations between 248 Zhongjing formulae and IBD typical symptoms were analyzed. Next, from the top three formulae with predicted relationship with IBD, TCM fractions were prepared and screened on a transgenic zebrafish IBD model for their therapeutic effects. Subsequently, the chemical compositions of the fraction hits were analyzed by mass spectrometry, and the major compounds were further studied for their anti-IBD effects and potential mechanisms. Results Through knowledge mining, Peach Blossom Decoction, Pulsatilla Decoction, and Gegen Qinlian Decoction were predicted to be the three Zhongjing formulae mostly related to symptoms typical of IBD. Seventy-four fractions were prepared from the three formulae and screened in TNBS-induced zebrafish IBD model by high-content analysis, with the inhibition on the intestinal neutrophil accumulation and ROS level quantified as the screening criteria. Six herbal fractions showed significant effects on both pathological processes, which were subsequently analyzed by mass spectrometry to determine their chemical composition. Based on the major compounds identified by mass spectrometry, a second-round screen was conducted and six compounds (palmatine, daidzin, oroxyloside, chlorogenic acid, baicalin, aesculin) showed strong inhibitory effects on the intestinal inflammation phenotypes. The expression of multiple inflammatory factors, including il1β, clcx8a, mmp and tnfα, were increased in TNBS-treated fish, which were variously inhibited by the compounds, with aesculin showing the most potent effects. Moreover, aesculin and daidzin also upregulated e-cadherin’s expression. Conclusion Taken together, we demonstrated the regulatory effects of several TCM formulae and their active compounds in the treatment of IBD, through a highly efficient research strategy, which can be applied in the discovery of effective TCM formulae and components in other diseases. Graphic abstract

Cardiac fibrosis occurs in most cardiac diseases, which reduces cardiac muscle compliance, impairs both systolic and diastolic heart function and, ultimately, leads to heart failure. Long noncoding RNAs (lncRNAs) have recently emerged as important regulators of a variety of biological processes; however, little is known about the expression and function of lncRNAs in cardiac fibrosis. Using unbiased transcriptome profiling in a mouse model of myocardial infarction (MI), we identified a cardiac fibroblast-enriched lncRNA (AK048087) named cardiac fibroblast-associated transcript (Cfast), which is significantly elevated after MI. Silencing Cfast expression by small interfering RNAs (siRNAs) or lentiviral short hairpin RNAs (shRNAs) resulted in suppression of fibrosis-related gene expression and transdifferentiation of myofibroblasts into cardiac fibroblasts. Depletion of Cfast by lentiviral shRNAs in mouse hearts significantly attenuated cardiac fibrosis induced by MI or isoproterenol-infusion. Importantly, inhibition of Cfast ameliorated cardiac function following cardiac injury. RNA pull-down followed by mass spectrometry analyses identified COTL1 (coactosin-like 1) as one of the Cfast interacting proteins. Mechanistically, Cfast competitively inhibits the COTL1 interaction with TRAP1 (transforming growth factor-β receptor-associated protein 1), which enhances TGF-β signaling by augmenting SMAD2/SMAD4 complex formation. Therefore, our study identifies Cfast as a novel cardiac fibroblast-enriched lncRNA that regulates cardiac fibroblast activation in response to pathophysiological stress. Cfast could serve as a potential therapeutic target for the prevention of cardiac fibrosis and cardiac diseases.

Epichloë endophytes and arbuscular mycorrhizal fungi (AMFs) are two important symbiotic microorganisms of tall fescue (Lolium arundinaceum). Our research explores the combined effects of endophytes and AMF on saline-alkali stress. The finding revealed that a significant interaction between Epichloë endophytes and AMF, and saline-alkali stress occurred in the growth and physiological parameters of tall fescue. Endophyte infection significantly enhanced tall fescue resistance to saline-alkali stress by increasing shoot and root biomass and nutrient uptake (organic carbon, total nitrogen, and total phosphorus concentration), and accumulating K+ while decreasing Na+ concentration. Furthermore, the beneficial effect of endophytes was enhanced by the beneficial AMF, Claroideoglomus etunicatum (CE) but was reduced by the detrimental AMF, Funneliformis mosseae (FM). Our findings highlight the importance of interactions among multiple microorganisms for plant performance under saline-alkali stress.

The instability of weak surrounding rock around shallow buried tunnels induced by rainfall is a challenge for tunnel engineering and threatens construction safety. To reveal the influence of rainfall on the rock surrounding a tunnel, the results of experiments on the failure of surrounding rock under different rainfall intensities and durations using a self-developed test system are presented. First, the stress and seepage behaviors of the surrounding rock under rainfall were analysed, and the results showed that the stress increased while the pore water pressure decreased as the rainfall intensity decreased. It was more difficult to maintain vault collapse as rainfall intensity increased, and the particle erosion in the model intensified as the rainfall duration increased. The change in pore water pressure was greater than the change in stress, but the stress and pore water pressures influenced each other during rainfall. The influence of rainfall on the rock at the top of the tunnel was greater than that at the two sides of the tunnel because the seepage channels at the top of the tunnel were more developed and collapsed more easily due to smaller stresses. According to the phenomena of the surrounding rock observed during the test, the evolution of progressive failure under rainfall was roughly divided into eight stages: stability, water drop, continuous water flow, partial collapse, mud and water mixture, vault collapse, throughgoing collapse, and massive water and mud gushing. Furthermore, the final failure pattern of the surrounding rock consists of an excavation disturbance zone, vault damage zone and collapse failure zone. This research helps to reveal the progressive failure of surrounding rock around tunnels under rainfall conditions and can be used as a reference for designing disaster prevention strategies in practical engineering.

Abstract Growth differentiation factor 11 (GDF11) has been shown to promote stem cell activity, but little is known about the effect of GDF11 on viability and therapeutic efficacy of cardiac mesenchymal stem cells (MSCs) for cardiac injury. To understand the roles of GDF11 in MSCs, mouse heart‐derived MSCs were transduced with lentiviral vector carrying genes for both GDF11 and green fluorescent protein (GFP) (MSCsLV‐GDF11) or cultured with recombinant GDF11 (MSCsrGDF11). Either MSCsrGDF11 or MSCs LV‐GDF11 displayed less cell apoptosis and better paracrine function, as well as preserved mitochondrial morphology and function under hypoxic condition as compared with control MSCs. GDF11 enhanced phosphorylation of Smad2/3, which upregulated expression of YME1L, a mitochondria protease that balances OPA1 processing. Inhibitors of TGF‐β receptor (SB431542) or Smad2/3 (SIS3) attenuated the effects of GDF11 on cell viability, mitochondrial function, and expression of YME1L. Transplantation of MSCsGDF11 into infarct heart resulted in improved cell survival and retention, leading to more angiogenesis, smaller scar size, and better cardiac function in comparison with control MSCs. GDF11 enhanced viability and therapeutic efficiency of MSCs by promoting mitochondrial fusion through TGF‐β receptor/Smad2/3/YME1L‐OPA1 signaling pathway. This novel role of GDF11 may be used for a new approach of stem cell therapy for myocardial infarction.

It is critical to develop sustainable, effective, and innovative technologies for society, particularly for processing of biomass, so that the green/ sustainable advantages can be extended to the final products. This review examined two-step biological-mechanical defiberization of lignocellulosic biomass to produce fibers. Two biological pretreatment methods of fungi and enzymes were mainly introduced, with particular focus on the energy consumption. Potential application methods, advantages, disadvantages, process economics, and future prospects of two biological pretreatment methods were considered to derive a complete road map for the proposed process. With the help of biological pretreatment, the mechanical pulping production could not only improve the paper strength, but also decrease energy consumption at about 40%. This process fits well with the green/sustainable strategy to produce lignocellulosic fibers with reasonable quality while having minimal environmental impact.

Water inrush seriously restricts the safe construction of a karst tunnel. Once it occurs, it will cause serious consequences such as economic loss and casualties. Due to the complexity of an underground environment, it is difficult to calculate the probability of karst tunnel water inrush. Therefore, it is of great engineering significance to establish an effective risk assessment model. Based on the Bayesian theory, interpretation structure model, and generative adversarial network, a Bayesian network risk assessment model is established. The results show that firstly, twelve indexes selected can not only characterize the karst tunnel water inrush but also are easy to be counted, which effectively improves the accuracy of the Bayesian risk assessment model. Secondly, the Bayesian network risk assessment model overcomes the shortcomings of other risk assessment models that rely too much on geological data and improves the accuracy through massive data training. Thirdly, the corresponding noninrush samples are generated by the generative adversarial network and analytic hierarchy process, which effectively solve the problem of an unbalanced database. Finally, the Bayesian network risk assessment model is applied to the DK490+373 section of the Shangshan Tunnel. The assessment model is operable, effective, and practical, and it is also suitable for the situation of incomplete index statistics.

Abstract Cardiac hypertrophy is a pivotal pathophysiological step of various cardiovascular diseases, which eventually leads to heart failure and death. Extracts of Rhodiola species (Ext.R), a class of commonly used medicinal herbs in Europe and East Asia, can attenuate cardiac hypertrophy both in vitro and in vivo. Serum/glucocorticoid regulated kinase 1 (SGK1) is identified as a potential target of Ext. R. By mass spectrometry‐based kinase inhibitory assay, herbacetin (HBT) from Ext.R is identified as a novel SGK1 inhibitor with IC50 of 752 nmol. Thermal shift assay, KINOMEscan in vitro assay combined with molecular docking proves a direct binding between HBT and SGK1. Site‐specific mutation of Asp177 in SGK1 completely ablates the inhibitory activity of HBT. The presence of OH groups at the C‐3, C‐8, C‐4’ positions of flavonoids is suggested to be favorable for the inhibition of SGK1 activity. Finally, HBT significantly suppresses cardiomyocyte hypertrophy in vitro and in vivo, reduces reactive oxygen species (ROS) synthesis and calcium accumulation. HBT decreases phosphorylation of SGK1 and regulates its downstream forkhead box protein O1 (FoxO1) signaling pathway. Taken together, the findings suggest that a panel of flavonoids structurally related to HBT may be novel leads for developing new therapeutics against cardiac hypertrophy.

Tunnel excavation has always been an important reason for the stability failure of the tunnel-slope system at the portal section. In case of rainfall, it is likely to cause serious disasters such as tunnel vault collapse, water inrush from the tunnel face, and slope slip. In this study, the Sunjiaya tunnel of the Daping slope group was taken as the engineering background, and the tunnel model experiment system under the condition of rainfall and groundwater seepage was designed independently to explore the failure laws of slope instability induced by tunnel excavation under the condition of rainfall. Meanwhile, a fiber grating monitoring system was also used to measure the displacement, water content, earth pressure, and seepage pressure at different positions of the tunnel-slope system in the process of tunnel excavation under the condition of rainfall. The results show that the slope instability caused by rainfall infiltration is gradual. At the beginning of rainfall, the rainfall infiltration has little effect on the stability of the tunnel-slope system and then gradually increases with the continuous rainfall. Finally, the slope surface is uneven, and the phenomenon of gully and surface flow is serious. The foot of slope moves back continuously, resulting in overall collapse. Moreover, during the process of tunnel excavation, the cracks on the tunnel vault of the unburied tunnel lining develop in quadratic along the tunnel excavation direction, and the closer to the excavation section, the larger the collapse range. Finally, there is an integral collapse of the vault of tunnel excavation section. In addition, variation laws of parameters in the tunnel-slope system also provide an important explanation for the hysteresis of the stability failure of the tunnel-slope system. The results have important guiding significance for the stability of the tunnel-slope system during construction.

Abstract Background Age and other cardiovascular risk factors have been reported to impair the activities of mesenchymal stem cells (MSCs), which will affect the efficacy of stem cell transplantation. The objective of the study is to investigate whether exosomes derived from human umbilical cord MSCs (UMSCs) could enhance the activities of bone marrow MSCs from old person (OMSCs), and improve their capacity for cardiac repair. Methods Exosomes extracted from conditioned medium of UMSCs were used to treat OMSCs to generate OMSCsExo. The key molecule in the exosomes that have potential to rejuvenate aged MSCs were screened, and the role of OMSC was tested in the mouse model of mycardial infarction (MI). Results We found the activity of senescence-associated β-galactosidase and the expression of aging-related factors such as p53, p21, and p16 were significantly higher in OMSCs than those in UMSCs. After treatment with UMSC exosomes, these senescence phenotypes of OMSCs were remarkably reduced. The proliferation, migration, differentiation, and anti-apoptotic and paracrine effect were increased in OMSCsExo. In vivo study, mice with cardiac infarction had significantly better cardiac function, less fibrosis, and more angiogenesis after they were injected with OMSCsExo as compared with those with OMSC. There was more miR-136 expression in UMSCs and OMSCsExo than in OMSCs. Upregulation of miR-136 by transfection of miR-136 mimic into OMSCs significantly attenuated the apoptosis and senescence of OMSCs. Apoptotic peptidase activating factor (Apaf1) was found to be the downstream gene that is negatively regulated by miR-136 via directly targeting at its 3′UTR. Conclusion Our data suggest that exosomes from young MSCs can improve activities of aged MSCs and enhance their function for myocardial repair by transferring exosomal miR-136 and downregulating Apaf1.

Abstract Background Although it has been preclinically suggested that adipose tissue-derived mesenchymal stem cell (ADSC)-based therapy could effectively treat chronic liver diseases, the hepatic engraftment of ADSCs is still extremely low, which severely limits their long-term efficacy for chronic liver diseases. This study was designed to investigate the impact of antioxidant preconditioning on hepatic engraftment efficiency and therapeutic outcomes of ADSC transplantation in liver fibrotic mice. Methods Liver fibrosis model was established by using intraperitoneal injection of carbon tetrachloride (CCl4) in the male C57BL/6 mice. Subsequently, the ADSCs with or without antioxidant pretreatment (including melatonin and reduced glutathione (GSH)) were administrated into fibrotic mice via tail vein injection. Afterwards, the ADSC transplantation efficiency was analyzed by ex vivo imaging, and the liver functions were assessed by biochemical analysis and histopathological examination, respectively. Additionally, a typical hydrogen peroxide (H2O2)-induced cell injury model was applied to mimic the cell oxidative injury to further investigate the protective effects of antioxidant preconditioning on cell migration, proliferation, and apoptosis of ADSCs. Results Our data showed that antioxidant preconditioning could enhance the therapeutic effects of ADSCs on liver function recovery by reducing the level of AST, ALT, and TBIL, as well as the content of hepatic hydroxyproline and fibrotic area in liver tissues. Particularly, we also found that antioxidant preconditioning could enhance hepatic engraftment efficiency of ADSCs in liver fibrosis model through inhibiting oxidative injury. Conclusions Antioxidant preconditioning could effectively improve therapeutic effects of ADSC transplantation for liver fibrosis through enhancing intrahepatic engraftment efficiency by reducing oxidative injuries. These findings might provide a practical strategy for enhancing ADSC transplantation and therapeutic efficiency.

To study the strength properties and evolution laws of cracked sandstone samples in re-loading tests, strength and damage evolution properties of intact sandstone samples were first analyzed through the triaxial compression tests carried on TAW-2000 microcomputer control electro-hydraulic servo rock triaxial test system. Damage evolution models were established based on dilatancy properties realizing the real-time and quantitative evaluation of samples damage state in loading process. On this basis, samples with different damage were obtained by pre-peak, peak point, post-peak and residual strength stage unloading tests in the loading process of intact samples. The characteristics of the stress-strain curves and strength evolution laws were studied through the re-loading tests of samples with different damage under different stress states. The experimental results showed that the slope of stress-strain curves, peak strength and residual strength of cracked samples increased linearly with confining pressure and decreased linearly with damage. The equivalent cohesion decreased with damage in the exponential decay curves. The mechanics properties of samples transformed from strain softening to strain hardening with damage. Keywords: Rock mechanics, Damage, Re-loading, Strength characteristics, Strain hardening

Induced by tunnel excavation, the particles constantly shift in broken porous rock of faults until failure occurs, which provides channels for water inrush. Therefore, it is essential to investigate the particle migration of broken porous rock. Thus, a visual experimental system of particle migration was developed independently. Further study on the mass loss evolution of broken porous rock induced by seepage failure was performed using physical model tests, and the effect of the grain gradation of broken porous rock was also analyzed. According to the composition and lost characteristics of the samples, the samples were divided into dense-suspension structure and void-skeleton structure. The results indicated that the mass loss of the particles decreased with the increase in the gradation coefficient when the sample had a dense-suspension structure, while there was no significant change in the lost quality with the increase of gradation coefficient when the sample had a void-skeleton structure. Moreover, the time required for water inrush decreased with the increase in the gradation coefficient, which is because the higher the content of the fine particles is, the lower the permeability of the sample. Sample settlement is positively correlated with the lost quality of particles.

In order to evaluate the risk level of water inrush caused by karst cave accurately and effectively, a novel quantitative assessment model was established based on the reliability theory and genetic algorithm-back propagation (GA-BP) neural network. First, the reliability theory and the calculation formula of the minimum safe thickness were used to calculate the water inrush probability. Second, the GA-BP neural network was applied to predict the disaster consequence caused by water inrush. Six factors, including water pressure, hydraulic supply, type of gap, filling situation, degree of water enrichment and reserves of cave, were selected as the input layer of the neural network. The disaster consequence was selected as the output layer. Similar projects were screened to obtain statistical information for indices, and the Normand function in MATLAB was used to transform the information into quantitative data. Finally, the model was established by combining the probability and disaster consequence of water inrush. The 602cave in Yesanguan tunnel was taken as an engineering sample to verify the feasibility of the novel model. The obtained results showed that the proposed model is comprehensive and accurate in quantitative assessment, which has good application prospects in engineering.

Increasing evidence has demonstrated the essential role of inflammatory micro-environment in tumorigenesis and tumor progression. Some cancer cells in tumor maintain typical stemness properties and, with the capacity of self-renewal, are thought to be crucial for the initiation and maintenance of tumors as well as their metastasis. Although both inflammatory micro-environment and stemness properties played crucial roles in tumor initiation and development, currently it is still unclear whether and how the inflammatory micro-environment promotes cancer stemness properties. Here, we show the first evidence that the inflammatory micro-environment promotes the stemness properties and metastatic potential of hepatocellular carcinoma (HCC) via the NF-κB/miR-497/SALL4 axis. We discover that miR-497 directly targets SALL4, negatively regulates its expression, and further inhibits the self-renewal and metastasis of HCC; more importantly, inflammatory factor TNF-α inhibits the expression of miR-497 via NF-kB-mediated negative transcriptional regulation and simultaneously upregulates the expression of SALL4 and promotes the self-renewal and metastasis phenotypes of HCC cells. Moreover, lower expression of miR-497 is significantly associated with poor prognosis in HCC patients. Taken together, our findings not only revealed a novel signaling pathway (NF-κB/miR-497/SALL4 axis) to connect inflammation with stemness properties, and clarified the molecular mechanisms underlying the inflammation-mediated self-renewal and metastasis phenotypes, but also provided novel molecular targets for developing new anticancer strategies. Keywords: miR-497, SALL4, stemness, metastasis, inflammation, hepatocellular carcinoma, NF-κB

Abstract Background Adipose tissue-derived mesenchymal stem cells (ADSCs) are promising candidates for regenerative medicine. However, long-term in vitro passaging leads to stemness loss and cell senescence of ADSCs, resulting in failure of ADSC-based therapy. Methods In this study, ADSCs were treated with low dose of antioxidants (reduced glutathione and melatonin) with anti-aging and stem cell protection properties in the in vitro passaging, and the cell functions including stem cell senescence, cell migration, cell multidirectional differentiation potential, and ROS content were carefully analyzed. Results We found that GSH and melatonin could maintain ADSC cell functions through reducing cell senescence and promoting cell migration, as well as by preserving stemness and multidirectional differentiation potential, through inhibiting ROS generation during long-term expansion of ADSCs. Conclusions Our results suggested that antioxidant treatment could efficiently prevent the dysfunction and preserve cell functions of ADSCs after long-term passaging, providing a practical strategy to facilitate ADSC-based therapy.

Abstract Angiogenesis is essential for vascular development. The roles of regulatory long noncoding RNAs (lncRNAs) in mediating angiogenesis remain under‐explored. Human embryonic stem cell‐derived mesenchymal stem cells (hES‐MSCs) are shown to exert more potent cardioprotective effects against cardiac ischemia than human bone marrow‐derived MSCs (hBM‐MSCs), associated with enhanced neovascularization. The purpose of this study is to search for angiogenic lncRNAs enriched in hES‐MSCs, and investigate their roles and mechanisms. AC103746.1 is one of the most highly expressed intergenic lncRNAs detected in hES‐MSCs versus hBM‐MSCs, and named as SCDAL (stem cell‐derived angiogenic lncRNA). SCDAL knockdown significantly reduce the angiogenic potential and reparative effects of hES‐MSCs in the infarcted hearts, while overexpression of SCDAL in either hES‐MSCs or hBM‐MSCs exhibits augmented angiogenesis and cardiac function recovery. Mechanistically, SCDAL induces growth differentiation factor 6 (GDF6) expression via direct interaction with SNF5 at GDF6 promoter. Secreted GDF6 promotes endothelial angiogenesis via non‐canonical vascular endothelial growth factor receptor 2 activation. Furthermore, SCDAL‐GDF6 is expressed in human endothelial cells, and directly enhances endothelial angiogenesis in vitro and in vivo. Thus, these findings uncover a previously unknown lncRNA‐dependent regulatory circuit for angiogenesis. Targeted intervention of the SCDAL‐GDF6 pathway has potential as a therapy for ischemic heart diseases.

In this study, a novel amphiphilic KL-AA-MMA nanoparticle was prepared through the graft copolymerization of kraft lignin (KL) with acrylic acid (AA) and methyl methacrylate (MMA), using potassium persulfate as an initiator in a water/dimethyl sulfoxide solvent medium, which was followed by the nanoprecipitation technique using dimethylformamide as a solvent and deionized water as an antisolvent. The successful graft polymerization was verified by 1H-nuclear magnetic resonance (NMR), 31P-NMR, and Fourier transform infrared (FTIR) analyses; and the grafting yield of the generated KL-AA-MMA copolymer ranged from 68.2% to 96.5%. Transmission electron microscopy (TEM) observation revealed the formation of amorphous KL-AA-MMA nanoparticles. Additionally, KL-AA-MMA9 nanoparticles with the highest yield exhibited the minimum hydrodynamic diameter and polydispersity of 261 nm and 0.153, respectively. Moreover, the amphiphilicity of KL-AA-MMA nanoparticles was significantly improved by the grafting of MMA monomers. Finally, the adsorption performance of KL-AA-MMA nanoparticles at the xylene interface was evaluated by a quartz crystal microbalance with dissipation (QCM-D). The results demonstrated that the most amphiphilic sample, KL-AA-MMA9 nanoparticles, with the smallest hydrodynamic size displayed the highest adsorption on the oil/water interface. This product provides a wide range of applications in oil/water emulsions.