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Abstract The interplay between gut microbiota and host is crucial for maintaining host health. When this balance is broken, various diseases can arise, including colorectal cancer (CRC). However, the mechanism by which gut microbiota and host interactions mediate CRC development remains unclear. Here, we found that Gasdermin D (GSDMD), an inflammasome effector responsible for forming membrane pores to mediate cell pyroptosis, was upregulated in both human and mouse intestinal tumor samples. GSDMD deficiency significantly suppressed intestinal tumor development in Apc min/+ mice, a spontaneous CRC mouse model. Apc min/+ Gsdmd −/− mice exhibited reduced IL-1β release in the intestine, and the administration of recombinant mouse IL-1β partially restored intestinal tumor development in Apc min/+ Gsdmd −/− mice. Moreover, 16s rRNA sequencing showed a substantial increase in Lactobacillus abundance in the feces of Apc min/+ Gsdmd −/− mice compared to Apc min/+ mice. Concurrently, Kynurenine (Kyn), a metabolite derived from host tryptophan (Trp) metabolism, was significantly decreased in the feces of Apc min/+ Gsdmd −/− mice, as shown by metabolite analysis. Additionally, Kyn levels were inversely correlated with Lactobacillus abundance. Furthermore, the administration of exogenous Kyn also promoted intestinal tumor development in Apc min/+ Gsdmd −/− mice. Thus, GSDMD promotes spontaneous CRC development through increasing IL-1β release and Kyn production. Our data suggest an association between GSDMD, gut microbiota, the host Trp/Kyn pathway, and CRC development.

Abstract The deformation law of pipelines crossing landslide areas is an important prerequisite for the scientific design of pipelines. Most current studies find it difficult to simulate the real stress and strain state of pipelines on site. This study conducted two centrifuge model tests to observe pipeline failure indicators (deformation, stress, strain) and slope failure indicators (crack width, soil pressure, landslide displacement) in response to changes in acceleration. The experimental findings align with the results obtained from numerical simulations. The findings indicate that slope failure with high moisture content is more serious. At a moisture content of 15%, the slope has a maximum displacement of 70 mm in close reach to the buried pipeline. The pipeline has a “bimodal distribution” of strain along its axial length. The largest amount of deformation occurs at a distance of L/4 from the center of the pipeline, and the deformation value is 9000 με. Moreover, the maximum deformation in the mid-span is 21 mm, which corresponds to the result accumulated from the numerical simulation. Thus, the pipeline needs to improve the disaster prevention capabilities at the mid-span and L/4 of the pipeline.

ObjectivesTo systematically evaluate the efficacy and safety of enteral nutrition with ω-3 polyunsaturated fatty acid preparations or standard enteral nutrition preparations used in patients with gastric cancer during perioperative period, and to provide reference for clinical rational drug use.MethodsPubmed, EMbase, The Cochrane Library, CNKI and Wanfang Medical databases were searched by computer to collect relevant literature. The search period was from the establishment of the database to August 1, 2024. Meta-analysis was performed using Revman5.4 software after two researchers independently screened literature, extracted data, and evaluated the risk of bias in included studies.ResultsA total of 20 randomized controlled studies were included. The Meta results showed that there was no statistical difference in mortality between the enteral nutrition with ω-3 polyunsaturated fatty acid group and the control group (RR = 0.46, P = 0.17). However, the IEN group demonstrated superior advantages in reducing infection complications (RR = 0.81, P = 0.05) and wound infection (RR = 0.61, P = 0.04) among gastric cancer patients, as well as improving immune-related indicators (including IgG, IgA, IgM, CD4, and CD4/CD8), inflammation-related markers (including CRP, IL-1β, and IL-6), and nutritional indicators (including Total protein, Albumin, and Transferrin).Conclusionenteral nutrition with ω-3 polyunsaturated fatty acid preparation has advantages in the efficacy and safety of perioperative nutritional therapy in patients with gastric cancer, and can be used as a clinical choice. Due to the limited number and quality of included studies, the above conclusions need to be verified by more high-quality studies.

The dense structure of solid tumor tissues and the selective permeability of cell membranes impede the effective penetration of chemotherapeutic agent-loaded liposomes into tumors and their subsequent uptake by cells. Dermaseptin-PP, a cationic antimicrobial peptide, has demonstrated the ability to enhance the penetration and accumulation of drugs within solid tumors due to its unique membrane-breaking action. Based on this, we designed glutathione (GSH)-sensitive paclitaxel liposomes modified with Dermaseptin-PP. Dermaseptin-PP was modified through disulfide bonding, which could be broken at the tumor site due to high GSH levels. This cleavage resulted in the release of Dermaseptin-PP, thereby enhancing the permeability of the paclitaxel liposomes within the tumor. We found that the paclitaxel liposomes modified with Dermaseptin-PP were extensively distributed to the tumor site, and the Dermaseptin-PP modification significantly enhanced liposome penetration within the tumor. Our study significantly increased the anti-tumor efficacy of paclitaxel liposomes. Our study confirms that paclitaxel liposomes modified with Dermaseptin-PP is an effective anti-tumor therapy that enhances deep penetration into tumors. Additionally, this broadens the applications of cationic antimicrobial peptides.

Abstract With the large-scale construction of oil and gas pipelines, the safety issues of long-distance buried pipelines in the service and construction have become increasingly prominent. The complex geological and topographical conditions of the special zone will put forwards extremely high requirements on pipe trench laying backfill materials and construction technology. For example, pipelines are inevitable to cross the active fault, while the trench backfilled with soil has limitations in protecting them from failure under the active fault displacement caused by the earthquake. Therefore, it is necessary to study the pipe–soil interaction mechanism, determine the stress state of the pipeline and propose a new backfilling material that can protect the pipeline from failure. Foam concrete (FC) provides a new choice to backfill the buried pipeline trench due to its high-homogeneity, lightweight, controllable-strength, and self-compacting. To further determine the applicability of the FC, the pipe-FC interaction mechanism is studied. Then, a FE model of the FC-pipeline-soil interaction system is established by Abaqus to quantitatively analyze the applicability of the FC based on the experimental data of the mechanical performance of the FC. It proves that using FC as trench backfill material has a noticeable protective effect on the pipeline under the earthquake-induced displacement of the normal fault. Furthermore, FC has a better protective effect on the pipeline subjected to compressive than tensile. Therefore, the reference for applying FC in trench backfilling of pipelines crossing normal fault is provided.

Abstract Background Diffusion kurtosis imaging (DKI) and neurite orientation dispersion and density imaging (NODDI) provide more comprehensive and informative perspective on microstructural alterations of cerebral white matter (WM) than single-shell diffusion tensor imaging (DTI), especially in the detection of crossing fiber. However, studies on systemic lupus erythematosus patients without neuropsychiatric symptoms (non-NPSLE patients) using multi-shell diffusion imaging remain scarce. Methods Totally 49 non-NPSLE patients and 41 age-, sex-, and education-matched healthy controls underwent multi-shell diffusion magnetic resonance imaging. Totally 10 diffusion metrics based on DKI (fractional anisotropy, mean diffusivity, axial diffusivity, radial diffusivity, mean kurtosis, axial kurtosis and radial kurtosis) and NODDI (neurite density index, orientation dispersion index and volume fraction of the isotropic diffusion compartment) were evaluated. Tract-based spatial statistics (TBSS) and atlas-based region-of-interest (ROI) analyses were performed to determine group differences in brain WM microstructure. The associations of multi-shell diffusion metrics with clinical indicators were determined for further investigation. Results TBSS analysis revealed reduced FA, AD and RK and increased ODI in the WM of non-NPSLE patients (P

Objective: To investigate the potential beneficial effects of sciadonic acid (SA) on improving obesity induced by a high-fat diet in mice. Methods: Forty-eight male C57BL/6 mice were adaptively fed for one week and then randomly divided into the following groups: Control group (C), positive control group (S), model group (M), low-dose sciadonic acid group (LSA), medium-dose sciadonic acid group (MSA), and high-dose sciadonic acid group (HSA). The modeling process lasted for 16 weeks, and the low and high-dose groups were orally administered different doses of SA solution at a fixed time each day. After the modeling period, potential mechanisms of SA in regulating lipid metabolism in obese mice were explored, including aspects such as blood lipid metabolism, hepatic fat metabolism, hepatic oxidative stress, hepatic lipid synthesis, and expression of metabolism-related genes. Results: The high-dose SA intervention in obese mice significantly decreased the levels of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) in serum, while increasing high-density lipoprotein cholesterol (HDL-C) (P

The pool-type demonstrative China Fast Reactor 600 (CFR-600) adopted a series of improved safety designs, among which the hydraulic suspended passive shutdown subassembly (HS-PSS) is employed for inherent safety enhancement, especially suitable against unprotected loss of flow accident (ULOF). In this article, functional requirements for HS-PSS design in hydro-dynamic aspects are proposed, with the corresponding performance indicators discussed. To address these functional requirements, qualitative analysis on the equilibrium solution properties of the nonlinear dynamical model equation of the hydraulic moving body (HMB) in the HS-PSS are conducted, which leads to the determination of an applicable design parameter domain of the HMB for its practical design from the broad range of structural and parametric design options available for HS-PSS. Furtherly, hydraulically characterizing and modeling the constituent paths and consequent fluid network, hydraulic characteristics of the HS-PSS, as well as the coupled hydro-dynamic motion behaviors of the HMB for suspension and dropping states, were simulated and test-validated. Considering the HS-PSS hydro-dynamic behaviors, key indicators such as critical flowrate, drop time, hydraulic self-tightening performance, as well as the hydraulic characteristics curve are for fulfilling the functional requirements. Meanwhile, through sensitivity study of some structural parameters‘ impact on hydraulic characteristics, some most sensible structural parameters for adjusting and optimizing detailed design are observed. The work is quite significant in supporting the conceptual design of the HS-PSS as well as its engineering improvement.

PurposeTo develop and validate a nomogram based on extracellular volume (ECV) fraction derived from dual-energy CT (DECT) for preoperatively predicting microsatellite instability (MSI) status in gastric cancer (GC).Materials and methodsA total of 123 patients with GCs who underwent contrast-enhanced abdominal DECT scans were retrospectively enrolled. Patients were divided into MSI (n=41) and microsatellite stability (MSS, n=82) groups according to postoperative immunohistochemistry staining, then randomly assigned to the training (n=86) and validation cohorts (n=37). We extracted clinicopathological characteristics, CT imaging features, iodine concentrations (ICs), and normalized IC values against the aorta (nICs) in three enhanced phases. The ECV fraction derived from the iodine density map at the equilibrium phase was calculated. Univariate and multivariable logistic regression analyses were used to identify independent risk predictors for MSI status. Then, a nomogram was established, and its performance was evaluated by ROC analysis and Delong test. Its calibration performance and clinical utility were assessed by calibration curve and decision curve analysis, respectively.ResultsThe ECV fraction, tumor location, and Borrmann type were independent predictors of MSI status (all P < 0.05) and were used to establish the nomogram. The nomogram yielded higher AUCs of 0.826 (0.729–0.899) and 0.833 (0.675–0.935) in training and validation cohorts than single variables (P

Abstract Background Nuclear respiratory factor 1 (NRF1) is a transcription factor that participates in several kinds of tumor, but its role in hepatocellular carcinoma (HCC) remains elusive. This study aims to explore the role of NRF1 in HCC progression and investigate the underlying mechanisms. Results NRF1 was overexpressed and hyperactive in HCC tissue and cell lines and high expression of NRF1 indicated unfavorable prognosis of HCC patients. NRF1 promoted proliferation, migration and invasion of HCC cells both in vitro and in vivo. Mechanistically, NRF1 activated ERK1/2-CREB signaling pathway by transactivating lysophosphatidylcholine acyltransferase 1 (LPCAT1), thus promoting cell cycle progression and epithelial mesenchymal transition (EMT) of HCC cells. Meanwhile, LPCAT1 upregulated the expression of NRF1 by activating ERK1/2-CREB signaling pathway, forming a positive feedback loop. Conclusions NRF1 is overexpressed in HCC and promotes HCC progression by activating LPCAT1-ERK1/2-CREB axis. NRF1 is a promising therapeutic target for HCC patients.

The oil derived from Psidium guajava seeds (TKSO) exhibits an abundance of diverse unsaturated fatty acids, notably oleic, linoleic, and α-linolenic acids, conferring substantial health advantages in addressing metabolic irregularities and human diseases. This research endeavor focused on elucidating the impacts of TKSO on colonic inflammatory responses and intestinal microbiota alterations in a murine model of colitis induced by dextran sulfate sodium (DSS), demonstrated that substantial supplementation with TKSO reduces the severity of colitis induced by DSS. Furthermore, TKSO effectively attenuated the abundance and expression of proinflammatory mediators while augmenting the expression of tight junction proteins in DSS-challenged mice. Beyond this, TKSO intervention modulated the intestinal microbial composition in DSS-induced colitis mice, specifically by enhancing the relative presence of Lactobacillus, Norank_f_Muribaculaceae, and Lachnospiraceae_NK4A136_group, while concurrently diminishing the abundance of Turicibacter. Additionally, an analysis of short-chain fatty acids (SCFAs) revealed noteworthy elevations in acetic, propionic, isobutyric, and butyric acids, and total SCFAs levels in TKSO-treated mice. In summary, these findings underscore the potential of TKSO to reduce the severity of colitis induced by DSS in mice through intricate modulation of the intestinal microbiota, metabolite profiles, and intestinal barrier repair, thereby presenting a promising avenue for the development of therapeutic strategies against intestinal inflammatory conditions.

Obesity has become one of the most serious chronic diseases threatening human health. Its onset and progression are closely related to the intestinal microbiota, as disruption of the intestinal flora promotes the production of endotoxins and induces an inflammatory response. This study aimed to investigate the variations in the physicochemical properties of various refined tea seed oils and their impact on intestinal microbiota disorders induced by a high-fat diet (HFD) through dietary intervention. In the present study, C57BL/6J mice on a HFD were randomly divided into three groups: HFD, T-TSO, and N-TSO. T-TSO and N-TSO mice were given traditionally refined and optimized tea seed oil for 12 weeks. The data revealed that tea seed oil obtained through degumming at 70 °C, deacidification at 50 °C, decolorization at 90 °C, and deodorization at 180 °C (at 0.06 MPa for 1 h) effectively removed impurities while minimizing the loss of active ingredients. Additionally, the optimized tea seed oil mitigated fat accumulation and inflammatory responses resulting from HFD, and reduced liver tissue damage in comparison to traditional refining methods. More importantly, N-TSO can serve as a dietary supplement to enhance the diversity and abundance of intestinal microbiota, increasing the presence of beneficial bacteria (norank_f__Muribaculaceae, Lactobacillus, and Bacteroides) while reducing pathogenic bacteria (Alistipes and Mucispirillum). Therefore, in HFD-induced obese C57BL/6J mice, N-TSO can better ameliorate obesity compared with a T-TSO diet, which is promising in alleviating HFD-induced intestinal microbiota disorders.

Abstract As a first‐line anticancer drug, paclitaxel has shortcomings, such as poor solubility and lack of tumour cell selectivity, which limit its further applications in clinical practice. Therefore, the authors aimed to utilise the characteristics of prodrug and nanotechnology to prepare a reactive oxygen species (ROS) and GSH dual‐responsive targeted tumour prodrug nanoparticle Man‐PEG‐SS‐PLGA/ProPTX to improve the clinical application status of paclitaxel limitation. The characterisation of Man‐PEG‐SS‐PLGA/ProPTX was carried out through preparation. The cytotoxicity of nanoparticles on tumour cells and the effect on apoptosis of tumour cells were investigated by cytotoxicity assay and flow cytometry analysis. The ROS responsiveness of nanoparticles was investigated by detecting the ROS level of tumour cells. The tumour cell selectivity of the nanoparticles was further investigated by receptor affinity assay and cell uptake assay. The particle size of Man‐PEG‐SS‐PLGA/ProPTX was (132.90 ± 1.81) nm, the dispersion coefficient Polymer dispersity index was 0.13 ± 0.03, and the Zeta potential was (−8.65 ± 0.50) mV. The encapsulation rate was 95.46 ± 2.31% and the drug load was 13.65 ± 2.31%. The nanoparticles could significantly inhibit the proliferation and promote apoptosis of MCF‐7, HepG2, and MDA‐MB‐231 tumour cells. It has good ROS response characteristics and targeting. The targeted uptake mechanism is energy‐dependent and endocytosis is mediated by non‐clathrin, non‐caveolin, lipid raft/caveolin, and cyclooxygenase (COX)/caveolin with a certain concentration dependence and time dependence. Man‐PEG‐SS‐PLGA/ProPTX is a tumour microenvironment‐responsive nanoparticle that can actively target tumour cells. It restricts the release of PTX in normal tissues, enhances its selectivity to tumour cells, and has significant antitumour activity, which is expected to solve the current limitations of PTX use.

Abstract Objective Dermaseptin‐PP is a newly discovered anticancer peptide with a unique antitumour mechanism and remarkable effect. However, this α‐helix anticancer peptide risks haemolysis when used at high doses, which limits its further application. This study aims to prepare a pH‐responsive liposome, Der‐loaded‐pHSL, using nanotechnology to avoid the haemolysis risk of Dermaseptin‐PP and increase its accumulation in tumour sites to enhance efficacy and reduce toxicity. Methods The characterisation of Der‐loaded‐pHSL was carried out employing preparation. The effect of haemolysis and tumour inhibition were investigated by in vitro haemolysis assay and cytotoxicity assay. The cell uptake under different pH conditions was investigated by flow cytometry, and the effect of pH on tumour cell selectivity was evaluated. In order to evaluate the in vivo targeting and antitumour effect of Der‐loaded‐pHSL, the in vivo distribution experiment and the pharmacodynamic experiment were performed using the nude mouse tumour model. Results The preparation method of the Der‐loaded‐pHSL is simple, and the liposome has good nanoparticle characteristics. When Dermaseptin‐PP was prepared as liposome, haemolysis was significantly decreased, and tumour cell inhibition was significantly enhanced. Compared with ordinary liposomes, this change was more significant in Der‐loaded‐pHSL. The uptake of pH‐sensitive liposomes was higher in the simulated acidic tumour microenvironment, and the uptake showed a specific acid dependence. In vivo experiments showed that Der‐loaded‐pHSL had a significant tumour‐targeting effect and could significantly enhance the antitumour effect of Dermaseptin‐PP. Conclusion Der‐loaded‐pHSL designed in this study is a liposome with a quick, simple, effective preparation method, which can significantly reduce the haemolytic toxicity of Dermaseptin‐PP and enhance its antitumour effect by increasing the tumour accumulation and cell intake. It provides a new idea for applying Dermaseptin‐PP and other anticancer peptides with α‐helical structure.

Abstract Parkinson’s disease (PD) is one of the most prevalent movement disorders and its diagnosis relies heavily on the typical clinical manifestations in the late stages. This study aims to screen and identify biomarkers of PD for earlier intervention. We performed a differential analysis of postmortem brain transcriptome studies. Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify biomarkers related to Braak stage. We found 58 genes with significantly different expression in both PD brain tissue and blood samples. PD gene signature and risk score model consisting of nine genes were constructed using least absolute shrinkage and selection operator regression (LASSO) and logistic regression. PLOD3 and LRRN3 in gene signature were identified to serve as key genes as well as potential risk factors in PD. Gene function enrichment analysis and evaluation of immune cell infiltration revealed that PLOD3 was implicated in suppression of cellular metabolic function and inflammatory cell infiltration, whereas LRRN3 exhibited an inverse trend. The cellular subpopulation expression of the PLOD3 and LRRN3 has significant distributional variability. The expression of PLOD3 was more enriched in inflammatory cell subpopulations, such as microglia, whereas LRRN3 was more enriched in neurons and oligodendrocyte progenitor cells clusters (OPC). Additionally, the expression of PLOD3 and LRRN3 in Qilu cohort was verified to be consistent with previous results. Collectively, we screened and identified the functions of PLOD3 and LRRN3 based the integrated study. The combined detection of PLOD3 and LRRN3 expression in blood samples can improve the early detection of PD.

METRNL is a recently identified secreted protein with emerging functions. This study is to find major cellular source of circulating METRNL and to determine METRNL novel function. Here, we show METRNL is abundant in human and mouse vascular endothelium and released by endothelial cells using endoplasmic reticulum-Golgi apparatus pathway. By creating endothelial cell-specific Metrnl knockout mice, combined with bone marrow transplantation to produce bone marrow-specific deletion of Metrnl, we demonstrate that most of circulating METRNL (approximately 75%) originates from the endothelial cells. Both endothelial and circulating METRNL decrease in atherosclerosis mice and patients. By generating endothelial cell-specific Metrnl knockout in apolipoprotein E-deficient mice, combined with bone marrow-specific deletion of Metrnl in apolipoprotein E-deficient mice, we further demonstrate that endothelial METRNL deficiency accelerates atherosclerosis. Mechanically, endothelial METRNL deficiency causes vascular endothelial dysfunction including vasodilation impairment via reducing eNOS phosphorylation at Ser1177 and inflammation activation via enhancing NFκB pathway, which promotes the susceptibility of atherosclerosis. Exogenous METRNL rescues METRNL deficiency induced endothelial dysfunction. These findings reveal that METRNL is a new endothelial substance not only determining the circulating METRNL level but also regulating endothelial function for vascular health and disease. METRNL is a therapeutic target against endothelial dysfunction and atherosclerosis.

Cement-stabilized soil is a commonly used pavement base/bottom base material. Adding a suitable curing agent to cement-stabilized soil can effectively reduce the dosage of cement, meet the strength requirements, and also greatly improve its water stability. In this paper, three kinds of cement dosage (6%, 8%, and 10%) of cement-stabilized soil were selected to add a 0.04% organic liquid curing agent, and then compared with high-dose cement (10% and 12%)-stabilized soil. The influence of wetting–drying cycles on the mechanical properties of the five stabilized soils was discussed. The mineral composition of cement-stabilized soils before and after the addition of a curing agent was analyzed by X-ray diffraction (XRD), and the microscopic morphology of 10% cement-stabilized soils with a curing agent was studied by scanning electron microscopy (SEM). The macroscopic test shows that the unconfined compressive strength of solidified cement-stabilized soil can be divided into three stages with the increase in the times of the wetting–drying cycles, which are the rapid decay stage, stable enhancement stage, and stable decay stage. The wetting–drying stability coefficient first increases, and then decreases with the increase in the times of the wetting–drying cycles. The microscopic test shows that the addition of a curing agent can enhance the content of hydration products in the cement-stabilized soil specimen; at the curing age of 28 d, with the increase in the times of the wet–dry cycles, the structure of the solidified cement-stabilized soil gradually broke down. The surface porosity P and pore diameter d showed an overall upward trend but decreased at the fifth wetting–drying cycle. The pore orientation weakened. The results show that the resistance of cement-stabilized soil with a curing agent is obviously better than that of cement-stabilized soil under wet–dry conditions.

Abstract Background Cytokines secreted in the tumor microenvironment function in cancer cachexia (CC), a common clinicopathological syndrome associated with adipocyte wasting and skeletal muscle atrophy. Extracellular vesicles (EVs) secreted by cancer cells actively engage in inter-tissue communication; EVs and enclosed cytokines are largely undefined in CC adipocytes wasting. Methods EVs derived from Lewis lung carcinoma (LLC) and colorectal cancer C26 cells were extracted and characterized. Conditioned medium and EVs from cancer cells were applied to 3 T3-L1 adipocytes. Recombinant IL-8, IL-8 neutralizing antibody, CXCR2 and NF-κB inhibitor were examined in functional assays. Lipolysis of adipocytes was monitored by Western blots, Oil red O staining and glycerol assays. Furthermore, LLC and C26 cell lines were established as cachexia model to explore the relevance of IL-8 and NF-κB signaling in CC adipose wasting. Adipose tissues were collected for histology analyses. Results LLC and C26 cell-derived EVs induced lipolysis of 3 T3-L1 adipocytes. Specially, Dil-labeled EVs were effectively taken up by 3 T3-L1 adipocytes, which were motivated by the delivered IL-8 to elicit the NF-κB pathway. In comparison, special IL-8 neutralizing antibody relieved that lipolysis of 3 T3-L1 adipocytes induced by EVs together with conditioned medium of LLC and C26 cells, respectively. Consistently, both CXCR2 and NF-κB inhibitors would lessen the phenotype of lipolysis in 3 T3-L1 adipocytes. In the in vivo settings, both LLC and C26-tumor bearing mice had higher serum IL-8 levels as compared to the control groups. Two typical lipolysis markers, PGC1α and UCP1, were also up-regulated in the adipose tissues of LLC and C26-tumor mice groups, respectively. Conclusions EVs secreted by LLC and C26 tumor cells would induce adipocyte wasting via extracellular IL-8-mediated NF-κB signaling. Our study pointed out the physiological and therapeutic values of exosomal IL-8 in CC lipolysis.

Abstract Seismic fault displacement is the main factor leading to local buckling failure of the buried pipeline, especially crossing the oblique-reverse fault. The local buckling behavior of the buried pipeline is complex under the 3-D displacement of the oblique-reverse fault. In this work, the pipe local buckling mechanism was discussed, then a shell and solid element nonlinear contact coupling model of the pipeline crossing oblique-reverse fault was established based on the ABAQUS program. The local buckling behavior (potential local buckling locations, developing process) of the pipeline under oblique-reverse fault displacement was systematically analyzed, comparing against the same under single fault displacement. Subsequently, the influence of internal pressure, diameter thickness ratio and burial depth on the local buckling behavior of the pipeline were discussed. The numerical results revealed two potential locations and three stages of the local buckling, then the potential local buckling locations and three stages of the local buckling under different internal pressure, diameter thickness ratio and burial depth were obtained. It proves that the local buckling of the pipeline is more sensitive to the oblique-reverse fault displacement than single fault displacement and provides a reference for the aseismic design and reinforcement of the pipeline crossing the oblique-reverse fault.

Colitis is characterized by colonic inflammation and impaired gut health, and alterations in the gut microbiota may lead to the development of inflammatory bowel disease (IBD). Camellia oil (CO) possesses high nutritional value and offers various health benefits for human metabolic disorders and diseases. However, it is unclear whether CO ameliorates IBD and plays a role in the gut microbiota. This study aimed to investigate the effect of CO on colonic inflammation and gut microbiota using a mice model of dextran sodium sulfate (Dss)-induced ulcerative colitis (UC). Our findings demonstrated that CO inhibited weight loss and colon shortening and improved intestinal barrier function. Additionally, CO treatment reduced oxidative stress and inflammatory responses in Dss-induced colitis. Furthermore, CO significantly inhibited p65 and IκBα phosphorylation and alleviated colonic inflammation. Moreover, we observed that CO treatment increased the abundance of Bacteroides, Lactobacillus, and Odoribacter, while decreasing the abundance of Alistipes, Lachnospiraceae NK4A136 group, Ruminococcaceae UCG-014, uncultured Bacteroidales bacterium, and Prevotellaceae_UCG-001. Additionally, CO treatment promoted the production of SCFAs. These data indicated the promising potential of CO to prevent UC by maintaining gut barrier function, inhibiting the NF-κB signaling pathway, and modulating the gut microbiota.

Abstract Developing plasmonic biosensors that are low‐cost, portable, and relatively simple to operate remains challenging. Herein, a novel metasurface plasmon‐etch immunosensor is described, namely a nanozyme‐linked immunosorbent surface plasmon resonance biosensor, for the ultrasensitive and specific detection of cancer biomarkers. Gold‐silver composite nano cup array metasurface plasmon resonance chip and artificial nanozyme‐labeled antibody are used in two‐way sandwich analyte detection. Changes in the biosensor's absorption spectrum are measured before and after chip surface etching, which can be applied to immunoassays without requiring separation or amplification. The device achieved a limit of alpha‐fetoprotein (AFP) detection < 21.74 fM, three orders of magnitude lower than that of commercial enzyme‐linked immunosorbent assay kits. Additionally, carcinoembryonic antigen (CEA) and carbohydrate antigen 125 (CA125) are used for quantitative detection to verify the universality of the platform. More importantly, the accuracy of the platform is verified using 60 clinical samples; compared with the hospital results, the three biomarkers achieve high sensitivity (CEA: 95.7%; CA125: 90.9%; AFP: 86.7%) and specificity (CEA: 97.3%; CA125: 93.9%; AFP: 97.8%). Due to its rapidity, ease of use, and high throughput, the platform has the potential for high‐throughput rapid detection to facilitate cancer screening or early diagnostic testing in biosensing.

A novel reinforcement deep learning deterministic policy gradient agent-based sliding mode control (DDPG-SMC) approach is proposed to suppress the chattering phenomenon in attitude control for quadrotors, in the presence of external disturbances. First, the attitude dynamics model of the quadrotor under study is derived, and the attitude control problem is described using formulas. Second, a sliding mode controller, including its sliding mode surface and reaching law, is chosen for the nonlinear dynamic system. The stability of the designed SMC system is validated through the Lyapunov stability theorem. Third, a reinforcement learning (RL) agent based on deep deterministic policy gradient (DDPG) is trained to adaptively adjust the switching control gain. During the training process, the input signals for the agent are the actual and desired attitude angles, while the output action is the time-varying control gain. Finally, the trained agent mentioned above is utilized in the SMC as a parameter regulator to facilitate the adaptive adjustment of the switching control gain associated with the reaching law. The simulation results validate the robustness and effectiveness of the proposed DDPG-SMC method.

Deep learning technique has been widely used for decoding motor related electroencephalography (EEG) signals, which has considerably driven the development of motor related brain–computer interfaces (BCIs). However, traditional convolutional neural networks (CNNs) cannot fully represent spatial topology information and dynamic temporal characteristics of multi-channel EEG signals, resulting in limited decoding accuracy. To address such challenges, a novel multi-scale multi-graph embedding CNN (MSMGE-CNN) is proposed in this study. The proposed MSMGE-CNN contains two crucial components: multi-scale time convolution and multi-graph embedding. Specifically, we design a multi-branch CNN architecture with mixed-scale time convolutions based on EEGNet to sufficiently extract robust time domain features. Afterward, we embed multi-graph information obtained based on physical distance proximity and functional connectivity of multi-channel EEG signals into the time-domain features to capture rich spatial topological dependencies via multi-graph convolution operation. We extensively evaluated the proposed method on three benchmark EEG datasets commonly used for motor imagery/execution (MI/ME) classification and obtained accuracies of 79.59% (BCICIV-2a Dataset), 69.77% (OpenBMI Dataset) and 96.34% (High Gamma Dataset), respectively. These results powerfully demonstrate that MSMGE-CNN outperforms several state-of-the-art algorithms. In addition, we further conducted a series of ablation experiments to validate the rationality of our network architecture. Overall, the proposed MSMGE-CNN method dramatically improves the accuracy and robustness of MI/ME-EEG decoding, which can effectively enhance the performance of motor related BCI system.

Abstract Background Human mesenchymal stem cells (hMSCs) have been proven to have inherent chondrogenic differentiation potential, which appears to be used in cartilage regeneration. Increasing evidence suggests that irisin enhances osteoblast differentiation of MSCs, but little is known about its potential on chondrogenic differentiation. Methods In the study, we investigated the effects of irisin on chondrogenic differentiation of hMSCs using a high-density pellet culture system. The cartilage pellets were evaluated by morphology, and the metabolism of cartilage matrix was detected by qPCR, western blot and immunohistochemistry. Next, RNA-seq was performed to explore the underlying mechanism. Furthermore, using the transduction of plasmid, miRNAs mimics and inhibitor, the activation of Rap1/PI3K/AKT axis, the expression level of SIPA1L2, and the functional verification of miR-125b-5p were detected on day 7 of chondrogenic differentiation of hMSCs. Results Compared with the controls, we found that irisin treatment could significantly enhance the chondrogenic differentiation of hMSCs, enlarge the induced-cartilage tissue and up-regulate the expression levels of cartilage markers. RNA-seq indicated that irisin activated the Rap1 and PI3K/AKT signaling pathway, and the lower expression level of SIPA1L2 and the higher expression level of miR-125b-5p were found in irisin-treated group. Further, we found that irisin treatment could up-regulate the expression level of miR-125b-5p, targeting SIPA1L2 and consequently activating the Rap1/PI3K/AKT axis on the process of chondrogenic differentiation of hMSCs. Conclusions Collectively, our study reveals that irisin can enhance chondrogenic differentiation of hMSCs via the Rap1/PI3K/AKT pathway, suggesting that irisin possesses prospects in cartilage regeneration.

Abstract Background With the widespread use of the posterior surgery, more and more surgeons chose posterior surgery to treat thoracic and lumbar tuberculosis. But others still believed that the anterior surgery is more conducive to eradicating the lesions, and easier to place larger bone pieces for bone graft fusion. We compared the clinical and radiological outcomes of anterior and posterior surgical approaches and presented our views. Methods This study included 52 thoracic and lumbar tuberculosis patients at Sun Yat-sen Memorial Hospital from January 2010 to June 2018. All cases underwent radical debridement, nerve decompression, intervertebral bone graft fusion and internal fixation. Cases were divided into anterior group (24 cases) and posterior group (28 cases). Statistical analysis was used to compare the clinical effectiveness, radiological outcomes, complications and other related information. Results Patients in the anterior group and the posterior group were followed up for an average of 27.4 and 22.3 months, respectively. There were no statistically significant differences between groups in the preoperative, postoperative and last follow-up VAS score, ASIA grade and Cobb angle of local kyphosis. Moreover, there were no statistically significant differences in the improvement of neurological function, loss of kyphotic correction, total incidence of complications, operative time, intraoperative blood loss and hospital stay between the two groups (P > 0.05). But there was greater correction of kyphosis, earlier bone fusion, lower incidence of poor wound healing, less interference with the normal spine and less internal fixation consumables and medical cost in the anterior group (P

Abstract Background Biliary adenofibroma (BAF) is a rare primary hepatic tumor with the potential risk of malignant transformation. Given the extreme rarity of the disease, the imaging features of BAF are unclear. We presented a case of malignant BAF and conducted a systematic literature review. We highlighted the key imaging features in the diagnosis and aggressiveness assessment of BAF, as well as the role of various imaging modalities in evaluating BAF. Case presentation We reported a 64-year-old woman with a 5-months history of pain in the right upper quadrant abdomen. US of the liver showed a hypoechoic subcapsular nodule. CT scan revealed a subcapsular solid-cystic mass in segment V of the liver. The mass showed a marked enhancement in the arterial phase followed by wash-out in the venous phase. The patient underwent partial resection of liver’s right lobe. The mass was diagnosed as BAF with malignant transformation by postoperative pathology. Conclusions CT and MRI are helpful in recognizing and characterizing BAF. The imaging features of BAF include a solitary, large solid-cystic mass with a well-defined margin, lobulated shape, and internal septa; subcapsular location; no intrahepatic bile duct communication; the presence of von Meyenberg complexes in background liver. The enhancement patterns may have the potential to assess the aggressiveness of BAF, and that marked enhancement in the arterial phase followed by wash-out in the venous phase is suggestive of malignant BAF.

Cancer cells producing ligands for the immune checkpoint molecules PD-1 and CTLA-4 is an important mechanism of tumour immune resistance. Here authors show that BTNL2 expression on cancer cells generates a dysfunctional tumour immune microenvironment via promoting IL-17A-producing γδ T cells.

Olive suffers from cold damage when introduced to high-latitude regions from its native warm climes. Therefore, this study aims to improve the adaption of olive to climates in which it is cold for part of the year. The phenotype, physiological performance, nutrient content, and gene expression of olive leaves (from two widely planted cultivars) were examined after cultivation in normal and cold stress conditions. The results showed that the cold-tolerant cultivar possessed stronger photosynthesis efficiency and higher anti-oxidase activity after cold treatment than the cold-sensitive cultivar. Alteration of gene expression and metabolites in the amino acid metabolism, glycerolipid metabolism, diterpenoid biosynthesis, and oleuropein metabolism pathways played an important role in the cold responses of olive. Furthermore, the construction of the network of genes for ubiquitination and metabolites suggested that polyubiquitination contributes most to the stable physiology of olive under cold stress. Altogether, the results of this study can play an important role in helping us to understand the cold hardiness of olive and screen cold-resistant varieties for excellent quality and yield.

Abstract Background Cancer cachexia is a wasting disorder characterized by significant weight loss, and is attributed to skeletal muscle weakness. In the process of cancer development, microRNAs act as oncogenes or tumor suppressors. Moreover, they are implicated in muscle development and wasting. This study sought to explore the mechanisms and correlation between miR-29c and muscle wasting in lung cancer cachexia. Methods Data for expression analysis were retrieved from the Cancer Genome Atlas (TCGA) database. qRT-PCR analyses were performed to explore the expression levels of miR-29c and Leukemia Inhibitory Factor (LIF). Lewis lung carcinoma (LLC) cell line was used to establish a cachexia model to explore the functions of miR-29c and LIF in lung cancer cachexia. Furthermore, in vitro (in C2C12 myotubes) and in vivo (in LLC tumor-bearing mice) experiments were performed to explore the mechanisms of miR-29c and LIF in lung cachexia. Results Analysis of the lung cancer cachexia model showed that miR-29c was down-regulated, and its expression was negatively correlated with muscle catabolic activity. Overexpression of miR-29c mitigated the cachectic phenotype. Mechanistic studies showed that LIF was a direct target gene of miR-29c, and LIF was upregulated in vitro and in vivo. Analysis showed that LIF promoted muscle wasting through the JAK/STAT and MAP-kinase pathways. Conclusions The findings indicated that miR-29c was negatively correlated with the cachectic phenotype, and the miR-29c-LIF axis is a potential therapeutic target for cancer cachexia.

Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by hyperglycemia. The aim of this work was to investigate the effect of sciadonic acid (SA) on disorders of glucolipid metabolism and intestinal flora imbalance and to further investigate its potential molecular mechanism of anti-diabetes. The experimental data indicated that SA could alleviate hyperlipidemia, insulin resistance, oxidative stress, the inflammatory response, repair liver function damage, and promote glycogen synthesis caused by T2DM. SA could also activate the PI3K/AKT/GLUT-2 signaling pathway, promote glucose metabolism gene expression, and maintain glucose homeostasis. Furthermore, 16S rRNA analysis revealed that SA could reduce the Firmicutes/Bacteroidota (F/B) ratio; promote norank_f__Muribaculaceae, Allobaculum, Akkermansia, and Eubacterium_siraeum_group proliferation; increase the levels of major short-chain fatty acids (SCFAs), such as acetic acid, propionic acid, and butyric acid; and maintain the homeostasis of the intestinal flora. In conclusion, these results suggested that SA could reshape the structural composition of intestinal microbes, activate the PI3K/AKT/GLUT2 pathway, improve insulin resistance, and decrease blood glucose levels.

Accurate determination of the concentration and viability of the viral vaccine vectors is urgently needed for preventing the spread of the viral infections, but also supporting the development and assessment of recombinant virus-vectored vaccines. Herein, we describe a nanoplasmonic biosensor with nanoscale robot hand structure (Nano RHB) for the rapid, direct, and specific capture and quantification of adenovirus particles. The nanorobot allows simple operation in practical applications, such as real-time monitoring of vaccine quantity and quality, and evaluation of vaccine viability. Modification of the Nano RHB with branched gold nanostructures allow rapid and efficient assessment of human adenovirus viability, with ultrahigh detection sensitivity of only 100 copies/mL through one-step sandwich method. Nano RHB detection results were consistent with those from the gold standard median tissue culture infectious dose and real-time polymerase chain reaction assays. Additionally, the Nano RHB platform showed high detection specificity for different types of viral vectors and pseudoviruses. Altogether, these results demonstrate that the Nano RHB platform is a promising tool for efficient and ultrasensitive assessment of vaccines and gene delivery vectors.

Study DesignRetrospective analysis.ObjectiveTo evaluate bone quality and investigate asymmetrical development of the thoracic vertebral body in adolescent idiopathic scoliosis (AIS) based on Hounsfield unit (HU) measurements obtained from computed-tomography (CT) scans.Summary of Background DataHU value demonstrated higher reliability and accuracy than the traditional method, indicating that they could be used to individually evaluate and effectively assess the bone quality of every vertebra in the CT films.MethodsTotal 30 AIS patients classified as Lenke Type 1A and 30 paired controls were included in this study. Regions of interest for HU value were measured on three horizontal images of the thoracic vertebrae. HU measurements of the whole vertebral body in each vertebra were obtained. Using HU value, we separately measured the concave and convex sides of each vertebral body in patients' group, as well as within the left and right sides in controls.ResultsIn controls, the mean HU value of T1–T12 thoracic vertebral bodies was 240.03 ± 39.77, with no statistical differences among different levels. As for AIS patients, in the structural curve, the apical region had a significantly lower HU compared with the other regions, and asymmetrical change was found between the concave and convex sides, most significantly in the apical region. In the non-structural curve, the average HU value was 254.99 ± 44.48, and no significant difference was found either among the different levels of vertebrae or between the concave and convex sides.ConclusionsAbnormal and asymmetrical changes in bone quality of the thoracic vertebral body in patients with Lenke 1A AIS were indicated. Low bone quality in the convex side of the structural curve indicated stronger internal fixation in surgery to correct the deformity.

Abstract Cancer cachexia is a metabolic disorder characterized by skeletal muscle wasting and white adipose tissue browning. Specific functions of several hormones, growth factors, and cytokines derived from tumors can trigger cachexia. Moreover, adipose tissue lipolysis might explain weight loss that occurs owing to cachexia. Extracellular vesicles (EVs) are involved in intercellular communication. However, whether EVs participate in lipolysis induced by cancer cachexia has not been thoroughly investigated. Using Lewis lung carcinoma (LLC) cell culture, we tested whether LLC cell-derived EVs can induce lipolysis in 3T3-L1 adipocytes. EVs derived from LLC cells were isolated and characterized biochemically and biophysically. Western blotting and glycerol assay were used to study lipolysis. LLC cell-derived EVs induced lipolysis in vivo and vitro. EVs fused directly with target 3T3-L1 adipocytes and transferred parathyroid hormone-related protein (PTHrP), activating the PKA signaling pathway in 3T3-L1 adipocytes. Blocking PTHrP activity in LLC-EVs using a neutralizing antibody and by knocking down PTHR expression prevented lipolysis in adipocytes. Inhibiting the PKA signaling pathway also prevents the lipolytic effects of EVs. In vivo, suppression of LLC-EVs release by knocking down Rab27A alleviated white adipose tissue browning and lipolysis. Our data showed that LLC cell-derived EVs induced adipocyte lipolysis via the extracellular PTHrP-mediated PKA pathway. Our data demonstrate that LLC-EVs induce lipolysis in vitro and vivo by delivering PTHrP, which interacts with PTHR. The lipolytic effect of LLC-EVs was abrogated by PTHR knockdown and treatment with a neutralizing anti-PTHrP antibody. Together, these data show that LLC-EV-induced lipolysis is mediated by extracellular PTHrP. These findings suggest a novel mechanism of lipid droplet loss and identify a potential therapeutic strategy for cancer cachexia.

The emerging link flooding attacks (LFAs) are one type of attacks that attract significant attention in both academia and industry against the routing infrastructure. The attack traffic flows originating from bots (e.g., compromised IoT devices) are deliberately aggregated at upstream critical links and grow intensified, gradually making a network connected to the critical links disconnected. Although LFAs are far more sophisticated than traditional DDoS attacks, whether such sophistication comes without a downside has never been investigated. In this paper, by modeling link flooding attacks and defenses, we tackle a series of questions concerning the practical issues of LFAs. Specifically, from the perspective of attacks, we advance a novel notion of strike precision, and reveal that LFAs may exhibit attack interference (i.e., unexpectedly interfere the connectivity of innocent networks) which might undermine the stealthiness and persistence of LFAs. From the perspective of defenses, we make the first step to study attack intention, i.e., inversely inferring the target network to disconnect based on the identified links under attack. Furthermore, we consider a strong defender who employs traffic engineering to mitigate LFAs, and formulate the game-theoretic interactions between attackers and defenders. The experiment results show that attack interference is pervasive, and our proposed SPAH flooding strategy can substantially lower attack interference and increase strike precision. Moreover, we demonstrate that LFAs can be effectively mitigated based on traffic engineering from a game-theoretic perspective, wherein the defender can adopt non-cooperative measurement techniques to achieve light-weight and multi-protocol-based robust probe deployment.

Immune rejection is the major limitation for porcine xenograft survival in primate recipients. Proinflammatory cytokines play important roles in immune rejection and have been found to mediate the pathological effects in various clinical and experimental transplantation trials. IL-17 and TNF-α play critical pathological roles in immune disorders, such as psoriasis and rheumatoid arthritis. However, the pathological roles of human IL-17 (hIL-17) and human TNF-α (hTNF-α) in xenotransplantation remain unclear. Here we found that hIL-17 and hTNF-α additively or synergistically regulate the expression of 697 genes in porcine aortic endothelial cells (PAECs). Overall, 415 genes were found to be synergistically regulated, while 282 genes were found to be additively regulated. Among these, 315 genes were upregulated and 382 genes were downregulated in PAECs. Furthermore, we found that hIL-17 and hTNF-α additively or synergistically induced the expression of various proinflammatory cytokines and chemokines (e.g., IL1α, IL6, and CXCL8) and decreased the expression of certain anti-inflammatory genes (e.g., IL10). Moreover, hIL-17 plus hTNF-α increased the expression of IL1R1 and IL6ST, receptors for IL1 and IL6, respectively, and decreased anti-inflammatory gene receptor expression (IL10R). hIL-17 and hTNF-α synergistically or additively induced CXCL8 and CCL2 expression and consequently promoted primary human neutrophil and human leukemia monocytic cell migration, respectively. In addition, hIL-17 and hTNF-α induced pro-coagulation gene (SERPINB2 and F3) expression and decreased anti-coagulation gene (TFPI, THBS1, and THBD) expression. Additionally, hIL-17 and hTNF-α synergistically decreased occludin expression and consequently promoted human antibody-mediated complement-dependent cytotoxicity. Interestingly, hTNF-α increased swine leukocyte antigen (SLA) class I expression; however, hIL-17 decreased TNF-α-mediated SLA-I upregulation. We concluded that hIL-17 and hTNF-α likely promote the inflammatory response, coagulation cascade, and xenoantibody-mediated cell injury. Thus, blockade of hIL-17 and hTNF-α together might be beneficial for xenograft survival in recipients.

Abstract Diabetic foot is one of the severest complications of diabetes. In severe cases, this disease may be lead to amputation or even death due to secondary infection and ischemic necrosis. Since the ineffectiveness of traditional therapy, autologous stem cell transplantation has been used to treat diabetic foot. This simple, safe, and effective therapy is expected to be applied and promoted in the future. In this review, we described the detailed pathogenesis of diabetic foot and the common clinical treatments currently used. We also revealed vascular remodeling as the potential mechanism of therapeutic functions of adipose-derived stromal vascular fraction (SVF) in treating diabetic foot.

Abstract Apatinib has been demonstrated to be effective and safe among patients with gastric cancer failing after at least two lines chemotherapy. This study aimed to evaluate its effectiveness and safety of low‐dose apatinib for the treatment of gastric cancer in real‐world practice. We performed a prospective, multicenter observation study in a real‐world setting. Patients with advanced gastric cancer more than 18 years old were eligible and received low‐dose apatinib (500 mg or 250mg per day) therapy. The median progression‐free survival (PFS), median overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety were assessed. Between September 2017 and April 2019, a total of 747 patients were enrolled. The mPFS was 5.56 months (95% CI 4.47‐6.28), and mOS was 7.5 months (95% CI 6.74‐8.88). Four patients achieved complete response, 47 achieved partial response, and 374 patients achieved stable disease. The ORR was 6.83% and DCR was 56.89%. In addition, multivariate Cox regression analysis indicated that hand‐foot syndrome was one independent predictor for PFS and OS. The most common adverse events (AEs) at any grade were hypertension (36.55%), proteinuria (10.26%), hand‐foot syndrome (33.53%), fatigue (24.9%), anemia (57.35%), leukopenia (44.49%), thrombocytopenia (34.21%), and neutropenia (53.33%). Grade 3‐4 AEs with incidences of 5% or greater were anemia (13.97%), thrombocytopenia (7.14%), and neutropenia (6.67%). No treatment‐related death was observed during the treatment of apatinib. The prospective study suggested that low‐dose apatinib was an effective regimen for the treatment of advanced gastric cancer with tolerable or controlled toxicity in real world. Trial registration: NCT03333967.

Abstract Evolutionary game dynamics has become a hot topic in recent years. In this paper, we combine game theory and dynamical systems to investigate the stability of imitative dynamics in two-community with different kinds of delays. First, we establish a new model of imitative dynamics in two-community. Then, three sufficient conditions of the asymptotical stability for the neutrally stable strategy of the imitative dynamics are obtained. Finally, numerical simulations are consistent with the theoretical analysis.

Intervertebral disc degeneration (IDD) is a degenerative disease that is characterized by decreased matrix synthesis and extra degradation, nucleus pulposus cells (NPCs) apoptosis, and infiltration of inflammatory factors. Aloin, a colored compound from aloe plants, has been shown to be effective against skeletal degenerative diseases, but it is unclear whether it is protective against IDD. Herein, we investigated the role of aloin in NPCs. In our study, the upregulation of proinflammatory factors, apoptosis, and unbalanced matrix metabolism were observed in degenerative NP tissues. We found that aloin had a curative effect on extracellular matrix metabolism and apoptosis in TNF-alpha- (TNF-α-) treated NPCs by inhibiting oxidative stress and the proinflammatory factor expression. Further investigation revealed that aloin treatment suppressed the TAK1/NF-κB pathway. Moreover, the expression level of the NLPR3 inflammasome was downregulated after aloin treatment in TNF-α-treated NPCs. In summary, our results demonstrated that aloin treatment can reverse TNF-α-induced unbalanced matrix metabolism and apoptosis of NPCs via the TAK1/NF-κB/NLRP3 axis. This study supports that aloin can be a promising therapeutic agent for IDD.

Karst landforms constitute one of the most harmful geological conditions, which have an adverse effect on the deep foundation structures of bridges. During earthquakes, the existence of karst caves can cause serious seismic damage to the bridge pile foundation. In order to investigate the seismic response of rock-socketed piles under vertical loads in complex karst cave conditions, finite element numerical simulation analyses were carried out, referring to the practical major bridge structure rock-socketed pile project in China. The peak strain distributions of rock-socketed pile foundation influenced by single-karst cave factors under the combined action of vertical loads and ground motions were investigated, and the influences of complex multi-caves were further explored. The results showed that the restraint effect of the bedrock near the pile would gradually decrease with the increase of the height of the karst cave and the decrease of the height of the karst cave roof; under the condition of a beaded karst cave, the constraint of bedrock between the karst caves makes the pile present the distribution characteristics of “multi-segment and multi-broken line”; under the condition of an underlying karst cave, the existence of the underlying karst cave would decrease the restraint of the bedrock at the bottom pile and increase the peak strain of the pile to a certain extent. This paper revealed the seismic response law of the rock-socketed pile under vertical loads within various complex karst cave conditions and developed reasonable reinforcement measures aiming at dangerous locations, providing important engineering guidance and a reference for the seismic design of rock-socketed pile foundation in complex karst areas.

The balance between gut microbiota and host is critical for maintaining host health. Although dysregulation of the gut microbiota triggers the development of various inflammatory diseases, including colitis, the molecular mechanism of microbiota-driven colitis development is largely unknown. Here, we found that gasdermin D (GSDMD) was activated during acute colitis. In the dextran sulfate sodium (DSS)-induced colitis model, compared to wild-type mice, Gsdmd-deficient mice had less colitis severity. Mechanistically, GSDMD expression in intestinal epithelial cells (IECs), but not infiltrating immune cells, was critical for GSDMD-mediated colitis progression. Moreover, commensal Escherichia coli (E. coli) largely overgrew during colitis, and then the dysregulated commensal E. coli mediated GSDMD activation. Furthermore, the activated GSDMD promoted the release of interleukin-18 (IL-18), but not the transcript or maturation level of IL-18, which in turn mediated goblet cell loss to induce colitis development. Thus, GSDMD promotes colitis development by mediating IL-18 release, and the microbiota can mediate colitis pathogenesis through regulation of GSDMD activation. Our results provide a potential molecular mechanism by which the microbiota-driven GSDMD activation contributes to colitis pathogenesis.

Aging is a major risk factor contributing to neurodegeneration and dementia. However, it remains unclarified how aging promotes these diseases. Here, we use machine learning and weighted gene co-expression network (WGCNA) to explore the relationship between aging and gene expression in the human frontal cortex and reveal potential biomarkers and therapeutic targets of neurodegeneration and dementia related to aging. The transcriptional profiling data of the human frontal cortex from individuals ranging from 26 to 106 years old was obtained from the GEO database in NCBI. Self-Organizing Feature Map (SOM) was conducted to find the clusters in which gene expressions downregulate with aging. For WGCNA analysis, first, co-expressed genes were clustered into different modules, and modules of interest were identified through calculating the correlation coefficient between the module and phenotypic trait (age). Next, the overlapping genes between differentially expressed genes (DEG, between young and aged group) and genes in the module of interest were discovered. Random Forest classifier was performed to obtain the most significant genes in the overlapping genes. The disclosed significant genes were further identified through network analysis. Through WGCNA analysis, the greenyellow module is found to be highly negatively correlated with age, and functions mainly in long-term potentiation and calcium signaling pathways. Through step-by-step filtering of the module genes by overlapping with downregulated DEGs in aged group and Random Forest classifier analysis, we found that MAPT, KLHDC3, RAP2A, RAP2B, ELAVL2, and SYN1 were co-expressed and highly correlated with aging.

Nanotechnology has attracted much attention, and may become the key to a whole new world in the fields of food, agriculture, building materials, machinery, medicine, and electrical engineering, because of its unique physical and chemical properties, including high surface area and outstanding electrical and optical properties. The bottom-up approach in nanofabrication involves the growth of particles, and we were inspired to propose a novel nanoplasmonic method to detect the formation of nanoparticles in real time. This innovative idea may contribute to the promotion of nanotechnology development. An increase in nanometer particle size leads to optical extinction or density (OD)-value changes in our nanosensor chip at a specific wavelength measured in a generic microplate reader. Moreover, in applying this method, an ultrasensitive nanoplasmonic immunoturbidimetry assay (NanoPITA) was carried out for the high-throughput quantification of hypersensitive C-reactive protein (CRP), a well-known biomarker of cardiovascular, inflammatory, and tumor diseases. The one-step detection of the CRP concentration was completed in 10 min with high fidelity, using the endpoint analysis method. The new NanoPITA method not only produced a linear range from 1 ng/mL to 500 ng/mL CRP with the detection limit reduced to 0.54 ng/mL, which was an improvement of over 1000 times, with respect to regular immunoturbidity measurement, but was also effective in blood detection. This attractive method, combined with surface plasmon resonance and immunoturbidimetry, may become a new technology platform in the application of biological detection.

Abstract Background N-myc downstream-regulated gene 1 (NDRG1) has been shown to play a key role in tumor metastasis. Recent studies demonstrate that NDRG1 can suppress tumor growth and is related to tumor proliferation; however, the mechanisms underlying these effects remain obscure. Methods Immunohistochemistry (IHC) was used to detect NDRG1 and p21 protein expression in colorectal cancer tissue, and clinical significance of NDRG1 was also analyzed. CCK-8 assay, colony formation assay, flow cytometry, and xenograft model were used to assess the effect of NDRG1 on tumor proliferation in vivo and in vitro. The mechanisms underlying the effect of NDRG1 were investigated using western blotting, immunofluorescence, immunoprecipitation, and ubiquitylation assay. Results NDRG1 was down-regulated in CRC tissues and correlated with tumor size and patient survival. NDRG1 inhibited tumor proliferation through increasing p21 expression via suppressing p21 ubiquitylation. NDRG1 and p21 had a positive correlation both in vivo and in vitro. Mechanistically, E3 ligase NEDD4 could directly interact with and target p21 for degradation. Moreover, NDRG1 could emulatively antagonize NEDD4-mediated ubiquitylation of p21, increasing p21 expression and inhibit tumor proliferation. Conclusion Our study could fulfill potential mechanisms of the NDRG1 during tumorigenesis and metastasis, which may serve as a tumor suppressor and potential target for new therapies in human colorectal cancer.

Abstract Background The efficacy of tranexamic acid (TXA) to reduce perioperative blood loss and allogeneic blood transfusion in cardiac surgeries has been proved in previous studies, but its adverse effects especially seizure has always been a problem of concern. This meta-analysis aims to provide information on the optimal dosage and delivery method which is effective with the least adverse outcomes. Methods We searched Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE for all relevant articles published before 2018/12/31. Inclusion criteria were adult patients undergoing elective heart surgeries, and only randomized control trials comparing TXA with placebo were considered. Two authors independently assessed trial quality and extracted relevant data. Results We included 49 studies with 10,591 patients into analysis. TXA significantly reduced transfusion rate (RR 0.71, 95% CI 0.65 to 0.78, P

Abstract Background IDO1 (Indoleamine 2,3-dioxygenase 1) inhibits host anti-tumor immune response by exhausting tryptophan in tumor microenvironment, but the pathogenic mechanisms of IDO1 in gastric cancer (GC) cells need to be further explored. Methods The aim of this study was to use CCLE (Cancer Cell Line Encyclopedia) transcriptomic data of GC cell lines for WGCNA (Weighted Gene Co-expression Network Analysis) analysis, and explore the potential functions and mechanisms of IDO1 in GC progression in vitro and in vivo. Results The higher expression level of IDO1 was identified in 4 out of 7 GC cell lines. Increased IDO1 expression strongly promoted cell migration via its metabolite kynurenine and was associated with pathways of immune activation according to GSEA (Gene Set Enrichment Analysis). The functions of IDO1 were closely associated with extracellular matrix, collagen metabolic and catabolic process by WGCNA analysis. Among five hub genes (AXL, SGCE, COL12A1, ANTXR1, LOXL2), COL12A1 and LOXL2 were upregulated in GC tissues. IDO1 disclosed positive correlation with six collagen genes by coefficient matrix diagram. Knockdown of IDO1 decreased the expression of LOXL2, COL6A1, COL6A2 and COL12A1 in GC cells in both mRNA and protein levels. Of them, knockdown of COL12A1 inhibited cell migration more apparently than knockdown of others. IDO1 and COL12A1 revealed synergistic efficacy on promoting cell migration via a positive feedback sustained by MAPK pathway. This bioprocess was mediated by IDO1 metabolite kynurenine and integrin β1. A popliteal lymph nodemetastasis model was established for verifying metastatic promotion of IDO1 and COL12A1 in GC. Conclusions IDO1 and COL12A1 synergistically promoted GC metastasis. The novel findings suggested that both IDO1 and COL12A1 may be promising targets on anti-cancer treatment in GC.

Substantial heterogeneity exists within cervical cancer that is generally infected by human papillomavirus (HPV). However, the most common histological subtype of cervical cancer, cervical squamous cell carcinoma (CSCC), is poorly characterized regarding the association between its heterogeneity and HPV oncoprotein expression. We filtered out 138 CSCC samples with infection of HPV16 only as the first step; then we compressed HPV16 E6/E7 expression as HPVpca and correlated HPVpca with the immunological profiling of CSCC based on supervised clustering to discover subtypes and to characterize the differences between subgroups in terms of the HPVpca level, pathway activity, epigenetic dysregulation, somatic mutation frequencies, and likelihood of responding to chemo/immunotherapies. Supervised clustering of immune signatures revealed two HPV16 subtypes (namely, HPV16-IMM and HPV16-KRT) that correlated with HPVpca and clinical outcomes. HPV16-KRT is characterized by elevated expression of genes in keratinization, biological oxidation, and Wnt signaling, whereas HPV16-IMM has a strong immune response and mesenchymal features. HPV16-IMM exhibited much more epigenetic silencing and significant mutation at FBXW7, while MUC4 and PIK3CA were mutated frequently for HPV16-KRT. We also imputed that HPV16-IMM is much more sensitive to chemo/immunotherapy than is HPV16-KRT. Our characterization tightly links the expression of HPV16 E6/E7 with biological and clinical outcomes of CSCC, providing valuable molecular-level information that points to decoding heterogeneity. Together, these results shed light on stratifications of CSCC infected by HPV16 and shall help to guide personalized management and treatment of patients.

Evolutionary game dynamics is a combination of game theory and dynamical systems. Using dynamical theory, we investigate chaotic behavior in asymmetric Rock-Paper-Scissors games under imitative dynamics with two different populations. Our theoretical analysis and numerical simulations demonstrate that the dynamical system can give rise to chaotic behavior in zero-sum and positive-sum asymmetric games. However, chaos cannot occur in a negative-sum asymmetric game. In particular, the numerical simulations show that there is a limit cycle in a negative-sum asymmetric game.