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Abstract. Background:. Ainuovirine (ANV) is a new generation of non-nucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus (HIV) type 1 infection. This study aimed to evaluate the population pharmacokinetic (PopPK) profile and exposure–response relationship of ANV among people living with HIV. Methods:. Plasma concentration-time data from phase 1 and phase 3 clinical trials of ANV were pooled for developing the PopPK model. Exposure estimates obtained from the final model were used in exposure–response analysis for virologic responses and safety responses. Results:. ANV exhibited a nonlinear pharmacokinetic profile, which was best described by a two-compartment model with first-order elimination. There were no significant covariates correlated to the pharmacokinetic parameters of ANV. The PopPK parameter estimate (relative standard error [%]) for clearance adjusted for bioavailability (CL/F) was 6.46 (15.00) L/h, and the clearance of ANV increased after multiple doses. The exposure–response model revealed no significant correlation between the virologic response (HIV-RNA

Abstract Background The regulator of calcineurin 1 (RCAN1) is expressed in multiple organs, including the heart, liver, brain, and kidney, and is closely linked to the pathogenesis of cardiovascular diseases, Down syndrome, and Alzheimer’s disease. It is also implicated in the development of various organ tumors; however, its potential role in hepatocellular carcinoma (HCC) remains poorly understood. Therefore, the objective of this study was to investigate the potential mechanisms of RCAN1 in HCC through bioinformatics analysis. Methods We conducted a joint analysis based on the NCBI and TCGA databases, integrating both bulk transcriptome and single-cell analyses to examine the principal biological functions of RCAN1 in HCC, as well as its roles related to phenotype, metabolism, and cell communication. Subsequently, an RCAN1-overexpressing cell line was established, and the effects of RCAN1 on tumor cells were validated through in vitro experiments. Moreover, we endeavored to identify potential related drugs using molecular docking and molecular dynamics simulations. Results The expression of RCAN1 was found to be downregulated in 19 types of cancer tissues and upregulated in 11 types of cancer tissues. Higher levels of RCAN1 expression were associated with improved patient survival. RCAN1 was predominantly expressed in hepatocytes, macrophages, endothelial cells, and monocytes, and its high expression not only closely correlated with the distribution of cells related to the HCC phenotype but also with the distribution of HCC cells themselves. Additionally, Rcan1 may directly or indirectly participate in metabolic pathways such as alanine, aspartate, and glutamate metabolism, as well as butanoate metabolism, thereby influencing tumor cell proliferation and migration. In vitro experiments confirmed that RCAN1 overexpression promoted apoptosis while inhibiting proliferation and invasion of HCC cells. Through molecular docking of 1615 drugs, we screened brompheniramine as a potential target drug and verified our results by molecular dynamics. Conclusion In this study, we revealed the relationship between RCAN1 and HCC through bioinformatics methods, verified that RCAN1 can affect the progress of the disease through experiments, and finally identified potential therapeutic drugs through drug molecular docking and molecular dynamics.

Abstract. Background:. Antiretroviral therapy (ART) was often associated with dyslipidemia among human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) patients. This study aimed to assess treatment-naïve adult male patients with HIV/AIDS who initiated ART with either co-formulated bictegravir, emtricitabine, and tenofovir alafenamide (BIC/FTC/TAF) or lamivudine, efavirenz, and tenofovir disoproxil fumarate (3TC+EFV+TDF), monitoring at weeks 4, 12, 24, and 48. Methods:. A case-control retrospective study was conducted. The newly diagnosed HIV-infected individuals attending the sexual transmission disease (STD)/AIDS clinic of Beijing Youan Hospital, Capital Medical University, from January to December 2021. The patients were divided into BIC/FTC/TAF group or 3TC+EFV+TDF group. High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and total cholesterol (TC) at different time points over 48 weeks between two groups were compared. A multivariate Cox regression model was used to identify relevant influencing factors for the population at high risk of increased LDL-C. Results:. A total of 870 participants, with 510 in BIC/FTC/TAF group and 360 in 3TC+EFV+TDF group. There were no statistically significant differences in median age, baseline CD4/CD8 ratio, median body mass index (BMI) between the two groups. In both two groups, levels of TG, TC, and LDL-C were higher at 4 weeks, 12 weeks, and 24 weeks of treatment (all P 0.05). In addition, the differences in average changes of the level of TG, TC, HDL-C, and LDL-C from weeks 4, 12, 24, and 48 to baseline between two groups were not statistically significant (all P >0.05). Multivariate Cox proportional risk model analysis showed that initiating ART with HIV RNA ≥105 copies/mL (compared with

Abstract Polysaccharopeptide (PSP) is a potential active component in traditional Chinese medicine because of its anticancer effects on a variety of cancer cells and as immune enhancers of the immune system. Previous studies on the role of PSP in breast cancer have been limited, and the mechanism has not been clarified. This study is based on network pharmacology and molecular docking technology to predict the possible target of PSP treatment of breast cancer, and use experiments to verify the effect and mechanism of PSP on breast cancer. In this study, 287 PSP targets were obtained using SwissTargetPrediction database and PharmMapper database, and 183 breast cancer targets were obtained using DisGenNET database. By intersections of PSP targets and breast cancer targets, a total of 10 intersections were obtained. GO functional enrichment, KEGG pathway enrichment and molecular docking of these 10 target genes were performed to obtain the potential targets of PSP on breast cancer. In vitro experiments, we found that PSP significantly inhibited the proliferation and induced apoptosis of breast cancer cell lines MDA-MB-231, SUM-159 and MCF-7. Western Blot results showed that PSP could down-regulate the expression of p-JAK2 and p-STAT3 proteins. Similarly, the results of in vivo experiments showed that PSP can directly inhibit the tumor of MDA-MB-231 tumor-bearing mice, and the mechanism of action is mainly to inhibit the JAK2-STAT3 pathway. The above results were consistent with the results of network pharmacology, which provides a scientific basis for the clinical application of PSP in breast cancer patients.

Abstract Whether intestinal Leucine-rich repeat containing G-protein-coupled receptor 4 (LGR4) impacts nutrition absorption and energy homeostasis remains unknown. Here, we report that deficiency of Lgr4 (Lgr4 iKO ) in intestinal epithelium decreased the proportion of enterocytes selective for long-chain fatty acid absorption, leading to reduction in lipid absorption and subsequent improvement in lipid and glucose metabolism. Single-cell RNA sequencing demonstrates the heterogeneity of absorptive enterocytes, with a decrease in enterocytes selective for long-chain fatty acid-absorption and an increase in enterocytes selective for carbohydrate absorption in Lgr4 iKO mice. Activation of Notch signaling and concurrent inhibition of Wnt signaling are observed in the transgenes. Associated with these alterations is the substantial reduction in lipid absorption. Decrement in lipid absorption renders Lgr4 iKO mice resistant to high fat diet-induced obesity relevant to wild type littermates. Our study thus suggests that targeting intestinal LGR4 is a potential strategy for the intervention of obesity and liver steatosis.

Abstract As a strategy to improve the therapeutic success of chimeric antigen receptor T cells (CART) directed against solid tumors, we here test the combinatorial use of CART and IMSA101, a newly developed stimulator of interferon genes (STING) agonist. In two syngeneic tumor models, improved overall survival is observed when mice are treated with intratumorally administered IMSA101 in addition to intravenous CART infusion. Transcriptomic analyses of CART isolated from tumors show elevated T cell activation, as well as upregulated cytokine pathway signatures, in particular IL-18, in the combination treatment group. Also, higher levels of IL-18 in serum and tumor are detected with IMSA101 treatment. Consistent with this, the use of IL-18 receptor negative CART impair anti-tumor responses in mice receiving combination treatment. In summary, we find that IMSA101 enhances CART function which is facilitated through STING agonist-induced IL-18 secretion.

Flax is a crucial fiber crop that exhibits excellent textile properties and serves as a model plant for investigating phloem fiber development. The regulation of multiple genes significantly influences fiber development, notably involving NAC (NAM, ATAF1/2, CUC2) transcription factors in forming the fiber secondary cell wall (SCW). Overexpression of LuNAC61 in flax resulted in sparse top meristematic zone leaves and significantly reduced stem cellulose content. Scanning electron microscopy and staining observations revealed a significant reduction in fiber bundles. β-Glucuronidase (GUS) staining analysis demonstrated high activity of the LuNAC61 promoter in the bast fibers of the flax stem. Additionally, several members of the LuPLATZ and LuCesA families exhibited significant coexpression with LuNAC61. Subcellular localization indicated the presence of LuPLATZ24 protein in the nucleus and cytoplasm, LuNAC61 protein exclusively in the nucleus, and LuCesA10 in the nucleus and endoplasmic reticulum. LuPLATZ24 positively regulates LuNAC61, whereas LuNAC61 negatively affects LuCesA10, suggesting the involvement of a metabolic network in regulating flax fiber development. In conclusion, this study provides a critical opportunity for a comprehensive and in-depth analysis of the mechanisms governing flax fiber development and the potential use of biotechnology to enhance flax fiber yield.

Abstract Shear failure often occurs in engineering rock mass (such as inclined pillar) in gently inclined strata. Prediction and characterization the orientation of shear failure plane is the foundation of rock mass engineering reinforcement. In this paper, sandstone samples are used to perform uniaxial and shear tests to obtain the basic mechanical parameters. Then, by employing the numerical method, the combined compression–shear loading tests were carried out for inclined specimens varied from 0° to 25° at an interval of 5°, to obtain the dip effect on the orientation of rock failure plane. The results show that the failure plane of rock changes with the change of dip angle of rock sample. Based on the Mohr–Coulomb criterion, the ultimate stress state of rock was characterized under combined compression–shear loading. The ultimate strength of rock is equal to the ratio of the stress circle radius of rock under combined compression–shear condition to the stress circle radius of rock under uniaxial compression condition, multiplied by the uniaxial compressive strength. The fracture angle of rock was defined under combined compression–shear loading. A theoretical model was developed for predicting the fracture angle. The developed model could be characterized by internal friction angle, dip angle of rock sample and Poisson's ratio. Finally, the numerical results of the fracture angle were analyzed, which are consistent with the predicted results of the model. The investigation shows that the rock fracture angle has a dip effect, which decreases with the increase of the inclination angle of the sample. The research results provide a new means to identify the potential failure plane of engineering rock mass, and lay a theoretical foundation for calculating the orientation of rock fracture plane.

Zeolite foamed asphalt - warm mix mixture (ZFA-WMM) has been applied in large quantities in asphalt pavement, however, a lower construction temperature, residual zeolite water and zeolite minerals have different effects on the cohesion and adhesion properties of zeolite foamed asphalt (ZFA), which indirectly affects the water stability of its mixture. This study analyzed the interface behavior in ZFA-WMM using molecular dynamics simulation. First, the molecular model of ZFA was constructed, and its thermodynamic properties were calculated and compared with experimental values and related simulated values to validated the reasonable of model. Then, the interface models of ZFA-aggregate (quartz and calcite) and ZFA-ZFA were established, simulating the effects of the zeolite mineral dosage, temperature, and interface moisture (residual zeolite water) content on the cohesion and adhesion of ZFA. Furthermore, the occurrence mode of cohesion or adhesion failures in ZFA-WMM were predicted by comparing the ZFA-aggregate adhesion work with ZFA cohesion work. The simulation results indicated that as the zeolite mineral dosage increased, the ZFA cohesion and ZFA-calcite adhesion increased, while ZFA-quartz adhesion first grew and then dropped, reaching its maximum at 9.4 % zeolite mineral dosage. Under the pavement operating temperature range (-15°C∼65°C), higher pavement temperatures are beneficial to ZFA-aggregate adhesion; the cohesion of ZFA first increases and then decrease as temperature rises, reaching its maximum at 25℃. The larger the interface moisture content, the higher the possibility of water separating ZFA from the aggregate surface and the water sensitivity of ZFA-WMM. The ZFA-WMM is prone to adhesion failure, especially at higher zeolite dosages.

ABSTRACTBackground Inflammatory bowel disease (IBD) is characterized by immune-mediated, chronic inflammation of the intestinal tract. The occurrence of IBD is driven by the complex interactions of multiple factors. The objective of this study was to evaluate the therapeutic effects of IAA in colitis.Method C57/BL6 mice were administered 2.5% DSS in drinking water to induce colitis. IAA, Bifidobacterium pseudolongum, and R-equol were administered by oral gavage and fed a regular diet. The Disease Activity Index was used to evaluate disease activity. The degree of colitis was evaluated using histological morphology, RNA, and inflammation marker proteins. CD45+ CD4+ FOXP3+ Treg and CD45+ CD4+ IL17A+ Th17 cells were detected by flow cytometry. Analysis of the gut microbiome in fecal content was performed using 16S rRNA gene sequencing. Gut microbiome metabolites were analyzed using Untargeted Metabolomics.Result In our study, we found IAA alleviates DSS-induced colitis in mice by altering the gut microbiome. The abundance of Bifidobacterium pseudolongum significantly increased in the IAA treatment group. Bifidobacterium pseudolongum ATCC25526 alleviates DSS-induced colitis by increasing the ratio of Foxp3+T cells in colon tissue. R-equol alleviates DSS-induced colitis by increasing Foxp3+T cells, which may be the mechanism by which ATCC25526 alleviates DSS-induced colitis in mice.Conclusion Our study demonstrates that IAA, an indole derivative, alleviates DSS-induced colitis by promoting the production of Equol from Bifidobacterium pseudolongum, which provides new insights into gut homeostasis regulated by indole metabolites other than the classic AHR pathway.

For randomly degraded products undergoing a two-stage degradation process, traditional random effects models assume that the degradation rate follows a symmetrically normal distribution. However, certain products exhibit asymmetric degradation rates. In light of this, this paper proposes an approach for reliability analysis based on the inverse Gaussian (IG) degeneration process, which considers both asymmetric random effects and the two-stage nature simultaneously. To begin with, we establish a two-stage IG degradation process model that incorporates a skew normal random effect. Subsequently, we determine the location of change points using the Schwarz Information Criterion (SIC). The estimation of parameters is then conducted by combining Maximum Likelihood Estimations (MLEs) with the Genetic Algorithm (GA). Finally, we validate and demonstrate the practicality for the proposed model through Monte Carlo (MC) simulation and examples involving lithium batteries.

Asphalt mixtures are multiphase heterogeneous composites, the random distribution of the components leads to variability in the internal mechanical parameters of the material, but this variability has a certain degree of spatial correlation. In this study, the spatial variability and correlation of mechanical parameters of asphalt mixture materials are studied. Firstly, the viscoelastic and fracture parameters of asphalt mixtures were obtained by uniaxial compression test and semicircular bending (SCB) test. Then, the covariance decomposition method and Latin hypercubic sampling method were used to build the parameter random fields of long-term equilibrium modulus, flexural tensile strength and fracture energy of asphalt mixtures. Finally, using the extended finite element method to simulate the SCB test in ABAQUS. The results show that the application of the random field technique and the consideration of the spatial variability correlation of asphalt mixture material parameters can well simulate the randomness of the mechanical response of asphalt mixture materials caused by the randomness of the internal mechanical parameters in the laboratory test. The spatial variability of different parameters has different effects on the fracture response of semicircular specimens: the long-term equilibrium modulus and flexural and tensile strength mainly affect the loading stage of the load-displacement curve, while the fracture energy has a greater effect on the unloading stage.

In this study activated carbon powder (ACP) was incorporated into asphalt to substitute a portion of the conventional filler (mineral powder, MP). The dynamic modulus at elevated temperatures, temperature-dependent viscosity sensitivity, low-temperature creep, and the interaction between asphalt and ACP were examined through dynamic shear rheometer testing, viscosity testing, and bending beam rheometer testing. Moreover, statistical methodologies such as the entropy weight method (EWM) and the Technique for Order Preference by Similarity to an Ideal Solution (TOPSIS) were employed to optimize the proportion of ACP by evaluating the comprehensive rheological behavior of asphalt mastic (including high temperature performance, low temperature performance, flowability, and asphalt-ACP interaction). The findings demonstrate that ACP can enhance the resistance of asphalt mastic to high-temperature deformation to a certain degree. The ratio of creep rate to stiffness (m/S) decreases with the addition of ACP, indicating that ACP may exacerbate the occurrence of low-temperature thermal cracking in asphalt mastic. The interaction ability of asphalt mastic is significantly enhanced when a portion of the filler is replaced with ACP. The loss factor shows significant impact on the comprehensive evaluation. According to TOPSIS analysis, asphalt mastic with a blending proportion of 40% ACP and 60% MP performs better in terms of comprehensive rheological properties.

Abstract Background Interpregnancy interval (IPI) is associated with a variety of adverse maternal and infant outcomes. However, reports of its associations with early infant neurodevelopment are limited and the mechanisms of this association have not been elucidated. Maternal–fetal glucose metabolism has been shown to be associated with infant neurodevelopmental. The objective of this study was to determine whether this metabolism plays a role in the relationship between IPI and neurodevelopment. Methods This prospective birth cohort study included 2599 mother-infant pairs. The IPI was calculated by subtracting the gestational age of the current pregnancy from the interval at the end of the previous pregnancy. Neurodevelopmental outcomes at 12 months in infants were assessed by the Ages and Stages Questionnaire Edition 3 (ASQ-3). Maternal fasting venous blood was collected at 24–28 weeks and cord blood was collected at delivery. The association between IPI and neurodevelopment was determined by logistic regression. Mediation and sensitivity analyses were also conducted. Results In our cohort, 14.0% had an IPI

System-level fault diagnosis model, namely, the PMC model, detects fault nodes only through the mutual testing of nodes in the system without physical equipment. In order to achieve server nodes fault diagnosis in large-scale data center networks (DCNs), the traditional algorithm based on the PMC model cannot meet the characteristics of high diagnosability, high accuracy and high efficiency due to its inability to ensure that the test nodes are fault-free. This paper first proposed a fault-tolerant Hamiltonian cycle fault diagnosis (FHFD) algorithm, which tests nodes in the order of the Hamiltonian cycle to ensure that the test nodes are faultless. In order to improve testing efficiency, a hierarchical diagnosis mechanism was further proposed, which recursively divides high scale structures into a large number of low scale structures based on the recursive structure characteristics of DCNs. Additionally, we proved that $ 2(n-2){n^{k-1}} $ and $ (n-2){t_{n, k}}/{t_{n, 1}} $ faulty nodes could be detected for $ BCub{e_{n, k}} $ and $ DCel{l_{n, k}} $ within a limited time for the proposed diagnosis strategy. Simulation experiments have also shown that our proposed strategy has improved the diagnosability and test efficiency dramatically.

Abstract The α‐amylase inhibition and binding behaviors of shikimic acid and its structural analogues were studied. Uncompetitive inhibition characteristic of shikimic acid was identified through several linear transformation equations of enzymatic data considering the good linearity. Interestingly, the change in concentrations of starch would not decrease the inhibitory effects of shikimic acid with various concentrations used in present study. The inhibitory effect reduced greatly after the ethyl esterification of shikimic acid. Gallic acid was distinguished from shikimic acid by a benzene ring and exhibited lower inhibition than shikimic acid. Shikimic acid affected the α‐amylase structure by binding to the non‐active site but did not quench the α‐amylase fluorescent intensity. However, gallic acid anchored with a subsite containing some fluorescent residues at the entrance of active pocket, quenching the fluorescence intensity of α‐amylase strongly. The difference in shikimic acid and gallic acid made the changes in their binding sites as well as the binding behavior. Conclusively, the carboxyl and hexatomic ring with one double‐bond played an important role in binding of shikimic acid with the non‐active sites of α‐amylase. Shikimic acid has potentials as a functional‐factor in α‐amylase inhibition for controlling the postprandial blood sugar level.

The development, differentiation, and function of immune cells are precisely regulated by transcription factors. The E26 transformation-specific (ETS) transcription factor family is involved in various physiological and pathological processes by regulating cell proliferation, differentiation, and apoptosis. Emerging evidence has suggested that ETS family proteins are intimately involved in the development and function of immune cells. This review summarizes the role of the ETS family in immune cells and immune-related disorders. Seven transcription factors within the ETS family, including PU.1, ETV5, ETV6, ETS1/2, ELK3, and ELF1, play essential roles in the development and function of T cells, B cells, macrophages, neutrophils, and dendritic cells. Furthermore, they are involved in the occurrence and development of immune-related diseases, including tumors, allergies, autoimmune diseases, and arteriosclerosis. This review is conducive to a comprehensive overview of the role of the ETS family in immune cells, and thus is informative for the development of novel therapeutic strategies targeting the ETS family for immune-related diseases.

BackgroundTrastuzumab emtansine (T-DM1) has been approved worldwide for treating metastatic breast cancer (mBC) in patients who have received first-line therapy, shown disease progression, and are human epidermal growth factor receptor 2 (HER2)-positive. T-DM1 received approval in China to treat early-stage breast cancer (BC) in 2020 and for mBC in 2021. In March 2023, T-DM1 was included in medical insurance coverage, significantly expanding the eligible population.Materials and methodsThis post-marketing observational study aimed to assess the safety and effectiveness of T-DM1 in real-world clinical practice in China. This study enrolled 31 individuals with HER2-positive early-stage BC and 70 individuals with HER2-positive advanced BC from 8 study centers in Shandong Province, China. The T-DM1 dosage was 3.6 mg/kg injected intravenously every 3 weeks until the disease advanced or the drug toxicity became uncontrollable, whichever occurred earlier. Additionally, efficacy and safety information on T-DM1 were collected.ResultsDuring the 7-month follow-up period, no recurrence or metastases were observed in patients who had early-stage BC. The disease control rate was 31.43% (22/70) in patients with advanced BC. The most common adverse effect of T-DM1 was thrombocytopenia, with an incidence of 69.31% (70/101), and the probability of Grade ≥ 3 thrombocytopenia was 11.88% (12/101).ConclusionThis real-world study demonstrated that T-DM1 had good efficacy and was well tolerated by both HER2-positive early-stage BC and mBC patients.

Abstract The progression of chronic kidney diseases (CKD) is complex, influenced by a myriad of factors including gut microbiota. While emerging evidence suggests that gut microbiota can have beneficial effects in managing CKD, it is also recognized that dysbiosis may contribute to the progression of CKD and associated uremic complications. Our previous research has demonstrated the efficacy of lanthanum hydroxide in delaying kidney failure and preserving renal function. However, the role of lanthanum hydroxide in modulating gut microbiota in this context remains unclear. In our study, we induced CKD in rats using adenine, leading to gut microbial dysbiosis, kidney pathology, and disturbances in amino acid metabolism. In this adenine‐induced CKD model with hyperphosphatemia, treatment with lanthanum hydroxide improved renal function. This improvement was associated with the restoration of gut microbial balance and an increase in urine ammonium metabolism. These results suggest that the therapeutic potential of lanthanum hydroxide in CKD may be partly due to its ability to reshape gut microbiota composition. This study underscores the significance of lanthanum hydroxide in kidney protection, attributing its benefits to the modulation of gut microbiota in a rat model of CKD.

Rapid and accurate identification of lactic acid bacteria (LAB) species would greatly improve the screening rate for functional LAB. Although many conventional and molecular methods have proven efficient and reliable, LAB identification using these methods has generally been slow and tedious. Single-cell Raman spectroscopy (SCRS) provides the phenotypic profile of a single cell and can be performed by Raman spectroscopy (which directly detects vibrations of chemical bonds through inelastic scattering by a laser light) using an individual live cell. Recently, owing to its affordability, non-invasiveness, and label-free features, the Ramanome has emerged as a potential technique for fast bacterial detection. Here, we established a reference Ramanome database consisting of SCRS data from 1,650 cells from nine LAB species/subspecies and conducted further analysis using machine learning approaches, which have high efficiency and accuracy. We chose the ensemble meta-classifier (EMC), which is suitable for solving multi-classification problems, to perform in-depth mining and analysis of the Ramanome data. To optimize the accuracy and efficiency of the machine learning algorithm, we compared nine classifiers: LDA, SVM, RF, XGBoost, KNN, PLS-DA, CNN, LSTM, and EMC. EMC achieved the highest average prediction accuracy of 97.3% for recognizing LAB at the species/subspecies level. In summary, Ramanomes, with the integration of EMC, have promising potential for fast LAB species/subspecies identification in laboratories and may thus be further developed and sharpened for the direct identification and prediction of LAB species from fermented food.

Background: Nur77 belongs to the member of orphan nuclear receptor 4A family that plays critical roles in maintaining vascular homeostasis. This study aims to determine whether Nur77 plays a role in attenuating vascular dysfunction, and if so, to determine the molecular mechanisms involved. Methods: Both Nur77 knockout (Nur77 KO) and Nur77 endothelial specific transgenic mice (Nur77-Tg) were employed to examine the functional significance of Nur77 in vascular endothelium in vivo. Endothelium-dependent vasodilatation to acetylcholine (Ach) and reactive oxygen species (ROS) production was determined under inflammatory and high glucose conditions. Expression of genes was determined by real-time PCR and western blot analysis. Results: In response to tumor necrosis factor alpha (TNF-α) treatment and diabetes, the endothelium-dependent vasodilatation to Ach was significantly impaired in aorta from Nur77 KO as compared with those from the wild-type (WT) mice. Endothelial specific overexpression of Nur77 markedly prevented both TNF-α- and high glucose-induced endothelial dysfunction. Compared with WT mice, after TNF-α and high glucose treatment, ROS production in aorta was significantly increased in Nur77 KO mice, but it was inhibited in Nur77-Tg mice, as determined by dihydroethidium (DHE) staining. Furthermore, we demonstrated that Nur77 overexpression substantially increased the expression of several key enzymes involved in nitric oxide (NO) production and ROS scavenging, including endothelial nitric oxide synthase (eNOS), guanosine triphosphate cyclohydrolase 1 (GCH-1), glutathione peroxidase-1 (GPx-1), and superoxide dismutases (SODs). Mechanistically, we found that Nur77 increased GCH1 mRNA stability by inhibiting the expression of microRNA-133a, while Nur77 upregulated SOD1 expression through directly binding to the human SOD1 promoter in vascular endothelial cells. Conclusion: Our results suggest that Nur77 plays an essential role in attenuating endothelial dysfunction through activating NO production and anti-oxidant pathways in vascular endothelium. Targeted activation of Nur77 may provide a novel therapeutic approach for the treatment of cardiovascular diseases associated with endothelial dysfunction.

Mechanism underlying the metabolic benefit of intermittent fasting remains largely unknown. Here, we reported that intermittent fasting promoted interleukin-22 (IL-22) production by type 3 innate lymphoid cells (ILC3s) and subsequent beigeing of subcutaneous white adipose tissue. Adoptive transfer of intestinal ILC3s increased beigeing of white adipose tissue in diet-induced-obese mice. Exogenous IL-22 significantly increased the beigeing of subcutaneous white adipose tissue. Deficiency of IL-22 receptor (IL-22R) attenuated the beigeing induced by intermittent fasting. Single-cell sequencing of sorted intestinal immune cells revealed that intermittent fasting increased aryl hydrocarbon receptor signaling in ILC3s. Analysis of cell-cell ligand receptor interactions indicated that intermittent fasting may stimulate the interaction of ILC3s with dendritic cells and macrophages. These results establish the role of intestinal ILC3s in beigeing of white adipose tissue, suggesting that ILC3/IL-22/IL-22R axis contributes to the metabolic benefit of intermittent fasting.

In this study, we have developed a novel fluorescent ''OFF-ON'' quantum dots (QDs) sensor based on CdTe/CdS/SiO2 cores. Ammonium pyrrolidine dithiocarbamate (APDC), ethylenediamine tetraacetic acid (EDTA), and 1,10-phenanthroline (Phen) served as potential chemical etchants. Among these three etchants, APDC exhibited the most pronounced quenching effect (94.06%). The APDC-etched CdTe/CdS/SiO2 QDs demonstrated excellent optical properties: the fluorescence of the APDC-etched CdTe/CdS/SiO2 QDs system (excitation wavelength: 365 nm and emission wavelength: 622 nm) was significantly and selectively restored upon the addition of cadmium ions (Cd2+) (89.22%), compared to 15 other metal ions. The linear response of the APDC-etched CdTe/CdS/SiO2 QDs was observed within the cadmium ion (Cd2+) concentration ranges of 0–20 μmol L−1 and 20–160 μmol L−1 under optimized conditions (APDC: 300 μmol L−1, pH: 7.0, reaction time: 10 min). The detection limit (LOD) of the APDC-etched CdTe/CdS/SiO2 QDs for Cd2+ was 0.3451 μmol L−1 in the range of 0–20 μmol L−1. The LOD achieved by the QDs in this study surpasses that of the majority of previously reported nanomaterials. The feasibility of using APDC-etched CdTe/CdS/SiO2 QDs for Cd2+ detection in seawater, freshwater, and milk samples was verified, with average recoveries of 95.27%–110.68%, 92%–106.47%, and 90.73%–111.60%, respectively, demonstrating satisfactory analytical precision (RSD ≤ 8.26).

Abstract Reducing greenhouse gas emissions has turned into a pillar of climate change mitigation. Truck platooning is proposed as a strategy to lower emissions from vehicles on roads. However, the potential interactive impacts of this technology on road infrastructure emissions remain unclear. Here, we evaluate the decarbonization effects of truck platooning on the integrated vehicle-road system at a large-scale road network level, spanning 1457 road sections across North America. We show that truck platooning decreases emissions induced by truck operations, but it degrades faster the durability of road infrastructure and leads to a 27.9% rise in road emissions due to more frequent maintenance work. Overall, truck platooning results in a 5.1% emission reduction of the integrated vehicle-road system. In contrast to the benefits of emission reduction, truck platooning leads to additional financial burdens on car users and transportation agencies, calling for the consideration of tradeoffs between emissions and costs and between agencies and users. Our research provides insights into the potential applications of truck platooning to mitigate climate change.

This study employed molecular dynamics simulation to investigate the mechanism of action of graphene-modified asphalt. A series of molecular models of graphene-modified asphalt were constructed and validated using thermodynamic parameters. The impact of the graphene (PGR) size and number of layers on its interaction with asphalt components were examined, and the self-healing process and mechanism of action of PGR-modified asphalt were analyzed. The results demonstrated that the size and number of layers of PGR significantly influenced its interaction with asphalt components, with polar components demonstrating a stronger affinity for PGR. When the size and number of layers of PGR were held constant, the interfacial binding energy between it and ACR-modified asphalt was the highest, followed by SBS-modified asphalt, and 70# matrix asphalt exhibited the lowest interfacial binding strength. This interfacial binding strength is primarily attributed to intermolecular van der Waals interactions. Furthermore, the incorporation of multi-layer PGR can markedly enhance the mechanical properties of matrix asphalt, whereas small-sized PGR is more efficacious in improving the low-temperature performance of polymer-modified asphalt. PGR can act as a bridge between asphalt molecules through rapid heat transfer and π-π stacking with aromatic ring-containing substances, which markedly increases the free diffusion ability of asphalt molecules, shortens the healing time of asphalt, and enhances the collective self-healing performance of asphalt. This study provides an essential theoretical basis for understanding the mechanism and application of PGR in asphalt modification.

Cadmium (Cd) is a toxic heavy metal that causes nephrosis, including acute kidney injury. To prevent and treat acute kidney injury (AKI) following Cd exposure, a tripeptide, Ser-Arg-Pro (SRP), from Sipunculus nudus L. was employed, and its potential efficacy in AKI was assessed. Oral administration of SRP significantly alleviated Cd-induced kidney damage, leading to improved renal function and the attenuation of structural abnormalities. A network pharmacology analysis revealed the potential of SRP in renal protection by targeting various pathways, including mitogen-activated protein kinase (MAPK) signaling, inflammatory response, and apoptosis pathways. Mechanistic studies indicated that SRP achieves renal protection by inhibiting the activation of MAPK pathways (phosphorylation of p38, p56, ERK, and JNK) in the oxidative stress cascade, suppressing inflammatory responses (iNOS, Arg1, Cox2, TNF-α, IL-1β, and IL-6), and restoring altered apoptosis factors (caspase-9, caspase-3, Bax, and Bcl-2). Hence, SRP has the potential to be used as a therapeutic agent for the treatment of Cd-induced nephrotoxicity.

Previous reports have mainly investigated the long-term effects (>30 d), such as gut microbiota dysbiosis and systemic low-grade inflammation, in mice fed fried oil. However, short-term intake of deep-fried oil is more likely to occur in daily life, and such studies are lacking. This study aimed to investigate the short-term effects of fried oil intake on systemic low-grade inflammation. Male Kunming mice were fed non-fried soybean oil or low (25%), medium (50%), or high (100%)—fried oil at 4.4 g/kg for 6 d. Serum and fecal samples were collected on day 7. In all groups fed fried oil, the serum levels of tumor necrosis factor (TNF-α) were significantly elevated 2-4-fold. Among the gut microbiota, the abundance of Alloprevotella significantly decreased by up to 76%, while Lactobacilli significantly increased by up to 385%. The fecal valeric acid content was significantly increased and positively correlated with TNF-α levels. Both valeric acid and TNF-α levels were positively correlated with the abundance of Lactobacilli and negatively correlated with that of Alloprevotella. In summary, a short-term ingestion of even low doses of fried oil alters the gut microbiota Alloprevotella and Lactobacilli and increases fecal valeric acid content, which correlates with increased serum TNF-α levels.

Chronic stress (CS) endangers the physical and mental health of adolescents. Therefore, alleviating and preventing such negative health impacts are a top priority. This study explores the effect of feeding shrimp head hydrolysate (SHH) on gut microbiota, short-chain fatty acids (SCFAs), and neurotransmitters in growing C57BL/6 mice subjected to chronic unpredictable mild stress. Mice in the model group and three SHH groups were exposed to CS for 44 days, distilled water and SHH doses of 0.18, 0.45, 0.90 g/kg·BW were given respectively by gavage daily for 30 days from the 15th day. The results showed that SHH can significantly reverse depression-like behaviour, amino acids degradation, α diversity and β diversity, proportion of Firmicutes and Bacteroidota, abundance of genera such as Muribaculaceae, Bacteroides, Prevotellaceae_UCG-001, Parabacteroides and Alistipes, concentration of five short-chain fatty acids (SCFAs), 5-HT and glutamate induced by CS. Muribaculaceae and butyric acid may be a controlled target. This study highlights the potential and broad application of SHH as an active ingredient in food to combat chronic stress damage.

Waste tire rubber powder-modified asphalt (RMA) has been widely used in road construction, which was traditionally limited by the poor compatibility of RMA, affecting pavement performance. By synthesizing epoxy soybean oil with amide groups (ESO/TETA) and grafting it onto desulfurized rubber powder (DCR) through microwave irradiation, a surface-functionalized rubber powder (MDCR) was produced successfully. The effects of the physical properties, storage stability, thermal stability, and rheological behavior of the modified asphalt were studied. The results show that the MDCR with a polar surface improved the compatibility and adhesive interactions between the modified crumb rubber and the asphalt. The MDCR content could reach 50%, and the phase separation could meet the requirements of 2.2 °C, which has application conditions in engineering for stable storage. Additionally, the inclusion of MDCR in the asphalt formulations significantly mitigated the temperature sensitivity of the modified asphalt. Importantly, when the MDCR constituted from 20% to 50% of the asphalt, there was a noted reduction in the phase angle at temperatures above 70 °C, indicating a significant improvement in the elastic efficiency. The MDCR also led to substantial enhancements in the resistance of the asphalt to high-temperature and high-stress rutting, addressing the crucial limitations in the consumption ability of waste tire rubber powder and improving the overall performance of RMA in pavement applications.

A comprehensive experimental investigation of Portland cement hydration kinetics in a wide temperature range from 35 °C to 150 °C with pressure up to 50 MPa was performed by heat of hydration, chemical shrinkage and ultrasonic measurements. Increasing curing temperature was found to have a stronger acceleration effect during the main hydration period while increasing curing pressure had a stronger acceleration effect during the pre-induction period of cement hydration. By comparing chemical shrinkage test results with other methods of estimating cement degree of hydration, such as quantitative X-ray diffraction, non-evaporable water content measured by thermogravimetric analysis, as well as heat of hydration, it was observed that total chemical shrinkage of cement at complete hydration decreased with curing temperature from 35 °C to 75 °C and then stayed stable between 75 °C and 150 °C. Similarly, the P-wave velocity of cement (which is an indicator of physical and mechanical properties) as a function of hydration degree decreased with increasing curing temperature in the range between 35 °C to 75 °C, then remained relatively stable between 75 °C and 130 °C. The reduction of gel water content in C–S–H from 35 °C to 75 °C is believed to be the primary cause of these observed phenomena.

Abstract Background To assess the association of pregnancy loss history with an elevated risk of Gestational diabetes mellitus (GDM) and to investigate whether this association was mediated by high-sensitivity C-reactive protein (hs-CRP). Methods We prospectively collected venous blood and pregnancy loss history information from 4873 pregnant women at 16–23 weeks of gestation from March 2018 to April 2022. Hs-CRP concentrations were measured from collected blood samples. A 75 g fasting glucose test was performed at 24 to 28 weeks of gestation for the diagnosis of GDM, with data obtained from medical records. Multivariate linear or logistic regression models and mediation analysis were used to examine the relationships between pregnancy loss history, hs-CRP, and GDM. Results A multivariable-adjusted logistic regression analysis revealed that compared with pregnant women with no induced abortion history, subjects with 1 and ≥ 2 induced abortions had a higher risk for GDM (RR = 1.47, 95% CI = 1.19–1.81; RR = 1.63, 95% CI = 1.28–2.09). Additionally, the mediation analysis indicated this association was mediated by an increased hs-CRP level with a 20.4% of indirect effect ratio. However, no significant association between a history of miscarriage and the prevalence of GDM was observed. Conclusions A history of induced abortion was significantly associated with an increased risk of GDM, and this association occurred in a dose-response effect. Hs-CRP may be accounted for a mediation effect in the pathways linking induced abortion history with GDM.

BackgroundWilson's disease (WD) is an inherited disorder characterized by impaired biliary excretion of copper and excessive copper accumulation in multiple organs, primarily leading to hepatic, neurological, and psychiatric manifestations. The coexistence of WD and systemic lupus erythematosus (SLE) has rarely been reported, posing challenges in accurately diagnosing these two conditions because of overlapping clinical symptoms.Case presentationWe presented the case of a 17-year-old girl initially suspected of having SLE due to positive anti-nuclear antibodies and lupus anticoagulants, decreased platelet count, hypocomplementemia, and pleural effusion. However, the patient also exhibited an unusual manifestation of decompensated liver cirrhosis, which is not typical of SLE. Further investigation revealed low serum ceruloplasmin levels, high 24-h urine copper levels, the presence of Kayser–Fleischer rings, and a compound heterozygous mutation in the ATP7B gene, confirming the diagnosis of WD.ConclusionThe co-occurrence of WD and SLE poses a significant diagnostic challenge, often leading to misdiagnosis and delayed diagnosis. Therefore, in patients with well-controlled SLE presenting with unexplained liver fibrosis, neurological involvement, or psychiatric symptoms, it is crucial to consider the possibility of WD. However, further studies are required to elucidate the underlying pathophysiological mechanisms.

BackgroundIdiopathic membranous nephropathy (IMN) is the most common pathological type in adults with nephrotic syndrome. Many target antigens have been discovered. However, dual antigen-positive IMN patients are very rare, with only a few such cases being briefly described in various studies. There is no specific study on the clinicopathological and prognostic characteristics of dual antigen-positive IMN patients, and the disease characteristics of such patients remain unclear.MethodsImmunohistochemical staining of PLA2R, THSD7A, and NELL-1 was conducted on kidney tissue samples obtained from patients diagnosed with IMN. Simultaneously, the presence of corresponding serum antibodies was determined. Patients exhibiting positivity for dual antigens were included in the study, identified either through tissue staining or serum antibody detection. We retrospectively collected their clinical, pathological, and follow-up data and measured their serum antibody levels at multiple time points. Additionally, the same type of dual antigen-positive IMN cases reported in the literature were reviewed to extract clinical, pathological, and prognostic information. We compared the data for all of the above dual antigen-positive and PLA2R single-positive IMN cases at our center.ResultsWe identified 6 IMN patients with dual antigen positivity at our center, approximately 0.7% of whole MN series; the previous literature reports 43 IMN patients with dual antigen positivity, the proportion ranged from 0.2% to 2.8%. The IgG1 positivity rate in the renal tissue of the dual antigen-positive patients at our center was significantly lower than that of dual antigen-positive patients previously reported (16.7% vs. 100.0%, p=0.015), but there was no significant difference in clinical or prognostic aspects. Patients with dual antigen positivity reported at our center and in the literature were combined and compared with PLA2R single-positive IMN reported at our center. Compared with PLA2R single-positive IMN patients, dual antigen-positive IMN patients had a higher renal tissue IgG1 positivity rate (58.3% vs. 22.3%, p=0.016), and the time required to achieve remission was longer [13.5 (3.3,35.0) vs. 3.0 (1.0,8.0), p=0.052]. Overall, The changes in urine protein were consistent with the changes in serum PLA2R antibody levels in dual antigen-positive IMN patients.ConclusionsFor patients with primary membranous nephropathy who did not attain remission following prolonged treatment, multiple target antigen staining should still be actively performed, even with positivity for the PLA2R target antigen.

The technology of warm-mix regeneration has been frequently used in the production of asphalt pavement; however, the viscosity and self-healing properties of warm-mix recycled asphalt (WMRA) need further study. Therefore, the viscosity and self-healing properties of WMRA were analyzed by combining laboratory tests and molecular dynamics (MD) simulations. First, WMRA with different SWA and reclaimed asphalt pavement (RAP) contents were prepared in the laboratory. Then, different simulations, including viscosity simulation and self-healing simulation and Brookfield Viscosity test, were developed to analyze the performance variation rule. Experimental results showed that the Sasobit warm-mix agent (SWA) significantly reduced asphalt viscosity, and the recycled asphalt’s viscosity increased with asphalt aging deeply. In contrast, the addition of 2% SWA made the viscosity of 100% RAP similar to that of new asphalt. Considering the viscosity reduction effect, asphalt performance and economy, a 3% SWA content is recommended. Both SWA and the degree of aging can reduce the healing performance of WMRA. There is little difference between the two factors in reducing self-healing performance. In general, the study's findings serve as a useful guide for the performance analysis of WMRA.

Hanseniaspora uvarum is a prevalent yeast species in vineyards. However, its application in grape wine fermentation remains limited. This study used culture-dependent and -independent approaches to investigate the dynamics of H. uvarum during the spontaneous fermentation of Cabernet Sauvignon grapes. The results revealed that H. uvarum constituted 77.49 % of the non-Saccharomyces yeast population during fermentation. An indigenous strain, QTX-C10, was isolated from the 148 H. uvarum strains using a multistep screening strategy. The 1:1 co-inoculation of QTX-C10 with Saccharomyces cerevisiae proved to be an optimal strategy for mixed fermentation, resulting in a 48.54 %–59.55 % increase in ethyl esters in Cabernet Sauvignon wine and a 96.94 %–110.92 % increase in Chardonnay wine. Furthermore, this approach reduced the acetic acid levels by 12.50 %–17.07 % for Cabernet Sauvignon wine and 10.81 %–17.78 % for Chardonnay wine. Additionally, increased ethyl ester content may enhance the tropical fruit flavor of Cabernet Sauvignon wines.

IntroductionMicrobial infections are associated with the occurrence of autoimmune diseases, but the mechanisms of microbial infection inducing autoimmune diseases are not fully understood. The existence of heterophilic antigens between microorganisms and human tissues may explain part of the pathogenesis of autoimmune diseases. Here, we investigate the distribution of heterophilic antigens and its relationship with autoimmune diseases.MethodsMonoclonal antibodies against a variety of microorganisms were prepared. The titer, subclass and reactivity of antibodies with microorganisms were identified, and heterophilic antibodies that cross-reacted with human tissues were screened by human tissue microarray. The reactivity of these heterophilic antibodies with different individuals and different species was further examined by immunohistochemistry.ResultsIn this study, 21 strains of heterophilic antibodies were screened. The results showed that these heterophilic antibodies were produced due to the existence of heterophilic antigens between microorganism and human body and the distribution of heterophilic antigens had individual, tissue and species differences.ConclusionOur study showed that heterophilic antigens exist widely between microorganisms and human body, and the heterophilic antigens carried by microorganisms may break the immune tolerance of the body through carrier effect and initiate immune response, which may be one of the important mechanisms of infection inducing autoimmune diseases.

This research aimed to investigate the attenuation mode of the layer modulus of asphalt pavement in accelerated pavement testing (APT). A full-scale experimental section was constructed and tested using the APT facility. Two non-destructive testing (NDT) methods, named falling weight deflectometer (FWD) technique and portable seismic property analyzer (PSPA) test, were used to obtain the layer moduli of asphalt pavement during the APT test. The variation patterns of layer moduli obtained by FWD and PSPA tests were calculated and compared after the temperature was corrected to 20 ℃. It was found that the variation pattern of surface layer modulus based on field FWD measurements was consistent with the one measured from PSPA tests. That is the modulus of the surface layer increases with the APT load repetitions firstly and then decreases with the rise of the repetitions. The modulus values of the surface layer measured from PSPA tests are obviously larger than those backcalculated based on deflection basins. The ratio of the measured surface layer modulus based on the PSPA test to the backcalculated one based on the FWD test ranges between 2.06 and 2.71. The backcalculated base layer modulus always declines with the increasing loading repetitions. The attenuation patterns of the surface layer modulus and the base layer modulus in the damage stage are described as Ea=421100*N-0.6119 and Eb=128000*N-0.1096, respectively.

Pickled cabbage, a traditional fermented food rich in functional microorganisms, can effectively control hyperuricemia and gout. In this study, a Priestia megaterium ASC-1 strain with strong uric acid (UA) degradation ability was isolated from pickled cabbage. After oral administration for 15 days, ASC-1 was stably colonized in the rats in this study. ASC-1 significantly reduced UA levels (67.24%) in hyperuricemic rats. Additionally, ASC-1 alleviated hyperuricemia-related inflammatory response, oxidative stress, and blood urea nitrogen. Intestinal microbial diversity results showed that ASC-1 restored intestinal injury and gut flora dysbiosis caused by hyperuricemia. These findings suggest that P. megaterium ASC-1 may be used as a therapeutic adjuvant for the treatment of hyperuricemia.

ABSTRACT Although gut microbiota alteration and related blood microbe profiles in human immunodeficiency virus (HIV)-infected individuals are associated with the disease progression, how abnormal blood microbe profiles influence the inflammation and immune restoration are not fully understood. To address these issues, this study enrolled 24 healthy controls (HCs) and 91 HIV-infected individuals, including 30 treatment-naïve individuals (TNs), 31 immunological non-responders (INRs), and 30 immunological responders (IRs); subsequently, we analyzed blood microbe profiles using metagenomic sequencing and Olink proteomics technology, and identify inflammation-related proteins in peripheral blood samples of these individuals. The results showed increased translocation of microbes in the blood of TNs. This translocation did not return to normal level in either IRs or INRs who received antiretroviral therapy. In addition, Porphyromonas gingivalis significantly increased in TNs, IRs, and INRs compared to HCs. P. gingivalis was inversely associated with CD4+ T-cell counts, CD4/CD8 ratio, latency-associated peptide transforming growth factor-β1, and tumor necrosis factor-related activation-induced cytokine (TRANCE) and positively associated with HIV reservoirs. Burkholderia multivorans and Bacillus thuringiensis significantly decreased in TNs, IRs, and INRs compared to HCs and were positively associated with CD4+ T-cell counts and the CD4/CD8 ratio and negatively associated with HIV reservoir size and pro-inflammatory factors. We identified several species of microbes that were associated with CD4+ T-cell restoration on antiretroviral therapy, Prevotella sp. CAG:5226, Eubacterium sp. CAG:251, Phascolarctobacterium succinatutens, Anaerobutyricum hallii, Prevotella sp. AM34-19LB, and Phocaeicola plebeius were positively associated with HIV reservoir size and pro-inflammatory proteins. Another group of bacteria, B. multivorans, B. thuringiensis, Vibrio vulnificus, and Acinetobacter baumannii, which were negatively associated and pro-inflammatory proteins. In conclusion, different microbes within blood of HIV-infected individuals were found to be closely associated with persistent inflammation and immune restoration, suggesting the blood microbe profiles of HIV-infected individuals also influence disease progression. IMPORTANCE The characteristics of blood microbiota in HIV-infected individuals and their relevance to disease progression are still unknown, despite alterations in gut microbiota diversity and composition in HIV-infected individuals. Here, we present evidence of increased blood microbiota diversity in HIV-infected individuals, which may result from gut microbiota translocation. Also, we identify a group of microbes, Porphyromonas gingivalis, Prevotella sp. CAG:5226, Eubacterium sp. CAG:251, Phascolarctobacterium succinatutens, Anaerobutyricum hallii, Prevotella sp. AM34-19LB, and Phocaeicola plebeius, which are linked to poor immunological recovery. This work provides a scientific foundation toward therapeutic strategies targeting blood microbiota for immune recovery of HIV infection.

BackgroundThe innovative method of sentiment analysis based on an emotional lexicon shows prominent advantages in capturing emotional information, such as individual attitudes, experiences, and needs, which provides a new perspective and method for emotion recognition and management for patients with breast cancer (BC). However, at present, sentiment analysis in the field of BC is limited, and there is no emotional lexicon for this field. Therefore, it is necessary to construct an emotional lexicon that conforms to the characteristics of patients with BC so as to provide a new tool for accurate identification and analysis of the patients’ emotions and a new method for their personalized emotion management. ObjectiveThis study aimed to construct an emotional lexicon of patients with BC. MethodsEmotional words were obtained by merging the words in 2 general sentiment lexicons, the Chinese Linguistic Inquiry and Word Count (C-LIWC) and HowNet, and the words in text corpora acquired from patients with BC via Weibo, semistructured interviews, and expressive writing. The lexicon was constructed using manual annotation and classification under the guidance of Russell’s valence-arousal space. Ekman’s basic emotional categories, Lazarus’ cognitive appraisal theory of emotion, and a qualitative text analysis based on the text corpora of patients with BC were combined to determine the fine-grained emotional categories of the lexicon we constructed. Precision, recall, and the F1-score were used to evaluate the lexicon’s performance. ResultsThe text corpora collected from patients in different stages of BC included 150 written materials, 17 interviews, and 6689 original posts and comments from Weibo, with a total of 1,923,593 Chinese characters. The emotional lexicon of patients with BC contained 9357 words and covered 8 fine-grained emotional categories: joy, anger, sadness, fear, disgust, surprise, somatic symptoms, and BC terminology. Experimental results showed that precision, recall, and the F1-score of positive emotional words were 98.42%, 99.73%, and 99.07%, respectively, and those of negative emotional words were 99.73%, 98.38%, and 99.05%, respectively, which all significantly outperformed the C-LIWC and HowNet. ConclusionsThe emotional lexicon with fine-grained emotional categories conforms to the characteristics of patients with BC. Its performance related to identifying and classifying domain-specific emotional words in BC is better compared to the C-LIWC and HowNet. This lexicon not only provides a new tool for sentiment analysis in the field of BC but also provides a new perspective for recognizing the specific emotional state and needs of patients with BC and formulating tailored emotional management plans.

Summary: Plant-based flavonoids have been evaluated as inhibitors of β-coronavirus replication and as therapies for COVID-19 on the basis of their safety profile and widespread availability. The SARS-CoV-2 main protease (Mpro) has been implicated as a target for flavonoids in silico. Yet no comprehensive in vitro testing of flavonoid activity against SARS-CoV-2 Mpro has heretofore been performed. We screened 1,019 diverse flavonoids for their ability to inhibit SARS-CoV-2 Mpro. Multiple structure-activity relationships were identified among active compounds such as enrichment of galloylated flavonoids and biflavones, including multiple biflavone analogs of apigenin. In a cell-based SARS-CoV-2 replication assay, the most potent inhibitors were apigenin and the galloylated pinocembrin analog, pinocembrin 7-O-(3''-galloyl-4'',6''-(S)-hexahydroxydiphenoyl)-beta-D-glucose (PGHG). Molecular dynamic simulations predicted that PGHG occludes the S1 binding site via a galloyl group and induces a conformational change in Mpro. These studies will advance the development of plant-based flavonoids—including widely available natural products—to target β-coronaviruses.

This study sought to investigate the anti-amyloid β (Aβ) and anti-neuroinflammatory effects of catalpol in an Alzheimer’s disease (AD) mouse model. Methods: The effects of catalpol on Aβ formation were investigated by thioflavin T assay. The effect of catalpol on generating inflammatory cytokines from microglial cells and the cytotoxicity of microglial cells on HT22 hippocampal cells were assessed by real-time quantitative PCR, ELISA, redox reactions, and cell viability. APPswe/PS1ΔE9 mice were treated with catalpol, and their cognitive ability was investigated using the water maze and novel object recognition tests. Immunohistochemistry and immunofluorescence were used to probe for protein markers of microglia and astrocyte, Aβ deposits, and NF-κB pathway activity. Aβ peptides, neuroinflammation, and nitric oxide production were examined using ELISA and redox reactions. Results: Catalpol potently inhibited Aβ fibril and oligomer formation. In microglial cells stimulated by Aβ, catalpol alleviated the expression of the proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and inducible nitric oxide synthase (iNOS) but promoted the expression of the anti-inflammatory cytokine IL-10. Catalpol alleviated the cytotoxic effects of Aβ-exposed microglia on HT22 cells. Treatment with catalpol in APPswe/PS1ΔE9 mice downregulated neuroinflammation production, decreased Aβ deposits in the brains and alleviated cognitive impairment. Catalpol treatment decreased the number of IBA-positive microglia and GFAP-positive astrocytes and their activities of the NF-κB pathway in the hippocampus of APPswe/PS1ΔE9 mice. Conclusion: The administration of catalpol protected neurons by preventing neuroinflammation and Aβ deposits in an AD mouse model. Therefore, catalpol may be a promising strategy for treating AD.

In this paper, by using the baseband noise cancellation, a CMOS mixer-first analog receiver with power reduction is proposed. Based on a current-mirror transimpedance amplifier structure, positive capacitive feedback is applied to manipulate poles/zeros location, enabling a wide baseband bandwidth and out-of-band second-order filtering profile. The additional radio frequency N-path filtering and baseband 40dB/dec roll-off absorb out-of-band interferences. The presented receiver frontend is fabricated in a standard 65 nm CMOS process. Measured results demonstrate a minimal noise figure of 2.2 dB, and an average voltage gain of 32.2 dB across the 220 MHz intermediate frequency range. The in-band and out-of-band third-order input intercept point manifests −12.8 dBm and 15.5 dBm respectively. The presented receiver circuit draws $\sim $ 32 mW at a typical 1 GHz local oscillator stimulus.

Long-term intermediate fasting before pregnancy in mice disrupts intestinal homeostasis of offspring with subsequent glucose and lipid metabolism disorder, mediated by a reduction in beneficial microbiota such as Lactobacillus intestinalis.

Objective Aseptic femoral shaft nonunion constitutes approximately 1%–10% of all femoral shaft fractures treated with intramedullary nail (IMN) fixation, possibly attributable to the lack of anti‐rotational stability. Although a lateral locking plate (LP) with retainment of original IMN has shown the most success, lateral LP inflicts significant surgical trauma on patients. Therefore, the Multidimensional Cross Locking Plate (MDC‐LP) was designed based on a mini‐open femoral anterior approach. We aim to report and compare the technical aspects and clinical outcomes of using anterior MDC‐LP or lateral LP with retention of original IMN for the treatment of aseptic femoral shaft nonunion. Methods In this single center retrospective cohort study, records of 49 patients who had undergone revision of femoral shaft aseptic nonunion with anterior MDC‐LP or lateral LP while retaining the original IMN from January 2015 to October 2019 were retrospectively reviewed. Information on patients' demographics, clinical data, and surgical outcomes were gathered and analyzed. X‐ray and CT scans were used for bone union evaluation and the lower extremity functional scale (LEFS) was used for follow‐up functional evaluation. For quantitative data, the Student's t‐test was used if the data were normally distributed. The Mann–Whitney U‐test was used for non‐normally distributed data. For qualitative data, the Chi‐square test was used for comparisons. Results Twenty‐seven patients were treated with anterior MDC‐LP, and 22 patients were treated with lateral LP. There are no significant differences in age, sex, BMI, time since initial femoral shaft fracture, initial fracture type (close/open), nonunion type, or nonunion location between patients' group. Among patients treated with anterior MDC‐LP, an average of 2‐months advantage in time to union was observed (4.09 months vs. 6.8 months in the lateral LP group: P = 0.000), smaller incision was required for MDC‐LP installment (7.7 cm vs 17.1 cm in lateral LP group: P = 0.000). Conclusions For the treatment of aseptic femoral shaft nonunion with retainment of original IMN, anterior MDC‐LP via mini‐open femoral anterior approach described in this study is a better option than lateral LP for achieving faster bone union and satisfactory functional outcome with less surgical trauma.

Summary: Fatigue performance evaluation on asphalt mixture provides an essential reference for asphalt mixture design and pavement structure design. Laboratory fatigue test has been widely used by researchers and engineers to assess the fatigue performance of asphalt mixture, due to its low cost, high efficiency, and strong operability. To ensure performance assessment reliability, fatigue test operated in the laboratory needs to simulate the loading and environmental conditions occurring in the field asphalt layer. As a result, loading setups in laboratory fatigue tests, including loading mode, loading frequency, loading waveform, temperature, and the controlled mode, have been carefully devised by researchers. This paper reviews the above common setups in fatigue tests, which aims to illustrate the classical and latest considerations as well as ideas proposed by researchers for improving fatigue test procedures. As fatigue response data of asphalt mixture is measured from fatigue test, an analysis method is required to process the data and identify fatigue behaviors of the material. Presently, the frequently-used fatigue data analysis methods include the fatigue life model, stiffness-modulus-based method, energy-based method, and viscoelastic continuum damage (VECD) method. This paper also provides a review survey on the main concepts, indicators, and models included in those methods to facilitate their applications. Meanwhile, the latest research progress and outputs related to the four methods are also introduced and discussed to reveal the state-of-the-art developments in this research area.