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Sophora flavescens, a traditional Chinese herb, produces a wide range of secondary metabolites with a broad spectrum of biological activities. In this study, we isolated six isopentenyl flavonoids (1–6)from the roots of S. flavescensand evaluated their activities against phytopathogenic fungi. In vitro activities showed that kurarinone and sophoraflavanone G displayed broad spectrum and superior activities, among which sophoraflavanone G displayed excellent activity against tested fungi, with EC50values ranging from 4.76 to 13.94 μg/mL. Notably, kurarinone was easily purified and showed potential activity against Rhizoctonia solani, Botrytis cinerea, and Fusarium graminearumwith EC50values of 16.12, 16.55, and 16.99 μg/mL, respectively. Consequently, we initially investigated the mechanism of kurarinone against B. cinerea. It was found that kurarinone disrupted cell wall components, impaired cell membrane integrity, increased cell membrane permeability, and affected cellular energy metabolism, thereby exerting its effect against B. cinerea. Therefore, kurarinone is expected to be a potential candidate for the development of plant fungicides.

The purpose of this study was to explore the histopathological staging and differential diagnosis of marginal zone lymphoma in gastric mucosa-associated lymphoid tissue (MALT lymphoma). We performed detailed histomorphology and immunohistochemistry investigations as well as genetic testing on endoscopic biopsy and endoscopic mucosal resection specimens from 18 patients with gastric MALT lymphoma. We found that gastric MALT lymphoma typically begins as a small, isolated area outside the lymphoid follicular mantle zone or proliferates in a multifocal, patchy manner, gradually spreads to the interfollicular zone, forming diffuse proliferation, invades the gastric mucosal glands, and infiltrates or proliferates into the center of peripheral reactive lymphoid follicles. Abnormally proliferating lymphocytes invade the surrounding lymphoid follicles, resulting in damage, atrophy, and disappearance of their normal follicles as well as of the gastric mucosa glands, forming diffuse proliferation. Redifferentiation and proliferation lead to the transformation of lymphocytes; that is, MALT transitions into highly invasive lymphoma. Based on our findings in this study, we propose the following five stages in the process of development and progression of gastric MALT lymphoma: the stage of cell proliferation outside the lymphoid follicular mantle zone; the stage of heterogeneous proliferative lymphoepithelial lesion; the stage of reactive lymphoid follicular implantation; the stage of lymphoid follicular clonal proliferation; and the stage of MALT transforming into highly invasive lymphoma. We examined the differential diagnosis of histopathological features at each stage. The clinicopathological staging of gastric MALT lymphoma can help clinicians provide accurate treatment and track malignant cell transformation, thus playing a significant role in controlling its development and progression.

AbstractHIV-1 reverse transcriptase is an important target for developing effective anti-HIV-1 inhibitors. Different types of small molecules have been designed based on this target, showing different levels of inhibitory activity against various types of HIV-1 strains. The relationship between structure and activity of DABO derivatives was investigated by means of 3D-QSAR molecular model, molecular docking, molecular dynamics and ADMET properties. The statistical results of molecular models show that the CoMFA and CoMSIA models have good internal stability (CoMFA: q2= 0.623, r2= 0.946; CoMSIA: q2= 0.668, r2= 0.983) and external prediction ability (CoMFA: rpred2= 0.961; CoMSIA: rpred2= 0.961). In addition, molecular docking has explored the mechanism of action between small molecules and receptor proteins, and the results show that hydrogen bonding between amino acid Lys101 and small molecules can improve the affinity of ligands to receptor binding. A total of 12 novel molecules were designed and their activities were predicted based on the 3D-QSAR model and molecular docking results. The results showed that the designed molecules had higher predictive activity. Subsequently, 100 ns MD simulation and binding free energy verified the stability of molecular docking results. Finally, the pharmacokinetic properties of the novel designed molecule were verified by using ADMET to predict its properties. These results can provide reference for the design and development of novel and effective HIV-1 RT inhibitors, and provide new ideas for the design of subsequent drugs.Communicated by Ramaswamy H. Sarma

ABSTRACTIL-33 has been associated with pro- and anticancer functions in cancer. However, its role in pancreatic cancer metastasis remains unknown. This study aimed to explore the role of miR-548t-5p/IL-33 axis in the metastasis of pancreatic cancer. Luciferase activity assay, qRT-PCR, Western blot and ELISA were performed to prove whether IL-33 is the target of miR-548t-5p. In vivo metastasis assay and cellular transwell assay were performed to explore the role of miR-548t-5p/IL-33 axis in the invasion and metastasis of pancreatic cancer. Co-culture experiments and immunohistochemistry were performed to observe whether IL-33 affects cell invasion and metastasis dependent on the involvement of M2 macrophages. THP-1 cell induction experiment and flow cytometry were performed to explore the effect of IL-33 on macrophage polarization. CCK-8, colony formation, cell apoptosis, cell cycle, cell wound healing and transwell assay were performed to investigate the effect of IL-33 induced M2 macrophages on cell malignant biological behavior by coculturing pancreatic cancer cells with the conditioned medium (CM) from macrophages. We found that miR-548t-5p regulated the expression and secretion of IL-33 in pancreatic cancer cells by directly targeting IL-33 mRNA. IL-33 secreted by cancer cells promoted the recruitment and activation of macrophages to a M2-like phenotype. In turn, IL-33 induced M2 macrophages promoted the migration and invasion of cancer cells. Moreover, IL-33 affected pancreatic cancer cell invasion dependent on the involvement of M2 macrophages in the co-culture system. Thus, our study suggested that manipulation of this IL-33-dependent crosstalk has a therapeutic potential for the treatment of pancreatic cancer metastasis.

ObjectiveThe remodelling of gut mycobiome (ie, fungi) during pregnancy and its potential influence on host metabolism and pregnancy health remains largely unexplored. Here, we aim to examine the characteristics of gut fungi in pregnant women, and reveal the associations between gut mycobiome, host metabolome and pregnancy health.DesignBased on a prospective birth cohort in central China (2017 to 2020): Tongji-Huaxi-Shuangliu Birth Cohort, we included 4800 participants who had available ITS2 sequencing data, dietary information and clinical records during their pregnancy. Additionally, we established a subcohort of 1059 participants, which included 514 women who gave birth to preterm, low birthweight or macrosomia infants, as well as 545 randomly selected controls. In this subcohort, a total of 750, 748 and 709 participants had ITS2 sequencing data, 16S sequencing data and serum metabolome data available, respectively, across all trimesters.ResultsThe composition of gut fungi changes dramatically from early to late pregnancy, exhibiting a greater degree of variability and individuality compared with changes observed in gut bacteria. The multiomics data provide a landscape of the networks among gut mycobiome, biological functionality, serum metabolites and pregnancy health, pinpointing the link between Mucorand adverse pregnancy outcomes. The prepregnancy overweight status is a key factor influencing both gut mycobiome compositional alteration and the pattern of metabolic remodelling during pregnancy.ConclusionThis study provides a landscape of gut mycobiome dynamics during pregnancy and its relationship with host metabolism and pregnancy health, which lays the foundation of the future gut mycobiome investigation for healthy pregnancy.

Reducing sediment is important for the utilization and production of green tea infusion and concentrate. The effect of tannase on sediment formation in green tea infusion and concentrate was investigated. The results showed that the amount of sediment of green tea infusion significantly decreased after tannase treatment, which was due to the decrease in the concentration of gallated catechins. Significant positive correlations between the sediment amount and the gallated catechin (r= 0.980, p< 0.01) concentration were found. The formation of sediment in green tea infusion was significantly influenced by the tannase concentration and hydrolysis time. 0.5 mg/mL tannase concentration, 120 min hydrolysis time, and 35 °C hydrolysis temperature were found to be the optimized hydrolysis parameters for reducing the sediment. Tannase treatment not only lowered the amount of sediment of green tea concentrate (74.63%), but it also improved the taste quality of green tea concentrate after storage. These results could be used to improve the quality and utilization of green tea infusion and concentrate.

Objective: Open-sided field-free line magnetic particle imaging (OS FFL MPI) is a novel medical imaging system configuration that has received significant attention in recent years. However, the measurement-based system matrix (SM) image reconstruction for OS FFL MPI typically requires multiple angle calibration (MAC), which is time-consuming in practice. Methods: To address this issue, we propose a fast 2D SM generation method that requires only a single angle calibration (SAC). The SAC method exploits the rotational invariance of the system function. Based on the measured single angle system function, the system function is rotated to generate system functions at other angles, and then the SM for image reconstruction is constructed. Then, we conducted various simulation experiments and built an OS FFL MPI scanner to evaluate the proposed SAC method. Results: The experiments demonstrating the effectiveness of SAC in reducing calibration workload, requiring fewer scanning numbers while maintaining a similar image reconstruction quality compared to MAC method. Furthermore, the SM generated by SAC produces consistent imaging results with the SM generated by MAC, regardless of the interpolation algorithms, the number of rotation angles, or the signal-to-noise ratios employed in phantom imaging experiments. Conclusion: SAC has been experimentally verified to reduce acquisition time while maintaining accurate and robust reconstruction performance. Significance: The significance of SAC lies in its contribution to improving calibration efficiency in OS FFL MPI, potentially facilitating the implementation of MPI in a wider range of applications.

Magnetic particle imaging (MPI) is an emerging molecular imaging technique that relies on the nonlinear magnetization response of superparamagnetic iron oxide nanoparticles. Open-sided MPI (OS-MPI) has attracted considerable interest for its potential to enhance interventional procedures. However, improving the spatial resolution of OS-MPI poses a significant challenge, mainly due to the inefficiencies of selection coils in generating, rotating, and shifting a high-gradient field-free line (FFL). To address this issue, we propose a novel approach called the permanent magnet-based sequential scan to develop a high-resolution 3-D OS-MPI system with ultralow power consumption. By utilizing permanent magnets, we can create high-gradient selection fields without any power consumption. The sequential scan technique involves rotating the FFL angle by angle and shifting the FFL layer by layer. To maintain thermal stability during sequential scans, we used drive coils wound with hollow copper wires and implemented forced oil cooling. Additionally, measures such as copper shielding, feed-through compensation, and filtering were employed to minimize interference from the permanent magnets, drive coils, and motor drivers. Experimental results demonstrated that the developed system successfully achieved a spatial resolution of 1 mm while operating with an overall low power consumption of 282.16 W.

Animal and human studies have suggested that trihalomethane (THM) has toxicity to bone. In this study, we included adolescents from the National Health and Nutrition Examination Survey who had quantified blood and tap water THM concentrations [chloroform (TCM), bromodichloromethane (BDCM), dibromochloromethane (DBCM), and bromoform (TBM)] and lumbar spine or total body less head (TBLH) bone mineral density (BMD). A 2.7-fold increase in concentrations of blood TCM, DBCM, chlorinated THMs (the sum of TCM, BDCM, and DBCM), and total THMs (the sum of 4 THMs) was associated with lower lumbar spine BMD z-scores by −0.06 [95% confidence interval (CI): −0.12, −0.01], −0.06 (95% CI: −0.11, −0.003), −0.08 (95% CI: −0.14, −0.02), and −0.07 (95% CI: −0.13, −0.003), respectively, in adjusted models. Similarly, a 2.7-fold increase in blood BDCM, DBCM, and chlorinated THM concentrations was associated with lower TBLH BMD z-scores by −0.10 (95% CI: −0.17, −0.02), −0.10 (95% CI: −0.17, −0.03), and −0.11 (95% CI: −0.20, −0.01), respectively. Low-to-moderate predictive power was attained when tap water THM concentrations were used to predict blood THM measurements. Notably, the inverse associations for blood THMs persisted exclusively between water concentrations of DBCM and Br-THMs and the TBLH BMD z-scores. Our findings suggest that exposure to THMs may adversely affect the adolescent BMD.

Detecting anomalies for dynamic graphs has drawn increasing attention due to their wide applications in social networks, e-commerce, and cybersecurity. Recent deep learning-based approaches have shown promising results over shallow methods. However, they fail to address two core challenges of anomaly detection in dynamic graphs: the lack of informative encoding for unattributed nodes and the difficulty of learning discriminate knowledge from coupled spatial-temporal dynamic graphs. To overcome these challenges, in this paper, we present a novel Transformer-based Anomaly Detection framework for DYnamic graphs (TADDY). Our framework constructs a comprehensive node encoding strategy to better represent each node’s structural and temporal roles in an evolving graphs stream. Meanwhile, TADDY captures informative representation from dynamic graphs with coupled spatial-temporal patterns via a dynamic graph transformer model. The extensive experimental results demonstrate that our proposed TADDY framework outperforms the state-of-the-art methods by a large margin on six real-world datasets.

With consideration of double-line-frequency instantaneous power in two-stage single-phase system, a double-line-frequency power control method is proposed in this article to achieve optimization and tradeoff control between the current stress of dual-active-bridge (DAB) dc/dc converter and the dc bus voltage ripples in both sides. Different double-line-frequency powers in DAB will lead to different values of DAB current stress and dc bus voltage ripples in both sides. To find out the best double-line-frequency power in DAB, the optimal control trajectory (OCT) is proposed in this article so that the current stress of DAB can be minimized under any certain voltage ripple. An approximate analytical calculation method is derived to solve the optimal double-line-frequency power in OCT. The comparative analysis indicates that the approximate OCT has similar optimization effects as OCT. Based on the OCT, two tradeoff control methods for the DAB current stress and the dc bus voltage ripples are presented so that the current stress and the voltage ripples can be flexibly adjusted to adapt various load conditions. The initial phase of the single-phase ac load is also optimized to maximize the adjustable range of voltage ripple. The experimental results verify the feasibility and effectiveness of the proposed OCT and control methods.

Quantifying historical developments is crucial for understanding a large variety of complex processes from economy to political conflict, population dynamics and urban evolution. Yet the driving force of emergent processes in history is a product of complex interactions among massive individuals, in which the elite class plays a vital role. With the social relations of elites in ancient China, the dynamical elite social networks are compiled from the year 618 to 1840. We systematically investigate the dynamical structure of elite social networks, which significantly evolves with major historical events. We detect that the macroeconomic performance affects the structure of elite social networks comprehensively, while only the assortative coefficient and average shortest path length have a predictive ability on the economy. Then the evolutionary game theory is introduced to simulate how the structure of elite social network influences the economy. Our work provides a framework to study the economic function of real-world social networks from the perspective of the elite class.

Traditionally, a relatively big urine volume (e.g., 500 μL) is used in nuclear magnetic resonance (NMR)-based human metabolomics, which is not feasible for studies with limited/precious samples. Although urine may be diluted before conventional high-throughput metabolomics analysis, the comprehensive effect of urine dilution on metabolic profiles is unknown. Here, for the first time, we systematically investigated the effect of urine dilution on 1H NMR metabolic profiles, by evaluating signal detectability, integration, signal-to-noise ratio (SNR), chemical shift (δ) and its variation, and signal overlapping of 47 metabolites in 10 volunteers. We observed significant linear changes along with increased dilution, including decreased integration and SNR, altered δ, decreased intersample variation of δ, and increased separation between overlapped signals, e.g., lactate and threonine, β-d-glucose and an unassigned signal, and histidine and 3-methylhistidine. We further tested the 40% dilution level (i.e., employing 300 μL urine) in an epidemiological study containing 1018 pregnant women from the Tongji-Shuangliu Birth Cohort, showing acceptable detectability and chemical shift variability for most of the 47 metabolites profiled. It indicated that mild (e.g., 40%) dilution of human urine can largely preserve the high-abundance metabolites profiled, reduce intersample chemical shift variations, and increase separations of overlapped signals, which is an improvement of routine sample preparation methods in NMR-based metabolomics and is applicable for studies with limited urine volumes, including large-scale epidemiological studies.

Until recently, a novel spatial crowdsourcing paradigm, namely Three-Dimensional (3D) spatial crowdsourcing, has emerged, in which the task requestors and the workers need travel to their designated third-party workplaces, e.g., shared offices, to deliver certain services, such as DiDi station ride-sharing service, Quyundong sport training service in the Online-To-Offline (O2O) applications. In 3D spatial crowdsourcing applications, a core issue is to develop an efficient global tasklist plan, based on the tripartite matching among the three parties, i.e., task requestors, workers and workplaces, which is different from the conventional spatial crowdsourcing. In this context, one key challenge is how to suitably schedule the available workers with the consideration of the interests of all the parties, under the constraint of worker resource. To answer the questions, in this paper, we propose and study a new problem, namely Social-Welfare-driven Task Scheduling (SWTS) problem, which strives to schedule the workers’ continuous routines, i.e., successively implementing tasks for different requestors at different workplaces, to promote the social welfare for all the involved parties. We prove our studied problem is NP-hard, and devise two heuristic optimization algorithms to solve it. Finally, we conduct extensive experiments which verify the efficiency and effectiveness of the proposed algorithms on both real and synthetic data sets.

• We propose a cascade prediction model via a hierarchical attention neural network. • Features of user influence and community redundancy are quantitatively characterized. • Two features are fused effectively through two-layer attention mechanisms. • Experiments show that the proposed model can improve the prediction accuracy. Online social networking platforms have drastically facilitated the phenomenon of information cascades, making cascade prediction an important task for both researchers and practitioners. In cascade propagation paths, influential users can often attract more attention. Moreover, the community structure formed by users with similar interests creates information redundancy, thereby restricting the propagation process. These two features greatly affect the growth of the cascades. This paper investigates the incremental prediction of cascades during a future time period based on the evolution of cascades in early stages and proposes a neural network framework with hierarchical attention mechanisms, named Hierarchical Attention Cascade Neural Network (CasHAN). This network has a node-level attention mechanism based on user influence and a sequence-level attention mechanism based on community redundancy. User influence considers the user's own attributes and the influence feedback provided by neighbors, while community redundancy measures information redundancy characteristics that limit cascade propagation. Through hierarchical attention mechanisms, the effective combination of these two features improves the accuracy of cascade increment prediction. Extensive experiments on real-world datasets demonstrate that our approach outperforms other state-of-the-art prediction methods. [ABSTRACT FROM AUTHOR]

A series of quinoline derivatives were designed and synthesized by the structural simplification of cryptolepine and evaluated for their fungicidal activity against six phytopathogenic fungi. Most of these compounds exhibited remarkable activities against Botrytis cinereain vitro. Among them, compounds A18and L01showed superior antifungal activity. Significantly, compared to cryptolepine, compound A18exhibited broad-spectrum inhibitory activities against B. cinerea, Sclerotinia sclerotiorum, Rhizoctonia solani, Phytophthora capsica, Magnaporthe oryzae, and Fusarium graminearumwith the respective EC50values of 0.249, 1.569, 3.915, 0.505, 0.246, and 4.999 μg/mL. Compound L01displayed the best antifungal activity against B. cinereawith an EC50value of 0.156 μg/mL. Preliminary mechanistic studies showed that compound A18could inhibit spore germination, affect the permeability of the cell membrane, increase the content of reactive oxygen species, and affect the morphology of hyphae and cells. Moreover, compound A18showed excellent in vivoprotective effect against B. cinerea, which was more potent than pyrimethanil and equitant to cryptolepine. These results evidenced that compound A18displayed superior fungicidal activities and could be a potential fungicidal candidate against plant fungal diseases.

Research Object: Taking the acquisition mechanism of oscillatory flapping-wing wave energy as the research object, the scheme design and dynamic analysis of the acquisition mechanism are studied. Research Methods: According to the working principle of the acquisition mechanism of oscillatory flapping-wing wave energy, the rotation dynamics model of the acquisition mechanism and the corresponding relationship between the model parameters and the design parameters of the mechanism are established. Based on the momentum moment theorem, the differential equation of the dynamics of the acquisition mechanism and the transfer function of the system are established. The dynamic response of the acquisition mechanism is analyzed, the system parameters are optimized, and the scheme design is carried out. The conversion efficiency of the acquisition mechanism and the energy collection efficiency under different sea conditions are calculated. The motion response of the acquisition mechanism is simulated and analyzed by MATLAB and AQWA software. Research Results: The results show that the response of the crank and swing slider acquisition mechanism is fast and stable, and the average conversion efficiency is 34%. The research process provides an effective reference for the development of the acquisition mechanism of oscillatory flapping-wing wave energy.

To prospectively examine the associations of combined lifestyle factors with incident cardiovascular disease (CVD) and mortality in patients with diabetes.

The inhibitory effect of tavaborole on the invasion of Botrytis cinereain grapes and tomatoes, as well as the potential mechanism involved, was discovered in this study. Our findings showed that tavaborole inhibited Botrytis cinereaspore germination and mycelial expansion in vitro and that the control efficiency in vivo on fruit decay was dose-dependent, which was effective in reducing disease severity and maintaining the organoleptic quality of the fruit, such as reducing weight loss and retaining fruit hardness and titratable acid contents during storage. Furthermore, the precise mechanism of action was investigated further. Propidium iodide staining revealed that Botrytis cinereatreated with tavaborole lost membrane integrity. For further validation, cytoplasmic malondialdehyde accumulation and leakage of cytoplasmic constituents were determined. Notably, the inhibitory effect was also dependent on inhibiting the activities of aminoacyl-tRNA synthetases involved in the aminoacyl-tRNA biosynthesis pathway in Botrytis cinerea. The above findings concluded that tavaborole was effective against Botrytis cinereainfection in postharvest fruit, and a related mechanism was also discussed, which may provide references for the drug repurposing of tavaborole as a postharvest fungicide.

To explore the feasibility of using wide-body detector Computed Tomography (CT) combined with Cardiac Motion Correction (CMC) technology for coronary Computed Tomography angiography (CCTA) in free breathing state and its impact on image quality.

In this work, a series of derivatives with disulfide bonds containing pyridine, pyrimidine, thiophene, thiazole, benzothiazole, and quinoline were designed and synthesized based on the various biological activities of allicin disulfide bond functional groups. The antimicrobial activities of the target compounds were determined, and the structure–activity relationships were discussed. Among them, compound S8demonstrated the most potent antifungal activity in vitro against Monilinia fructicola(M. fructicola), with an EC50value of 5.92 μg/mL. Furthermore, an in vivo bioassay revealed that compound S8exhibited equivalent curative and higher protective effects as the positive drug thiophanate methyl at a concentration of 200 μg/mL. The preliminary mechanism experiments showed that compound S8could inhibit the growth of M. fructicola’ s hyphae in a time- and concentration-dependent manner, and compound S8could induce the shrinkage of hyphae, disrupt the integrity of the plasma membrane, and cause the damage and leakage of cell contents. More than that, compound S5also demonstrated an excellent antibacterial effect on Xanthomonas oryzae(X. oryzae), with a MIC90value of 1.56 μg/mL, which was superior to the positive control, thiodiazole copper.

OBJECTIVE--Skeletal muscle myopathy is a common diabetes complication. One possible cause of myopathy is myocyte failure to repair contraction-generated plasma membrane injuries. Here, we test the hypothesis that diabetes induces a repair defect in skeletal muscle myocytes. RESEARCH DESIGN AND METHODS--Myocytes in intact muscle from type 1 ([INS2.sup.Akita+/-]) and type 2 (db/db) diabetic mice were injured with a laser and dye uptake imaged confocally to test repair efficiency. Membrane repair defects were also assessed in diabetic mice after downhill running, which induces myocyte plasma membrane disruption injuries in vivo. A cell culture model was used to investigate the role of advanced glycation end products (AGEs) and the receptor for AGE (RAGE) in development of this repair defect. RESULTS--Diabetic myocytes displayed significantly more dye influx after laser injury than controls, indicating a repair deficiency. Downhill running also resulted in a higher level of repair failure in diabetic mice. This repair defect was mimicked in cultured cells by prolonged exposure to high glucose. Inhibition of the formation of AGE eliminated this glucose-induced repair defect. However, a repair defect could be induced, in the absence of high glucose, by enhancing AGE binding to RAGE, or simply by increasing cell exposure to AGE. CONCLUSIONS--Because one consequence of repair failure is rapid cell death (via necrosis), our demonstration that repair fails in diabetes suggests a new mechanism by which myopathy develops in diabetes., The long-term complications of diabetes are diverse and include cardiac dysfunction, renal disease, stroke, nerve damage, blindness, and vascular damage (1). Many of these complications are the direct result of [...]

Exposure to trichloroacetic acid (TCAA) has been associated with impaired semen quality; however, its association with spermatozoa apoptosis and DNA damage remains unclear. We, therefore, collected single semen and repeated urine samples from male partners of couples attending a reproductive center, which were measured for spermatozoa apoptosis and DNA damage parameters and TCAA concentrations, respectively. Multivariable linear regression models were used to explore the associations between urinary TCAA concentrations and spermatozoa apoptosis (n= 462) and DNA damage parameters (n= 512). After adjusting for potential confounders, positive dose–response relationships were found between urinary TCAA concentrations and percentage of tail DNA (tail%) and tail-distributed moment (TDM) (both pfor trend <0.10). Compared with men in the lowest tertile of urinary TCAA concentrations, men in the highest tertile had a greater tail% and TDM of 6.2% (95% CI: 0.7, 12.2%) and 8.9% (95% CI: −1.9, 20.5%), respectively. Urinary TCAA concentrations were unrelated to spermatozoa apoptosis parameters in a dose–response manner. However, urinary TCAA concentrations were positively associated with the percentage of Annexin V+/PI–spermatozoa (apoptotic cells), when urinary TCAA concentrations were modeled as continuous variables. Our results suggest that exposure to TCAA at concentrations in real-world scenarios may be associated with spermatozoa apoptosis and DNA damage.

Background: Little is known about the impact of haemodialysis (HD) and peritoneal dialysis (PD) on health-related quality of life (HRQoL). We compared HRQoL between conventional in-centre HD and home-based PD in 1082 newly diagnosed kidney failure patients.Methods: This was an open-label, randomised, non-inferiority trial of adult patients with a diagnosis of end-stage kidney disease (estimated glomerular filtration rate ≤ 15 mL/min/1.73 m2) requiring maintenance dialysis from 36 sites in China randomised 1:1 to receive PD or conventional in-centre HD. The primary outcome was the ‘Burden of Kidney Disease’ assessed using the Kidney Disease Quality of Life-Short Form (KDQoL-SF) survey over 48 weeks and the main secondary outcomes were the remaining scales of KDQoL-SF and all-cause mortality. The effect of PD versus HD on the primary outcome was compared by their geometric mean (GM) ratio, and non-inferiority was defined by the lower bound of a one-sided 95% confidence interval (CI) >0.9.Results: A total of 725 subjects completed the trial per protocol (395 PD and 330 HD, mean age 49.8 (standard deviation (SD) 14.4) years, 41.4% women). For the primary outcome, the mean (SD) change in ‘Burden of Kidney Disease’ over 48 weeks was 2.61 (1.27) in PD group and 2.58 (1.35) in HD group, and the GM ratio (95% CI) was 1.059 (0.908–1.234), exceeding the limit for non-inferiority. For the secondary outcomes, the PD and HD groups were similar in all scales. There were 17 and 31 deaths in PD and HD groups, respectively. Patients receiving PD had more adverse events, adverse event leading to hospitalisation and serious adverse events compared to those allocated to HD, but adverse events leading to death and discontinuation of the trial were not different between PD and HD.Conclusions: In this trial, PD may be non-inferior to HD on the ‘Burden of Kidney Disease’ among Chinese kidney failure patients who are of younger age and have lower comorbidity after 48 weeks’ follow-up.

SOD-like activity of CeO2nanoparticles (Ce NPs) is driven by Ce3+/Ce4+, high oxidative stress can oxidize Ce3+to reduce the ratio of Ce3+/Ce4+, inactivating the SOD activity of Ce NPs. Herein, we found Au@Ce NPs, assembled by Au NPs and Ce NPs, exhibited high-performance of SOD mimetic enzyme activity even upon the oxidation of H2O2. Ce NPs supported by nano-Au can acquire the electrons from Au NPs through the enhanced localized surface plasmon resonance (LSPR), maintaining the stability of Ce3+/Ce4+and SOD-like activity. Meanwhile, Au@Ce NPs retained the peroxidase function and catalase function. As a result, Au@Ce NPs effectively scavenged O2•- and the derived ROS in AML cells, which are the important signaling source that drives AML cell proliferation and accelerates cell cycle progression. When HL-60 cells were treated by Au@Ce NPs, the removal of endogenous ROS signal significantly arrested cell cycle at G1 phase and suppressed the cell proliferation by blocking the mitogen-activated protein kinases (MAPKs) signaling and the Akt/Cyclin D1 cell cycle signaling. Importantly, this treatment strategy showed therapeutic effect for subcutaneous transplantation of AML model as well as a satisfactory result in diminishing the leukocyte infiltration of liver and spleen particularly. Thus, assembled Au@Ce NPs show the high-performance SOD-like activity, promising the potential in treating AML and regulating abnormal ROS in other diseases safely and efficiently.

Predicting rock cracking is important for assessing the stability of underground engineering. The effects of the intersecting angle αand the distribution orientation angle βof intersecting fissures on the uniaxial compressive strength and the failure characteristics of sandstone containing intersecting fissures are investigated through laboratory experiments and two-dimensional particle flow code (PFC2D). The relationship between the mechanical properties of sandstone and the intersecting angle αand the distribution orientation angle βis analysed. Crack initiation forms and the final failure modes are then categorised and determined via empirical methods. In addition, the cracking processes of intersecting fissures with different αand βvalues are discussed. The results show that variations in the peak stress, peak strain, average modulus, and crack initiation stress of sandstone containing intersecting fissures show a “moth” shape in the space of the α-β-mechanical parameters. Two crack initiation forms are identified: inner tip cracking (usually accompanied by one outer tip cracking) and only outer tips cracking. Two failure modes are observed: (1) the main fracture planes are created at the inner tip and one outer tip, and (2) the main fracture planes are formed at the two outer tips. Two main crack evolution processes of sandstone containing intersecting fissures under uniaxial compression are found. Approaches for quickly determining the crack initiation form and the failure mode are proposed. The combination of the determination equations for the crack initiation form and the failure mode can be used to predict the crack evolution. The approach for determining the crack evolution processes is hence proposed with acceptable precision.

Taxus chinensisvar. mairei fruit polysaccharide (TMFP) is a natural resource with effective hypoglycemic and anti-tumor properties. However, its impact on melanogenesis remains largely unexploited. This study explores the anti-melanogenic activity of TMFP using in vitroand in vivomodels. It was found that TMFP can safely and effectively eliminate melanin and inhibit tyrosinase activity without cytotoxicity. More specifically, the inhibitory effect of TMFP on melanin synthesis was verified in zebrafish embryos. In addition, nine formulations of TMFP-Liposomes were prepared to improve drug transdermal absorption, and TMFP-Liposome E was determined as the optimal formulation after characterization and transdermal comparison experiments. Most importantly, in vivoskin whitening experiments gave that TMFP-Liposome E has better skin whitening activity than control, model, blank liposomes, TMFP aqueous, and arbutin groups. The cell viability and animal safety tests confirmed the good biosafety of TMFP-Liposome E. Overall, this research suggests that TMFP may serve as a potential therapeutic agent for skin diseases and a potent whitening agent for cosmetic use. TMFP-Liposome E may enhance the therapeutic effect of melanin through improved transdermal absorption.

Based on the structural characteristics of the cryptolepine alkaloid, a series of new quindoline derivatives bearing various substituents were prepared and evaluated for their fungicidal and antibacterial activities. Bioassay results showed that compound D7displayed superior in vitrofungicidal activities against Sclerotinia sclerotiorum, Botrytis cinerea, Fusarium graminearum, and Rhizoctonia solaniwith EC50values of 0.780, 3.62, 1.59, and 2.85 μg/mL, respectively. Compound A7showed apparent antibacterial activities toward Xanthomonas oryzaepv. oryzaewith a minimum inhibitory concentration (MIC) value of 3.12 μg/mL. Significantly, in vivoantifungal activity suggested that the curative effect (98.3%) of compound D7was comparable to that of the positive control azoxystrobin (96.7%) at 100 μg/mL. Preliminary mechanistic studies showed that compound D7might cause mycelial abnormality of S. sclerotiorum, cell membrane breakage, accumulation of reactive oxygen species (ROS), and inhibition of sclerotia formation. Therefore, compound D7could be a novel broad-spectrum fungicidal candidate against plant fungal diseases.

The methyl-CpG-binding domain 2 (MBD2) interprets DNA methylome-encoded information through binding to the methylated CpG DNA, by which it regulates target gene expression at the transcriptional level. Although derailed DNA methylation has long been recognized to trigger or promote autoimmune responses in type 1 diabetes (T1D), the exact role of MBD2 in T1D pathogenesis, however, remains poorly defined. Herein, we generated an Mbd2knockout model in the NOD background and found that Mbd2deficiency exacerbated the development of spontaneous T1D in NOD mice. Adoptive transfer of Mbd2−/−CD4 T cells into NOD.scidmice further confirmed the observation. Mechanistically, Th1 stimulation rendered the Stat1promoter to undergo a DNA methylation turnover featured by the changes of DNA methylation levels or patterns along with the induction of MBD2 expression, which then bound to the methylated CpG DNA within the Stat1promoter, by which MBD2 maintains the homeostasis of Th1 program to prevent autoimmunity. As a result, ectopic MBD2 expression alleviated CD4 T cell diabetogenicity following their adoptive transfer into NOD.scidmice. Collectively, our data suggest that MBD2 could be a viable target to develop epigenetic-based therapeutics against T1D in clinical settings.

Toxicological studies show that exposure to disinfection byproducts, including trihalomethanes (THMs), negatively affects thyroid function; however, few epidemiological studies have explored this link. This study included 2233 adults (ages ≥20 years) from the 2007–2008 National Health and Nutrition Examination Survey (NHANES) who were measured for blood THM concentrations [chloroform (TCM), bromodichloromethane (BDCM), dibromochloromethane (DBCM), or bromoform (TBM)] and serum thyroid function biomarkers [thyroid-stimulating hormone, free thyroxine (FT4), total thyroxine (TT4), free triiodothyronine (FT3), total triiodothyronine (TT3), thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb)]. Multivariable linear regression models showed positive associations between blood TCM, BDCM, and total THMs (the sum of all four THMs) concentrations and serum FT4, whereas inverse associations were found between blood DBCM and total brominated THM (Br-THM; the sum of BDCM, DBCM, and TBM) concentrations and serum TT3 (all p< 0.05). Besides, positive associations were observed between blood TCM concentrations and FT4/FT3 ratio, between BDCM, DBCM, and Br-THM concentrations and TT4/TT3 ratio, and between DBCM and Br-THM concentrations and FT3/TT3 ratio (all p< 0.05). Blood THM concentrations were unrelated to the serum levels of thyroid autoantibodies TgAb or TPOAb. In summary, exposure to THMs was associated with altered serum biomarkers of thyroid function but not with thyroid autoimmunity among U.S. adults.

Graphitic carbon nitride-graphene oxide (g-C3N4/GO) composite membranes were fabricated via filtrating g-C3N4and a small amount of GO on a porous polymer support. GO nanosheets were incorporated in g-C3N4-based membranes to prevent interedge defects or voids from forming. Accordingly, the selective molecular sieving pores and interlayer channels of g-C3N4can effectively separate H2molecules from larger gas molecules (CH4, N2, O2, and CO2). When the GO weight loading reaches 5%, the g-C3N4/GO composite membrane shows an enhanced H2/CO2separation performance with a H2permeance of 3.66 × 10–6mol m–2s–1Pa–1(H2/CO2ideal selectivity: 179.6).

N-Phenylpropenoyl-l-amino acids (NPAs) are inducible nitric oxide synthase (iNOS) inhibitors possessing preventive effects for Parkinson’s disease (PD). Here, structural modifications for improving the iNOS inhibitory activity and blood–brain barrier (BBB) permeability of NPAs were conducted, leading to 20 optimized NPA derivatives (1–20). Compound 18, with the most potent activity (IC50= 74 nM), high BBB permeability (Pe= 19.1 × 10–6cm/s), and high selectivity over other NOS isoforms, was selected as the lead compound. Further studies demonstrated that 18directly binds to iNOS. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced acute PD model, the oral administration of 18(1 and 2 mg/kg) exerted preventive effects by alleviating the loss of dopaminergic (DAergic) neurons. Notably, in the MPTP-/probenecid-induced chronic PD model, the same dose of 18also displayed a therapeutic effect by repairing the damaged DAergic neurons. Finally, good pharmacokinetic properties and low toxicity made 18a promising candidate for the treatment of PD.

Obesity has become a major public health issue in China. Overweight and obesity have increased rapidly in the past four decades, and the latest national prevalence estimates for 2015–19, based on Chinese criteria, were 6·8% for overweight and 3·6% for obesity in children younger than 6 years, 11·1% for overweight and 7·9% for obesity in children and adolescents aged 6–17 years, and 34·3% for overweight and 16·4% for obesity in adults (≥18 years). Prevalence differed by sex, age group, and geographical location, but was substantial in all subpopulations. Strong evidence from prospective cohort studies has linked overweight and obesity to increased risks of major non-communicable diseases and premature mortality in Chinese populations. The growing burden of overweight and obesity could be driven by economic developments, sociocultural norms, and policies that have shaped individual-level risk factors for obesity through urbanisation, urban planning and built environments, and food systems and environments. Substantial changes in dietary patterns have occurred in China, with increased consumption of animal-source foods, refined grains, and highly processed, high-sugar, and high-fat foods, while physical activity levels in all major domains have decreased with increasing sedentary behaviours. The effects of dietary factors and physical inactivity intersect with other individual-level risk factors such as genetic susceptibility, psychosocial factors, obesogens, and in-utero and early-life exposures. In view of the scarcity of research around the individual and collective roles of these upstream and downstream factors, multidisciplinary and transdisciplinary studies are urgently needed to identify systemic approaches that target both the population-level determinants and individual-level risk factors for obesity in China.

China has one of the largest populations with obesity in the world, and obesity has become a major challenge for the country's health-care system. Current guidelines for obesity management are not adequately supported by evidence from clinical studies in Chinese populations. Effective lifestyle interventions suitable for Chinese populations are scarce, insufficient weight-loss medications have been approved by regulatory bodies, and there is low acceptance of non-lifestyle interventions (ie, medications and surgery) among both health-care providers and the general public. Large, well designed, and well implemented clinical trials are needed to strengthen the evidence base for the clinical management of obesity in China. Obesity management can be improved through use of a tiered system involving health management centres, integrated lifestyle interventions and medical treatments, strengthened obesity education and training, and use of advanced electronic health technologies. Resource mobilisation, support from major stakeholders for people with overweight or obesity, and education and changes to social norms among the wider public are also needed. National health policies should prioritise both obesity prevention and improvement of the treatment and management of obesity.

Kdm2a catalyzes H3K36me2 demethylation to play an intriguing epigenetic regulatory role in cell proliferation, differentiation, and apoptosis. Herein we found that myeloid-specific knockout of Kdm2a(LysM-Cre-Kdm2af/f, Kdm2a−/−) promoted macrophage M2 program by reprograming metabolic homeostasis through enhancing fatty acid uptake and lipolysis. Kdm2a−/−increased H3K36me2 levels at the Pparglocus along with augmented chromatin accessibility and Stat6 recruitment, which rendered macrophages with preferential M2 polarization. Therefore, the Kdm2a−/−mice were highly protected from high-fat diet (HFD)-induced obesity, insulin resistance, and hepatic steatosis, and featured by the reduced accumulation of adipose tissue macrophages and repressed chronic inflammation following HFD challenge. Particularly, Kdm2a−/−macrophages provided a microenvironment in favor of thermogenesis. Upon HFD or cold challenge, the Kdm2a−/−mice manifested higher capacity for inducing adipose browning and beiging to promote energy expenditure. Collectively, our findings demonstrate the importance of Kdm2a-mediated H3K36 demethylation in orchestrating macrophage polarization, providing novel insight that targeting Kdm2a in macrophages could be a viable therapeutic approach against obesity and insulin resistance.