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Abstract Background UMEC/VI administered via a combination inhaler is associated with a clinically significant improvement in lung function and health-related quality of life in patients with mild-to-moderate COPD. However, their efficacy compared to other bronchodilator mono or dual therapies still remains unclear. Objective The objective of this research was to evaluate the therapeutic efficacy of UMEC/VI dual and UMEC/VI/FF triple therapies versus alternative bronchodilator regimens in COPD patients. Methods A systematic search was conducted using four electronic databases (PubMed, EMBASE, Scopus, and Cochrane Library) to select publications published in peer-reviewed journals written in English. The odds ratio (OR) and risk ratio (RR) was calculated, along with their 95% confidence intervals. We assessed heterogeneity using Cochrane Q and I [2] statistics and the appropriate p-value. The analysis used RevMan 5.4. Results The current meta-analysis includes 31,814 COPD patients from 17 RCTs. The meta-analysis results demonstrate that the combination of LABA and LAMA provides additive bronchodilation and improved lung function in COPD patients. We found that UMEC/VI dual therapy significantly improved FEV1 (OR 1.98 [95% CI 1.70–2.30]), TDI values (OR 1.97 [95% CI 1.72–2.26]), and reduced SGRQ total scores (OR 1.99 [95% CI 1.71–2.32]), with fewer drug-related adverse events (RR 0.58 [95% CI 0.53–0.64]). Similarly, UMEC/VI/FF triple therapy also showed similar benefits, with significant improvements in FEV1 (OR 1.93 [95% CI 1.73–2.15]), TDI values (OR 2.37 [95% CI 2.15–2.61]), and reduced SGRQ total scores (OR 1.83 [95% CI 1.63–2.05]), and fewer drug-related adverse events (RR 0.53 [95% CI 0.49–0.58]). Conclusion This systematic review and meta-analysis concludes that UMEC and VI combinations are an efficacious treatment option for symptomatic COPD patients.

CCL2, a pivotal cytokine within the chemokine family, functions by binding to its receptor CCR2. The CCL2/CCR2 signaling pathway plays a crucial role in the development of fibrosis across multiple organ systems by modulating the recruitment and activation of immune cells, which in turn influences the progression of fibrotic diseases in the liver, intestines, pancreas, heart, lungs, kidneys, and other organs. This paper introduces the biological functions of CCL2 and CCR2, highlighting their similarities and differences concerning fibrotic disorders in various organ systems, and reviews recent progress in the diagnosis and treatment of clinical fibrotic diseases linked to the CCL2/CCR2 signaling pathway. Additionally, further in-depth research is needed to explore the clinical significance of the CCL2/CCR2 axis in fibrotic conditions affecting different organs.

Abstract In recent years, the extensive participation of turbine generator in deep peak regulation has caused significant damage to the rotor windings, which is rooted in the frequent and significant changes in the electrical load of the rotor, accompanied by thermal expansion and contraction, causing harm to the rotor insulation and stress fatigue of the metal conductor. Hydrogen, as the cooling medium for the rotor windings of turbine generators, has a direct impact on the windings temperature through its parameters. Starting from suppressing the harm of deep peak regulation on the rotor windings, the inhibitory effect of hydrogen parameter changes on the temperature of the gap‐pickup diagonal‐flow rotor is studied. A calculation model for the rotor temperature field of the turbo‐generator with gap‐pickup diagonal‐flow ventilation is established. The finite volume method is used to iteratively calculate the control equations in the fluid‐thermal‐solid coupling heat transfer problem, and the temperature field distribution of various components of the rotor under different excitation loads is obtained. On this basis, the effects of individual adjustment of hydrogen temperature and pressure, as well as the combined adjustment, on the temperature of the rotor windings are studied. Finally, a variable hydrogen parameter adjustment strategy is proposed for the operation of turbo‐generators under deep peak regulation conditions. To a certain extent, the winding temperature fluctuation can be suppressed, which provides a potential solution for the thermal stable operation of the rotor.

The exceptional energy absorption, deformability, and tuneable Poisson’s ratio properties of negative Poisson’s ratio (NPR) honeycomb biomimetic structures make them highly suitable for applications in aerospace, medical, and acoustic stealth industries. The present study proposes a re-entrant hybrid honeycomb (REHH) structure comprising a re-entrant octagonal unit cell and a re-entrant hexagonal unit cell. Theoretical models of the in-plane elastic modulus and Poisson’s ratio are established based on beam theory, and these models are validated through finite element (FE) simulations and tensile experiments conducted on the REHH samples. The influence of the cell geometry parameters on the in-plane elastic behaviours is investigated. The results indicate that the NPR performance of the REHH structure exhibits superior deformation capability compared with the four-point star hybrid honeycomb (FSHH) structure. The experimental REHH structure samples exhibit significant tensile displacement capabilities in the x-direction.

The photo-self-Fenton collaborative system, which combines Fenton reaction with photocatalytic system, exhibits excellent oxidation ability over pollutants without external addition of hydrogen peroxide. Herein, the PDI-C/Fe3+ photo-self-Fenton system, combining carboxylic acid side chain modified perylene diimide supramolecule (PDI-C) and Fe3+, is used to obtain an extremely efficient and durable degradation efficiency of Phenol (a model pollutant in phenolic wastewater). The research systematically investigates the catalytic reaction mechanism by examining the changes in the form and content of iron species, the production mechanism and content changes of hydrogen peroxide and the content changes of various active species. The interaction between Fe3+ and the carboxylic acid side chain of PDI-C promotes photo-generated electron capture by Fe3+ and the resultant conversion to Fe2+, accordingly facilitating the separation of photogenerated carriers. On the other hand, the hydrogen peroxide generated in-situ during the photocatalytic process pairs with the effective circulation of iron ions to form a photo-self-Fenton system, which synergically promotes the efficient and durable phenol degradation. It is also found that as the reaction prolonged, α-FeOOH formed on the surface of PDI-C not only results in iron loss, but also leads to the obscuration of light-absorbing sites, thus becoming a non-negligible factor for the decrease of catalytic activity. Notably, acid addition can not only inhibit the generation of α-FeOOH, but also aid the leaching of formed α-FeOOH, enabling an efficient iron ion circulation and the photo-self-Fenton system's efficient operation. The work also identifies two pathways of hydrogen peroxide production and reveals a competitive relationship between ·OH and ·O2– in the presence of Fe3+. These findings highlight the high efficiency and durability of the PDI-C/Fe3+ photo-self-Fenton system in degrading phenol pollutants under visible light irradiation, while showcasing its potential for practical applications due to its cost-effectiveness and simplicity.

ABSTRACTChina's population and development land have changed dramatically over the last decade. Yet, our understanding of the spatial distribution patterns of the population and built-up areas remains limited. To fill this gap, we employ China's Population Census and GlobeLand30 remote sensing data from 2010 to 2020 at the county level to geovisualize the evolution of the population and built-up area. We find an increasing correlation between built-up areas and population as a result of the urbanization of rural areas, but the rapid expansion of built-up areas has not fundamentally changed concentration of China's population over the period 2010–20.

Abstract There is increasing attention to the production of cellulose nanocrystals (CNCs) from lignocellulosic biomass by enzymatic hydrolysis with cellulase. In this study, the feasibility of the application of a cellulase system from engineered strain Penicillium oxalicum cEES in the production of CNCs was assessed. Using commercial eucalyptus dissolving pulp (EDP) as substrate, the CNCs were successfully obtained by enzymatic hydrolysis with the cellulase cEES, and the total yields of CNCs reached 15.7% through three-step enzymatic hydrolysis of total 72 h (24 h for each step). The prepared CNCs were characterized and found that their crystallinity and thermal stability were higher than that of EDP. In the later stage of enzymatic hydrolysis, the process efficiency of enzymatic preparation of CNCs greatly decreased because of the high crystallinity of cellulosic substrate, and a simple homogenization treatment can promote the enzymatic hydrolysis, as well as produce fusiform CNCs with more uniform size and more fermentable sugar that could be further converted into fuels and bulk chemicals through fermentation. This study provides a feasible enzymatic preparation process for CNCs with engineered cellulase and commercial cellulosic materials. Graphical Abstract

Many methods have been proposed to estimate biodiversity using remote sensing. However, most approaches are often limited by ecosystem type, sensor type, and study scale. Although the Spectral Variation Hypothesis has been successfully tested in diverse conditions, a controversial spectral diversity–biodiversity relationship was reported in some studies. The rapid loss of biodiversity forces us to develop more new techniques. This work proposed a novel approach to estimating biodiversity based on the scale effects of remote sensing, applicable to a range of ecosystem and sensor types. This study provides a rigorous mathematical proof of the proposed method and validates it in two distinct ecosystems: grassland and shrubland. The correlation between the scale effects of vegetation indices and in situ plant diversity (Shannon’ H and Species Richness) was analyzed across different spatial scales and sensor types. Results reveal that the scale effect of the vegetation index serves as an effective proxy of plant diversity. Vegetation indices that incorporate near-infrared bands demonstrate superior performance, with the optimal index being the Green Ratio Vegetation Index, which utilizes only near-infrared and green bands. In shrubland, r = 0.609, while in grassland, r = 0.489. The study recommends that for low-resolution images, the pixel size should be aligned with the dimensions of field quadrats. In contrast, high-resolution images should approximate the size of individual plants. A comparison with classical methods reports a good performance for the novel method. Moreover, this method is more effective under high vegetation coverage. Specifically, when the vegetation coverage exceeds 60 %, the correlation coefficient rises to 0.718. These findings suggest that the scale effect of the vegetation index is a valuable tool for monitoring plant diversity. Using this method and long time-series remote sensing data to estimate plant diversity in different periods, ecologists can effectively identify degraded areas of plant diversity and formulate conservation measures in time.

Abstract Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR‐associated nuclease 9 (Cas9) has emerged as a powerful tool to generate targeted loss‐of‐function mutations for functional genomic studies. As a next step, tools to generate genome modifications in a spatially and temporally precise manner will enable researchers to further dissect gene function. Here, we present two heat shock–inducible genome‐editing (IGE) systems that efficiently edit target genes when the system is induced, thus allowing us to target specific developmental stages. For this conditional editing system, we chose the natural heat‐inducible promoter from heat‐shock protein 18.2 (HSP18.2) from Arabidopsis thaliana and the synthetic heat–inducible promoter heat shock–response element HSE‐COR15A to drive the expression of Cas9. We tested these two IGE systems in Arabidopsis using cyclic or continuous heat‐shock treatments at the seedling and bolting stages. A real‐time quantitative polymerase chain reaction analysis revealed that the HSP18.2 IGE system exhibited higher Cas9 expression levels than the HSE‐COR15A IGE system upon both cyclic and continuous treatments. By targeting brassinosteroid‐insensitive 1 (BRI1) and phytoene desaturase (PDS), we demonstrate that both cyclic and continuous heat inductions successfully activated the HSP18.2 IGE system at the two developmental stages, resulting in highly efficient targeted mutagenesis and clear phenotypic outcomes. By contrast, the HSE‐COR15A IGE system was only induced at the seedling stage and was less effective than the HSP18.2 IGE system in terms of mutagenesis frequencies. The presented heat shock–IGE systems can be conditionally induced to efficiently inactivate genes at any developmental stage and are uniquely suited for the dissection and systematic characterization of essential genes.

Abstract Background T1 colorectal cancers have a low lymph node metastasis rate and good prognosis. Thus, endoscopic resection is an attractive choice. This study aimed to describe the value of poorly differentiated cluster grade in identifying endoscopically curable T1 colorectal cancers. Methods We included 183 T1 colorectal cancer patients who underwent curative resection. Univariate and multivariate logistic regressions were used to identify lymph node metastasis predictors. The Akaike information criterion was used to determine whether poorly differentiated cluster grade was the best predictor. Backward regression was used to screen the variables. Survival analyses were conducted to determine the prognostic predictive power of poorly differentiated cluster grade. Correlations among predictors and concordance between our pathologists were also investigated. Results Poorly differentiated cluster grade was an independent predictor for lymph node metastasis (adjusted odds ratio [OR]G 3 = 0.001; 95% confidence interval [95% CI]G 3 =

Abstract Corn fiber, a by-product from the corn processing industry, mainly composed of residual starch, cellulose, and hemicelluloses, is a promising raw material for producing cellulosic ethanol and value-added products due to its abundant reserves and low costs of collection and transportation. Now, several technologies for the production of cellulosic ethanol from corn fiber have been reported, such as the D3MAX process, Cellerate™ process, etc., and part of the technologies have also been used in industrial production in the United States. The ethanol yields range from 64 to 91% of the theoretical maximum, depending on different production processes. Because of the multicomponent of corn fiber and the complex structures highly substituted by a variety of side chains in hemicelluloses of corn fiber, however, there are many challenges in cellulosic ethanol production from corn fiber, such as the low conversion of hemicelluloses to fermentable sugars in enzymatic hydrolysis, high production of inhibitors during pretreatment, etc. Some technologies, including an effective pretreatment process for minimizing inhibitors production and maximizing fermentable sugars recovery, production of enzyme preparations with suitable protein compositions, and the engineering of microorganisms capable of fermenting hexose and pentose in hydrolysates and inhibitors tolerance, etc., need to be further developed. The process integration of cellulosic ethanol and value-added products also needs to be developed to improve the economic benefits of the whole process. This review summarizes the status and progresses of cellulosic ethanol production and potential value-added products from corn fiber and presents some challenges in this field at present.

Shield tunnels are inevitably damaged by complex diseases during operation, so repair and reinforcement are essential. The stainless steel corrugated plate (SSCP) has many advantages for tunnel structure reinforcement because of its high strength, lightweight, convenient construction and installation, and corrosion resistance. Mechanical behaviors of an unreinforced segmental joint and a segmental joint reinforced with a new SSCP were investigated by full-scale tests. The reinforcement test took into account the actual reinforcement conditions in the field, i.e. the joint bore the load alone before reinforcement, maintained the load during reinforcement, and bore the load together with the SSCP after reinforcement. The experimental results demonstrate that: (1) both unreinforced and reinforced joints exhibit a compressive-flexural failure mechanism, and their failure is manifested by concrete crushing in the compressed zone of the joint. (2) Compared to that unreinforced joint, the bending moment and ultimate vertical load of the reinforced one are increased by 73.7% and 119.3%, respectively. And the reinforced joint is stiffer than the unreinforced one, reflecting that SSCP reinforcement enables higher stiffness. (3) Trends of strain-moment curves of the bent bolts and concrete are similar in the unreinforced and reinforced joints. Under the same load, the strains in the reinforced group are smaller than those in the unreinforced group, indicating that the SSCP in the reinforced group shares the load. (4) The strains of the SSCP exhibits a symmetrical distribution in the length direction with the joint section as the symmetrical plane. The strains at the trough show tensile strain, while the strains at the crest show compressive strain. The combined force of the corrugated steel plate cross-section is tensile (i.e., SSCP shares the tension load in the tensile zone of the joint), reflecting the reinforcement effect of SSCP.

ABSTRACT Epstein-Barr virus (EBV) infects host cells and establishes a latent infection that requires evasion of host innate immunity. A variety of EBV-encoded proteins that manipulate the innate immune system have been reported, but whether other EBV proteins participate in this process is unclear. EBV-encoded envelope glycoprotein gp110 is a late protein involved in virus entry into target cells and enhancement of infectivity. Here, we reported that gp110 inhibits RIG-I-like receptor pathway-mediated promoter activity of interferon-β (IFN-β) as well as the transcription of downstream antiviral genes to promote viral proliferation. Mechanistically, gp110 interacts with the inhibitor of NF-κB kinase (IKKi) and restrains its K63-linked polyubiquitination, leading to attenuation of IKKi-mediated activation of NF-κB and repression of the phosphorylation and nuclear translocation of p65. Additionally, gp110 interacts with an important regulator of the Wnt signaling pathway, β-catenin, and induces its K48-linked polyubiquitination degradation via the proteasome system, resulting in the suppression of β-catenin-mediated IFN-β production. Taken together, these results suggest that gp110 is a negative regulator of antiviral immunity, revealing a novel mechanism of EBV immune evasion during lytic infection. IMPORTANCE Epstein-Barr virus (EBV) is a ubiquitous pathogen that infects almost all human beings, and the persistence of EBV in the host is largely due to immune escape mediated by its encoded products. Thus, elucidation of EBV’s immune escape mechanisms will provide a new direction for the design of novel antiviral strategies and vaccine development. Here, we report that EBV-encoded gp110 serves as a novel viral immune evasion factor, which inhibits RIG-I-like receptor pathway-mediated interferon-β (IFN-β) production. Furthermore, we found that gp110 targeted two key proteins, inhibitor of NF-κB kinase (IKKi) and β-catenin, which mediate antiviral activity and the production of IFN-β. gp110 inhibited K63-linked polyubiquitination of IKKi and induced β-catenin degradation via the proteasome, resulting in decreased IFN-β production. In summary, our data provide new insights into the EBV-mediated immune evasion surveillance strategy.

To apply the discrete element method (DEM) to simulate the interaction process between soda saline–alkali soil and subsoiling component in Northeast China, establishing the soda saline–alkali soil particle model and selecting more accurate simulation parameters are important. In this paper, we studied the soda saline–alkali soil of the Songnen Plain in China. First, we studied the geometric shape of soda saline–alkali soil particles and proposed a modeling method for single soil particles based on the multisphere combination method. Considering the cohesion of soda saline–alkali soil particles, the Hertz–Mindlin with JKR (JKR) model was used as the contact model between soil particles. Then, the calibration method was used to obtain simulation parameters of soils that are difficult to obtain experimentally. We conducted soil angle of repose (AoR) tests, the Plackett–Burman (PB) tests, and steepest ascent (SA) tests in turn to perform a sensitivity analysis for microscopic contact parameters and select the parameters that have a significant effect on the response value (static AoR), i.e., soil surface energy, soil–soil static friction coefficient, and soil–soil rolling friction coefficient. Then, the optimal combination of simulation parameters was obtained via the Box–Behnken (BB) tests, using ANOVA to optimize the multiple regression equation. Finally, the optimal parameter combination was verified by the AoR test and the direct shear (DS) test. The results showed that the parameters had good adaptability for the AoR test. However, the simulation results of the DS test were significantly different from the experimental values. Therefore, the contact model needs to be further modified by adding Bonding bonds between soil particles based on the JKR model and further correcting for Rayleigh time step, shear modulus, and surface energy. By comparing the simulation and the experimental results, it was found that the simulation results obtained from both the DS test and AoR test had relatively small errors relative to physical tests, the two trends are the same, and the values are similar. This verified the feasibility and effectiveness of the soda saline–alkali soil particle modeling method and parameter selection proposed in this paper.

Shield tunnels inevitably endure various forms of damage as their service times increase. Steel corrugated plates have been used extensively under multiple conditions and have proven effective in strengthening segmental joints, according to full-scale tests. A numerical model is proposed to probe the feasibility of using a new stainless-steel corrugated plate (SSCP) to reinforce shield-tunnel segments. A new method, called virtual-tracking-element technology, is employed to achieve the simulation of a realistic stress state of the segmental joint. Moreover, a segmental-joint-component analysis and a parametric study were conducted based on the numerical model. The results demonstrate that: (1) the virtual-tracking-element technology is a valid and efficient approach to the simulation of the secondary-stress state of segmental joints; (2) SSCP reinforcement is not fully utilized when the grade of segmental concrete is C50, and it has a wide safety margin for potential overload; (3) SSCP reinforcement performs well regardless of the burial depth, and reinforcement in advance is recommended.

BackgroundThe purpose of this study was to systematically review the effectiveness of regular traditional Chinese fitness exercises on negative emotions and sleep disorders in college students, and to provide evidence-based evidence and new ideas for the negative emotions and sleep disorders among the college students.MethodsA systematic search using 5 English (PubMed, Embase, Scopus, EBSCO, and the Cochrane Library) and 4 Chinese (CNKI, WanFang, VIP, and CBM) databases were initiated to identify randomized controlled trials (RCT) assessing the effect of traditional Chinese fitness exercises on negative emotions and sleep disorders among college students. Standardized mean differences (SMD) and their 95% confidence intervals (CI) were used to determine the pooled effect of the intervention. The Cochrane bias risk assessment tool was used to evaluate the methodological quality and the data were analyzed with Review Manager 5.4.ResultsA total of 12 RCTs were included, including 1,052 subjects. The results showed a potential beneficial effect of traditional Chinese fitness exercises on reducing depression [SMD = −0.93, 95 %CI (−1.76, −0. 10)], anxiety [SMD = −0.74, 95%CI (−0.93, −0.54)], and the sleep disorders [SMD = −2.77, 95%CI (−4.57, −0.97)] symptoms, and these effects were better than in the control group.ConclusionThe findings of this review suggested the traditional Chinese fitness exercises could improve both the negative moods and sleep disorders compared with that of healthy students, the effect on college students with mild to moderate psychological symptoms was obviously improved. The SCL-90 scale is better than the SDS scale in evaluating the improvement effect of traditional Chinese fitness exercises on depression. It was the best intervention program on negative emotions and sleep disorders among college students, with the intervention lasting 5 sessions per week for 30–60 min/session for over 12 weeks.

Fungal cellulases usually contain a family 1 carbohydrate-binding module (CBM1), and its role was considered to recognize the substrate specifically. This study testified that the CBM1s derived from cellobiohydrolase I of Trichoderma reesei, Penicillium oxalicum, and Penicillium funiculosum could be used as an effective accessory protein in cellulase cocktails to enhance the saccharification of lignocellulose, and its enhancement effect was significantly superior to some reported accessory proteins, such as bovine serum albumin (BSA). The promoting effects of the CBM1s were related to not only the CBM1 sources and protein dosages, but also the substrate characteristics and solid consistency during enzymatic hydrolysis. The adsorption capacity of the CBM1s, the adsorption kinetic of TrCBM from T. reesei and cellobiohydrolase, endoglucanase, and β-glucosidase from P. oxalicum, and the effect of adding TrCBM on enzyme activities of free cellulases in the hydrolysis system were investigated, and the binding conformations and affinities of CBM1s to cellulose and lignin were predicted by molecular docking. It was speculated that the higher affinity of the CBM1s to lignin than cellulases could potentially enable the CBM1s to displace cellulase adsorbed on lignin or to preferentially adsorb onto lignin to avoid ineffective adsorption of cellulase onto lignin, which enhanced cellulase system efficiency during enzymatic hydrolysis of lignocellulose.

Danon disease is a rare X-linked dominant genetic disorder that manifests with a clinical triad of cardiomyopathy, skeletal myopathy, and intellectual disability. It is caused by mutations in the lysosome-associated membrane 2 (LAMP2) gene. We report one case of Danon disease and his family members, characterized by ventricular pre-excitation, ventricular hypertrophy, abnormal muscle enzymes, and aberrant liver function. All the patients were confirmed to have Danon disease through genetic screening. Relevant literature was reviewed as a reference for the diagnosis and treatment of the disease.

Radiation belt electron dropouts indicate electron flux decay to the background level during geomagnetic storms, which is commonly attributed to the effects of wave-induced pitch angle scattering and magnetopause shadowing. To investigate the loss mechanisms of radiation belt electron dropouts triggered by a solar wind dynamic pressure pulse event on 12 September 2014, we comprehensively analyzed the particle and wave measurements from Van Allen Probes. The dropout event was divided into three periods: before the storm, the initial phase of the storm, and the main phase of the storm. The electron pitch angle distributions (PADs) and electron flux dropouts during the initial and main phases of this storm were investigated, and the evolution of the radial profile of electron phase space density (PSD) and the (μ, K) dependence of electron PSD dropouts (where μ, K, and L* are the three adiabatic invariants) were analyzed. The energy-independent decay of electrons at L > 4.5 was accompanied by butterfly PADs, suggesting that the magnetopause shadowing process may be the major loss mechanism during the initial phase of the storm at L > 4.5. The features of electron dropouts and 90°-peaked PADs were observed only for >1 MeV electrons at L < 4, indicating that the wave-induced scattering effect may dominate the electron loss processes at the lower L-shell during the main phase of the storm. Evaluations of the (μ, K) dependence of electron PSD drops and calculations of the minimum electron resonant energies of H+-band electromagnetic ion cyclotron (EMIC) waves support the scenario that the observed PSD drop peaks around L* = 3.9 may be caused mainly by the scattering of EMIC waves, whereas the drop peaks around L* = 4.6 may result from a combination of EMIC wave scattering and outward radial diffusion.

Polyethylene glycols (PEGs) in general use are polydisperse molecules with molecular weight (MW) distributed around an average value applied in their designation e.g., PEG 4000. Previous research has shown that PEGs can act as P-glycoprotein (P-gp) inhibitors with the potential to affect the absorption and efflux of concomitantly administered drugs. However, questions related to the mechanism of cellular uptake of PEGs and the exact role played by P-gp has not been addressed. In this study, we examined the mechanism of uptake of PEGs by MDCK-mock cells, in particular, the effect of MW and interaction with P-gp by MDCK-hMDR1 and A549 cells. The results show that: (a) the uptake of PEGs by MDCK-hMDR1 cells is enhanced by P-gp inhibitors; (b) PEGs stimulate P-gp ATPase activity but to a much lesser extent than verapamil; and (c) uptake of PEGs of low MW (5000 Da) occurs by a combination of passive diffusion and caveolae-mediated endocytosis. These findings suggest that PEGs can engage in P-gp-based drug interactions which we believe should be taken into account when using PEGs as excipients and in PEGylated drugs and drug delivery systems.

Abstract Background To compare the efficacy of three types of palliative therapy for advanced hepatocellular carcinoma (HCC), including transarterial chemoembolisation (TACE) monotherapy, sorafenib alone and their combination. Methods The databases of PubMed, Embase and Cochrane Library were retrieved. The odds ratio (OR) with its 95% confidence interval (CI) was used to investigate the binary variables, and the standardised mean difference (SMD) with its 95% CI was employed to evaluate the continuous variables. All statistical tests were performed by using Stata/SE, version 12.0. Results Thirty-one clinical studies, containing 5125 unique cases of patients with advanced HCC, were included. There were significant improvements in overall survival (OS) (pooled SMD = 2.54; 95% CI 1.74–3.34) and time to progression (TTP) (pooled SMD = 2.49; 95% CI 0.87–4.12) of the patients after receiving the combination therapy of TACE and sorafenib, compared to TACE monotherapy, and the OS in the combined treatment cohort was also longer than that in the sorafenib-alone cohort (pooled SMD = 2.92; 95% CI 1.72–4.13). The combination therapy group in comparison to the TACE group benefited a significantly increased overall response rate (ORR) (pooled OR = 2.61; 95% CI 1.43–4.77), 1-year (pooled OR = 2.96; 95% CI 1.71–5.14) and 2-year (pooled OR = 1.64; 95% CI 1.18–2.28) survival rates and reduced disease progression rate (DPR) (pooled OR = 0.47; 95% CI 0.33–0.68); in parallel, the ORR in the group was also significantly higher than that in the sorafenib-alone group (pooled OR = 3.62; 95% CI 1.28–10.22), although without a difference in the DPR (pooled OR = 0.28; 95% CI 0.05–1.48). In addition, we discovered that the 1-year (pooled OR = 1.39; 95% CI 0.84–2.29) and 2-year (pooled OR = 1.70; 95% CI 0.69–4.18) survival rates in the TACE monotherapy cohort were not significantly different to those in the sorafenib-alone cohort. Conclusion The combination therapy is more effective than monotherapy in improving the prognostic outcomes of patients with advanced HCC. Therefore, we recommend it as the preferred treatment intervention for those patients.

Using wave measurements from the EMFISIS instrument onboard Van Allen Probes, we investigate statistically the spatial distributions of the intensity of plasmaspheric hiss waves. To reproduce these empirical results, we establish a fitting model that is a third-order polynomial function of L-shell, magnetic local time (MLT), magnetic latitude (MLAT), and AE*. Quantitative comparisons indicate that the model’s fitting functions can reflect favorably the major empirical features of the global distribution of hiss wave intensity, including substorm dependence and the MLT asymmetry. Our results therefore provide a useful analytic model that can be readily employed in future simulations of global radiation belt electron dynamics under the impact of plasmaspheric hiss waves in geospace.

Corn fiber, a by-product from the corn-processing industry, is an attractive feedstock for cellulosic ethanol because of its rich carbohydrate content (mainly residual starch, cellulose, and hemicellulose), abundant reserves, easy collection, and almost no transportation cost. However, the complex structure and components of corn fiber, especially hemicellulose, make it difficult to be effectively hydrolyzed into fermentable sugars through enzymatic hydrolysis. This study developed a simple and easy industrialized process without detoxification treatment for high-yield ethanol produced from corn fiber. Corn fiber was pretreated by dilute acid under the conditions optimized by Box-Behnken design (0.5% H2SO4 at 105°C for 43 min), and 81.8% of total sugars, including glucose, xylose, and arabinose, could be recovered, then the mixture (solid and hydrolysates) was directly used for semi-simultaneous saccharification and fermentation without detoxification, and ethanol yield reached about 81% of the theoretical yield.

The genome editing toolbox based on CRISPR/Cas9 has brought revolutionary changes to agricultural and plant scientific research. With the development of stable genetic transformation protocols, a highly efficient genome editing system for foxtail millet (Setaria italica) is required. In the present study, we use the CRISPR/Cas9 single- and multi-gene knockout system to target the SiFMBP, SiDof4, SiBADH2, SiGBSS1, and SiIPK1 genes in the foxtail millet protoplasts to screen out highly efficient targeted sgRNAs. Then, we recovered homozygous mutant plants with most of the targeted genes through an Agrobacterium-mediated genetic transformation of foxtail millet. The mutagenesis frequency in the T0 generation was as high as 100%, and it was passed stably on to the next generation. After screening these targeted edited events, we did not detect off-target mutations at potential sites. Based on this system, we have achieved base editing successfully using two base editors (CBE and ABE) to target the SiALS and SiACC genes of foxtail millet. By utilizing CBE to target the SiALS gene, we created a homozygous herbicide-tolerant mutant plant. The current system could enhance the analysis of functional genomics and genetic improvement of foxtail millet.

The CDKN2A (cyclin dependent kinase inhibitor 2A/multiple tumor suppressor 1) gene, also known as the P16 gene, encodes multiple tumor suppressor 1 (MTS1), which belongs to the INK4 family. In tumor tissue, CDKN2A has a high expression level compared with normal tissue and reflects prognosis in tumor patients. Our research targeted the analysis of CDKN2A expression in 33 tumors and clinical parameters, patient prognosis and tumor immunity roles. The CDKN2A expression level was significantly correlated with the tumor mutation burden (TMB) in 10 tumors, and the expression of CDKN2A was also correlated with MSI (microsatellite instability) in 10 tumors. CDKN2A expression was associated with infiltrating lymphocyte (TIL) levels in 22 pancancers, thus suggesting that CDKN2A expression is associated with tumor immunity. Enrichment analysis indicated that CDKN2A expression was involved in natural killer cell-mediated cytotoxicity pathways, antigen processing and presentation, olfactory transduction pathways, and regulation of the autophagy pathway in multiple cancers. CDKN2A was significantly associated with several immune cell infiltrates in pantumors. CDKN2A may serve as a promising prognostic biomarker and is associated with immune infiltrates across cancers.

Among the myriad of statistical methods that identify gene–gene interactions in the realm of qualitative genome-wide association studies, gene-based interactions are not only powerful statistically, but also they are interpretable biologically. However, they have limited statistical detection by making assumptions on the association between traits and single nucleotide polymorphisms. Thus, a gene-based method (GGInt-XGBoost) originated from XGBoost is proposed in this article. Assuming that log odds ratio of disease traits satisfies the additive relationship if the pair of genes had no interactions, the difference in error between the XGBoost model with and without additive constraint could indicate gene–gene interaction; we then used a permutation-based statistical test to assess this difference and to provide a statistical p-value to represent the significance of the interaction. Experimental results on both simulation and real data showed that our approach had superior performance than previous experiments to detect gene–gene interactions.

Unexplained genetic variation that causes complex diseases is often induced by gene-gene interactions (GGIs). Gene-based methods are one of the current statistical methodologies for discovering GGIs in case-control genome-wide association studies that are not only powerful statistically, but also interpretable biologically. However, most approaches include assumptions about the form of GGIs, which results in poor statistical performance. As a result, we propose gene-based testing based on the maximal neighborhood coefficient (MNC) called gene-based gene-gene interaction through a maximal neighborhood coefficient (GBMNC). MNC is a metric for capturing a wide range of relationships between two random vectors with arbitrary, but not necessarily equal, dimensions. We established a statistic that leverages the difference in MNC in case and in control samples as an indication of the existence of GGIs, based on the assumption that the joint distribution of two genes in cases and controls should not be substantially different if there is no interaction between them. We then used a permutation-based statistical test to evaluate this statistic and calculate a statistical p-value to represent the significance of the interaction. Experimental results using both simulation and real data showed that our approach outperformed earlier methods for detecting GGIs.

Grazing is a crucial anthropogenic disturbance on grasslands. However, it is unknown how livestock grazing affects the relationship between biodiversity and productivity of alpine grasslands in Tibet. We carried out a grazing-manipulated experiment from 2016 to 2019 with grazing intensity levels of null (control, grazing exclusion, C.K.), moderate grazing [1.65 standardized sheep unit (SSU) per hectare, M.G.], and heavy grazing (2.47 SSU per hectare, H.G.) on a typical alpine grassland in the Lhasa River Basin, central Tibet. We measured aboveground biomass (AGB), species assembly (alpha and beta diversity indices), and soil nutrients’ availability. The results showed that grazing differently affected plant community in different treatments. Notably, the total dissimilarity value between C.K. and H.G. is 0.334. Grazing decreased the Shannon–Wiener index, increased the Berger–Parker index from 2016 to 2018 significantly, and decreased AGB and total soil nitrogen (STN) significantly. Our results also showed that the grazing affected the relationship between AGB and diversity indices and soil nutrients, including soil organic carbon (SOC) and total soil phosphorus (STP). Specifically, AGB decreased with increasing SOC and STP in all treatments, and heavy grazing changed the positive relationships between AGB, STP, and Shannon–Wiener index to negative correlations significantly compared with grazing exclusion. There was a significant negative correlation between Berger–Parker and Shannon–Wiener indices under each treatment. The general linear models showed that H.G. altered the relationship between diversity and productivity of grassland in central Tibet, and AGB and Shannon–Wiener index positively correlated in C.K. but negatively correlated in H.G. Our study suggests that H.G. caused a negative relationship between plant diversity and productivity. Therefore, sustainable grazing management calls for a need of better understanding the relationship between biodiversity and productivity of alpine grassland in central Tibet.

Epstein–Barr virus (EBV), the pathogen of several human malignancies, encodes many proteins required to be transported into the nucleus for viral DNA reproduction and nucleocapsids assembly in the lytic replication cycle. Here, fluorescence microscope, mutation analysis, interspecies heterokaryon assays, co-immunoprecipitation assay, RNA interference, and Western blot were performed to explore the nuclear import mechanism of EBV encoded BLLF2 protein. BLLF2 was shown to be a nucleocytoplasmic shuttling protein neither by a chromosomal region maintenance 1 (CRM1)- nor by a transporter associated with antigen processing (TAP)-dependent pathway. Yet, BLLF2’s two functional nuclear localization signals (NLSs), NLS1 (16KRQALETVPHPQNRGR31) and NLS2 (44RRPRPPVAKRRRFPR58), were identified, whereas the predicted NES was nonfunctional. Finally, BLLF2 was proven to transport into the nucleus via a Ran-dependent and importin β1-dependent pathway. This mechanism may contribute to a more extensive insight into the assembly and synthesis of EBV virions in the nucleus, thus affording a new direction for the treatment of viruses.

A wearable device system was proposed in the present work to address the problem of facial emotion recognition disorders. The proposed system could comprehensively analyze the user’s own stress status, emotions of people around, and the surrounding environment. The system consists of a multi-dimensional physiological signals acquisition module, an image acquisition and transmission module, a user interface of the user mobile terminal, and a cloud database for data storage. Moreover, a deep learning based multi-model physiological signal pressure recognition algorithm and a facial emotion recognition algorithm were designed and implemented in the system. Some publicly available data sets were used to test the two algorithms, and the experiment results showed that the two algorithms could well realize the expected functions of the system.

Abstract As a common boundary layer that distinctly separates the regions of high‐density plasmasphere and low‐density plasmatrough, the plasmapause is essential to comprehend the dynamics and variability of the inner magnetosphere. Using the machine learning framework PyTorch and high‐quality Van Allen Probes data set, we develop a neural network model to predict the global dynamic variation of the plasmapause location, along with the identification of 6,537 plasmapause crossing events during the period from 2012 to 2017. To avoid the overfitting and optimize the model generalization, 5,493 events during the period from September 2012 to December 2015 are adopted for division into the training set and validation set in terms of the 10‐fold cross‐validation method, and the remaining 1,044 events are used as the test set. The model parameterized by only AE or Kp index can reproduce the plasmapause locations similar to those modeled using all five considered solar wind and geomagnetic parameters. Model evaluation on the test set indicates that our neural network model is capable of predicting the plasmapause location with the lowest RMSE. Our model can also produce a smooth magnetic local time variation of the plasmapause location with good accuracy, which can be incorporated into global radiation belt simulations and space weather forecasts under a variety of geomagnetic conditions.

Sini Decoction (SND), as a classic prescription of Traditional Chinese Medicine (TCM), has been proved to be clinically useful in cardiomyopathy and inflammatory bowel diseases. However, the role and mechanism of SND in colitis-associated cancer remains unclear. This study aims to evaluate the effect of SND on colorectal cancer(CRC) symptoms and further explore the changes of gut microbes mediated by SND extract in azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CRC mice through 16 S rRNA sequencing. Our results indicated that treatment with SND extract could ameliorate the tumors' malignant degree by decreasing tumor number and size. Also, the expression levels of Cyclooxygenase 2 and Mucin-2, which are typical CRC biomarkers, were reduced compared to the CRC group. In the meantime, SND extract can upregulate CD8+ T lymphocytes' expression and Occludin in the colonic mucosal layer. Besides, SND inhibited the expression of CD4+ T cells and inflammatory cytokines in CRC tissue. According to bioinformatics analysis, SND extract was also suggested could modulate the gut microbial community. After the SND treatment, compared with the CRC mice model, the number of pathogenic bacteria showed a significant reduction, including Bacteroides fragilis and Sulphate-reducing bacteria; and SND increased the relative contents of the beneficial bacteria, including Lactobacillus, Bacillus coagulans, Akkermansia muciniphila, and Bifidobacterium. In summary, SND can effectively intervene in colorectal cancer development by regulating intestinal immunity, protecting the colonic mucosal barrier, and SND can change the intestinal microbiota composition in mice.

To infect plants successfully, pathogens adopt various strategies to overcome their physical and chemical barriers and interfere with the plant immune system. Plants deploy a large number of resistance (R) proteins to detect invading pathogens. The R proteins are encoded by resistance genes that contain cell surface-localized receptors and intracellular receptors. In this study, a new plant R protein predictor called prPred was developed based on a support vector machine (SVM), which can accurately distinguish plant R proteins from other proteins. Experimental results showed that the accuracy, precision, sensitivity, specificity, F1-score, MCC, and AUC of prPred were 0.935, 1.000, 0.806, 1.000, 0.893, 0.857, and 0.948, respectively, on an independent test set. Moreover, the predictor integrated the HMMscan search tool and Phobius to identify protein domain families and transmembrane protein regions to differentiate subclasses of R proteins. prPred is available at https://github.com/Wangys-prog/prPred. The tool requires a valid Python installation and is run from the command line.

Epstein-Barr virus (EBV) is the causative agent of infectious mononucleosis that is closely associated with several human malignant diseases, while type I interferon (IFN-I) plays an important role against EBV infection. As we all know, EBV can encode some proteins to inhibit the production of IFN-I, but it’s not clear whether other proteins also take part in this progress. EBV early lytic protein BFRF1 is shown to be involved in viral maturation, however, whether BFRF1 participates in the host innate immune response is still not well known. In this study, we found BFRF1 could down-regulate sendai virus-induced IFN-β promoter activity and mRNA expression of IFN-β and ISG54 during BFRF1 plasmid transfection and EBV lytic infection, but BFRF1 could not affect the promoter activity of NF-κB or IRF7. Specifically, BFRF1 could co-localize and interact with IKKi. Although BFRF1 did not interfere the interaction between IKKi and IRF3, it could block the kinase activity of IKKi, which finally inhibited the phosphorylation, dimerization, and nuclear translocation of IRF3. Taken together, BFRF1 may play a critical role in disrupting the host innate immunity by suppressing IFN-β activity during EBV lytic cycle.

Herpes simplex virus 1 (HSV-1) is a large double-stranded DNA virus that encodes at least 80 viral proteins, many of which are involved in the virus–host interaction and are beneficial to the viral survival and reproduction. However, the biological functions of some HSV-1–encoded proteins are not fully understood. Nuclear factor κB (NF-κB) activation is the major antiviral innate response, which can be triggered by various signals induced by cellular receptors from different pathways. Here, we demonstrated that HSV-1 UL2 protein could antagonize the tumor necrosis factor α (TNF-α)–mediated NF-κB activation. Co-immunoprecipitation assays showed that UL2 could interact with the NF-κB subunits p65 and p50, which also revealed the region of amino acids 9 to 17 of UL2 could suppress the NF-κB activation and interact with p65 and p50, and UL2 bound to the immunoglobulin-like plexin transcription factor functional domain of p65. However, UL2 did not affect the formation of p65/p50 dimerization and their nuclear localizations. Yet, UL2 was demonstrated to inhibit the NF-κB activity by attenuating TNF-α–induced p65 phosphorylation at Ser536 and therefore decreasing the expression of downstream inflammatory chemokine interleukin 8. Taken together, the attenuation of NF-κB activation by UL2 may contribute to the escape of host’s antiviral innate immunity for HSV-1 during its infection.

Viperin is an interferon-inducible protein that responsible for a variety of antiviral responses to different viruses. Our previous study has shown that the ribonuclease UL41 of herpes simplex virus 1 (HSV-1) can degrade the mRNA of viperin to promote HSV-1 replication. However, it is not clear whether other HSV-1 encoded proteins can regulate the function of viperin. Here, one novel viperin associated protein, glycoprotein D (gD), was identified. To verify the interaction between gD and viperin, gD and viperin expression plasmids were firstly co-transfected into COS-7 cells, and fluorescence microscope showed they co-localized at the perinuclear region, then this potential interaction was confirmed by co-immunoprecipitation (Co-IP) assays. Moreover, confocal microscopy demonstrated that gD and viperin co-localized at the Golgi body and lipid droplets. Furthermore, dual-luciferase reporter and Co-IP assays showed gD and viperin interaction leaded to the increase of IRF7-mediated IFN-β expression through promoting viperin and IRAK1 interaction and facilitating K63-linked IRAK1 polyubiquitination. Nevertheless, gD inhibited TRAF6-induced NF-κB activity by decreasing the interaction of viperin and TRAF6. In addition, gD restrained viperin-mediated interaction between IRAK1 and TRAF6. Eventually, gD and viperin interaction was corroborated to significantly inhibit the proliferation of HSV-1. Taken together, this study would open up new avenues toward delineating the function and physiological significance of gD and viperin during HSV-1 replication cycle.

Genome-Wide association studies (GWAS), based on testing one single nucleotide polymorphism (SNP) at a time, have revolutionized our understanding of the genetics of complex traits. In GWAS, there is a need to consider confounding effects such as due to population structure, and take groups of SNPs into account simultaneously due to the “polygenic” attribute of complex quantitative traits. In this paper, we propose a new approach SGL-LMM that puts together sparse group lasso (SGL) and linear mixed model (LMM) for multivariate associations of quantitative traits. LMM, as has been often used in GWAS, controls for confounders, while SGL maintains sparsity of the underlying multivariate regression model. SGL-LMM first sets a fixed zero effect to learn the parameters of random effects using LMM, and then estimates fixed effects using SGL regularization. We present efficient algorithms for hyperparameter tuning and feature selection using stability selection. While controlling for confounders and constraining for sparse solutions, SGL-LMM also provides a natural framework for incorporating prior biological information into the group structure underlying the model. Results based on both simulated and real data show SGL-LMM outperforms previous approaches in terms of power to detect associations and accuracy of quantitative trait prediction.

Background and Aims. Endoscopic removal of GISTs (gastrointestinal stromal tumors) is recently recognized, but less is known about its efficacy and safety. This study is aimed at assessing the feasibility, clinical efficacy, and safety of the endoscopic removal of gastric GISTs. Patients and Methods. Endoscopic removal (ER) of GISTs was performed in 134 patients at our hospital between January 2015 and January 2019. The clinical features, surgical outcomes, complications, pathological diagnosis, and risk classification were evaluated retrospectively. Results. ER was successful in 131 cases (98%), including 58 by ESD (endoscopic submucosal dissection), 43 by ESE (endoscopic submucosal excavation), 25 by EFTR (endoscopic full-thickness resection), and 5 by STER (submucosal tunneling endoscopic resection). In addition, GISTs of two cases were resected using LECS (laparoscopic and luminal endoscopic cooperative surgery) for the extraluminal and intraluminal growth pattern. The average tumor size was 1.89±1.25 cm (range: 0.5-6.0 cm). Of these patients, 26 cases had a large tumor size (range: 2.0-6.0 cm), and endoscopic removal was successful in all of them. During the procedure, endoclips were used to close the perforation in all cases, without conversion to open surgery. The average length of hospital stay was 5.50±2.15 days (range: 3-10 days). In the risk classification, 106 (79.7%) were of a very low risk, 25 (18.8%) of a low risk, and 2 (1.5%) of a moderate risk. The moderate-risk cases were treated with imatinib mesylate after ER. No recurrence or metastasis was observed during the follow-up period of 23±8 months (range: 3-48 months). Conclusions. The endoscopic treatment is feasible, effective, and safe for gastric GISTs, and individualized choice of approaches is recommended for GISTs.

BACKGROUND:Pancreatic cancer is a highly malignant disease with an extremely poor prognosis. Histone deacetylase inhibitors (HDACIs) have shown promising antitumor activities against preclinical models of pancreatic cancer, either alone or in combination with chemotherapeutic agents. In this study, we sought to identify clinically relevant histone deacetylases (HDACs) to guide the selection of HDAC inhibitors (HDACIs) tailored to the treatment of pancreatic cancer. METHODOLOGY:HDAC expression in seven pancreatic cancer cell lines and normal human pancreatic ductal epithelial cells was determined by Western blotting. Antitumor interactions between class I- and class II-selective HDACIs were determined by MTT assays and standard isobologram/CompuSyn software analyses. The effects of HDACIs on cell death, apoptosis and cell cycle progression, and histone H4, alpha-tubulin, p21, and γH2AX levels were determined by colony formation assays, flow cytometry analysis, and Western blotting, respectively. RESULTS:The majority of classes I and II HDACs were detected in the pancreatic cancer cell lines, albeit at variable levels. Treatments with MGCD0103 (a class I-selective HDACI) resulted in dose-dependent growth arrest, cell death/apoptosis, and cell cycle arrest in G2/M phase, accompanied by induction of p21 and DNA double-strand breaks (DSBs). In contrast, MC1568 (a class IIa-selective HDACI) or Tubastatin A (a HDAC6-selective inhibitor) showed minimal effects. When combined simultaneously, MC1568 significantly enhanced MGCD0103-induced growth arrest, cell death/apoptosis, and G2/M cell cycle arrest, while Tubastatin A only synergistically enhanced MGCD0103-induced growth arrest. Although MC1568 or Tubastatin A alone had no obvious effects on DNA DSBs and p21 expression, their combination with MGCD0103 resulted in cooperative induction of p21 in the cells. CONCLUSION:Our results suggest that classes I and II HDACs are potential therapeutic targets for treating pancreatic cancer. Accordingly, treating pancreatic cancer with pan-HDACIs may be more beneficial than class- or isoform-selective inhibitors.

The debate on Chinse cultural nationalism, as on nationalism in general, is often polarised by a number of theoretical positions, value judgements, practical concerns and methodological choices. While there is no consensus that cultural nationalism has developed into a formidable force in China, few would deny that it has been on the rise since June 4, 1989, and that it is a cultural-political movement with no parallel in the People’s Republic, except perhaps for the period following May 4, 1919. Of central concern in this special issue of PORTAL Journal of Multidisciplinary International Studies are the manifestations of cultural nationalism, the causation of its resurgence in post-Tiananmen China, and the ways in which it is likely to impact on China’s future development.

In order to filter out the noise effects of Vacuum Switches Arc(VSA)images, enhance the characteristic details of the VSA images, and improve the visual effects of VSA images, in this paper, the VSA images were implemented pre-processing such as noise removal, edge detection, processing of image’s pseudo color and false color, and morphological processing by MATLAB software. Furthermore, the morphological characteristics of the VSA images were extracted, including isopleths of the gray value, arc area and perimeter.