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Abstract Background The combination of oncolytic viruses (OVs) with immune checkpoint blockades is a research hotspot and has shown good efficacy. Here, we present the first attempt to combine oncolytic herpes simplex virus 2 (OH2) with an anti-SIRPα antibody as an antitumour treatment. Our results provide unique insight into the combination of innate immunity with OV. Methods We verified the polarization and activation of OH2 in RAW264.7 cells in vitro. Subsequently, we evaluated the antitumour ability of OH2 and anti-SIRPα combined therapy in a tumour-bearing mouse model. RNA-seq and Single-cell RNA-seq were used to characterize the changes in the tumour microenvironment. Results The OH2 lysates effectively stimulated RAW264.7 cells to polarize towards the M1 but not the M2 phenotype and activated the function of the M1 phenotype in vitro. In the macrophage clearance experiment, OH2 therapy induced polarization of M1 macrophages and participated in the antitumour immune response in a tumour-bearing mouse model. Treatment with a combination of OH2 and anti-SIRPα effectively inhibited tumour growth and significantly prolonged the survival time of the mice, and this result was more obvious in the mouse model with a larger tumour volume at the beginning of the treatment. These results suggest that combination therapy can more profoundly reshape the TME and activate stronger innate and adaptive immune responses. Conclusions Our data support the feasibility of oncolytic virus therapy in combination with anti-SIRPα antibodies and suggest a new strategy for oncolytic virus therapy.

Purpose: The number of families who lost their only child was over one million in 2012 in China, and it is growing rapidly every year. Without their only child, they will inevitably worry about their health and life for their later years. It is important to explore the quality of life and influencing factors of the parents.Methods: The cluster sampling method was adopted to select the participants in Wuhu city, Anhui province, central China. The generalized linear regression models were performed to analyze factors influencing EQ-VAS scores.Results: The parents with different monthly income (P = 0.001) and self-rated health status (P < 0.001) had different EQ-VAS scores. Educational level, self-rated health status, number of chronic diseases, depression and having grandchildren were significantly associated with their EQ-VAS score.Conclusion: The government should encourage public medical institutions to provide convenient health management and medical services to this vulnerable group. Priority treatment should be given to the parents who already have multiple diseases. The parents who were depressed should be given timely intervention. The government should give more financial subsidies to the parents who need to raise their grandchildren.

Abstract Background Manganese ions (Mn2+) combined with adjuvants capable of damaging and lysing tumor cells form an antitumor nano-modulator that enhances the immune efficacy of cancer therapy through the cascade activation of the cyclic GMP-AMP interferon gene synthase-stimulator (cGAS-STING) pathway, which underscores the importance of developing antitumor nano-modulators, which induce DNA damage and augment cGAS-STING activity, as a critical future research direction. Methods and Results We have successfully synthesized an antitumor nano-modulator, which exhibits good dispersibility and biosafety. This nano-modulator is engineered by loading manganese dioxide nanosheets (M-NS) with zebularine (Zeb), known for its immunogenicity-enhancing effects, and conducting targeted surface modification using hyaluronic acid (HA). After systemic circulation to the tumor site, Mn2+, Zeb, and reactive oxygen species (ROS) are catalytically released in the tumor microenvironment by H+ and H2O2. These components can directly or indirectly damage the DNA or mitochondria of tumor cells, thereby inducing programmed cell death. Furthermore, they promote the accumulation of double-stranded DNA (dsDNA) in the cytoplasm, enhancing the activation of the cGAS-STING signalling pathway and boosting the production of type I interferon and the secretion of pro-inflammatory cytokines. Additionally, Zeb@MH-NS enhances the maturation of dendritic cells, the infiltration of cytotoxic T lymphocytes, and the recruitment of natural killer cells at the tumor site. Conclusions This HA-modified manganese-based hybrid nano-regulator can enhance antitumor therapy by boosting innate immune activity and may provide new directions for immunotherapy and clinical translation in cancer. Graphical Abstract

Abstract In the realm of multiferroicity in 2D magnets, whether magnetic and polar skyrmions can coexist within a single topological entity has emerged as an important question. Here, we study Janus 2D magnets CrInX 3 (X=Se, Te) for a comprehensive investigation of the magnetic ground state, magnetic excited state, and corresponding ferroelectric polarization by first-principles electronic structure calculations and Monte Carlo simulations. Specifically, we have thoroughly elucidated the magnetic exchange mechanisms, and have fully exemplified the magnetic field dependence of the magnon spectrum. More importantly, our study reveals a previously unrecognized, remarkably large spin-spiral-induced ferroelectric polarization (up to 194.9 μC/m2) in both compounds. We propose an approach to identify polar skyrmions within magnetic skyrmions, based on the observed direct correlation between spin texture and polarization density. Elucidating this correlation not only deepens our understanding of magnetic skyrmions but also paves the way for innovative research in the realm of multiferroic skyrmions.

Abstract Translating RNA-seq into clinical diagnostics requires ensuring the reliability and cross-laboratory consistency of detecting clinically relevant subtle differential expressions, such as those between different disease subtypes or stages. As part of the Quartet project, we present an RNA-seq benchmarking study across 45 laboratories using the Quartet and MAQC reference samples spiked with ERCC controls. Based on multiple types of ‘ground truth’, we systematically assess the real-world RNA-seq performance and investigate the influencing factors involved in 26 experimental processes and 140 bioinformatics pipelines. Here we show greater inter-laboratory variations in detecting subtle differential expressions among the Quartet samples. Experimental factors including mRNA enrichment and strandedness, and each bioinformatics step, emerge as primary sources of variations in gene expression. We underscore the profound influence of experimental execution, and provide best practice recommendations for experimental designs, strategies for filtering low-expression genes, and the optimal gene annotation and analysis pipelines. In summary, this study lays the foundation for developing and quality control of RNA-seq for clinical diagnostic purposes.

The stability and mobility of proppant packs in hydraulic fractures during hydrocarbon production are numerically investigated by the lattice Boltzmann-discrete element coupling method (LB-DEM). This study starts with a preliminary proppant settling test, from which a solid volume fraction of 0.575 is calibrated for the proppant pack in the fracture. In the established workflow to investigate proppant flowback, a displacement is applied to the fracture surfaces to compact the generated proppant pack as well as further mimicking proppant embedment under closure stress. When a pressure gradient is applied to drive the fluid-particle flow, a critical aperture-to-diameter ratio of 4 is observed, above which the proppant pack would collapse. The results also show that the volumetric proppant flowback rate increases quadratically with the fracture aperture, while a linear variation between the particle flux and the pressure gradient is exhibited for a fixed fracture aperture. The research outcome contributes towards an improved understanding of proppant flowback in hydraulic fractures, which also supports an optimised proppant size selection for hydraulic fracturing operations.

As the new orientation, new requirement and new task to develop higher education, it is necessary to deeply implement the digital strategic action, construct a new form of higher education teaching, give full play to the role of the main channel in the classroom education, and comprehensively promote the ideological and political construction of curriculum. On the basis of the digital intelligence era, this paper deeply explores the ideological and political elements in each chapter according to the characteristics of the course, teaching objectives and teaching contents; it also draws the conclusion about the teaching reform and practice of the ideological and political construction of the course on Food Chemistry and Analysis. It puts forward some strategies: the improvement on educator' ideological and political teaching ability, the digital construction and improvement of high-quality ideological and political resources, the optimization of curriculum setting, and the innovation on "gene implantation" and "one, two, three, four" teaching modes. The ideological and political classroom of professional courses is taken as the carrier, the unity of inner knowledge and action is realized, and meanwhile the ideological and political education system is constructed about the course on Food Chemistry and Analysis, with the purpose to promote both the translation of professional knowledge and value guidance of students', and create a new pattern for the moral education.

Long noncoding RNAs (lncRNAs) are RNA transcripts longer than 200 nucleotides that do not code for proteins but have been linked to cancer development and metastasis. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) influences crucial cancer hallmarks through intricate molecular mechanisms, including proliferation, invasion, angiogenesis, apoptosis, and the epithelial-mesenchymal transition (EMT). The current article highlights the involvement of MALAT-1 in drug resistance, making it a potential target to overcome chemotherapy refractoriness. It discusses the impact of MALAT-1 on immunomodulatory molecules, such as major histocompatibility complex (MHC) proteins and PD-L1, leading to immune evasion and hindering anti-tumor immune responses. MALAT-1 also plays a significant role in cancer immunology by regulating diverse immune cell populations. In summary, MALAT-1 is a versatile cancer regulator, influencing tumorigenesis, chemoresistance, and immunotherapy responses. Understanding its precise molecular mechanisms is crucial for developing targeted therapies, and therapeutic strategies targeting MALAT-1 show promise for improving cancer treatment outcomes. However, further research is needed to fully uncover the role of MALAT-1 in cancer biology and translate these findings into clinical applications.

Summary: Fecal DNA-based Syndecan 2 (SDC2) methylation detection is a promising non-invasive strategy for early colorectal cancer (CRC) screening. In China, commercial assays for SDC2 methylation detection vary in sensitivity and specificity, yet there is no standardized external quality assessment (EQA) to ensure accuracy. This study utilized CRISPR-Cas9 and homology-directed repair (HDR) technologies to edit the SDC2 promoter in 293T cells, creating hypermethylated and heterogeneous cell lines. These cell lines were used to develop an EQA panel for SDC2 methylation. We established a 10-sample panel, encompassing a range of methylation levels, and conducted an EQA across 140 laboratories. Among 1,400 results, 0.57% were incorrect. The optimized EQA materials effectively monitor the accuracy of SDC2 methylation detection in CRC, supporting reliable and consistent clinical testing and contributing to early CRC screening and diagnosis in China.

To solve the problem of complex and difficult to quantify factors affecting investment returns and risks in clean energy power grids, this study comprehensively applies the interpretive structural model and Monte Carlo model to the analysis of investment risk-returns in clean energy power grid projects. The interpretive structural model is utilized to analyze project investment returns, while the Monte Carlo model is used to analyze project investment risks. The project investment risk is based on the factor analysis of project investment returns, and key risk factors are identified through 1000 simulations, and the impact of these risks on project returns is quantified. By combining the two, the investability of the project is analyzed. The results showed that grid electricity prices, kilowatt hour subsidies, technology learning rates, total annual sunshine hours, and system power generation efficiency were key factors driving investment returns. The average expected value of investment return was about 20%, and the probability of investment return below 6% was close to 0. The overall project is worth investing in. From this, it can be seen that the research designed investment risk-return analysis methods for clean energy grid projects can effectively distinguish the main factors affecting investment returns and risks, and pre simulate the risk situation of returns. This study can provide reference for investor decision-making.

In this study, we examine the peer effect on climate risk information disclosure by analyzing A-share listed companies in China. We find that industry peers influence target firms’ climate risk information disclosure through active (passive) imitation resulting from cost–benefit considerations (institutional pressures). Leader companies are more likely to be emulated by within-industry follower companies and target firms prefer to learn from similar within-industry firms. Executive overconfidence and performance pressure negatively affect target firms’ willingness to emulate their peers. Finally, the peer effect of climate risk information disclosure demonstrates a regional aspect. Our findings have implications for reasonable climate risk information disclosure at the micro level and effective regulation to move toward achieving carbon peak/neutrality at the macro level.

Abstract The integrated design of traffic signal control (TSC) and reversible lane (RL) is an effective way to solve the problem of tidal congestion with uncertainty at isolated intersections, because of its advantage in making full use of temporal‐spatial transportation facilities. Considering the contradiction between the dynamic TSC scheme and the fixed RL scheme in one period, a two‐stage optimization method based on improved mean‐standard deviation (MSD) model for isolated intersections with historical and real‐time uncertain traffic flow is proposed. In the first stage, applying the same‐period historical data of multiple days, a robust optimal traffic signal control model with reversible lane based on MSD model (MSD‐RTR model) is put forward to obtain the fixed RL scheme and the compatible initial TSC scheme. A double‐layer nested genetic algorithm (DN‐GA) is designed to solve this model. In the second stage, applying real‐time period data and multi‐day same‐period historical data, a robust optimal dynamic traffic signal control model based on MSD model (MSD‐RDT model) is put forward to obtain the dynamic TSC scheme. Three modes which reflect the different weights of historical period and real‐time period in this MSD‐RDT model are presented to improve the model stability, and a multi‐mode genetic algorithm (MM‐GA) is designed. Finally, a case study is presented to demonstrate the efficiency and applicability of the proposed models and algorithms.

Real-time monitoring technologies of surface deformation represented by the global navigation satellite system (GNSS) are essential for landslides early warning. Monitoring methods such as GNSS require on-site manual installation. Therefore, it becomes nearly impossible to deploy surface monitoring equipment when landslides are located in high mountain valleys that are challenging for personnel to access, and/or in hazardous situations. We propose an intelligent real-time monitoring and early-warning technology that employs an unmanned aerial vehicle (UAV) as a carrier to deploy GNSS equipment. A system was initially designed with five components: an adaptive sampling GNSS receiver, an intelligent cooperative network transmission module, UAV-dropped GNSS equipment, special delivery UAV, and an intelligent monitoring and early warning cloud platform. This new technology was applied to a real landslide in Gansu Province, China, in 2020. The mean absolute error of 30 days in the east, north, and upward directions were 1.2, 1.3, and 2.9 mm/d, respectively, comparing the deformation velocity between the traditional monitoring station and the UAV-dropped monitoring station. This observation facilitated the successful prediction of a landslide hazard on 27 January 2021, allowing for a timely alert to be issued. Collectively, the results of this study established that UAV-deployed GNSS technology can accomplish unmanned deployment of GNSS equipment for landslide monitoring to ensure early warning issuance in inaccessible and/or high-risk areas.

To investigate the substitutability of the simulation results using the single-dome combustor as the computational domain to the triple-dome combustor, three-dimensional numerical simulations were conducted on both models and the differences in various performances between the two combustors were compared and analyzed. The findings reveal that the simulation results obtained using the single-dome combustor as the computational domain can effectively substitute for those of the triple-dome combustor in terms of critical performance metrics, including velocity distribution in the central cross-section, morphology and size of back-flow regions, total pressure loss coefficient, combustion efficiency, outlet temperature distribution and pollutant emissions. Under takeoff conditions, the flame tube outlet of the single-dome combustor exhibits higher OTDF and RTDF values compared to the triple-dome combustor, with similar radial temperature distribution shapes. Additionally, the NOx emissions of the flame tube outlet are slightly lower in the single-dome combustor compared to the triple-dome combustor, while the Soot emissions are slightly higher. However, both the NOx and Soot emissions are within the same order of magnitude for both combustors. Under idle conditions, both the single-dome and triple-dome combustors show almost zero CO emissions at the flame tube outlet section.

IntroductionGlioma, a prevalent and deadly brain tumor, is marked by significant cellular heterogeneity and metabolic alterations. However, the comprehensive cell-of-origin and metabolic landscape in high-grade (Glioblastoma Multiforme, WHO grade IV) and low-grade (Oligoastrocytoma, WHO grade II) gliomas remains elusive.MethodsIn this study, we undertook single-cell transcriptome sequencing of these glioma grades to elucidate their cellular and metabolic distinctions. Following the identification of cell types, we compared metabolic pathway activities and gene expressions between high-grade and low-grade gliomas.ResultsNotably, astrocytes and oligodendrocyte progenitor cells (OPCs) exhibited the most substantial differences in both metabolic pathways and gene expression, indicative of their distinct origins. The comprehensive analysis identified the most altered metabolic pathways (MCPs) and genes across all cell types, which were further validated against TCGA and CGGA datasets for clinical relevance.DiscussionCrucially, the metabolic enzyme phosphodiesterase 8B (PDE8B) was found to be exclusively expressed and progressively downregulated in astrocytes and OPCs in higher-grade gliomas. This decreased expression identifies PDE8B as a metabolism-related oncogene in IDH-mutant glioma, marking its dual role as both a protective marker for glioma grading and prognosis and as a facilitator in glioma progression.

The joint use of hyperspectral image (HSI) and light detection and ranging (LiDAR) data has gained significant performance on land-cover classification. Although spatial–spectral feature learning methods based on convolutional neural networks and transformer networks have achieved prominent advances, contextual information described by fixed convolutional kernels and all self-attention heads selected have limited ability to characterize the detailed information and nonredundant features of land-covers on multimodal data. In this article, a multiscale head selection transformer (MHST) network, is proposed to fully explore detailed and nonredundant features in spatial and spectral dimensions of HSI and LiDAR data. To better acquire detailed information of spatial and spectral features at different scales, a multiscale spectral–spatial feature extraction module, including cascaded multiscale 3-D and 2-D convolutional layers, is inserted into MHST. Simultaneously, an adaptive global feature extraction module based on head selection pooling transformer is given after transformer encoder module for alleviating token redundancy in an adaptive computation style. Finally, we develop a multimodal–multiscale feature fusion classification module with local features and global class token, to exploit a powerful global–local fuse style. The extensive experiments on three popular datasets demonstrate that MHST significantly outperforms other related networks.

Abstract Targeted panel-based tumor mutation burden (TMB) assays are widely employed to guide immunotherapy for patients with solid tumors. However, the accuracy and consistency of this method can be compromised due to the variability in technical details across different laboratories, particularly in terms of panel size, somatic mutation detection and TMB calculation rules. Currently, systematic evaluations of the impact of these technical factors on existing assays and best practice recommendations remain lacking. We assessed the performance of 50 participating panel-based TMB assays involving 38 unique methods using cell line samples. In silico experiments utilizing TCGA MC3 datasets were performed to further dissect the impact of technical factors. Here we show that the panel sizes beyond 1.04 Mb and 389 genes are necessary for the basic discrete accuracy, as determined by over 40,000 synthetic panels. The somatic mutation detection should maintain a reciprocal gap of recall and precision less than 0.179 for reliable psTMB calculation results. The inclusion of synonymous, nonsense and hotspot mutations could enhance the accuracy of panel-based TMB assay. A 5% variant allele frequency cut-off is suitable for TMB assays using tumor samples with at least 20% tumor purity. In conclusion, this multicenter study elucidates the major technical factors as sources of variability in panel-based TMB assays and proposed comprehensive recommendations for the enhancement of accuracy and consistency. These findings will assist clinical laboratories in optimizing the methodological details through bioinformatic experiments to enhance the reliability of panel-based methods.

Abstract Previous studies on the molecular classification of cholangiocarcinoma (CCA) focused on certain anatomical sites, and disregarded tissue contamination biases in transcriptomic profiles. We aim to provide universal molecular classification scheme and prognostic biomarker of CCAs across anatomical locations. Comprehensive bioinformatics analysis is performed on transcriptomic data from 438 CCA cases across various anatomical locations. After excluding CCA tumors showing normal tissue expression patterns, we identify two universal molecular subtypes across anatomical subtypes, explore the molecular, clinical, and microenvironmental features of each class. Subsequently, a 30-gene classifier and a biomarker (called “CORE-37”) are developed to predict the molecular subtype of CCA and prognosis, respectively. Two subtypes display distinct molecular characteristics and survival outcomes. Key findings are validated in external cohorts regardless of the stage and anatomical location. Our study provides a CCA classification scheme that complements the conventional anatomy-based classification and presents a promising prognostic biomarker for clinical application.

BackgroundHeat stroke is a severe heat-related illness, and it is necessary to explain in depth the effect of high temperature on heat stroke in the context of global warming. ObjectiveTo describe the epidemiological characteristics of reported heat stroke cases in Shanghai from 2013 to 2022, analyze the influence of daily mean temperature threshold on heat stroke, and identify susceptible populations, so as to provide data support for the development of relevant social and public policies. MethodsData from case reports on heat stroke were collected in Shanghai from 2013 to 2022. Heat stroke associated daily mean temperature threshold, lag effects, and susceptible populations were estimated using piecewise regression model and distributed lag non-linear model. ResultsAmong the 3479 cases reported from June to August of 2013—2022 in Shanghai, the male-to-female ratio was 3.34. A positive association between daily mean temperature and heat stroke was found, the association was strongest on the day of exposure and persisted until lag day 2, with an estimated threshold at 33.1 ℃. Using the median value of daily mean temperature as the reference value (28.1 ℃), the peak cumulative effect of extreme high temperature (33.1 ℃) appeared at lag 0-2 days with a relative risk (RR) value and its 95%CI of 25.32 (17.49-36.64) for all included cases; the RRs for male and female were 26.33 (17.78, 38.98) and 25.20 (12.52, 50.72), respectively, and no statistically significant difference was found between sexes (P＞0.05); the RRs were much greater in population aged 45-64 years (25.17, 95%CI: 15.54, 40.78) and 65 years and above (76.98, 95%CI: 34.80, 170.30), significantly higher than the values in those aged 16-44 years (20.22, 95%CI: 12.22, 33.44) (P＜0.05); urban areas showed a greater RR (49.09, 95%CI: 19.60, 122.95) than rural areas (23.65, 95%CI: 16.13, 34.67) (P＜0.05). ConclusionHigh temperature is significantly associated with heat stroke cases reported in Shanghai, with a threshold of 33.1℃ for daily mean temperature. The middle-aged and elderly adults and urban residents are more vulnerable to heat stress than those younger and living in rural areas.

Polyanionic structures, (MO4)n−, can be beneficial to the transport of lithium ions by virtue of the open three-dimensional frame structure. However, an unstable interface suppresses the life of the (MO4)n−-based anode. In this study, MnWO4@C nanorods with dense nanocavities have been synthesized through a hydrothermal route, followed by a chemical deposition method. As a result, the MnWO4@C anode exhibits better cycle and rate performance than MnWO4 as a Li-ion battery; the capacity is maintained at 718 mAh g−1 at 1000 mA g−1 after 400 cycles because the transport of lithium ions and the contribution of pseudo-capacitance are increased. Generally, benefiting from the carbon shell and electrolyte additive (e.g., FEC), the cycle performance of the MnWO4@C electrode is also effectively improved for lithium storage.

The separation and turbulent transition of the flow in a compressor blade channel are investigated through direct numerical simulations (DNS) at a Reynolds number of 1.367 × 105. Based on the original DNS data, both time-averaged statistics and instantaneous vortex structures of the flow field are extensively analyzed. The vortices are visualized and studied by the Liutex method, and the streaming dynamic mode decomposition (SDMD), a low-storage variant of conventional DMD, is applied to the large datasets obtained on both pressure and suction sides. The physical quantity analyzed with SDMD is the Liutex magnitude R. The DNS results indicate that flow separation occurs on both sides of the blade. On the pressure surface, the separation is weak and the flow remains in a natural transition dominated by viscous Tollmien–Schlichting instabilities. In contrast, owing to the presence of a large laminar separation bubble, the flow experiences a separation transition governed by inviscid Kelvin–Helmholtz instabilities on the suction surface. The SDMD results suggest that a broad range of vortex frequencies exist in the transition flow, and the scale of the spatial structures is negatively correlated with the frequency of the mode. On the pressure surface, the extracted SDMD modes are primarily related to Kelvin–Helmholtz rolls, whereas on the suction side, influenced by the separated boundary layer, the modal structures exhibit greater diversity.

Abstract The Real-Time Kinematic (RTK) positioning method of the Global Navigation Satellite System (GNSS) has been widely used for landslide monitoring. The stability of its reference station is crucial to obtain accurate and reliable monitoring results. Unstable reference stations due to the geological environment and human activities are difficult to detect and in practical applications often ignored. As a result, it affects the positioning solutions and subsequently the interpretation and detection of landslide motions, which must be addressed in GNSS landslide monitoring. To solve this problem, we propose using the Precise Point Positioning (PPP) technique to analyze the stability of the reference station by verifying its position. The deformations of the monitoring stations are then compensated. First, the reference station coordinates are obtained by the PPP technique and tectonic motion is considered in data processing. The change or breakout of the reference station position is then determined using a cumulative sum control chart method. Finally, each monitoring station’s displacements are compensated according to the displacements of the reference station. According to the results of the Tengqing landslide experiment, the PPP technique can be used in GNSS landslide monitoring to analyze the stability of reference stations. With PPP, millimeter-level accuracy for the coordinates of reference stations is achieved. Compared to the traditional deformation series, the compensated displacement series more reliably reflects the landslide motions. This study will increase the reliability of monitoring results and contribute to implementing GNSS in monitoring landslides.

A novel method is proposed for accurately determining the local wall friction through the near-wall measurement of time-average velocity profile in a Type-A turbulent boundary layer (TBL). The method is based on the newly established analytical wall-law in Type-A TBL. The direct numerical simulations (DNS) data of turbulence on a zero-pressure-gradient flat-plate (ZPGFP) is used to demonstrate the accuracy and the robustness of the approach. To verify the reliability and applicability of the method, a two-dimensional particle image velocimetry (PIV) measurement was performed in a ZPGFP TBL with a low-to-moderate Reynolds number (Re). Via utilizing the algorithm of single-pixel ensemble correlation (SPEC), the velocity profiles in the ZPGFP TBL were resolved at a significantly improved spatial resolution, which greatly enhanced the measurement accuracy and permitted us to accurately capture the near-wall velocity information. The accuracy of the approach is then quantitatively validated for the high Reynolds number turbulence using the ZPGFP TBL data. The research demonstrates that the current method can provide the precise estimation of wall friction with a mean error of less than 2%, which not only possesses the advantage of its insensitivity to the absolute wall-normal distance of the measuring point, but also its capability of providing an accurate prediction of wall shear stress based on fairly sparse experimental data on the velocity profile. The current study demonstrates that the wall shear stress can be accurately estimated by a velocity even at a single-point either measured or calculated in the near-wall region.

Astragalus membranaceus is a famous traditional medicinal plant. However, drought and cadmium (Cd) pollution are the main abiotic stress factors that affect plant growth and yield and the ability to improve the host’s stress resistance through the use of beneficial endophytic fungi. To evaluate the tolerance of dark septate endophytes (DSE) to various abiotic stresses, 10 DSE strains [Microsphaeropsis cytisi (Mc), Alternaria alstroemeriae (Aa), Stagonosporopsis lupini (Sl), Neocamarosporium phragmitis (Np), Paraphoma chlamydocopiosa (Pc), Macrophomina phaseolina (Mp’), Papulaspora equi (Pe), Alternaria tellustris (At), Macrophomina pseudophaseolina (Mp), and Paraphoma radicina (Pr)] were investigated under different drought and Cd stressors in vitro by using solid-plate cultures and liquid-shaker cultures in the current study. The experiments involved using varying concentrations of PEG (0, 9, 18, and 27%) and Cd2+ (0, 25, 50, and 100 mg/L) to simulate different stress conditions on DSE. Additionally, the effect of DSE (Np and At) on the growth of A. membranaceus at different field water capacities (70% and 40%) and at different CdCl2 concentrations (0, 5, 10, and 15 mg Cd/kg) in soil was studied. The results demonstrated that the colony growth rates of Aa, Np, Pc, Mp’, and Mp were the first to reach the maximum diameter at a PEG concentration of 18%. Aa, Np, and At remained growth-active at 100 mg Cd/L. In addition, Aa, Np, and At were selected for drought and Cd stress tests. The results of the drought-combined-with-Cd-stress solid culture indicated that the growth rate of Np was significantly superior to that of the other strains. In the liquid culture condition, the biomasses of Np and Aa were the highest, with biomasses of 1.39 g and 1.23 g under the concentration of 18% + 25 mg Cd/L, and At had the highest biomass of 1.71 g at 18% + 50 mg Cd/L concentration, respectively. The CAT and POD activities of Np reached their peak levels at concentrations of 27% + 50 mg Cd/L and 27% + 25 mg Cd/L, respectively. Compared to the control, these levels indicated increases of 416.97% and 573.12%, respectively. Aa, Np, and At positively influenced SOD activity. The glutathione (GSH) contents of Aa, Np, and At were increased under different combined stressors of drought and Cd. The structural-equation-modeling (SEM) analysis revealed that Aa positively influenced biomass and negatively affected Cd content, while Np and At positively influenced Cd content. Under the stress of 40% field-water capacity and the synergistic stress of 40% field-water capacity and 5 mg Cd/kg soil, Np and At significantly increased root weight of A. membranaceus. This study provides guidance for the establishment of agricultural planting systems and has good development and utilization value.

In modern scientific practice, it is necessary to consistently observe predetermined zones, with the expectation of detecting and identifying emerging targets or events inside such areas. This research presents an innovative imaging spectrometer system for the continuous monitoring of specific areas. This study begins by providing detailed information on the features and optical structure of the constructed instrument. This is then followed by simulations using optical design tools. The device has an F-number of 5, a focal length of 100 mm, a field of view of 3 × 7, and a wavelength range spanning from 400 nm to 600 nm. The optical path diagram demonstrates that the system’s dispersion and imaging pictures can be distinguished, hence fulfilling the system’s specifications. Furthermore, the utilization of a Modulation Transfer Function (MTF) graph has substantiated that the image quality indeed satisfies the specified criteria. To evaluate the instrument’s performance in the spectrum observation of fixed regions, a region-monitoring-type slitless imaging spectrometer was built. The equipment has the capability to identify a specific region and rapidly capture the spectra of objects or events that are present inside that region. The spectral data were collected effectively by the implementation of image processing techniques on the captured photos. The correlation coefficient between these data and the reference data was 0.9226, showing that the device successfully measured the target’s spectrum. Therefore, the instrument that was created successfully demonstrated its ability to capture images of the observed areas and collect spectral data from the targets located within those regions.

Abstract Background and Aims Sex determining region Y related high-mobility group box protein 9 (Sox9) is expressed in a subset of hepatocytes, and it is important for chronic liver injury. However, the roles of Sox9+ hepatocytes in response to the acute liver injury and repair are poorly understood. Methods In this study, we developed the mature hepatocyte-specific Sox9 knockout mouse line and applied three acute liver injury models including PHx, CCl4 and hepatic ischemia reperfusion (IR). Huh-7 cells were subjected to treatment with hydrogen peroxide (H2O2) in order to induce cellular damage in an in vitro setting. Results We found the positive effect of Sox9 deletion on acute liver injury repair. Small heterodimer partner (SHP) expression was highly suppressed in hepatocyte-specific Sox9 deletion mouse liver, accompanied by less cell death and more cell proliferation. However, in mice with hepatocyte-specific Sox9 deletion and SHP overexpression, we observed an opposite phenotype. In addition, the overexpression of SOX9 in H2O2-treated Huh-7 cells resulted in an increase in cytoplasmic SHP accumulation, accompanied by a reduction of SHP in the nucleus. This led to impaired mitochondrial function and subsequent cell death. Notably, both the mitochondrial dysfunction and cell damage were reversed when SHP siRNA was employed, indicating the crucial role of SHP in mediating these effects. Furthermore, we found that Sox9, as a vital transcription factor, directly bound to SHP promoter to regulate SHP transcription. Conclusions Overall, our findings unravel the mechanism by which hepatocyte-specific Sox9 knockout ameliorates acute liver injury via suppressing SHP signaling and improving mitochondrial function. This study may provide a new treatment strategy for acute liver injury in future. Graphical Abstract

The accurate estimation of the infiltration boundary of a buried point source is required in the hydraulic design of a subsurface drip irrigation (SDI) system, as well as in the numerical simulation of soil water movement. In this study, an experiment was conducted to measure the variation in emitter flow rate and soil back pressure in silty loam soil. The infiltration cavity was observed, and the radius was estimated by matching the measured emitter flow rate and soil back pressure using HYDRUS-2D simulations. The relationship between the cavity radius, emitter flow rate, and soil back pressure, as affected by the soil bulk density, working pressure, and nominal emitter flow rate, are discussed. The results indicate that the infiltration cavity formed rapidly during irrigation with an irregular shape. The surface area increased as nominal emitter flow rate increased and soil bulk density increased. The variation of flow rate as a function of time had no necessary relationship with that of soil back pressure, due to the formation of the cavity. When the infiltration process became stable, higher soil bulk density resulted in increase in soil back pressure and decrease in emitter flow rate. However, the effects of working pressure and nominal emitter flow rate on soil back pressure were unclear. The emitter flow rate and back pressure, solved by an existing analytical model using estimated radius, demonstrated satisfactory agreement with the measured data, with the minimum root-mean-square error (RMSE), compared with those using a constant radius. When the infiltration boundary was taken as a constant head, the soil back pressure and cavity both significantly affected the simulated soil wetting patterns. The effect of cavity radius on the wetting front could be neglected for the constant flux boundary.

Hyperthermia therapy is considered an effective anticancer strategy. However, high temperature can trigger an excessive inflammatory response, leading to tumor self-protection, immunosuppression, metastasis, and recurrence. To address this issue, we reported a multifunctional photothermal nanoplatform to achieve mild hyperthermia photothermal therapy (mild PTT) based on cisplatin (DDP) and a ferrocene metal-organic framework (MOF-Fc) nanocomposite, which can specifically enhance ferroptosis-triggered oxidative stress levels and synchronously amplify mild hyperthermia PTT-mediated anticancer responses. Both in vitro and in vivo antineoplastic results verify the superiority of mild PTT with DDP/MOF-Fc@HA. The combination of DDP and MOF-Fc exhibits Fenton catalytic activity and glutathione depletion capacity, magnifying mild hyperthermia effects via the radical oxygen species (ROS)-adenosine triphosphate (ATP)-HSP silencing pathway, with important implications for clinical hyperthermia therapy.

PurposeA tertiary lymphoid structure (TLS) refers to an organized infiltration of immune cells that is linked to a positive prognosis and improved response to immunotherapy. However, methods that promote TLS formation are limited and challenging to implement in clinical settings. In this study, we aimed to promote the formation and maturation of TLSs in lung adenocarcinoma (LUAD) by combining low-dose radiotherapy (LDRT) with immunotherapy.MethodsTissue sections from 198 patients who had undergone surgery were examined. Risk factors for patient survival were assessed, and the relationship between TLSs and five-year survival was analyzed. The Kras-LSL-G12D spontaneous lung cancer mouse model was used to screen the optimal irradiation dose (0/1/2 Gy whole lung irradiation) for promoting TLS formation. LDRT combined with anti-PD-1 was used to promote the formation and maturation of TLSs.ResultsTLS+, TLSHigh, TLS+GC+ and CD8High within TLS+ were associated with a favorable prognosis. LDRT increased the formation of early TLSs in the Kras-LSL-G12D lung cancer mouse model. In addition, LDRT combined with anti-PD-1 treatment can significantly improve the maturity of TLSs in mouse LUAD, resulting in greater antitumor effects. This antitumor effect was strongly associated with the number of CD8+ T cells within the TLSs.ConclusionWe successfully applied LDRT combined with PD-1 inhibitor therapy for the first time, which increased both the quantity and maturity of TLSs in lung cancer. This approach achieved a promising antitumor effect.

In this comprehensive meta-analysis, our objective was to evaluate the diagnostic utility of graft-derived cell-free DNA (GcfDNA) in kidney allograft rejection and explore associated factors. We conducted a thorough search of PubMed, Embase, and the Cochrane Library databases, spanning from their inception to September 2022. Statistical analysis was executed utilizing Stata 15, Meta-DiSc 1.4, and Review Manager 5.4 software. The combined pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the area under the summary receiver operating characteristics (SROC) curve from the synthesis of findings across ten studies were as follows: 0.75 (0.67–0.81), 0.78 (0.72–0.83), 3.36 (2.89–4.35), 0.32 (0.24–0.44), 8.77 (4.34–17.74), and 0.83 (0.80–0.86), respectively. Among the ten studies primarily focused on GcfDNA’s diagnostic potential for antibody-mediated rejection (ABMR), the optimal cut-off threshold demonstrated substantial diagnostic efficacy, with pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, DOR, and area under the summary receiver operating characteristics curve values of 0.83 (0.74–0.89), 0.75 (0.70–0.80), 3.37 (2.64–4.30), 0.23 (0.15–0.36), 14.65 (7.94–27.03), and 0.85 (0.82–0.88), respectively. These results underscore the high diagnostic accuracy of GcfDNA in detecting rejection. Furthermore, the optimal cut-off threshold proves effective in diagnosing ABMR, while a 1% threshold remains a robust diagnostic criterion for rejection. Notably, for ABMR diagnosis, droplet digital PCR digital droplet polymerase chain reaction emerges as a superior method in terms of accuracy when compared to other techniques. Nonetheless, further research is warranted to substantiate these findings.

STING (Stimulator of Interferon Genes) agonists have emerged as promising agents in the field of cancer immunotherapy, owing to their excellent capacity to activate the innate immune response and combat tumor-induced immunosuppression. This review provides a comprehensive exploration of the strategies employed to develop effective formulations for STING agonists, with particular emphasis on versatile nano-delivery systems. The recent advancements in delivery systems based on lipids, natural/synthetic polymers, and proteins for STING agonists are summarized. The preparation methodologies of nanoprecipitation, self-assembly, and hydrogel, along with their advantages and disadvantages, are also discussed. Furthermore, the challenges and opportunities in developing next-generation STING agonist delivery systems are elaborated. This review aims to serve as a reference for researchers in designing novel and effective STING agonist delivery systems for cancer immunotherapy.

AbstractBackground The kidney transplant recipients (KTRs) were diagnosed with Chronic Kidney Disease after transplantation (CKD-T). CKD-T can be affected by the microbial composition and metabolites. The present study integrates the analysis of gut microbiome and metabolites to further identify the characteristics of CKD-T.Methods We collected 100 fecal samples of KTRs and divided them into two groups according to the stage progression of CKD-T. Among them, 55 samples were analyzed by Hiseq sequencing, and 100 samples were used for non-targeted metabolomics analysis. The gut microbiome and metabolomics of KTRs were comprehensively characterized.Results As well as significant differences in gut microbiome diversity between the CKD G1-2T group and CKD G3T group. Eight flora including Akkermansia were found to be enriched in CKD G3T group. As compared with CKD G1-2T group, the relative abundance of some amino acid metabolism, glycerophospholipid metabolism, amino acid biosynthesis, carbohydrate metabolism and purine metabolism in CKD G3T group were differential expressed significantly. In addition, fecal metabolome analysis indicated that CKD G3T group had a unique metabolite distribution characteristic. Two differentially expressed metabolites, N-acetylornithine and 5-deoxy-5'-(Methylthio) Adenosine, were highly correlated with serum creatinine, eGFR and cystatin C. The enrichment of gut microbial function in CKD-T is correlated with the expression of gut metabolites.Conclusion Gut microbiome and metabolites in the progression of CKD-T display some unique distribution and expression characteristics. The composition of the gut microbiome and their metabolites appears to be different between patients with CKD G3T and those with CKD G1-2T.

Abstract Osteoarthritis (OA) is an age-related degenerative disease without disease-modifying therapy. The lack of aging-induced osteoarthritis models makes the discovery of therapeutic drugs more challenging. The deficiency of ZMPSTE24 could induce Hutchinson–Gilford progeria syndrome (HGPS), a genetic disorder of rapid aging. However, the relationship between HGPS and OA remains unclear. Our results found that the expression of Zmpste24 was decreased in the articular cartilage during the aging process. Zmpste24 knockout mice, Prx1-Cre; Zmpste24 fl/fl mice and Col2-CreERT2; Zmpste24 fl/fl mice displayed OA phenotype. Loss of Zmpste24 in articular cartilage could exacerbate the occurrence and development of osteoarthritis. Transcriptome sequencing revealed that deletion of Zmpste24 or accumulation of progerin affects chondrocyte metabolism, inhibits cell proliferation and promotes cell senescence. Using this animal model, we elucidate the upregulation of H3K27me3 during chondrocyte senescence and discover the molecular mechanism by which lamin A mutant stabilizes EZH2 expression. The construction of aging-induced osteoarthritis models and the elucidation of the signaling pathways and molecular mechanisms of articular chondrocyte senescence would benefit the discovery and development of new drugs for OA.