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Abstract Golden buckwheat, also called Fagopyrum dibotrys (D. Don) H. Hara, is a plant of the genus Buckwheat in the buckwheat family. The aim of this study was to screen the bioactive ingredients of golden buckwheat extract and investigate the protective effect on acute lung injury (ALI). The ethyl acetate extract (EAE) was identified as the active fraction in LPS‐induced RAW264.7 cells, with gallic acid, proanthocyanidin B2, and epicatechin at 0.0563%, 0.3707%, and 0.3868%, respectively. At the same time, 20 compounds (mainly flavonoids and organic acids) were identified by UPLC‐Q‐Exactive Orbitrap‐HRMS in EAE. Furthermore, the EAE reduced lung histopathology scores in mice with ALI, decreased the dry‐to‐wet weight ratio of lung tissue, and significantly inhibited the concentrations of IL‐1β, TNFα, and IL‐6 in bronchoalveolar lavage fluid (BALF). It also reduced the number of leukocytes, decreased the activity of MPO in lung tissue, and inhibited the levels of TLR4/NLRP3 pathway mRNA and protein in lung tissue. Our study indicated that golden buckwheat as a source of functional food prevents or treats associated lung diseases by modulating the activation of the TLR4/NLRP3 signaling pathway.

Abstract Small cell lung cancer (SCLC) is a recalcitrant cancer characterized by early metastasis, rapid tumor growth and poor prognosis. In recent decades, the epidemiology, initiation and mutation characteristics of SCLC, as well as abnormal signaling pathways contributing to its progression, have been widely studied. Despite extensive investigation, fewer drugs have been approved for SCLC. Recent advancements in multi-omics studies have revealed diverse classifications of SCLC that are featured by distinct characteristics and therapeutic vulnerabilities. With the accumulation of SCLC samples, different subtypes of SCLC and specific treatments for these subtypes were further explored. The identification of different molecular subtypes has opened up novel avenues for the treatment of SCLC; however, the inconsistent and uncertain classification of SCLC has hindered the translation from basic research to clinical applications. Therefore, a comprehensives review is essential to conclude these emerging subtypes and related drugs targeting specific therapeutic vulnerabilities within abnormal signaling pathways. In this current review, we summarized the epidemiology, risk factors, mutation characteristics of and classification, related molecular pathways and treatments for SCLC. We hope that this review will facilitate the translation of molecular subtyping of SCLC from theory to clinical application.

Abstract This multicentre, two-arm, phase 2 study aimed to explore the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy or apatinib in patients with initially unresectable stage II–III non-small-cell lung cancer (NSCLC). Eligible patients regardless of PD-L1 expression received neoadjuvant camrelizumab 200 mg and platinum-doublet chemotherapy every 3 weeks (arm A) or those with PD-L1-positive tumors received neoadjuvant camrelizumab and apatinib 250 mg once daily (arm B), for 2–4 cycles, followed by surgery. The primary endpoint was major pathological response (MPR) rate. Thirty patients in arm A and 21 in arm B were enrolled. Surgery rates were 50.0% (15/30) in arm A and 42.9% (9/21) in arm B, with all patients achieving R0 resections. Of these patients, the MPR and pathological complete response rates were both 20.0% (95% CI 4.3–48.1) in arm A and were 55.6% (95% CI 21.2–86.3) and 11.1% (95% CI 0.3–48.2) in arm B, respectively. The corresponding objective response rates were 33.3% (95% CI 11.8–61.6) and 55.6% (95% CI 21.2–86.3). With a median follow-up of 22.4 months (95% CI 19.0–26.0), the median event-free survival was not reached (NR; 95% CI 13.6-NR) in arm A and 16.8 months (95% CI 8.6-NR) in arm B. Grade 3 or above treatment-related adverse events occurred in eight (26.7%) patients in arm A and three (14.3%) in arm B. Biomarker analysis showed baseline TYROBP expression was predictive of treatment response in arm B. Neoadjuvant camrelizumab plus chemotherapy or apatinib exhibits preliminary efficacy and manageable toxicity in patients with initially unresectable stage II–III NSCLC.

Transformer requires a fixed number of layers and heads which makes them inflexible to the complexity of individual samples and expensive in training and inference. To address this, we propose a sample-based Dynamic Hierarchical Transformer (DHT) model whose layers and heads can be dynamically configured with single data samples via solving contextual bandit problems. To determine the number of layers and heads, we use the Uniform Confidence Bound algorithm while we deploy combinatorial Thompson Sampling in order to select specific head combinations given their number. Different from previous work that focuses on compressing trained networks for inference only, DHT is not only advantageous for adaptively optimizing the underlying network architecture during training but also has a flexible network for efficient inference. To the best of our knowledge, this is the first comprehensive data-driven dynamic transformer without any additional auxiliary neural networks that implement the dynamic system. According to the experiment results, we achieve up to 74% computational savings for both training and inference with a minimal loss of accuracy.

Federated learning (FL) is an emerging paradigm for decentralized training of machine learning models on distributed clients, without revealing the data to the central server. The learning scheme may be horizontal, vertical or hybrid (both vertical and horizontal). Most existing research work with deep neural network (DNN) modeling is focused on horizontal data distributions, while vertical and hybrid schemes are much less studied. In this paper, we propose a generalized algorithm FedEmb, for modeling vertical and hybrid DNN-based learning. The idea of our algorithm is characterized by higher inference accuracy, stronger privacy-preserving properties, and lower client-server communication bandwidth demands as compared with existing work. The experimental results show that FedEmb is an effective method to tackle both split feature & subject space decentralized problems. To be specific, there are 0.3% to 4.2% improvement on inference accuracy and 88.9 % time complexity reduction over baseline method.

Abstract Background The characteristics and therapeutic potential of subtypes of bone marrow mesenchymal stem cells (BMSCs) are largely unknown. Also, the application of subpopulations of BMSCs in cartilage regeneration remains poorly characterized. The aim of this study was to explore the regenerative capacity of CD146-positive subpopulations of BMSCs for repairing cartilage defects. Methods CD146-positive BMSCs (CD146 + BMSCs) were sorted by self-developed CD146-specific lipid magnetic spheres (CD146-LMS). Cell surface markers, viability, and proliferation were evaluated in vitro. CD146 + BMSCs were subjected to in vitro chondrogenic induction and evaluated for chondrogenic properties by detecting mRNA and protein expression. The role of the CD146 subpopulation of BMSCs in cartilage damage repair was assessed by injecting CD146 + BMSCs complexed with sodium alginate gel in the joints of a mouse cartilage defect model. Results The prepared CD146-LMS had an average particle size of 193.7 ± 5.24 nm, an average potential of 41.9 ± 6.21 mv, and a saturation magnetization intensity of 27.2 Am2/kg, which showed good stability and low cytotoxicity. The sorted CD146 + BMSCs highly expressed stem cell and pericyte markers with good cellular activity and cellular value-added capacity. Cartilage markers Sox9, Collagen II, and Aggrecan were expressed at both protein and mRNA levels in CD146 + BMSCs cells after chondrogenic induction in vitro. In a mouse cartilage injury model, CD146 + BMSCs showed better function in promoting the repair of articular cartilage injury. Conclusion The prepared CD146-LMS was able to sort out CD146 + BMSCs efficiently, and the sorted subpopulation of CD146 + BMSCs had good chondrogenic differentiation potential, which could efficiently promote the repair of articular cartilage injury, suggesting that the sorted CD146 + BMSCs subpopulation is a promising seed cell for cartilage tissue engineering.

Abstract Nasopharyngeal carcinoma (NPC), a squamous cell carcinoma originating in the nasopharynx, is a leading malignancy in south China and other south and east Asia areas. It is frequently associated with Epstein‐Barr virus (EBV) infection, while there are also some NPC patients without EBV infection. Here, it is shown that the EBV+ (EBV positive) and EBV‐ (EBV negative) NPCs contain both shared and distinct genetic abnormalities, among the latter are increased mutations in TP53. To investigate the functional roles of NPC‐associated genetic alterations, primary, orthotopic, and genetically defined NPC models were developed in mice, a key tool missed in the field. These models, initiated with gene‐edited organoids of normal nasopharyngeal epithelium, faithfully recapitulated the pathological features of human disease. With these models, it is found that Trp53 and Cdkn2a deficiency are crucial for NPC initiation and progression. And latent membrane protein1 (LMP1), an EBV‐coding oncoprotein, significantly promoted the distal metastasis. Further, loss of TGFBR2, which is frequently disrupted both in EBV‐ and EBV+ NPCs, dramatically accelerated the progression and lung metastasis of NPC probably by altering tumor microenvironment. Taken together, this work establishes a platform to dissect the genetic mechanisms underlying NPC pathogenesis and might be of value for future translational studies.

BackgroundType 2 diabetes mellitus (T2DM) is widely acknowledged as a vital warning sign contributing to cognitive dysfunction. However, there is still a lack of consensus on whether hypoglycemic events resulting from poor glycemic control increase the risk of cognitive dysfunction in people with diabetes, and the potential dose–response correlation between hypoglycemic events and cognitive dysfunction remains unexplored. The primary objective of the current study was to assess the contribution of hypoglycemic events to cognitive dysfunction in T2DM patients and the dose–response correlation between the two.MethodsA comprehensive search of nine major databases was executed from inception to May 2023. We screened all observational studies examining the connection between hypoglycemia and cognitive dysfunction. The DerSimonian-Laird method was used to compute the combined risk ratio (RR) and its 95% confidence interval (CI). Additionally, dose–response analysis was employed to investigate the correlation between the frequency of hypoglycemia and the likelihood of cognitive dysfunction.ResultsA total of 30 studies of different levels in 17 articles with 3,961,352 participants were included in this review. The pooled RR for the connection of hypoglycemia and the likelihood of cognitive dysfunction was 1.47 (95% CI: 1.35–1.60). Subgroup analyses showed that the pooled RR for the likelihood of cognitive dysfunction was 1.20 (95% CI: 1.11–1.31) for one episode of hypoglycemia, 1.41 (95% CI: 1.05–1.88) for two episodes of hypoglycemia, and 1.62 (95% CI: 1.20–2.91) for three or more episodes of hypoglycemia. Dose–response analysis showed a linear dose–response relationship between hypoglycemia and the likelihood of cognitive dysfunction (exp (b) = 1.178694, z = 7.12, p

With the rapid development of application fields, such as the green energy industry, has resulted in increased demand for magnetic characteristics, especially the coercivity (Hcj). In this paper, two types of (Nd, Dy)-Fe-B magnets with comparable Hcj values were prepared using by grain boundary diffusion (GBD) method and dual alloy (DA) method. The composition, microstructure, domain structure, and magnetization reversal process of GBD and DA magnets were subjected to comparison. Additionally, an analysis of the specific coercivity mechanism was also conducted by fitting the Brown's equation. The results of composition and microstructure analysis revealed the formation of core-shell structural grains were formed in both GBD and DA methods. Specifically, the GBD method exhibited a higher concentration of Dy in the shell, constituting 26.8 % of the total rare earth (RE) content. In contrast the DA magnets had Dy accounting for 15.8 % of the total RE content in the shell. This discrepancy was identified as the primary factor contributing to the superior efficiency in enhancing the coercivity (Hcj) observed in the GBD method. The fitting results showed that GBD magnets were more inclined to nucleate in the core region in grain, whereas DA magnets nucleate at the edge of the grain shell layer. Both the observation of magnetic domains and magnetization reversal processes analysis revealed that the demagnetization process in GBD magnets is more uniform, which leads to better squareness. Our finding can provide theoretical and experimental basis for the preparation of high-performance Nd-Fe-B magnets.

Abstract Background The emergence of the COVID-19 pandemic towards the end of 2019 triggered a relentless spread of online misinformation, which significantly impacted societal stability, public perception, and the effectiveness of measures to prevent and control the epidemic. Understanding the complex dynamics and characteristics that determine the duration of rumors is crucial for their effective management. In response to this urgent requirement, our study takes survival analysis method to analyze COVID-19 rumors comprehensively and rigorously. Our primary aim is to clarify the distribution patterns and key determinants of their persistence. Through this exploration, we aim to contribute to the development of robust rumor management strategies, thereby reducing the adverse effects of misinformation during the ongoing pandemic. Methods The dataset utilized in this research was sourced from Tencent's “Jiao Zhen” Verification Platform's “Real-Time Debunking of Novel Coronavirus Pneumonia” system. We gathered a total of 754 instances of rumors from January 18, 2020, to January 17, 2023. The duration of each rumor was ascertained using the Baidu search engine. To analyze these rumors, survival analysis techniques were applied. The study focused on examining various factors that might influence the rumors' longevity, including the theme of the content, emotional appeal, the credibility of the source, and the mode of presentation. Results Our study's results indicate that a rumor's lifecycle post-emergence typically progresses through three distinct phases: an initial rapid decline phase (0–25 days), followed by a stable phase (25–1000 days), and ultimately, an extinction phase (beyond 1000 days). It is observed that half of the rumors fade within the first 25 days, with an average duration of approximately 260.15 days. When compared to the baseline category of prevention and treatment rumors, the risk of dissipation is markedly higher in other categories: policy measures rumors are 3.58 times more likely to perish, virus information rumors have a 0.52 times higher risk, epidemic situation rumors are 4.86 times more likely to die out, and social current affairs rumors face a 2.02 times increased risk. Additionally, in comparison to wish rumors, bogie rumors and aggression rumors have 0.26 and 0.27 times higher risks of dying, respectively. In terms of presentation, graphical and video rumors share similar dissolution risks, whereas textual rumors tend to have a longer survival time. Interestingly, the credibility of the rumor's source does not significantly impact its longevity. Conclusion The survival time of rumors is strongly linked to their content theme and emotional appeal, whereas the credibility of the source and the format of presentation have a more auxiliary influence. This study recommends that government agencies should adopt specific strategies to counter rumors. Experts and scholars are encouraged to take an active role in spreading health knowledge. It's important for the public to proactively seek trustworthy sources for accurate information. Media platforms are advised to maintain journalistic integrity, verify the accuracy of information, and guide the public towards improved media literacy. These actions, collectively, can foster a collaborative alliance between the government and the media, effectively combating misinformation.

Abstract Background Preeclampsia is a life-threatening disease of pregnancy that lacks effective pharmaceuticals which can target its pathogenesis. Since preeclampsia involves complex pathological processes, including autophagy, this study aims to explore autophagy-related mechanisms of preeclampsia and to screen potential drugs. Methods Firstly, the datasets GSE75010, GSE24129, GSE66273, and autophagic genes lists were downloaded from public databases. Then, a weighted gene co-expression network analysis (WGCNA) was applied to filter autophagic-related hub genes of preeclampsia. The differential expression levels of the hub genes were validated with datasets GSE24129 and GSE66273. Next, the GO and KEGG enrichment, protein-protein interacting (PPI) network, as well as the downstream pathways was analyzed via the starBase, STRING and Cytoscape to determine the functions and regulatory network of the hub genes. Additionally, the immune microenvironment of preeclampsia was investigated by the CIBERSORTX database. Finally, three herb ingredients, berberine, baicalein, and luteolin were screened by molecular docking in comparison to pravastatin, metformin, and aspirin, to predict potential drugs for treating preeclampsia. Results A total of 54 autophagy-related genes were filtered by WGCNA. After filtering with |GS| > 0.5 and |MM| > 0.8, three hub genes, namely PKM, LEP, and HK2, were identified and validated. Among these genes, PKM and LEP were overexpressed in women older than 35 years old ( p

Abstract β‐Catenin (CTNNB) is a core downstream mediator in the Wnt/β‐catenin signaling pathway, which plays a role in immune regulation and cell differentiation. In the present study, two CTNNB genes were identified by genomic analysis of Hippocampus erectus and named He‐CTNNB1 and He‐CTNNB2. He‐CTNNB1 was more conserved than He‐CTNNB2. The full length of He‐CTNNB1 was 2369 bp, including an open reading frame of 2275 bp that encoded 737 amino acids containing 12 armadillo repeats. Phylogenetic analysis revealed that He‐CTNNB1 clusters had homologs in other bony fishes. Tissue distribution analysis showed the highest mRNA expression of He‐CTNNB1 in the ovary, liver, and kidney of the lined seahorse under normal physiological conditions. The transcription level of He‐CTNNB1 was significantly increased in the liver and kidney in response to LPS, poly I:C, and Edwardsiella tarda challenge (p

BackgroundTumor initiation and metastasis influence tumor immune exclusion and immunosuppression. Long non-coding RNA (lncRNA) LINC01614 is associated with the prognosis and metastasis of several cancers. However, the relationship between LINC01614 and cancer immune infiltration and the biofunction of LINC01614 in head and neck squamous cell carcinoma (HNSC) remain unclear.MethodsThe Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets were used to analyze the expression difference and diagnostic value of LINC01614 in normal and tumor tissues. The correlation of pan-cancer prognosis and tumor stage of LINC01614 was analyzed based on the TCGA database. The pan-cancer association of LINC01614 expression with the tumor microenvironment (TME) including immune infiltration, expression of immune-related genes, and genomic instability parameters, was analyzed using the Spearman correlation method. The correlation between LINC01614 and tumor stemness evaluation indicators, RNA methylation-related genes, and drug resistance was also analyzed. The functional analysis of LINC01614 was performed using the clusterProfiler R package. The protein–protein interaction (PPI) network and ceRNA network of LINC01614 co-expressed genes and miRNA were constructed and visualized by STRING and Cytoscape, respectively. Finally, the cell location and influence of LINC01614 on cell proliferation and metastasis of HNSC cell lines were evaluated using FISH, CCK-8, wound-healing assay, and transwell assay.ResultsLINC01614 was found to be overexpressed in 23 cancers and showed a highly sensitive prediction value in nine cancers (AUC >0.85). LINC01614 dysregulation was associated with tumor stage in 12 cancers and significantly influenced the survival outcomes of 26 cancer types, with only Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (DLBC), uterine corpus endometrial carcinoma (UCEC), and bladder urothelial carcinoma (BLCA) showing a benign influence. LINC01614 was also associated with immune cell infiltration, tumor heterogeneity, cancer stemness, RNA methylation modification, and drug resistance. The potential biological function of LINC01614 was verified in HNSC, and it was found to play important roles in proliferation, immune infiltration, immunotherapy response, and metastasis of HNSC.ConclusionLINC01614 may serve as a cancer diagnosis and prognosis biomarker and an immunotherapy target for specific cancers.

Abstract Background This paper analyzed the cases of dural arteriovenous fistula (DAVF) with spinal dural arteriovenous fistula (SDAVF) in the diagnosis and treatment process. Case presentation One case involving dural arteriovenous fistula (DAVF) with spinal dural arteriovenous fistula (SDAVF) from the 306th Hospital of PLA was retrospectively analyzed. The patient consulted the doctor due to lower limb sensory and motor disorders while exhibiting symptoms of urinary dysfunction. A computed tomographic angiography (CTA) and cerebral angiography confirmed the diagnosis of dural arteriovenous fistula (DAVF), necessitating surgical treatment. The patient was referred to our hospital for an magnetic resonance imaging (MRI) and a spinal angiography to obtain a confirmed diagnosis for spinal arteriovenous fistula, after which they underwent surgical fistula resection. The invasive intracranial dural arteriovenous fistula (DAVF) resection proceeded smoothly but did not ease the patient's symptoms. However, postoperative symptoms were partially relieved by the lumbar open spinal dural arteriovenous fistula adminstration. Conclusions Since not enough is understood about these two diseases, the rate of misdiagnosis is significantly increased. Early diagnosis and treatment of spinal dural arteriovenous fistula (SDAVF) can play a positive role during the recovery from neural function damage.

Astragalus membranaceus saponins are the main components of A. membranaceus, a plant widely used in traditional Chinese medicine. Recently, research on the anti-cancer effects of A. membranaceus saponins has received increasing attention. Numerous in vitro and in vivo experimental data indicate that A. membranaceus saponins exhibit significant anti-cancer effects through multiple mechanisms, especially in inhibiting tumor cell proliferation, migration, invasion, and induction of apoptosis, etc. This review compiles relevant studies on the anti-cancer properties of A. membranaceus saponins from various databases over the past two decades. It introduces the mechanism of action of astragalosides, highlighting their therapeutic benefits in the management of cancer. Finally, the urgent problems in the research process are highlighted to promote A. membranaceus saponins as an effective drug against cancer.

ObjectivesTo explore the feasibility and importance of deep learning (DL) based on 68Ga-prostate-specific membrane antigen (PSMA)-11 PET/CT in predicting pathological upgrading from biopsy to radical prostatectomy (RP) in patients with prostate cancer (PCa).MethodsIn this retrospective study, all patients underwent 68Ga-PSMA-11 PET/CT, transrectal ultrasound (TRUS)-guided systematic biopsy, and RP for PCa sequentially between January 2017 and December 2022. Two DL models (three-dimensional [3D] ResNet-18 and 3D DenseNet-121) based on 68Ga-PSMA-11 PET and support vector machine (SVM) models integrating clinical data with DL signature were constructed. The model performance was evaluated using area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity.ResultsOf 109 patients, 87 (44 upgrading, 43 non-upgrading) were included in the training set and 22 (11 upgrading, 11 non-upgrading) in the test set. The combined SVM model, incorporating clinical features and signature of 3D ResNet-18 model, demonstrated satisfactory prediction in the test set with an AUC value of 0.628 (95% confidence interval [CI]: 0.365, 0.891) and accuracy of 0.727 (95% CI: 0.498, 0.893).ConclusionA DL method based on 68Ga-PSMA-11 PET may have a role in predicting pathological upgrading from biopsy to RP in patients with PCa.

Myxobacteria have a complex life cycle and unique social behavior. They can prey on plant pathogenic fungi, bacteria, and oomycetes in the soil by producing some enzymes and small molecule compounds. The enzymes mainly include β-1,6-glucanase, β-1,3-glucanase, chitinase, protease, peptidase, and formaldehyde dismutase. β-1,6-glucanase, β-1,3-glucanase, and chitinase can degrade the glycosidic bonds in the cell wall of plant pathogen, causing some holes to form on the cell walls of the plant pathogen. Proteases and peptidases can break plant pathogenic cells into many small fragments and facilitate extracellular digestion of proteins during myxobacterial predation. Formaldehyde dismutase converts formaldehyde to formate and methanol, it can help myxobactria protect themselves in the process of predation. Small molecule substances produced by myxobacteria include isooctanol, di-isobutyl phthalate, myxovirescin, cystobactamid derivatives, hyalodione, argyrin derivatives, Methyl (2R)-2-azido-3-hydroxyl-2-methylpropanoate and N-(3-Amino-2-hydroxypropyl)-N-meth-ylsulfuric diamide, etc. Isooctanol destroyed the cell wall and cell membrane of plant pathogen, causing intracellular reactive oxygen species (ROS) to accumulate, leading to apoptosis and cell death. Di-isobutyl phthalate had biofilm inhibitory activity against bacteria. Myxovirescin could inhibit the incorporation of diamibopimelic acid and uridine diphosphate-Nacetylglucosamine intobacterial cell wall and interfered with the polymerizaton of the lipid-disacchar-pentapeptide. Cystobactamid derivatives exerted their natural antibacterial properties by inhibition of bacterial gyrases. Hyalodione had broad antibacterial and antifungal activity. Argyrin derivatives inhibited protein synthesis by interfering with the binding of elongation factor G (EF-G) to ribosomes. Methyl (2R)-2-azido-3-hydroxyl-2-methylpropanoate and N-(3-Amino-2-hydroxypropyl)-N-meth-ylsulfuric diamide reduced the content of soluble proteins and the activity of protective enzymes (PPO, POD, PAL, and SOD) in plant pathogen, increased oxidative damage and cell membrane permeability. Myxobacteria, as a new natural compound resource bank, can control plant pathogenic fungi, oomycetes and bacteria by producing some enzymes and small molecule compounds, so it has great potential in plant disease control.

The formation and distribution of marsh wetlands are influenced by both climate changes and human activities. Quantifying the driving factors of marsh wetlands is essential for understanding the sustainable utilization of wetland ecosystems. The current study simulated the potential marsh wetlands’ spatial distribution in the Qilian Mountains of Qinghai (QMQ) by a random forest (RF) model with a series of environmental indicators, including climate, vegetation, soil, topography, and human activity factors in 2020. Simultaneously, a structural equation modeling (SEM) was utilized to explore driving factors of formation and distribution of marsh wetlands. Results showed that: (1) The potential marsh wetlands area was determined to be 2502.01 km2 in the QMQ, mainly distributed in the watershed source and along the river. (2) Normalized difference vegetation index (NDVI), normalized difference water index (NDWI), digital elevation model (DEM), fraction vegetation coverage (FVC), and ground surface temperature (GST) were the most critical factors in marsh wetland simulation, with the relative importance index of 11.14 %, 9.70 %, 9.07 %, 8.39 %, and 6.50 %, respectively. (3) The topography acted on the potential marsh wetlands’ distribution by influencing the nutrient input function of potential marsh wetlands (indirect effect 0.28). The climate was the fundamental factor that directly controls the distribution of potential marsh wetlands (direct effect 0.44), and vegetation had a total effect of 0.24. The current study may provide information for policy decisions on wetland conservation and restoration.

Abstract The footpad structure of a deep space exploration lander is a critical system that makes the initial contact with the ground, and thereby plays a crucial role in determining the stability and energy absorption characteristics during the impact process. The conventional footpad is typically designed with an aluminum honeycomb structure that dissipates energy through plastic deformation. Nevertheless, its effectiveness in providing cushioning and energy absorption becomes significantly compromised when the structure is crushed, rendering it unusable for reusable landers in the future. This study presents a methodology for designing and evaluating structural energy absorption systems incorporating recoverable strain constraints of shape memory alloys (SMA). The topological configuration of the energy absorbing structure is derived using an equivalent static load method (ESL), and three lightweight footpad designs featuring honeycomb-like Ni-Ti shape memory alloys structures and having variable stiffness skins are proposed. To verify the accuracy of the numerical modelling, a honeycomb-like structure subjected to compression load is modeled and then compared with experimental results. Moreover, the influence of the configurations and thickness distribution of the proposed structures on their energy absorption performance is comprehensively evaluated using finite element simulations. The results demonstrate that the proposed design approach effectively regulates the strain threshold to maintain the SMA within the constraint of maximum recoverable strain, resulting in a structural energy absorption capacity of 362 J/kg with a crushing force efficiency greater than 63%.

Abstract Afatinib, an irreversible ErbB-family blocker, could improve the survival of advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer patients (NSCLCm+). This phase II trial (NCT04201756) aimed to assess the feasibility of neoadjuvant Afatinib treatment for stage III NSCLCm+. Forty-seven patients received neoadjuvant Afatinib treatment (40 mg daily). The primary endpoint was objective response rate (ORR). Secondary endpoints included pathological complete response (pCR) rate, pathological downstaging rate, margin-free resection (R0) rate, event-free survival, disease-free survival, progression-free survival, overall survival, treatment-related adverse events (TRAEs). The ORR was 70.2% (95% CI: 56.5% to 84.0%), meeting the pre-specified endpoint. The major pathological response (MPR), pCR, pathological downstaging, and R0 rates were 9.1%, 3.0%, 57.6%, and 87.9%, respectively. The median survivals were not reached. The most common TRAEs were diarrhea (78.7%) and rash (78.7%). Only three patients experienced grade 3/4 TRAEs. Biomarker analysis and tumor microenvironment dynamics by bulk RNA sequencing were included as predefined exploratory endpoints. CISH expression was a promising marker for Afatinib response (AUC = 0.918). In responders, compared to baseline samples, increasing T-cell- and B-cell-related features were observed in post-treatment tumor and lymph-node samples, respectively. Neoadjuvant Afatinib is feasible for stage III NSCLC+ patients and leads to dynamic changes in the tumor microenvironment.

Abstract Background Hepatocellular carcinoma (HCC) is the second malignancy worldwide. POLA2 initiates DNA replication, regulates cell cycle and gene repair that promote tumorigenesis and disease progression. However, the prognostic and biological function roles of POLA2 in HCC had not been conclusively determined. Methods The expression levels and prognosis role of POLA1 and POLA2 in HCC were analyzed based on TCGA-LIHC database and recruited 24 HCC patients. Gene mutations were analyzed using “maftools” package. POLA2 and immune cells correlations were analyzed by TIMER. POLA2 co-expressed genes functional enrichment were evaluated using Metascape. The mRNA and protein level of POLA2 was detected in HCC cells and tissues. Cell migration, invasion, proliferation, cell cycle and HCC cell lines derived xenograft model were performed to investigate POLA2 biological function. Results POLA2 was significantly high expressed in HCC than in normal liver tissue in both TCGA-LIHC and our collected HCC samples. In validation cohort, POLA2 significantly related to tumor differentiation, tumor size and Ki-67 (p

The accurate prediction of landslide susceptibility relies on effectively handling landslide absence samples in machine learning (ML) models. However, existing research tends to generate these samples in feature space, posing challenges in field validation, or using physics-informed models, thereby limiting their applicability. The rapid progress of interferometric synthetic aperture radar (InSAR) technology may bridge this gap by offering satellite images with extensive area coverage and precise surface deformation measurements at millimeter scales. Here, we propose an InSAR-based sampling strategy to generate absence samples for landslide susceptibility mapping in the Badong–Zigui area near the Three Gorges Reservoir, China. We achieve this by employing a Small Baseline Subset (SBAS) InSAR to generate the annual average ground deformation. Subsequently, we select absence samples from slopes with very slow deformation. Logistic regression, support vector machine, and random forest models demonstrate improvement when using InSAR-based absence samples, indicating enhanced accuracy in reflecting non-landslide conditions. Furthermore, we compare different integration methods to integrate InSAR into ML models, including absence sampling, joint training, overlay weights, and their combination, finding that utilizing all three methods simultaneously optimally improves landslide susceptibility models.

The grain size of the full lamellae TiAl-based alloy changes from ~400 μm to ~40 μm through the precipitation of metastable structures by cyclic heat treatment. Based on this, two kinds of variant selection processes—coherent metastable γ variants precipitated during the air-cooling process and αs variants precipitated during the holding at a single α phase region process—are identified to promote the formation of refined Type I and Type II coherent grain boundaries. The oxidation tests at 1000 °C for 100 h show that the formation of refined coherent grain boundaries can greatly improve oxidation resistance by inducing the continuous multi-layer protective barrier consisting of (Ti, (Nb, Ta))O2, TiN, and Al(Nb,Ta)2. This protective barrier inhibits the inward diffusion of oxygen and nitrogen.

The improvement of corrosion resistance for sintered Nd-Fe-B magnets is usually focused on the modification of grain boundary phase. The main phase is similarly a key point to enhance corrosion resistance. In this work, a novel sintered Nd-Fe-B magnet is designed with the addition of Ni and Cr. This kind of sintered Nd-Ni-Fe-Cr-B magnet maintains a typical 2:14:1 tetragonal phase, and the metallurgical behavior of Ni and Cr is characterized by the distribution of Ni in the grain boundary and Cr in the main phase. Accelerated corrosion and electrochemical corrosion tests were conducted to compare the corrosion resistance of traditional sintered Nd-Fe-B magnet and Nd-Ni-Fe-Cr-B magnet. Results show that sintered Nd-Ni-Fe-Cr-B magnet exhibits superior corrosion resistance. It is found that the corrosion resistance of the grain boundary phase and the main phase is simultaneously increased. Moreover, the reduced potential difference between the grain boundary phase and the main phase further enhances the corrosion resistance of sintered Nd-Ni-Fe-Cr-B magnet. This work could provide an insight into the research aimed at improving the corrosion resistance of uncoated sintered Nd-Fe-B magnets.

Abstract Background The frequently occurred chemotherapy-induced diarrhea (CID) caused by irinotecan (CPT-11) administration has been the most representative side-effects of CPT-11, resulting in the chemotherapy suspension or failure. Our previous studies indicated that Gegen Qinlian formula exhibited a significant alleviation effect on CPT-11-induced diarrhea. However, referencing to Japanese Kampo medicine, the TCM standard decoction would supply the gap between ancient preparation application and modern industrial production. Methods The LC–MS technology combined with network pharmacology was employed to identify the active ingredients and mechanisms of GQD standard decoction for CPT-11-induced diarrhea. The anti-inflammatory activities associated with intestinal barrier function of GQD standard decoction were studied by SN-38 activated NCM460 cells in vitro and CPT-11-induced diarrhea in vivo. Proteins involved in inflammation, mRNA levels, disease severity scores, and histology involved in intestinal inflammation were analysed. Results There were 37 active compounds were identified in GQD standard decoction. Network pharmacology analyses indicated that PI3K-AKT signaling pathway were probably the main pathway of GQD standard decoction in CPT-11-induced diarrhea treatment, and PIK3R1, AKT1, NF-κB1 were the core proteins. Moreover, we found that the key proteins and pathway predicted above was verified in vivo and in vitro experiments, and the GQD standard decoction could protect the cellular proliferation in vitro and ameliorate CPT-11-induced diarrhea in mice model. Conclusions This study demonstrated the molecular mechanism of 37 active ingredients in GQD standard decoction against CPT-11-induced diarrhea. And the core proteins and pathway were validated by experiment. This data establishes the groundwork for particular molecular mechanism of GQD standard decoction active components, and this research can provide a scientific reference for the TCM therapy of CID.

Abstract Limited numbers of available hematopoietic stem cells (HSCs) limit the widespread use of HSC-based therapies. Expansion systems for functional heterogenous HSCs remain to be optimized. Here, we present a convenient strategy for human HSC expansion based on a biomimetic Microniche. After demonstrating the expansion of HSC from different sources, we find that our Microniche-based system expands the therapeutically attractive megakaryocyte-biased HSC. We demonstrate scalable HSC expansion by applying this strategy in a stirred bioreactor. Moreover, we identify that the functional human megakaryocyte-biased HSCs are enriched in the CD34+CD38-CD45RA-CD90+CD49f lowCD62L-CD133+ subpopulation. Specifically, the expansion of megakaryocyte-biased HSCs is supported by a biomimetic niche-like microenvironment, which generates a suitable cytokine milieu and supplies the appropriate physical scaffolding. Thus, beyond clarifying the existence and immuno-phenotype of human megakaryocyte-biased HSC, our study demonstrates a flexible human HSC expansion strategy that could help realize the strong clinical promise of HSC-based therapies.

Abstract Background Immunotherapy has revolutionized cancer treatment, but most patients are refractory to immunotherapy or acquire resistance, with the underlying mechanisms remaining to be explored. Methods We characterized the transcriptomes of ~92,000 single cells from 3 pre-treatment and 12 post-treatment patients with non-small cell lung cancer (NSCLC) who received neoadjuvant PD-1 blockade combined with chemotherapy. The 12 post-treatment samples were categorized into two groups based on pathologic response: major pathologic response (MPR; n = 4) and non-MPR (NMPR; n = 8). Results Distinct therapy-induced cancer cell transcriptomes were associated with clinical response. Cancer cells from MPR patients exhibited a signature of activated antigen presentation via major histocompatibility complex class II (MHC-II). Further, the transcriptional signatures of FCRL4+FCRL5+ memory B cells and CD16+CX3CR1+ monocytes were enriched in MPR patients and are predictors of immunotherapy response. Cancer cells from NMPR patients exhibited overexpression of estrogen metabolism enzymes and elevated serum estradiol. In all patients, therapy promoted expansion and activation of cytotoxic T cells and CD16+ NK cells, reduction of immunosuppressive Tregs, and activation of memory CD8+T cells into an effector phenotype. Tissue-resident macrophages were expanded after therapy, and tumor-associated macrophages (TAMs) were remodeled into a neutral instead of an anti-tumor phenotype. We revealed the heterogeneity of neutrophils during immunotherapy and identified an aged CCL3+ neutrophil subset was decreased in MPR patients. The aged CCL3+ neutrophils were predicted to interact with SPP1+ TAMs through a positive feedback loop to contribute to a poor therapy response. Conclusions Neoadjuvant PD-1 blockade combined with chemotherapy led to distinct NSCLC tumor microenvironment transcriptomes that correlated with therapy response. Although limited by a small patient sample size subjected to combination therapy, this study provides novel biomarkers to predict therapy response and suggests potential strategies to overcome immunotherapy resistance.

Radar specific emitter identification (SEI) distinguishes different radar emitters, which is the research hotspot in the fields of electronic countermeasures and intelligence reconnaissance. To enhance the identification accuracy of the real radar SEI system with limited training data, we propose the multi-kernel extreme learning machine-based discriminant auto-encoder (MK-ELM-DAE) method by combining representation learning and multi-kernel fusion in this paper. Firstly, ELM-DAE is applied to each primary feature of radar signals to extract the more discriminative low-dimensional feature representations. With the features extracted by ELM-DAE, the linear discriminant ratio-based two stage multiple kernel ELM algorithm is then employed to conduct the multi-feature fusion. The most important module of MK-ELM-DAE is ELM-DAE, which is an effective supervised dimensionality reduction method for representation learning. ELM-DAE incorporates the label information into ELM auto-encoder by introducing a supersized regularization term, so it is more suitable for classification tasks. Specifically, we use the ambiguity function (AF) to extract primary features, and subsequently design an AF-based MK-ELM-DAE method for radar SEI. Experiments show that our method has significant advantages in accuracy and testing efficiency.

Abstract When simulating the process from elastic–plastic deformation, damage to failure in a metal structure collision, it is necessary to use the large shell element due to the calculation efficiency, but this would affect the accuracy of damage evolution simulation. The compensation algorithm adjusting failure strain according to element size is usually used in the damage model to deal with the problem. In this paper, a new nonlinear compensation algorithm between failure strain and element size was proposed, which was incorporated in the damage model GISSMO (Generalized incremental stress state dependent damage model) to characterize ductile fracture. And associated material parameters were calibrated based on tensile experiments of aluminum alloy specimens with notches. Simulation and experimental results show that the new compensation algorithm significantly reduces the dependence of element size compared with the constant failure strain model and the damage model with the linear compensation algorithm. During the axial splitting process of a circular tubular structure, the new compensation algorithm keeps the failure prediction errors low over the stress states ranging from shear to biaxial tension, and achieves the objective prediction of the damage evolution process. This study demonstrates how the compensation algorithm resolves the contradiction between large element size and fracture prediction accuracy, and this facilitates the use of the damage model in ductile fracture prediction for engineering structures.

Abstract Objectives To investigate whether intravenous thrombolysis (IVT) with alteplase (a recombinant tissue plasminogen activator, rt-PA) before endovascular treatment (EVT) is beneficial for acute ischemic stroke (AIS) patients in different periods. Methods This study enrolled a total of 140 patients hospitalized between 2019 and 2022 with AIS from large vessel occlusion (LVO) in the anterior circulation. Those patients were divided into the EVT alone group and IVT + EVT group, in which EVT was preceded by intravenous rt-PA. According to the time from onset to femoral artery puncture, the above two groups were divided into the following subgroups: 0.05). After adjusting for confounding factors, a lower incidence of intracerebral hemorrhage was observed in the EVT group (P

We study the free vibration of a piezoelectric bi-layered plate composed of a piezoelectric semiconductor (PS) layer and a piezoelectric dielectric (PD) layer. The macroscopic theory of a PS consisting of the conventional theory of piezoelectricity and the drift-diffusion theory of semiconductors is used. The nonlinear equations for drift currents of electrons and holes are linearized for small perturbation of carrier density. The first-order zigzag approximation for in-plane displacements and electric potential through the thickness of each layer is used. Interfacial continuity of the displacement, the transverse shear stress, and the electric potential between the PS layer and the PD layer is ensured, which is very important and also experienced by layered structures. The number of independent unknown variables is reduced from 11 to 5 by using the interfacial continuity and the zero shear stress conditions at the top and bottom surfaces. The governing equation and corresponding boundary condition are derived using Hamilton’s principle. An analytical solution of a simply supported composite plate is obtained. The effects of steady-state electron density, axial force, and the geometric parameters on the vibration frequency and modes are discussed. The obtained results may be useful for further theoretical analysis of PS composites and practical application of piezotronic devices made from PS and PD materials.

Summary: Inadequate remnant volume and regenerative ability of the liver pose life-threatening risks to patients after partial liver transplantation (PLT) or partial hepatectomy (PHx), while few clinical treatments focus on safely accelerating regeneration. Recently, we discovered that supplementing 5-aminolevulinate (5-ALA) improves liver cold adaptation and functional recovery, leading us to uncover a correlation between 5-ALA metabolic activities and post-PLT recovery. In a mouse 2/3 PHx model, 5-ALA supplements enhanced liver regeneration, promoting infiltration and polarization of anti-inflammatory macrophages via P53 signaling. Intriguingly, chemokine receptor CX3CR1 functions to counterbalance these effects. Genetic ablation or pharmacological inhibition of CX3CR1 (AZD8797; phase II trial candidate) augmented the macrophagic production of insulin-like growth factor 1 (IGF-1) and subsequent hepatocyte growth factor (HGF) production by hepatic stellate cells. Thus, short-term treatments with both 5-ALA and AZD8797 demonstrated pro-regeneration outcomes superior to 5-ALA-only treatments in mice after PHx. Overall, our findings may inspire safe and effective strategies to better treat PLT and PHx patients.

Polygonati rhizoma (known as Huangjing in Chinese), an edible medicinal herb with homology of medicine and food, was also commonly used as food additives in Asian countries to provide many health benefits. Currently, the amelioration of fatigue induced by excessive exercise has become a health concern. In the present study, we studied the anti-fatigue effect of P. rhizoma polysaccharides (PRP) and also explored its potential mechanism by gut flora regulation. The molecular weight, monosaccharide composition, morphology, and FT-IR analysis of PRP were performed. Following intragastric administration of PRP, the exhaustive swimming model mice demonstrated increased swimming time, creatine kinase and malondialdehyde level, decreased lactic acid and blood urine nitrogen levels. Furthermore, the abundance of Akkermansia, Lactobacillus, and Faecalibacterium was remarkably enhanced, while the abundance of Streptococcus and Bacteroides was decreased, compared to model group. In summary, our findings offer compelling evidence supporting the beneficial effects of PRP on exercise-induced fatigue.

Arbuscular mycorrhizal fungi (AMF) are important in the phytoremediation of cadmium (Cd). Improving photosynthesis under Cd stress helps to increase crop yields. However, the molecular regulatory mechanisms of AMF on photosynthetic processes in wheat (Triticum aestivum) under Cd stress remain unclear. This study utilized physiological and proteomic analyses to reveal the key processes and related genes of AMF that regulate photosynthesis under Cd stress. The results showed that AMF promoted the accumulation of Cd in the roots of wheat but significantly reduced the content of Cd in the shoots and grains. The photosynthetic rates, stomatal conductance, transpiration rates, chlorophyll content, and accumulation of carbohydrates under Cd stress were increased by AMF symbiosis. Proteomic analysis showed that AMF significantly induced the expression of two enzymes involved in the chlorophyll biosynthetic pathway (coproporphyrinogen oxidase and Mg-protoporphyrin IX chelatase), improved the expression of two proteins related to CO2 assimilation (ribulose-1,5-bisphosphate carboxylase and malic enzyme), and increased the expression of S-adenosylmethionine synthase, which positively regulates abiotic stress. Therefore, AMF may regulate photosynthesis under Cd stress by promoting chlorophyll biosynthesis, carbon assimilation, and S-adenosylmethionine metabolism.

Landslides are major geological hazards and frequently occur in mountainous areas with steep slopes, often causing significant loss. Interferometric Synthetic Aperture Radar (InSAR) has been widely used in landslide measurement over the last three decades. However, InSAR only can measure one-dimensional displacements (i.e. those in the radar’s line of sight (LOS) direction), resulting in the uncertainty between LOS displacement and the real slope displacement. In this paper, based on ascending and descending data from Sentinel-1 satellite, a wide-area potential landslide early identification was carried out using SBAS-InSAR in the whole of Mao County, a mountainous area in western Sichuan (China), with a total of 41 potential landslides successfully detected. Based on the quantitative analysis, the results show that the InSAR LOS measurement values are slope aspect and gradient-dependent. Finally, we innovatively derived a LOS displacement sensitivity map of InSAR in landslide measurement, revealing the relationship between LOS displacement, real displacements on slopes with arbitrary aspects and gradients, and SAR geometric distortion. This is a generalized finding useful for any slopes. It provides theoretical support to acquire and understand the real slope displacement from InSAR landslide measurement, which is vital to assist in correctly interpreting LOS displacement and carrying out subsequent quantitative geological engineering analysis.

Abstract Background This trial aimed to analyse the safety, effectiveness and transcriptomic characteristics of neoadjuvant toripalimab plus chemotherapy in II–III non-small-cell lung cancer (NSCLC). Methods Patient eligibility mainly involved treatment-naive, clinical stage II–III and wild-type EGFR/ALK NSCLC. The patients received 2–4 cycles of toripalimab (240 mg q3w) plus carboplatin-based chemotherapy. After the second treatment cycle, all patients were re-evaluated by a multidisciplinary team. Candidates eligible for surgery underwent surgery; otherwise, patients received the remaining treatment cycles. The primary endpoints were safety and major pathological response (MPR). Secondary endpoints were R0 resection rate, progression-free survival (PFS) and overall survival (OS). RNA sequencing of baseline and post-treatment samples was conducted to explore the transcriptomic characteristics of the therapeutic response. Results In total, 50 eligible patients were enrolled, including 12 (24.0%) with resectable disease (RD) and 38 (76.0%) with potentially resectable disease (PRD). Treatment-related adverse events (TRAEs) were recorded in 48 cases (96.0%). Severe TRAEs occurred in 3 (6.0%) cases, including myelosuppression, drug-induced liver injury and death related to haemoptysis. The objective response rate (ORR) was 76.0%, with 8 (16.0%) patients having a complete response (CR), 30 (60.0%) partial response (PR), 10 (20.0%) stable disease (SD) and 2 (4.0%) progressive disease (PD). Surgery could be achieved in 12 (100%) patients with RD and 25 (65.8%) with PRD; 1 (2.0%) with PRD refused surgery. Therefore, R0 resection was performed for all 36 (100%) patients who underwent surgery; 20 (55.6%) achieved MPR, including 10 (27.8%) with a complete pathological response (pCR). The CHI3L1 (chitinase-3-like protein 1) immunohistochemistry (IHC) expression of baseline tumour samples could predict the therapeutic response (AUC=0.732), OS (P=0.017) and PFS (P=0.001). Increased PD-1 expression, T cell abundance and immune-related pathway enrichment were observed in post-treatment samples compared to baseline in the response group (CR+PR) but not in the non-response group (SD+PD). Conclusions Neoadjuvant toripalimab plus chemotherapy was safe and effective, with a high MPR and manageable TRAEs for II–III NSCLC, even converting initially PRD to RD. Disparate transcriptomic characteristics of therapeutic efficiency were observed, and CHI3L1 expression predicted therapeutic response and survival. Trial registration ChiCTR1900024014, June 22, 2019.

Modeling futures market risk simultaneously influenced by macro low-frequency information and daily risk factors is a valuable challenge. We propose a new general framework for it based on the flexible GARCH-MIDAS model. It uses a skewed t distribution to describe the asymmetry of long and short trading positions, allows for a different number of trading days per month, and can identify the optimal combination of risky factors. We also derive its impact response function on how low-frequency factors directly influence the high-frequency futures market risk. Through an exhaustive empirical analysis of the Chinese soybean futures market, we not only find its excellent out-of-sample market risk forecasting performance but also offer systematic recommendations for improving risk management.

Abstract Background The diversity of histologic composition reflects the inter- and intra-tumor heterogeneity of lung adenocarcinomas (LUADs) macroscopically. Insights into the oncological characteristics and tumor microenvironment (TME) of different histologic subtypes of LUAD at the single-cell level can help identify potential therapeutic vulnerabilities and combinational approaches to improve the survival of LUAD patients. Methods Through comparative profiling of cell communities defined by scRNA-seq data, we characterized the TME of LUAD samples of distinct histologic subtypes, with relevant results further confirmed in multiple bulk transcriptomic, proteomic datasets and an independent immunohistochemical validation cohort. Results We find that the hypoxic and acidic situation is the worst in the TME of solid LUADs compared to other histologic subtypes. Besides, the tumor metabolic preferences vary across histologic subtypes and may correspondingly impinge on the metabolism and function of immune cells. Remarkably, tumor cells from solid LUADs upregulate energy and substance metabolic activities, particularly the folate-mediated one-carbon metabolism and the key gene MTHFD2, which could serve as a potential therapeutic target. Additionally, ubiquitination modifications may also be involved in the progression of histologic patterns. Immunologically, solid LUADs are characterized by a predominance of exhausted T cells and immunosuppressive myeloid cells, where the hypoxic, acidified and nutrient-deprived TME has a non-negligible impact. Discrepancies in stromal cell function, evidenced by varying degrees of stromal remodeling and fibrosis, may also contribute to the specific immune phenotype of solid LUADs. Conclusions Overall, our research proposes several potential entry points to improve the immunosuppressive TME of solid LUADs, thereby synergistically potentiating their immunotherapeutic efficacy, and may provide precise therapeutic strategies for LUAD patients of distinct histologic subtype constitution.

Abstract Background Circulating tumour DNA (ctDNA)-based sequencing might provide a simple test for the stratified model of non-small cell lung cancer (NSCLC). Here, we aimed to assess the ctDNA sequencing-based tumour mutation index (TMI) model for screening responders (from non-responders) among NSCLC patients who received monotherapy with docetaxel or atezolizumab. Methods We performed a retrospective analysis of the POPLAR (NCT01903993) and OAK (NCT02008227) trials. We identified three biomarkers, blood tumour mutation burden (bTMB), sensitive blood tumour mutation burden (sbTMB) and unfavourable mutation score (UMS), of the ctDNA profiles. After integrating the advantages and disadvantages of the three independent biomarkers, we developed the TMI model and identified NSCLC patients who may benefit from monotherapy with docetaxel or atezolizumab in terms of overall survival (OS). Results The TMI model as a stratified biomarker for docetaxel responders provided a median OS duration of 5.55 months longer than non-responders in the OAK cohort, with a significantly decreased hazard ratio (HR). Moreover, atezolizumab responders had a 10.21-month OS advantage over atezolizumab non-responders in the OAK cohort via TMI stratification, and the HR was also decreased significantly. The TMI demonstrated effectiveness for stratifying responders in the POPLAR cohort. Importantly, we found that the TMI model could screen additional responders upon combining the cohorts from the POPLAR and OAK trials after adjustment. Conclusion In the present study, we provide a novel TMI model for screening responders (from non-responders) among NSCLC patients who received the 2nd-line monotherapy with docetaxel or atezolizumab. We believe that the biomarker TMI will potentially be effective for the clinical treatment of NSCLC in the future.

Introduction: The current quality evaluation of traditional Chinese medicine (TCM) is difficult to attribute to clinical efficacy due to the complexity of TCM. Zishen Yutai pill (ZYP), a well-known traditional Chinese patent medicine, has been widely used to prevent recurrent miscarriage and treat threatened abortion. However, the chemical components of ZYP are unknown, and there is no convincing quality control method applied on ZYP. Although ZYP has been found to promote endometrial receptivity and treat impending abortion, the substantial basis of the therapeutic effects is unclear. The aim of this study was to clarify the quality markers correlated with the potential medicinal activities and provide a theoretical foundation for scientific quality control and product quality improvement of ZYP.Methods: The chemical constituents of ZYP were comprehensively analyzed by offline two-dimensional liquid chromatography-mass spectrometry (2DLC-LTQ-Orbitrap-MS). The efficacy of the 27 ZYP orthogonal groups was investigated using the HTR-8/SVneo oxidative damage model and migration model in vitro, as well as the endometrial receptivity disorder mouse model and premature ovarian failure mouse model in vivo. Based on the efficacy and mass spectral results, spectrum–effect relationship analysis was used to identify the chemical components with corresponding pharmacological activities.Results: A total of 589 chemical components were found in ZYP, of which 139 were not identified in the literature. The potential quality markers for ZYP were successfully identified through orthogonal design and spectrum–effect relationship analysis. By combining mass spectrum data and pharmacological results of 27 orthogonal groups, 39 substances were identified as potential quality markers.Conclusion: The approaches used in this study will provide a feasible strategy for the discovery of quality markers with bioactivity and further investigation into the quality evaluation of TCM.

Lasianthus, belonging to Rubiaceae, has been verified to improve clinical syndrome in immune diseases (e.g., hepatitis, nephritis, and rheumatoid arthritis). Both the anti-inflammatory function and chemical composition of Lasianthus vary considerably between different species but few studies focus. So essential it is to explore lasianthus and further search for anti-inflammatory substances. The target of this artical is to analyze the anti-inflammatory activity and chemical composition of lasianthus of different species. And the subsequent active compounds were explored. Primary, the anti-inflammatory activity among seven species of lasianthus (e.g., L. fordii., L. wallichii., L. hookeri C., L. verticillatus., L. sikkimensis., L. appressihirtus., and L. hookeri var) were evaluated by vitro experiments (RAW 264.7 cells). Next, UHPLC/Q-Orbitrap-MS-based metabolomics and the mass defect filter (MDF) algorithm were performed to explore metabolites. In addition, principal component analysis (PCA) was to screen out differential compounds in seven species. Finally, the correlation analysis between activities and composition to rapidly discover the active compounds (compounds were verified pharmacologically). Among the 7 species of lasianthus, the L. fordii. and L. hookeri C indicated the best anti-inflammatory activity. Untargeted metabolomics and MDF show 112 compounds, classified into six dominant types (e.g., flavonoids, phenolic acids, alkaloids, iridoids, coumarins, and anthraquinones). Furthermore, 33 differential metabolites were confirmed by PCA. Then according to correlation analysis and pharmacological validation, 7 compounds IC50＜100 (e.g., scopoletin, asperulosidic acid, chlorogenic acid, ferulic acid, betaine, syringic acid, and emodin) were verified as anti-inflammatory compounds and conduct quantitative analysis. Metabolomics integrated with activities evaluation might be a rapid and effective strategy to explore the active compounds from natural products.

Uncovering the mechanism underlying the pathogenesis of Edwardsiella piscicida-induced enteritis is essential for global aquaculture. In the present study, we identified E. piscicida as a lethal pathogen of the big-belly seahorse (Hippocampus abdominalis) and revealed its pathogenic pattern and characteristics by updating our established bacterial enteritis model and evaluation system. Conjoint analysis of metagenomic and metabolomic data showed that 15 core virulence factors could mutually coordinate the remodeling of intestinal microorganisms and host metabolism and induce enteritis in the big-belly seahorse. Specifically, the Flagella, Type IV pili, and Lap could significantly increase the activities of the representative functional pathways of both flagella assembly and bacterial chemotaxis in the intestinal microbiota (P < 0.01) to promote pathogen motility, adherence, and invasion. Legiobactin, IraAB, and Hpt could increase ABC transporter activity (P < 0.01) to compete for host nutrition and promote self-replication. Capsule1, HP-NAP, and FarAB could help the pathogen to avoid phagocytosis. Upon entering epithelial cells and phagocytes, Bsa T3SS and Dot/Icm could significantly increase bacterial secretion system activity (P < 0.01) to promote the intracellular survival and replication of the pathogen and the subsequent invasion of the neighboring tissues. Finally, LPS3 could significantly increase lipopolysaccharide biosynthesis (P < 0.01) to release toxins and kill the host. Throughout the pathogenic process, BopD, PhoP, and BfmRS significantly activated the two-component system (P < 0.01) to coordinate with other VFs to promote deep invasion. In addition, the levels of seven key metabolic biomarkers, Taurine, L-Proline, Uridine, L-Glutamate, Glutathione, Xanthosine, and L-Malic acid, significantly decreased (P < 0.01), and they can be used for characterizing E. piscicida infection. Overall, the present study systematically revealed how a combination of virulence factors mediate E. piscicida-induced enteritis in fish for the first time, providing a theoretical reference for preventing and controlling this disease in the aquaculture of seahorses and other fishes.

High spatial–temporal resolution surface net radiation (RN) data are of great significance to the study of climate, ecology, hydrology and cryosphere changes on the Tibetan Plateau (TP), but the verification of the surface net radiation products on the plateau is not sufficient. In this study, the China Meteorological Administration Global Land Surface Reanalysis Products (CRA/Land) and ECMWF Land Surface Reanalysis version 5 (ERA5-Land) RN data were validated using ground measurements at daily and monthly time scales, and the spatiotemporal patterns were also analyzed. The results indicate the following: (1) CRA/Land overestimated while ERA5-Land underestimated RN, but CRA/Land RN outperformed ERA5-Land in observations at the daily and monthly scale. (2) The CRA/Land RN data had a larger error in the central part and a smaller error in the northeast of the TP, while ERA5-Land showed the opposite. (3) The spatial patterns of RN revealed by CRA/Land and ERA5-Land data showed differences in most regions. The CRA/Land data showed that the RN of the TP had a downward trend during 2000 and 2020 with a slope of −0.112 W·m−2/a, while the ERA5-Land data indicated an upward trend with a change rate of 0.016 W·m−2/a. (4) Downwelling shortwave radiation (DSR), upwelling shortwave radiation (USR), downwelling longwave radiation (DLR) and upwelling longwave radiation (ULR) are the four components of RN, and the evaluation results indicate that the DSR, DLR and ULR recorded via CRA/Land and ERA5-Land are consistent with the observed data, but the consistency between the USR recorded via CRA/Land and ERA5-Land and the observed data is poor. (5) The inconsistency of the USR data is the main reason for the large differences in the spatiotemporal distribution of CRA/Land and ERA5-Land RN data across the TP.