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The study of mechanical properties and failure mechanism of propellants under impact loads is crucial for analyzing structural integrity of propellant charges. An experimental investigation was conducted on NEPE propellant using a separated Hopkinson pressure bar to conduct high strain rate uniaxial impact tests. Deformation and failure processes of the propellant under impact conditions were recorded with a high-speed camera. The microscopic failure forms of the propellants were observed using a scanning electron microscope and an optical microscope. Stress-strain curves and high-speed images revealed that the damage behavior and failure mechanism of NEPE propellants are significantly influenced by strain rate. As the strain rate increases, there is a notable increase in the deformation degree of the propellant specimens, with a more pronounced shear effect. This leads to an earlier occurrence of failure and a more severe degree of failure. The predominant failure forms observed in NEPE propellants include transgranular failure, matrix tearing, and cavity merging. A nonlinear visco-hyperelastic constitutive model with damage at high strain rates was established to provide a precise account of the mechanical response of NEPE propellant under high strain rates., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Ion-conducting polymer membranes are essential in many separation processes and electrochemical devices, including electrodialysis 1 , redox flow batteries 2 , fuel cells 3 and electrolysers 4,5 . Controlling ion transport and selectivity in these membranes largely hinges on the manipulation of pore size. Although membrane pore structures can be designed in the dry state 6 , they are redefined upon hydration owing to swelling in electrolyte solutions. Strategies to control pore hydration and a deeper understanding of pore structure evolution are vital for accurate pore size tuning. Here we report polymer membranes containing pendant groups of varying hydrophobicity, strategically positioned near charged groups to regulate their hydration capacity and pore swelling. Modulation of the hydrated micropore size (less than two nanometres) enables direct control over water and ion transport across broad length scales, as quantified by spectroscopic and computational methods. Ion selectivity improves in hydration-restrained pores created by more hydrophobic pendant groups. These highly interconnected ion transport channels, with tuned pore gate sizes, show higher ionic conductivity and orders-of-magnitude lower permeation rates of redox-active species compared with conventional membranes, enabling stable cycling of energy-dense aqueous organic redox flow batteries. This pore size tailoring approach provides a promising avenue to membranes with precisely controlled ionic and molecular transport functions., Competing Interests: Competing interests A.W. and Q.S. are inventors on UK patent application no. PCT/EP2024/075338 submitted by Imperial College London, which covers the cPIM polymers and aspects of their use., (© 2024. The Author(s).)

The coal-gangue recognition technology plays an important role in the intelligent realization of fully mechanized caving face and the improvement of coal quality. Although great progress has been made for the coal-gangue recognition in recent years, most of them have not taken into account the impact of the complex environment of top coal caving on recognition performance. Herein, a hybrid multi-branch convolutional neural network (HMBCNN) is proposed for coal-gangue recognition, which based on improved Mel Frequency Cepstral Coefficient (MFCC) as well as Mel spectrogram, and attention mechanism. Firstly, the MFCC and its smooth feature matrix are input into each branch of one-dimensional multi-branch convolutional neural network, and the spliced features are extracted adaptively through multi-head attention mechanism. Secondly, the Mel spectrogram and its first-order derivative are input into each branch of the two-dimensional multi-branch convolutional neural network respectively, and the effective time-frequency information is paid attention to through the soft attention mechanism. Finally, at the decision-making level, the two networks are fused to establish a model for feature fusion and classification, obtaining optimal fusion strategies for different features and networks. A database of sound pressure signals under different signal-to-noise ratios and equipment operations is constructed based on a large amount of data collected in the laboratory and on-site. Comparative experiments and discussions are conducted on this database with advanced algorithms and different neural network structures. The results show that the proposed method achieves higher recognition accuracy and better robustness in noisy environments., (© 2024. The Author(s).)

Transformer-based methods effectively capture global dependencies in images, demonstrating outstanding performance in multiple visual tasks. However, existing Transformers cannot effectively denoise large noisy images captured under low-light conditions owing to (1) the global self-attention mechanism causing high computational complexity in the spatial dimension owing to a quadratic increase in computation with the number of tokens; (2) the channel-wise self-attention computation unable to optimise the spatial correlations in images. We propose a local-global interaction Transformer (LGIT) that employs an adaptive strategy to select relevant patches for global interaction, achieving low computational complexity in global self-attention computation. A top-N patch cross-attention model (TPCA) is designed based on superpixel segmentation guidance. TPCA selects top-N patches most similar to the target image patch and applies cross attention to aggregate information from them into the target patch, effectively enhancing the utilisation of the image's nonlocal self-similarity. A mixed-scale dual-gated feedforward network (MDGFF) is introduced for the effective extraction of multiscale local correlations. TPCA and MDGFF were combined to construct a hierarchical encoder-decoder network, LGIT, to compute self-attention within and across patches at different scales. Extensive experiments using real-world image-denoising datasets demonstrated that LGIT outperformed state-of-the-art (SOTA) convolutional neural network (CNN) and Transformer-based methods in qualitative and quantitative results., (© 2024. The Author(s).)

The aim of this study was to investigate the effect of zoledronic acid (ZA) on postoperative healing and functional rehabilitation in osteoporotic patients with rotator cuff (RC) injury. 96 Patients were divided into three groups according to bone mineral density and ZA use (Group A: normal BMD; Group B: osteoporosis and intravenous ZA use; Group C: osteoporosis, without ZA use). Radiologic, functional and Serological outcomes were evaluated 6 months after surgery. The functional scores in all groups exhibited significant improvement 6 months after surgery. Inter-group comparison showed that Constant Shoulder joint function Score (CSS) of group A not significantly differing from that of group B, the other indicators were significantly better than those of group B and C. There were no significant differences in shoulder forward flexion, abductive Range of Motion between group B and C. Other indicators of group B were significantly improved compared to group C. The retear rate in group C (30.3%, 10/33) was higher than group A (6.1%, 2/33) and group B (13.3%, 4/30). In conclusion, the application of ZA can significantly reduce the rate of RC retear in elderly patients with osteoporosis after surgery, which is significant for postoperative shoulder joint functional rehabilitation., (© 2024. The Author(s).)

Idiopathic orbital inflammation, formerly known as NSOI (nonspecific orbital inflammation), is characterized as a spectrum disorder distinguished by the polymorphic infiltration of lymphoid tissue, presenting a complex and poorly understood etiology. Recent advancements have shed light on the HLF (Human lactoferrin), proposing its critical involvement in the regulation of hematopoiesis and the maintenance of innate mucosal immunity. This revelation has generated significant interest in exploring HLF's utility as a biomarker for NSOI, despite the existing gaps in our understanding of its biosynthetic pathways and operational mechanisms. Intersecting multi-omic datasets-specifically, common differentially expressed genes between GSE58331 and GSE105149 from the Gene Expression Omnibus and immune-related gene compendiums from the ImmPort database-we employed sophisticated analytical methodologies, including Lasso regression and support vector machine-recursive feature elimination, to identify HLF. Gene set enrichment analysis and gene set variation analysis disclosed significant immune pathway enrichment within gene sets linked to HLF. The intricate relationship between HLF expression and immunological processes was further dissected through the utilization of CIBERSORT and ESTIMATE algorithms, which assess characteristics of the immune microenvironment, highlighting a noteworthy association between increased HLF expression and enhanced immune cell infiltration. The expression levels of HLF were corroborated using data from the GSE58331 dataset, reinforcing the validity of our findings. Analysis of 218 HLF-related differentially expressed genes revealed statistically significant discrepancies. Fifteen hub genes were distilled using LASSO and SVM-RFE algorithms. Biological functions connected with HLF, such as leukocyte migration, ossification, and the negative regulation of immune processes, were illuminated. Immune cell analysis depicted a positive correlation between HLF and various cells, including resting mast cells, activated NK cells, plasma cells, and CD8 T cells. Conversely, a negative association was observed with gamma delta T cells, naive B cells, M0 and M1 macrophages, and activated mast cells. Diagnostic assessments of HLF in distinguishing NSOI showed promising accuracy. Our investigation delineates HLF as intricately associated with NSOI, casting light on novel biomarkers for diagnosis and progression monitoring of this perplexing condition., (© 2024. The Author(s).)

This study investigates the processing methods of artistic images within the context of Smart city (SC) initiatives, focusing on the visual healing effects of artistic image processing to enhance urban residents' mental health and quality of life. Firstly, it examines the role of artistic image processing techniques in visual healing. Secondly, deep learning technology is introduced and improved, proposing the overlapping segmentation vision transformer (OSViT) for image blocks, and further integrating the bidirectional long short-term memory (BiLSTM) algorithm. An innovative artistic image processing and classification recognition model based on OSViT-BiLSTM is then constructed. Finally, the visual healing effect of the processed art images in different scenes is analyzed. The results demonstrate that the proposed model achieves a classification recognition accuracy of 92.9% for art images, which is at least 6.9% higher than that of other existing model algorithms. Additionally, over 90% of users report satisfaction with the visual healing effects of the artistic images. Therefore, it is found that the proposed model can accurately identify artistic images, enhance their beauty and artistry, and improve the visual healing effect. This study provides an experimental reference for incorporating visual healing into SC initiatives., (© 2024. The Author(s).)

Non-small cell lung cancer (NSCLC) is a common malignancy whose prognosis and treatment outcome are influenced by many factors. Some studies have found that tertiary lymphoid structures (TLSs) in cancer may contribute to prognosis and the prediction of immunotherapy efficacy However, the combined role of TLSs in NSCLC remains unclear. We accessed The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to obtain mRNA sequencing data and clinical information as the TCGA cohort, and used our own sample of 53 advanced NSCLC as a study cohort. The samples were divided into TLS+ and TLS- groups by pathological tissue sections. Patients of the TLS+ group had a better OS (p = 0.022), PFS (p = 0.042), and DSS (p = 0.004) in the TCGA cohort, and the results were confirmed by the study cohort (PFS, p = 0.012). Furthermore, our result showed that the count and size of TLSs are closely associated with the efficacy of immunotherapy. In addition, the TLS+ group was associated with better immune status and lower tumor mutation load. In the tumor microenvironment (TME), the expression levels of CD4+ T cells and CD8+ T cells of different phenotypes were associated with TLSs. Overall, TLSs are a strong predictor of survival and immunotherapeutic efficacy in advanced NSCLC, and T cell-rich TLSs suggest a more ordered and active immune response site, which aids in the decision-making and application of immunotherapy in the clinic., (© 2024. The Author(s).)

Patient portal messages often relate to specific clinical phenomena (e.g., patients undergoing treatment for breast cancer) and, as a result, have received increasing attention in biomedical research. These messages require natural language processing and, while word embedding models, such as word2vec, have the potential to extract meaningful signals from text, they are not readily applicable to patient portal messages. This is because embedding models typically require millions of training samples to sufficiently represent semantics, while the volume of patient portal messages associated with a particular clinical phenomenon is often relatively small. We introduce a novel adaptation of the word2vec model, PK-word2vec (where PK stands for prior knowledge), for small-scale messages. PK-word2vec incorporates the most similar terms for medical words (including problems, treatments, and tests) and non-medical words from two pre-trained embedding models as prior knowledge to improve the training process. We applied PK-word2vec in a case study of patient portal messages in the Vanderbilt University Medical Center electric health record system sent by patients diagnosed with breast cancer from December 2004 to November 2017. We evaluated the model through a set of 1000 tasks, each of which compared the relevance of a given word to a group of the five most similar words generated by PK-word2vec and a group of the five most similar words generated by the standard word2vec model. We recruited 200 Amazon Mechanical Turk (AMT) workers and 7 medical students to perform the tasks. The dataset was composed of 1389 patient records and included 137,554 messages with 10,683 unique words. Prior knowledge was available for 7981 non-medical and 1116 medical words. In over 90% of the tasks, both reviewers indicated PK-word2vec generated more similar words than standard word2vec (p = 0.01).The difference in the evaluation by AMT workers versus medical students was negligible for all comparisons of tasks' choices between the two groups of reviewers ( p = 0.774 under a paired t-test). PK-word2vec can effectively learn word representations from a small message corpus, marking a significant advancement in processing patient portal messages., (© 2024. The Author(s).)

High medication burden is associated with poor treatment effect and high risk of cardiovascular outcomes. This study aimed to investigate the association between the antihypertensive medication burden and cardiovascular outcomes in the STEP trial. This post-hoc analysis of the STEP trial enrolled 8511 participants, including 8041 with low burden and 470 with high burden. High antihypertensive medication burden was defined as being treated with ≥3 different classes of prescribed antihypertensive medications. The primary outcome was a composite of cardiovascular outcomes. Fine-Gray model was used in this study. Among all participants, high antihypertensive medication burden was associated with a higher risk of the primary outcome compared with low medication burden (HR, 1.52; 95% CI, 1.03-2.24), which was consistent in the standard group (HR, 1.95; 95% CI, 1.20-3.18) and the intensive group (HR, 1.10; 95% CI, 0.57-2.13; P interaction  = 0.18). The beneficial effects of intensive systolic blood pressure (SBP) control on the primary outcome remained significant in the high burden group (HR, 0.42; 95% CI, 0.19-0.95) and the low burden group (HR, 0.79; 95% CI, 0.63-0.98; P interaction  = 0.18). At 24 months, the percentage of participants achieving the target SBP was lower in the high medication burden group (risk ratio, 0.93; 95% CI, 0.89-0.98). In both standard and intensive treatment groups, participants with a high medication burden were harder to achieve the target SBP (P interaction  = 0.65). High antihypertensive medication burden was associated with worse SBP control and a greater risk of cardiovascular events. Intensive SBP control showed cardiovascular benefits in both medication burden groups. Trial registration: STEP ClinicalTrials.gov number, NCT03015311. Registered 2 January 2017., (© 2024. The Author(s).)

Code search aims to search for code snippets from large codebase that are semantically related to natural query statements. Deep learning is a valuable method for solving code search tasks in which the quality of training data directly impacts the performance of deep-learning models. However, most existing deep-learning models for code search research have overlooked the critical role of training data within batches, particularly hard negative samples, in optimizing model parameters. In this paper, we propose contrastive-metric learning CMCS for code search based on vector-level sampling and augmentation. Specifically, we propose a sampling method to obtain hard negative samples based on the K-means algorithm and a hardness-controllable sample augmentation method to obtain positive and hard negative samples based on vector-level augmentation techniques. We then design an optimization objective composed of metric learning and multimodal contrastive learning using obtained positive and hard negative samples. Extensive experiments were conducted on the large-scale dataset CodeSearchNet using seven advanced code search models. The results show that our proposed method significantly enhances the training efficiency and search performance of code search models, which is conducive to promoting software engineering development., (© 2024. The Author(s).)

The current research on the relationship between 24-h central pressure and 24-h brachial pressure with left ventricular hypertrophy (LVH) is characterised by limited sample size and inconsistent findings. Furthermore, the association has never been explored in chronic kidney disease (CKD). A multicentre, cross-sectional study among non-dialysis patients with CKD was conducted. All participants underwent brachial and central ambulatory blood pressure monitoring using MobilO-Graph PWA, while trained cardiologists performed echocardiography. In this study, 2117 non-dialysis patients with CKD were examined. 24-h central systolic blood pressure with c2 calibration (24-h c2SBP) demonstrated a stronger association with left ventricular mass index and LVH compared with 24-h brachial systolic blood pressure (24-h bSBP) in the univariate and multivariate regression analyses. The multivariate net reclassification index (NRI) analysis revealed that 24-h c2SBP exhibited greater discriminatory power over 24-h bSBP (NRI = 0.310, 95% CI [0.192-0.429], P < 0.001). Applying 130/135 mmHg as the threshold for 24-h bSBP/c2SBP to cross-classify, the patients were divided into concordant normotension (1509 individuals), isolated brachial hypertension (155 individuals), isolated central hypertension (11 individuals), and concordant hypertension (442 individuals). With concordant normotension as the reference, the multivariable-adjusted ORs were 0.954 (95% CI, 0.534-1.640; P = 0.870) for isolated brachial hypertension and 2.585 (95%CI, 1.841-3.633; P < 0.001) for concordant hypertension. Among non-dialysis patients with CKD, 24-h c2SBP exhibits greater efficacy in identifying the presence of LVH compared with 24-h bSBP. The presence of LVH was greater in cases of concordant hypertension compared with cases of isolated brachial hypertension and concordant normotension., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

This study aimed to develop an optimal radiomics model for preoperatively predicting microsatellite instability (MSI) in patients with rectal cancer (RC) based on multiparametric magnetic resonance imaging. The retrospective study included 308 RC patients who did not receive preoperative antitumor therapy, among whom 51 had MSI. Radiomics features were extracted and dimensionally reduced from T2-weighted imaging (T2WI), T1-weighted imaging (T1WI), diffusion-weighted imaging (DWI), and T1-weighted contrast enhanced (T1CE) images for each patient, and the features of each sequence were combined. Multifactor logistic regression was used to screen the optimal feature set for each combination. Different machine learning methods were applied to construct predictive MSI status models. Relative standard deviation values were determined to evaluate model performance and select the optimal model. Receiver operating characteristic (ROC) curve, calibration curve, and decision curve analyses were performed to evaluate model performance. The model constructed using the k-nearest neighbor (KNN) method combined with T2WI and T1CE images performed best. The area under the curve values for prediction of MSI with this model were 0.849 (0.804-0.887), with a sensitivity of 0.784 and specificity of 0.805. The Delong test showed no significant difference in diagnostic efficacy between the KNN-derived model and the traditional logistic regression model constructed using T1WI + DWI + T1CE and T2WI + T1WI + DWI + T1CE data (P > 0.05) and the diagnostic efficiency of the KNN-derived model was slightly better than that of the traditional model. From ROC curve analysis, the KNN-derived model significantly distinguished patients at low- and high-risk of MSI with the optimal threshold of 0.2, supporting the clinical applicability of the model. The model constructed using the KNN method can be applied to noninvasively predict MSI status in RC patients before surgery based on radiomics features from T2WI and T1CE images. Thus, this method may provide a convenient and practical tool for formulating treatment strategies and optimizing individual clinical decision-making for patients with RC., (© 2024. The Author(s).)

Pancreatic intraepithelial neoplasias (PanINs) are the most common precursors of pancreatic cancer, but their small size and inaccessibility in humans make them challenging to study 1 . Critically, the number, dimensions and connectivity of human PanINs remain largely unknown, precluding important insights into early cancer development. Here, we provide a microanatomical survey of human PanINs by analysing 46 large samples of grossly normal human pancreas with a machine-learning pipeline for quantitative 3D histological reconstruction at single-cell resolution. To elucidate genetic relationships between and within PanINs, we developed a workflow in which 3D modelling guides multi-region microdissection and targeted and whole-exome sequencing. From these samples, we calculated a mean burden of 13 PanINs per cm 3 and extrapolated that the normal intact adult pancreas harbours hundreds of PanINs, almost all with oncogenic KRAS hotspot mutations. We found that most PanINs originate as independent clones with distinct somatic mutation profiles. Some spatially continuous PanINs were found to contain multiple KRAS mutations; computational and in situ analyses demonstrated that different KRAS mutations localize to distinct cell subpopulations within these neoplasms, indicating their polyclonal origins. The extensive multifocality and genetic heterogeneity of PanINs raises important questions about mechanisms that drive precancer initiation and confer differential progression risk in the human pancreas. This detailed 3D genomic mapping of molecular alterations in human PanINs provides an empirical foundation for early detection and rational interception of pancreatic cancer., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Diverse development paths among cities within an urban agglomeration can lead to uneven changes in their agricultural production scale, which reshape the inter-city food supply patterns and the spatiotemporal characteristics of nitrogen (N) pollution from the food system. Here, using Guangdong-Hong Kong-Macao Greater Bay Area of China as a case, we found a substantial decrease in N use efficiency of crop production from 45.2% to 29.3% during 1989-2007, along with a growing level of concentration of food N production in less-urbanized cities. From 1989 to 2018, 12.3% to 42.2% of total N pollution in food production became embedded in inter-city trade, leading to aggregation of N pollution in peripheral cities with relatively low levels of economic development. We suggest that protection and intensification of cropland from urban encroachment, as well as enhancing the economic and technical synergies among cities, can serve the sustainable transition of the food system with coordinated N pollution mitigation., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The Tetraspanins (Tspan) protein family, also known as the tetraspanin family, contains 33 family members that interact with other protein molecules such as integrins, adhesion molecules, and T cell receptors by forming dimers or heterodimers. The Tspan protein family regulates cell proliferation, cell cycle, invasion, migration, apoptosis, autophagy, tissue differentiation, and immune response. More and more studies have shown that Tspan proteins are involved in tumorigenesis, epithelial-mesenchymal transition, thrombosis, tumor stem cell, and exosome signaling. Some drugs and microRNAs can inhibit Tspan proteins, thus providing new strategies for tumor therapy. An in-depth understanding of the functions and regulatory mechanisms of the Tspan protein family, which can promote or inhibit tumor development, will provide new strategies for targeted interventions in the future., (© 2024. The Author(s).)

The survival significance of the number of positive lymph nodes in salivary gland carcinoma remains unclear. Thus, the current study aimed to determine the effect of the number of positive lymph nodes on disease-specific survival (DSS) and overall survival (OS) in cN0 mucoepidermoid carcinoma (MEC) of the major salivary gland. Patients surgically treated for MEC of the major salivary gland between 1975 and 2019 were retrospectively enrolled from the surveillance, epidemiology, and end results database. The total population was randomly divided into training and test groups (1:1). Primary outcome variables were DSS and OS. Prognostic models were constructed based on the independent prognostic factors determined using univariate and multivariate Cox analyses in the training group and were validated in the test group using C-index. A total of 3317 patients (1624 men and 1693 women) with a mean age of 55 ± 20 years were included. The number of positive lymph nodes was an independent prognostic factor for both DSS and OS, but the effect began when at least two positive lymph nodes for DSS and three positive lymph nodes for OS were found. Predictive models for DSS and OS in the training group had C-indexes of 0.873 (95% confidence interval [CI] 0.853-0.893) and 0.835 (95% CI 0.817-0.853), respectively. The validation of the test group showed C-indexes of 0.877 (95% CI 0.851-0.902) for DSS and 0.820 (95% CI 0.798-0.842) for OS. The number of positive lymph nodes was statistically associated with survival in cN0 major salivary gland MEC. The current prognostic model could provide individualized follow-up strategies for patients with high reliability., (© 2024. The Author(s).)

The central mechanisms underlying pain chronicity remain elusive. Here, we identify a reciprocal neuronal circuit in mice between the anterior cingulate cortex (ACC) and the ventral tegmental area (VTA) that mediates mutual exacerbation between hyperalgesia and allodynia and their emotional consequences and, thereby, the chronicity of neuropathic pain. ACC glutamatergic neurons (ACC Glu ) projecting to the VTA indirectly inhibit dopaminergic neurons (VTA DA ) by activating local GABAergic interneurons (VTA GABA ), and this effect is reinforced after nerve injury. VTA DA neurons in turn project to the ACC and synapse to the initial ACC Glu neurons to convey feedback information from emotional changes. Thus, an ACC Glu -VTA GABA -VTA DA -ACC Glu positive-feedback loop mediates the progression to and maintenance of persistent pain and comorbid anxiodepressive-like behavior. Disruption of this feedback loop relieves hyperalgesia and anxiodepressive-like behavior in a mouse model of neuropathic pain, both acutely and in the long term., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Implantation of the human embryo begins a critical developmental stage that comprises profound events including axis formation, gastrulation and the emergence of haematopoietic system 1,2 . Our mechanistic knowledge of this window of human life remains limited due to restricted access to in vivo samples for both technical and ethical reasons 3-5 . Stem cell models of human embryo have emerged to help unlock the mysteries of this stage 6-16 . Here we present a genetically inducible stem cell-derived embryoid model of early post-implantation human embryogenesis that captures the reciprocal codevelopment of embryonic tissue and the extra-embryonic endoderm and mesoderm niche with early haematopoiesis. This model is produced from induced pluripotent stem cells and shows unanticipated self-organizing cellular programmes similar to those that occur in embryogenesis, including the formation of amniotic cavity and bilaminar disc morphologies as well as the generation of an anterior hypoblast pole and posterior domain. The extra-embryonic layer in these embryoids lacks trophoblast and shows advanced multilineage yolk sac tissue-like morphogenesis that harbours a process similar to distinct waves of haematopoiesis, including the emergence of erythroid-, megakaryocyte-, myeloid- and lymphoid-like cells. This model presents an easy-to-use, high-throughput, reproducible and scalable platform to probe multifaceted aspects of human development and blood formation at the early post-implantation stage. It will provide a tractable human-based model for drug testing and disease modelling., (© 2023. The Author(s).)

We conducted a retrospective study to evaluate the efficacy of immune checkpoint inhibitor (ICI) rechallenge in patients with advanced non-small cell lung cancer (NSCLC). The study included 111 patients who had previously received ICI therapy and experienced disease progression. The primary endpoints assessed were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Our findings revealed that the ICI rechallenge showed promising results in improving patient outcomes. OS (r) is the time from rechallenging with immune checkpoint inhibitors to the last follow-up or death from any cause. The median OS (r) was 14.3 months (95% CI 11.3-17.3 months), with a median PFS (r) of 5.9 months (95% CI 4.1-7.7 months). The ORR was 17.1%; the DCR was 82.3%. Subgroup analysis demonstrated that patients without brain or liver metastases had a longer OS (r) compared to those with metastases (21.6 vs. 13.8 months, χ 2  = 3.873, P = 0.046; 20.8 vs. 9.1 months, χ 2  = 10.733, P = 0.001, respectively). Moreover, patients without driver gene mutations exhibited significantly longer OS than those with mutations or wild-type patients (22.9 vs. 16.1 vs. 7.5 months, χ 2  = 10.710, P = 0.005). Notably, patients who switched to a different ICI during the rechallenge had shorter OS than those who did not change medications (10.4 vs. 21.1 months, χ 2  = 9.014, P = 0.003). The incidence of immune-related adverse events did not significantly differ between the two treatment phases. These findings suggest that ICI rechallenge may be a viable therapeutic strategy for select NSCLC patients. Further prospective studies are needed to validate these results and guide treatment decisions for advanced NSCLC., (© 2024. The Author(s).)

Histone deacetylases (HDACs) are involved in tumorigenesis and progression, however, their role in diffuse large B-cell lymphoma (DLBCL) is not well understood. In this study, we examined the expression levels, mutations, and clinical significance of HDACs in DLBCL. Additionally, we investigated the therapeutic potential of Chidamide, a novel HDAC inhibitor, to provide scientific evidence for targeting HDACs in DLBCL patients. We extracted transcriptome data of DLBCLs--including 47 lymph node samples and 337 whole-blood-cell controls--from The Cancer Genome Atlas. Bioinformatic analyses of HDAC expression, mutation, and correlation with the clinical significance of DLBCL patients were performed with the Gene Expression Profiling Interactive Analysis, GENEMANIA, and web-based software including cBioPortal and WebGestalt. To examine the therapeutic effect of Chidamide, DLBCL cell lines (WSU-DLCL-2 and DB cells) were employed. Cell proliferation and apoptosis were analyzed with Cell Counting Kit-8 and flow cytometry assays. The impact of Chidamide treatment was also analyzed by RNA sequencing of treated DB cells. Western blot was used to explore the molecular mechanism of the cytotoxicity of Chidamide on DLBCL cell lines. The expression of some HDACs (HDAC1, 2, 3, 4, 6, 7, 8, and 9) were significantly higher in the lymph node samples of DLBCL than that in whole-blood-cell controls. Moreover, we found that the mutation rate of HDACs was also higher in DLBCL tissues, although the overall survival of DLBCL patients was not associated with HDAC expression. Chidamide was found to have a cytotoxic effect on DLBCL cells in a dose-dependent manner, while transcriptome analysis and western blot revealed that using it for treatment impacted several biological processes, including PI3K/AKT signaling, mTOR signaling, the cell cycle, and apoptosis pathways. Alterations of HDAC genes, including enhanced expression and mutations, are positively related to DLBCL. Targeting HDACs with specific inhibitors such as Chidamide may represent a potential therapeutic approach for DLBCL patients., (© 2024. The Author(s).)

Microstructural abnormalities of white matter fiber tracts are considered as one of the etiology of diabetes-induced neurological disorders. We explored the cerebral white matter microstructure alteration accurately, and to analyze its correlation between cerebral small vessel disease (CSVD) burden and cognitive performance in type 2 diabetes mellitus (T2DM). The clinical-laboratory data, cognitive scores [including mini-mental state examination (MMSE), Montreal cognitive assessment (MoCA), California verbal learning test (CVLT), and symbol digit modalities test (SDMT)], CSVD burden scores of the T2DM group (n = 34) and healthy control (HC) group (n = 21) were collected prospectively. Automatic fiber quantification (AFQ) was applied to generate bundle profiles along primary white matter fiber tracts. Diffusion tensor images (DTI) metrics and 100 nodes of white matter fiber tracts between groups were compared. Multiple regression analysis was used to analyze the relationship between DTI metrics and cognitive scores and CSVD burden scores. For fiber-wise and node-wise, DTI metrics in some commissural and association fibers were increased in T2DM. Some white matter fiber tracts DTI metrics were independent predictors of cognitive scores and CSVD burden scores. White matter fiber tracts damage in patients with T2DM may be characterized in specific location, especially commissural and association fibers. Aberrational specific white matter fiber tracts are associated with visuospatial function and CSVD burden., (© 2024. The Author(s).)

Uniaxial compression experiments of limestone-coal specimens at different inclination angles (0, 15, 30, 45, and 60°) were conducted using acoustic emission and three-dimensional, extension test digital image correlation, and full-field strain measurement systems to examine how dip angles affect deformation failure. The findings indicate that: (1) specimen groups demonstrate plastic yield characteristics in the pre-peak stage. However, slight variations exist due to inclination angles. (2) The localization zone for deformation evolution closely correlates to primary crack initiation and propagation within coal specimens and to slipping at the rock's and coal's interface. Failure in the coal specimen triggers rebound deformation in limestone when the rock coal inclination angle is set at 15°. Both the rebound deformation amount and its rate exhibit upward trends as a function of the inclination angle. (3) The percentage of pre-peak elastic property density in the combined specimen is augmented from 98.56 to 88.08% as the inclination angle augments and reduces to 75.80%. External energy's conversion into missile performance shows an initial increase followed by a decrease. (4) The energy rate of the acoustic emission (AE) signal exhibits distinct temporal characteristics in the combined specimen that can be associated with quiet, active, and sudden increases., (© 2023. The Author(s).)

Tumor-associated high endothelial venules (TA-HEVs) mediate lymphocyte entry into tumors. Therefore, combined anti-angiogenesis therapy and programmed death-1 (PD-1) inhibitors might stimulate tumor immunity. This study will explore the TA-HEVs and real-world data of the combination therapy in non-small cell lung cancer (NSCLC). Firstly, we found a certain relationship between HEVs and immune effector cells by multiple immunofluorescence staining. We then analyzed the efficacy of immunotherapy combined with anti-angiogenesis therapy in advanced NSCLC patients by collecting real-world clinical data. Finally, we explored the predictive value of HEVs in combination therapy by analyzing pre-treatment pathological slides of patients with multiple immunofluorescence and RNA sequencing. Immunofluorescence staining of high endothelial venules (PNAd+) reveals that the frequency of HEVs is positively correlated with tumor-infiltrating stem-like CD8+ T cells (TCF-1+PD-1+) in the TME of advanced NSCLC patients (P = 0.0221). We retrospectively analyzed the efficacy of 96 patients with advanced NSCLC who received PD-1 inhibitors combined with anti-angiogenesis therapy in the real-world. The median PFS of patients combined with anti-angiogenesis therapy was longer than that of patients without anti-angiogenesis therapy (9.7 vs 8.6 months, P = 0.041). Multiple immunofluorescence staining of tumor biopsies before treatment from 14 patients with advanced NSCLC reveals that PNAd+ is predictive of better response and survival upon PD-1 inhibitors combined with anti-angiogenesis therapy (P = 0.0274). In addition, we collected peripheral blood from an effective group of patients for RNA sequencing and found that immune cells activation-related gene expression scores were higher. Combined anti-angiogenic and anti-PD-1 therapy stimulates tumor immunity through TA-HEVs formation. TA-HEVs not only mediate immune cell entry into tumors, but also are associated with the efficacy of PD-1 inhibitors and anti-angiogenesis therapy in NSCLC., (© 2023. Springer Nature Limited.)

Plasma cleaning is an effective method for removing micro/nanoparticle particles, thus solving the pollution problem of micro/nanoparticle instruments. However, the lack of research on the phase transition evolution law of micro/nanoparticles under the action of plasma affects the popularization and application of this method and is the key factor that affects the cleaning quality. The focus of this study is to analyze this law. Through experimental observation and finite element simulation, the spatial phase transition distribution characteristics of particles and the influence law of laser parameters are analyzed. Moreover, the effect of the particle phase transition on the cleaning process is discussed. The removal threshold and the best removal area of different particles are presented, and a reference and guidance for the follow-up development of laser-plasma shock wave removal technology are provided., (© 2023. Springer Nature Limited.)

Soil texture is one of the important physical and natural properties of soil. Much of the current research focuses on soil texture monitoring using non-imaging geophysical spectrometers. However there are fewer studies utilizing unmanned aerial vehicle (UAV) hyperspectral data for soil texture monitoring. UAV mounted hyperspectral cameras can be used for quickly and accurately obtaining high-resolution spatial information of soil texture. A foundation has been laid for the realization of rapid soil texture surveys using unmanned airborne hyperspectral data without field sampling. This study selected three typical farmland areas in Huangshui Basin of Qinghai as the study area, and a total of 296 soil samples were collected. Data calibration of UAV spectra using laboratory spectra and field in situ spectra to explore the feasibility of applying laboratory soil texture models directly to field conditions. This results show that UAV hyperspectral imagery combined with machine learning can obtain a set of ideal processing methods. The pre-processing of the spectral data can obtain high accuracy of soil texture estimation and good mapping effect. The results of this study can provide effective technical support and decision-making assistance for future agricultural land planning on the Tibetan Plateau. The main innovation of this study is to establish a set of processing procedures and methods applicable to UAV hyperspectral imagery to provide data reference for monitoring soil texture in agricultural fields on the Tibetan Plateau., (© 2023. Springer Nature Limited.)

Drought stress can severely affect sugarcane growth and yield. The objective of this research was to identify candidate genes in sugarcane tillering seedlings in response to drought stress. We performed a comparative phenotypic, physiological and transcriptomic analysis of tiller seedlings of drought-stressed and well-watered "Guire 2" sugarcane, in a time-course experiment (5 days, 9 days and 15 days). Physiological examination reviewed that SOD, proline, soluble sugars, and soluble proteins accumulated in large amounts in tiller seedlings under different intensities of drought stress, while MDA levels remained at a stable level, indicating that the accumulation of osmoregulatory substances and the enhancement of antioxidant enzyme activities helped to limit further damage caused by drought stress. RNA-seq and weighted gene co-expression network analysis (WGCNA) were performed to identify genes and modules associated with sugarcane tillering seedlings in response to drought stress. Drought stress induced huge down-regulated in gene expression profiles, most of down-regulated genes were mainly associated with photosynthesis, sugar metabolism and fatty acid synthesis. We obtained four gene co-expression modules significantly associated with the physiological changes under drought stress (three modules positively correlated, one module negatively correlated), and found that LSG1-2, ERF1-2, SHKA, TIL, HSP18.1, HSP24.1, HSP16.1 and HSFA6A may play essential regulatory roles as hub genes in increasing SOD, Pro, soluble sugar or soluble protein contents. In addition, one module was found mostly involved in tiller stem diameter, among which members of the BHLH148 were important nodes. These results provide new insights into the mechanisms by which sugarcane tillering seedlings respond to drought stress., (© 2023. Springer Nature Limited.)

Traumatic brain injury (TBI) accelerates fracture healing, but the underlying mechanism remains largely unknown. Accumulating evidence indicates that the central nervous system (CNS) plays a pivotal role in regulating immune system and skeletal homeostasis. However, the impact of CNS injury on hematopoiesis commitment was overlooked. Here, we found that the dramatically elevated sympathetic tone accompanied with TBI-accelerated fracture healing; chemical sympathectomy blocks TBI-induced fracture healing. TBI-induced hypersensitivity of adrenergic signaling promotes the proliferation of bone marrow hematopoietic stem cells (HSCs) and swiftly skews HSCs toward anti-inflammation myeloid cells within 14 days, which favor fracture healing. Knockout of β3- or β2-adrenergic receptor (AR) eliminate TBI-mediated anti-inflammation macrophage expansion and TBI-accelerated fracture healing. RNA sequencing of bone marrow cells revealed that Adrb2 and Adrb3 maintain proliferation and commitment of immune cells. Importantly, flow cytometry confirmed that deletion of β2-AR inhibits M2 polarization of macrophages at 7th day and 14th day; and TBI-induced HSCs proliferation was impaired in β3-AR knockout mice. Moreover, β3- and β2-AR agonists synergistically promote infiltration of M2 macrophages in callus and accelerate bone healing process. Thus, we conclude that TBI accelerates bone formation during early stage of fracture healing process by shaping the anti-inflammation environment in the bone marrow. These results implicate that the adrenergic signals could serve as potential targets for fracture management., (© 2023. The Author(s).)

Although anion channel activities have been demonstrated in sarcoplasmic reticulum/endoplasmic reticulum (SR/ER), their molecular identities and functions remain unclear. Here, we link rare variants of Chloride Channel CLIC Like 1 (CLCC1) to amyotrophic lateral sclerosis (ALS)-like pathologies. We demonstrate that CLCC1 is a pore-forming component of an ER anion channel and that ALS-associated mutations impair channel conductance. CLCC1 forms homomultimers and its channel activity is inhibited by luminal Ca 2+ but facilitated by phosphatidylinositol 4,5-bisphosphate (PIP2). We identified conserved residues D25 and D181 in CLCC1 N-terminus responsible for Ca 2+ binding and luminal Ca 2+ -mediated inhibition on channel open probability and K298 in CLCC1 intraluminal loop as the critical PIP2-sensing residue. CLCC1 maintains steady-state [Cl - ] ER and [K + ] ER and ER morphology and regulates ER Ca 2+ homeostasis, including internal Ca 2+ release and steady-state [Ca 2+ ] ER . ALS-associated mutant forms of CLCC1 increase steady-state [Cl - ] ER and impair ER Ca 2+ homeostasis, and animals with the ALS-associated mutations are sensitized to stress challenge-induced protein misfolding. Phenotypic comparisons of multiple Clcc1 loss-of-function alleles, including ALS-associated mutations, reveal a CLCC1 dosage dependence in the severity of disease phenotypes in vivo. Similar to CLCC1 rare variations dominant in ALS, 10% of K298A heterozygous mice developed ALS-like symptoms, pointing to a mechanism of channelopathy dominant-negatively induced by a loss-of-function mutation. Conditional knockout of Clcc1 cell-autonomously causes motor neuron loss and ER stress, misfolded protein accumulation, and characteristic ALS pathologies in the spinal cord. Thus, our findings support that disruption of ER ion homeostasis maintained by CLCC1 contributes to ALS-like pathologies., (© 2023. The Author(s).)

Ovarian cancer is the leading cause of death among gynecological malignancies. Checkpoint blockade immunotherapy has so far only shown modest efficacy in ovarian cancer and platinum-based chemotherapy remains the front-line treatment. Development of platinum resistance is one of the most important factors contributing to ovarian cancer recurrence and mortality. Through kinome-wide synthetic lethal RNAi screening combined with unbiased datamining of cell line platinum response in CCLE and GDSC databases, here we report that Src-Related Kinase Lacking C-Terminal Regulatory Tyrosine And N-Terminal Myristylation Sites (SRMS), a non-receptor tyrosine kinase, is a novel negative regulator of MKK4-JNK signaling under platinum treatment and plays an important role in dictating platinum efficacy in ovarian cancer. Suppressing SRMS specifically sensitizes p53-deficient ovarian cancer cells to platinum in vitro and in vivo. Mechanistically, SRMS serves as a "sensor" for platinum-induced ROS. Platinum treatment-induced ROS activates SRMS, which inhibits MKK4 kinase activity by directly phosphorylating MKK4 at Y269 and Y307, and consequently attenuates MKK4-JNK activation. Suppressing SRMS leads to enhanced MKK4-JNK-mediated apoptosis by inhibiting MCL1 transcription, thereby boosting platinum efficacy. Importantly, through a "drug repurposing" strategy, we uncovered that PLX4720, a small molecular selective inhibitor of B-RafV 600E , is a novel SRMS inhibitor that can potently boost platinum efficacy in ovarian cancer in vitro and in vivo. Therefore, targeting SRMS with PLX4720 holds the promise to improve the efficacy of platinum-based chemotherapy and overcome chemoresistance in ovarian cancer., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Aberrant expression of XIST, a long noncoding RNA (lncRNA) initiating X chromosome inactivation (XCI) in early embryogenesis, is a common feature of breast cancer (BC). However, the roles of post-XCI XIST in breast carcinogenesis remain elusive. Here we identify XIST as a key regulator of breast cancer stem cells (CSCs), which exhibit aldehyde dehydrogenase positive (ALDH + ) epithelial- (E) and CD24 lo CD44 hi mesenchymal-like (M) phenotypes. XIST is variably expressed across the spectrum of BC subtypes, and doxycycline (DOX)-inducible knockdown (KD) of XIST markedly inhibits spheroid/colony forming capacity, tumor growth and tumor-initiating potential. This phenotype is attributed to impaired E-CSC in luminal and E- and M-CSC activities in triple-negative (TN) BC. Gene expression profiling unveils that XIST KD most significantly affects cytokine-cytokine receptor interactions, leading to markedly suppressed expression of proinflammatory cytokines IL-6 and IL-8 in ALDH - bulk BC cells. Exogenous IL-6, but not IL-8, rescues the reduced sphere-forming capacity and proportion of ALDH + E-CSCs in luminal and TN BC upon XIST KD. XIST functions as a nuclear sponge for microRNA let-7a-2-3p to activate IL-6 production from ALDH - bulk BC cells, which acts in a paracrine fashion on ALDH + E-CSCs that display elevated cell surface IL-6 receptor (IL6R) expression. This promotes CSC self-renewal via STAT3 activation and expression of key CSC factors including c-MYC, KLF4 and SOX9. Together, this study supports a novel role of XIST by derepressing let-7 controlled paracrine IL-6 proinflammatory signaling to promote CSC self-renewal., (© 2023. The Author(s).)

Traditional coal-gangue recognition methods usually do not consider the impact of equipment noise, which severely limits its adaptability and recognition accuracy. This paper mainly studies the more accurate recognition of coal-gangue in the noise site environment with the operation of shearer, conveyor, transfer machine and other device in the process of top coal caving. Mel Frequency Cepstrum Coefficients (MFCC) smoothing method was introduced to express the intrinsic feature of sound pressure more clearly in the coal-gangue recognition site. Then, a multi-branch convolution neural network (MBCNN) model with three branches was developed, and the smoothed MFCC feature was incorporated into this model to realize the recognition of falling coal and gangue in noisy environment. The sound pressure signal datasets under the operation of different device were constructed through a great deal of laboratory and site data acquisition. Comparative experiments were carried out on noiseless dataset, single noise dataset and simulated site dataset, and the results show that our method can provide higher correct recognition accuracy and better robustness. The proposed coal-gangue recognition approach based on MBCNN and MFCC smoothing can not only recognize the state of falling coal or gangue, but also recognize the operational state of site device., (© 2023. The Author(s).)

End-stage renal disease (ESRD) results in hippocampal volume reduction, but the hippocampal subfields atrophy patterns cannot be identified. We explored the volumes and asymmetry of the hippocampal subfields and their relationships with memory function and biochemical changes. Hippocampal global and subfields volumes were derived from 33 ESRD patients and 46 healthy controls (HCs) from structural MRI. We compared the volume and asymmetric index of each subfield, with receiver operating characteristic curve analysis to evaluate the differentiation between ESRD and HCs. The relations of hippocampal subfield volumes with memory performance and biochemical data were investigated in ESRD group. ESRD patients had smaller hippocampal subfield volumes, mainly in the left CA1 body, left fimbria, right molecular layer head, right molecular layer body and right HATA. The right molecular layer body exhibited the highest accuracy for differentiating ESRD from HCs, with a sensitivity of 80.43% and specificity of 72.73%. Worse learning process (r = 0.414, p = 0.032), immediate recall (r = 0.396, p = 0.041) and delayed recall (r = 0.482, p = 0.011) was associated with left fimbria atrophy. The left fimbria volume was positively correlated with Hb (r = 0.388, p = 0.05); the left CA1 body volume was negatively correlated with Urea (r = - 0.469, p = 0.016). ESRD patients showed global and hippocampal subfields atrophy. Left fimbria atrophy was related to memory function. Anemia and Urea level may be associated with the atrophy of left fimbria and CA1 body, respectively., (© 2023. The Author(s).)

Programmed cell death protein 1 (PD-1)-expressing T cells are expanded in individuals with established rheumatoid arthritis (RA). However, little is known about their functional role in the pathogenesis of early RA. To address this, we investigated the transcriptomic profiles of circulating CD4 + and CD8 + PD-1 + lymphocytes from patients with early RA (n = 5) using fluorescence activated cell sorting in conjunction with total RNA sequencing. Additionally, we assessed for alterations in CD4 + PD-1 + gene signatures in previously published synovial tissue (ST) biopsy data (n = 19) (GSE89408, GSE97165) before and after six-months of triple disease modifying anti-rheumatic drug (tDMARD) treatment. Comparisons of gene signatures between CD4 + PD-1 + vs. PD-1 - cells identified significant upregulation of genes including CXCL13 and MAF, and in pathways including Th1 and Th2, cross talk between dendritic cells and NK cells, B cell development and antigen presentation. Gene signatures from early RA ST before and after six-month tDMARD treatment revealed downregulation of the CD4 + PD-1 + signatures following treatment, identifying a mechanism through which tDMARDs exert their effect by influencing T cell populations. Furthermore, we identify factors associated with B cell help that are enhanced in the ST compared with PBMCs, highlighting their importance in driving synovial inflammation., (© 2023. Crown.)

The optimal myeloablative conditioning (MAC) regimens in adult patients with acute myeloid leukemia (AML) undergoing allogeneic hemopoietic stem cell transplantation (allo-HSCT) in complete remission (CR) remain unclear. We performed a systematic review and network meta-analysis to compare the effects of different MAC regimens. Bayesian network meta-analysis was performed using WinBUGS version 1.4.3. The commonly used MAC regimen Bu/Cy (4-day busulfan for toal 16 mg/kg orally or 12.8 mg/kg intravenously, plus 2-day cyclophosphamide for toal 120 mg/kg intravenously) is chosen as the common comparator. Pooled hazard ratios (HRs) with the associated 95% credibility interval (95% CrI) are obtained for all comparisons. We included 19 eligible studies, involving 8104 AML patients and 9 MAC regimens. Compared with Bu/Cy, 3-day busulfan plus fludarabine and thiotepa (Bu3/Flu/TT) is associated with significantly better overall survival (HR, 0.70; 95% CrI, 0.51 to 0.96) and lower risk of relapse (HR, 0.59; 95% CrI, 0.35 to 0.98). Bu3/Flu/TT is also associated with superior overall survival than Cy/TBI (cyclophosphamide plus total body irradiation), and lower risk of relapse than Bu4/Flu (4-day busulfan plus fludarabine). These results suggest that thiotepa-based new MAC regimen Bu3/Flu/TT is associated with improved outcomes in AML patients undergoing allo-HSCT in CR and worth further investigation., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Smoking is a trigger for asthma, which has led to an increase in asthma incidence in China. In smokers, asthma management starts with smoking cessation. Data on predictors of smoking cessation in Chinese patients with asthma are scarce. The objective of this study was to find the differences in clinical characteristics between current smokers and former smokers with asthma in order to identify factors associated with smoking cessation. Eligible adults with diagnosed asthma and smoking from the hospital outpatient clinics (n = 2312) were enrolled and underwent a clinical evaluation, asthma control test (ACT), and pulmonary function test. Information on demographic and sociological data, lung function, laboratory tests, ACT and asthma control questionnaire (ACQ) scores was recorded. Patients were divided into a current smokers group and a former smokers group based on whether they had quit smoking. Logistic regression analysis was used to analyze the factors associated with smoking cessation. Of all patients with asthma, 34.6% were smokers and 65.4% were former smokers, and the mean age was 54.5 ± 11.5 years. Compared with current smokers, the former smokers were older, had longer duration of asthma, had higher ICS dose, had more partially controlled and uncontrolled asthma, had more pack-years, had smoked for longer, and had worse asthma control. The logistic regression model showed that smoking cessation was positively correlated with age, female sex, pack-years, years of smoking, partially controlled asthma, uncontrolled asthma, and body mass index (BMI), but was negatively correlated with ACT, FEV 1 , FEV 1 %predicted, and widowed status. More than 30% of asthma patients in the study were still smoking. Among those who quit smoking, many quit late, often not realizing they need to quit until they have significant breathing difficulties. The related factors of smoking cessation identified in this study indicate that there are still differences between continuing smokers and former smokers, and these factors should be focused on in asthma smoking cessation interventions to improve the prognosis of patients with asthma., (© 2023. The Author(s).)

Gastric cancer (GC) is the fifth most common cancer and the third leading cause of cancer death worldwide. Discovery of diagnostic biomarkers prompts the early detection of GC. In this study, we used limma method combined with joint mutual information (JMI), a machine learning algorithm, to identify a signature of 11 genes that performed well in distinguishing tumor and normal samples in a stomach adenocarcinoma cohort. Other two GC datasets were used to validate the classifying performances. Several of the candidate genes were correlated with GC tumor progression and survival. Overall, we highlight the application of feature selection approaches in the analysis of high-dimensional biological data, which will improve study accuracies and reduce workloads for the researchers when identifying potential tumor biomarkers., (© 2022. The Author(s).)

The individual prognosis of chemotherapy is quite different in non-small cell lung cancer (NSCLC). There is an urgent need to precisely predict and assess the treatment response. To develop a deep multiple-instance learning (DMIL) based model for predicting chemotherapy response in NSCLC in pretreatment CT images. Two datasets of NSCLC patients treated with chemotherapy as the first-line treatment were collected from two hospitals. Dataset 1 (163 response and 138 nonresponse) was used to train, validate, and test the DMIL model and dataset 2 (22 response and 20 nonresponse) was used as the external validation cohort. Five backbone networks in the feature extraction module and three pooling methods were compared. The DMIL with a pre-trained VGG16 backbone and an attention mechanism pooling performed the best, with an accuracy of 0.883 and area under the curve (AUC) of 0.982 on Dataset 1. While using max pooling and convolutional pooling, the AUC was 0.958 and 0.931, respectively. In Dataset 2, the best DMIL model produced an accuracy of 0.833 and AUC of 0.940. Deep learning models based on the MIL can predict chemotherapy response in NSCLC using pretreatment CT images and the pre-trained VGG16 with attention mechanism pooling yielded better predictions., (© 2022. The Author(s).)

With the recent prevalence of COVID-19, cryptic transmission is worthy of attention and research. Early perception of the occurrence and development risk of cryptic transmission is an important part of controlling the spread of COVID-19. Previous relevant studies have limited data sources, and no effective analysis has been carried out on the occurrence and development of cryptic transmission. Hence, we collect Internet multisource big data (including retrieval, migration, and media data) and propose comprehensive and relative application strategies to eliminate the impact of national and media data. We use statistical classification and regression to construct an early warning model for occurrence and development. Under the guidance of the improved coronavirus herd immunity optimizer (ICHIO), we construct a "sampling-feature-hyperparameter-weight" synchronous optimization strategy. In occurrence warning, we propose an undersampling synchronous evolutionary ensemble (USEE); in development warning, we propose a bootstrap-sampling synchronous evolutionary ensemble (BSEE). Regarding the internal training data (Heilongjiang Province), the ROC-AUC of USEE3 incorporating multisource data is 0.9553, the PR-AUC is 0.8327, and the R 2 of BSEE2 fused by the "nonlinear + linear" method is 0.8698. Regarding the external validation data (Shaanxi Province), the ROC-AUC and PR-AUC values of USEE3 were 0.9680 and 0.9548, respectively, and the R 2 of BSEE2 was 0.8255. Our method has good accuracy and generalization and can be flexibly used in the prediction of cryptic transmission in various regions. We propose strategy research that integrates multiple early warning tasks based on multisource Internet big data and combines multiple ensemble models. It is an extension of the research in the field of traditional infectious disease monitoring and has important practical significance and innovative theoretical value., (© 2022. The Author(s).)

Acute kidney injury (AKI) is in high prevalence in the world. However, the therapeutic strategies for AKI are still in mystery. Studies have shown to improve autophagy and lysosomal function could inhibit AKI. But their modulators need to be explored in detail. Annexin A2 (ANXA2) is a phospholipid-binding protein involving in organelle membrane integrity function, suggesting its important role in autophagy and lysosome homeostasis. It implicates ANXA2 potentially protects against AKI. However, this has not been elucidated. Herein, we found that ANXA2 is increased in renal tubules in cisplatin-induced AKI mice. Ectopic expression of ANXA2 improved lysosomal functions and enhanced autophagic flux, further protecting against renal tubular cell apoptosis and kidney injury. Conversely, knockdown of ANXA2 inhibited lysosomal function and autophagy, which aggravated the progression of AKI. Transcriptome sequencing revealed β-catenin signaling is highly responsible for this process. In vitro, we found ANXA2 induced β-catenin activation, further triggering T-cell factor-4 (TCF4)-induced transcription factor EB (TFEB). Furthermore, TFEB promoted lysosome biogenesis to enhance autophagic flux, resulting in the alleviation of AKI. Our new findings underline ANXA2 is a new therapeutic potential for AKI through modulating autophagy and lysosomal function. The underlying mechanism is associated with its inductive effects on β-catenin/TFEB pathway., (© 2022. The Author(s).)

Non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH) has become the leading cause of liver disease worldwide. NASH, an advanced form of NAFL, can be progressive and more susceptible to developing cirrhosis and hepatocellular carcinoma. Currently, lifestyle interventions are the most essential and effective strategies for preventing and controlling NAFL without the development of fibrosis. While there are still limited appropriate drugs specifically to treat NAFL/NASH, growing progress is being seen in elucidating the pathogenesis and identifying therapeutic targets. In this review, we discussed recent developments in etiology and prospective therapeutic targets, as well as pharmacological candidates in pre/clinical trials and patents, with a focus on diabetes, hepatic lipid metabolism, inflammation, and fibrosis. Importantly, growing evidence elucidates that the disruption of the gut-liver axis and microbe-derived metabolites drive the pathogenesis of NAFL/NASH. Extracellular vesicles (EVs) act as a signaling mediator, resulting in lipid accumulation, macrophage and hepatic stellate cell activation, further promoting inflammation and liver fibrosis progression during the development of NAFL/NASH. Targeting gut microbiota or EVs may serve as new strategies for the treatment of NAFL/NASH. Finally, other mechanisms, such as cell therapy and genetic approaches, also have enormous therapeutic potential. Incorporating drugs with different mechanisms and personalized medicine may improve the efficacy to better benefit patients with NAFL/NASH., (© 2022. The Author(s).)

In 2016, China initiated the merge of the urban resident basic medical insurance scheme and new rural cooperative medical scheme into one unified health insurance scheme: the urban and rural resident basic medical insurance. This study investigates the impact of integrated insurance on the direct hospitalization cost of inpatients with catastrophic illnesses. An interrupted time series analysis was conducted based on a sample of 6174 inpatients with catastrophic illness from January 2014 to December 2018. The factors surveyed included per capita total inpatient expense, out-of-pocket expense, and reimbursement ratio. Univariate analysis indicated that after the implementation of the unified urban and rural medical insurance, the reimbursed expense increased from 9398 to 13,842 Yuan (P < 0.001), average reimbursement ratio increased from 0.57 to 0.59 (P < 0.05). Expenses on both western and traditional medicines increased, although the proportion of medicine expense decreased after the integration. Interrupted time series analysis showed that per capita total inpatient expense and per capita out-of-pocket expense increased but showed a gradually decreasing trend after the integration. After the integration of urban and rural medical insurance, the average reimbursement ratio increased slightly, which had limited effect on the alleviation of patients' financial burden. Furthermore, the integration effect on inpatient expense is offset by increased out-of-pocket medical expense due to suspected supplier-induced demand., (© 2022. The Author(s).)

The behavior intention estimation and interaction between Autonomous Vehicles (AV) and human traffic participants are the key problems in Automatic Driving System (ADS). When the classical decision theory studies implicitly assume that the behavior of human traffic participants is completely rational. However, according to the booming quantum decision theory in recent years and actual traffic cases, traffic behaviors and other human behaviors are often irrational and violate the assumptions of classical cognitive and decision theory. This paper explores the decision-making problem in the two-car game scene based on quantum decision theory and compares it with the current mainstream method of studying irrational behavior-Cumulative Prospect Theory (CPT) model. The comparative analysis proved that the Quantum Game Theory (QGT) model can explain the separation effect which the classical probability model can't reveal, and it has more advantages than CPT model in dealing with game scene decision-making. When two cars interact with each other, the QGT model can consider the interests of both sides from the perspective of the other car. Compared with the classical probability model and CPT model, the QGT is more realistic in the behavior decision-making of ADS., (© 2022. The Author(s).)

Spatially resolved vibrational mapping of nanostructures is indispensable to the development and understanding of thermal nanodevices 1 , modulation of thermal transport 2 and novel nanostructured thermoelectric materials 3-5 . Through the engineering of complex structures, such as alloys, nanostructures and superlattice interfaces, one can significantly alter the propagation of phonons and suppress material thermal conductivity while maintaining electrical conductivity 2 . There have been no correlative experiments that spatially track the modulation of phonon properties in and around nanostructures due to spatial resolution limitations of conventional optical phonon detection techniques. Here we demonstrate two-dimensional spatial mapping of phonons in a single silicon-germanium (SiGe) quantum dot (QD) using monochromated electron energy loss spectroscopy in the transmission electron microscope. Tracking the variation of the Si optical mode in and around the QD, we observe the nanoscale modification of the composition-induced red shift. We observe non-equilibrium phonons that only exist near the interface and, furthermore, develop a novel technique to differentially map phonon momenta, providing direct evidence that the interplay between diffuse and specular reflection largely depends on the detailed atomistic structure: a major advancement in the field. Our work unveils the non-equilibrium phonon dynamics at nanoscale interfaces and can be used to study actual nanodevices and aid in the understanding of heat dissipation near nanoscale hotspots, which is crucial for future high-performance nanoelectronics., (© 2022. The Author(s).)

Mitochondrial biology and behavior are central to the physiology of liver. Multiple mitochondrial quality control mechanisms remodel mitochondrial homeostasis under physiological and pathological conditions. Mitochondrial dysfunction and damage induced by overnutrition lead to oxidative stress, inflammation, liver cell death, and collagen production, which advance hepatic steatosis to nonalcoholic steatohepatitis (NASH). Accumulating evidence suggests that specific interventions that target mitochondrial homeostasis, including energy metabolism, antioxidant effects, and mitochondrial quality control, have emerged as promising strategies for NASH treatment. However, clinical translation of these findings is challenging due to the complex and unclear mechanisms of mitochondrial homeostasis in the pathophysiology of NASH., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

C9ORF72 GGGGCC repeat expansion is the most common genetic cause for amyotrophic lateral sclerosis and frontotemporal dementia, which generates abnormal DNA and RNA structures and produces toxic proteins. Recently, efficacy of CRISPR/Cas9-mediated editing has been proven in treatment of disease. However, DNA low complexity surrounding C9ORF72 expansion increases the off-target risks. Here we provide a dual-gRNA design outside of the low complexity region which enables us to remove the repeat DNA in a 'cutting-deletion-fusion' manner with a high fusion efficiency (50%). Our dual-gRNA design limits off-target effect and does not significantly affect C9ORF72 expression. In neurons carrying patient C9ORF72 expansion, our approach removes the repeat DNA and corrects the RNA foci in vitro and in vivo. Therefore, we conclude that our proof-of-concept design correct C9ORF72 repeat expansion, which may have potential therapeutic value for the patients., (© 2022. The Author(s).)