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Abstract Background At present, the main clinical application of local ablation therapy, such as radiofrequency ablation (RFA), is to heat the tissue to a certain temperature. However, high temperature will cause thermal damage. Irreversible electroporation (IRE) is a novel minimally invasive local ablation technology for tumors. By high-frequency pulse, the tumor cell membrane can be irretrievably perforated, resulting in the destruction of the intracellular environment, which can preserve important structures in the treatment area. However, there are no randomized controlled clinical trials comparing the efficacy of IRE with traditional local ablation in the treatment of liver cancer. Aims This study aims to conduct a randomized controlled clinical trial comparing the efficacy of IRE with RFA in the treatment of liver cancer. Methods We will conduct a multicenter, randomized, parallel-controlled non-inferiority clinical trial to compare the efficacy and safety of IRE and RFA for hepatocellular carcinoma (HCC). One hundred and ninety patients with HCC from five academic medical centers will be enrolled. The patients will be randomized into treatment arm (IRE) and control arm (RFA). The primary outcome is the progress -free survival (PFS) and the key secondary outcome is the Overall survival (OS). Results Forty-eight patients had been recruited from 5 centers, of which, 33 patients (median age, 59.1 years) with 38 tumors had completed the 1-month follow-up and 21 patients have complete the 3-month follow up, with 2.3 months median follow up period. The mean largest tumor diameter is 3.9 cm. No end point was observed for PFS or OS in both groups, and the complete ablation rate was 100% in both groups. The lesions in the IRE group showed obvious shrinkage 1 month after procedure. One major adverse event (AE) was occurred in the control group. Conclusion This is the first randomized controlled clinical trial to compare the clinical effects of IRE and RFA. The preliminary results suggest that both RFA and IRE are effective in the treatment of HCC, which can provide strong evidence for the use of IRE in HCC and provide more options for the treatment of patients with HCC. Clinical Trial Registration ClinicalTrials. gov, identifier NCT05451160.

Abstract Objectives Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with high rates of morbidity and mortality, largely because of its late diagnosis and metastatic potential. Lactate metabolism and protein lactylation are thought to play roles in NPC pathogenesis by modulating the tumor microenvironment and immune evasion. However, research specifically linking lactate-related mechanisms to NPC remains limited. This study aimed to identify lactate-associated biomarkers in NPC and explore their underlying mechanisms, with a particular focus on immune modulation and tumor progression. Methods To achieve these objectives, we utilized a bioinformatics approach in which publicly available gene expression datasets related to NPC were analysed. Differential expression analysis revealed differentially expressed genes (DEGs) between NPC and normal tissues. We performed weighted gene coexpression network analysis (WGCNA) to identify module genes significantly associated with NPC. Overlaps among DEGs, key module genes and lactate-related genes (LRGs) were analysed to derive lactate-related differentially expressed genes (LR-DEGs). Machine learning algorithms can be used to predict potential biomarkers, and immune infiltration analysis can be used to examine the relationships between identified biomarkers and immune cell types, particularly M0 macrophages and B cells. Results A total of 1,058 DEGs were identified between the NPC and normal tissue groups. From this set, 372 key module genes associated with NPC were isolated. By intersecting the DEGs, key module genes and lactate-related genes (LRGs), 17 lactate-related DEGs (LR-DEGs) were identified. Using three machine learning algorithms, this list was further refined, resulting in three primary lactate-related biomarkers: TPPP3, MUC4 and CLIC6. These biomarkers were significantly enriched in pathways related to “immune cell activation” and the “extracellular matrix environment”. Additionally, M0 and B macrophages were found to be closely associated with these biomarkers, suggesting their involvement in shaping the NPC immune microenvironment. Conclusion In summary, this study identified TPPP3, MUC4 and CLIC6 as lactate-associated clinical modelling indicators linked to NPC, providing a foundation for advancing diagnostic and therapeutic strategies for this malignancy.

Abstract In order to address the challenges of low lane line detection rates caused by complex road conditions,we propose a novel algorithm that integrates frost and ice optimisation with optimal thresholding. A pre-processing model based on Retinex theory is used to reduce noise and preserve grey scale detail. The optimal OTSU threshold is determined for segmentation, which is enhanced by tent mapping. To further enhance the precision of the detection process, the binarized image is transformed into a bird’s-eye view, and the lane line pixel features are identified through the use of an adaptive sliding window. Ultimately, the RANSAC algorithm is utilized in conjunction with a parabolic model for lane line fitting. The experimental results demonstrate that, in comparison to similar image segmentation algorithms, the proposed method exhibits a notable advantage in terms of threshold calculation error and computational efficiency. Moreover, in comparison to analogous line detection algorithms, the detection accuracy rate reaches 93.87%, effectively reducing the impact of interference factors and demonstrating remarkable robustness that surpasses the traditional Hough Transform, which has an accuracy of 43.2%, and sliding window and Hough transform, with an accuracy of 89.16%. The code of our research work is publicly available at: https://github.com/zx2000430/rime .

Abstract Lung Cancer remains the leading cause of cancer deaths in the USA and worldwide. Non-small cell lung cancer (NSCLC) harbors high transcriptomic intratumor heterogeneity (RNA-ITH) that limits the reproducibility of expression-based prognostic models. In this study, we used multiregional RNA-seq data (880 tumor samples from 350 individuals) from both public (TRACERx) and internal (MDAMPLC) cohorts to investigate the effect of RNA-ITH on prognosis in localized NSCLC at the gene, signature, and tumor microenvironment levels. At the gene level, the maximal expression of hazardous genes (expression negatively associated with survival) but the minimal expression of protective genes (expression positively associated with survival) across different regions within a tumor were more prognostic than the average expression. Following that, we examined whether multiregional expression profiling can improve the performance of prognostic signatures. We investigated 11 gene signatures collected from previous publications and one signature developed in this study. For all of them, the prognostic prediction accuracy can be significantly improved by converting the regional expression of signature genes into sample-specific expression with a simple function—taking the maximal expression of hazardous genes and the minimal expression of protective genes. In the tumor microenvironment, we found a similar rule also seems applicable to immune ITH. We calculated the infiltration levels of major immune cell types in each region of a sample based on expression deconvolution. Prognostic analysis indicated that the region with the lowest infiltration level of protective or highest infiltration level of hazardous immune cells determined the prognosis of NSCLC patients. Our study highlighted the impact of RNA-ITH on the prognostication of NSCLC, which should be taken into consideration to optimize the design and application of expression-based prognostic biomarkers and models. Multiregional assays have the great potential to significantly improve their applications to prognostic stratification.

Abstract The spatial arrangement of immune cells within the tumor microenvironment (TME) and their interactions play critical roles in the initiation and development of cancer. Several advanced technologies such as imaging mass cytometry (IMC) providing the immunological landscape of the TME with single-cell resolution. In this study, we develop a new method to quantify the spatial proximity between different cell types based on single-cell spatial data. Using this method on IMC data from 416 lung adenocarcinoma patients, we show that the proximity between different cell types is more correlated with patient prognosis compared to the traditional features such immune cell density and fractions. Consistent with previous reports, our results validate that proximity of T helper (Th) and B cells to cancer cells is associated with survival benefits. More importantly, we discover that the proximity of M2 macrophages to multiple immune cells is associated with poor prognosis. When Th/B cells are stratified into M2-distal and M2-proximal, the abundance of the former but not the latter category of Th/B cells is correlated with enhanced patient survival. Additionally, the abundance of M2-distal and M2-proximal cytotoxic T cells (Tc) is respectively associated with good and poor prognosis. Our results indicate that the prognostic effect of Th, Tc, and B cells in the tumor microenvironment is modulated by the nearby M2 macrophages. The proposed new method proposed can be readily applied to all single-cell spatial data for revealing functional impact of immune cell interactions.

Abstract Multiple synchronous lung cancers (MSLCs) constitute a unique subtype of lung cancer. To explore the genomic and immune heterogeneity across different pathological stages of MSLCs, we analyse 16 MSLCs from 8 patients using single-cell RNA-seq, single-cell TCR sequencing, and bulk whole-exome sequencing. Our investigation indicates clonally independent tumours with convergent evolution driven by shared driver mutations. However, tumours from the same individual exhibit few shared mutations, indicating independent origins. During the transition from pre-invasive to invasive adenocarcinoma, we observe a shift in T cell phenotypes characterized by increased Treg cells and exhausted CD8+ T cells, accompanied by diminished cytotoxicity. Additionally, invasive adenocarcinomas exhibit greater neoantigen abundance and a more diverse TCR repertoire, indicating heightened heterogeneity. In summary, despite having a common genetic background and environmental exposure, our study emphasizes the individuality of MSLCs at different stages, highlighting their unique genomic and immune characteristics.

Abstract Background Bone metastasis (BM) occurs when colon cancer cells disseminate from the primary tumor site to the skeletal system via the bloodstream or lymphatic system. The emergence of such bone metastases typically heralds a significantly poor prognosis for the patient. This study's primary aim is to develop a machine learning model to identify patients at elevated risk of bone metastasis among those with right-sided colon cancer undergoing complete mesocolonectomy (CME). Patients and methods The study cohort comprised 1,151 individuals diagnosed with right-sided colon cancer, with a subset of 73 patients presenting with bone metastases originating from the colon. We used univariate and multivariate regression analyses as well as four machine learning algorithms to screen variables for 38 characteristic variables such as patient demographic characteristics and surgical information. The study employed four distinct machine learning algorithms, namely, extreme gradient boosting (XGBoost), random forest (RF), support vector machine (SVM), and k-nearest neighbor algorithm (KNN), to develop the predictive model. Additionally, the model was assessed using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA), while Shapley additive explanation (SHAP) was utilized to visualize and analyze the model. Results The XGBoost algorithm performed the best performance among the four prediction models. In the training set, the XGBoost algorithm had an area under curve (AUC) value of 0.973 (0.953–0.994), an accuracy of 0.925 (0.913–0.936), a sensitivity of 0.921 (0.902–0.940), and a specificity of 0.908 (0.894–0.922). In the validation set, the XGBoost algorithm had an AUC value of 0.922 (0.833–0.995), an accuracy of 0.908 (0.889–0.926), a sensitivity of 0.924 (0.873–0.975), and a specificity of 0.883 (0.810–0.956). Furthermore, the AUC value of 0.83 for the external validation set suggests that the XGBoost prediction model possesses strong extrapolation capabilities. The results of SHAP analysis identified alkaline phosphatase (ALP) levels, tumor size, invasion depth, lymph node metastasis, lung metastasis, and postoperative neutrophil-to-lymphocyte ratio (NLR) levels as significant risk factors for BM from right-sided colon cancer subsequent to CME. Conclusion The prediction model for BM from right-sided colon cancer developed using the XGBoost machine learning algorithm in this study is both highly precise and clinically valuable.

Fault diagnosis of traction systems is important for the safety operation of high-speed trains. Long-term operation of the trains will degrade the performance of systems, which decreases the fault detection accuracy. To solve this problem, this paper proposes a fault detection method developed by a Generalized Autoencoder (GAE) for systems with performance degradation. The advantage of this method is that it can accurately detect faults when the traction system of high-speed trains is affected by performance degradation. Regardless of the probability distribution, it can handle any data, and the GAE has extremely high sensitivity in anomaly detection. Finally, the effectiveness of this method is verified through the Traction Drive Control System (TDCS) platform. At different performance degradation levels, our method’s experimental results are superior to traditional methods.

Oxidative stress and damage to macromolecules due to free radicals such as reactive oxygen species (ROS) are commonly considered factors that can impair health. This study investigated the potential antioxidant properties of of two subunit proteins associated with the pigment-protein complex phycocyanin derived from Nostoc sphaeroides (Gexianmi). Bacterial expression vectors were separately constructed to induce the two engineering subunit proteins, Ns-α and Ns-β. These engineering proteins were then examined for their potential to enhance antioxidative capacity in Caenorhabditis elegans. Firstly, a proper concentration of the proteins Ns-α and Ns-β in vitro exhibited 2, 2-azino-bis 3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging activity. Secondly, while there were no other observed effects on the nematodes, those treated with the proteins showed significant improvements in motility and reduced levels of lipofuscin compared to the control group. Furthermore, thirdly, the treated nematodes demonstrated increased resistance to oxidation, as evidenced by the higher survivals under oxidative conditions induced by 5 mM H2O2. Notably, the treated nematodes exhibited decline in endogenous ROS levels, and the redox-related genes, such as SOD-3 and CAT-1, were down-regulated following consumption of the engineering proteins. Taken together, these findings suggest that engineering proteins Ns-α and Ns-β improve the antioxidative capacity of C. elegans by modulating ROS-related regulation, making them potential modulators in responding to oxidative stressors.

Traditional chemical additives inevitably pollute, damage, and destroy the ecological environment and natural resources while simultaneously addressing the requirements of engineering construction in loess areas. Additionally, freeze–thaw cycles exert a substantial influence on the long-term durability of engineering structures located in areas with loess deposits. Thus, it is a considerable benefit to identify and utilize materials that are beneficial to the environment and which will augment the engineered performance and freeze–thaw resistant capacity of loess. The purpose of this research is to evaluate the impact of freezing and thawing cycles on the mesostructural attributes using loess reinforced with lignin fiber and to elucidate an effect of varying fiber doses in relation to the response of loess to freezing and thawing. The findings illustrate that the incorporation of fiber effectively eliminates the presence of overhead pores in the loess. Furthermore, the freeze–thaw action induces the formation of long-narrow pores along the fiber surface in the reinforced loess. Adding the fiber reduces the characteristic parameters of the loess mesostructure. On the other hand, the freezing and thawing action increases the apparent void ratio, the mean pore area, and the area probability distribution index of the reinforced loess, while decreasing the probability entropy and bringing the fractal dimension very close. Freeze–thaw has the least effect on the apparent void ratio and microfine pore area ratio of 1% fiber loess. The filling and bridge effects of lignin fiber serve as the primary means of enhancing the strength of loess. Through its control of water, fiber bears the influence of some loess particles and pores, thus improving the freeze–thaw resistant capacity of loess.

Elevated levels of oxidative stress, inflammation, and a dysregulated osteoclastogenesis balance frequently characterize the microenvironment of osteoporosis, which impedes the processes of healing and repair. Existing treatment approaches are limited in scope and rely primarily on factors and drugs. An injectable hydrogel designed for the ROS-responsive release of H2S gas is presented in this study. The first network of the hydrogel comprises sodium alginate (SA-SATO) chelated with S-aroylthiooxime (SATO) and an H2S-generating group, while the second network is composed of photocrosslinkable PEGDA. Through the integration of Cys-releasing microspheres that are reactive with ROS, a composite hydrogel was developed that exhibited advantageous mechanical characteristics and biosafety. The composite hydrogel effectively promoted osteogenic differentiation of mesenchymal stem cells, modulated macrophage polarization, decreased inflammatory responses, and halted cell apoptosis, as evidenced by in vitro experiments. Additionally, it released H2S gas and mitigated excess ROS in cells. The efficacy of the composite hydrogel in promoting bone defect repair and regeneration in an osteoporotic model was further validated by in vivo findings. In summary, the composite hydrogel exhibits potential as a viable approach to address osteoporotic bone defects by harmonizing osteogenesis and osteoclast activity, modulating the microenvironment of bone injuries, and reducing inflammation. Consequently, it presents a viable strategy for the efficient repair of bone defects.

Non-invasive determination of amyloid-β peptide (Aβ) and tau deposition are important for early diagnosis and therapeutic intervention for Alzheimer's disease (AD) and non-AD tauopathies. In the present study, we investigated the capacity of a novel radioiodinated compound AD-DRK (123/125I-AD-DRK) with 50% inhibitory concentrations of 11 nM and 2 nM for Aβ and tau aggregates, respectively, as a single photon emission computed tomography (SPECT) ligand in living brains. In vitro and ex vivo autoradiography with 125I-AD-DRK was performed in postmortem human and two transgenic (Tg) mice lines with either fibrillar Aβ or tau accumulation, APP23 and rTg4510 mice. SPECT imaging of 123I-AD-DRK was performed in APP23 mice to investigate the ability of AD-DRK to visualize fibrillar protein deposition in the living brain. In-vitro autoradiogram of 125I-AD-DRK showed high specific radioactivity accumulation in the temporal cortex and hippocampus of AD patients and the motor cortex of progressive supranuclear palsy (PSP) patients enriched by Aβ and/or tau aggregates. Ex-vivo autoradiographic images also demonstrated a significant increase in 125I-AD-DRK binding in the forebrain of both APP23 and rTg450 mice compared to their corresponding non-Tg littermates. SPECT imaging successfully captured Aβ deposition in the living brain of aged APP23 mice. The present study developed a novel high-contrast SPECT agent for assisting the diagnosis of AD and non-AD tauopathies, likely benefiting from its affinity for both fibrillar Aβ and tau.

In order to reduce personnel and increase efficiency in the underground slurry filling system of coal mines and accelerate the intelligent process of slurry filling technology, a filling control method based on intelligent PID algorithm was proposed to realize accurate pulping. A monitoring and fault intelligent identification method for slurry pipelines has been constructed, achieving early warning of pipeline blockage and rapid fault handling. Integrated with a data-driven production management system and AI+NOSA intelligent control platform, the safety production management of the entire slurry filling system has achieved intelligent and comprehensive coverage. The application effect shows that after the system is officially put into use, it has achieved integration of system monitoring, less manual filling production, digital production management, and standardized equipment control. The efficiency of slurry filling is increased by more than 40%, and the failure shutdown rate of the filling system is reduced by more than 60%. The labor quota has been reduced from 15 to 3, resulting in a significant decrease in labor intensity and a significant improvement in production efficiency.

Abstract Endophytes have been shown to promote plant growth and health. In the present study, a Bacillus velezensis CH1 (CH1) strain was isolated and identified from high-quality oats, which was capable of producing indole-3-acetic acid (IAA) and strong biofilms, and capabilities in the nitrogen-fixing and iron carriers. CH1 has a 3920 kb chromosome with 47.3% GC content and 3776 code genes. Compared genome analysis showed that the largest proportion of the COG database was metabolism-related (44.79%), and 1135 out of 1508 genes were associated with the function “biosynthesis, transport, and catabolism of secondary metabolites.” Furthermore, thirteen gene clusters had been identified in CH1, which were responsible for the synthesis of fifteen secondary metabolites that exhibit antifungal and antibacterial properties. Additionally, the strain harbors genes involved in plant growth promotion, such as seven putative genes for IAA production, spermidine and polyamine synthase genes, along with multiple membrane-associated genes. The enrichment of these functions was strong evidence of the antimicrobial properties of strain CH1, which has the potential to be a biofertilizer for promoting oat growth and disease resistance.

Abstract Introduction Bronchobiliary fistulas are rare and difficult to treat. Peacock first reported this entity in 1850 while treating a patient with hepatic encopresis. Case presentation A 67-year-old Chinese male patient presented to the outpatient clinic with a complaint of coughing up phlegm with chest tightness for 4 days with symptoms of intermittent bilirubin sputum with a sputum volume of about 500 ml per day but no symptoms of abdominal pain or jaundice and no yellow urine or steatorrhea. The examination revealed cyanosis of the lips and mouth, barrel chest, low breath sounds on the right side, and a large number of wet rales heard in both lungs. The imaging investigations were suggestive of bronchobiliary fistula. Therefore, the patient was operated on and discharged with no perioperative complications. Conclusion Bronchobiliary fistula should be considered diagnostically in patients with known liver disease who also experience trauma or medical treatment and cough up bile-colored sputum, regardless of the presence of concurrent infections, and in conjunction with radiological expertise to identify it. Here, we report a case of bronchobiliary fistula and a brief review of the literature on it.

Fatty acyl desaturases (Fads) are crucial enzymes that catalyze the rate-limiting step of the desaturation reactions by introducing a double bond into to pre-existing fatty acyl chains. As a group of key enzymes involved in the biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFAs), Fads have been well investigated in teleost fishes but they are still rarely known in chondrichthyans. In this study, we first identified a fatty acyl desaturases gene (fads2) from the Chinese sturgeon (Acipenser sinensis), a critically endangered cartilaginous species in China, by combining with bioinformatic analyses and molecular cloning methods. Then, the spatio-temporal distribution patterns, functional characteristics and transcriptional changes of this gene in response to different nutritional conditions were investigated. The coding sequences of the fads2 gene was 1350 bp in length, encoding a protein of 449 amino acids. Multiple protein sequences alignment, genetic synteny and phylogenetic analyses further suggested that fads2 gene was evolutionary conserved. Functional characterization by heterologous expression in yeast showed that Fads2 exhibited Δ6 and Δ8 bifunctional desaturation activities, and possessed capacities to convert 18:2n-6, 18:3n-3, 20:2n-6 and 20:3n-3–18:3n-6, 18:4n-3, 20:3n-6 and 20:4n-3, respectively. In vivo experiment, diets full with C18 PUFA but not LC-PUFA significantly induced the expression levels of fads2 in Chinese sturgeon brain and liver tissues. Our findings suggest that fads2 is an evolutionary and functionally conserved desaturase in Chinese sturgeon, and which plays important roles in regulation of endogenous LC-PUFAs biosynthesis. In summary, these findings will provide a new insight into the evolutionary history of key enzymes of LC-PUFA biosynthesis in vertebrates.

PurposeTo clarify the prognostic value of lymph node regression (LNR) status including the lymph node regression grade (LNRG) and N downstaging in patients with esophageal cancer receiving neoadjuvant therapy based on available evidence.MethodsSeveral databases were searched up to 25 March 2024. The main outcomes included overall survival (OS), disease-free survival (DFS) and cancer-specific survival (CSS). Hazard ratios (HRs) and 95% confidence intervals (CIs) were combined. Subgroup analyses based on the neoadjuvant therapy and pathological type were also conducted.ResultsIn total, 14 retrospective studies with 3,212 participants were included. Nine and five studies explored the relationship between LNRG and N downstaging and survival, respectively. Pooled results indicated that complete LNR predicted significantly improved OS (HR = 0.47, 95% CI: 0.41–0.55, P < 0.001) and DFS (HR = 0.42, 95% CI: 0.32–0.55, P < 0.001) and subgroup analysis based on neoadjuvant therapy and pathological type manifested similar results. Besides, N downstaging was also significantly related to improved OS (HR = 0.40, 95% CI: 0.21–0.77, P = 0.006) and CSS (HR = 0.27, 95% CI: 0.12–0.60, P < 0.001).ConclusionLNR could serve as a novel and reliable prognostic factor in patients with esophageal cancer receiving neoadjuvant therapy and complete LNR and N downstaging predict better survival.

Summary: This study aims to elucidate the pivotal role of aldolase A (ALDOA) in retinoblastoma (RB) and evaluate the potential of the ALDOA inhibitor itaconate in impeding RB progression. Utilizing single-cell RNA sequencing, ALDOA consistently exhibits overexpression across diverse cell types, particularly in cone precursor cells, retinoma-like cells, and retinoblastoma-like cells. This heightened expression is validated in RB tissues and cell lines. ALDOA knockdown significantly diminishes RB cell viability, impedes colony formation, and induces notable metabolic alterations. RNA-seq analysis identifies SUSD2, ARHGAP27, and CLK2 as downstream genes associated with ALDOA. The application of itaconate demonstrates efficacy in inhibiting RB cell proliferation, validated through in vitro and in vivo models. This study emphasizes ALDOA as a promising target for innovative RB therapies, with potential implications for altering tumor energy metabolism.

Lung cancer, one of the most prevalent cancers worldwide, stands as the primary cause of cancer-related deaths. As is well-known, the utmost crucial risk factor contributing to lung cancer is smoking. In recent years, remarkable progress has been made in treating lung cancer, particularly non-small cell lung cancer (NSCLC). Nevertheless, the absence of effective and accurate biomarkers for diagnosing and treating lung cancer remains a pressing issue. Interleukin 22 (IL-22) is a member of the IL-10 cytokine family. It exerts biological functions (including induction of proliferation and anti-apoptotic signaling pathways, enhancement of tissue regeneration and immunity defense) by binding to heterodimeric receptors containing type 1 receptor chain (R1) and type 2 receptor chain (R2). IL-22 has been identified as a pro-cancer factor since dysregulation of the IL-22-IL-22R system has been implicated in the development of different cancers, including lung, breast, gastric, pancreatic, and colon cancers. In this review, we discuss the differential expression, regulatory role, and potential clinical significance of IL-22 in lung cancer, while shedding light on innovative approaches for the future.

Abstract Background Tumors exhibit metabolic heterogeneity, influencing cancer progression. However, understanding metabolic diversity in retinoblastoma (RB), the primary intraocular malignancy in children, remains limited. Methods The metabolic landscape of RB was constructed based on single-cell transcriptomic sequencing from 11 RB and 5 retina samples. Various analyses were conducted, including assessing overall metabolic activity, metabolic heterogeneity, and the correlation between hypoxia and metabolic pathways. Additionally, the expression pattern of the monocarboxylate transporter (MCT) family in different cell clusters was examined. Validation assays of MCT1 expression and function in RB cell lines were performed. The therapeutic potential of targeting MCT1 was evaluated using an orthotopic xenograft model. A cohort of 47 RB patients was analyzed to evaluate the relationship between MCT1 expression and tumor invasion. Results Distinct metabolic patterns in RB cells, notably increased glycolysis, were identified. This metabolic heterogeneity correlated closely with hypoxia. MCT1 emerged as the primary monocarboxylate transporter in RB cells. Disrupting MCT1 altered cell viability and energy metabolism. In vivo studies using the MCT1 inhibitor AZD3965 effectively suppressed RB tumor growth. Additionally, a correlation between MCT1 expression and optic nerve invasion in RB samples suggested prognostic implications. Conclusions This study enhances our understanding of RB metabolic characteristics at the single-cell level, highlighting the significance of MCT1 in RB pathogenesis. Targeting MCT1 holds promise as a therapeutic strategy for combating RB, with potential prognostic implications.

Abstract Introduction Surgery for gliomas involving eloquent areas is a very challenging microsurgical procedure. Maximizing both the extent of resection (EOR) and preservation of neurological function have always been the focus of attention. Intraoperative neurophysiological monitoring (IONM) is widely used in this kind of surgery. The purpose of this study was to evaluate the efficacy of IONM in eloquent area glioma surgery. Methods Sixty-eight glioma patients who underwent surgical treatment from 2014 to 2019 were included in this retrospective cohort study, which focused on eloquent areas. Clinical indicators and IONM data were analysed preoperatively, two weeks after surgery, and at the final follow-up. Logistic regression, Cox regression, and Kaplan‒Meier analyses were performed, and nomograms were then established for predicting prognosis. The diagnostic value of the IONM indicator was evaluated by the receiver operating characteristic (ROC) curve. Results IONM had no effect on the postoperative outcomes, including EOR, intraoperative bleeding volume, duration of surgery, length of hospital stay, and neurological function status. However, at the three-month follow-up, the percentage of patients who had deteriorated function in the monitored group was significantly lower than that in the unmonitored group (23.3% vs. 52.6%; P

Abstract Multiple myeloma (MM) is a heterogenous plasma cell malignancy, for which the established prognostic models exhibit limitations in capturing the full spectrum of outcome variability. Leveraging single-cell RNA-sequencing data, we developed a novel plasma cell gene signature. We evaluated and validated the associations of the resulting plasma cell malignancy (PBM) score with disease state, progression and clinical outcomes using data from five independent myeloma studies consisting of 2115 samples (1978 MM, 65 monoclonal gammopathy of undetermined significance, 35 smoldering MM, and 37 healthy controls). Overall, a higher PBM score was significantly associated with a more advanced stage within the spectrum of plasma cell dyscrasias (all p

Tissue-resident memory T cells (TRM) are a specialized subset of long-lived memory T cells that reside in peripheral tissues. However, the impact of TRM-related immunosurveillance on the tumor-immune microenvironment (TIME) and tumor progression across various non-small-cell lung cancer (NSCLC) patient populations is yet to be elucidated. Our comprehensive analysis of multiple independent single-cell and bulk RNA-seq datasets of patient NSCLC samples generated reliable, unique TRM signatures, through which we inferred the abundance of TRM in NSCLC. We discovered that TRM abundance is consistently positively correlated with CD4+ T helper 1 cells, M1 macrophages, and resting dendritic cells in the TIME. In addition, TRM signatures are strongly associated with immune checkpoint and stimulatory genes and the prognosis of NSCLC patients. A TRM-based machine learning model to predict patient survival was validated and an 18-gene risk score was further developed to effectively stratify patients into low-risk and high-risk categories, wherein patients with high-risk scores had significantly lower overall survival than patients with low-risk. The prognostic value of the risk score was independently validated by the Cancer Genome Atlas Program (TCGA) dataset and multiple independent NSCLC patient datasets. Notably, low-risk NSCLC patients with higher TRM infiltration exhibited enhanced T-cell immunity, nature killer cell activation, and other TIME immune responses related pathways, indicating a more active immune profile benefitting from immunotherapy. However, the TRM signature revealed low TRM abundance and a lack of prognostic association among lung squamous cell carcinoma patients in contrast to adenocarcinoma, indicating that the two NSCLC subtypes are driven by distinct TIMEs. Altogether, this study provides valuable insights into the complex interactions between TRM and TIME and their impact on NSCLC patient prognosis. The development of a simplified 18-gene risk score provides a practical prognostic marker for risk stratification.

Abstract Malignant pleural mesothelioma (MPM) is a rare but lethal pleural cancer with high intratumor heterogeneity (ITH). A recent study in lung adenocarcinoma has developed a clonal gene signature (ORACLE) from multiregional transcriptomic data and demonstrated high prognostic values and reproducibility. However, such a strategy has not been tested in other types of cancer with high ITH. We aimed to identify biomarkers from multi-regional data to prognostically stratify MPM patients. We generated a multiregional RNA-seq dataset for 78 tumor samples obtained from 26 MPM patients, each with one sample collected from a superior, lateral, and inferior region of the tumor. By integrating this dataset with the Cancer Genome Atlas MPM RNA-seq data, we selected 29 prognostic genes displaying high variability across different tumors but low ITH, which named PRACME (Prognostic Risk Associated Clonal Mesothelioma Expression). We evaluated PRACME in two independent MPM datasets and demonstrated its prognostic values. Patients with high signature scores are associated with poor prognosis after adjusting established clinical factors. Interestingly, the PRACME and the ORACLE signatures defined respectively from MPM and lung adenocarcinoma cross-predict prognosis between the two cancer types. Further investigation indicated that the cross-prediction ability might be explained by the high similarity between the two cancer types in their genomic regions with copy number variation, which host many clonal genes. Overall, our clonal signature PRACME provided prognostic stratification in MPM and this study emphasized the importance of multi-regional transcriptomic data for prognostic stratification based on clonal genes.

Abstract Despite the central role of human leukocyte antigen class I (HLA-I) in tumor neoantigen presentation, quantitative determination of presentation capacity remains elusive. Based on a pooled pan-cancer genomic dataset of 885 patients treated with immune checkpoint inhibitors (ICIs), we developed a score integrating the binding affinity of neoantigens to HLA-I, as well as HLA-I allele divergence, termed the HLA tumor-Antigen Presentation Score (HAPS). Patients with a high HAPS were more likely to experience survival benefit following ICI treatment. Analysis of the tumor microenvironment indicated that the antigen presentation pathway was enriched in patients with a high HAPS. Finally, we built a neural network incorporating factors associated with neoantigen production, presentation, and recognition, which exhibited potential for differentiating cancer patients likely to benefit from ICIs. Our findings highlight the clinical utility of evaluating HLA-I tumor antigen presentation capacity and describe how ICI response may depend on HLA-mediated immunity.

Abstract Retinoblastoma (RB) is the most prevalent ocular tumor of childhood, and its extraocular invasion significantly increases the risk of metastasis. Nevertheless, a single-cell characterization of RB local extension has been lacking. Here, we perform single-cell RNA sequencing on four RB samples (two from intraocular and two from extraocular RB patients), and integrate public datasets of five normal retina samples, four intraocular samples, and three extraocular RB samples to characterize RB local extension at the single-cell level. A total of 128,454 qualified cells are obtained in nine major cell types. Copy number variation inference reveals chromosome 6p amplification in cells derived from extraocular RB samples. In cellular heterogeneity analysis, we identified 10, 8, and 7 cell subpopulations in cone precursor like cells, retinoma like cells, and MKI67+ photoreceptorness decreased (MKI67+ PhrD) cells, respectively. A high expression level of SOX4 was detected in cells from extraocular samples, especially in MKI67+ PhrD cells, which was verified in additional clinical RB samples. These results suggest that SOX4 might drive RB local extension. Our study presents a single-cell transcriptomic landscape of intraocular and extraocular RB samples, improving our understanding of RB local extension at the single-cell resolution and providing potential therapeutic targets for RB patients.

Abstract The Retinoic acid-Inducible Gene I (RIG-I) like receptors (RLRs) are the major viral RNA sensors essential for the initiation of antiviral immune responses. RLRs are subjected to stringent transcriptional and posttranslational regulations, of which ubiquitination is one of the most important. However, the role of ubiquitination in RLR transcription is unknown. Here, we screen 375 definite ubiquitin ligase knockout cell lines and identify Ubiquitin Protein Ligase E3 Component N-Recognin 5 (UBR5) as a positive regulator of RLR transcription. UBR5 deficiency reduces antiviral immune responses to RNA viruses, while increases viral replication in primary cells and mice. Ubr5 knockout mice are more susceptible to lethal RNA virus infection than wild type littermates. Mechanistically, UBR5 mediates the Lysine 63-linked ubiquitination of Tripartite Motif Protein 28 (TRIM28), an epigenetic repressor of RLRs. This modification prevents intramolecular SUMOylation of TRIM28, thus disengages the TRIM28-imposed brake on RLR transcription. In sum, UBR5 enables rapid upregulation of RLR expression to boost antiviral immune responses by ubiquitinating and de-SUMOylating TRIM28.

Human noroviruses (HuNoVs) are the main pathogens that cause acute gastroenteritis and lead to huge economic losses annually. Due to the lack of suitable culture systems, the pathogenesis of HuNoVs and the development of vaccines and drugs have progressed slowly. Although researchers have employed various methods to culture HuNoVs in vitro in the last century, problems relating to the irreducibility, low viral titer, and non-infectiousness of the progeny virus should not be ignored. In 2016, researchers achieved the cultivation and successive passaging of some HuNoV genotypes using human intestinal enteroids, initially demonstrating the potential use of organoids in overcoming this challenge. This paper reviews the efforts made in the last 20 years to culture HuNoVs in vitro and discusses the superiority and limitations of employing human intestinal enteroids/organoids as an in vitro culture model for HuNoVs.

The improvement of information sciences promotes the utilization of data for process monitoring. As the core of modern automation, time-stamped signals are used to estimate the system state and construct the data-driven model. Many recent studies claimed that the effectiveness of data-driven methods relies greatly on data quality. Considering the complexity of the operating environment, process data will inevitably be affected. This poses big challenges to estimating faults from data and delivers feasible strategies for electrical systems of industry. This paper addresses the missing data problem commonly in traction systems by designing a martingale posterior-based data generation method for the state-space model. Then, a data-driven approach is proposed for fault detection and estimation via the subspace identification technique. It is a general scheme using the Bayesian framework, in which the Dirichlet process plays a crucial role. The data-driven method is applied to a pilot-scale traction motor platform. Experimental results show that the method has good estimation performance.

Background: The fate and functions of RNAs are coordinately regulated by RNA-binding proteins (RBPs), which are often dysregulated in various cancers. Known as a splicing regulator, RNA-binding motif protein 6 (RBM6) harbors tumor-suppressor activity in many cancers; however, there is a lack of research on the molecular targets and regulatory mechanisms of RBM6. Methods: In this study, we constructed an RBM6 knock-down (shRBM6) model in the HeLa cell line to investigate its functions and molecular targets. Then we applied improved RNA immunoprecipitation coupled with sequencing (iRIP-seq) and whole transcriptome sequencing approaches to investigate the potential role and RNA targets of RBM6. Results: Using The Cancer Genome Atlas dataset, we found that higher expression of RBM6 is associated with a better prognosis in many cancer types. In addition, we found that RBM6 knockdown promoted cell proliferation and inhibited apoptosis, demonstrating that RBM6 may act as an anti-oncogenic protein in cancer cells. RBM6 can regulate the alternative splicing (AS) of genes involved in DNA damage response, proliferation, and apoptosis-associated pathways. Meanwhile, RBM6 knockdown activated type I interferon signaling pathways and inhibited the expression of genes involved in the cell cycle, cellular responses to DNA damage, and DNA repair pathways. The differentially expressed genes (DEGs) by shRBM6 and their involved pathways were likely regulated by the transcription factors undergoing aberrant AS by RBM6 knockdown. For iRIP-seq analysis, we found that RBM6 could interact with a large number of mRNAs, with a tendency for binding motifs GGCGAUG and CUCU. RBM6 bound to the mRNA of cell proliferation- and apoptosis-associated genes with dysregulated AS after RBM6 knockdown. Conclusions: In summary, our study highlights the important role of RBM6, as well as the downstream targets and regulated pathways, suggesting the potential regulatory mechanisms of RBM6 in the development of cancer.

AbstractThe complete mitochondrial genome of Rhinogobius maculagenys Wu et al., (Perciformes,Gobiidae) was sequenced and annotated in this study. The circular mitogenome is 16,500 bp long and consists of 13 protein-coding genes, two ribosomal RNA genes, 22 transfer RNA genes and two main non-coding regions (a putative control region and an L-strand replication origin). The overall base composition is 27.5% A, 25.5% T, 16.9% G, and 30.1% C. The gene order and composition are similar to those of other Gobionellinae species. Phylogenetic analysis revealed that R. maculagenys is closely related to Rhinogobius shennongensis in both the maximum likelihood tree and the Bayesian inference tree. The complete mitogenome of R. maculagenys will serve as a valuable resource for future studies on evolution, taxonomy, and genetic conservation of Rhinogobius.

Abstract Background Efferocytosis is a biological process in which phagocytes remove apoptotic cells and vesicles from tissues. This process is initiated by the release of inflammatory mediators from apoptotic cells and plays a crucial role in resolving inflammation. The signals associated with efferocytosis have been found to regulate the inflammatory response and the tumor microenvironment (TME), which promotes the immune escape of tumor cells. However, the role of efferocytosis in glioblastoma multiforme (GBM) is not well understood and requires further investigation. Methods In this study, we conducted a comprehensive analysis of 22 efferocytosis-related genes (ERGs) by searching for studies related to efferocytosis. Using bulk RNA-Seq and single-cell sequencing data, we analyzed the expression and mutational characteristics of these ERGs. By using an unsupervised clustering algorithm, we obtained ERG clusters from 549 GBM patients and evaluated the immune infiltration characteristics of each cluster. We then identified differential genes (DEGs) in the two ERG clusters and classified GBM patients into different gene clusters using univariate cox analysis and unsupervised clustering algorithms. Finally, we utilized the Boruta algorithm to screen for prognostic genes and reduce dimensionality, and the PCA algorithm was applied to create a novel efferocytosis-related scoring system. Results Differential expression of ERGs in glioma cell lines and normal cells was analyzed by rt-PCR. Cell function experiments, on the other hand, validated TIMD4 as a tumor risk factor in GBM. We found that different ERG clusters and gene clusters have distinct prognostic and immune infiltration profiles. The ERG signature we developed provides insight into the tumor microenvironment of GBM. Patients with lower ERG scores have a better survival rate and a higher likelihood of benefiting from immunotherapy. Conclusions Our novel efferocytosis-related signature has the potential to be used in clinical practice for risk stratification of GBM patients and for selecting individuals who are likely to respond to immunotherapy. This can help clinicians design appropriate targeted therapies before initiating clinical treatment.

Abstract Background Anaerobic fungi are effective fibre-degrading microorganisms in the digestive tract of horses. However, our understanding of their diversity and community structure is limited, especially in different parts of the gastrointestinal tract. Results For the first time, high-throughput sequencing technology was used to analyse and predict fungal microbial diversity in different parts of the gastrointestinal tract of Mongolian horses. The results revealed that the richness and diversity of fungi in the hindgut of Mongolian horses were much higher than those in the foregut. The foregut was dominated by Basidiomycota and Ascomycota, whereas the hindgut was dominated by Neocallimastigomycota and Basidiomycota. At the genus level, the relative abundance of many pathogenic fungi (Cryptococcus, Cladosporium, Alternaria, and Sarocladium) in the foregut was significantly higher than that in the posterior gut, indicating that Mongolian horses have strong disease resistance. The prediction of fungal function also showed significant differences in the fungal flora between the foregut and the hindgut. The fungi in Mongolian horses’ foreguts were mainly pathologically nutritive and contained many animal and plant pathogens, particularly in the small intestine (jejunum and ileum). This indicates that the foregut may be the most important immune site in the digestive system of Mongolian horses, which explains the high disease resistance of Mongolian horses. The number of unassigned functional groups in the posterior gut was significantly higher than that in the anterior gut, indicating that the functions of fungal groups in the posterior gut have not been fully explored, and further studies are required in the future. Conclusions Analysis of high-throughput sequencing results revealed that the fungal composition varied greatly among different gastrointestinal tract segments in Mongolian horses, whose hindgut contains many anaerobic fungi involved in plant cellulose degradation. This provides important basic data for studying fungal diversity in the digestive system of healthy horses, which can be used for the health assessment of horses and provides clues for further research on the disease resistance and digestive capacity of horses, as well as a reference for the early diagnosis of intestinal diseases and innovative treatment methods.

Investigating oat tissue microflora during its different developmental stages is necessary for understanding its growth and anti-disease mechanism. In this study, 16S rDNA and ITS (Internally Transcribed Spacer) high-throughput sequencing technology were used to explore the microflora diversity of oat tissue. Twenty-seven samples of leaves, stems, and roots from three developmental stages, namely the seedling stage (SS), jointing stage (JS), and maturity stage (MS), underwent sequencing analysis. The analysis showed that 6480 operational taxonomic units (OTUs) were identified in the examined samples, of which 1698 were fungal and 4782 were bacterial. Furthermore, 126 OTUs were shared by fungi, mainly Ascomycota, Basidiomycota, and Mucoromycota at the phylum level, and 39 OTUs were shared by bacteria, mainly Actinobacteriota and Proteobacteria at the phylum level. The microbial diversity of oat tissue in the three developmental stages showed differences, and the α-diversity of the bacteria and β-diversity of the bacteria and fungi in the roots were higher than those of the stems and leaves. Among the bacteria species, Thiiopseudomonas, Rikenellaceae RC9 gut group, and Brevibacterium were predominant in the leaves, MND1 was predominant in the roots, and Lactobacillus was predominant in the stems. Moreover, Brevibacterium maintained a stable state at all growth stages. In the fungal species, Phomatospora was dominant in the leaves, Kondoa was dominant in the roots, and Pyrenophora was dominant in the stems. All species with a high abundance were related to the growth process of oats and antagonistic bacteria. Furthermore, connection modules were denser in bacterial than in fungal populations. The samples were treated with superoxide dismutase and peroxidase. There were 42 strains associated with SOD (Superoxide dismutase), 60 strains associated with POD (Peroxidase), and 38 strains in total, which much higher than fungi. The network analysis showed that bacteria might have more dense connection modules than fungi, The number of bacterial connections to enzymes were much higher than that of fungi. Furthermore, these results provide a basis for further mechanistic research.

Summary: Tissue-resident memory T cells (TRM) are a specialized T cell population residing in peripheral tissues. The presence and potential impact of TRM in the tumor immune microenvironment (TIME) remain to be elucidated. Here, we systematically investigated the relationship between TRM and melanoma TIME based on multiple clinical single-cell RNA-seq datasets and developed signatures indicative of TRM infiltration. TRM infiltration is associated with longer overall survival and abundance of T cells, NK cells, M1 macrophages, and memory B cells in the TIME. A 22-gene TRM–derived risk score was further developed to effectively classify patients into low- and high-risk categories, distinguishing overall survival and immune activation, particularly in T cell-mediated responses. Altogether, our analysis suggests that TRM abundance is associated with melanoma TIME activation and patient survival, and the TRM-based machine learning model can potentially predict prognosis in melanoma patients.

Abstract Posttranslational modification dramatically enhances protein complexity, but the function and precise mechanism of novel lysine acylation modifications remain unknown. Chemoresistance remains a daunting challenge to successful treatment. We found that lysine butyrylation (Kbu) is specifically upregulated in chemoresistant tumor cells and tissues. By integrating butyrylome profiling and gain/loss-of-function experiments, lysine 754 in HSP90 (HSP90 K754) was identified as a substrate for Kbu. Kbu modification leads to overexpression of HSP90 in esophageal squamous cell carcinoma (ESCC) and its further increase in relapse samples. Upregulation of HSP90 contributes to 5-FU resistance and can predict poor prognosis in cancer patients. Mechanistically, HSP90 K754 is regulated by the cooperation of KAT8 and HDAC11 as the writer and eraser, respectively; SDCBP increases the Kbu level and stability of HSP90 by binding competitively to HDAC11. Furthermore, SDCBP blockade with the lead compound V020-9974 can target HSP90 K754 to overcome 5-FU resistance, constituting a potential therapeutic strategy.

Context: The incidence of urolithiasis is increasing year by year. Ureteral stents are a popular treatment option for this condition. Efforts to improve the material and structure of stents to increase comfort and reduce complications have led to the introduction of magnetic stents. Objective: To evaluate differences in removal efficiency and safety for magnetic and conventional stents. Evidence acquisition: This study was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Data were extracted according to the PRISMA principles. We collected and combined data from randomized controlled trials on magnetic versus conventional stents to evaluate the efficiency of their removal and the associated effects. Data synthesis was performed using RevMan 5.4.1 and heterogeneity was evaluated using I2 tests. A sensitivity analysis was also performed. Key metrics included the stent removal time, Visual Analog Scale (VAS) pain scores, and Ureteral Stent Symptom Questionnaire (USSQ) scores for various domains. Evidence synthesis: Seven studies were included in the review. We found that magnetic stents had a shorter removal time (mean difference [MD] −8.28 min, 95% confidence interval [CI] −15.6 to −0.95; p = 0.03) and their removal was associated with less pain (MD −3.01 points, 95% CI −3.83 to −2.19; p

Abstract Circular RNA HIPK3 (circHIPK3) mediates the progression of multiple cancers, including bladder cancer, by regulating cell migration, autophagy and epithelial mesenchymal transition. However, the mechanism by which circHIPK3 regulates autophagy in bladder cancer cells remains unclear. Autophagy is a common self-protection mechanism in eukaryotic cells and is essential for cell survival and death regulation. However, it is unclear whether circHIPK3 affects the level of autophagy in bladder cancer through binding proteins, and the potential regulatory mechanism is unknown. Here, we found that circHIPK3 levels were significantly lower and autophagy-related proteins were significantly upregulated in bladder cancer cells and tissues compared to normal controls. CircHIPK3 downregulation promoted bladder cancer cell proliferation, while circHIPK3 overexpression inhibited proliferation. CircHIPK3 overexpression significantly suppressed autophagy in bladder cancer cells. Overexpression of circHIPK3 did not affect VCP protein expression but inhibited the VCP/Beclin 1 interaction. VCP also stabilized Beclin 1 and promoted autophagy in bladder cancer cells by downregulating ataxin-3. Thus, circHIPK3 may play an important role in bladder cancer by inhibiting VCP-mediated autophagy.

Lead (Pb) is a common environmental neurotoxicant that results in abnormal neurobehavior and impaired memory. Avicularin (AVL), the main dietary flavonoid found in several plants and fruits, exhibits neuroprotective and hepatoprotective properties. In the present study, the effects of AVL on Pb-induced neurotoxicity were evaluated using ICR mice to investigate the molecular mechanisms behind its protective effects. Our study has demonstrated that AVL treatment significantly ameliorated memory impairment induced by lead (Pb). Furthermore, AVL mitigated Pb-triggered neuroinflammation, ferroptosis, and oxidative stress. The inhibition of Pb-induced oxidative stress in the brain by AVL was evidenced by the reduction in malondialdehyde (MDA) levels and the enhancement of glutathione (GSH) and glutathione peroxidase (GPx) activities. Additionally, in the context of lead-induced neurotoxicity, AVL mitigated ferroptosis by increasing the expression of GPX4 and reducing ferrous iron levels (Fe2+). AVL increased the activities of glycogenolysis rate-limiting enzymes HK, PK, and PYG. Additionally, AVL downregulated TNF-α and IL-1β expression while concurrently enhancing the activations of AMPK, Nrf2, HO-1, NQO1, PSD-95, SNAP-25, CaMKII, and CREB in the brains of mice. The findings from this study suggest that AVL mitigates the memory impairment induced by Pb, which is associated with the AMPK/Nrf2 pathway and ferroptosis.

Land intensive use reflects the spatial structure, agglomeration characteristics, and internal mechanisms of urban economic, social, and ecological system development, significantly impacting urban resilience. Based on panel data from 287 cities in China from 2010 to 2020, this paper measures the levels of land intensive use and urban resilience, and empirically examines the impact mechanism of land intensive use on urban resilience through baseline regression and panel quantile regression. The results reveal that: (1) During the study period, China’s urban land intensive use level has significantly improved. The land intensive use level shows a trend of “the strong become stronger, and the weak are always weak” and “high in the east and low in the west” spatial differentiation, while the urban resilience level showed a trend of accelerated “catching up” of low-resilience cities towards high-resilience cities and “high in the east and low in the west” spatial differentiation as well. (2) Land intensive use significantly promotes effect on urban resilience, and the effect depends on different conditions. (3) Among all dimensions of land intensive use, both land input intensity and land use benefits significantly promote urban resilience, while land use intensity shows an insignificant effect. (4) The impact of land intensive use on urban resilience demonstrates significant scale heterogeneity and geographic regional heterogeneity. Based on these findings, the paper proposes relevant policy suggestions for land intensive use aimed at improving urban resilience, offering guidance for promoting high-quality land use and sustainable urban resilience development.

The contact between a traditional crop divider and sugarcane is unstable, and the sugarcane easily slides off of its surface. By analyzing the movement process of sugarcane, the influence of traditional spiral flightings on lifting performance was studied, and shortcomings were also found. Based on previous research and analysis, the variable spiral spike-toothed crop divider was designed by research groups. For sugarcane with different lodging states, the contact separation rule between the sugarcane and the spike tooth was studied, and the action time and angle of the spike tooth on sugarcane were obtained. At the same time, the interaction mechanism between sugarcane and the spike tooth was analyzed, and the conditions for lodged canes to be lifted were obtained. The influence of the spike tooth on the lifting performance was explored, and the working advantages were found for the spike-toothed crop divider. Then, a simulation test was conducted to obtain the contact force between the sugarcane and the crop divider. Finally, the crop divider was optimized and integrated into the harvester, and a field harvesting test was carried out to verify the working performance of the crop divider. This study was expected to provide a reference for the design of crop dividers and a theoretical basis for the analysis of the lifting process.

ABSTRACTRuminal microbiota is gradually established after birth, while microbiota maturation could be highly diverse because of varied solid dietary accessibility. However, how the ruminal microbiota accreted from postnatal hay diets alters rumen epithelial development, and how this affects animal health remains largely unknown. Here, neonatal lambs were introduced to starchy corn-soybean starter or corn-soybean starter + alfalfa hay (AH) to investigate the influences of early life ruminal microbiome on rumen epithelial development using integrated 16s rRNA sequencing-metagenome-transcriptome approaches. The results showed that AH introduction elevated average daily weight gain, rumen weight and volume, rumen epithelial papillae length, and rumen muscle layer thickness. Meanwhile, the relative abundance of fibrolytic bacteria (Christensenellaceae R-7 group, Prevotellaceae UCG-001, and Succinivibrio), acetate producer (Acetitomaculum and Mitsuokella), and propionate producer Succiniclasticum was increased in the rumen content by AH supplementation (P < 0.05). Moreover, AH introduction decreased the relative abundance of total CAZymes, CBM, and GH and increased the abundance of KO genes related to volatile fatty acid (VFA) generation in the rumen content. AH lambs had a higher relative abundance of Succiniclasticum, Megasphaera, Succinivibrio, and Suttonella (P < 0.05), while a lower relative abundance of Cloacibacillus, Desulfovibrio, Dialister, Intestinimonas, Parabacteroides, and Pseudoscardovia (P < 0.05) in the rumen epithelial samples. Furthermore, these alterations in ruminal microbial structure and function resulted in ruminal epithelial cell proliferation and development pathways activation. In summary, AH introduction benefited ruminal fiber degradation and VFA generation bacteria colonization and promoted ruminal epithelial development. These findings provide new insights into ruminal microbial–host interactions in the early life.IMPORTANCEWhile it is established that a fiber-rich diet promotes rumen development in lambs, further research is needed to investigate the precise response of rumen microbiota and epithelium to high-quality alfalfa hay. Here, we observed that the inclusion of alfalfa hay led to a discernible alteration in the developmental trajectory of the rumen. Notably, there was a favorable shift in the rumen's volume, morphology, and the development of rumen papillae. Furthermore, ruminal microbial structure and function resulted in ruminal epithelial cell proliferation and development pathways activation, collectively provide compelling evidence supporting the capacity of alfalfa hay to enhance rumen development and health through ruminal micrbiota-host crosstalks. Our findings elucidate the functional response of the rumen to alfalfa hay introduction, providing new insights into strategies for promoting healthy development of the rumen in young ruminants.

Abstract To investigate the association between clonal haematopoiesis (CH) and lung cancer risk, we identified CH mutations in 1 059 lung cancer cases and 899 controls using the blood whole‐exome sequencing data generated from the Integrative Analysis of Lung Cancer Etiology and Risk project of the International Lung Cancer Consortium (INTEGRAL‐ILCCO). Based on the variant allele frequency (VAF) of these mutations, we stratified CH carriers into two groups, low VAF (1%–10%) and high VAF (≥10%), respectively. We observed a significant association between the presence of CH mutations and the risk of lung cancer after adjusting for known risk factors (odd ratio, OR = 1.37, 95% confidence interval, CI = 1.02–1.85). Such an association was largely driven by CH mutations with high‐VAF, the OR for high‐VAF CH and low‐VAF CH were 2.54 (1.38–4.93) and 1.14 (0.82–1.6), respectively. Trend analysis indicated a significant dose–response relationship (P trend = 0.004). This association between high‐VAF CH and lung cancer risk remained consistent when subjects were stratified by risk factors or lung cancer histological subtypes. A combination of results from INTEGRAL‐ILCCO, UKBB, and MGBB cohorts resulted in a meta‐analysed OR of 1.36 (95% CI = 1.14–1.62) for all CH carriers and of 1.76 (95% CI = 1.34–2.31) for high‐VAF CH carriers, respectively. In conclusion, our analysis revealed a significant association between CH and increased risk of lung cancer as supported by three independent cohorts.

Backfill materials are used in underground engineering to fill voids and buried excavated parts. In this study, solid waste was utilised as a raw material mixed with different amounts of polypropylene fibres to determine the optimal sodium hydroxide content, water-solid ratio, and fibre content. The uniaxial compressive strength (UCS) of the produced backfill materials was measured, and the interfacial structures were analysed via scanning electron microscopy. The results revealed that the mechanical properties of the backfill materials were influenced in the order sodium hydroxide doping > water-solid ratio > fibre doping. The optimal material composition corresponded to a sodium hydroxide content of 3%, water-solid ratio of 0.28, and fibre content of 5 ‰. The slag produced a C-S-H gel. Meanwhile, the fly ash and gangue contained large amounts of aluminium, which formed hydrated aluminosilicates. The addition of polypropylene fibres reduced the number of internal defects in the backfill structure and increased the UCS.

Summary: Exploring the clinical relevance of diverse immune cell types within the tumor microenvironment is pivotal for unraveling cancer intricacies and developing treatments. Here, we present a protocol for using tumor immune microenvironment illustration based on gene pairs, an R package to deduce cell-cell interactions, unveiling the association between immune cell relative abundance and patient prognoses from bulk gene expression and survival data. We describe steps for harnessing cell-type markers derived from single-cell RNA sequencing data to map the tumor immune microenvironment across a spectrum of cancer types.For complete details on the use and execution of this protocol, please refer to Li et al. (2023).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract Acute kidney injury is common among hospitalized individuals, particularly those exposed to certain medications, and is associated with substantial morbidity and mortality. In a pragmatic, open-label, National Institutes of Health-funded, parallel group randomized controlled trial (clinicaltrials.gov NCT02771977), we investigate whether an automated clinical decision support system affects discontinuation rates of potentially nephrotoxic medications and improves outcomes in patients with AKI. Participants included 5060 hospitalized adults with AKI and an active order for any of three classes of medications of interest: non-steroidal anti-inflammatory drugs, renin-angiotensin-aldosterone system inhibitors, or proton pump inhibitors. Within 24 hours of randomization, a medication of interest was discontinued in 61.1% of the alert group versus 55.9% of the usual care group (relative risk 1.08, 1.04 – 1.14, p = 0.0003). The primary outcome – a composite of progression of acute kidney injury, dialysis, or death within 14 days - occurred in 585 (23.1%) of individuals in the alert group and 639 (25.3%) of patients in the usual care group (RR 0.92, 0.83 – 1.01, p = 0.09). Trial Registration Clinicaltrials.gov NCT02771977.

Abstract Background Immune checkpoint proteins play critical functions during the immune response to cancer and have been targeted by immune checkpoint blockade therapy. V‐domain Ig suppressor of T cell activation (VSIR) is one of these immune checkpoint genes and has been investigated extensively in recent years due to its conflicting roles in cancer immunity. Specifically, in acute myeloid leukemia (AML), the prognostic value of VSIR is debated. Results In both patient tumor samples and cancer cell lines we find that VSIR has the highest expression in AML out of all cancer types and, in AML, has the highest expression out of all other immune checkpoint genes. Survival analysis indicated that AML patients with higher VSIR expression have significantly shorter survival than those patients with lower expression, even within established AML subgroups (e.g., FAB subtypes). Importantly, VSIR expression is predictive of progression from myelodysplastic syndromes (MDS) patients into AML, suggesting its potential role during the very early stage of AML development and progression. In addition to AML, VSIR also demonstrates prognostic values in other cancer types, including multiple myeloma and mesothelioma. Conclusion In summary, our analyses revealed the prognostic value of VSIR and its potential as a target for immunotherapy, especially in AML.

Abstract Despite mitochondrial DNA (mtDNA) mutations are common events in cancer, their global frequency and clinical impact have not been comprehensively characterized in patients with myelodysplastic neoplasia (also known as myelodysplastic syndromes, MDS). Here we performed whole-genome sequencing (WGS) on samples obtained before allogenic hematopoietic cell transplantation (allo-HCT) from 494 patients with MDS who were enrolled in the Center for International Blood and Marrow Transplant Research. We evaluated the impact of mtDNA mutations on transplantation outcomes, including overall survival (OS), relapse, relapse-free survival (RFS), and transplant-related mortality (TRM). A random survival forest algorithm was applied to evaluate the prognostic performance of models that include mtDNA mutations alone and combined with MDS- and HCT-related clinical factors. A total of 2666 mtDNA mutations were identified, including 411 potential pathogenic variants. We found that overall, an increased number of mtDNA mutations was associated with inferior transplantation outcomes. Mutations in several frequently mutated mtDNA genes (e.g., MT-CYB and MT-ND5) were identified as independent predictors of OS, RFS, relapse and/or TRM after allo-HCT. Integration of mtDNA mutations into the models based on the Revised International Prognostic Scores (IPSS-R) and clinical factors related to MDS and allo-HCT could capture more prognostic information and significantly improve the prognostic stratification efforts. Our study represents the first WGS effort in MDS receiving allo-HCT and shows that there may be clinical utility of mtDNA variants to predict allo-HCT outcomes in combination with more standard clinical parameters.

Abstract Stage III non‐small cell lung cancer (NSCLC) encompasses a group of diseases with high heterogeneity. Such patients should actively receive comprehensive treatments. It is imperative for all stage III NSCLC patients to receive consultation with a multiple disciplinary team, which allows the development of a proposal for clinical diagnosis and treatment. In this consensus, stage III NSCLC is divided into two types (operable and inoperable) according to different clinical conditions. Resectable NSCLC is further subdivided into two conditions (with or without driver genes). For each clinical scenario, this consensus emphasizes that the foundation of any medical decisions regarding the optimal diagnostic or therapy procedure is scientific evidence from clinical research. Finally, based on the level of evidence and strength of recommendations, this consensus provides recommendations for the management of stage III NSCLC from six perspectives. The objective of this consensus is to help clinicians choose the best treatment and promote the standardization of stage III NSCLC diagnosis and treatment in China.