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Abstract The stabilization of reactive anionic main group species utilizing carbenes constitutes a burgeoning and scarcely explored field. Herein, we report the synthesis of an anionic triphosphorus [P3]ˉ unit, supported by two cyclic (alkyl)(amino)carbenes (CAACs) in the form of potassium salts. This anion features a planar W-shaped conjugated C-P-P-P-C framework, characterized by 5-center-6-electron π delocalization and an additional σ lone pair located on each of the three phosphorus atoms. Remarkably, this anion is not only strongly basic and nucleophilic but also reductive, positioning versatile functionalization of the [P3] unit. This approach has advanced the isolation of unique carbene-supported cores, including [HP3], [P3N3R]−, [P3O]− and [P6], thus expanding the frontiers of phosphorus chemistry. Moreover, the addition of the two phosphorus fragments upon P-P bond cleavage of the [P3] unit to the triple bond of diphenylacetylene for the synthesis of an extended conjugated system was described. more...

In this work, we take advantage of the characteristic of bulk Dirac semimetals (BDS) that their Fermi level can be controlled by electrostatic doping, as well as the phase transition characteristics of vanadium dioxide (VO2). Combining these two materials, we designed a terahertz metamaterial absorber with multiple control methods. It has four absorption peaks in the range of 1.5 THz to 6 THz, and the absorption rates are all above 95 %, reaching a maximum of 99.8 %. When the Fermi level of Dirac semimetals rises from 80 to 100 meV, the resonance frequency of four absorption bands of our equipment goes up, and the absorption rate remains stable, some even magnifying. The absorption peak with the largest increase in amplitude changed from 92.4 % to 99.9 %, an increase of 7.5 %. The maximum regulation range of the absorption peaks is as high as 0.34 THz. In addition, we explained the absorption principle of the equipment from two aspects: relative impedance matching and analysis of the electric field intensity distribution map, and we demonstrated the rationality of our absorber structure design through parameter scanning. Our absorber also has excellent polarization insensitivity and high refractive index sensitivity. It has potential application value in sensing, detection, medical and other fields, and our design provides new reference value for absorber designs with multiple regulation methods. more...

Abstract Purpose The soil-borne diseases have limited the development of agricultural production in Guizhou Province of southwest China which was caused by long-term continuous cropping of crops. To reduce the limit factors of continuous cropping of corps has become an urgent problem. Methods Reductive soil disinfestation (RSD) is an environmentally friendly soil amendment technology. In this study, high-throughput sequencing was used to investigate the mechanisms of RSD technology to improve long-term continuous cropping soil health. The examination focused on discerning how RSD influences the composition and structure of the rhizosphere microbial community. Result The results demonstrated that: (1) RSD treatment increased the content of soil organic matter (SOM), alkaline hydrolyzed nitrogen (AN), available phosphorus (AP), available potassium (AK) and pH; (2) RSD changed the fungal and bacterial community structure and the relative abundance of pathogenic microorganisms (e.g., Fusarium) was reduced, while the beneficial microorganisms (e.g., Trichoderma and Penicillium) was increased. (3) AN and pH had a greater impact on the bacterial community in the rhizosphere soil than on the fungal community. (4) RSD treatment improved the agronomic traits of tobacco and reduced the disease incidence of root rot disease. Conclusion Our results revealed that RSD treatment improved the physicochemical properties of continuous cropping tobacco soil and maintain the soil nutrient balance, resulting in the effective alleviation of continuous cropping barriers. more...

Highlights A self-constructed catalyst with in situ formed IrO2/IrTaO x bi-layer nanostructure was fabricated for high-efficiency acidic oxygen evolution reaction by using an Ir–Ta-based metallic glass as the matrix. The coordinated nature of the catalyst’s active site is manipulated through electronic interaction between Ir and Ta, resulting in superior activity and stability. The underlying amorphous IrTaO x layer dynamically replenishes the depletion of surface Ir sites through inward crystallization and selective dissolution to ensure long-term durability. more...

Abstract Prostate cancer (PCa) ranks as the second most common malignancy and the fifth leading cause of cancer-related deaths among men. A critical challenge lies in accurately identifying those patients at high risk for transitioning rapidly from hormone-sensitive PCa (HSPC) to lethal castration-resistant PCa (CRPC). In our study, we employed a multiomics approach involving bioinformatics analysis on datasets GSE2443 and GSE35988, along with proteomics studies, to discover that cysteine- and glycine-rich protein 1 (CSRP1) expression significantly impacts the progression of HSPC. This hypothesis was substantiated through experiments using PC3 and LNCaP prostate cancer cells, where we conducted scratch assays and apoptosis assays, all of which confirmed CSRP1’s role in suppressing tumor growth. Furthermore, we elucidated the inhibitory effect of CSRP1 on tumors by performing xenograft experiments on castrated mice models. To solidify these findings in a clinical context, we constructed a nomogram model integrating CSRP1’s immunohistochemistry data and clinical parameters from an actual patient cohort with HSPC. This model revealed that low CSRP1 expression indeed promotes the advancement towards CRPC. In conclusion, the level of CSRP1 expression can serve as a valuable biomarker for clinicians to predict disease progression in their patients. It has the potential to guide personalized clinical management and decision-making strategies, thereby contributing to more effective and targeted treatment approaches for HSPC patients. more...

Abstract Background Coronary artery disease (CAD), one of the most prevalent cardiovascular diseases, is a critical health issue that affects millions of individuals worldwide. It has been reported that miR-146b-5p exhibited a strong correlation with inflammatory responses and atherosclerosis. However, its association with the incidence and severity of CAD has not been substantiated in a large cohort. In the study, we focus on the expression of miR-146b-5p in peripheral blood mononuclear cells (PBMCs) of patients with CAD and preliminarily investigate its function and underlying mechanism. Methods and results The study encompassed a total of 452 participants, consisting 295 patients with CAD and 157 individuals without CAD. Quantitative reverse transcription–polymerase chain reaction (qRT–PCR) was performed to assess miR-146b-5p expression in PBMCs. We found that miR-146b-5p was significantly increased in PBMCs of patients with CAD compared with the control group. Binary logistic regression revealed that miR-146b-5p was associated with CAD. Receiver Operation Characteristic (ROC) analysis showed that the sensitivity and specificity of miR-146b-5p in discriminating CAD patients from non-CAD patients were meaningful. Subsequent subgroup analysis showed that miR-146b-5p was related to the severity of CAD. Furthermore, gain- and loss-of-function experiments in THP-1 cells showed that miR-146b-5p inhibited inflammation, cell proliferation, and migration. Mechanically, miR-146b-5p was involved in the classical NF-κB inflammatory pathway by directly targeting IKKβ. Conclusion Our study revealed that miR-146b-5p was higher in the PBMCs of CAD patients than non-CAD individuals, and established a correlation between miR-146b-5p and occurrence and severity of CAD. In addition, the inflammatory role of miR-146b-5p is mediated by targeting IKKβ. more...

The complex structures and intricate hyperparameters of existing deep learning (DL) models make achieving higher accuracy in landslide susceptibility assessment (LSA) time-consuming and labor-intensive. Deep forest (DF) is a decision tree-based DL framework that uses a cascade structure to process features, with model depth adapting to the input data. To explore a more ideal landslide susceptibility model, this study designed a landslide susceptibility model combining convolutional neural networks (CNNs) and DF, referred to as CNN-DF. The Bailong River Basin, a region severely affected by landslides, was chosen as the study area. First, the landslide inventory and influencing factors of the study area were obtained. Second, an equal number of landslide and nonlandslide samples were selected under similar environmental constraints to establish the dataset. Third, CNN was used to extract high-level features from the raw data, which were then input into the DF model for training and testing. Finally, the trained model was used to predict landslide susceptibility. The results showed that the CNN-DF model achieved high prediction accuracy, with an AUC of 0.9061 on the testing set, outperforming DF, CNN, and other commonly used machine learning models. In landslide susceptibility maps (LSMs), the proportion of historical landslides in the very high susceptibility category of CNN-DF was also higher than that of other models. CNN-DF is feasible for LSA, offering higher efficiency and more accurate results. In addition, the SHAP algorithm was used to quantify the contribution of features to the prediction results both globally and locally, further explaining the model. The LSM based on CNN-DF can provide a scientific basis for landslide prevention and disaster management in the target area. more...

The pivotal role of color imagery analysis and activation has been insufficiently explored in the realm of historic heritage conservation. This study addresses this issue by introducing a comprehensive methodological framework that encompasses acquisition, analysis, activation, and application of color information based on the NCD (Nippon Color & Design) color system, an innovative color semantic quantification theory. Utilizing the venerable Yuelu Academy (from A.D. 976) as a case study, color imagery analysis methods across diverse spatial scales have been summarized. Subsequently, these results are applied to activate the surrounding environment color, as well as its cultural souvenirs. The methodologies outlined herein hold profound significance in addressing challenges concerning visual color continuity in the preservation of historic architectural landscapes, offering innovative perspectives. more...

Abstract Background Lidocaine is a traditional local anesthetic, which has been reported to trigger apoptosis through the mitochondrial pathway, independent of death receptor signaling. Cuproptosis is a copper triggered mitochondrial cell death mode. In this study, we explored the biological effects of lidocaine on cuproptosis in Hep-2 cells and studied the relevant mechanisms. Methods quantitative RT-PCR was used to measure the expression level of long noncoding RNA (IncRNA) DNMBP-AS1. DNMBP-AS1 siRNA (si-DNMBP-AS1) were transfected into Hep-2 cells to verify the roles of DNMBP-AS1 in cuproptosis. 24 h treatment with 20 nM elesclomol and 2 µM CuCl2 was performed to promote the occurrence of Cuproptosis. Cell proliferation, migration and apoptosis assays ware utilized to analyze biological effect of lidocaine and DNMBP-AS1 on Hep-2 cells. Active caspase-3 were also determined after treatment. Results DNMBP-AS1 was significantly upregulated during cuproptosis in Hep-2 cells. The si-DNMBP-AS1 significantly increased the cell viability with nonactivated caspase-3, promoted the cell migration and suppress the cuproptosis. Lidocaine was cytotoxic to the Hep-2 cells in a dose- and time-dependent manner. Exposure to 10 µM of lidocaine for 24 h did not reduce the viability or activated the caspase-3, but significantly increased the expression of DNMBP-AS1, and promote the cuproptosis. Anymore, si-DNMBP-AS1 reversed the pro-cuproptosis function of lidocaine. Conclusions lidocaine was cytotoxic to Hep-2 cells in a time- and dose-dependent manner, promoted the cuproptosis through up-regulating DNMBP-AS1. The results of this study offered initial optimism that lidocaine could be used in an adjuvant or neoadjuvant fashion in cancer treatment. more...

Abstract Biochar is a promising technology for carbon storage and greenhouse gas (GHG) reduction, but optimizing it is challenging due to the complexity of natural systems. Machine learning (ML) and natural language processing (NLP) offer solutions through enhanced data analysis and pattern recognition, ushering in a new era of biochar research. Graphical Abstract more...

Abstract Background Surgical intervention is critical in the treatment of hip developmental dysplasia in children. Perioperative analgesia, usually based on high opioid dosages, is frequently used in these patients. In some circumstances, regional anesthetic procedures such as caudal block and lumbar plexus block have also been used. Previous research has shown that pericapsular nerve group (PENG) block provides excellent anesthetic efficacy during open hip surgery in adults. PENG block is thought to provide a similar analgesia effect comparable to caudal block. Methods This study is a single-center, prospective, randomized, double-blinded, non-inferiority experiment that enrolled children aged 6 months to 7 years who were scheduled for developmental dysplasia hip surgery. Following general anesthesia and regional blocks (0.25% ropivacaine at a dose of 2.5 mg·kg−1 with epinephrine at a concentration of 1:200,000), 48 individuals will be randomly assigned to either the PENG or caudal groups. The primary outcome measure is the highest FLACC (face, legs, activity, crying, consolability) score achieved within 24 h of surgery. Secondary outcomes include intraoperative opioid consumption, analgesic dosage within 24 h of surgery, time to start rescue analgesia, number of PCA pump activations, time to remove SLIPA (streamlined liner of the pharynx airway), duration of regional block procedures, incidence of adverse events, plasma ropivacaine concentrations, and hospital stays and costs. All data will be collected by blinded investigators. The trial’s final results will be published in a peer-reviewed scientific journal. Discussion We expect this trial to provide some evidences that PENG block is safe and effective for perioperative analgesia in pediatric patients undergoing open hip surgery. Trial registration Chinese Clinical Trial Registry ChiCTR2100053128. Registered on November 12, 2021. more...

Abstract Background Lung ultrasound-guided alveolar recruitment manoeuvres (RMs) may reduce the lung ultrasound score. However, whether the use of this strategy can reduce the incidence of postoperative pulmonary complications (PPCs) in the adult obese population has not yet been tested. Methods/design This is a single-centre, two-arm, prospective, randomised controlled trial. A total number of 476 obese patients scheduled for bariatric surgeries will be enrolled. They will be randomly assigned to receive either lung ultrasound-guided RMs (intervention group) or conventional RMs (control group) intraoperatively. The occurrence of PPCs will be recorded as the primary outcome. Discussion To the best of our knowledge, this is the first trial to test the effect of lung ultrasound-guided RMs on PPCs. The results of this trial will support the anaesthesiologists in choosing a potentially more efficient method to perform RMs for bariatric surgery patients. Trial registration www.chictr.org.cn ChiCTR2400080203. Registered on 23 January 2024. more...

Abstract Cardiomyocyte proliferation in adult Xenopus tropicalis during heart regeneration has remained largely contentious due to the absence of genetic evidence. Here, we generated a transgenic reporter line Tg(mlc2:H2C) expressing mCherry specifically in cardiomyocyte nuclei driven by the promoter of myosin light chain 2 (mlc2). Using the reporter line, we found that traditional whole-cell staining is not a rigorous way to identify cardiomyocytes in adult Xenopus tropicalis when using a cryosection with common thickness (5 μm) which leading to a high error, but this deviation could be reduced by increasing section thickness. In addition, the reporter line confirmed that apex resection injury greatly increased the proliferation of mlc2 + cardiomyocytes at 3-30 days post-resection (dpr), thereby regenerating the lost cardiac muscle by 30 dpr in adult Xenopus tropicalis. Our findings from the reporter line have rigorously defined cardiomyocyte proliferation in adult heart upon injury, thereby contributing heart regeneration in adult Xenopus tropicalis. more...

Abstract Online streaming feature selection (OSFS), as an online learning manner to handle streaming features, is critical in addressing high‐dimensional data. In real big data‐related applications, the patterns and distributions of streaming features constantly change over time due to dynamic data generation environments. However, existing OSFS methods rely on presented and fixed hyperparameters, which undoubtedly lead to poor selection performance when encountering dynamic features. To make up for the existing shortcomings, the authors propose a novel OSFS algorithm based on vague set, named OSFS‐Vague. Its main idea is to combine uncertainty and three‐way decision theories to improve feature selection from the traditional dichotomous method to the trichotomous method. OSFS‐Vague also improves the calculation method of correlation between features and labels. Moreover, OSFS‐Vague uses the distance correlation coefficient to classify streaming features into relevant features, weakly redundant features, and redundant features. Finally, the relevant features and weakly redundant features are filtered for an optimal feature set. To evaluate the proposed OSFS‐Vague, extensive empirical experiments have been conducted on 11 datasets. The results demonstrate that OSFS‐Vague outperforms six state‐of‐the‐art OSFS algorithms in terms of selection accuracy and computational efficiency. more...

Abstract Eukaryotic Elongation Factor 2 Kinase (eEF2K), a member of the α-kinase family, services as a crucial negative regulator of protein synthesis, particularly under conditions of cellular stress. A pan-cancer analysis of eEF2K expression, genetic variants, and clinical relevance across multiple tumor types was performed using data from the Cancer Genome Atlas (TCGA) and GEO. Our findings suggest that eEF2K has dual roles in cancer progression, with its expression correlating with patient prognosis. Significant phosphorylation of eEF2 at T57, Y434, and T59 was observed, which may regulate protein synthesis during stress. The elevated T59 phosphorylation in COAD, despite the low eEF2K expression, indicates that this may be regulated by alternative kinases, such as AMPK or mTOR. This suggests that compensatory mechanisms may be involved. In addition to modulating eEF2 phosphorylation, eEF2K is involved in a number of other processes, including peptidyl-serine phosphorylation, the G2/M transition, and the MAPK cascade. The protein products of eEF2K are capable of localizing to the nucleus, cytoplasm, and cytosol, where they bind to a range of proteins, including ATP and calcium ions. These findings provide novel insights into the role of eEF2K in cancer biology and suggest that the targeting of eEF2K and eEF2 phosphorylation may offer promising therapeutic strategies. more...

Abstract Urea’s transmembrane transport through urea transporters (UT) is a fundamental physiological behavior for life activities. Here, we present 11 cryo-EM structures of four UT members in resting states, urea transport states, or inactive states bound with synthetic competitive, uncompetitive or noncompetitive inhibitor. Our results indicate that the binding of urea via a conserved urea recognition motif (URM) and the urea transport via H-bond transfer along the QPb-T5b-T5a-QPa motif among different UT members. Moreover, distinct binding modes of the competitive inhibitors 25a and ATB3, the uncompetitive inhibitor CF11 and the noncompetitive inhibitor HQA2 provide different mechanisms for blocking urea transport and achieved selectivity through L-P pocket, UCBP region and SCG pocket, respectively. In summary, our study not only allows structural understanding of urea transport via UTs but also afforded a structural landscape of hUT-A2 inhibition by competitive, uncompetitive and noncompetitive inhibitors, which may facilitate developing selective human UT-A inhibitors as a new class of salt-sparing diuretics. more...

Abstract Studies of laminopathy-based progeria offer insights into aging-associated diseases and highlight the role of LMNA in chromatin organization. Mandibuloacral dysplasia type A (MAD) is a largely unexplored form of atypical progeria that lacks lamin A post-translational processing defects. Using iPSCs derived from a male MAD patient carrying homozygous LMNA p.R527C, premature aging phenotypes are recapitulated in multiple mesenchymal lineages, including mesenchymal stem cells (MSCs). Comparison with 26 human aging MSC expression datasets reveals that MAD-MSCs exhibit the highest similarity to senescent primary human MSCs. Lamina-chromatin interaction analysis reveals reorganization of lamina-associating domains (LADs) and repositioning of non-LAD binding peaks may contribute to the observed accelerated senescence. Additionally, 3D genome organization further supports hierarchical chromatin disorganization in MAD stem cells, alongside dysregulation of genes involved in epigenetic modification, stem cell fate maintenance, senescence, and geroprotection. Together, these findings suggest LMNA missense mutation is linked to chromatin alterations in an atypical progeroid syndrome. more...

MXene-based fire-responsive composites are promising candidates for next-generation fire alarm sensors with high sensitivity and good mechanical properties. However, the low dispersibility and inherent thermal oxidation of MXene combined with the unsuitable spatial scale of polymer particles in hybrid systems impede the rapid response and alarm duration when suffering a fire. Herein, a strategy based on an interlocked “brick/mortar” structure was proposed for integrating faster response, high sensitivity, and longer duration in flames via a dimension-hybrid nanoparticle network, which was assembled by 2D MXene, 1D cellulose nanocrystals (CNCs), and ammonium polyphosphate (APP). The CNCs with a high aspect ratio of 114 and close length to MXene assisted uniform dispersion of MXene and coupled with APP impeding thermal oxidation of MXene. This assembled MXene/CNC@APP sensor can quickly trigger an alarm signal via substance conversion from insulating to conductive within 1.79 s when suffering a high thermal of 260 °C from fire, thus sensitive fire identification and rapid response were obtained. This MXene/CNC@APP film also maintained good mechanical performance with a tensile strength of 52.5 MPa and elongation at a break of 7.6%, which combined excellent flame retardancy leading to a continuous fire alarm signal over 442 s of the sensor in the fire. This multifunctional integrated enhancement strategy for MXene-based sensors may be conducive to the upgrade of fire alarm systems for better safeguarding of life and property. more...

Abstract Background While measuring meniscal extrusion quantitatively is an early risk factor for knee osteoarthritis (KOA), the biomechanics involved in this process are not well understood. This study aimed to investigate the effects of varying degrees of medial and lateral meniscal extrusion and their material softening on knee osteoarthritis progression. Methods Finite element analysis (FEA) was utilized to simulate varying degrees of meniscal extrusion (1–5 mm) in 72 knee joint models, representing progressive meniscal degeneration and material softening due to injury. Changes in von Mises stress of the cartilage and menisci and the load distribution on the tibial plateau’s meniscus and cartilage were studied under balanced standing posture in both healthy and injured knees, and statistical analysis was performed using Spearman correlation. Results Compared to healthy knees, peak stress in medial compartment tissues increased by over 40% with 4 mm of medial meniscus extrusion, and in lateral compartment tissues with 2 mm of lateral meniscus extrusion. Meniscus extrusion reduced the contact load between the meniscus and femoral cartilage but increased it between the tibial and femoral cartilages, with a maximum increase up to fivefold. Spearman correlation analysis indicated that meniscal extrusion significantly affected peak stress and contact loads in the respective knee compartment (p more...

Abstract Gastrointestinal stromal tumor (GISTs) are clinically heterogenous exhibiting varying degrees of disease aggressiveness in individual patients. We comprehensively describe the genomic and transcriptomic landscape of a cohort of 117 GISTs including 31 low-risk, 18 intermediate-risk, 29 high-risk, 34 metastatic and 5 neoadjuvant GISTs from 105 patients. GISTs have notably low tumor mutation burden but widespread copy number variations. Aggressive GISTs harbor remarkably more genomic aberrations than low-/intermediate-risk GISTs. Complex genomic alterations, chromothripsis and kataegis, occur selectively in aggressive GISTs. Despite the paucity of mutations, recurrent inactivating YLPM1 mutations are identified (10.3%, 7 of 68 patients), enriched in high-risk/metastatic GIST and functional study further demonstrates YLPM1 inactivation promotes GIST proliferation, growth and oxidative phosphorylation. Spatially and temporally separated GISTs from individual patients demonstrate complex tumor heterogeneity in metastatic GISTs. Finally, four prominent subtypes are proposed with different genomic features, expression profiles, immune characteristics, clinical characteristics and subtype-specific treatment strategies. This large-scale analysis depicts the landscape and provides further insights into GIST pathogenesis and precise treatment. more...

Abstract Background Previous studies have been limited by their inability to differentiate between the effects of insulin sensitivity and β-cell function on the risk of kidney function decline, cardiovascular disease (CVD), and all-cause mortality. To address this knowledge gap, we aimed to investigate whether the physiological subtypes based on homeostasis model assessment-2 (HOMA2) indices of β-cell function (HOMA2-B) and insulin sensitivity (HOMA2-S) could be used to identify individuals with subsequently high or low of clinical outcome risk. Methods This retrospective cohort study included 7,317 participants with a follow-up of up to 5 years. Based on HOMA2 indices, participants were categorized into four physiologic subtypes: the normal phenotype (high insulin sensitivity and high β-cell function), the insulinopenic phenotype (high insulin sensitivity and low β-cell function), the hyperinsulinaemic phenotype (low insulin sensitivity and high β-cell function), and the classical phenotype (low insulin sensitivity and low β-cell function). The outcomes included kidney function decline, CVD events (fatal and nonfatal), and all-cause mortality. Cox regression models were used to calculate hazard ratios (HRs) for outcomes, and spline models were used to examine the dose-dependent associations of HOMA2-B and HOMA2-S with outcomes. Results A total of 1,488 (20.3%) were classified as normal, 2,179 (29.8%) as insulinopenic, 2,173 (29.7%) as hyperinsulinemic, and 1,477 (20.2%) as classical subtypes. Compared with other physiological subtypes, the classical subtype presented the highest risk of kidney function decline (classical vs. normal HR 11.50, 95% CI 4.31–30.67). The hyperinsulinemic subtype had the highest risk of CVD and all-cause mortality (hyperinsulinemic vs. normal: fatal CVD, HR 6.56, 95% CI 3.09–13.92; all-cause mortality, HR 4.56, 95% CI 2.97–7.00). Spline analyses indicated the dose-dependent associations of HOMA2-B and HOMA2-S with outcomes. Conclusions The classical subtype had the strongest correlation with the risk of kidney function decline, and the hyperinsulinemic subtype had the highest risk of CVD and all-cause mortality, which should be considered for interventions with precision medicine. Graphical abstract more...

Cardamine zhangjiajieensis, a new species from Hunan Province, China, is described and illustrated. Cardamine zhangjiajieensis is similar to C. circaeoides. From the latter, C. zhangjiajieensis is readily distinguished by the terminal leaflet of the cauline leaf 4.5–7 cm (vs. 2.5–4.5 cm), mostly round or oblong (vs. oblong-oval to triangular-oval), margin undulating sinuses (vs. crenate or subentire), seed apically narrow wing (vs. wingless). more...

Abstract Pancreatic cancer is among the most immune-resistant tumor types due to its unique tumor microenvironment and low cancer immunogenicity. Single-agent immune modulators have thus far proven clinically ineffective. However, a growing body of evidence suggests that combination of these modulators with other strategies could unlock the potential of immunotherapy in pancreatic cancer. Herein, we describe the case of a 59-year-old male with metastatic pancreatic ductal adenocarcinoma, referred to our center to receive immunotherapy (serplulimab, a novel anti-PD-1 antibody) combined with chemotherapy (gemcitabine/nab-paclitaxel). During the initial three treatment cycles, the patient was assessed as having stable disease (SD) according to RECIST 1.1 criteria. However, following two additional cycles of combination therapy, the primary tumor mass increased from 4.9 cm to 13.2 cm, accompanied by the development of new lung lesions, ascites, and pelvic metastases. He succumbed to respiratory failure one month later. Retrospective analysis revealed that the patient had MDM4 amplification, identified as a high-risk factor for hyperprogressive disease (HPD). To our knowledge, this is the first reported case of HPD in pancreatic cancer with multiple metastases treated using combination therapy. We investigated the potential mechanisms and reviewed the latest literature on predictive factors for HPD. These findings suggest that while chemotherapy combined with immunotherapy may hold promise for treating pancreatic cancer, it is imperative to identify and closely monitor patients with high-risk factors for HPD when using immunotherapy. more...

Abstract Intrahepatic circulation is essential for the repair of acute liver injury (ALI); however, very limited information is available concerning changes in the circulatory pathways during ALI. Therefore, multi-scale X-ray phase-contrast CT combined with three-dimensional (3D) visualization is used to quantitatively analyze the intrahepatic circulation pathway (including the hepatic vein, portal vein and hepatic sinusoid) in the mouse model via the intraperitoneal injection of carbon tetrachloride (CCl4) from acute injury to recovery. The results demonstrate that the liver still preserves some vessel-like channels accessed to the central vein when the injury causes the severe collapse of the hepatic sinusoids that cannot be observed in two-dimensional pathologic slices. Moreover, angiogenesis is observed in the terminal branches of the hepatic vein and portal vein. Additionally, we extend the two-dimensional primary lobule to a 3D model and find that the sinusoids in zone III have the most severe injury. The sinusoids in different zones also show changes in parameters such as density and mean diameter during the ALI. In conclusion, phase-contrast CT can reveal the intact vascular system within the liver lobes, thus providing critical information for studying the mechanisms involved in the evolution of circulatory structures from damage to repair. more...

Abstract Grain hardness has important effects on grain quality and the end-use of wheat. In this study, a collection of 103 common wheat germplasms and a DH population of 194 lines were used to identify new quantitative trait loci (QTL) for grain hardness. Two stable genetic loci on chromosome 5D were detected under different locations and years with one of them being the Ha locus on 5DS where the major gene Puroindolines for wheat grain hardness is located. Another locus of qTaHa-5DL also showed a significant impact on grain hardness index (HI) with HI increasing from ~ 20 to ~ 45 and hardness type changing from soft to mixed when Puroindolines are wild type. A kompetitive allele-specific PCR (KASP) marker for qTaHa-5DL was developed and the effectiveness of the QTL was confirmed in 184 breeding lines with the marker K-Ha5DL dividing wheat into two distinct categories. This new QTL can be effectively used to select soft or medium hard wheat. more...

Background: Irritable Bowel Syndrome (IBS) is a chronic disease with recurrent functional gastrointestinal. The pathogenesis and pathophysiology of this disease are highly complex, and the existing pharmaceutical treatment methods do not address all IBS symptoms. It is very important to develop a drug that can treat the disease and clarify its mechanism of action. This study aimed to address the effects of Changkang granules on IBS rats and then exploring the possible underlying mechanism using the gut microbiota -metabolomics method. Methods: The IBS rats was established by administering senna leaf water and applying restraint stress to investigate the efficacy of Changkang granules. With the methods of 16S rRNA sequencing technology and non-targeted metabolomics to explore the role of Changkang granules in IBS and identify the potential mechanisms involved. Results: Changkang granules can improve the visceral hypersensitivity of IBS by inhibiting the serum SP level of model rats, increasing the expression of serum CGRP and VIP in colon tissue. The underlying mechanism of action could involve increase the beneficial bacteria such as Bifidobacteria, Clostridium and Coprococcus, thereby up-regulating the levels of metabolites such as arachidonic acid (DHA) and γ-aminobutyric acid (GABA), down-regulating the expression of 2-hydroxybutyric acid (HA), inhibiting intestinal microecological disorders, improving the protective effect on the intestine, interfering with the MAPK metabolic pathway by reducing HA content, reducing inflammatory factors such as NF-κB, preventing inflammation, improving disease resistance, and relieving IBS symptoms. Conclusion: Changkang granule has a therapeutic effect on IBS rats, and its mechanism may be achieved by regulating gut microbiota and regulating metabolites such as GABA and 2-hydroxybutyric acid HA, which highlights a novel method for the treatment of IBS. more...

As the energy internet and integrated energy systems develop, the interconnections among different systems increase operational risks, highlighting the need for urgent reliability research. Recent large-scale blackouts, often caused by cascading failures, reveal that current reliability assessments frequently overlook dynamic equipment conditions and the risk of such failures. Traditional model-driven methods for single energy systems are becoming inadequate due to rapid operational changes. To address these challenges, this study proposes a reliability assessment method for integrated energy systems that considers equipment operational states and cascading failures. It introduces an equipment reliability model for simulating cascading failures due to equipment overloads after initial failures. A hybrid data-model driven approach is proposed to improve the efficiency of load reduction calculations. Then the reliability evaluation is realized by combining the analysis of system energy flow state and index calculation. The modified model simulates more failure events than conventional model and the reliability level reflected by the calculated index is lower than that of the conventional model assessment by 25.39 % to 179.13 %. Evaluation time is reduced by 98.10 % while maintaining an average relative error within 6 %. The subsystem reliability level increases by 69.72 % and decreases by 2.25 % depending on the coupling degree. Failures of less than 20 % of all fault types contributed 43.34 % to 69.59 % of the load reduction. In summary, this model effectively simulates cascading failures from changes in operating states and provides a rapid, accurate reflection of system reliability.Based on this method, the reliability influencing factors can be analyzed and the weak link can be identified. more...

We used diffusion MRI and x-ray synchrotron imaging on monkey and mice brains to examine the organisation of fibre pathways in white matter across anatomical scales. We compared the structure in the corpus callosum and crossing fibre regions and investigated the differences in cuprizone-induced demyelination in mouse brains versus healthy controls. Our findings revealed common principles of fibre organisation that apply despite the varying patterns observed across species; small axonal fasciculi and major bundles formed laminar structures with varying angles, according to the characteristics of major pathways. Fasciculi exhibited non-straight paths around obstacles like blood vessels, comparable across the samples of varying fibre complexity and demyelination. Quantifications of fibre orientation distributions were consistent across anatomical length scales and modalities, whereas tissue anisotropy had a more complex relationship, both dependent on the field-of-view. Our study emphasises the need to balance field-of-view and voxel size when characterising white matter features across length scales. more...

Reliable and accurate determination of chloramphenicol (CAP) is urgently needed due to its significant implications for food safety and human health concerns. In this study, we successfully synthesized MIL-101(Fe)-NH2@MIP, which exhibits peroxidase activity and a specific recognition function for CAP, through in situ polymerization of dopamine on the surface of MIL-101(Fe)-NH2, utilizing molecular imprinting technology. Our bifunctional MIL-101(Fe)-NH2@MIP probe offers a ratiometric fluorescent and colorimetric dual-mode sensing strategy for sensitive and selective detection of chloramphenicol. The detection limits for CAP can reach down to 36.45 nM and 93.38 nM, respectively. Furthermore, we developed a smartphone-based visual sensing platform that employs MIL-101(Fe)-NH2@MIP nanozymes for rapid, portable, low-cost on-site detection of CAP. Successful spike recovery experiments conducted in fresh milk samples further validate the potential practical application of our proposed dual-mode strategy. Thus, this approach expands the applications of MOFs-based nanozymes and holds promise for antibiotic determination. more...

BackgroundLimited evidence exists regarding the association between oxidative stress induced by dietary and lifestyle factors and cardiovascular diseases (CVDs).MethodsWe conducted a weighted analysis using data from 13,530 adults in the National Health and Nutrition Examination Survey (NHANES), covering the period from 2003 to 2018. The total oxidative balance score (OBS) was derived from 20 oxidative stress-related exposures, including dietary and lifestyle factors. Survey-weighted multivariable logistic regression and stratified analyses were performed to examine the association between OBS and CVDs. To further investigate the nonlinear relationship, we employed restricted cubic spline analysis and threshold effect analysis. Additionally, we assessed whether hepatic function and blood lipid levels mediate the OBS-CVDs relationship.ResultsThis study included 13,530 participants, representing a weighted population of 81,006,649.2 individuals. After adjusting for potential confounders, a linear relationship was observed between total OBS, dietary OBS, and CVDs, while lifestyle OBS exhibited a nonlinear association, with a significant threshold effect at a score of 4. When the lifestyle OBS exceeded this threshold, a marked negative correlation with CVDs was observed. Furthermore, albumin (Alb) mediated 23.59% of the relationship between the total OBS and CVDs.ConclusionsLower levels of total OBS were inversely associated with CVDs. This association was partially mediated by blood lipid levels and hepatic function. Interventions focusing on antioxidant-rich dietary and lifestyle modifications may play a pivotal role in reducing the possibility of CVDs. more...

BackgroundThe Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, is known for its capacity to cause severe neurological disease in Asia. Neurotropic flaviviruses within the Japanese encephalitis (JE) serogroup possess the distinctive feature of expressing a unique nonstructural protein, NS1'. The NS1' protein consists of the full NS1 protein with an additional 52 amino acid extension at the C-terminus and has been demonstrated to exhibit virulence in mammalian hosts upon infection. However, the precise role of the NS1' protein in the mosquito vectors has yet to be elucidated.Methodology/principal findingsIn this study, an NS1'-defective virus (rG66A) was engineered, and its effect on the infection of mosquito cells was investigated. The results demonstrated a significant reduction in the infectivity of the rG66A virus in mosquito cells by RT-qPCR, indicating that the absence of the NS1' protein impedes JEV replication in Culex mosquitoes. Additionally, this research elucidated the underlying mechanism by which the NS1' protein enhances viral infection in mosquitoes by RNA-Seq analysis. Specifically, the NS1' protein was found to facilitate infection through the suppression of antimicrobial peptides (AMPs) regulated by the Toll pathway.Conclusions/significanceOur research demonstrated that the JEV NS1' protein contributes to immune escape, thereby enhancing viral infection in mosquitoes. This finding offers new insights into the transmission mechanisms of JEV, elucidating novel aspects of viral propagation. more...

BackgroundHigh-grade colorectal neuroendocrine carcinoma (HCNEC) is a rare but aggressive subset of neuroendocrine tumors. This study was designed to construct a risk model based on comprehensive clinical and mutational genomics data to facilitate clinical decision making.MethodsA retrospective analysis was conducted using data from the Surveillance, Epidemiology, and End Results (SEER) database, spanning 2000 to 2019. The external validation cohort was sourced from two tertiary hospitals in Southwest China. Independent factors influencing both overall survival (OS) and cancer-specific survival (CSS) were identified using LASSO, Random Forest, and XGBoost regression techniques. Molecular data with the most common mutations in CNEC were extracted from the Catalogue of Somatic Mutations in Cancer (COSMIC) database.ResultsIn this prognostic analysis, the data from 714 participants with HCNEC were evaluated. The median OS for the cohort was 10 months, whereas CSS was 11 months. Six variables (M stage, LODDS, Nodes positive, Surgery, Radiotherapy, and Chemotherapy) were screened as key prognostic indicators. The machine learning model showed reliable performance across multiple evaluation dimensions. The most common mutations of CNEC identified in the COSMIC database were TP53, KRAS, and APC.ConclusionsIn this study, a refined machine learning predictive model was developed to assess the prognosis of HCNEC accurately and we briefly analyzed its genomic features, which might offer a valuable tool to address existing clinical challenges. more...

IntroductionUltrasound-guided needle biopsy is a commonly employed technique in modern medicine for obtaining tissue samples, such as those from breast tumors, for pathological analysis. However, it is limited by the low signal-to-noise ratio and the complex background of breast ultrasound imaging. In order to assist physicians in accurately performing needle biopsies on pathological tissues, minimize complications, and avoid damage to surrounding tissues, computer-aided needle segmentation and tracking has garnered increasing attention, with notable progress made in recent years. Nevertheless, challenges remain, including poor ultrasound image quality, high computational resource requirements, and various needle shape.MethodsThis study introduces a novel Spatio-Temporal Memory Network designed for ultrasound-guided breast tumor biopsy. The proposed network integrates a hybrid encoder that employs CNN-Transformer architectures, along with an optical flow estimation method. From the Ultrasound Imaging Department at the First Affiliated Hospital of Shantou University, we developed a real-time segmentation dataset specifically designed for ultrasound-guided needle puncture procedures in breast tumors, which includes ultrasound biopsy video data collected from 11 patients.ResultsExperimental results demonstrate that this model significantly outperforms existing methods in improving the positioning accuracy of needle and enhancing the tracking stability. Specifically, the performance metrics of the proposed model is as follows: IoU is 0.731, Dice is 0.817, Precision is 0.863, Recall is 0.803, and F1 score is 0.832. By advancing the precision of needle localization, this model contributes to enhanced reliability in ultrasound-guided breast tumor biopsy, ultimately supporting safer and more effective clinical outcomes.DiscussionThe model proposed in this paper demonstrates robust performance in the computer-aided tracking and segmentation of biopsy needles in ultrasound imaging, specifically for ultrasound-guided breast tumor biopsy, offering dependable technical support for clinical procedures. more...

ABSTRACT Objectives This study aimed to analyze lymph node metastasis (LNM) distribution in superficial esophageal squamous cell carcinoma (ESCC) and its impact factors on survival. Methods We reviewed 241 pT1N+ ESCC cases between February 2012 and April 2022 from 10 Chinese hospitals with a high volume of esophageal cancer (EC). We analyzed clinicopathological data to identify overall survival (OS) risk factors and LNM distribution in relation to tumor invasion depth. Results Of the 241 patients, 26 (10.8%) had pT1a cancer and 215 (89.2%) had pT1b cancer. We showed that N3 stage, ≤ 28 lymphadenectomies, and nerve infiltration (NI) were negative factors for OS in superficial pN+ ESCC, whereas the OS was not definitively affected by the tumor depth and the choice of adjuvant therapy. In general, the LNM rates of the 193 pT1N+ ESCC cases can be ranked in the following order: station 106recR > station 106recL > station 1 > station 7 > station 2. With deeper tumor invasion, the higher LNM rate was observed near the bilateral recurrent laryngeal nerves (RLN), but there was no statistically significant difference. Conclusions In superficial ESCC, LNM was frequently observed along the 106recR (35.8%) and 106recL (25.6%) stations. Advanced N‐staging (N3) was a major negative impact factor in prognosis, and adequate lymph nodes dissected (LND) (N > 28) improved OS of pT1N+ ESCC. However, in superficial ESCC, tumor infiltration depth did not affect patients' OS or the distribution of positive LNs. The optimal adjuvant treatment that favors survival for these patients required further investigation. more...

Background: The vascular endothelial growth factor (VEGF) signaling pathway is closely related to pathological angiogenesis in liver disease. Anti-angiogenesis is an effective intervention in the clinical treatment of liver disease. Some antiangiogenic drugs are resistant and have limitations in clinical use. Methods: This research uses bibliometric methods to assess the literature on the VEGF signaling pathway in liver disease from 2008 to 2023. Results: The number of publications has generally increased over the past 16 years, meaning that enormous researchers are interested in this field. China and the USA have published the most articles and cooperate closely with each other. Plos one has published the largest number of articles in this area, and Hepatology and Journal of Hepatology is the most authoritative journal. Llovet JM is an outstanding researcher in the field with the highest citations. Keywords and research hotspots analysis indicated that researchers are very concerned about the application and clinical research status of anti-angiogenic drugs in hepatocellular carcinoma (HCC). Continuing to deepen the research on the use of anti-angiogenic drugs alone and in combination is necessary. In addition, the resistance of anti-angiogenic therapeutic drugs leads to a complex mechanism of angiogenesis response caused by hypoxia, which requires further research. Conclusions: This study analyzed the research situation related to the VEGF signaling pathway in liver disease from a bibliometric and visual perspective. Our analysis helps researchers better understand the research directions and hotspots in this area, enabling them to better carry out research in the future. more...

ATG5 is one of the core autophagy proteins with additional functions such as noncanonical membrane atg8ylation, which among a growing number of biological outputs includes control of tuberculosis in animal models. Here, we show that ATG5 associates with retromer’s core components VPS26, VPS29, and VPS35 and modulates retromer function. Knockout of ATG5 blocked trafficking of a key glucose transporter sorted by the retromer, GLUT1, to the plasma membrane. Knockouts of other genes essential for membrane atg8ylation, of which ATG5 is a component, affected GLUT1 sorting, indicating that membrane atg8ylation as a process affects retromer function and endosomal sorting. The contribution of membrane atg8ylation to retromer function in GLUT1 sorting was independent of canonical autophagy. These findings expand the scope of membrane atg8ylation to specific sorting processes in the cell dependent on the retromer and its known interactors. more...

IntroductionHematopoietic stem cell transplantation (HSCT) and chemotherapy are considered potentially curative options for post-remission therapy in acute myeloid leukemia (AML). However, the comparative effectiveness of these approaches in favorable- and intermediate-risk AML remains unclear and requires further investigation.MethodsIn this retrospective study, 111 patients diagnosed with de novo favorable- and intermediate-risk AML, categorized according to the ELN 2022 guidelines, were investigated to compare outcomes following autologous HSCT (auto-HSCT), matched sibling donor HSCT (MSD-HSCT), and chemotherapy. Through propensity score matching for disease status before HSCT, 42 cases in first complete remission were selected for each of the auto-HSCT group and the MSD-HSCT group. Additionally, 27 cases in the chemotherapy group, excluding patients with early relapse or death, were included for comparison.ResultsIn the overall population, the 3-year overall survival (OS) rates were 85.7%, 83.1%, and 70.4% (p = 0.043), while the disease-free survival (DFS) rates were 78.6%, 83.2%, and 57.1% (p = 0.002) in the auto-HSCT, MSD-HSCT, and chemotherapy groups, respectively. Notably, both auto-HSCT and MSD-HSCT demonstrated significantly improved DFS compared to chemotherapy in patients with favorable-risk AML. Multivariate analysis further revealed that chemotherapy was significantly associated with inferior DFS compared to auto-HSCT (HR=2.82; 95% CI, 1.26–6.32, p=0.012), while DFS was similar between the MSD-HSCT and auto-HSCT groups (HR=0.80; 95% CI, 0.31–2.09, p=0.645).DiscussionThe findings suggested the advantages of both MSD-HSCT and auto-HSCT over chemotherapy as post-remission therapy for AML patients with favorable and intermediate risk. Further research is needed to support these conclusions. more...