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Abstract Chronic allodynia stemming from peripheral stump neuromas can persist for extended periods, significantly compromising patients’ quality of life. Conventional managements for nerve stumps have demonstrated limited effectiveness in ensuring their orderly termination. In this study, we present a spatially confined conduit strategy, designed to enhance the self-organization of regenerating nerves after truncation. This innovative approach elegantly enables the autonomous slowing of axonal outgrowth in response to the gradually constricting space, concurrently suppressing neuroinflammation through YAP-mediated mechanotransduction activation. Meanwhile, the decelerating axons exhibit excellent alignment and remyelination, thereby helping to prevent failure modes in nerve self-organization, such as axonal twisting in congested regions and overgrowth beyond the conduit’s capacity. Additionally, proteins associated with mechanical allodynia, including TRPA1 and CGRP, exhibit a gradual reduction in expression as spatial constraints tighten, a trend inversely validated by the administration of the YAP-targeted inhibitor Verteporfin. This spatially confined conduit strategy significantly alleviates allodynia, thus preventing autotomy behavior and reducing pain-induced gait alterations.

Wound healing in chronic diabetic patients remains challenging due to the multiple types of cellular dysfunction and the impairment of multidimensional microenvironments. The physical signals of structural anisotropy offer significant potential for orchestrating multicellular regulation through physical contact and cellular mechanosensing pathways, irrespective of cell type. In this study, we developed a highly oriented anisotropic nanofiber hydrogel designed to provide directional guidance for cellular extension and cytoskeletal organization, thereby achieving pronounced multicellular modulation, including shape-induced polarization of macrophages, morphogenetic maturation of Schwann cells, oriented extracellular matrix (ECM) deposition by fibroblasts, and enhanced vascularization by endothelial cells. Additionally, we incorporated a VEGF-mimicking peptide to further reinforce angiogenesis, a pivotal phase that interlocks with immune regulation, neurogenesis, and tissue regeneration, ultimately contributing to optimized inter-microenvironmental crosstalk. In vivo studies validated that the anisotropic bioactive nanofiber hydrogel effectively accelerated diabetic wound healing by harnessing the triadic synergy of the immune-angiogenic-neurogenic microenvironments. Our findings highlight the promising potential of combining physical and bioactive signals for the modulation of various cell types and the refinement of the multidimensional microenvironment, offering a novel strategy for diabetic wound healing.

Abstract This study first investigated how FNDC5 affected the development of oral cancer and revealed the role of FNDC5 in the migration and invasion of oral cancer. The present work evaluated differential FNDC5 expression within oral cancer samples versus matched non-carcinoma samples based on GEO database analysis and immunohistochemistry. We then generated oral cancer cell lines with FNDC5 overexpression and knockdown to determine the role of altered FNDC5 expression in the migration and invasion of oral cancer. PI3K inhibitor was used for investigating the possible mechanism underlying FNDC5 during EMT of oral cancer. Finally, these in-vitro results were validated using the lung metastatic nude mouse model. According to our results, FNDC5 level markedly decreased within oral cancer compared with adjacent samples and FNDC5 overexpression inhibited migration, invasion as well as EMT of oral cancer, while FNDC5 knockdown promoted oral cancer cell EMT. In addition, PI3K inhibitors blocked the induction of oral cancer cells EMT by FNDC5 knockdown. In vivo experiments further demonstrated the above results. This work is the first to illustrate the impact of FNDC5 on inhibiting migration and invasion of oral cancer, and our results suggest that FNDC5 affects EMT of oral cancer via the inhibition of PI3K/Akt/Snail pathway.

Bone, renowned for its elegant hierarchical structure and unique mechanical properties, serves as a constant source of inspiration for the development of synthetic materials. However, achieving accurate replication of bone features in artificial materials with remarkable structural and mechanical similarity remains a significant challenge. In this study, we employed a cascade of continuous fabrication processes, including biomimetic mineralization of collagen, bidirectional freeze-casting, and pressure-driven fusion, to successfully fabricate a macroscopic bulk material known as artificial compact bone (ACB). The ACB material closely replicates the composition, hierarchical structures, and mechanical properties of natural bone. It demonstrates a lamellated alignment of mineralized collagen (MC) microfibrils, similar to those found in natural bone. Moreover, the ACB exhibits a similar high mineral content (70.9 %) and density (2.2 g/cm3) as natural cortical bone, leading to exceptional mechanical properties such as high stiffness, hardness, and flexural strength that are comparable to those of natural bone. Importantly, the ACB also demonstrates excellent mechanical properties in wet, outstanding biocompatibility, and osteogenic properties in vivo, rendering it suitable for a broad spectrum of biomedical applications, including orthopedic, stomatological, and craniofacial surgeries.

Osteoarthritis (OA) is characterized by symptoms such as abnormal lubrication function of synovial fluid and heightened friction on the cartilage surface in its early stages, prior to evident cartilage damage. Current early intervention strategies employing lubricated hydrogels to shield cartilage from friction often overlook the significance of hydrogel-cartilage adhesion and enhancement of the cartilage extracellular matrix (ECM). Herein, we constructed a hydrogel based on dihydrazide-modified hyaluronic acid (HA) (AHA) and catechol-conjugated aldehyde-modified HA (CHA), which not only adheres to the cartilage surface as an effective lubricant but also improves the extracellular environment of chondrocytes in OA. Material characterization experiments on AHA/CHA hydrogels with varying concentrations validated their exceptional self-healing capabilities, superior injectability and viscoelasticity, sustained adhesion strength to cartilage, and a low friction coefficient. Chondrocytes exhibited robust adhesion and proliferation on the AHA/CHA hydrogel surface, with the upregulation of cartilage matrix protein expression. Intra-articular injection of AHA/CHA hydrogels was performed following destabilization of the medial meniscus (DMM) surgery in mice to assess its protective effect on cartilage. The AHA/CHA hydrogel effectively attenuated the degree of cartilage wear, facilitated chondrocytes' anabolic metabolism, and restored the ECM of cartilage. Therefore, the AHA/CHA hydrogel emerges as a promising therapeutic approach in clinical practices of OA treatment.

Abstract Background As a new type of intravenous anesthetic, ciprofol has the advantages of fast onset of action, fast recovery and high clearance rate. This study aimed to investigate the effectiveness and safety of ciprofol versus traditional propofol for anesthesia and sedation in and out of the operating room. Methods We searched the literature in PubMed, Web of Science, Cochrane Library, and Embase databases from January 2021 to December 2023. All clinical studies comparing the sedative effects of propofol and ciprofol, both inside and outside the operating room, were included in our trial. The main outcome measures were induction time and incidence of injection-site pain. Data are merged using risk ratio and standardized mean difference with 95% confidence interval. Subgroup analysis, meta-regression, sensitivity analysis, and publication bias were performed. The study protocol was prospectively registered with PROSPERO (CRD42023447747). Results A total of 15 randomized, controlled trials involving 2002 patients were included in this study. Compared with propofol, ciprofol has a longer induction time in the operating room but a shorter induction time in non-operating room settings. Ciprofol can effectively reduce the risk of injection-site pain and respiratory depression both inside and outside the operating room. In addition, the risk of drug-related hypotension induced with ciprofol in the operating room is lower, but the awakening time is also longer. Meta-regression analysis showed that neither age nor BMI were potential sources of heterogeneity. Funnel plot, egger and begg tests showed no significant publication bias. Sensitivity analyzes indicate that our results are robust and reliable. Conclusion Ciprofol has absolute advantages in reducing the risk of injection-site pain and respiratory depression, both in and outside operating room. Intraoperative use of ciprofol reduces the risk of drug-related hypotension and may also reduce the risk of intraoperative physical movements. However, ciprofol may have longer induction and awakening time than propofol.

Utilizing biomaterials in tissue engineering has shown considerable promise for tissue regeneration, particularly through delivering multimodel cell-regulatory signals, including the material-related signals and extrinsic stimuli. In this research, we developed a magnetic-responsive aligned nanofiber fibrin hydrogel (MAFG), integrating the structured alignment of nanofibers and the pliability of fibrin hydrogel with an external magnetic field. This design aimed to enhance the regenerative response in spinal cord injury treatment. A medium-strength magnetic field, aligned with the spinal cord, was applied to aid motor function recovery in rats with spinal cord injuries. The use of MAFG in this context not only intensified the effect of the magnetic field but also encouraged the activation and differentiation of native neural stem cells. Furthermore, this method effectively steered macrophage polarization towards a beneficial M2 phenotype, addressing immune dysregulation at the injury site. The parallel application of magnetic field stimulation through MAFG in a spinal cord injury model contributed to the concurrent promotion of neurogenesis, angiogenesis, and immunomodulation, resulting in marked improvement in motor function in rats. This investigation underscores the therapeutic potential of magnetic field stimulation and highlights how aligning this stimulation with the spinal cord can significantly enhance the regenerative milieu at the injury site.

Abstract Background Although RANK‐LRANK interaction is essential for osteoclastogenesis, the mechanisms by which cancer cells invade bone tissues and initiate osteolytic metastasis remain unclear. Here, we show that the hyperactivation of RelB fosters prostate cancer (PCa) osteolytic metastasis by coordinating interleukin‐8 (IL‐8) and calcium‐binging protein A4 (S100A4). Methods The factors promoting PCa bone metastasis were investigated in sera from PCa patients and tumour tissues derived from nude mice using immunohistochemical analysis and enzyme‐linked immunosorbent assays (ELISA). Cell mobility and mineralization were quantified using BioStation CT and Osteolmage assay. The relative cistrome was investigated in advanced PCa cells by standard transcriptional analyses, including the luciferase reporter response, site‐directed mutagenesis, and chromatin immunoprecipitation (ChIP) assay. PCa cell‐initiated tumour formation, expansion, and bone metastasis were validated in mice using multiple approaches, including orthotopic, intraskeletal, and caudal arterial implantation models. Results IL‐8 and S100A4 correlated with patient Gleason scores and bone metastasis. RelB upregulated IL‐8, facilitating androgen receptor (AR)‐independent growth. RelB‐Sp1 interaction enhanced epithelial‐mesenchymal transition (EMT) by activating Snail and Twist. RelB‐NFAT1c super‐enhancer upregulated S100A4 in the organization of the cytoskeleton and bone metastasis. The RelB‐IL‐8‐S100A4 signalling axis was confirmed to promote osteolytic metastasis in nude mice. Conclusion RelB‐IL‐8 reciprocally promoted EMT by activating inflammatory signalling and inactivating AR signalling. IL‐8 is essential for provoking PCa metastasis but insufficient to drive bone metastasis. IL‐8‐S100A4 cooperation was necessary for metastatic cells to target the bone. Highlights RelB activates inflammatory signalling by upregulating IL‐8 and suppressing AR. RelB upregulates S100A4 by cooperating with NFATC1. IL‐8 boosts EMT by activating Snail 1 and Twist 1, and S100A4 exacerbates osteolytic metastasis via calcium consumption. RelB harnesses IL‐8 and S100A4 to drive PCa osteolytic metastasis.

BackgroundThe aberrant expression of AEG-1 is significantly correlated with tumorigenesis, development, neurodegeneration and inflammation. However, the relationship between AEG-1 expression and immune infiltration in OSCC, as well as other tumor types, has yet to be comprehensively analyzed.MethodsThe expression levels, prognostic and clinicopathological characteristics, mutation patterns and methylation landscapes of AEG-1 in various tumors were obtained from multiple databases, including TIMER, GEPIA, HPA, TCGA, UALCAN, cBioPortal, SMART and TISIDB, in addition to single-cell RNA-seq data. The integration of these datasets facilitated the elucidation of the relationships among pan-cancer cellular heterogeneity, immune infiltration and AEG-1 expression levels. In vitro experiments created AEG-1 overexpressing cell lines, and mRNA-seq analyzed AEG-1-related differential genes in OSCC. RT-PCR validated these findings in vivo using xenograft tumors. Tumor cell lines were developed to study AEG-1’s effects through H&E, Masson, and PAS staining. Immunohistochemistry examined AEG-1-related gene expression patterns.ResultsOur analysis demonstrated that AEG-1 is highly expressed across various cancer types and is associated with tumor grade and patient prognosis. Additionally, AEG-1 amplification was observed in multiple cancers. Notably, we identified a significant elevation of AEG-1 expression in OSCC, which strongly correlated with patient prognosis and immune infiltration. Through mRNA-seq analysis of differentially expressed genes and immune-related gene sets, we identified a strong correlation between AEG-1 and immune infiltration markers such as LCP2, CD247, HLA-DPA1, HLA-DRA, HLA-DRB1, CIITA and CD74 in OSCC. Additionally, AEG-1 was found to regulate Th1/Th2 immune homeostasis, promote glycogen accumulation, and contribute to tumor fibrosis.ConclusionIn conclusion, AEG-1 significantly correlates with prognosis and immune infiltration across various cancer types and holds potential as a novel prognostic immune biomarker for OSCC. This finding may facilitate the identification of patients who are most likely to benefit from adjuvant immunotherapy.

Stem cell-mediated bio-root regeneration is an alternative tooth replacement strategy; however, physiologically functional bio-root regeneration with distinctive dentin structure remains challenging. In this study, the distinct arrangements of collagen fibril bundles were identified that account for hierarchical structural differences between dentin, cementum, and alveolar bone. Thus, an “engineered pre-dentin” was fabricated, which was a dentin hierarchical structure mimicking collagen (MC) scaffold, with well-aligned hierarchical mineralized collagen fibril bundles. The results revealed that it has a stronger effect on promoting biological root regeneration in nude mice and miniature pigs with dental pulp stem cell (DPSC) and periodontal ligament stem cell (PDLSC) sheets compared to hydroxyapatite tricalcium phosphate (HA/TCP). The success rate in the MC group was also higher than that in the HA/TCP group (67% and 33%, respectively). In conclusion, the hierarchical dentin-mimicking scaffold can enhance the regeneration of bio-roots, which provides a promising strategy for tooth regeneration.

Rehabilitation and regenerative medicine are two promising approaches for spinal cord injury (SCI) recovery, but their combination has been limited. Conductive biomaterials could bridge regenerative scaffolds with electrical stimulation by inducing axon regeneration and supporting physiological electrical signal transmission. Here, we developed aligned conductive hydrogel fibers by incorporating carbon nanotubes (CNTs) into methacrylate acylated gelatin (GelMA) hydrogel via rotating liquid bath electrospinning. The electrospun CNT/GelMA hydrogel fibers mimicked the micro-scale aligned structure, conductivity, and soft mechanical properties of neural axons. For in vitro studies, CNT/GelMA hydrogel fibers supported PC12 cell proliferation and aligned adhesion, which was enhanced by electrical stimulation (ES). Similarly, the combination of aligned CNT/GelMA hydrogel fibers and ES promoted neuronal differentiation and axon-like neurite sprouting in neural stem cells (NSCs). Furthermore, CNT/GelMA hydrogel fibers were transplanted into a T9 transection rat spinal cord injury model for in vivo studies. The results showed that the incorporating CNTs could remain at the injury site with the GelMA fibers biodegraded and improve the conductivity of regenerative tissue. The aligned structure of the hydrogel could induce the neural fibers regeneration, and the ES enhanced the remyelination and axonal regeneration. Behavioral assessments and electrophysiological results suggest that the combination of aligned CNT/GelMA hydrogel fibers and ES could significantly restore motor function in rats. This study demonstrates that conductive aligned CNT/GelMA hydrogel fibers can not only induce neural regeneration as a scaffold but also support ESto promote spinal cord injury recovery. The conductive hydrogel fibers enable merging regenerative medicine and rehabilitation, showing great potential for satisfactory locomotor recovery after SCI.

An edge $e$ of a matching covered graph $G$ is removable if $G-e$ is also matching covered. Carvalho, Lucchesi, and Murty showed that every brick $G$ different from $K_4$ and $\overline{C_6}$ has at least $\Delta-2$ removable edges, where $\Delta$ is the maximum degree of $G$. In this paper, we generalize the result to irreducible near-bricks, where a graph is irreducible if it contains no single ear of length three or more.

Abstract Background Facial nerve injury often results in poor prognosis due to the challenging process of nerve regeneration. Neuregulin-1, a human calmodulin, is under investigation in this study for its impact on the reparative capabilities of Dental Pulp Stem Cells (DPSCs) in facial nerve injury. Methods Lentivirus was used to transfect and construct Neuregulin-1 overexpressed DPSCs. Various techniques assessed the effects of Neuregulin-1: osteogenic induction, lipid induction, Reverse Transcription Polymerase Chain Reaction, Western Blot, Cell Counting Kit-8 assay, wound healing, immunofluorescence, Phalloidin staining, nerve stem action potential, Hematoxylin-eosin staining, transmission electron microscopy, and immunohistochemistry. Results Neuregulin-1 effectively enhanced the proliferation, migration, and cytoskeletal rearrangement of DPSCs, while simultaneously suppressing the expression of Ras homolog gene family member A (RhoA) and Microfilament actin (F-actin). These changes facilitated the neural differentiation of DPSCs. Additionally, in vivo experiments showed that Neuregulin-1 expedited the restoration of action potential in the facial nerve trunk, increased the thickness of the myelin sheath, and stimulated axon regeneration. Conclusion Neuregulin-1 has the capability to facilitate the repair of facial nerve injuries by promoting the regenerative capacity of DPSCs. Thus, Neuregulin-1 is a significant potential gene in the reparative processes of nerve damage.

Biomedical materials scientific research is increasingly data-driven, thanks to advancements in machine learning technology. The application of biological sequencing technology for assessing the biological functions of biomedical materials demands further optimization. To facilitate comprehensive analysis, it is essential to establish an open, shared infrastructure for storing diverse scientific data from various research fields. This paper presents BioMGE, a case study in database construction, utilizing the flexible and user-defined NMDMS platform (National Materials Data Management and Service Platform). BioMGE is designed for the collection of biomedical materials and multiomics sequencing data. Leveraging NMDMS’s dynamic container framework, users can tailor data submission schemas to their preferences and store data from the domains of biomedical materials and multiomics research. To ensure data interoperability, the data schema creation module is combined with data standards. We also propose a standard specification for biomedical materials data. Employing the dynamic container framework and standard specifications, data submission schemas were established for biomedical material and multiomics data, covering aspects such as material names, experimental design, grouping information for experimental materials, and high-throughput omics sequencing. Since 2019, BioMGE has amassed 1547100 datasets of biomedical material and multiomics data based on these schemas. In order to enable users to analyze this data, BioMGE provides a data export interface. For instance, the BioMGE-viewer module offers one-dimensional, two-dimensional, and three-dimensional visualizations for omics data. The one-dimensional visualization displays gene information in tabular form. The two-dimensional visualization exhibits the topologically associating domains of chromatin using a heatmap. The three-dimensional visualization offers a three-dimensional representation of chromatin structure, aiding users in exploring the relationship between gene function and gene structure. What sets BioMGE apart is that it was constructed directly by researchers, not database designers. This means that researchers without programming expertise in various fields can design personalized data schemas that align with their research characteristics. This approach maximizes the interoperability and usability of NMDMS data. BioMGE has the potential to foster collaborative research across different domains and the joint analysis of biomedical materials and biological sequencing data. It offers fresh insights for the advancement of cell therapy and, concurrently, introduces a novel idea and platform for data sharing in various cross-field research endeavors.

The jackfruit seed dietary fiber was modified by high temperature cooking combined with ultrasonic enzymatic method. Single factor combined with response surface method was applied to optimize the modification process conditions. The structure of soluble dietary fiber (SDF) before and after modification was compared and analyzed by scanning electron microscope (SEM), X-ray diffraction (XRD), thermogravimetry (TGA) and Fourier transform infrared spectrometer (FTIR). The functional properties of SDF before and after modification were determined with water holding capacity, expansion capacity, oil holding capacity and adsorption capacity for nitrite ion, glucose, bile salt and cholesterol as indicators. The results showed that the optimum modification conditions of DF were as follows: The ratio of material to liquid 1:21 g/mL, cooking temperature 121 ℃, cooking time 43 min, cellulase amount 8%, ultrasonic-assisted enzymatic (UAE) power 360 W, UAE temperature 40 ℃, UAE time 52 min. Under these conditions, the yield of SDF was 24.39%±0.03%, the yield of unmodified SDF was 16.93%±0.60%. Compared with unmodified SDF, FTIR results showed that the cellulose components of jackfruit seeds were redistributed. SEM indicated a more porous structure. XRD results showed an increase in crystallinity, and TGA results showed better thermal stability. The water holding capacity, expansion capacity, oil retention capacity, nitrite ion adsorption capacity, glucose adsorption capacity, bile salt adsorption capacity, and cholesterol adsorption capacity of modified SDF were significantly better than those of unmodified SDF (P

Abstract Background Job stress has significant influence on the mental health of health care providers. The mental health and job stress of operating room nurses remain unclear. This study aimed to evaluate the mental health and job stress of nurses in surgical system in China, to provide evidences for clinical nurse management and care. Methods The nurses in the surgical system of our hospital were investigated by questionnaire in December 2022. The general information questionnaire, symptom check list 90 (SCL-90) and nurses’ job stressor scale (NJSS) were used for data collection. Pearson correlation and logistic analysis were conducted to evaluate the related influencing factors. Results A total of 171 nurses in surgical system were investigated. The mental health level of nurses in operating room was low. The job pressure of the nurses in the operating room was in the middle level. The nursing profession and work, workload and distribution, working environment and resources, patient care, management and interpersonal relationship were all positively correlated with SCL-90 score of nurses in operating room. Logistic regression analysis indicated that age, year of work experience, professional ranks and titles both are the influencing factors of SCL-90 score and of nurses in operating room. Conclusions The mental health of nurses in surgical system is affected by work pressure, ages, working years and professional titles. These factors should be considered in the psychological intervention of nurses in operating room in order to improve the health of clinical nurses.

3D bioprinting holds great promise toward fabricating biomimetic living constructs in a bottom-up assembly manner. To date, various emergences of living constructs have been bioprinted for in vitro applications, while the conspicuous potential serving for in vivo implantable therapies in spinal cord injury (SCI) has been relatively overlooked. Herein, living nerve-like fibers are prepared via extrusion-based 3D bioprinting for SCI therapy. The living nerve-like fibers are comprised of neural stem cells (NSCs) embedded within a designed hydrogel that mimics the extracellular matrix (ECM), assembled into a highly spatial ordered architecture, similar to densely arranged bundles of the nerve fibers. The pro-neurogenesis ability of these living nerve-like fibers is tested in a 4 mm-long complete transected SCI rat model. Evidence shows that living nerve-like fibers refine the ecological niche of the defect site by immune modulation, angiogenesis, neurogenesis, neural relay formations, and neural circuit remodeling, leading to outstanding functional reconstruction, revealing an evolution process of this living construct after implantation. This effective strategy, based on biomimetic living constructs, opens a new perspective on SCI therapies.

Spinal cord injury (SCI) is an overwhelming and incurable disabling condition, for which increasing forms of multifunctional biomaterials are being tested, but with limited progression. The promising material should be able to fill SCI-induced cavities and direct the growth of new neurons, with effective drug loading to improve the local micro-organism environment and promote neural tissue regeneration. In this study, a double crosslinked biomimetic composite hydrogel comprised of acellularized spinal cord matrix (ASCM) and gelatin-acrylated-β-cyclodextrin-polyethene glycol diacrylate (designated G-CD-PEGDA) hydrogel, loaded with WAY-316606 to activate canonical Wnt/β-catenin signaling, and reinforced by a bundle of three-dimensionally printed aligned polycaprolactone (PCL) microfibers, was constructed. The G-CD-PEGDA component endowed the composite hydrogel with a dynamic structure with a self-healing capability which enabled cell migration, while the ASCM component promoted neural cell affinity and proliferation. The diffusion of WAY-316606 could recruit endogenous neural stem cells and improve neuronal differentiation. The aligned PCL microfibers guided neurite elongation in the longitudinal direction. Animal behavior studies further showed that the composite hydrogel could significantly recover the motor function of rats after SCI. This study provides a proficient approach to produce a multifunctional system with desirable physiological, chemical, and topographical cues for treating patients with SCI.

Nerve guidance conduits (NGCs) have been widely accepted as a promising strategy for peripheral nerve regeneration. Fabricating ideal NGCs with good biocompatibility, biodegradability, permeability, appropriate mechanical properties (space maintenance, suturing performance, etc.), and oriented topographic cues is still current research focus. From the perspective of translation, the technique stability and scalability are also an important consideration for industrial production. Recently, blow-spinning technique shows great potentials in nanofibrous scaffolds fabrication, possessing high quality, high fiber production rates, low cost, ease of maintenance, and high reliability. In this study, we proposed for the first time the preparation of a novel NGC via blow-spinning technique to obtain optimized performances and high productivity. A new collagen nanofibrous neuro-tube with the bilayered design was developed, incorporating inner oriented and outer random topographical cues. The bilayer structure enhances the mechanical properties of the conduit in dry and wet, displaying good radial support and suturing performance. The porous nature of the blow-spun collagen membrane enables good nutrient delivery and metabolism. The in vitro and in vivo evaluations indicated the bilayer-structure conduit could promoted Schwann cells growth, neurotrophic factors secretion, and axonal regeneration and motor functional recovery in rat.

Above-ground biomass (AGB) is a critical criterion for assessing the ecological value and productivity of grasslands. Quickly and accurately estimating the AGB of grasslands has become a matter of great concern in grassland ecosystem research. By combining ground ASD hyperspectral data and airborne hyperspectral data, this study successfully extracted the sensitive bands of canopy reflectance and calculated the various vegetation indexes, thus providing information of more dimensions for above-ground biomass estimation. Biomass inversion-based yield modeling results reveal that the 377 nm raw band reflectance of the ASD data and the narrow-band vegetation index of the Resonon data exhibit outstanding performance in yield modeling. Comparative analysis indicates that the Resonon hyperspectral data demonstrate a distinct advantage in assessing meadow steppe yield, and the quadratic polynomial model based on its narrow-band SAVI achieves an R2 of 0.553 and an RMSE of 37.53.

Triple-negative breast cancer (TNBC) is currently the worst prognostic subtype of breast cancer, and there is no effective treatment other than chemotherapy. Processing of precursors 1 (POP1) is the most substantially up-regulated RNA-binding protein (RBP) in TNBC. However, the role of POP1 in TNBC remains clarified. A series of molecular biological experiments in vitro and in vivo and clinical correlation analyses were conducted to clarify the biological function and regulatory mechanism of POP1 in TNBC. Here, we identified that POP1 is significantly up-regulated in TNBC and associated with poor prognosis. We further demonstrate that POP1 promotes the cell cycle and proliferation of TNBC in vitro and vivo. Mechanistically, POP1 directly binds to the coding sequence (CDS) region of CDKN1A mRNA and degrades it. The degradation process depends on the N6-methyladenosine (m6A) modification at the 497th site of CDKN1A and the recognition of this modification by YTH N6-methyladenosine RNA binding protein 2 (YTHDF2). Moreover, the m6A inhibitor STM2457 potently impaired the proliferation of POP1-overexpressed TNBC cells and improved the sensitivity to paclitaxel. In summary, our findings reveal the pivotal role of POP1 in promoting TNBC proliferation by degrading the mRNA of CDKN1A and that inhibition of m6A with STM2457 is a promising therapeutic strategy for TNBC.

Tamoxifen (TAM) resistance remains a major obstacle in the treatment of advanced breast cancer (BCa). In addition to the competitive inhibition of the estrogen receptor (ER) signaling pathway, damping of mitochondrial function by increasing reactive oxygen species (ROS) is critical for enhancing TAM pharmacodynamics. Here, we showed that RelB contributes to TAM resistance by inhibiting TAM-provoked ferroptosis. TAM-induced ROS level promoted ferroptosis in TAM-sensitive cells, but the effect was alleviated in TAM-resistant cells with high constitutive levels of RelB. Mechanistically, RelB inhibited ferroptosis by transcriptional upregulating glutathione peroxidase 4 (GPX4). Consequently, elevating RelB and GPX4 in sensitive cells increased TAM resistance, and conversely, depriving RelB and GPX4 in resistant cells decreased TAM resistance. Furthermore, suppression of RelB transcriptional activation resensitized TAM-resistant cells by enhancing ferroptosis in vitro and in vivo. The inactivation of GPX4 in TAM-resistant cells consistently resensitized TAM by increasing ferroptosis-mediated cell death. Together, this study uncovered that inhibition of ferroptosis contributes to TAM resistance of BCa via RelB-upregulated GPX4.

Nur77 modulators have emerged as a promising therapeutic approach for hepatocellular carcinoma. In this study, a structure-based rational drug design approach was used to design and synthesise a series of 4-((8-hydroxy-2-methylquinolin-4-yl)amino)benzoylhydrazone derivatives based on the binding characteristics of our previously reported 10g and the native ligand 3NB at the binding Site C of Nur77. Cell-based cytotoxicity assays revealed that compound TMHA37 demonstrated the highest cytotoxicity against all tested cancer cells. The induced fit docking and binding pose metadynamics simulation suggested that TMHA37 was the most promising Nur77 binder at Site C. Molecular dynamics simulation validated the stable binding of TMHA37 to Nur77’s Site C but not to Sites A or B. Specifically, TMHA37 bound strongly to Nur77-LBD (KD = 445.3 nM) and could activate Nur77’s transcriptional activity. Furthermore, TMHA37 exhibited antitumor effects by blocking the cell cycle at G2/M phase and inducing cell apoptosis in a Nur77-dependent manner.

The disruption and reconstruction of the TREM2+ tissue resident macrophage (TRM) barrier on the surface of synovial lining play a key role in the activation and "remission" of rheumatoid arthritis (RA), which engender the prediction of this immunologic barrier as a potential driver for the achievement of "cure" in RA. However, strategies to promote the reconstruction of this barrier have not been reported, and the effect of patching this barrier remains unidentified. On the other hand, appropriate piezoelectric stimulation can reprogram macrophages, which has never been exerted on this barrier TRM yet. Herein, we design piezoelectric tetragonal BaTiO3 (BTO) ultrasound-driven nanorobots (USNRs) by the solvothermal synthesis method, which demonstrates satisfactory electro-mechanical conversion effects, paving the way to generate controllable electrical stimulation under ultrasound to reprogram the barrier TRM by minimally invasive injection into joint cavity. It is demonstrated that the immunologic barrier could be patched by this USNR effectively, thereby eliminating the hyperplasia of vessels and nerves (HVN) and synovitis. Additionally, TREM2 deficiency serum-transfected arthritis (STA) mice models are applied and proved the indispensable role of TREM2 in RA curing mediated by USNR. In all, our work is an interesting and important exploration to expand the classical tetragonal BTO nanoparticles in the treatment of autoimmune diseases, providing a new idea and direction for the biomedical application of piezoelectric ceramics.

Abstract This study analyzed the impact of factors affecting overall survival in patients with pT2N0M0 esophageal squamous carcinoma (ESCC) and developed a nomogram to predict overall survival (OS). We reviewed the clinical data of 413 patients with pathological T2N0M0 ESCC after radical esophagectomy in two hospitals. Data from one institution was used as the training cohort. A nomogram was established using Cox proportional hazard regression for identifying the prognostic factors affecting for OS in ESCC patients. The area under the curve (AUC), calibration curves and decision curve analysis (DCA) were used to evaluate prognostic efficacy, which was validated in an independent validation cohort. In the training cohort (N = 304), the median OS was 69.33 months, and the 3-, 5- and 10-year OS rates were 76.80%, 67.00% and 56.90%, respectively. The median OS of the validation cohort (N = 109) was 73.50 months, and the 3-, 5- and 10-year OS rates were 77.00%, 67.80% and 55.60%, respectively. According to Cox univariate and multivariate analyses, sex, age, tumor length and the number of resected lymph nodes were identified as predictors of OS. We developed nomograms and performed internal and external validation. The time-dependent receiver operating characteristic (ROC) curve and area under the curve (AUC) value, calibration curve and decision curve analysis (DCA) showed good prediction ability of the nomogram. The developed nomogram can effectively predict OS after esophagectomy in patients with pT2N0M0 ESCC.

Designing efficient sensing-memory-computing systems remains a challenge. Here, the authors propose a self-powered vertical tribo-transistor based on MXenes to implement the multi-sensing-memory-computing function and the interaction of multisensory integration.

Summary: Depletion of CD8+ T cells is a major obstacle in immunotherapy; however, the relevant mechanisms remain largely unknown. Here, we showed that prostate cancer (PCa) cell-derived exosomes hamper CD8+ T cell function by transporting interleukin-8 (IL-8). Compared to the low IL-8 levels detected in immune cells, PCa cells secreted the abundance of IL-8 and further accumulated in exosomes. The delivery of PCa cell-derived exosomes into CD8+ T cells exhausted the cells through enhanced starvation. Mechanistically, exosomal IL-8 overactivated PPARα in recipient cells, thereby decreasing glucose utilization by downregulating GLUT1 and HK2 but increasing fatty acid catabolism via upregulation of CPT1A and ACOX1. PPARα further activates uncoupling protein 1 (UCP1), leading to fatty acid catabolism for thermogenesis rather than ATP synthesis. Consequently, inhibition of PPARα and UCP1 restores CD8+ T cell proliferation by counteracting the effect of exosomal IL-8. This study revealed that the tumor exosome-activated IL-8-PPARα-UCP1 axis harms tumor-infiltrating CD8+ T cells by interfering with energy metabolism.

Remarkable advances in fast magic-angle spinning (MAS) techniques significantly improve the resolution of 1H solid-state nuclear magnetic resonance (NMR) spectra. Here, we introduce a heteronuclear-filtered 1H homonuclear multi-quantum (MQ) correlation strategy available at a MAS rate of 100 kHz by combining 1H{X} heteronuclear-filtered methods and 1H homonuclear MQ correlation experiments. The proposed strategy was applied to selectively extract 1H signals of aluminum lactate (Al-Lac) in a mixture of Al-Lac and zinc lactate (Zn-Lac) using 27Al-filtered methods (i.e., 1H{27Al} heteronuclear multiple quantum correlation (HMQC) or 1H{27Al} symmetry-based resonance-echo saturation-pulse double-resonance (S-RESPDOR)). We demonstrate that incorporating these 27Al-filtered methods into two-dimensional (2D) 1H–1H double-quantum (DQ)/single-quantum (SQ), triple-quantum (TQ)/SQ, and even three-dimensional (3D) 27Al/1H(DQ)/1H(SQ) experiments can facilitate the acquisition of spectra without signal overlap and targeted characterization of the 1H species surrounding 27Al sites. The proposed strategy is considered to efficiently extract key structural information from complex spin systems.

Background: Posterior internal fixation is the main method used for the treatment of thoracolumbar fractures. Fractures often occur in the upper 1/3 of the vertebral body. However, they can also occur in the middle or lower 1/3 of the vertebral body. At present, there is no report discussing the potential effects of sagittal location on instrument biomechanics or surgical strategy. The object of this study was to investigate the effect of the sagittal location of the fracture region of the vertebral body on the biomechanics of the internal fixation system and surgical strategy.Methods: A finite element model of the T11-L3 thoracolumbar segment was established based on a healthy person’s CT scan. Different sagittal fracture location finite element models were created by resection of the upper 1/3, middle 1/3, and lower 1/3 of the L1 vertebral body. Three surgical strategies were utilized in this study, namely, proximal 1 level and distal 1 level (P1-D1), proximal 2 level and distal 1 level (P2-D1), and proximal 1 level and distal 2 levels (P1-D2). Nine fixation finite element models were created by combining fracture location and fixation strategies. Range of motion, von Mises stress, and stress distribution were analyzed to evaluate the effects on the instrument biomechanics and the selection of surgical strategy.Results: In all three different fixation strategies, the maximum von Mises stress location on the screw did not change with the sagittal location of the fracture site; nevertheless, the maximum von Mises stress differed. The maximum rod stress was located at the fracture site, with its value and location changed slightly. In the same fixation strategy, a limited effect of sagittal location on the range of motion was observed. P2D1 resulted in a shorter range of motion and lower screw stress for all sagittal locations of the fracture compared with the other strategies; however, rod stress was similar between strategies.Conclusion: The sagittal location of a fracture may affect the intensity and distribution of stress on the fixation system but does not influence the selection of surgical strategy.

Abstract Radiation is a curative treatment for localized prostate cancer (PCa). Unfortunately, radiotherapeutic efficacy is often diminished when patients develop more aggressive or metastatic phenotypes. Recent studies have demonstrated that extracellular vesicles participate in cancer therapeutic resistance by delivering small bioactive molecules, such as small non‐coding RNAs. Here, we show that stromal cell‐derived small extracellular vesicles (sEVs) facilitate the radioresistance of PCa cells by transporting interleukin‐8 (IL‐8). Indeed, prostatic stromal cells secrete more IL‐8 than AR‐positive PCa cells, which can be accumulated in sEVs. Intriguingly, the uptake of stromal cells‐derived sEVs by radiosensitive PCa cells enhanced their radioresistance, which could be attenuated by silencing CXCL8 in stromal cells or inhibiting its receptor CXCR2 in PCa cells. sEV‐mediated radioresistance has been validated in zebrafish and mouse xenograft tumours. Mechanistically, the uptake of stromal sEVs triggers the AMPK‐activated autophagy pathway in PCa cells under the irradiation condition. Consequently, inactivating AMPK efficiently resensitized radiotherapy either by utilizing an AMPK inhibitor or silencing AMPKα in PCa cells. Furthermore, chloroquine (CQ), a lysosomal inhibitor, sufficiently resensitized radiotherapy via blockade of autophagolysosome fusion, leading to autophagosome accumulation in PC cells. Collectively, these results suggest that stromal cells enhance the radioresistance of PCa cells mainly through sEVs that deliver IL‐8.

Background: The therapeutic efficacy of cytokine-induced killer (CIK) cells versus dendritic cells (DC) co-cultured with CIK cells (DC-CIK) in treating esophageal cancer (EC) remains unclear due to the absence of a direct comparison of these two regimens. This study evaluated the comparative efficacy and safety of CIK cells versus DC-CIK using network meta-analysis in treating EC.Material and methods: We identified eligible studies from previous meta-analyses, then conducted an updated search to retrieve additional trials between February 2020 and July 2021. The primary outcomes included overall survival (OS), objective response rate (ORR), and disease control rate (DCR), and the secondary outcomes included quality of life improved rate (QLIR) and adverse events (AEs). A network meta-analysis of 12 studies was conducted using ADDIS software.Results: Twelve studies were identified, including six comparing CIK or DC-CIK plus chemotherapy (CT) with CT alone. Immunotherapy plus CT significantly improved overall survival (OS) (odds ratio [OR] 4.10, 95% confidence interval [CI] 1.23–13.69), objective response rate (ORR) (OR 2.72, 95% CI 1.79–4.11), disease control rate (DCR) (OR 3.45, 95% CI 2.32–5.14), and quality of life improvement rate (QLIR) (OR 3.54, 95% CI 2.31–5.41). DC-CIK+CT decreased the risk of leukopenia compared with CT alone. However, no statistical difference was detected between CIK-CT and DC-CIK+CT.Conclusion: Based on the available evidence, we concluded that CIK cell treatment is superior to CT alone, but CIK-CT and DC-CIK+CT may be comparable in treating EC. However, comparing CIK-CT and DC-CIK+CT is only based on indirect evidence, so it is undoubtedly necessary to conduct studies to compare CIK-CT with DC-CIK+CT in EC patients directly.

We investigate the emergence of unconventional corner mode in a two-dimensional (2D) topolectrical circuits induced by asymmetric couplings. The non-Hermitian skin effect of two kinked one-dimensional (1D) lattices with multiple asymmetric couplings are explored. Then we extend to the 2D model, derive conditions for the non-Hermitian hybrid skin effect and show how the corner modes are formed by non-reciprocal pumping based on 1D topological modes. We provide explicit electrical circuit setups for realizing our observations via realistic LTspice simulation. Moreover, we show the time varying behaviors of voltage distributions to confirm our results. Our study may help to extend the knowledge on building the topological corner modes in the non-Hermitian presence.