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Abstract Diabetic neuropathic pain (DNP), one of the most common complications of diabetes, is characterized by bilateral symmetrical distal limb pain and substantial morbidity. To compare the differences is aimed at serum metabolite levels between 81 DNP and 73 T2DM patients without neuropathy and found that the levels of branched‐chain amino acids (BCAA) are significantly lower in DNP patients than in T2DM patients. In high‐fat diet/low‐dose streptozotocin (HFD/STZ)‐induced T2DM and leptin receptor‐deficient diabetic (db/db) mouse models, it is verified that BCAA deficiency aggravated, whereas BCAA supplementation alleviated DNP symptoms. Mechanistically, using a combination of RNA sequencing of mouse dorsal root ganglion (DRG) tissues and label‐free quantitative proteomic analysis of cultured cells, it is found that BCAA deficiency activated the expression of L‐type amino acid transporter 1 (LAT1) through ATF4, which is reversed by BCAA supplementation. Abnormally upregulated LAT1 reduced Kv1.2 localization to the cell membrane, and inhibited Kv1.2 channels, thereby increasing neuronal excitability and causing neuropathy. Furthermore, intraperitoneal injection of the LAT1 inhibitor, BCH, alleviated DNP symptoms in mice, confirming that BCAA‐deficiency‐induced LAT1 activation contributes to the onset of DNP. These findings provide fresh insights into the metabolic differences between DNP and T2DM, and the development of approaches for the management of DNP.

Abstract Two‐dimensional (2D) non‐layered materials, along with their unique surface properties, offer intriguing prospects for sensing applications. Introducing mechanical degrees of freedom is expected to enrich the sensing performances of 2D non‐layered devices, such as high frequency, high tunability, and large dynamic range, which could lead to new types of high performance nanosensors. Here, we demonstrate 2D non‐layered nanomechanical resonant sensors based on β‐In2S3, where the devices exhibit robust nanomechanical vibrations up to the very high frequency (VHF) band. We show that such device can operate as pressure sensor with broad range (from 10−3 Torr to atmospheric pressure), high linearity (with a nonlinearity factor as low as 0.0071), and fast response (with an intrinsic response time less than 1 μs). We further unveil the frequency scaling law in these β‐In2S3 nanomechanical sensors and successfully extract both the Young's modulus and pretension for the crystal. Our work paves the way towards future wafer‐scale design and integrated sensors based on 2D non‐layered materials.

Abstract With the continuous transformation of the global power system, ensuring the flexibility and stability of the power system has become a direction that the global energy industry has been striving for. This puts forward higher requirements for load forecasting, especially high‐precision short‐term residential load forecasting. However, the high volatility and uncertainty of electric consumption make this problem challenging. Existing methods usually focus on capturing temporal correlations and ignore the underlying spatial correlations in historical loads, which is crucial for accurate forecasting. In this paper, we propose a novel spatial–temporal gated fusion network (STGNet) for short‐term residential load forecasting including not only individual residential load but also aggregated load. By seeking both adaptive neighbors and temporal similarity neighbors, we construct a dynamic graph based on a data‐driven method. On this basis, we provide an adaptive graph gated fusion mechanism to capture fine‐grained node‐specific spatial dependence more accurately and comprehensively. Finally, a bidirectional gated recurrent unit (BiGRU) is utilized to learn the temporal dependence of load data. Extensive experiments on real‐world datasets are conducted and demonstrate the superiority of STGNet over the existing approaches.

Abstract Esophageal squamous cell carcinoma (ESCC) is a prevalent gastrointestinal cancer characterized by high mortality and an unfavorable prognosis. While combination therapies involving surgery, chemotherapy, and radiation therapy are advancing, targeted therapy for ESCC remains underdeveloped. As a result, the overall five‐year survival rate for ESCC is still below 20%. Herein, ESCC‐specific DNA aptamers and an innovative aptamer‐modified nano‐system is introduced for targeted drug and gene delivery to effectively inhibit ESCC. The EA1 ssDNA aptamer, which binds robustly to ESCC cells with high specificity and affinity, is identified using cell‐based systematic evolution of ligands by exponential enrichment (cell‐SELEX). An EA1‐modified nano‐system is developed using a natural egg yolk lipid nanovector (EA1‐EYLNs‐PTX/siEFNA1) that concurrently loads paclitaxel (PTX) and a small interfering RNA of Ephrin A1 (EFNA1). This combination counters ESCC's proliferation, migration, invasion, and lung metastasis. Notably, EFNA1 is overexpressed in ESCC tumors with lung metastasis and has an inverse correlation with ESCC patient prognosis. The EA1‐EYLNs‐PTX/siEFNA1 nano‐system offers effective drug delivery and tumor targeting, resulting in significantly improved therapeutic efficacy against ESCC tumors. These insights suggest that aptamer‐modified nano‐systems can deliver drugs and genes with superior tumor‐targeting, potentially revolutionizing targeted therapy in ESCC.

Abstract Oral squamous cell carcinoma (OSCC) stands as a predominant and perilous malignant neoplasm globally, with the majority of cases originating from oral potential malignant disorders (OPMDs). Despite this, effective strategies to impede the progression of OPMDs to OSCC remain elusive. In this study, we established mouse models of oral carcinogenesis via 4‐nitroquinoline 1‐oxide induction, mirroring the sequential transformation from normal oral mucosa to OPMDs, culminating in OSCC development. By intervening during the OPMDs stage, we observed that combining PD1 blockade with photodynamic therapy (PDT) significantly mitigated oral carcinogenesis progression. Single‐cell transcriptomic sequencing unveiled microenvironmental dysregulation occurring predominantly from OPMDs to OSCC stages, fostering a tumor‐promoting milieu characterized by increased Treg proportion, heightened S100A8 expression, and decreased Fib_Igfbp5 (a specific fibroblast subtype) proportion, among others. Notably, intervening with PD1 blockade and PDT during the OPMDs stage hindered the formation of the tumor‐promoting microenvironment, resulting in decreased Treg proportion, reduced S100A8 expression, and increased Fib_Igfbp5 proportion. Moreover, combination therapy elicited a more robust treatment‐associated immune response compared with monotherapy. In essence, our findings present a novel strategy for curtailing the progression of oral carcinogenesis.

Abstract Background To comprehensively elucidate the genomic and mutational features of lung cancer cases, and lung adenocarcinoma (LUAD), it is imperative to conduct ongoing investigations into the genomic landscape. In this study, we aim to analyze the somatic mutation profile and assessed the significance of these informative genes utilizing a retrospective LUAD cohort. Methods A total of 247 Chinese samples were analyzed to exhibit the tumor somatic genomic alterations in patients with LUAD. The Cox regression analysis was employed to identify prognosis‐related genes and establish a predictive model for stratifying patients with LUAD. Results In the Dianjiang People's Hospital (DPH) cohort, the top five frequent mutated genes were (Epidermal growth factor receptor) EGFR (68%), TP53 (30%), RBM10 (13%), LRP1B (9%), and KRAS (9%). Of which, EGFR is a mostly altered driver gene, and most mutation sites are located in tyrosine kinase regions. Oncogene pathway alteration and mutation signature analysis demonstrated the RTK‐RAS pathway alteration, and smoking was the main carcinogenic factor of the DPH cohort. Furthermore, we identified 34 driver genes in the DPH cohort, including EGFR (68%), TP53 (30.4%), RBM10 (12.6%), KRAS (8.5%), LRP1B (8.5%), and so on, and 45 Clinical Characteristic‐Related Genes (CCRGs) were found to closely related to the clinical high‐risk factors. We developed a Multiple Parameter Gene Mutation (MPGM) risk model by integrating critical genes and oncogenic pathway alterations in LUAD patients from the DPH cohort. Based on publicly available LUAD datasets, we identified five genes, including BRCA2, Anaplastic lymphoma kinase (ALK), BRAF, EGFR, and Platelet‐Derived Growth Factor Receptor Alpha (PDGFRA), according to the multivariable Cox regression analysis. The MPGM‐low group showed significantly better overall survival (OS) compared to the MPGM‐high group (p

Abstract Head and neck cancer (HNC) is the seventh most prevalent malignancy worldwide in 2020. Cancer metastasis is the main cause of poor prognosis in HNC patients. Recently, circular RNAs (circRNAs), initially thought to have no biological function, are attracting increasing attention, and their crucial roles in mediating HNC metastasis are being extensively investigated. Existing studies have shown that circRNAs primarily function through miRNA sponges, transcriptional regulation, interacting with RNA‐binding proteins (RBPs) and as translation templates. Among these functions, the function of miRNA sponge is the most prominent. In this review, we summarized the reported circRNAs involved in HNC metastasis, aiming to elucidate the regulatory relationship between circRNAs and HNC metastasis. Furthermore, we summarized the latest advances in the epidemiological information of HNC metastasis and the tumor metastasis theories, the biogenesis, characterization and functional mechanisms of circRNAs, and their potential clinical applications. Although the research on circRNAs is still in its infancy, circRNAs are expected to serve as prognostic markers and effective therapeutic targets to inhibit HNC metastasis and significantly improve the prognosis of HNC patients.

E3 SUMO‐protein ligase CBX4 (CBX4), a key component of polycomb‐repressive complexes 1 (PRC1), has been reported to regulate a variety of genes implicated in tumor growth, metastasis, and angiogenesis. However, its role in T‐cell‐mediated antitumor immunity remains elusive. To shed light on this issue, we generated mice with T‐cell‐specific deletion of Cbx4. Tumor growth was increased in the knockout mice. Additionally, their tumor‐infiltrating lymphocytes exhibited impaired tumor necrosis factor‐alpha (TNF‐α) and interferon‐gamma (IFN‐γ) production, with an elevated programmed cell death protein 1 (PD‐1) level. In fact, dysregulated Pdcd1 expression was observed in all major subsets of peripheral T cells from the knockout mice, which was accompanied by a functional defect in response to T‐cell receptor (TCR) stimulation. In support of a direct link between CBX4 and PD‐1, Cbx4 overexpression resulted in the downregulation of Pdcd1 expression. Epigenetic analyses indicated that Cbx4 deficiency leads to diminished accumulation of inhibitory histone modifications at conserved region (CR)‐C and CR‐B sites of the Pdcd1 promoter, namely mono‐ubiquitinated histone H2A at lysine 119 (H2AK119ub1) and trimethylated histone H3 at lysine 27 (H3K27me3). Moreover, inhibition of either the E3 ligase activity of polycomb‐repressive complexes 1 (PRC1) or the methyltransferase activity of polycomb‐repressive complexes 2 (PRC2) restores Pdcd1 expression in Cbx4‐transfected cells. Cumulatively, this study reveals a novel function of CBX4 in the regulation of T‐cell function and expands our understanding of the epigenetic control of Pdcd1 expression.

Abstract The chemo‐regulation abilities of chemotherapeutic medications are appealing to address the low immunogenicity, immunosuppressive lactate microenvironment, and adaptive immune resistance of colorectal cancer. In this work, the proteolysis targeting chimera (PROTAC) of BRD4 (dBET57) is found to downregulate colorectal cancer glycolysis through the transcription inhibition of c‐Myc, which also inhibits the expression of programmed death ligand 1 (PD‐L1) to reverse immune evasion and avoid adaptive immune resistance. Based on this, self‐delivery nano‐PROTACs (designated as DdLD NPs) are further fabricated by the self‐assembly of doxorubicin (DOX) and dBET57 with the assistance of DSPE‐PEG2000. DdLD NPs can improve the stability, intracellular delivery, and tumor targeting accumulation of DOX and dBET57. Meanwhile, the chemotherapeutic effect of DdLD NPs can efficiently destroy colorectal cancer cells to trigger a robust immunogenic cell death (ICD). More importantly, the chemo‐regulation effects of DdLD NPs can inhibit colorectal cancer glycolysis to reduce the lactate production, and downregulate the PD‐L1 expression through BRD4 degradation. Taking advantages of the chemotherapy and chemo‐regulation ability, DdLD NPs systemically activated the antitumor immunity to suppress the primary and metastatic colorectal cancer progression without inducing any systemic side effects. Such self‐delivery nano‐PROTACs may provide a new insight for chemotherapy‐enabled tumor immunotherapy.

Abstract Cost‐effective non‐noble metal‐based catalysts for selective hydrogenation with excellent activity, selectivity, and durability are still the holy grail. Herein, an oxygen‐doped carbon (OC) chainmail encapsulated dilute Cu–Ni alloy is developed by simple pyrolysis of Cu/Ni‐metal–organic framework. The CuNi0.05@OC catalyst displays superior performance for atmospheric pressure transfer hydrogenation of p‐chloronitrobenzene and p‐nitrophenol, and for hydrogenation of furfural, all in water and with exceptional durability. Comprehensive characterizations confirm the close interactions between the diluted Ni sites, the base Cu, and optimized three‐layered graphene chainmail. Theoretical calculations demonstrate that the properly tuned lattice strain and Schottky junction can adjust electron density to facilitate specific adsorption on the active centers, thus enhancing the catalytic activity and selectivity, while the OC shell also offers robust protection. This work provides a simple and environmentally friendly strategy for developing practical heterogeneous catalysts that bring the synergistic effect into play between dilute alloy and functional carbon wrapping.

Abstract The Jilin clawed salamander (Onychodactylus zhangyapingi) is an endemic, endangered, and level‐two protected amphibian species of China. In the context of serious threats to amphibians worldwide, conservation studies of this endangered species are urgently needed. In this study, mitogenomic conservation genetics and species distribution modeling analyses were performed for O. zhangyapingi. Sixty‐three samples were collected from nine different locations, and the complete mitochondrial genome was sequenced. Population genetic analyses revealed that O. zhangyapingi exhibits only one genetic structure with extremely low nucleotide diversity. Late Pleistocene climate cooling may have led to a reduction in effective population size and extremely low mitogenomic nucleotide diversity in this salamander, and the subsequent temperature increase (~20 kya to present) provided the opportunity for rapid population growth. The continuous highly suitable region for O. zhangyapingi is only approximately 3000 km2 on the southeastern boundary of Jilin Province, China. Fortunately, there are three large forested national nature reserves within the distribution of O. zhangyapingi that can effectively protect endangered species. Our findings suggest that O. zhangyapingi is a vulnerable species with a narrow distribution and extremely low genetic diversity, and we should pay more attention to the conservation management of this species.

Abstract Metastasis is the leading cause of death in hepatocellular carcinoma (HCC) patients, and autophagy plays a crucial role in this process by orchestrating epithelial–mesenchymal transition (EMT). Stromal interaction molecule 1 (STIM1), a central regulator of store‐operated calcium entry (SOCE) in nonexcitable cells, is involved in the development and spread of HCC. However, the impact of STIM1 on autophagy regulation during HCC metastasis remains unclear. Here, we demonstrate that STIM1 is temporally regulated during autophagy‐induced EMT in HCC cells, and knocking out (KO) STIM1 significantly reduces both autophagy and EMT. Interestingly, STIM1 enhances autophagy through both SOCE‐dependent and independent pathways. Mechanistically, STIM1 directly interacts with microtubule‐associated protein 1A/1B‐light chain 3B (LC3B) to form a complex via the sterile‐α motif (SAM) domain, which promotes autophagosome formation. Furthermore, deletion of the SAM domain of STIM1 abolishes its binding with LC3B, leading to a decrease in autophagy and EMT in HCC cells. These findings unveil a novel mechanism by which the STIM1/LC3B complex mediates autophagy and EMT in HCC cells, highlighting a potential target for preventing HCC metastasis.

Abstract Atomically precise metal nanoclusters (MNCs), as a potential type of photoacoustic (PA) contrast agent, are limited in application due to their low PA conversion efficiency (PACE). Here, with hydrophilic Au25SR18 (SR = thiolate) as model NCs, we present a result that weakly polar solvent induces aggregation, which effectively enhances PA intensity and PACE. The PA intensity and PACE are highly dependent on the degree of aggregation, while the aggregation‐enhanced PA intensity (AEPA) positively correlates to the protected ligands. Such an AEPA phenomenon indicates that aggregation actually accelerates the intramolecular motion of Au NCs, and enlarges the proportion of excited state energy dissipated through vibrational relaxation. This result conflicts with the restriction of intramolecular motion mechanism of aggregation‐induced emission. Further experiments show that the increased energy of AEPA originates from the aggregation inhibiting the intermolecular energy transfer from excited Au NCs to their surrounding medium molecules, including solvent molecule and dissolved oxygen, rather than restricting radiative relaxations. This study develops a new strategy for enhancing the PA intensity of Au NCs, and contributes to a deeper understanding of the origin of the PA signal and the excited state energy dissipation processes for MNCs.

Abstract Plasma etching treatment is an effective strategy to improve the electrocatalytic activity, but the improvement mechanism is still unclear. In this work, a nitrogen‐doped carbon nanotube‐encased iron nanoparticles (Fe@NCNT) catalyst is synthesized as the model catalyst, followed by plasma etching treatment with different parameters. The electrocatalytic activity improvement mechanism of the plasma etching treatment is revealed by combining the physicochemical characterizations and electrochemical results. As a result, highly active metal–nitrogen species introduced by nitrogen plasma etching treatment are recognized as the main contribution to the improved electrocatalytic activity, and the defects induced by plasma etching treatment also contribute to the improvement of the electrocatalytic activity. In addition, the prepared catalyst also demonstrates superior ORR activity and stability than the commercial Pt/C catalyst.

Abstract With the advantage of fast charge transfer, heterojunction engineering is identified as a viable method to reinforce the anodes' sodium storage performance. Also, vacancies can effectively strengthen the Na+ adsorption ability and provide extra active sites for Na+ adsorption. However, their synchronous engineering is rarely reported. Herein, a hybrid of Co0.85Se/WSe2 heterostructure with Se vacancies and N‐doped carbon polyhedron (CoWSe/NCP) has been fabricated for the first time via a hydrothermal and subsequent selenization strategy. Spherical aberration‐corrected transmission electron microscopy confirms the phase interface of the Co0.85Se/WSe2 heterostructure and the existence of Se vacancies. Density functional theory simulations reveal the accelerated charge transfer and enhanced Na+ adsorption ability, which are contributed by the Co0.85Se/WSe2 heterostructure and Se vacancies, respectively. As expected, the CoWSe/NCP anode in sodium‐ion battery achieves outstanding rate capability (339.6 mAh g−1 at 20 A g−1), outperforming almost all Co/W‐based selenides.

Abstract PIWI‐interacting RNAs (piRNAs) are highly expressed in various cardiovascular diseases. However, their role in cardiomyocyte death caused by ischemia/reperfusion (I/R) injury, especially necroptosis, remains elusive. In this study, a heart necroptosis‐associated piRNA (HNEAP) is found that regulates cardiomyocyte necroptosis by targeting DNA methyltransferase 1 (DNMT1)‐mediated 5‐methylcytosine (m5C) methylation of the activating transcription factor 7 (Atf7) mRNA transcript. HNEAP expression level is significantly elevated in hypoxia/reoxygenation (H/R)‐exposed cardiomyocytes and I/R‐injured mouse hearts. Loss of HNEAP inhibited cardiomyocyte necroptosis and ameliorated cardiac function in mice. Mechanistically, HNEAP directly interacts with DNMT1 and attenuates m5C methylation of the Atf7 mRNA transcript, which increases Atf7 expression level. ATF7 can further downregulate the transcription of Chmp2a, an inhibitor of necroptosis, resulting in the reduction of Chmp2a level and the progression of cardiomyocyte necroptosis. The findings reveal that piRNA‐mediated m5C methylation is involved in the regulation of cardiomyocyte necroptosis. Thus, the HNEAP‐DNMT1‐ATF7‐CHMP2A axis may be a potential target for attenuating cardiac injury caused by necroptosis in ischemic heart disease.

Abstract Objective Immunoglobulin G4‐related disease (IgG4‐RD) is a systemic immune‐mediated fibroinflammatory condition. Previous studies have indicated relationships between malignancy and autoimmunity. This retrospective cohort study aimed to determine IgG4‐RD incidence and clinical features in patients with a family history of malignancy. Methods To analyze the relationship between IgG4‐RD and family history of malignancy, we reviewed IgG4‐RD patients with a family history of malignancy diagnosed in various departments in West China Hospital, Sichuan University from December 2012 to September 2019. Clinical data and laboratory features were compared between IgG4‐RD patients with and without a family history of malignancy. Results Among 168 enrolled patients with IgG4‐RD, 22 (13.1%) had a family history of malignancy. The most frequently involved system in family members with malignancy was the digestive system (38.5%). Among patients with a family history of malignancy, the most frequently involved organs in IgG4‐RD were the pancreas (31.9%) and lymph nodes (31.9%). Age at symptom onset was older in IgG4‐RD patients with a family history of malignancy than in patients without a family history of malignancy (50–59 years: 36.3% vs. 16.4%, p = 0.0393). Hemoglobin (p = 0.0172) and albumin (p = 0.0247) levels were higher and globulin (p = 0.0232) levels were lower in patients with a family history of malignancy. Conclusions Our findings suggest that a family history of malignancy may be associated with IgG4‐RD development. We hypothesize that genetic susceptibility may be involved in the pathogenesis of IgG4‐RD.

Abstract Background This study aimed to evaluate the feasibility and clinical response of LVSP as an alternative to LBBP. Methods This was a retrospective study of pacemaker implantation, and 46 consecutive patients with pacemaker implantation were enrolled in the study. The patients were divided into the LBBP and LVSP groups. Electrocardiogram characteristics, pacing parameters, cardiac function, and safety events were assessed during implantation and 12‐month follow‐up. Results The procedure time was significantly increased in the LBBP group compared with the LVSP group (53.52 ± 14.39 min vs. 38.13 ± 11.52 min, respectively, p = .000). The pacing QRS duration (PQRSD) decreased by 14.09 ± 41.80 ms in the LBBP group and increased by 9.70 ± 29.60 ms in the LVSP group (p = .031). Furthermore, the left ventricle activation time (LVAT) was shorter in the LBBP group than in the LVSP group (48.70 ± 13.67 ms vs. 58.70 ± 13.67 ms, p = .032). During the 12‐month follow‐up, pacing thresholds remained low and stable, and there was no significant decrease in cardiac function. No adverse event was observed during the follow‐up period. Conclusions Both LBBP and LVSP are safe and feasible methods. LVSP is a good option when multichannel electrophysiological instruments are not available and when the time available for the procedure is limited.

Abstract Assisted ultrasonic vibration technique can significantly improve the efficiency of hard rock drilling in petroleum and mineral engineering. In this study, to determine the fragmentation mechanism of rocks under ultrasonic vibration, numerical simulations using the discrete element method (DEM) were performed. A novel flat‐joint model (FJM), combined with an ultra‐high‐frequency loading boundary condition, was used to model the damage process of the hard rock under ultrasonic vibration loading. The numerical results demonstrated that the evolution of local strain and fragmentation were in good agreement with the experimental results. Based on the established model, the influence of loading parameters was investigated. Furthermore, by analyzing the development of the full strain field, crack orientations, and crack distribution, the fragmentation mechanism was revealed for the rock under ultrasonic vibration. Under ultra‐high‐frequency loading, the rock deformed in a heterogeneous manner and produced both compressive and tensile strain zones. The compressive zones were mainly distributed in the fringe and tensile zones in the top center. The generated tensile cracks caused by compression and tension in these two strain zones led to the rock failure.

Abstract Allergic rhinitis (AR) is an allergic disease characterized by immunoglobulin E (IgE)‐mediated type I hypersensitivity disorder. In the current study, we illuminated the potential roles of microRNA‐141‐3p (miR‐141‐3p) in lipopolysaccharide (LPS)‐induced mucus production and the apoptosis in nasal epithelial cells (NECs). We demonstrated that miR‐141‐3p was significantly downregulated in nasal tissues from patients with AR and LPS‐treated NECs. Upregulation of miR‐141‐3p decreased the level of mucin 5AC (MUC5AC) in LPS‐treated NECs and induced NECs apoptosis. High Mobility Group Box 1 (HMGB1) was proved as a target of miR‐141‐3p and miR‐141‐3p negatively regulated its expression. In addition, we observed that HMGB1 was overexpressed in nasal mucosal tissues from patients with AR and LPS‐treated NECs. Finally, we proved that miR‐141‐3p decreased the level of MUAC5AC in LPS‐treated NECs through regulating HMGB1. In conclusion, miR‐141‐3p inhibited LPS‐induced MUAC5AC production and the apoptosis of LPS‐treated NECs by targeting HMGB1.

Objective Antimicrobial peptides are widely present in nature, with many of the antimicrobial peptides having antimicrobial activity against Gram‐positive and Gram‐negative bacteria, fungi, parasites, and even coated viruses. Internal fixation of fractures is a reliable technique. However, the fracture is difficult to heal and internal fixation is not easy to maintain after infection. This study aims to verify the antibacterial effect of cationic peptide LL‐37 on Staphylococcus aureus, explore the anti‐biofilm effects of LL‐37, and compare the effects of the cationic peptide LL‐37 and Cefalexin in treatment of postoperative infection of femoral fracture in vivo. Methods The Staphylococcus aureus was clinically isolated from one patient with clinical infection after the fracture fixation at Wuxi 9th People's Hospital. The cationic peptide LL‐37 was synthesized by Shanghai Apeptide Co. Ltd. To compare the effects of the cationic peptide LL‐37 and Cefalexin in the treatment of postoperative infection of femoral fracture in vivo, 63 rabbits with internal fixation of femoral fractures were inoculated intravenously with clinically isolated pathogenic bacteria suspensions. Rabbits in the treatment groups were treated with peptide LL‐37 and Cefalexin after surgery. Rabbits in the control groups were treated with physiological saline after surgery. The biofilms on internal fixtures were harvested from euthanized rabbits 1 h, 12 h, 1 day, 2 days, and 7 days after injection of LL‐37, Cefalexin, or saline and calculated by colony count. The biofilms from treatment and control groups at 7 days were analyzed by fluorescence microscopy. Blood samples were collected at 1 h, 12 h, 1 day, 2 days, and 7 days following peptide LL‐37 and Cefalexin injection. Results The results were compared statistically using Student's t‐test or two‐way analysis of variance (ANOVA). Cationic peptide LL‐37 showed significant inhibitory effects on clinically isolated Staphylococcus aureus (P

Objective Endoplasmic reticulum stress (ERS) is present in chondrocytes of osteoarthritis, and the intensity of ERS is related to the degree of cartilage degeneration. In vitro intervention strategies can change the status of ERS and induce the inhibition of ERS‐related pathway. Therefore, this study is designed to explore the role and molecular mechanism of cartilage stem cells (ACSCs) of ERS in chondrocytes after hip replacement. Methods Human cartilage cell lines C28/I2 were cultured as the control group. The ERS inducer was added into C28/I2 as ERS group. The third ERS + stem cells group was formed by adding cartilage stem cells into ERS group, and further transfection of si‐PERK was defined as si‐PERK + ERS + stem cells group. Cell cycle and apoptosis in the four groups were determined by flow cytometry. The protein expression of GRP78, PERK, ATF4, TMEM119, CDK4, Cyclin D, and BMP6 in chondrocytes in the four groups were investigated by western blot, and the distribution of PERK, TMEM119, and BMP6 in chondrocytes were observed by immunofluorescence assay. In addition, the transcriptional levels of Bcl2, Bax, and Caspase 3 were also determined by RT‐PCR. Results In cell cycle assay, ERS increased the accumulation of cells in G0/G1 and G2/M, while cartilage stem cells weakened the effects. The apoptosis rates in control group, ERS, ERS + stem cells, si‐PERK + ERS + stem cells were 0%, 21.3%, 18.9%, and 15.9%, respectively, and the difference of apoptosis rate between the latter three groups and control group was statistically significant (P

Receptor for activated C kinase 1 (RACK1) has been shown to promote oral squamous cell carcinoma (OSCC) progression, and RACK1 expression levels have been negatively correlated with prognosis in patients with OSCC. Here, we investigated the impact of RACK1 OSCC expression on the recruitment and differentiation of tumor‐associated macrophages. High RACK1 expression in OSCC cells correlated with increased M2 macrophage infiltration in tumor samples from a clinical cohort study. Moreover, the combination of RACK1 expression and the M2/M1 ratio could successfully predict prognosis in OSCC. OSCC cells with high RACK1 expression inhibited the migration of THP‐1 cells, promoted M2‐like macrophage polarization in vitro, and increased the proportion of M2‐like macrophages in a xenograft mouse model. Moreover, both M1‐ and M2‐like macrophage polarization‐associated proteins were induced in macrophages cocultured with RACK1‐silenced cell supernatant. A mechanistic study revealed that the expression and secretion of C‐C motif chemokine 2 (CCL2), C‐C motif chemokine 5 (CCL5), interleukin‐6 (IL‐6), and interleukin‐1 (IL‐1) are closely related to RACK1 expression. In addition, blocking nuclear factor‐kappa B (NF‐κB) could promote M2‐like macrophage polarization. These results indicate that RACK1 and the M2/M1 ratio are predictors of a poor prognosis in OSCC. RACK1 promotes M2‐like polarization by regulating NF‐κB and could be used as a potential therapeutic target for antitumor immunity.

Abstract Background To ascertain if concurrent chemotherapy (CCT) benefits people with stage II nasopharyngeal carcinoma (NPC) treated with two‐dimensional radiotherapy (2DRT) or intensity‐modulated radiotherapy (IMRT). Methods A total of 4157 patients diagnosed with stage II NPC were evaluated. Patients received radiotherapy (RT) with/without CCT. Patients were divided into 2DRT and IMRT subgroups. After propensity score matching, the role of CCT was explored in these two subgroups. Overall survival (OS) was the primary endpoint and progression‐free survival (PFS), locoregional relapse‐free survival (LRFS) and distant metastasis‐free survival (DMFS) were secondary endpoints. Results In the 2DRT subgroup, CCT addition to RT benefited cases with T1N1/T2N1 in OS, PFS and LRFS (P

In recent years, ultrasonic vibration rock-breaking technology has aroused great interest in tunnel excavation and underground mineral. To apply this technology to practical engineering, it is necessary to compare the difference between cumulative damage and crack propagation of rock under static load and ultrahigh frequency alternating load. Numerical simulation and laboratory experimental methods were used in this paper to study the damage and fracture characteristics of rock under static loading and ultrasonic vibration. The variation laws of rock infrared temperature characteristics, porosity and compressive strength under different ultrasonic static loads were studied. The discrete element model of rock under ultrasonic vibration was established, and the numerical simulation was carried out by PFC2D software. We designed the ultrasonic rotary drilling device to verify the drilling effect. The process and mechanism of rock fragmentation under static load and ultrasonic vibration load were analyzed from the perspective of energy. Numerical simulation and experimental results showed that the combination of static load and ultrasonic vibration accelerates the failure speed of rock sample. The thermal infrared temperature characteristic test showed that the rock-breaking process under ultrasonic load and static load has three stages: stage I, elastic deformation and the temperature rises linearly; stage II, the development of microcrack and the temperature is further increased uniformly, and stage III, macrobreaking and rock chips falling off, and the temperature fluctuates sharply. There is a minimum threshold value for the promotion of static loading to break rock by ultrasonic vibration. Only when the static load is greater than 200 N, the crack propagation will occur in the rock sample. At this time, with the increase of static load, the crack propagation will further intensify, and the rock-breaking effect is more obvious. Under the same weight on bit (WOB), the penetration of rotary ultrasonic drilling can be increased by 13.93% ∼ 38.11% compared with conventional rotary drilling.

Background. Impaired bile acid (BA) metabolism has been associated with the progression of type 2 diabetes (T2D). However, the contribution of BAs to the pathogenesis of latent autoimmune diabetes in adults (LADA) remains unclear. This study was aimed at investigating the association of serum BAs with different diabetes types and analyzing its correlation with main clinical and laboratory parameters. Methods. Patients with LADA, patients with T2D, and healthy controls (HCs) were enrolled. Serum BA profiles and inflammatory cytokines were measured. The correlation of BA species with different indicators was assessed by Spearman’s correlation method. Results. Patients with diabetes (LADA and T2D) had significantly higher serum BAs, especially conjugated BAs, compared with those in HCs. Nevertheless, serum BA profiles had no special role in the progression of LADA, because no significant differences in BAs were observed between LADA and T2D patients. Interestingly, HbA1c levels and HOMA-β were found to be correlated with a series of BA species. Proinflammatory cytokines (IL-1β, IL-6, and TNF-α) and anti-inflammatory cytokine (IL-10) were all positively associated with several BA species, especially the conjugated secondary BAs. Conclusion. Serum BAs regulate glucose homeostasis, but have no special value in the pathogenesis of LADA patients. Our study adds further information about the potential value of serum BAs in different types of diabetes.

To explore the influence of microexpansive concrete self-stress on the performance of steel pipe concrete, the expansion rate test of microexpansive concrete confined by steel tube was carried out with different expansion rates. Then, the mechanical properties of high-strength steel tube-confined microexpansive concrete (HSTCMC) short columns were conducted by the uniaxial compression test. The length-to-diameter ratio, the expansion rate of the microexpansive concrete, and the steel tube thickness were investigated in the study. Furthermore, the ABAQUS software was employed to analyze the microexpansive mechanism of the concrete, and it was verified by the uniaxial compression test. The test results show that the concrete possesses a remarkable volume expansion phenomenon, which was up to 150 με after four days of maintenance time. The mechanical properties of the HSTCMC short columns were greatly improved compared to the control RC pier. The yield and ultimate strength of the HSTCMC short columns can be enhanced to 8.9% and 14.6%, and with the content of expansive agent that increased from 8% to 12%. The finite element analysis results highlighted that the end constraint at the two ends has the biggest influence on the mechanical performance of the HSTCMC short columns, followed by the thickness of the steel tube and the content of the expansive agent. It should be noted that the self-stress of microexpansive concrete will be decreased with the increase in the length-to-diameter ratio, when the length-to-diameter ratio is less than four. Furthermore, the constraint effect of the circular steel tube on the microexpansive concrete is better than that of the rectangular section steel tube.

The constant normal stiffness (CNS) boundary condition is more representative for the underground engineering, in which the shear-induced dilation is restricted by surrounding rocks, resulting in an increase in the normal stress. Therefore, the use of CNS boundary conditions in the research of shear-slip failure of underground rock engineering is more in line with the actual situation. Taking the instability and failure of surrounding rock in underground engineering as the background, the present study introduces the engineering background of CNS boundary conditions and the research progress on shear characteristics of rock joints under CNS boundary conditions. Three key directions for future research are proposed based on the latest research results of shear characteristics of rock joint under CNS boundary conditions: ① developing a rock joint shear test system that can realize the function of “CNS boundary conditions + shear-seepage test + visualization”; ② carrying out the shear tests of real rock joints under CNS boundary conditions based on 3D scanning and 3D carving technology; and ③ carrying out the shear tests of rock joint network under CNS boundary conditions.

Abstract N6‐methyladenosine (m6A) is rapidly being studied and uncovered to play a significant role in various biological processes as well as in RNA fate and functions, while the effects of defined m6A sites are rarely characterized for the lack of convenient tools. To provide an applicable method to remove m6A modification at specific loci, an m6A editing system called “targeted RNA demethylation by SunTag system (TRADES)” is engineered. In this system, the targeting element dCas13b is fused to ten copies of GCN4 peptides which can recruit multiple scFv‐fusion RNA demethylase to demethylate the target m6A site. Owing to this design, TRADES is more flexible to the indistinct m6A sites for its wide editing window. By site‐specific demethylation of messenger RNA (mRNA) SON A2699, the lifetime of SON RNA is successfully prolonged in HeLa cells. Meanwhile, TRADES negligibly influences the lifetime of other non‐targeted transcripts. TRADES also can regulate the gene expression of target transcript in an m6A‐dependent manner. Moreover, the interference occuring for HBV and HIV replications demonstrates that the TRADES system holds potential in viral life cycle regulation and clinical applications.

Abstract Introduction Excessive neuroinflammation aggravates the brain injury caused by intracerebral hemorrhage (ICH), while the upstream mechanisms that initiate neuroinflammation remain unclear. Toll‐like receptor 4 (TLR4) signaling is important to trigger inflammatory responses in ICH, and cold‐inducible RNA‐binding protein (CIRP) has been shown as a novel ligand of TLR4 by recent studies. However, whether the CIRP could trigger the neuroinflammation via activating TLR4 signaling in ICH still needs to be investigated. Methods Human serum CIRP levels were measured using the ELISA kits. Western blot, FJB staining, brain water content, and neurological deficit scores were used to investigate the roles of CIRP in brain injury caused by ICH. Result First, we found increased CIRP levels in the blood of patients with ICH when compared to the control individuals, and the ICH patients with mRS > 2 have higher serum CIRP levels in contrast to those with mRS ≤ 2. In the ICH mice, we also found that brain CIRP protein and mRNA levels were also increased after ICH. Furthermore, using the CIRP−/− mice, we found that CIRP−/− mice had less brain damages showing in less FJB+ cells, reduced brain water content (BWC) and lower neurological deficit scores (NDS) compared to that in WT mice after ICH. Cytokines including IL‐6, TNF‐α, and IL‐1β from CIRP−/− mice were attenuated after ICH. CIRP−/− mice also exhibited reduced TLR4 expression which was accompanied by the decreased activity of NF‐κB. This suggests that TLR4 signaling might be involved in CIRP‐mediated inflammatory injury possibly via NF‐κB activation after ICH. Conclusion Our findings suggest that CIRP may activate TLR4 signaling, and further inducing NF‐κB activation to increase the expression levels of cytokines and aggravate inflammatory injury in ICH. Targeting CIRP may be a promising strategy for ICH treatment.

Abstract Breast cancer brain metastases (BCBM) is a devastating disease with dismal prognosis. Although chemotherapy is widely used for clinical management of most tumors, it is often ineffective for BCBM. Therefore, alternative approaches for improved treatment of BCBM are in great demand. Here, an innovative gene therapy regimen is reported that is designed for effective treatment of BCBM. First, poly(lactone‐co‐β‐amino ester) nanoparticles that are capable of efficient gene delivery are synthesized and are engineered for targeted delivery to BCBM through surface conjugation of AMD3100, which interacts with CXCR4 enriched in the tumor microenvironment. Next, an artificial gene, proMel, is designed for the expression of secretory promelittin protein, which has limited toxicity on its own but releases cytolytic melittin after activation by MMP‐2 accumulated in tumors. It is demonstrated that delivery of the proMel via the AMD3100‐conjugated nanoparticles effectively inhibits tumor progression in a BCBM mouse model. This study suggests a new direction to treat BCBM through targeted delivery of promelittin‐mediated gene therapy.