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Background: Pulmonary hypertension (PH) represents a progressive condition characterized by the remodeling of pulmonary arteries, ultimately culminating in right heart failure and increased mortality rates. Substantial evidence has elucidated the pivotal role of perivascular inflammatory factors and immune dysregulation in the pathogenesis of PH. Chemokines, a class of small secreted proteins, exert precise control over immune cell recruitment and functionality, particularly with respect to their migration to sites of inflammation. Consequently, chemokines emerge as critical drivers facilitating immune cell infiltration into the pulmonary tissue during inflammatory responses. This review comprehensively examines the significant contributions of CC chemokines in the maintenance of immune cell homeostasis and their pivotal role in regulating inflammatory responses. The central focus of this discussion is directed towards elucidating the precise immunoregulatory actions of CC chemokines concerning various immune cell types, including neutrophils, monocytes, macrophages, lymphocytes, dendritic cells, mast cells, eosinophils, and basophils, particularly in the context of pH processes. Furthermore, this paper delves into an exploration of the underlying pathogenic mechanisms that underpin the development of PH. Specifically, it investigates processes such as cellular pyroptosis, examines the intricate crosstalk between bone morphogenetic protein receptor type 2 (BMPR2) mutations and the immune response, and sheds light on key signaling pathways involved in the inflammatory response. These aspects are deemed critical in enhancing our understanding of the complex pathophysiology of PH. Moreover, this review provides a comprehensive synthesis of findings from experimental investigations targeting immune cells and CC chemokines. Aim of review: In summary, the inquiry into the inflammatory responses mediated by CC chemokines and their corresponding receptors, and their potential in modulating immune reactions, holds promise as a prospective avenue for addressing PH. The potential inhibition of CC chemokines and their receptors stands as a viable strategy to attenuate the inflammatory cascade and ameliorate the pathological manifestations of PH. Nonetheless, it is essential to acknowledge the current state of clinical trials and the ensuing progress, which regrettably appears to be less than encouraging. Substantial hurdles exist in the successful translation of research findings into clinical applications. The intention is that such emphasis could potentially foster the advancement of potent therapeutic agents presently in the process of clinical evaluation. This, in turn, may further bolster the potential for effective management of PH.

Mitogenome data of Odonata is accumulating and widely used in phylogenetic analysis. However, noncoding regions, especially control region, were usually omitted from the phylogenetic reconstruction. In an effort to uncover the phylogenetic insights offered by the control region, we have amassed 65 Odonata mitogenomes and conducted an examination of their control regions. Our analysis discovered that species belonging to Anisoptera and Anisozygoptera exhibited a stem-loop structure, which was formed by a conserved polyC-polyG stretch located near the rrns gene (encoding 12S rRNA). Conversely, the polyC-polyG region was not a conserved fragment in Zygoptera. The length and number of repetitions within the control region were identified as the primary determinants of its overall length. Further, sibling species within Odonata, particularly those in the genus Euphaea, displayed similar patterns of repetition in their control region. Collectively, our research delineates the structural variations within the control region of Odonata and suggests the potential utility of this region in elucidating phylogenetic relationships among closely related species.

Abstract Platinum-based neoadjuvant chemotherapy (NACT) followed by radical hysterectomy has been proposed as an alternative treatment approach for cervical cancer (CC) in stage Ib2-IIb, who had a strong desire to be treated with surgery. Our study aims to develop a model based on multimodal MRI by using radiomics and deep learning to predict the treatment response in CC patients treated with neoadjuvant chemoradiotherapy (NACRT). From August 2009 to June 2013, CC patients in stage Ib2-IIb (FIGO 2008) who received NACRT at Fujian Cancer Hospital were enrolled in our study. Clinical information, contrast-enhanced T1-weighted imaging (CE-T1WI), and T2-weighted imaging (T2WI) data were respectively collected. Radiomic features and deep abstract features were extracted from the images using radiomics and deep learning models, respectively. Then, ElasticNet and SVM-RFE were employed for feature selection to construct four single-sequence feature sets. Early fusion of two multi-sequence feature sets and one hybrid feature set were performed, followed by classification prediction using four machine learning classifiers. Subsequently, the performance of the models in predicting the response to NACRT was evaluated by separating patients into training and validation sets. Additionally, overall survival (OS) and disease-free survival (DFS) were assessed using Kaplan-Meier survival curves. Among the four machine learning models, SVM exhibited the best predictive performance (AUC=0.86). Among the seven feature sets, the hybrid feature set achieved the highest values for AUC (0.86), ACC (0.75), Recall (0.75), Precision (0.81), and F1-score (0.75) in the validation set, outperforming other feature sets. Furthermore, the predicted outcomes of the model were closely associated with patient OS and DFS (p = 0.0044; p = 0.0039). A model based on MRI images with features from multiple sequences and different methods could precisely predict the response to NACRT in CC patients. This model could assist clinicians in devising personalized treatment plans and predicting patient survival outcomes.

Abstract To explore the clinical characteristics of patients infected with SARS-CoV-2 nationwide, especially the effect factors of asymptomatic infection and disappearance of clinical symptoms. A total of 66,448 COVID-19 patients in China who have been diagnosed by nucleic acid test or rapid antigen test were surveyed online (December 24, 2022 to January 16, 2023). Our cross-sectional study used descriptive analyses and binary Logistics regression model to assess the correlation between the clinical characteristics and relative factors, including age, gender, pre-existing conditions, reinfection, vaccination and treatment. A total of 64,515 valid questionnaires were collected. Among included participants, 5969 of which were asymptomatic. The symptoms were mainly upper respiratory symptoms, including dry and itchy throat (64.16%), sore throat (59.95%), hoarseness (57.90%), nasal congestion (53.39%). In binary Logistics regression model, we found that male, no pre-existing conditions, reinfection and vaccination have positive correlations with the appearance of asymptomatic COVID-19 patients. In Cox proportional-hazards regression model, considering all clinical symptoms disappeared in 14 days as outcome, we found that ≤ 60 years old, male, no pre-existing conditions, vaccination and adopted treatment have positive correlations with rapid amelioration of clinical symptoms in COVID-19 patients. The clinical symptoms of the participants were mainly upper respiratory symptoms which were according with the infection of Omicron variant. Factors including age, gender, pre-existing conditions and reinfection could influence the clinical characteristics and prognosis of COVID-19 patients. Importantly, vaccination has positive significance for the prevention and treatment of COVID-19. Lastly, the use of Chinese medicine maybe beneficial to COVID-19 patients, however, reasonable guidance is necessary.

Abstract Chimeric antigen receptor (CAR)-T-cell therapy is one of the most effective immunotherapies. CAR-T-cell therapy has achieved great success in the treatment of hematological malignancies. However, due to the characteristics of solid malignant tumors, such as on-target effects, off-tumor toxicity, an immunosuppressive tumor microenvironment (TME), and insufficient trafficking, CAR-T-cell therapy for solid tumors is still in the exploration stage. Mesothelin (MSLN) is a molecule expressed on the surface of various solid malignant tumor cells that is suitable as a target of tumor cells with high MSLN expression for CAR-T-cell therapy. This paper briefly described the development of CAR-T cell therapy and the structural features of MSLN, and especially summarized the strategies of structure optimization of MSLN-targeting CAR-T-cells and the enhancement methods of MSLN-targeting CAR-T cell anti-tumor efficacy by summarizing some preclinical experiment and clinical trials. When considering MSLN-targeting CAR-T-cell therapy as an example, this paper summarizes the efforts made by researchers in CAR-T-cell therapy for solid tumors and summarizes feasible treatment plans by integrating the existing research results.

Abstract Study design A systematic review and Bayesian network meta-analysis (NMA). Objective To compare the effectiveness and safety of different posterior decompression techniques for LSS. Summary of background data Lumbar spinal stenosis (LSS) is one of the most common degenerative spinal diseases that result in claudication, back and leg pain, and disability. Currently, posterior decompression techniques are widely used as an effective treatment for LSS. Methods An electronic literature search was performed using the EMBASE, Web of Science, PubMed, and Cochrane Library databases. Two authors independently performed data extraction and quality assessment. A Bayesian random effects model was constructed to incorporate the estimates of direct and indirect treatment comparisons and rank the interventions in order. Results In all, 14 eligible studies comprising 1,260 patients with LSS were included. Five interventions were identified, namely, spinal processes osteotomy (SPO), conventional laminotomy/laminectomy (CL), unilateral laminotomy/laminectomy (UL), bilateral laminotomy/ laminectomy (BL), and spinous process-splitting laminotomy/laminectomy (SPSL). Among these, SPO was the most promising surgical option for decreasing back and leg pain and for lowering the Oswestry Disability Index (ODI). SSPL had the shortest operation time, while SPSL was associated with maximum blood loss. SPO and UL were superior to other posterior decompression techniques concerning lesser blood loss and shorter length of hospital stay, respectively. Patients who underwent BL had the lowest postoperative complication rates. Conclusion Overall, SPO was found to be a good surgical choice for patients with LSS.

Abstract Pregnane X receptor (PXR) has been reported to regulate glycolipid metabolism. The dysfunction of intestinal barrier contributes to metabolic disorders. However, the role of intestinal PXR in metabolic diseases remains largely unknown. Here, we show that activation of PXR by tributyl citrate (TBC), an intestinal-selective PXR agonist, improves high fat diet (HFD)-induced obesity. The metabolic benefit of intestinal PXR activation is associated with upregulation of β-1,3 galactosyltransferase 5 (B3galt5). Our results reveal that B3galt5 mainly expresses in the intestine and is a direct PXR transcriptional target. B3galt5 knockout exacerbates HFD-induced obesity, insulin resistance and inflammation. Mechanistically, B3galt5 is essential to maintain the integrity of intestinal mucus barrier. B3galt5 ablation impairs the O-glycosylation of mucin2, destabilizes the mucus layer, and increases intestinal permeability. Furthermore, B3galt5 deficiency abolishes the beneficial effect of intestinal PXR activation on metabolic disorders. Our results suggest the intestinal-selective PXR activation regulates B3galt5 expression and maintains metabolic homeostasis, making it a potential therapeutic strategy in obesity.

Abstract Positron emission tomography (PET) is a noninvasive molecular imaging technique that utilizes biologically active radiolabeled compounds to image biochemical processes. As such, PET can provide important pathophysiological information associated with pain of different etiologies. Consequently, the information obtained using PET often combined with magnetic resonance imaging or computed tomography can provide useful information for diagnosing and monitoring changes associated with pain. This review covers the most important PET tracers that have been used to image pain including tracers for fundamental biological processes such as glucose metabolism and cerebral blood flow, to receptor‐specific tracers such as ion channels and neurotransmitters. For each tracer, we describe the structure and radiochemical synthesis of the tracer followed by a brief summary of the available preclinical and clinical studies. By providing a summary of the PET tracers that have been employed for PET imaging of pain, this review aims to serve as a reference for preclinical, translational, and clinical investigators interested in molecular imaging of pain. Finally, the review ends with an outlook of the needs and opportunities in this area.

Abstract Anti-programmed death 1/programmed death ligand 1 (anti-PD-1/PD-L1) antibodies exert significant antitumor effects by overcoming tumor cell immune evasion and reversing T-cell exhaustion. However, the emergence of drug resistance causes most patients to respond poorly to these immune checkpoint inhibitors (ICIs). Studies have shown that insufficient T-cell infiltration, lack of PD-1 expression, deficient interferon signaling, loss of tumor antigen presentation, and abnormal lipid metabolism are all considered to be closely associated with immunotherapy resistance. To address drug resistance in tumor immunotherapy, a lot of research has concentrated on developing combination therapy strategies. Currently, ICIs such as anti-PD-1 /PD-L1 antibody combined with chemotherapy and targeted therapy have been approved for clinical treatment. In this review, we analyze the mechanisms of resistance to anti-PD-1/PD-L1 therapy in terms of the tumor microenvironment, gut microbiota, epigenetic regulation, and co-inhibitory immune checkpoint receptors. We also discuss various promising combination therapeutic strategies to address resistance to anti-PD-1/PD-L1 drugs, including combining these therapies with traditional Chinese medicine, non-coding RNAs, targeted therapy, other ICIs, and personalized cancer vaccines. Moreover, we focus on biomarkers that predict resistance to anti-PD-1/PD-L1 therapy as well as combination therapy efficacy. Finally, we suggest ways to further expand the application of immunotherapy through personalized combination strategies using biomarker systems.

Abstract Microspherical structures find broad application in chemistry and materials science, including in separations and purifications, energy storage and conversion, organic and biocatalysis, and as artificial and bioactive scaffolds. Despite this utility, the systematic diversification of their morphology and function remains hindered by the limited range of their molecular building blocks. Drawing upon the design principles of reticular synthesis, where diverse organic molecules generate varied porous frameworks, we show herein how analogous microspherical structures can be generated under mild conditions. The assembly of simple organic molecules into microspherical structures with advanced morphologies represents a grand challenge. Beginning with a partially condensed Schiff base which self-assembles into a hierarchical organic microsphere, we systematically synthesized sixteen microspheres from diverse molecular building blocks. We subsequently explicate the mechanism of hierarchical assembly through which these hierarchical organic microspheres are produced, isolating the initial monomer, intermediate substructures, and eventual microspheres. Furthermore, the open cavities present on the surfaces of these constructs provided distinctive adsorptive properties, which we harnessed for the immobilization of enzymes and bacteriophages. Holistically, these hierarchical organic microspheres provide an approach for designing multi-functional superstructures with advanced morphologies derived from simple organic molecules, revealing an extended length scale for reticular synthesis.

Abstract The differentiation of the stroma is a hallmark event during postnatal uterine development. However, the spatiotemporal changes that occur during this process and the underlying regulatory mechanisms remain elusive. Here, we comprehensively delineated the dynamic development of the neonatal uterus at single-cell resolution and characterized two distinct stromal subpopulations, inner and outer stroma. Furthermore, single-cell RNA sequencing revealed that uterine ablation of Pr-set7, the sole methyltransferase catalyzing H4K20me1, led to a reduced proportion of the inner stroma due to massive cell death, thus impeding uterine development. By combining RNA sequencing and epigenetic profiling of H4K20me1, we demonstrated that PR-SET7-H4K20me1 either directly repressed the transcription of interferon stimulated genes or indirectly restricted the interferon response via silencing endogenous retroviruses. Declined H4K20me1 level caused viral mimicry responses and ZBP1-mediated apoptosis and necroptosis in stromal cells. Collectively, our study provides insight into the epigenetic machinery governing postnatal uterine stromal development mediated by PR-SET7.

Abstract Water eutrophication has emerged as a pressing concern for massive algal blooms, and these harmful blooms can potentially generate harmful toxins, which can detrimentally impact the aquatic environment and human health. Consequently, it is imperative to identify a safe and efficient approach to combat algal blooms to safeguard the ecological safety of water. This study aimed to investigate the procedure for extracting total flavonoids from Z. bungeanum residue and assess its antioxidant properties. The most favorable parameters for extracting total flavonoids from Z. bungeanum residue were a liquid–solid ratio (LSR) of 20 mL/g, a solvent concentration of 60%, an extraction period of 55 min, and an ultrasonic temperature of 80 °C. Meanwhile, the photosynthetic inhibitory mechanism of Z. bungeanum residue extracts against M. aeruginosa was assessed with a particular focus on the concentration-dependent toxicity effect. Z. bungeanum residue extracts damaged the oxygen-evolving complex structure, influenced energy capture and distribution, and inhibited the electron transport of PSII in M. aeruginosa. Furthermore, the enhanced capacity for ROS detoxification enables treated cells to sustain their photosynthetic activity. The findings of this study hold considerable relevance for the ecological management community and offer potential avenues for the practical utilization of resources in controlling algal blooms.

Abstract Background Surgery is the primary treatment for benign breast disease and causes some disruption to the normal physiology of the breast, even when this disruption is localised, it remains unclear whether it affects women’s ability to breastfeed. There are only a few studies describing the experience of breastfeeding in women who have undergone benign breast disease (BBD) surgery. Methods We retrospectively analysed data from patients aged 20–40 years in Guangdong, China, who underwent breast lumpectomy for BBD in our department between 01 January 2013 and 30 June 2019, with a follow-up date of 01 February 2022. Patients were included who had a history of childbirth between the time of surgery and the follow-up date. By collecting general information about this group of patients and information about breastfeeding after surgery, we described the breastfeeding outcomes of women of a fertile age who had previously undergone surgery for benign breast disease. Results With a median follow-up of 5.9 years, a total of 333 patients met the inclusion criteria. From the breastfeeding data of the first child born postoperatively, the mean duration of ‘exclusive breastfeeding’ was 5.1 months, and the mean duration of ‘any breastfeeding’ was 8.8 months. The rate of ‘ever breastfeeding’ is 91.0%, which is lower than the national average of 93.7%, while the exclusive breastfeeding rate at six months was 40.8%, was higher than the 29.2% national average. The any breastfeeding rate at 12 months was 30.0%, which was well below the 66.5% national average. The common reason for early breastfeeding cessation was insufficient breast milk. A total of 29.0% of patients who had ever breastfed after surgery voluntarily reduced the frequency and duration of breastfeeding on the operated breast because of the surgery. Conclusions There are some impacts of BBD surgery on breastfeeding and some may be psychological. Institutions should provide more facilities for mothers who have undergone breast surgery to help them breastfeed, such as conducting community education on breastfeeding after breast surgery, training professional postoperative lactation consultants in hospitals, and extending maternity leave. Families should encourage mothers to breastfeed with both breasts instead of only the non-operated breast.

Src homology 2 domain-containing tyrosine phosphatase 2 (SHP2) is an essential tyrosine phosphatase that is pivotal in regulating various cellular signaling pathways such as cell growth, differentiation, and survival. The activation of SHP2 has been shown to have a therapeutic effect in colitis and Parkinson's disease. Thus, the identification of SHP2 activators and a complete understanding of their mechanism is required. We used a two-step screening assay to determine a novel allosteric activator of SHP2 that stabilizes it in an open conformation. Oleanolic acid was identified as a suitable candidate. By binding to R362, K364, and K366 in the active center of the PTP domain, oleanolic acid maintained the active open state of SHP2, which facilitated the binding between SHP2 and its substrate. This oleanolic acid-activated SHP2 hindered Th17 differentiation by disturbing the interaction between STAT3 and IL-6Rα and inhibiting the activation of STAT3. Furthermore, via the activation of SHP2 and subsequent attenuation of the STAT3–Th17 axis, oleanolic acid effectively mitigated colitis in mice. This protective effect was abrogated by SHP2 knockout or administration of the SHP2 inhibitor SHP099. These findings underscore the potential of oleanolic acid as a promising therapeutic agent for treating inflammatory bowel diseases.

Abstract Introduction Listeriosis is a severe food-borne disease caused by Listeria monocytogenes infection. The data of listeriosis in Xi’an population are limited. The aim of this study is to evaluate the clinical features and fatality risk factors for listeriosis in three tertiary-care hospitals in Xi’an, China Methods The characteristics of demographic data, underlying diseases, clinical manifestations, laboratory indicators, cranial imaging examination, antibiotics therapeutic schemes, and clinical outcomes were collected between 2011 and 2023. Logistic regression analysis was performed. Results Seventy-one etiologically confirmed listeriosis patients were enrolled, including 12 neonatal and 59 non-neonatal cases. The majority of neonatal listeriosis presented as preterm (50%) and fetal distress (75%). The main clinical manifestations of non-neonatal listeriosis included fever (88%), headache (32%), disorder of consciousness (25%), vomiting (17%), abdominal pain (12%), and convulsions (8%). The fatality rate in neonatal cases was higher than in non-neonatal listeriosis (42 vs. 17%). Although no deaths were reported in maternal listeriosis, only two of 23 patients had an uneventful obstetrical outcome. Five maternal listeriosis delivered culture-positive neonates, three of whom decreased within 1 week post-gestation due to severe complications. Twenty-eight cases were neurolisteriosis and 43 cases were bacteremia. Neurolisteriosis had a higher fatality rate compared with bacteremia listeriosis (36 vs. 12%). The main neuroradiological images were cerebral edema/hydrocephalus, intracranial infection, and cerebral hernia. Listeria monocytogenes showed extremely low resistance to ampicillin (two isolates) and penicillin (one isolate). The fatality risk factors were the involvement of the central nervous system, hyperbilirubinemia, and hyponatremia for all enrolled subjects. Hyperuricemia contributed to the elevation of fatality risk in non-neonatal listeriosis. Conclusions When the patients suffered with symptoms of fever and central nervous system infection, they should be alert to the possibility of listeriosis. Early administration of ampicillin- or penicillin-based therapy might be beneficial for recovery of listeriosis.

Cancer is the leading cause of morbidity and mortality worldwide and is an important barrier to lengthening life expectancy in every country. Natural products are receiving increased attention from researchers globally and increasing numbers of natural products are approved for clinical studies involving cancer in recent years. To gain more insight into natural products that have undergone clinical trials for cancer treatment, a comprehensive search was conducted. The https://clinicaltrials.gov website was searched for relevant clinical trials and natural product information up to December 2022. The search terms included different types of cancers, such as colorectal, lung, breast, gynecologic, kidney, bladder, melanoma, pancreatic, hepatocellular, gastric and haematologic. Then, PubMed and Web of Science were searched for relevant articles up to February 2024. Hence, we listed existing clinical trials about natural products used in the treatment of cancers and discussed the preclinical and clinical studies of some promising natural products and their targets, indications, and underlying mechanisms of action. Our intent was to provide basic information to readers who are interested or majoring in natural products and obtain a deeper understanding of the progress and actions of natural product mechanisms of action.

Abstract 4-aminopyridine (4AP) is a potassium (K+) channel blocker used clinically to improve walking in people with multiple sclerosis (MS). 4AP binds to exposed K+ channels in demyelinated axons, reducing the leakage of intracellular K+ and enhancing impulse conduction. Multiple derivatives of 4AP capable of blocking K+ channels have been reported including three radiolabeled with positron emitting isotopes for imaging demyelinated lesions using positron emission tomography (PET). However, there remains a demand for novel molecules with suitable physicochemical properties and binding affinity that can potentially be radiolabeled and used as PET radiotracers. In this study, we introduce 3-fluoro-5-methylpyridin-4-amine (5Me3F4AP) as a novel trisubstituted K+ channel blocker with potential application in PET. 5Me3F4AP has comparable potency to 4AP and the PET tracer 3-fluoro-4-aminopyridine (3F4AP). Compared to 3F4AP, 5Me3F4AP exhibits comparable basicity (pK a = 7.46 ± 0.01 vs. 7.37 ± 0.07, P-value = 0.08), greater lipophilicity (logD = 0.664 ± 0.005 vs. 0.414 ± 0.002, P-value

Abstract Background Glycometabolism and lipid metabolism are critical in cancer metabolic reprogramming. The primary aim of this study was to develop a prognostic model incorporating glycometabolism and lipid metabolism-related genes (GLRGs) for accurate prognosis assessment in patients with endometrial carcinoma (EC). Methods Data on gene expression and clinical details were obtained from publicly accessible databases. GLRGs were obtained from the Genecards database. Through nonnegative matrix factorization (NMF) clustering, molecular groupings with various GLRG expression patterns were identified. LASSO Cox regression analysis was employed to create a prognostic model. Use rich algorithms such as GSEA, GSVA, xCELL ssGSEA, EPIC,CIBERSORT, MCPcounter, ESTIMATE, TIMER, TIDE, and Oncoppredict to analyze functional pathway characteristics of the forecast signal, immune status, anti-tumor therapy, etc. The expression was assessed using Western blot and quantitative real-time PCR techniques. A total of 113 algorithm combinations were combined to screen out the most significant GLRGs in the signature for in vitro experimental verification, such as colony formation, EdU cell proliferation, wound healing, apoptosis, and Transwell assays. Results A total of 714 GLRGs were found, and 227 of them were identified as prognostic-related genes. And ten GLRGs (AUP1, ESR1, ERLIN2, ASS1, OGDH, BCKDHB, SLC16A1, HK2, LPCAT1 and PGR-AS1) were identified to construct the prognostic model of patients with EC. Based on GLRGs, the risk model’s prognosis and independent prognostic value were established. The signature of GLRGs exhibited a robust correlation with the infiltration of immune cells and the sensitivity to drugs. In cytological experiments, we selected HK2 as candidate gene to verify its value in the occurrence and development of EC. Western blot and qRT-PCR revealed that HK2 was substantially expressed in EC cells. According to in vitro experiments, HK2 knockdown can increase EC cell apoptosis while suppressing EC cell migration, invasion, and proliferation. Conclusion The GLRGs signature constructed in this study demonstrated significant prognostic value for patients with endometrial carcinoma, thereby providing valuable guidance for treatment decisions.

Abstract Objective To investigate the effect of concentrated growth factor (CGF) combined with sodium hyaluronate (SH) on temporomandibular joint osteoarthritis (TMJOA). Methods Sixty patients with TMJOA who were diagnosed by cone-beam computed tomography (CBCT) between March 2020 and March 2023 at the Stomatological Hospital of Xi’an Jiaotong University were randomly divided into a control group (n = 30) and an experimental group (n = 30). The patients in the experimental group were treated with CGF + SH, and those in the control group were treated with SH only. The visual analogue scale (VAS) score indicating pain in the temporomandibular joint (TMJ) area; the Helkimo Clinical Dysfunction Index (Di); and changes in condylar CBCT at the first visit and 2 weeks, 3 months and 6 months after treatment were recorded. The CBCT data of the patients in the experimental and control groups were collected, and the three-dimensional CBCT image sequences were imported into Mimics Medical 19.0 software in DICOM format for condylar reconstruction. Results The VAS scores at 2 weeks, 3 months and 6 months after treatment were significantly lower in the experimental group than in the control group (P

Abstract Background Glioblastoma is an aggressive brain tumor linked to significant angiogenesis and poor prognosis. Anti-angiogenic therapies with vascular endothelial growth factor receptor 2 (VEGFR2) inhibition have been investigated as an alternative glioblastoma treatment. However, little is known about the effect of VEGFR2 blockade on glioblastoma cells per se. Methods VEGFR2 expression data in glioma patients were retrieved from the public database TCGA. VEGFR2 intervention was implemented by using its selective inhibitor Ki8751 or shRNA. Mitochondrial biogenesis of glioblastoma cells was assessed by immunofluorescence imaging, mass spectrometry, and western blot analysis. Results VEGFR2 expression was higher in glioma patients with higher malignancy (grade III and IV). VEGFR2 inhibition hampered glioblastoma cell proliferation and induced cell apoptosis. Mass spectrometry and immunofluorescence imaging showed that the anti-glioblastoma effects of VEGFR2 blockade involved mitochondrial biogenesis, as evidenced by the increases of mitochondrial protein expression, mitochondria mass, mitochondrial oxidative phosphorylation (OXPHOS), and reactive oxygen species (ROS) production, all of which play important roles in tumor cell apoptosis, growth inhibition, cell cycle arrest and cell senescence. Furthermore, VEGFR2 inhibition exaggerated mitochondrial biogenesis by decreased phosphorylation of AKT and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which mobilized PGC1α into the nucleus, increased mitochondrial transcription factor A (TFAM) expression, and subsequently enhanced mitochondrial biogenesis. Conclusions VEGFR2 blockade inhibits glioblastoma progression via AKT-PGC1α-TFAM-mitochondria biogenesis signaling cascade, suggesting that VEGFR2 intervention might bring additive therapeutic values to anti-glioblastoma therapy.

Xanthomonas spp. cause severe bacterial diseases. However, effective strategies for prevention and management of these diseases are scarce. Thus, it is necessary to improve the efficiency of control of diseases caused by Xanthomonas. In this study, Xanthomonas oryzae pv. oryzae (Xoo), which causes rice bacterial leaf blight, has been studied as a representative. A transposon insertion library of Xoo, comprising approximately 200,000 individual insertion mutants, was generated. Transposon sequencing data indicated that the mariner C9 transposase mapped at 35.7–36.4% of all potential insertion sites, revealing 491 essential genes required for the growth of Xoo in rich media. The results show that, compared to the functions of essential genes of other bacteria, the functions of some essential genes of Xoo are unknown, 25 genes might be dangerous for the Xanthomonas group, and 3 are specific to Xanthomonas. High-priority candidates for developing broad-spectrum, Xanthomonas-specific, and environment-friendly bactericides were identified in this study. In addition, this study revealed the possible targets of dioctyldiethylenetriamine using surface plasmon resonance (SPR) in combination with high performance liquid chromatography–mass spectrometry (HPLC–MS). The study also provided references for the research of some certain bactericides with unknown anti-bacterial mode of action. In conclusion, this study urged a better understanding of Xanthomonas, provided meaningful data for the management of bacterial leaf blight, and disclosed selected targets of a novel bactericide.

The number of layers and ply orientations determined the service performance of carbon fiber-reinforced polymer (CFRP) materials. Under low-temperature service conditions, the unclear weakening mechanism of mechanical properties of CFRP aggravates the failure risks of aerospace structures. In present work, the unclear correlation between layers with alternating orientations and the tensile-failure mechanisms of CFRP, the low temperature-mechanical coupling micromechanical behavior, and the failure mechanism of CFRP was experimentally revealed by using a horizontal testing instrument integrated with a low-temperature loading module and real-time optical imaging function. Based on various temperatures in a range from −40 °C to room temperature (RT) and two strain rates, the gradually decreasing trends of tensile strength, Young's modulus, and elongation after fracture with decreasing temperature are obtained. Three failure modes including fiber brittle fracture, fiber pull-out, and interface debonding are proposed to reveal the low temperature-mechanical coupling failure mechanism. Low-temperature asynchronous shrinkage of carbon fiber and epoxy resin promoted the transition from fiber brittle fracture to delamination at the interface. The proposed instrument could establish the approximatively actual service conditions involving low temperature and mechanical load.

Abstract Background Ovarian cancer (OC) is a gynecological malignancy tumor with high recurrence and mortality rates. Programmed cell death (PCD) is an essential regulator in cancer metabolism, whose functions are still unknown in OC. Therefore, it is vital to determine the prognostic value and therapy response of PCD-related genes in OC. Methods By mining The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx) and Genecards databases, we constructed a prognostic PCD-related genes model and performed Kaplan-Meier (K-M) analysis and Receiver Operating Characteristic (ROC) curve for its predictive ability. A nomogram was created via Cox regression. We validated our model in train and test sets. Quantitative real-time PCR (qRT-PCR) was applied to identify the expression of our model genes. Finally, we analyzed functional analysis, immune infiltration, genomic mutation, tumor mutational burden (TMB) and drug sensitivity of patients in low- and high-risk group based on median scores. Results A ten-PCD-related gene signature including protein phosphatase 1 regulatory subunit 15 A (PPP1R15A), 8-oxoguanine-DNA glycosylase (OGG1), HECT and RLD domain containing E3 ubiquitin protein ligase family member 1 (HERC1), Caspase-2.(CASP2), Caspase activity and apoptosis inhibitor 1(CAAP1), RB transcriptional corepressor 1(RB1), Z-DNA binding protein 1 (ZBP1), CD3-epsilon (CD3E), Clathrin heavy chain like 1(CLTCL1), and CCAAT/enhancer-binding protein beta (CEBPB) was constructed. Risk score performed well with good area under curve (AUC) (AUC3 − year =0.728, AUC5 − year = 0.730). The nomogram based on risk score has good performance in predicting the prognosis of OC patients (AUC1 − year =0.781, AUC3 − year =0.759, AUC5 − year = 0.670). Kyoto encyclopedia of genes and genomes (KEGG) analysis showed that the erythroblastic leukemia viral oncogene homolog (ERBB) signaling pathway and focal adhesion were enriched in the high-risk group. Meanwhile, patients with high-risk scores had worse OS. In addition, patients with low-risk scores had higher immune-infiltrating cells and enhanced expression of checkpoints, programmed cell death 1 ligand 1 (PD-L1), indoleamine 2,3-dioxygenase 1 (IDO-1) and lymphocyte activation gene-3 (LAG3), and were more sensitive to A.443,654, GDC.0449, paclitaxel, gefitinib and cisplatin. Finally, qRT-PCR confirmed RB1, CAAP1, ZBP1, CEBPB and CLTCL1 over-expressed, while PPP1R15A, OGG1, CASP2, CD3E and HERC1 under-expressed in OC cell lines. Conclusion Our model could precisely predict the prognosis, immune status and drug sensitivity of OC patients.

Abstract Background Vasculogenic mimicry (VM), when microvascular channels are formed by cancer cells independent of endothelial cells, often occurs in deep hypoxic areas of tumors and contributes to the aggressiveness and metastasis of triple-negative breast cancer (TNBC) cells. However, well-developed VM inhibitors exhibit inadequate efficacy due to their low drug utilization rate and limited deep penetration. Thus, a cost-effective VM inhibition strategy needs to be designed for TNBC treatment. Results Herein, we designed a low-intensity focused ultrasound (LIFU) and matrix metalloproteinase-2 (MMP-2) dual-responsive nanoplatform termed PFP@PDM-PEG for the cost-effective and efficient utilization of the drug disulfiram (DSF) as a VM inhibitor. The PFP@PDM-PEG nanodroplets effectively penetrated tumors and exhibited substantial accumulation facilitated by PEG deshielding in a LIFU-mediated and MMP-2-sensitive manner. Furthermore, upon exposure to LIFU irradiation, DSF was released controllably under ultrasound imaging guidance. This secure and controllable dual-response DSF delivery platform reduced VM formation by inhibiting COL1/pro-MMP-2 activity, thereby significantly inhibiting tumor progression and metastasis. Conclusions Considering the safety of the raw materials, controlled treatment process, and reliable repurposing of DSF, this dual-responsive nanoplatform represents a novel and effective VM-based therapeutic strategy for TNBC in clinical settings. Graphical Abstract

Abstract Background Waardenburg syndrome type 2 (WS2) has been reported to be a rare hereditary disorder, which is distinguished by vivid blue eyes, varying degrees of hearing impairment, and abnormal pigment deposition in the skin and hair. Variants in the sex-determining region Y-box containing gene 10 (SOXl0) gene may cause congenital deafness and have been demonstrated to be important during the development of WS2. Methods Complete clinical data of the proband and her family members (her parents and 2 sisters) was collected and physical examinations were performed in the hospital. The laboratory examination including hemoglobin, Coomb’s test, urine protein, ENA, autoimmune hepatitis-related autoantibodies and ultrasonography were all conducted. We obtained the peripheral blood samples from all the participants and performed whole exome sequencing and sanger sequencing validation. Results The present study identified a family of 5 members, and only the proband exhibited typical WS2. Beyond the characteristics of WS2, the proband also manifested absence of puberty. The proband and her younger sister manifested systemic lupus erythematosus (SLE). Whole exome sequencing revealed a de novo variant in the SOX10 gene. The variant c.175 C > T was located in exon 2 of the SOX10 gene, which is anticipated to result in early termination of protein translation. Conclusion The present study is the first to report a case of both WS2 and SLE, and the present findings may provide a new insight into WS2.

Abstract Background Soft tissue recurrence of giant cell tumor of bone (GCTB) is rare. This study aims to provide its prevalence, recurrent locations, risk factors, effective detection methods and a modified classification for this recurrence. Methods Patients with soft tissue recurrence after primary surgery for GCTB were screened from January 2003 to December 2022. General data, recurrence frequency, types according to an original classification (type-I: peripheral ossification; type-II: central ossification; type-III: without ossification), a modified classification with more detailed subtypes (type I-1: ≤ 1/2 peripheral ossification; type I-2: ≥ 1/2 peripheral ossification; type II-1: ≤ 1/2 central ossification; type II-2: ≥ 1/2 central ossification; type III: without ossification), locations, detection methods such as ultrasonography, X-ray, CT or MRI, Musculoskeletal Tumor Society (MSTS) scores were recorded. Multivariate regression analysis was conducted to identify risk factors for recurrence frequency. Results A total of 558 recurrent cases were identified from 2009 patients with GCTB. Among them, 32 were soft tissue recurrence. The total recurrence rate was 27.78% (558/2009). Soft tissue recurrence rate was 5.73% among 558 recurrent cases, and 1.59% among 2009 GCTB patients, respectively. After excluding one patient lost to follow-up, 10 males and 21 females with the mean age of 28.52 ± 9.93 (16–57) years were included. The definitive diagnosis of all recurrences was confirmed by postoperative pathology. The interval from primary surgery to the first recurrence was 23.23 ± 26.12 (2–27) months. Eight recurrences occurred from primary GCTB located at distal radius, followed by distal femur (6 cases). Recurrence occurred twice in 12 patients and 3 times in 7 patients. Twenty-seven recurrences were firstly detected by ultrasonography, followed by CT or X-ray (10 cases in each). Types at the first recurrence were 5 cases in type-I, 8 in type-II and 18 in type-III. According to the modified classification, 3 patients in type I-1, 2 in type I-2, 1 in type II-1, 7 in type II-2, and 18 in type III. The mean MSTS score was 26.62 ± 4.21 (14—30). Neither Campanacci grade nor recurrence type, modified classification and other characters, were identified as risk factors. Conclusions Soft tissue recurrence of GCTB may recur for more than once and distal radius was the most common location of primary GCTB that would suffer a soft tissue recurrence. Ultrasonography was a useful method to detect the recurrence. Since no risk factors were discovered, a careful follow-up with ultrasonography was recommended.

Osteosarcoma (OS) is a rare but aggressive malignancy. Despite previous reports, molecular characterization of this disease is not well understood, and little is known regarding OS in Chinese patients. Herein, we analyzed the genomic signatures of 73 Chinese OS cases. TP53, NCOR1, LRP1B, ATRX, RB1, and TFE3 were the most frequently mutated gene in our OS cohort. In addition, the genomic analysis of Western OS patients was performed. Notably, there were remarkable disparities in mutational landscape, base substitution pattern, and tumor mutational burden between the Chinese and Western OS cohorts. Specific molecular mechanisms, including DNA damage repair (DDR) gene mutations, copy number variation (CNV) presence, aneuploidy, and intratumoral heterogeneity, were associated with disease progression. Additionally, 30.1% of OS patients carried clinically actionable alterations, which were mainly enriched in PI3K, MAPK, DDR, and RTK signaling pathways. A specific molecular subtype incorporating DDR alterations and CNVs was significantly correlated with distant metastasis‐free survival and event‐free survival, and this correlation was observed in all subgroups with different characteristics. These findings comprehensively elucidated the genomic profile and revealed novel prognostic factors in OS, which would contribute to understanding this disease and promoting precision medicine of this population.

Objective: This study aimed to verify whether pancreatic steatosis (PS) is an independent risk factor for type 2 diabetes mellitus (T2DM). We also developed and validated a deep learning model for the diagnosis of PS using ultrasonography (US) images based on histological classifications. Methods: In this retrospective study, we analysed data from 139 patients who underwent US imaging of the pancreas followed by pancreatic resection at our medical institution. Logistic regression analysis was employed to ascertain the independent predictors of T2DM. The diagnostic efficacy of the deep learning model for PS was assessed using receiver operating characteristic curve analysis and compared with traditional visual assessment methodology in US imaging. Results: The incidence rate of PS in the study cohort was 64.7 %. Logistic regression analysis revealed that age (P = 0.003) and the presence of PS (P = 0.048) were independent factors associated with T2DM. The deep learning model demonstrated robust diagnostic capabilities for PS, with areas under the curve of 0.901 and 0.837, sensitivities of 0.895 and 0.920, specificities of 0.700 and 0.765, accuracies of 0.814 and 0.857, and F1-scores of 0.850 and 0.885 for the training and validation cohorts, respectively. These metrics significantly outperformed those of conventional US imaging (P

Given the current enthusiasm for lunar exploration, the 2:1 resonant distant retrograde orbit (DRO) in Earth-Moon space is of interest. To gain an in-depth understanding of the complex dynamic environment in cislunar space and provide more options for parking orbits, this paper investigates the existence of quasi-periodic orbits near the 2:1 resonant DRO in the circular restricted three-body problem (CR3BP). Firstly, the numerical computation approach, continuation strategy, and stability analysis method of quasi-periodic orbits are introduced. Then, addressing the primary challenges in the continuation progress, we have developed an adaptive continuation algorithm with automatic adjustment of the step size and the number of discrete points that characterize the invariant torus. Finally, two types of 2D quasi-DROs and their linear stability properties are explored. Using Poincaré sections, we investigated the boundaries of the maximum extent attainable by both 2D quasi-DRO families in the CR3BP at a specific Jacobi energy, confirming that both types of quasi-periodic families have reached their respective boundaries. The algorithm described in this paper is beneficial for facilitating the computation of quasi-periodic families and aids in discovering additional potential dynamical structures.

Evidence from epidemiological studies suggests that hearing loss is associated with an accelerated decline in cognitive function, but the underlying pathophysiological mechanism remains poorly understood. Studies using auditory tasks have suggested that degraded auditory input increases the cognitive load for auditory perceptual processing and thereby reduces the resources available for other cognitive tasks. Attention-related networks are among the systems overrecruited to support degraded auditory perception, but it is unclear how they function when no excessive recruitment of cognitive resources for auditory processing is needed. Here, we implemented an EEG study using a nonauditory visual attentional selection task in 30 individuals with age-related hearing loss (ARHLs, 60–73 years) and compared them with aged (N = 30, 60–70 years) and young (N = 35, 22–29 years) normal-hearing controls. Compared with their normal-hearing peers, ARHLs demonstrated a significant amplitude reduction for the posterior contralateral N2 component, which is a well-validated index of the allocation of selective visual attention, despite the comparable behavioral performance. Furthermore, the amplitudes were observed to correlate significantly with hearing acuities (pure tone audiometry thresholds) and higher-order hearing abilities (speech-in-noise thresholds) in aged individuals. The target-elicited alpha lateralization, another mechanism of visuospatial attention, demonstrated in control groups was not observed in ARHLs. Although behavioral performance is comparable, the significant decrease in N2pc amplitude in ARHLs provides neurophysiologic evidence that may suggest a visual attentional deficit in ARHLs even without extra-recruitment of cognitive resources by auditory processing. It supports the hypothesis that constant degraded auditory input in ARHLs has an adverse impact on the function of cognitive control systems, which is a possible mechanism mediating the relationship between hearing loss and cognitive decline.

In order to limit the phenomenon that the global stability safety factor (GSF) of the diaphragm wall slurry trench calculated by the two-dimensional (2D) wedge method is too small, the 2D calculation model on global instability of trench wall is established by assuming the whole critical failure surface (CFS) is a quarter elliptic cylindrical surface, and the determination method of CFS is given too. In view of the successful application of the minimum potential energy principle in slope stability checking calculation and on the basis of the new model established, the 2D minimum potential energy method for calculating the GSF is proposed according to the minimum potential energy principle. The correctness of the 2D calculation model built and the rationality of the 2D calculation method proposed are verified based on ten engineering cases, and the sensitivity of the GSF to various parameters is analyzed on the basis of six design examples. Finally, the new calculation method is applied to the global stability checking calculation of trench wall in practical engineering, and the result shows the new calculation method given in this paper is still conservative, so the result calculated by the new calculation method is advised to be multiplied by a modification factor of 1.67 in practical application.

ABSTRACT Background Non–small cell lung cancer (NSCLC) is one of the cancers with the highest mortality and morbidity in the world. Circular RNAs (circRNAs) are newly identified players in carcinogenesis and development of various cancers. This study is aimed at exploring the functional effects and mechanism of circ_0028826 in the development of NSCLC. Methods Real‐time quantitative PCR (RT‐qPCR) was used to detect the expression levels of circ_0028826, IDH2 mRNA, and miR‐758‐3p. IDH2, Bcl2, Bax, and E‐cadherin protein levels were detected using a western blot. Cell Counting Kit‐8 (CCK‐8), 5‐ethynyl‐2′‐deoxyuridine (EdU), flow cytometry, wound healing, and transwell assays were used to assess the capacities of proliferation, apoptosis, migration, and invasion. Interaction between miR‐758‐3p and circ_0028826 or IDH2 was validated using a dual‐luciferase reporter assay. The role of circ_0028826 in vivo was checked based on a xenograft tumor model. Results Circ_0028826 was elevated in NSCLC, and its absence inhibited NSCLC cell proliferation, migration, invasion, and induced apoptosis. In terms of mechanism, circ_0028826 increased IDH2 expression by targeting miR‐758‐3p. In addition, circ_0028826 knockdown also regulated IDH2 by targeting miR‐758‐3p to inhibit tumor growth in vivo. Conclusion Circ_0028826 promoted the development of NSCLC via regulation of the miR‐758‐3p/IDH2 axis, providing a new strategy for NSCLC treatment.

Introduction With the advancements in cancer prevention and diagnosis, the proportion of newly diagnosed early-stage cervical cancers has increased. Adjuvant therapies based on high-risk postoperative histopathological factors significantly increase the morbidity of treatment complications and seriously affect patients’ quality of life. Objectives Our study aimed to establish a diagnostic nomogram for vaginal invasion (VI) among early-stage cervical cancer (CC) that can be used to reduce the occurrence of positive or close vaginal surgical margins. Methods We assembled the medical data of early-stage CC patients between January 2013 and December 2021 from the Fujian Cancer Hospital. Data on demographics, laboratory tests, MRI features, physical examination (PE), and pathological outcomes were collected. Univariate and multivariate logistic regression analyses were employed to estimate the diagnostic variables for VI in the training set. Finally, the statistically significant factors were used to construct an integrated nomogram. Results In this retrospective study, 540 CC patients were randomly divided into training and validation cohorts according to a 7:3 ratio. Multivariate logistic analyses showed that age [odds ratio (OR) = 2.41, 95% confidence interval (CI), 1.29-4.50, P = 0.006], prognostic nutritional index (OR = 0.18, 95% CI, 0.04-0.77, P = 0.021), histological type (OR = 0.28, 95% CI, 0.08-0.94, P = 0.039), and VI based on PE (OR = 3.12, 95% CI, 1.52-6.45, P = 0.002) were independent diagnostic factors of VI. The diagnostic nomogram had a robust ability to predict VI in the training [area under the receiver operating characteristic curve (AUC) = 0.76, 95% CI: 0.70-0.82] and validation (AUC = 0.70, 95% CI: 0.58-0.83) cohorts, and the calibration curves, decision curve analysis, and confusion matrix showed good prediction power. Conclusion Our diagnostic nomograms could help gynaecologists quantify individual preoperative VI risk, thereby optimizing treatment options, and minimizing the incidence of multimodality treatment-related complications and the economic burden.

Abstract Purpose Neuroendocrine carcinoma of the cervix (NECC) is rare but results in poor prognosis. The causes of death (CODs) in NECC patients are rarely reported. Our study aimed to explore the distributions of death causes of NECC patients compared with squamous cell carcinoma (SCC) and adenocarcinoma (ADC) and to develop a validated survival prediction model. Methods Patients diagnosed with NECC, SCC, or ADC were identified from the Surveillance, Epidemiology, and End Results Program database from 1975 to 2019. We analyzed the standardized mortality ratio (SMR) to determine each cause of death for each survival time category. The Kaplan–Meier method was used for survival analysis. Univariate and multivariate Cox regression analyses were used to establish a nomogram model. Results A total of 358 NECC patients were included in this study, and 270 (75.4%) died during the follow‐up period. Patients with NECC had 5.55 times (95% CI, 4.53–6.79, p

With the widespread use of tetracycline antibiotics (TCs) and the application of manure fertilizer in farmland, TCs and their metabolites especially 4-epimers have been heavily detected in agricultural soil. However, existing studies have focused on the residual and environmental behavior of maternal TCs, and few studies have looked at the ecotoxicity of their 4-epimers in soil. In this study, the degradation and interconversion of tetracycline (TC), oxytetracycline (OTC) and their 4-epimers (4-epitetracycline, ETC; 4-epioxytetracycline, OTC) were revealed. Their effects on antibiotic resistance genes (ARGs), mobile genetic elements (MGEs) and bacterial community in soil were also investigated in comparison. The results showed that the 4-epimers could be substantially transformed to their parents and degraded as a whole. The degradation rates of four selected pollutants are followed: TC > OTC > ETC > EOTC. This indicated that when TCs entered the soil, part of TCs transformed into slower-degraded 4-epimers, and these 4-epimers could also be converted back to their antibiotic parents, causing the long-term residue of TCs in soil. When added to the soil alone, TC and OTC significantly promoted the proliferation of most ARGs and MGEs, among them, trb-C, IS1247 and IS1111 were the top three genes in abundance. ETC and EOTC had little effect at the beginning. However, as the 4-epimers continuously converted into their parents after one month of cultivation, ETC and EOTC treatments showed similar promoting effect on ARGs and MGEs, indicating that the effect of ETC and EOTC on soil resistome was lagged and mainly caused by their transformed parents. Nocardioides, unclassified_Rhizobiaceae, norank_Sericytochromatia, Microlunatus, Solirubrobacter and norank_67-14 were the most frequent hosts of ARGs, Most of which belong to the phylum Actinobacteria. Due to their large transformation to TCs, slow degradation rate and potential effects on soil microbes and ARGs, the harm of TCs’ 4-epimers on soil ecosystem cannot be ignored.

Osteochondral lesions are common pathological alterations in synovial joints. Different techniques have been designed to achieve osteochondral repair, and tissue-engineered osteochondral grafts have shown the most promise. Histological assessments and related scoring systems are crucial for evaluating the quality of regenerated tissue, and the interpretation and comparison of various repair techniques require the establishment of a reliable and widely accepted histological method. To date, there is still no consensus on the type of histological assessment and scoring system that should be used for osteochondral repair. In this review, we summarize common osteochondral staining methods, discuss the criteria regarding high-quality histological images, and assess the current histological scoring systems for osteochondral regeneration. Safranin O/Fast green is the most widely used staining method for the cartilage layer, whereas Gomori and Van Gieson staining detect new bone formation. We suggest including the graft–host interface and more sections together with the basic histological information for images. An ideal scoring system should analyze both the cartilage and bone regions, especially for the subchondral bone plate. Furthermore, histological assessments should be performed over a longer period of time to minimize discrepancies caused by defect size and animal species.

Pyroptosis is a lytic and pro-inflammatory form of regulated cell death characterized by the formation of membrane pores mediated by the gasdermin protein family. Two main activation pathways have been documented: the caspase-1-dependent canonical pathway and the caspase-4/5/11-dependent noncanonical pathway. Pyroptosis leads to cell swelling, lysis, and the subsequent release of inflammatory mediators, including interleukin-1β (IL-1β) and interleukin-18 (IL-18). Chronic inflammation is a well-established foundation and driver for the development of metabolic diseases. Conversely, metabolic pathway dysregulation can also induce cellular pyroptosis. Recent studies have highlighted the significant role of pyroptosis modulation in various metabolic diseases, including type 2 diabetes mellitus, obesity, and metabolic (dysfunction) associated fatty liver disease. These findings suggest that pyroptosis may serve as a promising novel therapeutic target for metabolic diseases. This paper reviews an in-depth study of the current advancements in understanding the role of pyroptosis in the progression of metabolic diseases.

Sex and thyroid hormones are critical for male reproductive health. However, the associations between haloacetic acid (HAA) exposure – a known endocrine disruptor – and sex and thyroid hormones in humans remains unclear. We thus recruited 502 male participants seeking fertility evaluation from a reproductive center. We measured concentrations of sex and thyroid hormones in a single blood sample and dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA) in repeated urine samples. Multivariable linear regression models were constructed to evaluate the associations between HAA concentrations and hormone measurements. After adjusting for potential confounders and urinary creatinine concentrations, urinary concentrations of TCAA were inversely associated with serum levels of sex hormone-binding globulin (SHBG), testosterone (T), T/luteinizing hormone ratio (T/LH), and thyroid stimulating hormone (TSH) (all P for trend

Bladder cancer is one of the most common malignancies of the urinary tract and a prevalent cancer worldwide, still requiring efficient therapeutic agents and approaches. 20-Hydroxyecdysone (20-HE), a steroid hormone, can be found in insects and few plants and mediate numerous biological events to control the progression of varying diseases; however, its impacts on bladder cancer remain unclear. In the study, we found that 20-HE treatments effectively inhibited the viability and proliferation of bladder cancer cells and induced apoptosis by activating Caspase-3. The migratory and invasive potential of bladder cancer cells was markedly repressed by 20-HE in a dose-dependent manner. The inhibitory effects of 20-HE on bladder cancer were confirmed in an established xenograft mouse model, as indicated by the markedly reduced tumor growth rates and limited lung and lymph node metastasis. High-throughput RNA sequencing was performed to explore dysregulated genes in bladder cancer cells after 20-HE treatment. We identified ubiquitin-specific protease 21 (USP21) as a key deubiquitinating enzyme for bladder cancer progression and a positive correlation between USP21 and nuclear factor-κB (NF-κB)/p65 in patients. Furthermore, 20-HE treatments markedly reduced USP21 expression, NF-κB/p65 mRNA, stability and phosphorylated NF-κB/p65 expression levels in bladder cancer cells, which were validated in animal tumor tissues. Mechanistic studies showed that USP21 directly interacted with and stabilized p65 by deubiquitinating its K48-linked polyubiquitination in bladder cancer cells, which could be abolished by 20-HE treatment, contributing to p65 degradation. Finally, we found that USP21 overexpression could not only facilitate the proliferation, migration, and invasion of bladder cancer cells, but also significantly eliminated the suppressive effects of 20-HE on bladder cancer. Notably, 20-HE could still perform its anti-tumor role in bladder cancer when USP21 was knocked down with decreased NF-κB/p65 expression and activation, revealing that USP21 suppression might not be the only way for 20-HE during bladder cancer treatment. Collectively, all our results clearly demonstrated that 20-HE may function as a promising therapeutic strategy for bladder cancer treatment mainly through reducing USP21/p65 signaling expression.

Abstract The development of accurate and efficient interatomic potentials using machine learning has emerged as an important approach in materials simulations and discovery. However, the systematic construction of diverse, converged training sets remains challenging. We develop a deep learning-based interatomic potential for the Li7La3Zr2O12 (LLZO) system. Our interatomic potential is trained using a diverse dataset obtained from databases and first-principles simulations. We propose using the coverage of the training and test sets as the convergence criteria for the training iterations, where the coverage is calculated by principal component analysis. This results in an accurate LLZO interatomic potential that can describe the structure and dynamical properties of LLZO systems meanwhile greatly reducing computational costs compared to density functional theory calculations. The interatomic potential accurately describes radial distribution functions and thermal expansion coefficient consistent with experiments. It also predicts the tetragonal-to-cubic phase transition behaviors of LLZO systems. Our work provides an efficient training strategy to develop accurate deep-learning interatomic potential for complex solid-state electrolyte materials, providing a promising simulation tool to accelerate solid-state battery design and applications.

Abstract Background Hyperuricemia and low level of high-density lipoprotein cholesterol (HDL-C) are both risk factors for coronary artery disease (CAD). The uric acid to HDL-C ratio (UHR) has recently been identified as a new inflammatory and metabolic biomarker. However, the relationship between the UHR and coronary culprit plaques has not been fully investigated in patients with acute coronary syndrome (ACS). Methods A total of 346 patients with ACS were enrolled in this study. Culprit lesion characteristics were assessed by optical coherence tomography (OCT). Logistic regression and linear correlation analyses were performed to assess the association between the UHR and culprit plaques. The predictive value of the UHR was investigated by receiver operating characteristic (ROC) curve analysis. Results The percentages of typical culprit plaques, including ruptures, erosions and thrombi, were greater in the high-UHR subgroup than those in the low-UHR subgroup. A positive relationship was also found between the UHR and diameter stenosis (r = 0.160, P = 0.003) and between the UHR and area stenosis (r = 0.145, P = 0.007). The UHR was found to be independently associated with plaque rupture, erosion and thrombus. Furthermore, ROC analysis suggested that the UHR had a better predictive value than low-density lipoprotein cholesterol. Conclusions An elevated UHR level was independently related to the occurrence rate of culprit plaques. The UHR is a simple and easily acquired parameter for detecting culprit plaques in patients with ACS.

Abstract Although celebrity endorsements and promotional videos dominated by destination marketing organizations (DMOs) are critical in travel decision-making and destination marketing, as a new type of endorsement, the impact of internet celebrities’ short travel videos on social platforms remains not well understood. To bridge this gap, the current study applied source credibility theory and the match-up hypothesis to construct a conceptual model for examining the impact of internet celebrity endorsements on audiences’ visit intentions. FangQi Kiki, a typical producer of short travel videos on TikTok, was used as a case study. 649 valid samples were taken from respondents who were asked to complete a questionnaire after watching a short video. The results showed that internet celebrities’ trustworthiness and expertise significantly affect audiences’ visit intentions. However, attractiveness in terms of the physical characteristics of internet celebrities and internet celebrity–destination congruence had no significant effect on audiences’ visit intentions. The implications show that “Appearance Fallacy” exists in online influencers’ marketing, and physical appearance may affect the popularity of short travel videos online, but it has no significant effect on promoting destination marketing. Unlike the celebrity effect in conventional endorsements, internet celebrities’ short videos belong to content marketing, where popular content is more important than an internet celebrity’s personality. This research adds to the body of knowledge concerned with internet celebrity endorsements in tourism, providing valuable insights for DMOs to project short video marketing.

Abstract Background Psoriasis is a chronic inflammatory genetic disease, mainly manifesting in the skin. Conventional therapies, such as glucocorticosteroids and corticosteroids, have adverse effects that limit drug use. Hence, it is imperative to identify a new therapeutic strategy that exhibits a favorable safety profile. Shi-Bi-Man (SBM) is a safe herbal supplement sourced from various natural plants, including ginseng, angelica sinensis, polygonum multiflorum, and aloe vera. Purpose We aimed to find a potential treatment for psoriasis and investigate the underlying mechanism through which SBM alleviates psoriatic-like skin inflammation in mice. Methods We investigated the effects of supplementing with SBM through intragastric administration or smear administration in a murine model of imiquimod-induced psoriasis. The changes in body weight and Psoriasis Area and Severity Index (PASI) score were recorded throughout the entire process. Additionally, we used hematoxylin–eosin staining to observe the skin structure and performed single-cell RNA sequencing to explore the underlying mechanism of SBM in influencing the psoriasis-like phenotype. Immunofluorescence was conducted to verify our findings. Furthermore, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was employed to investigate the impact of Tetrahydroxy stilbene glycoside (TSG) on the expression levels of IL23 in HaCaT cells. Results SBM remarkably alleviated the psoriasis-like phenotype by inhibiting IL-23/Th17 cell axis. Single-cell RNA sequencing analysis revealed a decrease in the expression of Il17 and Il23 in keratinocytes and T cells, concomitant with a reduction in the proportion of Th17 cells. Meanwhile, the activation of endothelial cells was inhibited, accompanied by a decrease in the expression of Cxcl16. In vitro, the addition of TSG to HaCaT cells resulted in significant suppression of IL23 expression stimulated by tumor necrosis factor-alpha (TNF-α).

Background: Treatment of chronic osteomyelitis (bone infection) remains a clinical challenge; in particular, it requires enhanced delivery of antibiotic drugs for the treatment of intracellular Staphylococcus aureus (S. aureus), which prevents infection recurrence and resistance. Previous studies have found that noninvasive shock waves used to treat musculoskeletal diseases can alter cell permeability, however, it is unclear whether shock waves alter cell membrane permeability in chronic osteomyelitis. Furthermore, it remains unknown whether such changes in permeability promote the entry of antibiotics into osteoblasts to exert antibacterial effects. Methods: In our study, trypan blue staining was used to determine the shock wave parameters that had no obvious damage to the osteoblast model; the effect of shocks waves on the cell membrane permeability of osteoblast model was detected by BODIPY®FL vancomycin; high performance liquid chromatography-mass spectrometry (HLPC-MS) was used to detect the effect of shock wave on the entry of antibiotics into the osteoblast model; plate colony counting method was used to detect the clearance effect of shock wave assisted antibiotics on S. aureus in the osteoblast model. To explore the mechanism, the effect of different pulses of shock waves on S. aureus was examined by plate colony counting method, besides, P2X7 receptor in osteoblast was detected by immunofluorescence and the extracellular ATP levels was detected. Furthermore, the effect of P2X7 receptor antagonists KN-62 or A740003 on the intracellular antibacterial activity of shock-assisted antibiotics was observed. Then, we used S. aureus to establish a rat model of chronic tibial osteomyelitis and investigated the efficacy and safety of shock-wave assisted antibiotics in the treatment of chronic osteomyelitis in rats. Results: The viability of the osteoblast models of intracellular S. aureus infection was not significantly affected by the application of up to 400 shock wave pulses at 0.21 mJ/mm2. Surprisingly, the delivery of BODIPY®FL vancomycin to osteoblast model cells was markedly enhanced by this shock wave treatment. Furthermore, the shock wave therapy increased the delivery of hydrophilic antibiotics (vancomycin and cefuroxime sodium), but not lipophilic antibiotics (rifampicin and levofloxacin), which improved the intracellular antibacterial effect. Afterwards, we discovered that shock wave treatment increased the extracellular concentration of ATP (the P2X7 receptor activator)， while KN-62 or A740003, a P2X7 receptor inhibitor, decreased intracellular antibacterial activity. We then found that 0.1 mL of 1 × 1011 CFU/mL ATCC25923 S. aureus was suitable for modeling chronic osteomyelitis in rats. Besides, the shock wave-assisted vancomycin treatment with the strongest antibacterial and osteogenic effects among the tested treatments was confirmed in vivo by imaging examination, microbiological cultures, and histopathology, with favorable safety. Conclusions: Our results suggest that shock waves can promote the entry of antibiotics into osteoblasts for antibacteria by changing the cell membrane permeability in a P2X7 receptor-dependent manner. Besides, considering antibacterial and osteogenic efficiency and a high degree of safety in rat osteomyelitis model, shock wave-assisted vancomycin treatment may thus represent a possible adjuvant therapy for chronic osteomyelitis.

Abstract Evidence regarding the association between dietary niacin intake and chronic obstructive pulmonary disease (COPD) is limited. Our study investigates the relationship between dietary niacin intake and the prevalance and incidence of COPD in the adult population of the United States, using data from the National Health and Nutrition Examination Survey (NHANES) from 2003 to 2018. Data on niacin intake were extracted through dietary intake interviews. COPD diagnoses were based on lung function, medical history, and medication usage. We analyzed the association between niacin consumption and COPD using multiple logistic regression and restricted cubic spline models. The study included 7055 adult participants, divided into COPD (n = 243; 3.44%) and non-COPD (n = 6812; 96.56%) groups. Those with COPD had lower average niacin intake (21.39 ± 0.62 mg/day) compared to the non-COPD group (25.29 ± 0.23 mg/day, p

Abstract The purpose of this study is to compare the accuracy and effectiveness of ultrasound-guided and fluoroscopy-guided lumbar selective nerve root block (SNRB), and to explore the feasibility of ultrasound-guided methods. This retrospective study included patients with lumbar radicular pain who underwent ultrasound-guided and fluoroscopy-guided selective nerve root block at Honghui Hospital Affiliated to Xi’an Jiaotong University from August 2020 to August 2022. Patients were divided into U-SNRB group and F-SNRB group according to ultrasound-guided or fluoroscopy-guided selective nerve root block. There were 43 patients in U-SNRB group and 20 patients in F-SNRB group. The pain visual analogue scale (VAS) scores, Japanese Orthopaedic Association (JOA) scores, related indexes and complications were recorded and compared between the two groups before, 30 min, 1 month and 6 months after block. To evaluate the feasibility, accuracy and effectiveness of ultrasound-guided selective nerve root block. There were no complications in the process of selective nerve root block in both groups. The operating time and the times of closing needle angle adjustment in U-SNRB group were better than those in F-SNRB group, and the difference was statistically significant (P 0.05). The accuracy of ultrasound-guided selective nerve root block and the degree of pain relief of patients were similar to those of fluoroscopy guidance, but the operation time and needle angle adjustment times were significantly less than that of fluoroscopy, and could effectively reduce radiation exposure. Therefore, it can be used as a better way to guide for choice.

Abstract Aims To present a case series of 11 rare uterine tumors resembling ovarian sex cord tumors (UTROSCTs), and review the literature on this topic to offer up-to-date treatment management for UTROSCTs. Method Eight cases from Fujian Cancer Hospital between January 2017 and May 2023 and three patients from Fujian Union Hospital between October 2012 and October 2020 were retrospectively reviewed. All cases were pathologically confirmed as UTROSCTs by two senior and experienced pathologists. Clinical behaviors, medical data, histopathological features, therapy approaches, and survival outcomes were discussed. Results The median age at initial diagnosis was 53 years (29–70 years). 3 (27.3%) patients were under 40. Seven cases presented with abnormal vaginal bleeding, one with menstrual disorder, one with abnormal vaginal secretion, and two patients were accidentally found by physical examination without any symptoms. Three patients were initially misdiagnosed with endometrial cancer by MRI. Curettage was performed in all cases. Nine of them were well diagnosed by routine curettage, except for two samples, which were identified after surgery. Immunohistochemical biomarkers, such as CD99, Desmin, WT-1, CK, Vimentin, SMA, α-Inhibin, Ki67, CD56, ER, PR, and CR, tend to be positive in UTRO SCs patients. Six patients underwent hysterectomy with bilateral salpingo-oophorectomy. Two cases received a radical hysterectomy with bilateral salpingo-oophorectomy, retroperitoneal lymph node dissection, and omentum dissection. Three UTROSCTs were under observation after mass resection. The median PFS was 24 months (range 1–125 months). Conclusion UTROSCT is a rare mesenchymal tumor with low malignant potential. Treatment modalities should be carefully considered to balance the therapy outcomes and patient needs. Surgery conservative management might be suitable for young women with fertility desires.

Abstract Objectives To develop a deep learning (DL) model for differentiating between osteolytic osteosarcoma (OS) and giant cell tumor (GCT) on radiographs. Methods Patients with osteolytic OS and GCT proven by postoperative pathology were retrospectively recruited from four centers (center A, training and internal testing; centers B, C, and D, external testing). Sixteen radiologists with different experiences in musculoskeletal imaging diagnosis were divided into three groups and participated with or without the DL model’s assistance. DL model was generated using EfficientNet-B6 architecture, and the clinical model was trained using clinical variables. The performance of various models was compared using McNemar’s test. Results Three hundred thirty-three patients were included (mean age, 27 years ± 12 [SD]; 186 men). Compared to the clinical model, the DL model achieved a higher area under the curve (AUC) in both the internal (0.97 vs. 0.77, p = 0.008) and external test set (0.97 vs. 0.64, p

Abstract Gut bacteriome dysbiosis is known to be implicated in the pathogenesis of inflammatory bowel disease (IBD). Crohn’s disease (CD) is an IBD subtype with extensive mucosal inflammation, yet the mucosal virome, an empirical modulator of the bacteriome and mucosal immunity, remains largely unclear regarding its composition and role. Here, we exploited trans-cohort CD patients and healthy individuals to compositionally and functionally investigate the small bowel (terminal ileum) virome and bacteriome. The CD ileal virome was characterised by an under-representation of both lytic and temperate bacteriophages (especially those targeting bacterial pathogens), particularly in patients with flare-up. Meanwhile, the virome-bacteriome ecology in CD ileal mucosa was featured by a lack of Bifidobacterium- and Lachnospiraceae-led mutualistic interactions between bacteria and bacteriophages; surprisingly it was more pronounced in CD remission than flare-up, underlining the refractory and recurrent nature of mucosal inflammation in CD. Lastly, we substantiated that ileal virions from CD patients causally exacerbated intestinal inflammation in IBD mouse models, by reshaping a gut virome-bacteriome ecology preceding intestinal inflammation (microbial trigger) and augmenting microbial sensing/defence pathways in the intestine cells (host response). Altogether, our results highlight the significance of mucosal virome in CD pathogenesis and importance of mucosal virome restoration in CD therapeutics.

Abstract Exploiting thin Li metal anode is essential for high-energy-density battery, but is severely plagued by the poor processability of Li, as well as the uncontrollable Li plating/stripping behaviors and Li/electrolyte interface. Herein, a thickness/capacity-adjustable thin alloy-type Li/LiZn@Cu anode is fabricated for high-energy-density Li metal batteries. The as-formed lithophilic LiZn alloy in Li/LiZn@Cu anode can effectively regulate Li plating/stripping and stabilize the Li/electrolyte interface to deliver the hierarchical Li electrochemistry. Upon charging, the Li/LiZn@Cu anode firstly acts as Li source for homogeneous Li extraction. At the end of charging, the de-alloy of LiZn nanostructures further supplements the Li extraction, actually playing the Li compensation role in battery cycling. While upon discharging, the LiZn alloy forms just at the beginning, thereby regulating the following Li homogeneous deposition. The reversibility of such an interesting process is undoubtedly verified from the electrochemistry and in-situ XRD characterization. This work sheds light on the facile fabrication of practical Li metal anodes and useful Li compensation materials for high-energy-density Li metal batteries.