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Cancer stem cells (CSCs) play a pivotal role in tumor initiation, proliferation, metastasis, drug resistance, and recurrence. Consequently, targeting CSCs has emerged as a promising avenue for cancer therapy. Recently, 3-phosphoglycerate dehydrogenase (PHGDH) has been identified as being intricately associated with the regulation of numerous cancer stem cells. Yet, reports detailing the functional regulators of PHGDH that can mitigate the stemness across cancer types are limited. In this study, the novel “molecular glue” LXH-3-71 was identified, and it robustly induced degradation of PHGDH, thereby modulating the stemness of colorectal cancer cells (CRCs) both in vitro and in vivo. Remarkably, LXH-3-71 was observed to form a dynamic chimera, between PHGDH and the DDB1-CRL E3 ligase. These insights not only elucidate the anti-CSCs mechanism of the lead compound but also suggest that degradation of PHGDH may be a more viable therapeutic strategy than the development of PHGDH inhibitors. Additionally, compound LXH-3-71 was leveraged as a novel ligand for the DDB1-CRL E3 ligase, facilitating the development of new PROTAC molecules targeting EGFR and CDK4 degradation.

Abstract Background Accurate breed identification is essential for the conservation and sustainable use of indigenous farm animal genetic resources. In this study, we evaluated the phylogenetic relationships and genomic breed compositions of 13 sheep breeds using SNP and InDel data from whole genome sequencing. The breeds included 11 Chinese indigenous and 2 foreign commercial breeds. We compared different strategies for breed identification with respect to different marker types, i.e. SNPs, InDels, and a combination of SNPs and InDels (named SIs), different breed-informative marker detection methods, and different machine learning classification methods. Results Using WGS-based SNPs and InDels, we revealed the phylogenetic relationships between 11 Chinese indigenous and two foreign sheep breeds and quantified their purities through estimated genomic breed compositions. We found that the optimal strategy for identifying these breeds was the combination of DFI_union for breed-informative marker detection, which integrated the methods of Delta, Pairwise Wright's FST, and Informativeness for Assignment (namely DFI) by merging the breed-informative markers derived from the three methods, and KSR for breed assignment, which integrated the methods of K-Nearest Neighbor, Support Vector Machine, and Random Forest (namely KSR) by intersecting their results. Using SI markers improved the identification accuracy compared to using SNPs or InDels alone. We achieved accuracies over 97.5% when using at least the 1000 most breed-informative (MBI) SI markers and even 100% when using 5000 SI markers. Conclusions Our results provide not only an important foundation for conservation of these Chinese local sheep breeds, but also general approaches for breed identification of indigenous farm animal breeds.

Objective: To investigate the differences in metabolites of Chinese nectarine, peento, yellow peach, Yangshan honey peach and Xinyi honey peach by using non-target metabolomics. Methods: 250 Fresh peaches of comparable maturity were used as test materials, and the fresh peach pulp was determined by high performance liquid chromatography-quadrupole tandem time-of-flight mass spectrometry (UPLC-QTOF-MS), and the metabolites of different varieties of fresh peaches were investigated by principal component analysis and metabolite variability analysis. Results: A total of 74 metabolites were detected, mainly phenolic acids, flavanols, flavonols, anthocyanins, amino acids, glycosides, iridoid glycosides, B vitamins, etc. PCA analysis revealed that compared with the other 4 fresh peaches, Yangshan honey peach had higher contents of 7-hydroxycoumarin, pinocembrin, chlorogenic acid, neochlorogenic acid, epicatechin, procyanidin A2, cryptochlorogenic acid, plantagoside, procyanidin B2, and lower levels of vitamin B2, kaempferol, rutin. Based on OPLS-DA analysis, 4 fresh peaches were screened for differential metabolites with Yangshan honey peach respectively. Nectarine had 18 species of procyanidin B3 and other metabolites, peento had 12 species of procyanidin B2 and other metabolites, yellow peach had 18 species of procyanidin A2 and other metabolites, and Xinyi honey peach had 15 species of procyanidin C1 and other metabolites, which could be used as a potential biomarker to differentiate between Yangshan honey peach and the other 4 fresh peaches. In this study, the differential metabolites of the 5 fresh peaches were mainly plant polyphenolic compounds, and chlorogenic acid and procyanidin metabolites were high in Yangshan honey peach, which were the key differential metabolites. Conclusion: The non-target metabolomics technology can effectively distinguish the five fresh peaches, which is feasible for the identification of fresh peaches, and can be used to assist the qualitative identification of fresh peaches and deep-processed fresh peaches as an important basis for the identification of true and false Yangshan honey peaches, and it is of great significance to protect the development of Yangshan honey peach speciality industry.

Abstract Hematopoietic stem cells (HSCs) exhibit significant functional and metabolic alterations within the lung cancer microenvironment, contributing to tumor progression and immune evasion by increasing differentiation into myeloid-derived suppressor cells (MDSCs). Our aim is to analyze the metabolic transition of HSCs from glycolysis to oxidative phosphorylation (OXPHOS) in lung cancer and determine its effects on HSC functionality. Using a murine Lewis Lung Carcinoma lung cancer model, we conducted metabolic profiling of long-term and short-term HSCs, as well as multipotent progenitors, comparing their metabolic states in normal and cancer conditions. We measured glucose uptake using 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino]-2-Deoxyglucose (2-NBDG) and assessed levels of lactate, acetyl-coenzyme A, and ATP. Mitochondrial functionality was evaluated through flow cytometry, alongside the impact of the glucose metabolism inhibitor 2-DG on HSC differentiation and mitochondrial activity. HSCs under lung cancer conditions showed increased glucose uptake and lactate production, with an associated rise in OXPHOS activity, marking a metabolic shift. Treatment with 2-DG led to decreased T-HSCs and MDSCs and an increased red blood cell count, highlighting its potential to influence metabolic and differentiation pathways in HSCs. This study provides novel insights into the metabolic reprogramming of HSCs in lung cancer, emphasizing the critical shift from glycolysis to OXPHOS and its implications for the therapeutic targeting of cancer-related metabolic pathways.

Abstract In August 2023, Xiaomi unveiled the Redmi K60 Ultra, the first multi-frequency smartphone integrated with BeiDou-3 Navigation Satellite System Precise Point Positioning (PPP-B2b) services and employing PPP technology as the primary positioning method. The positioning enhancement service is provided by the Assisted Global Navigation Satellite System (A-GNSS) location platform developed by the China Academy of Information and Communications Technology. The signaling interaction between the server and the users strictly adheres to the Third Generation of Mobile Communications Technology Partnership Project Long-Term Evolution Positioning Protocol and the Open Mobile Alliance Secure User Plane Location framework. To comprehensively evaluate the Redmi K60 Ultra’s capabilities, this study designed six distinct experimental scenarios and conducted comprehensive research on multi-frequency and multi-GNSS observation noise, Time to First Fix (TTFF), as well as the performance of both GNSS-based and network-based positioning. Experimental results indicate that the GNSS chipset within the Redmi K60 Ultra has achieved a leading position in the consumer market concerning supported satellite constellations, frequencies, and observation accuracy, and is comparable to some low-cost GNSS receivers. A-GNSS positioning can reduce the TTFF from 30 to under 5 s, representing an improvement of over 85% in the cold start speed compared to a standalone GNSS mode. The positioning results show that the A-GNSS PPP-B2b service can achieve positioning performance with RMS errors of less than 1.5 m, 2.5 m, and 4 m in open-sky, realistic, and challenging urban environments. Compared to GNSS-based positioning, cellular network-based Observed Time Difference of Arrival (OTDOA) positioning achieves an accuracy ranging from tens to hundreds of meters in various experimental scenarios and currently functions primarily as coarse location determination. Additionally, this study explores the potential of the Three-Dimensional Mapping-Aided (3DMA) GNSS algorithm in detecting Non-Line-of-Sight signals and enhancing positioning performance. The results indicate that 3DMA PPP, as compared to conventional PPP, can significantly accelerate PPP convergence and improve positioning accuracy by over 30%. Consequently, 3D city models can be utilized as future assistance data for the A-GNSS location platform.

Abstract Accurate segmentation of the tumor area is crucial for the treatment and prognosis of patients with bladder cancer. Cystoscopy is the gold standard for diagnosing bladder tumors. However, The vast majority of current work uses deep learning to identify and segment tumors from CT and MRI findings, and rarely involves cystoscopy findings. Accurately segmenting bladder tumors remains a great challenge due to their diverse morphology and fuzzy boundaries. In order to solve the above problems, this paper proposes a medical image segmentation network with boundary guidance called boundary guidance network. This network combines local features extracted by CNNs and long-range dependencies between different levels inscribed by Parallel ViT, which can capture tumor features more effectively. The Boundary extracted module is designed to extract boundary features and utilize the boundary features to guide the decoding process. Foreground-background dual-channel decoding is performed by boundary integrated module. Experimental results on our proposed new cystoscopic bladder tumor dataset (BTD) show that our method can efficiently perform accurate segmentation of tumors and retain more boundary information, achieving an IoU score of 91.3%, a Hausdorff Distance of 10.43, an mAP score of 85.3%, and a F1 score of 94.8%. On BTD and three other public datasets, our model achieves the best scores compared to state-of-the-art methods, which proves the effectiveness of our model for common medical image segmentation.

Abstract Electrochromic (EC) devices represent an emerging energy-saving technology, exhibiting the capability to dynamically modulate light and heat transmittance. Despite their promising potential, the commercialization of EC devices faces substantial impediments such as high cost, intricate fabrication process, and low optical contrast inherent in conventional EC materials relying on the ion insertion/extraction mechanism. In this study, we introduce an innovative “electrode-free” electrochromic (EC) device, termed the EECD, which lacks an EC-layer on the electrodes during device assembling and in the bleached state. This device features a simplified fabrication process and delivers superior optical modulation. It achieves a high optical contrast ranging from 68-85% across the visible spectrum and boasts a rapid response time, reaching 90% coloring in just 17 seconds. In addition, EECD exhibits stable cycling for over 10,000 cycles without noticeable degradation and maintains functionality across a broad temperature range (0 °C to 50 °C). Furthermore, the fabricated large-area devices (40 cm × 40 cm) demonstrate excellent tinting uniformity, suggesting excellent scalability of this approach. Our study establishes a paradigmatic breakthrough for EC smart windows.

Abstract Recapitulating the natural extracellular physical microenvironment has emerged as a promising method for tissue regeneration, as multiple physical interventions, including ultrasound, thermal and electrical therapy, have shown great potential. However, simultaneous coupling of multiple physical cues to highly bio-mimick natural characteristics for improved tissue regeneration still remains formidable. Coupling of intrinsic electrical and mechanical cues has been regarded as an effective way to modulate tissue repair. Nevertheless, precise and convenient manipulation on coupling of mechano-electrical signals within extracellular environment to facilitate tissue regeneration remains challengeable. Herein, a photothermal-sensitive piezoelectric membrane was designed for simultaneous integration of electrical and mechanical signals in response to NIR irradiation. The high-performance mechano-electrical coupling under NIR exposure synergistically triggered the promotion of osteogenic differentiation of stem cells and enhances bone defect regeneration by increasing cellular mechanical sensing, attachment, spreading and cytoskeleton remodeling. This study highlights the coupling of mechanical signals and electrical cues for modulation of osteogenesis, and sheds light on alternative bone tissue engineering therapies with multiple integrated physical cues for tissue repair. Graphical Abstract

Abstract Purpose Crowe IV developmental dysplasia of the hip (DDH) is a catastrophic hip disease. Moreover, obtaining ideal clinical efficacy in conventional total hip arthroplasty (THA) is often difficult. In this study, we aimed to assess the mid-term clinical results of THA with porous tantalum trabecular metal (TM) pads for acetabular reconstruction in the treatment of Crowe IV DDH. Methods A cohort of 28 patients (32 hips) diagnosed with Crowe type IV DDH who underwent acetabular reconstruction during THA using TM pads with scheduled follow-up between 2011 and 2018, were included in this study. Eight cases were men and 24 were women, with a mean age of 48.4 years (range, 36–72 years) and a mean follow-up was 74.3 months (range, 42–132 months). All patients underwent acetabular reconstruction using TM pads and total hip replacement with subtrochanteric osteotomy. Results At the final follow-up, 28 hips (87.5%) demonstrated mild or no postoperative limping. The Harris Hip Score improved from 58.4 ± 10.6 preoperatively to 85.6 ± 8.9. The mean pain, stiffness, and function scores on the Western Ontario and McMaster University Osteoarthritis index were 86.5 ± 10.2, 87.3 ± 12.4 and 85.4 ± 11.6 respectively. The mean score of patient satisfaction was 90.4 ± 7.6. Additionally, the SF-12 physical summary score was 41.8 ± 5.6 and the SF-12 mental summary score was 51.6 ± 5.4. TM construct survivorship due to all-cause failure was 90.6% at 5 years with 3 hips at risk, 87.5% at 10 years with 4 hips at risk. The survivorship due to failure from aseptic loosening was 96.9% at 5 years with 1hips at risk and 93.75% at 10 years with 2 hips at risk. Conclusion This study demonstrated satisfactory mid-term clinical and radiological results with the application of TM pads for acetabular reconstruction combined with THA in patients with Crowe IV DDH. Trial registration number ChiCTR1800014526, Date: 18/01/2018.

Abstract Compounding functional nanoparticles with highly conductive and porous carbon scaffolds is a basic pathway for engineering many important functional devices. However, enabling uniform spatial distribution of functional particles within a massively conjugated, monolithic and mesoporous structure remains challenging, as the high processing temperature for graphitization can arouse nanoparticle ripening, agglomerations and compositional changes. Herein, we report a unique “popcorn-making-mimic” strategy for preparing a highly conjugated and uniformly compounded graphene@NiFe2O4 composite film through a laser-assisted instantaneous compounding method in ambient condition. It can successfully inhibit the unwanted structural disintegration and mass loss during the laser treatment by avoiding oxidation, bursting, and inhomogeneous heat accumulations, thus achieving a highly integrated composite structure with superior electrical conductivity and high saturated magnetization. Such a single-sided film exhibits an absolute shielding effectiveness of up to 20906 dB cm2 g−1 with 75% absorption rate, superior mechanical flexibility and excellent temperature/humidity aging reliability. These performance indexes signify a substantial advance in EMI absorption capability, fabrication universality, small form-factor and device reliability toward commercial applications. Our method provides a paradigm for fabricating sophisticated composite materials for versatile applications.

Abstract In recent years, many methods for image super‐resolution (SR) have relied on pairs of low‐resolution (LR) and high‐resolution (HR) images for training, where the degradation process is predefined by bicubic downsampling. While such approaches perform well in standard benchmark tests, they often fail to accurately replicate the complexity of real‐world image degradation. To address this challenge, researchers have proposed the use of unpaired image training to implicitly model the degradation process. However, there is a significant domain gap between the real‐world LR and the synthetic LR images from HR, which severely degrades the SR performance. A novel unsupervised image‐blind super‐resolution method that exploits degradation feature‐based learning for real‐image super‐resolution reconstruction (RDFL) is proposed. Their approach learns the degradation process from HR to LR using a generative adversarial network (GAN) and constrains the data distribution of the synthetic LR with real degraded images. The authors then encode the degraded features into a Transformer‐based SR network for image super‐resolution reconstruction through degradation representation learning. Extensive experiments on both synthetic and real datasets demonstrate the effectiveness and superiority of the RDFL method, which achieves visually pleasing reconstruction results.

Abstract Background Early prediction of delayed cerebral ischemia (DCI) is critical to improving the prognosis of aneurysmal subarachnoid hemorrhage (aSAH). Machine learning (ML) algorithms can learn from intricate information unbiasedly and facilitate the early identification of clinical outcomes. This study aimed to construct and compare the ability of different ML models to predict DCI after aSAH. Then, we identified and analyzed the essential risk of DCI occurrence by preoperative clinical scores and postoperative laboratory test results. Methods This was a multicenter, retrospective cohort study. A total of 1039 post-operation patients with aSAH were finally included from three hospitals in China. The training group contained 919 patients, and the test group comprised 120 patients. We used five popular machine-learning algorithms to construct the models. The area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, precision, and f1 score were used to evaluate and compare the five models. Finally, we performed a Shapley Additive exPlanations analysis for the model with the best performance and significance analysis for each feature. Results A total of 239 patients with aSAH (23.003%) developed DCI after the operation. Our results showed that in the test cohort, Random Forest (RF) had an AUC of 0.79, which was better than other models. The five most important features for predicting DCI in the RF model were the admitted modified Rankin Scale, D-Dimer, intracranial parenchymal hematoma, neutrophil/lymphocyte ratio, and Fisher score. Interestingly, clamping or embolization for the aneurysm treatment was the fourth button-down risk factor in the ML model. Conclusions In this multicenter study, we compared five ML methods, among which RF performed the best in DCI prediction. In addition, the essential risks were identified to help clinicians monitor the patients at high risk for DCI more precisely and facilitate timely intervention.

Abstract Purpose This study aimed to construct an m6A and cuproptosis-related long non-coding RNAs (lncRNAs) signature to accurately predict the prognosis of kidney clear cell carcinoma (KIRC) patients using the information acquired from The Cancer Genome Atlas (TCGA) database. Methods First, the co-expression analysis was performed to identify lncRNAs linked with N6-methyladenosine (m6A) and cuproptosis in ccRCC. Then, a model encompassing four candidate lncRNAs was constructed via univariate, least absolute shrinkage together with selection operator (LASSO), and multivariate regression analyses. Furthermore, Kaplan–Meier, principal component, functional enrichment annotation, and nomogram analyses were performed to develop a risk model that could effectively assess medical outcomes for ccRCC cases. Moreover, the cellular function of NFE4 in Caki-1/OS-RC-2 cultures was elucidated through CCK-8/EdU assessments and Transwell experiments. Dataset outcomes indicated that NFE4 can have possible implications in m6A and cuproptosis, and may promote ccRCC progression. Results We constructed a panel of m6A and cuproptosis-related lncRNAs to construct a prognostic prediction model. The Kaplan–Meier and ROC curves showed that the feature had acceptable predictive validity in the TCGA training, test, and complete groups. Furthermore, the m6A and cuproptosis-related lncRNA model indicated higher diagnostic efficiency than other clinical features. Moreover, the NFE4 function analysis indicated a gene associated with m6A and cuproptosis-related lncRNAs in ccRCC. It was also revealed that the proliferation and migration of Caki-1 /OS-RC-2 cells were inhibited in the NFE4 knockdown group. Conclusion Overall, this study indicated that NFE4 and our constructed risk signature could predict outcomes and have potential clinical value.

Abstract Background The oxidative system plays an important role in the pathogenesis of schizophrenia. Inconsistent associations were found between hyperbilirubinemia and psychopathology as well as glycolipid metabolism in patients with schizophrenia at different episodes. This current study aimed to examine these associations in patients with acute-episode and drug-free (AEDF) schizophrenia. Methods This is a retrospective study using 5 years of data from May 2017 to May 2022 extracted from the electronic medical record system of Chaohu Hospital of Anhui Medical University. Healthy controls (HCs) from the local medical screening center during the same period were also included. Participants’ data of the bilirubin levels [total bilirubin (TB), conjugated bilirubin (CB), unconjugated bilirubin (UCB)], glycolipid metabolic parameters and the score of the Brief Psychiatric Rating Scale (BPRS) were collected. Results A total of 1468 case records were identified through the initial search. After screening, 89 AEDF patients and 100 HCs were included. Compared with HCs, patients had a higher CB level, and lower levels of glycolipid metabolic parameters excluding high density lipoprotein-cholesterol (HDL-C) (all P

Abstract Background Nowadays, moderate gaming behaviors can be a pleasant and relaxing experiences among adolescents. However, excessive gaming behavior may lead to gaming disorder (GD) that disruption of normal daily life. Understanding the possible risk factors of this emerging problem would help to suggest effective at preventing and intervening. This study aimed to investigate the prevalence of GD and analyze its possible risk factors that adolescents with GD. Methods Data were collected between October 2020 and January 2021. In total, a sample of 7901 students (4080 (52%) boys, 3742 (48%) girls; aged 12–18 years) completed questionnaires regarding the Gaming-Related Behaviors Survey, Gaming Disorder Symptom Questionnaire-21 (GDSQ-21); Behavioral Inhibition System and Behavioral Activation System Scale (BIS/BAS Scale); Emotion Regulation Questionnaire (ERQ); Short-form Egna Minnenav Barndoms Uppfostran for Chinese (s-EMBU-C); and Adolescent Self-Rating Life Events Checklist (ASLEC). Results The prevalence of GD was 2.27% in this adolescent sample. The GD gamers were a little bit older (i.e., a higher proportion of senior grades), more boys, with more gaming hours per week in the last 12 months, with more reward responsiveness, maternal rejecting and occurrence of negative life events (e.g., interpersonal relationships, being punished and bereavement factors). Conclusion These possible risk factors may influence the onset of GD. Future research in clinical, public health, education and other fields should focus on these aspects for provide target prevention and early intervention strategies.

Abstract Numerous myofibroblasts are arisen from endothelial cells (ECs) through endothelial to mesenchymal transition (EndMT) triggered by TGF-β. However, the mechanism of ECs transforms to a different subtype, or whether there exists an intermediate state of ECs remains unclear. In present study, we demonstrate Midkine (MDK) mainly expressed by CD31 + ACTA2+ECs going through partial EndMT contribute greatly to myofibroblasts by spatial and single-cell transcriptomics. MDK is induced in TGF-β treated ECs, which upregulates C/EBPβ and increases EndMT genes, and these effects could be reversed by siMDK. Mechanistically, MDK promotes the binding ability of C/EBPβ with ACTA2 promoter by stabilizing the C/EBPβ protein. In vivo, knockout of Mdk or conditional knockout of Mdk in ECs reduces EndMT markers and significantly reverses fibrogenesis. In conclusion, our study provides a mechanistic link between the induction of EndMT by TGF-β and MDK, which suggests that blocking MDK provides potential therapeutic strategies for renal fibrosis.

Abstract As a byproduct of manufacturing soybeans, okara is high in dietary fiber, protein, and fats, and it contains all of the essential amino acids. Wheat, the primary ingredient in noodles, will lose nutrients during manufacturing, creating an imbalance in nutrients. This experiment is for the purpose of studying the effects of okara on quality, antioxidant properties, amino acid content, resistant starch (RS) content, and microstructure of noodles. The results indicate that the addition of 9% okara noodles increased hardness and adhesiveness by 107.19% and 132.14%, respectively, and improved ABTS free radical scavenging activity by 60.78%. The addition of 12% okara noodles increased the DPPH free radical scavenging ability by 23.66%, reduced the rapidly digestible starch (RDS) content of the noodles to 21.21%, and the resistant starch content increased to 44.85% (p

The solution to the economic dispatch (ED) problem for power systems allows the power sector to reduce operating costs. However, the ED problem is a complex nonlinear and nonconvex optimization problem whose solution requires powerful algorithms. We propose a new version of the Marine Predator Algorithm (MPA), called IMPA, for solving complex ED problems. The algorithm introduces an asymmetric information exchange (AIE) mechanism, which not only accelerates to escape of local optima but also enriches the diversity of search. In this work, 12 benchmark functions were used to test the performance of the proposed algorithm IMPA. Then, the IMPA was used to solve the ED engineering problem of power system containing of 6, 13, 40, and complex 140 units. The minimum and average costs searched by IMPA are 1657962.7265$/h and 1657962.7265$/h, and they are much lower than the results of the MPA and NMPA, which means that our proposed improved IMPA improves the performance of MPA for solving the economic dispatch problem of large-scale power systems. The results show that the solutions obtained by IMPA are more competitive than those of MPA and NMPA, which provides an additional solution for cost reduction of the power system.

Tongue cancer, a prevalent form of oral malignancy, particularly manifests as tongue squamous cell carcinoma (TSCC), which holds the highest incidence among oral squamous cell carcinoma cases, representing 43.4 % of occurrences. Presently, surgical resection stands as the primary treatment for TSCC, with no effective pharmaceutical interventions identified. This study aims to search for the potential anti-tumor properties and molecular mechanisms of a rearranged abietane diterpenoid extracted from Clerodendrum mandarinorum. Within this investigation, six known rearranged abietane diterpenoids (1–6) were isolated and characterized from C. mandarinorum. Notably, compound 1 demonstrated the most robust inhibitory effect against CAL-27 cells. Pharmacological assays further substantiated that compound 1 significantly restrained the proliferation, migration, and invasion of CAL-27 cells. Moreover, it was revealed that compound 1 directly interacted with TGFβR2, a pivotal receptor in the downstream signaling pathways of TGF-β/Smad and PI3K/AKT. Transcriptome analysis provided additional confirmation of these observations. Overall, our study highlights the promising potential of compound 1 as a therapeutic agent for the treatment of oral squamous cell carcinoma.

Objective To explore whether sedentary behaviour could modulate the association between overweight or obesity and chronic low back pain (CLBP).Design A retrospective cross-sectional study.Setting and participants A total of 4289 participants in the US cohort from the National Health and Nutrition Examination Survey were included.Primary and secondary outcome measures CLBP was the outcome.Results After adjusting for confounding factors, an increased risk of CLBP was identified in people who were overweight (OR 1.41, 95% CI 1.13 to 1.76) and obesity (OR 1.48, 95% CI 1.01 to 2.18). No significant association between sedentary behaviour time and CLBP was observed. In body mass index (BMI)4.5 hours group, the risk of CLBP was increased as BMI elevation, indicating sedentary behaviour time >4.5 hours played a modulatory role in the relationship between obesity and CLBP.Conclusion Obesity was significantly associated with an increased risk of CLBP, and sedentary behaviour time modulated the association between obesity and CLBP. The findings might provide a reference for the lifestyle modifications among individuals with obesity and reducing sedentary behaviour is recommended for this population.

IntroductionDeglycosylated azithromycin (Deg-AZM), a newly developed Class I drug with good therapeutic effects on slow transit constipation, is a small-molecule transgelin agonist that has been approved for clinical trials in 2024. The preclinical pharmacokinetic profile of Deg-AZM was investigated to support further development.MethodsA LC-MS/MS method was established and validated to detected the concentration of Deg-AZM in various biological samples. In vivo tests such as pharmacokinetic studies in rats and dogs, tissue distribution studies in rats, and extraction studies in rats were conducted to investigated the preclinical pharmacokinetic behaviors of Deg-AZM comprehensively. The plasma protein rate of Deg-AZM was determined by rapid equilibrium dialysis method in vitro. The metabolic stability and metabolite profile of Deg-AZM was assessed using pooled mice, rats, dogs, monkeys and humans microsomes in vitro. The PK profiles of Deg-AZM in human was predicted based on physiologically based pharmacokinetic (PBPK) models.ResultsThe plasma protein binding rates of Deg-AZM were lower in mice and rats, higher in dogs, and moderate in humans. The metabolic process of Deg-AZM was similar in rat and human liver microsomes. From Pharmacokinetic studies in rats and dogs, Deg-AZM was rapidly absorbed into the blood and then quickly eliminated. Plasma exposure of Deg-AZM was dose dependent with no accumulation after continuous gavage administration. In addition, there is no significant gender difference in the pharmacokinetic behavior of Deg-AZM. Deg-AZM was widely distributed in the tissues without obvious accumulation, and mainly excreted from the urinary excretion pathway. Furthermore, the pharmacokinetic profiles of Deg-AZM in humans showed dose dependency.ConclusionThe pharmacokinetic profiles of Deg-AZM was fully explored, these results could provide valuable information to support the first-in-human dosage prediction and phase I clinical design.

Cerium oxide nanoparticles (CeNPs) have emerged as a potent therapeutic agent in the realm of wound healing, attributing their efficacy predominantly to their exceptional antioxidant properties. Mimicking the activity of endogenous antioxidant enzymes, CeNPs alleviate oxidative stress and curtail the generation of inflammatory mediators, thus expediting the wound healing process. Their application spans various disease models, showcasing therapeutic potential in treating inflammatory responses and infections, particularly in oxidative stress-induced chronic wounds such as diabetic ulcers, radiation-induced skin injuries, and psoriasis. Despite the promising advancements in laboratory studies, the clinical translation of CeNPs is challenged by several factors, including biocompatibility, toxicity, effective drug delivery, and the development of multifunctional compounds. Addressing these challenges necessitates advancements in CeNP synthesis and functionalization, novel nano delivery systems, and comprehensive bio effectiveness and safety evaluations. This paper reviews the progress of CeNPs in wound healing, highlighting their mechanisms, applications, challenges, and future perspectives in clinical therapeutics.

In recent years, cell therapy has provided desirable properties for promising new drugs. Mesenchymal stem cells are promising candidates for developing genetic engineering and drug delivery strategies due to their inherent properties, including immune regulation, homing ability and tumor tropism. The therapeutic potential of mesenchymal stem cells is being investigated for cancer therapy, inflammatory and fibrotic diseases, among others. Mesenchymal stem cells are attractive cellular carriers for synthetic nanoparticles for drug delivery due to their inherent homing ability. In this review, we comprehensively discuss the various genetic and non-genetic strategies of mesenchymal stem cells and their derivatives in drug delivery, tumor therapy, immune regulation, tissue regeneration and other fields. In addition, we discuss the current limitations of stem cell therapy and the challenges in clinical translation, aiming to identify important development areas and potential future directions.

ObjectiveTo evaluate the safety and efficacy of employing LEO stents in dual stent-assisted embolization (DSAE) for wide-necked intracranial bifurcation aneurysms, and to assess the effectiveness of combined IA and IV intra-procedural infusion of tirofiban in mitigating perioperative complications.MethodsClinical data and follow-up images from 562 patients with wide-necked intracranial bifurcation aneurysms treated at First Affiliated Hospital of Army Medical University from 2018–2022 were collected. Among them, 65 received DSAE with LEO stents. The study observed treatment success rates, procedure-related complications, perioperative thromboembolic events (TEs) and hemorrhagic events (HEs), immediate postoperative modified Raymond-Roy classification (mRR), and follow-up imaging. Glasgow Outcome Scale (GOS) at discharge and clinical follow-ups were recorded.ResultsThe study enrolled 65 patients (mean age: 56.77 ± 10.07) with wide-necked intracranial bifurcation aneurysms. Among them, 58 had unruptured aneurysms, 7 ruptured (Hunt-Hess II-III). All aneurysms were successfully embolized without significant stent or bleeding complications. Only one case had intraoprative thrombosis; two postoperative ischemic incidents occurred within three days, no severe bleeding events. Immediate imaging showed modified Raymond-Roy classification: mRRC I (92.3%), mRRC II (4.6%), mRRC III b (3.1%). A total of 43 patients were followed up postoperatively with DSA. Among them, 41 patients exhibited mRRC I, while 2 patients exhibited mRRC II. No aneurysm was recanalized. Discharge GOS: GOS 5–60, GOS 4–1, GOS 3–4. One patient, GOS 1, died from lung cancer; others improved.ConclusionThe utilization of LEO stents for dual stent-assisted embolization of wide-necked intracranial bifurcation aneurysms demonstrated remarkable success and safety, yielding favorable postoperative outcomes and no instances of aneurysm recurrence. The concomitant administration of perioperative antiplatelet medications alongside IA and IV intra-procedural infusion of tirofiban effectively attenuated thromboembolic events (TEs) without concomitant elevations in bleeding risks.

Based on the engineering background of the ultra-close adjacent coal seam group in the deep part of Pingdingshan No.8 coal mine, this paper studies the reasonable layering of bottom pumping roadway under the mining condition of deep ultra-close seam. FLAC3D numerical model is used to simulate the evolution law of the plastic zone, stress field and displacement field of coal seam under different net rock distances between the roof of bottom pumping roadway and Ⅵ16-17 coal seam. The results show that when the net rock distance is 3 m or 5 m, the coal seam above the bottom drainage roadway can be divided into pressure relief zone, stress concentration zone and primary rock stress zone under the influence of mining. When the net rock distance is 8 m or more, the coal seam above the bottom drainage roadway can be divided into pressure relief zone and primary rock stress zone under the influence of mining. The optimal layout of bottom drainage roadway is 8-10 m distance from the retained net rock. After the bottom pumping roadway is mined, the position directly above the roadway has the best pressure relief effect, the coal body in this area is fully deformed, the gas control is easier, is conducive to the support and maintenance of the coal roadway in the later period, and is the best position to arrange the coal roadway. Field monitoring effectively verified the reliability of the bottom pumping roadway in the net rock distance to control the gas outburst risk of the working face near the deep seam group.

The Qixia Formation in the foothills of Longmen Mountain in the western Sichuan Basin is gaining attention for oil and gas exploration. However, exploration of the Qixia Formation in the middle Longmen Mountain is insufficient. Consequently, it is essential to understand its stratigraphic sedimentary characteristics for guiding natural gas exploration. This study focuses on the Beichuan Tongkou section, combines field measurements, thin-section observation and trace element analyses to investigate the sequence stratigraphy and sedimentary features of the Qixia Formation, thereby defining its sedimentary environment. Within the Beichuan Tongkou section, which spans from the Liangshan Formation to the Qixia Formation, researchers have identified two third-order and one fourth-order sequence boundaries, delineating one third-order sequence and two fourth-order sequences. The sedimentary facies found in this interval include shore-swamp, open platform, and platform edge environments, which are further classified into four subfacies including open sea, intertidal sea, intra-platform beach, and platform edge beach. Additionally, three microfacies are identified including intra-platform bioclastic beach, platform edge bioclastic beach, and platform edge sand debris and bioclastic beach. The Qi1 member and lower part of the Qi2 member is located on an open platform, while the upper-middle part of the Qi2 member is found at the platform edge. This setup defines a sedimentary model for a carbonate-rimmed platform in the Qixia Formation of the middle Longmen Mountain. During the sedimentary period of the Qixia Formation, a warm, humid, and oxygen-rich marine environment supported abundant ancient organisms. In the highstand system tract of the upper-middle part of the Qi2 member, the Sr/Ba ratio is lowest, while the MgO/CaO ratio is highest, indicating elevated ancient water temperatures and specific chemical compositions. The m value, reflective of paleosalinity, is notably high, suggesting a shallow, high-energy platform edge environment away from the mainland. Thick, high-energy platform edge sand debris and bioclastic beaches in this area promote the development of high-quality porous dolomite reservoirs of beach facies. The sedimentary facies and reservoir conditions of the Qi2 member in the middle Longmen Mountain are comparable to those in other sections, making it a promising target for oil and gas exploration within the Qixia Formation and a potential strategic replacement area for reservoir expansion.

Long non-coding RNA (lncRNA) is considered to be a crucial regulator involved in various human biological processes, including the regulation of tumor immune checkpoint proteins. It has great potential as both a cancer biomolecular biomarker and therapeutic target. Nevertheless, conventional biological experimental techniques are both resource-intensive and laborious, making it essential to develop an accurate and efficient computational method to facilitate the discovery of potential links between lncRNAs and diseases. In this study, we proposed HRGCNLDA, a computational approach utilizing hierarchical refinement of graph convolutional neural networks for forecasting lncRNA-disease potential associations. This approach effectively addresses the over-smoothing problem that arises from stacking multiple layers of graph convolutional neural networks. Specifically, HRGCNLDA enhances the layer representation during message propagation and node updates, thereby amplifying the contribution of hidden layers that resemble the ego layer while reducing discrepancies. The results of the experiments showed that HRGCNLDA achieved the highest AUC-ROC (area under the receiver operating characteristic curve, AUC for short) and AUC-PR (area under the precision versus recall curve, AUPR for short) values compared to other methods. Finally, to further demonstrate the reliability and efficacy of our approach, we performed case studies on the case of three prevalent human diseases, namely, breast cancer, lung cancer and gastric cancer.

Abstract Background Varicocele is the most prevalent correctable cause of male infertility. Currently, surgical treatment is the primary method to enhance fertility.For many young varicocele patients who have postponed surgery due to time constraints, daytime surgery is especially crucial. Thus, this study aims to investigate the clinical and nursing application value of the Plan-Do-Check-Act (PDCA) cycle in daytime varicocelectomy. Methods Retrospective collection of clinical data was conducted on 130 patients undergoing laparoscopic varicocelectomy in the Third Affiliated Hospital of Southern Medical University, Guangzhou,China.Among them, 65 patients who underwent daytime surgery were assigned to the observation group, while 65 patients who underwent routine hospital surgeries were assigned to the control group.The former also implemented PDCA cycle management.A comparison was made between the two groups regarding hospitalization time, hospitalization costs, and patient satisfaction. Results The observation group exhibited a shorter hospitalization time and lower hospitalization costs compared to the control group, with higher patient satisfaction and pre-discharge visual analog scale (VAS) scores noted (P 0.05). The implementation of the PDCA cycle in the observation group has demonstrated its effectiveness, ensuring the smooth conduct of the daytime varicocelectomy. Conclusion In conclusion,daytime varicocelectomy can reduce hospitalization time,lower hospitalization costs, improve patient satisfaction. The PDCA Cycle enhances the rationality and efficacy of the daytime varicocelectomy procedure and is highly recommended. Furthermore, it offers valuable reference for the application of the PDCA Cycle in various other diseases and nursing management approaches. Trial Registration The Trial Registration Number: ChiCTR2300077465;Date of registration: November 9, 2023.

Abstract Background Epigenetic remodeling at effector gene loci has been reported to be critical in regulating T cell differentiation and function. However, efforts to investigate underlying epigenetic mechanisms that control T cell behaviors have been largely hindered by very limited experimental tools, especially in humans. Results In this study, we employed a flow cytometric assay to analyze histone acetylation at single-cell level in human T cells. The data showed that histone acetylation was increased during T cell activation. Among T cell subsets, terminally differentiated effector memory T (TEMRA) cells robustly producing effector cytokines were hyper-acetylated. Conversely, these TEMRA cells had lower expression levels of TCF-1, a key transcription factor for maintaining stem cell features. Pharmaceutical inhibition of histone acetylation using a small molecule C646 restrained the production of effector molecules, but retained stem cell-like properties in T cells after expansion. Conclusions Per-cell histone acetylation is associated with terminal differentiation and poor stemness in human T cells. These observations suggest a new approach to enhance the stem cell-like properties of T cells and improve the efficacy of immunotherapy.

Recently, deep learning-based methods have emerged as the preferred approach for ultrasound data analysis. However, these methods often require large-scale annotated datasets for training deep models, which are not readily available in practical scenarios. Additionally, the presence of speckle noise and other imaging artifacts can introduce numerous hard examples for ultrasound data classification. In this paper, drawing inspiration from self-supervised learning techniques, we present a pre-training method based on mask modeling specifically designed for ultrasound data. Our study investigates three different mask modeling strategies: random masking, vertical masking, and horizontal masking. By employing these strategies, our pre-training approach aims to predict the masked portion of the ultrasound images. Notably, our method does not rely on externally labeled data, allowing us to extract representative features without the need for human annotation. Consequently, we can leverage unlabeled datasets for pre-training. Furthermore, to address the challenges posed by hard samples in ultrasound data, we propose a novel hard sample mining strategy. To evaluate the effectiveness of our proposed method, we conduct experiments on two datasets. The experimental results demonstrate that our approach outperforms other state-of-the-art methods in ultrasound image classification. This indicates the superiority of our pre-training method and its ability to extract discriminative features from ultrasound data, even in the presence of hard examples.

Graph contrastive learning (GCL) has emerged as a promising paradigm for learning graph representations. Recently, the idea of hard negatives is introduced to GCL, which can provide more challenging self-supervised objectives and alleviate over-fitting issues. These methods use different graphs in the same mini-batch as negative examples, and assign larger weights to true hard negative ones. However, the influence of such weighting strategies is limited in practice, since a small mini-batch may not contain any challenging enough negative examples. In this paper, we aim to offer a more flexible solution to affect the hardness of negatives by directly manipulating the representations of negatives. By assuming that (1) good negative representations should not deviate far from the representations of real graph samples, and (2) the computation process of graph encoder may introduce biases to graph representations, we first design a negative representation generator (NRG) which (1) employs real graphs as prototypes to perturb, and (2) introduces parameterized perturbations through the feed-forward computation of the graph encoder to match the biases. Then we design a generation loss to train the parameters in NRG and adaptively generate negative representations for more challenging contrastive objectives. Experiments on eight benchmark datasets show that our proposed framework ANGCL has 1.6% relative improvement over the best baseline, and can be successfully integrated with three types of graph augmentations. Ablation studies and hyper-parameter experiments further demonstrate the effectiveness of ANGCL.

Abstract Background Cancer associated fibroblasts (CAFs) can remodel tumor microenvironment by secreting exosomes. This study aimed to investigate the role of exosomes derived from cancer-associated fibroblasts in colorectal cancer (CRC) progression. Methods Circular RNA (circRNA) array was used to identify differentially expressed circRNAs in exosomes from normal fibroblasts (NFs) and CAFs, and confirmed one differentially expressed circRNA circ_0067557 by real-time PCR. The effect of circ_0067557 on proliferation, metastasis, chemoresistance and apoptosis was verified by wound heal, tranwell, CCK8, sphere-forming and flow cytometry assay. Results Circ_0067557 expression in exosomes from CAFs was higher than those from NFs. CAF-derived exosomes promoted the proliferation, migration, invasion and chemoresistance of CRC cells while suppressed apoptosis. Silencing of circ_0067557 inhibited malignant phenotypes of CRC cells by targeting Lin28A and Lin28B. Moreover, CAF-derived exosomes enhanced the growth of CRC xenograft tumors. Conclusion Circ_0067557/Lin28A and Lin28B signal axis may be a potential therapy target for CRC.

Lycopene, a carotenoid with numerous physiological benefits, particularly in its Z-isomer form, faces challenges in its application due to low chemical stability. To address this limitation, high internal phase emulsion was successfully synthesized using ovalbumin-chitosan complexes. The aim was to enhance the stability of lycopene including Z-lycopene. The solubility, particle size, ζ-potential and uniformity of the mixture were dependent on pH value and biopolymer proportion. Notably, optimal ovalbumin-chitosan complex formation occurred at pH 2.5 with a ratio of 4:1 resulting in the highest solubility and optimal uniformity which contributed to its superior emulsification properties. Evaluation of encapsulating efficiency and loading amount revealed 98.19% and 1.7661 mg/g respectively for lycopene in ovalbumin-chitosan stabilized emulsions, inhibiting the transformation from Z-lycopene to (all-E)-lycopene. The encapsulated lycopene possessed UV stability where retention rate remained high at 81.86%. The retention rate was up to 65.37% and 41.82% at 45 °C and 80 °C, respectively.

Background To make the question text represent more information and construct an end-to-end text clustering model, we propose a double-target self-supervised clustering with multi-feature fusion (MF-DSC) for texts which describe questions related to the medical field. Since medical question-and-answer data are unstructured texts and characterized by short characters and irregular language use, the features extracted by a single model cannot fully characterize the text content. Methods Firstly, word weights were obtained based on term frequency, and word vectors were generated according to lexical semantic information. Then we fused term frequency and lexical semantics to obtain weighted word vectors, which were used as input to the model for deep learning. Meanwhile, a self-attention mechanism was introduced to calculate the weight of each word in the question text, i.e., the interactions between words. To learn fusing cross-document topic features and build an end-to-end text clustering model, two target functions, L cluster and L topic, were constructed and integrated to a unified clustering framework, which also helped to learn a friendly representation that facilitates text clustering. After that, we conducted comparison experiments with five other models to verify the effectiveness of MF-DSC. Results The MF-DSC outperformed other models in normalized mutual information (NMI), adjusted Rand indicator (ARI) average clustering accuracy (ACC) and F1 with 0.4346, 0.4934, 0.8649 and 0.5737, respectively.

Abstract Visible light‐based human–machine interactive media is capable of transmitting electrical readouts to machines and providing intuitive feedback to users simultaneously. Currently, many inorganic mechanoluminescent (ML) materials‐based interactive media, typically ZnS‐loaded phosphors (ZLPs), have been successfully demonstrated. However, organic ML materials‐based solutions were rarely exploited despite their huge merits of strong structural modification, abundant luminescence property, low cost, easy preparation, and so on. Here, we propose a novel interactive tactile display (ITD) based on organic ML materials (Cz‐A6‐dye) and triboelectric nanogenerator, with ultra‐brightness (130% enhancement) and ultra‐low threshold pressure (57% reduction) as compared to ZLPs. The proposed ITD achieves the conversion of weak mechanical stimuli into visible light and electrical signals simultaneously, without extra power supplies. Furthermore, the relationship between the luminous performance of organic ML materials and mechanical force is quantified, benefiting from the uniform ML layer prepared. Enabled by convolutional neural networks, the high‐accuracy recognition (97.1%) for handwriting and identity of users is realized at the same time. Thus, the ITD has great potential for intelligent wearable electronics and classified military applications.

Introduction: Genomic profiling has revolutionized therapeutic interventions and the clinical management of liver cancer. However, pathogenetic mechanisms, molecular determinants of recurrence, and predictive biomarkers for first-line treatment (anti-PD-(L)1 plus bevacizumab) in liver cancer remain incompletely understood.Materials and methods: Targeted next-generation sequencing (tNGS) (a 603-cancer-gene panel) was applied for the genomic profiling of 232 hepatocellular carcinoma (HCC) and 22 intrahepatic cholangiocarcinoma (ICC) patients, among which 47 unresectable/metastatic HCC patients underwent anti-PD-1 plus bevacizumab therapy. Genomic alterations were estimated for their association with vascular invasion (VI), location of onset, recurrence, overall survival (OS), recurrence-free survival (RFS), and anti-PD-1 plus bevacizumab therapy response.Results: The genomic landscape exhibited that the most commonly altered genes in HCC were TP53, FAT3, PDE4DIP, KMT2C, FAT1, and MYO18A, while TP53, FAT1, FAT3, PDE4DIP, ROS1, and GALNT11 were frequently altered in ICC; notably, KRAS (18.18% vs. 1.29%) and BAP1 (13.64% vs. 1.29%) alterations were significantly more prevalent in ICC. Comparison analysis demonstrated the distinct clinicopathological/genomic characterizations between Chinese and Western HCC cohorts. Genomic profiling of HCC underlying VI showed that LDLR, MSH2, KDM5D, PDE3A, and FOXO1 were frequently altered in the VI group compared to patients without VIs. Compared to the right hepatic lobes of HCC patients, the left hepatic lobe of HCC patients had superior OS (median OS: 36.77 months vs. unreached, p < 0.05). By further comparison, Notch signaling pathway-related alterations were significantly prevalent among the right hepatic lobes of HCC patients. Of note, multivariate Cox regression analysis showed that altered RB1, NOTCH3, MGA, SYNE1, and ZFHX3, as independent prognostic factors, were significantly correlated with the OS of HCC patients. Furthermore, altered LATS1 was abundantly enriched in the HCC-recurrent group, and impressively, it was independent of clinicopathological features in predicting RFS (median RFS of altered type vs. wild-type: 5.57 months vs. 22.47 months, p < 0.01). Regarding those treated HCC patients, TMB value, altered PTPRZ1, and cell cycle-related alterations were identified to be positively associated with the objective response rate (ORR), but KMT2D alterations were negatively correlated with ORR. In addition, altered KMT2D and cell cycle signaling were significantly associated with reduced and increased time to progression-free survival (PFS), respectively.Conclusion: Comprehensive genomic profiling deciphered distinct molecular characterizations underlying VI, location of onset, recurrence, and survival time in liver cancer. The identification of novel genetic predictors of response to anti-PD-1 plus bevacizumab in HCC facilitated the development of an evidence-based approach to therapy.

The Janus metastructure (JMS) is constructed in a special way so that the electromagnetic waves (EWs) propagate in the artificially constructed metastructure from different directions, which can show different electromagnetic characteristics and present a variety of functions at the same time. Its research is of great significance for breaking through the development bottleneck of traditional single-scale and single-function devices and can serve numerous novel application scenarios. This review discusses the design and research progress of JMS from three aspects: construction method, function realization, and application scenario. Finally, we discuss the key challenges currently facing the JMS and offer a vision for future research directions. We sincerely hope that this review will not only provide new insights into the development of JMS, which is a promising and dynamic hot research area but also promote research in this area from a more diverse and comprehensive perspective.

Chondrosarcoma (CHS) is a malignant bone tumor with insensitivity to both radiotherapy and chemotherapy, and a high recurrence rate. However, the latent mechanism of recurrent CHS (Re-CHS) remains elusive. Here, we discovered that FBXO22 was highly expressed in clinical samples of Re-CHS. FBXO22 played a significant role in various cancers. However, the role of FBXO22 in Re-CHS remained unclear. Our research demonstrated that suppressing FBXO22 abated the proliferation and migration of CHS cells and facilitated their apoptosis. In addition, suppressing FBXO22 raised the expression of PD-L1 in Re-CHS. All these findings provide new evidence for using FBXO22 and PD-L1 as combined targets to prevent and treat Re-CHS, which may prove to be a novel strategy for immunotherapy of CHS, especially Re-CHS.

Many clinical conditions can cause fever of unknown origin (FUO) in children, but the etiological diagnosis remains challenging despite the variety of inspection methods available at present. This study aims to investigate the effectiveness of droplet digital polymerase chain reaction (ddPCR) in identifying pathogens in children with FUO as a novel application. A 7-month-old boy failed to obtain etiology evidence for his disease through various tests. After collecting peripheral blood for ddPCR analysis, Staphylococcus aureus and Escherichia coli were detected, and Sanger sequencing confirmed the pathogens. During the disease, the child developed septic arthritis and osteomyelitis in the femur. Despite the patient's fever being removed, his limb activity improving, and inflammatory biomarkers decreasing, avascular necrosis of the femoral head remained after targeted antibiotic treatment and surgery. If the patient had undergone ddPCR analysis at an early stage, it may be possible to avoid sequelae. ddPCR helps identify pathogens in the diagnosis of children with FUO and could be a promising complementary tool.

Idiopathic pulmonary fibrosis (IPF) is one of the most fatal chronic interstitial lung diseases with unknown pathogenesis, current treatments cannot truly reverse the progression of the disease. Pulmonary macrophages, especially bone marrow derived pro-fibrotic macrophages, secrete multiple kinds of profibrotic mediators (SPP1, CD206, CD163, IL-10, CCL18…), thus further promote myofibroblast activation and fibrosis procession. IL20Rb is a cell-surface receptor that belongs to IL-20 family. The role of IL20Rb in macrophage activation and pulmonary fibrosis remains unclear. In this study, we established a bleomycin-induced pulmonary fibrosis model, used IL4/13-inducing THP1 cells to induce profibrotic macrophage (M2-like phenotype) polarization models. We found that IL20Rb is upregulated in the progression of pulmonary fibrosis, and its absence can alleviate the progression of pulmonary fibrosis. In addition, we demonstrated that IL20Rb promote the activation of bone marrow derived profibrotic macrophages by regulating the Jak2/Stat3 and Pi3k/Akt signaling pathways. In terms of therapeutic strategy, we used IL20Rb neutralizing antibodies for animal administration, which was found to alleviate the progression of IPF. Our results suggest that IL20Rb plays a profibrotic role by promoting profibrotic macrophage polarization, and IL20Rb may become a potential therapeutic target for IPF. Neutralizing antibodies against IL20Rb may become a potential drug for the clinical treatment of IPF.

Intracranial aneurysm is a high-risk disease, with imaging playing a crucial role in their diagnosis and treatment. The rapid advancement of artificial intelligence in imaging technology holds promise for the development of AI-based radiomics predictive models. These models could potentially enable the automatic detection and diagnosis of intracranial aneurysms, assess their status, and predict outcomes, thereby assisting in the creation of personalized treatment plans. In addition, these techniques could improve diagnostic efficiency for physicians and patient prognoses. This article aims to review the progress of artificial intelligence radiomics in the study of intracranial aneurysms, addressing the challenges faced and future prospects, in hopes of introducing new ideas for the precise diagnosis and treatment of intracranial aneurysms.

Purpose: To investigate the regulatory effect and mechanism of Vitamin D receptor (VDR) on mitochondrial function in renal tubular epithelial cell under diabetic status. Methods: The diabetic rats induced by streptozotocin (STZ) and HK-2 cells under high glocose(HG)/transforming growth factor beta (TGF-β) stimulation were used in this study. Calcitriol was administered for 24 weeks. Renal tubulointerstitial injury and some parameters of mitochondrial function including mitophagy, mitochondrial fission, mitochondrial ROS, mitochondrial membrane potential (MMP), mitochondrial ATP, Complex V activity and mitochondria-associated ER membranes (MAMs) integrity were examined. Additionally, paricalcitol, 3-MA (an autophagy inhibitor), VDR over-expression plasmid, VDR siRNA and Mfn2 siRNA were applied in vitro. Results: The expression of VDR, Pink1, Parkin, Fundc1, LC3II, Atg5, Mfn2, Mfn1 in renal tubular cell of diabetic rats were decreased significantly. Calcitriol treatment reduced the levels of urinary albumin, serum creatinine and attenuated renal tubulointerstitial fibrosis in STZ induced diabetic rats. In addition, VDR agonist relieved mitophagy dysfunction, MAMs integrity, and inhibited mitochondrial fission, mitochondrial ROS. Co-immunoprecipitation analysis demonstrated that VDR interacted directly with Mfn2. Mitochondrial function including mitophagy, mitochondrial membrane potential (MMP), mitochondrial Ca2+, mitochondrial ATP and Complex V activity were decreased dramatically in HK-2 cells under HG/TGF-β ambience. In vitro pretreatment of HK-2 cells with autophagy inhibitor 3-MA, VDR siRNA or Mfn2 siRNA negated the activating effects of paricalcitol on mitochondrial function. Pricalcitol and VDR over-expression plasmid activated Mfn2 and then partially restored the MAMs integrity. Additionally, VDR restored mitophagy was partially associated with MAMs integrity through Fundc1. Conclusion: Activated VDR could contribute to restore mitophagy through Mfn2-MAMs-Fundc1 pathway in renal tubular cell. VDR could recover mitochondrial ATP, complex V activity and MAMs integrity, inhibit mitochondrial fission and mitochondrial ROS. It indicating that VDR agonists ameliorate renal tubulointerstitial fibrosis in diabetic rats partially via regulation of mitochondrial function.

Abstract Mounting attention has been focused on defects of the autophagy-lysosomal pathway in sepsis, however, the precise mechanisms governing the autophagy-lysosomal process in sepsis are poorly known. We have previously reported that Erbin deficiency aggravated the inflammatory response and organ injuries caused by sepsis. In the present study, we found that Erbin knockout impaired the autophagy process in both muramyl dipeptide (MDP)-induced bone marrow-derived macrophages (BMDMs) and sepsis mouse liver and lung, as detected by the accumulation of LC3-II and SQSTM1/p62, and autophagosomes. Pretreatment with autophagy inhibitor chloroquine (CQ) further aggravated inflammatory response and organ injuries in vivo and in vitro sepsis model. We also observed that the impaired lysosomal function mediated autophagic blockade, as detected by the decreased expression of ATP6V, cathepsin B (CTSB) and LAMP2 protein. Immunoprecipitation revealed that the C-terminal of Erbin (aa 391–964) interacts with the N-terminal of transcription factor EB (TFEB) (aa 1–247), and affects the stability of TFEB-14-3-3 and TFEB-PPP3CB complexes and the phosphorylation status of TFEB, thereby promote the nucleus translocation of TFEB and the TFEB target genes transcription. Thus, our study suggested that Erbin alleviated sepsis-induced inflammatory responses and organ injuries by rescuing dysfunction of the autophagy-lysosomal pathway through TFEB-14-3-3 and TFEB-PPP3CB pathway.

Abstract The occurrence and progression of tumors can be established through a complex interplay among tumor cells undergoing epithelial-mesenchymal transition (EMT), invasive factors and immune cells. In this study, we employed single-cell RNA sequencing (scRNA-seq) and spatially resolved transcriptomics (ST) to evaluate the pseudotime trajectory and spatial interactive relationship between EMT-invasive malignant tumors and immune cells in primary colorectal cancer (CRC) tissues at different stages (stage I/II and stage III with tumor deposit). Our research characterized the spatiotemporal relationship among different invasive tumor programs by constructing pseudotime endpoint-EMT-invasion tumor programs (EMTPs) located at the edge of ST, utilizing evolution trajectory analysis integrated with EMT-invasion genes. Strikingly, the invasive and expansive process of tumors undergoes remarkable spatial reprogramming of regulatory and immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), regulatory T cells (Treg), and exhausted T cells (Tex). These EMTP-adjacent cell are linked to EMT-related invasion genes, especially the C-X-C motif ligand 1 (CXCL1) and CXCL8 genes that are important for CRC prognosis. Interestingly, the EMTPs in stage I mainly produce an inflammatory margin invasive niche, while the EMTPs in stage III tissues likely produce a hypoxic pre-invasive niche. Our data demonstrate the crucial role of regulatory and immunosuppressive cells in tumor formation and progression of CRC. This study provides a framework to delineate the spatiotemporal invasive niche in CRC samples. Graphical Abstract

Abstract Background Cell-based immunotherapy shows the therapeutic potential in sarcomas, in addition to angiogenesis-targeted tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI). Multi-antigen stimulated cell therapy-I (MASCT-I) technology is a sequential immune cell therapy for cancer, which composes of multiple antigen-loaded dendritic cell (DC) vaccines followed by the adoptive transfer of anti-tumor effector T-cells. Methods In this phase 1 study, we assessed MASCT-I plus camrelizumab (an ICI against PD-1) and apatinib (a highly selective TKI targeting VEGFR2) in patients with unresectable recurrent or metastatic bone and soft-tissue sarcoma after at least one line of prior systemic therapy. One MASCT-I course consisted of 3 DC subcutaneous injections, followed by 3 active T cell infusions administered 18–27 days after each DC injection. In schedule-I group, 3 DC injections were administered with a 28-day interval in all courses; in schedule-II group, 3 DC injections were administered with a 7-day interval in the first course and with a 28-day interval thereafter. All patients received intravenous camrelizumab 200 mg every 3 weeks and oral apatinib 250 mg daily. Results From October 30, 2019, to August 12, 2021, 19 patients were enrolled and randomly assigned to schedule-I group (n = 9) and schedule-II group (n = 10). Of the 19 patients, 11 (57.9%) experienced grade 3 or 4 treatment-related adverse events. No treatment-related deaths occurred. Patients in schedule-II group showed similar objective response rate (ORR) with those in schedule-I group (30.0% versus 33.3%) but had higher disease control rate (DCR; 90.0% versus 44.4%) and longer median progression-free survival (PFS; 7.7 versus 4.0 months). For the 13 patients with soft-tissue sarcomas, the ORR was 30.8%, DCR was 76.9%, and median PFS was 12.9 months; for the 6 patients with osteosarcomas, the ORR was 33.3%, the DCR was 50.0%, and median PFS was 5.7 months. Conclusions Overall, MASCT-I plus camrelizumab and apatinib was safe and showed encouraging efficacy in advanced bone and soft-tissue sarcoma, and schedule-II administration method was recommended. Trial registration ClinicalTrials.gov, NCT04074564.

Abstract Emerging infectious diseases are a critical public health challenge in the twenty-first century. The recent proliferation of such diseases has raised major social and economic concerns. Therefore, early detection of emerging infectious diseases is essential. Subjects from five medical institutions in Beijing, China, which met the spatial-specific requirements, were analyzed. A quality control process was used to select 37,422 medical records of infectious diseases and 56,133 cases of non-infectious diseases. An emerging infectious disease detection model (EIDDM), a two-layer model that divides the problem into two sub-problems, i.e., whether a case is an infectious disease, and if so, whether it is a known infectious disease, was proposed. The first layer model adopts the binary classification model TextCNN-Attention. The second layer is a multi-classification model of LightGBM based on the one-vs-rest strategy. Based on the experimental results, a threshold of 0.5 is selected. The model results were compared with those of other models such as XGBoost and Random Forest using the following evaluation indicators: accuracy, sensitivity, specificity, positive predictive value, and negative predictive value. The prediction performance of the first-layer TextCNN is better than that of other comparison models. Its average specificity for non-infectious diseases is 97.57%, with an average negative predictive value of 82.63%, indicating a low risk of misdiagnosing non-infectious diseases as infectious (i.e., a low false positive rate). Its average positive predictive value for eight selected infectious diseases is 95.07%, demonstrating the model's ability to avoid misdiagnoses. The overall average accuracy of the model is 86.11%. The average prediction accuracy of the second-layer LightGBM model for emerging infectious diseases reaches 90.44%. Furthermore, the response time of a single online reasoning using the LightGBM model is approximately 27 ms, which makes it suitable for analyzing clinical records in real time. Using the Knox method, we found that all the infectious diseases were within 2000 m in our case, and a clustering feature of spatiotemporal interactions (P

Abstract Background Gaming disorder is a new disease, which is included in the disease unit of disorder caused by addiction in the 11th revision of the International Classification of Diseases. This study examined the symptom characteristics of gaming disorders in Chinese adolescents using the latent profile analysis. Methods Totally, 5988 students (including 3285 boys and 2703 girls; aged 12–18 years) from junior high schools and senior high schools were enrolled. The Gaming Disorder Symptom Questionnaire-21 (GDSQ-21) was used to screen gaming disorder. A latent profile analysis was used for classifying the subgroups based on the extent of gaming usage. The relationship between adolescent gamers and demographic variables was analyzed by logistic regression. Results The results of latent profile analysis supported the models of four latent profiles, which were defined as healthy gamers (Profile 1, 56.83%), impaired control gamers (Profile 2, 26.09%), impaired control-game priority gamers (Profile 3, 9.72%) and gamers with disorder (Profile 4, 7.36%), respectively. Logistic regression analysis found that, compared with girls, boys were more likely to be classified into the group dominated by the impaired gamers, the impaired control-game priority gamers, and the gamers with disorder. Conclusions This study highlighted that the latent profile analysis identified four different groups of adolescent gamers, showing a clearer conceptualization of heterogeneous gamers. Gender and average weekly gaming time can predict the latent profile of adolescents. Our findings may facilitate the design of individualized assessment and early intervention programs for adolescent gamer users based on different gaming usage symptoms.