Single nucleotide polymorphisms in the development of osteomyelitis and prosthetic joint infection: a narrative review.

Currently, despite advancements in diagnostic and therapeutic modalities, osteomyelitis and prosthetic joint infection (PJI) continue to pose significant challenges for orthopaedic surgeons. These challenges are primarily attributed to the high degree of heterogeneity exhibited by these disorders, which are influenced by a combination of environmental and host factors. Recent research efforts have delved into the pathogenesis of osteomyelitis and PJI by investigating single nucleotide polymorphisms (SNPs). This review comprehensively summarizes the current evidence regarding the associations between SNPs and the predisposition to osteomyelitis and PJI across diverse populations. The findings suggest potential linkages between SNPs in genes such as IL-1, IL-6, IFN-γ, TNF-α, VDR, tPA, CTSG, COX-2, MMP1, SLC11A1, Bax, NOS2, and NLRP3 with the development of osteomyelitis. Furthermore, SNPs in genes like IL-1, IL-6, TNF-α, MBL, OPG, RANK, and GCSFR are implicated in susceptibility to PJI. However, it is noted that most of these studies are single-center reports, lacking in-depth mechanistic research. To gain a more profound understanding of the roles played by various SNPs in the development of osteomyelitis and PJI, future multi-center studies and fundamental investigations are deemed necessary.

LIG1 is a novel marker for bladder cancer prognosis: evidence based on experimental studies, machine learning and single-cell sequencing.

Background: Bladder cancer, a highly fatal disease, poses a significant threat to patients. Positioned at 19q13.2-13.3, LIG1, one of the four DNA ligases in mammalian cells, is frequently deleted in tumour cells of diverse origins. Despite this, the precise involvement of LIG1 in BLCA remains elusive. This pioneering investigation delves into the uncharted territory of LIG1's impact on BLCA. Our primary objective is to elucidate the intricate interplay between LIG1 and BLCA, alongside exploring its correlation with various clinicopathological factors. Methods: We retrieved gene expression data of para-carcinoma tissues and bladder cancer (BLCA) from the GEO repository. Single-cell sequencing data were processed using the "Seurat" package. Differential expression analysis was then performed with the "Limma" package. The construction of scale-free gene co-expression networks was achieved using the "WGCNA" package. Subsequently, a Venn diagram was utilized to extract genes from the positively correlated modules identified by WGCNA and intersect them with differentially expressed genes (DEGs), isolating the overlapping genes. The "STRINGdb" package was employed to establish the protein-protein interaction (PPI) network.Hub genes were identified through the PPI network using the Betweenness Centrality (BC) algorithm. We conducted KEGG and GO enrichment analyses to uncover the regulatory mechanisms and biological functions associated with the hub genes. A machine-learning diagnostic model was established using the R package "mlr3verse." Mutation profiles between the LIG1^high and LIG1^low groups were visualized using the BEST website. Survival analyses within the LIG1^high and LIG1^low groups were performed using the BEST website and the GENT2 website. Finally, a series of functional experiments were executed to validate the functional role of LIG1 in BLCA. Results: Our investigation revealed an upregulation of LIG1 in BLCA specimens, with heightened LIG1 levels correlating with unfavorable overall survival outcomes. Functional enrichment analysis of hub genes, as evidenced by GO and KEGG enrichment analyses, highlighted LIG1's involvement in critical function such as the DNA replication, cellular senescence, cell cycle and the p53 signalling pathway. Notably, the mutational landscape of BLCA varied significantly between LIG1high and LIG1low groups.Immune infiltrating analyses suggested a pivotal role for LIG1 in immune cell recruitment and immune regulation within the BLCA microenvironment, thereby impacting prognosis. Subsequent experimental validations further underscored the significance of LIG1 in BLCA pathogenesis, consolidating its functional relevance in BLCA samples. Conclusions: Our research demonstrates that LIG1 plays a crucial role in promoting bladder cancer malignant progression by heightening proliferation, invasion, EMT, and other key functions, thereby serving as a potential risk biomarker.

Measuring total hip arthroplasty liner wear using the EOS Imaging System: experimental and clinical results.

BACKGROUND AND PURPOSE: The low-dose EOS Imaging System is an emerging tool for 3-dimensional measurements in orthopedics. The clinical feasibility for measuring total hip arthroplasty (THA) liner wear has not yet been investigated. We aimed to evaluate the feasibility of using EOS to measure THA liner wear by examining the experimental accuracy using a THA phantom and clinical precision of patients with THA, considering a clinically relevant precision at the 95% repeatability limit to be 0.2 mm. METHODS: An experimental THA phantom with movable stem and a fixed cup with a plastic liner was constructed to simulate progressive 3D liner wear. Series of 11 pairs of radiographs with 50 µm femoral movement in between were obtained for each 3D axis in EOS. 30 patients with a THA were scanned twice using EOS to assess precision. Model-based radiostereometric analysis (RSA) was used for wear measurement. RESULTS: The mean difference (true minus simulated wear) with standard deviation (SD) and 95% limits of agreement for experimental THA wear were 0.005 (0.037) and [-0.069 to 0.079] mm for the vertical (y) axis. The mean (SD) and 95% repeatability limit for precision for clinical measurement were -0.029 (0.105) and 0.218 mm. CONCLUSION: Experimental THA liner wear using EOS was within clinically relevant tolerances and without bias. The clinical precision was just outside our defined clinically relevant precision. Compared with conventional RSA, EOS is less accurate and precise but may still be of value for certain clinical applications, provided larger sample size or longer follow-up are available.

[Spectral Characteristics of Dissolved Organic Matter in Sediments from Yuanhe River Basin].

Dissolved organic matter （DOM） plays an important role in indicating the pollution of the water environment, and sediment is the main source of endogenous pollution of the water environment. Research on the spectral characteristics of DOM in sediments was important for the interpretation of water environment pollution. In this study, UV-visible absorption spectroscopy and three-dimensional fluorescence spectroscopy combined with the parallel factor analysis （PARAFAC） were used to analyze the fluorescent components, sources, and influencing factors of DOM in sediments from the Yuanhe River Basin. The results showed that the average of ω（TN）, ω（TP）, and ω（OM） in sediments from the Yuanhe River Basin were 0.52, 0.66, and 21.22 g·kg-1, respectively. The concentrations of total nitrogen and total phosphorus increased along the flow direction. In addition, the sediment DOM from the Yuanhe River Basin mainly originated from terrestrial sources. The chromophoric DOM concentration and aromaticity of DOM from the downstream reaches were significantly higher than those from the upstream and midstream reaches. Based on PARAFAC, four fluorescent components of DOM in sediments from the Yuanhe River Basin were identified, including three humus-like components （C1, C3, and C4） and one protein-like component （C2）. The sediment DOM was dominated by humus-like materials. Moreover, the fluorescent intensity of the fluorescent components was higher in the downstream reaches. Redundancy analysis revealed that the physicochemical properties of sediments in the mainstream and downstream reaches played a more significant role in the spectral properties of DOM. Phosphorus pollution and the terrestrial humus-like substance of sediment DOM were homologous. These results indicated that the spectral properties of DOM were the indicator of water environmental pollution in the region with strong anthropogenic influence.

Effect of preoperative autologous platelet-rich plasmapheresis on postoperative bleeding in patients undergoing heart valve surgery.

Background: Cardiovascular surgeries often require deep hypothermic circulatory arrest and cardiopulmonary bypass (CPB), which can disrupt blood clotting and lead to excessive bleeding. Traditional treatments involve transfusing blood and blood products, which can have adverse effects and place significant strain on the global blood supply. Research suggests that autologous platelet-rich plasmapheresis (aPRP) may reduce the need for transfusions by preserving blood components. However, the impact of aPRP on postoperative blood loss and clinical outcomes in cardiovascular surgery remains controversial. This study aimed to examine the effects of aPRP on postoperative blood loss and recovery in patients undergoing heart valve surgery. Methods: A total of 183 patients were divided into either aPRP or control groups. The aPRP group received aPRP before CPB, whereas the control group did not. The primary endpoint was postoperative bleeding between the groups. The secondary endpoints were postoperative bleeding risk factors and clinical outcome assessment. Logistic regression analysis with covariate adjustment was used to calculate these risk factors. Results: A total of 76 patients (41.5%) in the aPRP group and 107 patients (58.5%) in the control group were included in the analysis. No significant difference was found in the occurrence of postoperative bleeding [odds ratio (OR) =0.53, 95% confidence interval (CI): 0.28-1.00, P=0.05], and the aPRP group had fewer complications than the controls (OR =0.28, 95% CI: 0.10-0.68, P=0.009). However, after adjusting for the New York Heart Association (NYHA) classification, diabetes, arrhythmology, mean activated clotting time (ACTmean), CPB, bleeding, thoracotomy, and body mass index (BMI), there was a significant difference in postoperative bleeding (adjusted OR =0.47, 95% CI: 0.22-0.98, P=0.04) and complications (adjusted OR =0.23, 95% CI: 0.07-0.64, P=0.008) between the two groups. Conclusions: Preoperative aPRP can improve postoperative outcomes and reduce complications in patients undergoing heart valve surgery.

Molecular Dynamics Investigation of Metastable Structure and Hybridization Bond Evolution in High-Entropy CoCrFeNi Heterostructured Amorphous Carbon Films.

Heterogeneous element doping in amorphous carbon films can reduce residual stresses and improve plastic deformation. Nevertheless, the effects of dopant content and size on the metastable transition mechanism between sp2-C and sp3-C atoms during the deformation process are unclear and difficult to be in situ observed and researched, experimentally. In this work, the mechanical properties and the structural evolution during the nanoindentation of amorphous CoCrFeNi sphere-doped carbon heterostructured films with different radii were simulated. The results indicate that the hardness H and elastic modulus E of the films decreased with the increase of the dopant addition. H decreases from 50.69 to 28.94 GPa, and E decreases from 664.39 to 448.62 GPa. The decrease in the elastic recovery and the enlargement of the shear transition zones indicate that the presence of the amorphous CoCrFeNi dopant can significantly improve the plastic deformation capacity of the films. During the nanoindentation process, the spherical dopants reduce the stress and shear strain of the regions under the indenter in a-C films. The reduction of compressive and shear stresses in the film can inhibit the C atom metastable transition from sp2-C to sp3-C. This can provide a theoretical basis for the development and design of heavy-load and high-deformation-rate a-C films.

Folylpolyglutamate synthetase inactivation in relapsed ALL induces a druggable folate metabolic vulnerability.

AIMS: The antifolate methotrexate (MTX) is an anchor drug used in acute lymphoblastic leukemia (ALL) with poorly understood chemoresistance mechanisms in relapse. Herein we find decreased folate polyglutamylation network activities and inactivating FPGS mutations, both of which could induce MTX resistance and folate metabolic vulnerability in relapsed ALL. METHODS: We utilized integrated systems biology analysis of transcriptomic and genomic data from relapse ALL cohorts to infer hidden ALL relapse drivers and related genetic alternations during clonal evolution. The drug sensitivity assay was used to determine the impact of relapse-specific FPGS mutations on sensitivity to different antifolates and chemotherapeutics in ALL cells. We used liquid chromatography-mass spectrometry (LC-MS) to quantify MTX and folate polyglutamate levels in folylpoly-γ-glutamate synthetase (FPGS) mutant ALL cells. Enzymatic activity and protein degradation assays were also conducted to characterize the catalytic properties and protein stabilities of FPGS mutants. An ALL cell line-derived mouse leukemia xenograft model was used to evaluate the in vivo impact of FPGS inactivation on leukemogenesis and sensitivity to the polyglutamatable antifolate MTX as well as non-polyglutamatble lipophilic antifolate trimetrexate (TMQ). RESULTS: We found a significant decrease in folate polyglutamylation network activities during ALL relapse using RNA-seq data. Supported by functional evidence, we identified multifactorial mechanisms of FPGS inactivation in relapsed ALL, including its decreased network activity and gene expression, focal gene deletion, impaired catalytic activity, and increased protein degradation. These deleterious FPGS alterations induce MTX resistance and inevitably cause marked intracellular folate shrinkage, which could be efficiently targeted by a polyglutamylation-independent lipophilic antifolate TMQ in vitro and in vivo. CONCLUSIONS: MTX resistance in relapsed ALL relies on FPGS inactivation, which inevitably induces a folate metabolic vulnerability, allowing for an efficacious antifolate ALL treatment strategy that is based upon TMQ, thereby surmounting chemoresistance in relapsed ALL.

[Interaction Effects of Vegetation and Soil Factors on Microbial Communities in Alpine Steppe Under Degradation].

To clarify the regulating effect of vegetation and soil factors on microbial communities in the alpine steppe under degradation on the Qinghai-Xizang Plateau, the alpine steppe in the Sanjiangyuan area of the Qinghai-Tibet Plateau was chosen. We analyzed the differences in vegetation and soil factors in different stages of degradation （non-degradation, moderate degradation, and severe degradation） and detected the variations in microbial community characteristics in the alpine steppe under different degradation stages using high-throughput sequencing technology. Eventually, redundancy analysis （RDA） and multiple regression matrixes （MRM） based on the similarity or dissimilarity matrix were used to identify key environmental factors regulating microbial （bacterial and fungal） community changes under degradation. The results showed that the degradation of the alpine steppe significantly changed the community coverage, height, biomass, and important value of graminae； significantly reduced the contents of soil organic matter, total nitrogen, total phosphorus, and silt； and increased the soil bulk density and sand content. Degradation did not change the composition of bacteria and fungi, but their composition proportions changed and also resulted in the loss of microbial richness （Chao1 index and Richness index） but did not significantly change the microbial diversity （Shannon index）. With the occurrence of degradation, the vegetation characteristics, soil physicochemical properties, and microbial diversity showed a consistent change trend. Combined with the characteristics of the network topology changes （the number of nodes and clustering coefficient significantly decreased）, it was found that degradation of the alpine steppe led to the decline of interspecies interactions, decentralization of network, and homogenization of microorganisms, but the cooperation relations among the species were maintained （positive correlation connections accounted for more than 90% in all degradation stages）. Under the alpine steppe degradation, the vegetation-soil interaction had the greatest effect on soil bacterial community, whereas soil physicochemical properties had the greatest influence on soil fungal community. Specifically, vegetation community height, biomass, and soil bulk density were the mutual factors regulating soil microorganisms, whereas the vegetation Simpson index, important value of graminae, soil total phosphorus, total potassium, and silt content were the unique factors affecting the soil bacterial community, and soil pH and total nitrogen content were the particular factors affecting the soil fungal community.

Dietary effects of vitamin C on antioxidant capacity, intestinal microbiota and the resistance of pathogenic bacteria in cultured Silver pomfret (Pampus argenteus).

As most teleosts are unable to synthesize vitamin C, supplemental diets containing vitamin C diets play a crucial role in fish health. The aim of this study was to investigate the effect of dietary vitamin C on the intestinal enzyme activity and intestinal microbiota of silver pomfre (Pampus argenteus). Four experimental diets were supplemented with basic diets containing 300 mg of vitamin C/kg (group tjl3), 600 mg of vitamin C/kg (group tjl6), and 1200 mg of vitamin C/kg (group tjl12), as well as vitamin C-free supplemental basic diet (group tjl0), respectively. The four diets were fed to juvenile P. argenteus (average initial weight: 4.68 ± 0.93 g) for 6 weeks. The results showed that the activity of SOD (superoxide dismutase) and CAT (catalase) increased significantly while that of MDA (malondialdehyde) decreased significantly in group tjl3 compared to vitamin group tjl0. At the genus level, groups tjl0, tjl6, and tjl12 contained the same dominant microbial community, Stenotrophomonas, Photobacterium, and Vibrio, whereas group tjl3 was dominated by Stenotrophomonas, Delftia, and Bacteroides. Among the fish fed with a basic diet containing 300 mg of vitamin C/kg, the intestines exhibited a notable abundance of probiotic bacteria, including lactic acid bacteria (Lactobacillus) and Bacillus. The abundance of Aeromonas in groups tjl3 and tjl6 was lower than that of the vitamin C-free supplemental basic diet group, whereas Aeromonas was not detected in group tjl12. In addition, a causative agent of the disease outbreak in cultured P. argenteus, Photobacterium damselae subsp. Damselae (PDD) was the dominant microbiota community in groups tjl0, tjl6 and tjl12, whereas the abundance of PDD in group tjl3 was the lowest among the diets. Taken together, the diets supplied with vitamin C could influence the composition microbial community of P. argenteus. The low level of vitamin C (300 mg of vitamin C/kg per basic diet) supplementation could not only improve the antioxidant capacity but also resist the invasion of pathogenic bacteria.

Clinical characteristics of membranous nephropathy after allogeneic hematopoietic stem cell transplantation: A real-world multicenter study.

Membranous nephropathy (MN) is a rare complication that can occur after allogeneic hematopoietic stem cell transplantation (allo-HSCT). MN patients may develop nephrotic syndrome or even kidney failure, which greatly affects their quality of life and prognosis. However, current knowledge regarding MN after allo-HSCT is limited. Thus, a multicenter nested case‒control study was conducted. Patients who had been diagnosed with MN after allo-HSCT were retrospectively identified at 8 HSCT centers. A total of 51 patients with MN after allo-HSCT were included. The median age of MN patients after allo-HSCT was 38 years, and the median duration from HSCT to MN was 18 months. The use of HLA-matched donors (P = 0.0102) and peripheral blood as the graft source (P = 0.0060) were identified as independent predisposing risk factors for the onset of MN after allo-HSCT. Compared to those in the control group, the incidence of extensive chronic graft-versus-host disease was greater in the MN patients (P = 0.0002). A total of 31 patients developed nephrotic syndrome. Patients receiving combination treatments of corticosteroids and immunosuppressants appeared to have better outcomes. In conclusion, MN is a rare but occasionally severe complication following HSCT and may require active treatment.

An Energy Efficient and Temperature Stable Digital FLL-based Wakeup Timer with Time-Domain Temperature Compensation.

This brief presents an on-chip digital intensive frequency-locked loop (DFLL)-based wakeup timer with a time-domain temperature compensation featuring a embedded temperature sensor. The proposed compensation exploits the deterministic temperature characteristics of two complementary resistors to stabilize the timer's operating frequency across the temperature by modulating the activation time window of the two resistors. As a result, it achieves a fine trimming step (± 1 ppm), allowing a small frequency error after trimming (<± 20 ppm). By reusing the DFLL structure, instead of employing a dedicated sensor, the temperature sensing operates in the background with negligible power (2 %) and hardware overhead (< 1 %). The chip is fabricated in 40 nm CMOS, resulting in 0.9 pJ/cycle energy efficiency while achieving 8 ppm/ºC from -40ºC to 80ºC.

Effects of secondary cross-linking on the physicochemical properties of sodium alginate-hydrogel and in vitro release of anthocyanins.

To enhance the physicochemical properties and extend the release duration of sodium alginate (SA) hydrogels, this study explored the impact of acidifier type and the number of cross-linking on the physicochemical characteristics and in vitro anthocyanin release from SA hydrogels, utilizing calcium carbonate as the cross-linking agent. The findings revealed that the utilization of gluconolactone (GDL) as an acidifying agent in the preparation of SA hydrogels, as opposed to hydrochloric acid, resulted in a deceleration of the hydrolysis process of calcium carbonate. This deceleration led to the strengthening of hydrogen-bonding interactions and the development of a more compact network structure within the SA hydrogels. Consequently, there was a noticeable enhancement in the hardness, relaxation time, and anthocyanin encapsulation efficiency of the gels. Additionally, the release of anthocyanins in simulated intestinal fluid was delayed. Secondary cross-linking was found to facilitate ionic interactions between SA and Ca2+, further intensifying the denseness of the network structure and enhancing the physicochemical characteristics of the SA hydrogels. Overall, SA hydrogels processed with GDL as the acidifier and subjected to secondary cross-linking exhibited improved physicochemical properties, delayed release effects, and proved to be an efficient system for the delayed release of anthocyanins.

Effectiveness and Safety of Superimposed High-Frequency Jet Ventilation in Rigid Bronchoscopy: A Single-Center, Retrospective Study.

Introduction: Superimposed high-frequency jet ventilation (SHFJV) is a new type of jet ventilation, but its safety and effectiveness in rigid bronchoscopy have not been fully verified, especially in patients with airway stenosis and preoperative cardiovascular disease. This study is intended to retrospectively analyze the effectiveness and safety of SHFJV in the endobronchial treatment under rigid bronchoscopy. Methods: A total of 363 patients were included in this study. They were divided into 2 groups: Group A (n = 176)-presence of airway stenosis; Group B (n = 187)-absence of airway stenosis. Mean arterial pressure, heart rate, and pulse oxygen saturation were recorded before anesthesia and during the procedure. Arterial blood gases was recorded before anesthesia, at the end of the procedure and second-day postoperation respectively. The duration of procedure, extubation time, length of stay in the postanesthesia care unit (PACU), length of postoperative hospitalization, incidence of intraoperative and postoperative complications as well as 30 day mortality were also recorded. Results: All the patients had stable circulation during the procedure, including that with preoperative cardiovascular and pulmonary diseases. There were no substantial differences observed in terms of extubation time, PACU stay, and postoperative hospital days. Patients with severe preoperative airway stenosis exhibited longer procedure duration compared to those with mild to moderate stenosis, but there was no difference noted in terms of the extubation and PACU time. Conclusion: SHFJV is effective and safe in the endobronchial treatment for patients with airway stenosis and preoperative cardiovascular disease. It can serve as an ideal airway management strategy for rigid bronchoscopy.

Recombinant Art v4.01 protein produces immunological tolerance by subcutaneous immunotherapy in a wormwood pollen-driven allergic asthma female mouse model.

Art v4.01 is a well-known profilin protein belonging to the pan-allergens group and is commonly involved in triggering allergic asthma, polyallergy, and cross-sensitization. It is also referred to as Wormwood due to its origin. Crude wormwood extracts are applied for allergen-specific immunotherapy (AIT). Whether the recombinant Art v4.01 (rArt v4.01) can produce in vivo immunological tolerance by subcutaneous immunotherapy (SCIT) remains elusive. In this study, to investigate the in vivo immunological response of rArt v4.01, Th2, Th1, Treg, Th17 type-related cytokines and phenotypes of immune cells were tested, facilitating the exploration of the underlying mechanisms. The expression and purification of Art v4.01 were carried out using recombinant techniques. Allergic asthma female BALB/c mice were induced by subcutaneous sensitization of wormwood pollen extract and intranasal challenges. SCIT without adjuvant was performed using the rArt v4.01 and wormwood pollen extract for 2 weeks. Following exposure to challenges, the levels of immunoglobulin E (IgE), cytokines, and inflammatory cells were assessed through enzyme-linked immunosorbent assay (ELISA) and histological examination of sera, bronchoalveolar lavage fluid (BALF), and lung tissue. These parameters were subsequently compared between treatment groups receiving rArt v4.01 and wormwood pollen extract. The rArt v4.01 protein was expressed, which had a high purity (>90%) and an allergenic potency. Compared with the pollen extract, rArt v4.01 was superior in terms of reducing the number of white blood cells (WBCs), total nucleated cells (TNCs), and monocytes (MNs) in BALF and the degree of lung inflammation (1.77±0.99 vs. 2.31±0.80, P > 0.05). Compared with the model group, only rArt v4.01 reduced serum IgE level (1.19±0.25 vs. 1.61±0.17 µg/ml, P = 0.062), as well as the levels of Th2 type-related cytokines (interleukin-4 (IL-4) (107.18±16.17 vs. 132.47±20.85 pg/ml, P < 0.05) and IL-2 (19.52±1.19 vs. 24.02±2.14 pg/ml, P < 0.05)). The study suggested that rArt v4.01 was superior to pollen extract in reducing the number of inflammatory cells in BALF, pneumonitis, levels of pro-inflammatory cytokines, and serum IgE level. These findings confirmed that Art v4.01 could be a potential candidate protein for allergen-specific immunotherapy.

Denosumab ameliorates osteoarthritis by protecting cartilage against degradation and modulating subchondral bone remodeling.

Osteoarthritis (OA) is the most prevalent degenerative joint disease worldwide. Effective management for early-stage OA is crucial. Denosumab (DS) has been widely used to treat osteoporosis (OP) and rheumatoid arthritis, but its potential for managing OA remains clear. We assessed the effects of DS on osteoclast activity and chondrocyte apoptosis using tartrate-resistant acid phosphatase (TRAP) assay, quantitative real-time polymerase chain reaction (qRT-PCR), flow cytometry, and TUNEL staining. To assess the impact of DS on the NF-κB pathway, we performed Western blot and immunofluorescence staining. Additionally, we used an OA model to explore the influence of DS on subchondral bone remodeling and cartilage degeneration in vivo. We found that DS hindered receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis by inhibiting the activity of the NF-κB pathway. Besides, DS alleviated reactive oxygen species (ROS)-induced apoptosis in chondrocytes by regulating the expression of genes related to apoptosis. Moreover, we observed an attenuation of OA-related subchondral bone remodeling and cartilage degeneration in vivo. Our findings indicate that DS could effectively suppress osteoclast activity and chondrocyte apoptosis, thereby mitigating OA-related subchondral bone remodeling and cartilage degeneration. These results provide a mechanistic basis for using DS to treat OA.

Novel Metal-Free Synthesis of 3-Substituted Isocoumarins and Evaluation of Their Fluorescence Properties for Potential Applications.

A novel metal-free synthesis of 3-substituted isocoumarins through a sequential O-acylation/Wittig reaction has been established. The readily accessible (2-carboxybenzyl)-triphenylphosphonium bromide and diverse chlorides produced various 1H-isochromen-1-one in the presence of triethylamine, employing sequential O-acylation and an intramolecular Wittig reaction of acid anhydride. Reactions using these facile conditions have exhibited high functional group tolerance and excellent yields (up to 90%). Moreover, the fluorescence properties of isocoumarin derivatives were evaluated at the theoretical and experimental levels to determine their potential application in fluorescent materials. These derivatives have good photoluminescence in THF with a large Stokes shift and an absolute fluorescence quantum yield of up to 14%.

Electrical impedance detects early stages of bone healing: An in vivo explanatory study of tibial fractures in rabbits.

Purpose: Healing after bone fracture is assessed by clinical examination and frequent radiographs, which expose patients to radiation and lack standardisation. This study aimed to explore electrical impedance patterns during bone healing using electrical impedance spectroscopy in 18 rabbits subjected to tibial fracture stabilised with an external fixator. Methods: Impedance was measured daily across the fracture site at a frequency range of 5 Hz to 1 MHz. Biweekly radiographs were analysed using modified anterior-posterior (AP) radiographic union score of the tibia (RUST). The animals were divided into three groups with different follow-up times: 1, 3 and 6 weeks for micro-computer tomography and mechanical testing. Results: A decreasing trend in impedance was observed over time for all rabbits at lower frequencies. Impedance closest to 5 Hz showed a statistically significant decrease over time, with greatest decrease occurring during the first 7 postoperative days. At 5 Hz, a statistically significant correlation was found between impedance and the modified AP RUST score and between impedance and bone volume fraction. Conclusions: This study showed that the electrical impedance can be measured in vivo at a distance from the fracture site with a consistent change in impedance over time and revealed significant correlation between increasing radiographic union score and decreasing impedance. Level of Evidence: Not applicable.

Discovery of LLC355 as an Autophagy-Tethering Compound for the Degradation of Discoidin Domain Receptor 1.

Discoidin domain receptor 1 (DDR1) is a potential target for cancer drug discovery. Although several DDR1 kinase inhibitors have been developed, recent studies have revealed the critical roles of the noncatalytic functions of DDR1 in tumor progression, metastasis, and immune exclusion. Degradation of DDR1 presents an opportunity to block its noncatalytic functions. Here, we report the discovery of the DDR1 degrader LLC355 by employing autophagosome-tethering compound technology. Compound LLC355 efficiently degraded DDR1 protein with a DC50 value of 150.8 nM in non-small cell lung cancer NCI-H23 cells. Mechanistic studies revealed compound LLC355 to induce DDR1 degradation via lysosome-mediated autophagy. Importantly, compound LLC355 potently suppressed cancer cell tumorigenicity, migration, and invasion and significantly outperformed the corresponding inhibitor 1. These results underline the therapeutic advantage of targeting the noncatalytic function of DDR1 over inhibition of its kinase activity.

R-Cut: Enhancing Explainability in Vision Transformers with Relationship Weighted Out and Cut.

Transformer-based models have gained popularity in the field of natural language processing (NLP) and are extensively utilized in computer vision tasks and multi-modal models such as GPT4. This paper presents a novel method to enhance the explainability of transformer-based image classification models. Our method aims to improve trust in classification results and empower users to gain a deeper understanding of the model for downstream tasks by providing visualizations of class-specific maps. We introduce two modules: the "Relationship Weighted Out" and the "Cut" modules. The "Relationship Weighted Out" module focuses on extracting class-specific information from intermediate layers, enabling us to highlight relevant features. Additionally, the "Cut" module performs fine-grained feature decomposition, taking into account factors such as position, texture, and color. By integrating these modules, we generate dense class-specific visual explainability maps. We validate our method with extensive qualitative and quantitative experiments on the ImageNet dataset. Furthermore, we conduct a large number of experiments on the LRN dataset, which is specifically designed for automatic driving danger alerts, to evaluate the explainability of our method in scenarios with complex backgrounds. The results demonstrate a significant improvement over previous methods. Moreover, we conduct ablation experiments to validate the effectiveness of each module. Through these experiments, we are able to confirm the respective contributions of each module, thus solidifying the overall effectiveness of our proposed approach.