A Robust Pyrazolate Metal-Organic Framework for Efficient Catalysis of Dehydrogenative C-O Cross Coupling Reaction.

Construction of robust heterogeneous catalysts with atomic precision is a long-sought pursuit in the catalysis field due to its fundamental significance in taming chemical transformations. Herein, we present the synthesis of a single-crystalline pyrazolate metal-organic framework (MOF) named PCN-300, bearing a lamellar structure with two distinct Cu centers and one-dimensional (1D) open channels when stacked. PCN-300 exhibits exceptional stability in aqueous solutions across a broad pH range from 1 to 14. In contrast, its monomeric counterpart assembled through hydrogen bonding displays limited stability, emphasizing the role of Cu-pyrazolate coordination bonds in framework robustness. Remarkably, the synergy of the 1D open channels, excellent stability, and the active Cu-porphyrin sites endows PCN-300 with outstanding catalytic activity in the cross dehydrogenative coupling reaction to form the C-O bond without the "compulsory" ortho-position directing groups (yields up to 96%), outperforming homogeneous Cu-porphyrin catalysts. Moreover, PCN-300 exhibits superior recyclability and compatibility with various phenol substrates. Control experiments reveal the synergy between the Cu-porphyrin center and framework in PCN-300 and computations unveil the free radical pathway of the reaction. This study highlights the power of robust pyrazolate MOFs in directly activating C-H bonds and catalyzing challenging chemical transformations in an environmentally friendly manner.

Clinical evidence for efficacy of pembrolizumab in MSI-H and TMB-H advanced solid tumor: results from three cancer centers in China.

BACKGROUND: Pembrolizumab has been indicated in the treatment of solid tumors with high frequency microsatellite instability (MSI-H) or high tumor mutational burden (TMB-H); however, real-world data on the effectiveness of pembrolizumab with or without chemotherapy in this molecular subset remain limited. Our retrospective study evaluated the clinical efficacy and safety of pembrolizumab in treating advanced solid tumors with either MSI-H or TMB-H. METHODS: This retrospective study analyzed data from 116 patients with MSI-H or TMB-H advanced solid cancers who received pembrolizumab with or without chemotherapy regardless of treatment setting. We analyzed objective response rate (ORR) and progression-free survival (PFS). RESULTS: The top three cancer types were colorectal (48.6% MSI-H, 6.5% TMB-H), lung (15.4% MSI-H, 84.4% TMB-H), and gastric (15.4% MSI-H, 5.1% TMB-H). The ORR with pembrolizumab was 52.6%, including complete response (CR) observed in 8.6% (n = 10) of cases and partial responses (PR) in 43.9% (n = 51). Of the 93 patients who received first-line pembrolizumab, 52 patients achieved objective response (10 CR, 42 PR), with a median PFS of 14.0 months (95% confidence intervals [CI] 6.6-21.4). Of the 23 who received subsequent-line pembrolizumab, the ORR was 39.1%, disease control rate was 91.3%, and median PFS was 5.7 months (95% CI 3.9-7.5). Treatment-related adverse events were observed in 32 patients (27.6%), with no reported treatment-related fatal adverse events. CONCLUSION: Our study provides real-world evidence on the clinical effectiveness of pembrolizumab with or without chemotherapy in the treatment of patients with MSI-H and TMB-H advanced solid cancers.

Theoretical modeling and simulation of fiber Bragg grating sensor interrogator based on linear variable filter.

With the increasing frequency of aviation accidents in recent years, aircraft safety has received increasing attention. Aircraft operating condition detection is an important part of aviation safety. Fiber Bragg grating (FBG) sensors, with their excellent characteristics, enable online monitoring of aircraft operating conditions. However, the application of FBG sensors in aviation is currently limited because it is difficult for FBG sensor interrogators to meet the requirements of small size, light weight, and good vibration resistance in the aviation field. Therefore, this paper proposes a linear variable filter (LVF)-based FBG sensor interrogator to meet the requirements. An optical model of the interrogator is established. The parameters which determine the performances of the interrogator are analyzed and the design criteria are discussed. According to the requirements in the aviation field, the optical system of the interrogator is designed. The simulation results show that the LVF-based FBG sensor interrogation system has a bandwidth range of 90 nm (1505 nm-1595 nm), a resolution of 2 pm, and a capacity of 15 FBG sensors.

Engineering Covalent Organic Frameworks with Polyethylene Glycol as Self-Sustained Humidity-Responsive Actuators.

Regarding the global energy crisis, it is of profound significance to develop spontaneous power generators that harvest natural energy. Fabricating humidity-responsive actuators that can conduct such energy transduction is of paramount importance. Herein, we incorporate covalent organic frameworks with flexible polyethylene glycol to fabricate rigid-flexible coupled membrane actuators. This strategy significantly improves the mechanical properties and humidity-responsive performance of the actuators, meanwhile, the existence of ordered structures enables us to unveil the actuation mechanism. These high-performance actuators can achieve various actuation applications and exhibit interesting self-oscillation behavior above a water surface. Finally, after being coupled with a piezoelectric film, the bilayer device can spontaneously output electricity over 2 days. This work paves a new avenue to fabricate rigid-flexible coupled actuators for self-sustained energy transduction.

A Class of Rigid-Flexible Coupling Crystalline Crosslinked Polymers as Vapomechanical Actuators.

Fabricating mechanically responsive actuators that can efficiently convert external stimuli into mechanical work is of great significance for real-world applications. Herein, we rationally design a class of rigid-flexible coupling crystalline crosslinked polymers (CCPs) to fabricate vapomechanically responsive actuators. Interfacial condensation reactions of flexible macromers with rigid monomers afford a series of freestanding CCP membranes. Notably, it is the first example where crosslinked polymers show high crystallinity and porosity. Moreover, the CCP membranes exhibit good mechanical properties and interesting vapor-triggered actuation performance, which is reversible and repeatable. We find that the unusual polymer structures, high vapor sorption, and anisotropic membranes contribute to the directional deformation performance of the CCP actuators. The synthesis approach in this work provides new insights into the design and fabrication of smart materials for advanced applications.

Fabrication of Moisture-Responsive Crystalline Smart Materials for Water Harvesting and Electricity Transduction.

It is of profound significance with regard to the global energy crisis to develop new techniques and materials that can convert the chemical potential of water into other forms of energy, especially electricity. To address this challenge, we built a new type of energy transduction pathway (humidity gradients → mechanical work → electrical power) using moisture-responsive crystalline materials as the media for energy transduction. Single-crystal data revealed that a flexible zeolitic pyrimidine framework material, ZPF-2-Co, could undergo a reversible structural transformation (ß to α phase) with a large unit cell change upon moisture stimulus. Dynamic water vapor sorption analysis showed a gate-opening effect with a steep uptake at as low as 10% relative humidity (RH). The scalable green synthesis approach and the fast water vapor adsorption-desorption kinetics made ZPF-2-Co an excellent sorbent to harvest water from arid air, as verified by real water-harvesting experiments. Furthermore, we created a gradient distribution strategy to fabricate polymer-hybridized mechanical actuators based on ZPF-2-Co that could perform reversible bending deformation upon a variation of the humidity gradient. This mechanical actuator showed remarkable durability and reusability. Finally, coupling the moisture-responsive actuator with a piezoelectric transducer further converted the mechanical work into electrical power. This work offers a new type of moisture-responsive smart material for energy transduction and provides an in-depth understanding of the responsive mechanism at the molecular level.

H2S exposure induces cell death in the broiler thymus via the ROS-initiated JNK/MST1/FOXO1 pathway.

Hydrogen sulfide (H2S) is a common toxic gas in chicken houses that endangers the health of poultry. Harbin has a cold climate in winter, and the conflict between heat preservation and ventilation in poultry houses is obvious. In this study, we investigated the H2S content in chicken houses during winter in Harbin and found that the H2S concentration exceeded the national standard in individual chicken houses. Then, a model of H2S exposure was established in an environmental simulation chamber. We also developed a NaHS exposure model of chicken peripheral blood lymphocytes in vitro. Proteomics analysis was used to reveal the toxicology of thymus injury in broilers, the FOXO signaling pathway was determined to be significantly enriched, ROS bursts and JNK/MST1/FOXO1 pathway activation induced by H2S exposure were detected, and ROS played an important switch role in the JNK/MST1/FOXO1 pathway. In addition, H2S exposure-induced thymus cell death involved immune dysregulation. Overall, the present study adds data for H2S contents in chicken houses, provides new findings for the mechanism of H2S poisoning and reveals a new regulatory pathway in immune injury.

PARP inhibitor resistance: the underlying mechanisms and clinical implications.

Due to the DNA repair defect, BRCA1/2 deficient tumor cells are more sensitive to PARP inhibitors (PARPi) through the mechanism of synthetic lethality. At present, several PAPRi targeting poly (ADP-ribose) polymerase (PARP) have been approved for ovarian cancer and breast cancer indications. However, PARPi resistance is ubiquitous in clinic. More than 40% BRCA1/2-deficient patients fail to respond to PARPi. In addition, lots of patients acquire PARPi resistance with prolonged oral administration of PARPi. Homologous recombination repair deficient (HRD), as an essential prerequisite of synthetic lethality, plays a vital role in killing tumor cells. Therefore, Homologous recombination repair restoration (HRR) becomes the predominant reason of PARPi resistance. Recently, it was reported that DNA replication fork protection also contributed to PARPi resistance in BRCA1/2-deficient cells and patients. Moreover, various factors, such as reversion mutations, epigenetic modification, restoration of ADP-ribosylation (PARylation) and pharmacological alteration lead to PARPi resistance as well. In this review, we reviewed the underlying mechanisms of PARP inhibitor resistance in detail and summarized the potential strategies to overcome PARPi resistance and increase PARPi sensitivity.

Novel ratiometric electrochemical sensor for no-wash detection of fluorene-9-bisphenol based on combining CoN nanoarrays with molecularly imprinted polymers.

No-wash detection of small molecules in real samples has been attracting attention in the field of sensors including electroanalytical biosensors. Based on the direct electrochemical oxidation of fluorene-9-bisphenol (BHPF) on a CoN nanoarray electrode, we developed a ratiometric molecularly imprinted polymeric electrochemical (MIP-EC) sensor to realize no-wash detection of BHPF in serum and tap water. The CoN nanoarray in situ grown on carbon cloth (CC) served as the working electrode, which could load the electroactive toluidine blue (TB) and be modified by the MIPs. As the MIP concentration on the modified electrode surface was increased, the amount of BHPF exposed on the electrode surface increased and the amount of exposed TB decreased. Thus, the values of ΔITB and ΔIBHPF decreased and increased, respectively, with an increasing amount of BHPF. Therefore, a ratiometric strategy was established by using the value of ΔITB/ΔIBHPF as the instruction response to realize detection of BHPF with high sensitivity and reliability. The developed ratiometric MIP-EC sensor showed strong anti-interference ability, good detection reproducibility and stability towards no-wash detection of BHPF as shown from tests with real samples. This work can further provide theoretical and practical guidance for the detection of other familiar small molecules.

Comparison of Hospital Anxiety and Depression Scale (HADS) and Zung Self-Rating Anxiety/Depression Scale (SAS/SDS) in Evaluating Anxiety and Depression in Patients with Psoriatic Arthritis.

BACKGROUND: This study aimed to compare the Hospital Anxiety and Depression Scale (HADS) and the Zung Self-Rating Anxiety/Depression Scale (SAS/SDS) in evaluating anxiety and depression in psoriatic arthritis (PsA) patients. METHODS: A total of 70 PsA patients were enrolled. Demographic and clinical characteristics were collected after enrollment. HADS-A and SAS were used to evaluate the anxiety of PsA patients, while HADS-D and SDS were used to evaluate the depression of PsA patients. RESULTS: Similar results were observed in detecting the rate of anxiety by HADS-A and SAS (27.1 vs. 21.4%, p = 0.424), and there was no difference in classifying the severity of anxiety by HADS-A and SAS (p = 0.347). The Spearman test also disclosed that HADS-A score was positively associated with SAS score (p <0.001). The rates of depression were similar by HADS-D and SDS (27.1 vs. 40.0%; p = 0.108). However, different results were observed in grading the severity of anxiety by HADS-D and SDS (p = 0.009), and no correlation was observed between HADS-D and SDS scores (p = 0.138). The consumption of time for HADS assessment was shorter than that for SAS/SDS assessment (p < 0.001). In addition, a positive correlation of HADS-A score with patients' global assessment (PGA) (p = 0.022) and fatigue scores (p = 0.028) was discovered, and HADS-D score was positively associated with PGA score (p = 0.019). SAS or SDS score presented less correlation with clinical features of PsA patients, which illuminated that only SAS score was positively associated with duration of psoriasis (p = 0.030). CONCLUSION: HADS seems to be a better option for anxiety and depression assessment than SAS/SDS in PsA patients.

Electrochemical assay of ampicillin using Fe3N-Co2N nanoarray coated with molecularly imprinted polymer.

Self-supported Fe3N-Co2N nanoarray with high electric conductivity and large surface area was prepared for growth of MIPs and further constructing a sensitive and stable electrochemical sensor. For the evaluation of its performance, Fe3N-Co2N is used as sensing electrode material, and AMP is used as template molecule to construct the MIP electrochemical sensor. Under the optimized conditions, the developed MIPs electrochemical sensor detects AMP with a low detection limit of 3.65 × 10-10 mol L-1 and shows outstanding reproducibility and stability. When the MIPs electrochemical sensor was applied to detect AMP in milk samples via standard addition method, the recovery within 97.06-102.43% with RSD of 1.05-2.11% was obtained. The fabrication of MIPs electrochemical sensor is highly promising for sensitive and selective electrochemical measurement and food safety testing. This work can provide theoretical guidance for truly challenging problems. Graphical abstract Principle diagram of MIP-EC sensor for detecting AMP Molecular imprinted polymers (MIPs) are widely performed for construction of electrochemical (EC) sensors especially for detecting small molecules in complex environment. However, the large-scale and robust preparation of MIPs in situ on sensor platform limits their practical applications. We fabricated a MIPs EC sensor based on Fe3N-Co2N in situ grown on carbon cloth (CC) as the substrate platform (Fe3N-Co2N/CC) combining with MIPs as the target recognition element for the label-free detection of AMP. Under the optimal conditions, the developed MIPs EC sensor can detect AMP with a low detection limit of 3.65 × 10-10 mol L-1. When the AMP in milk is detected by the proposed EC sensor, it shows ideal results. Therefore, the use of self-supported Fe3N-Co2N nanoarray as the platform for the fabrication of MIPs EC sensors is highly promising for sensitive and selective EC measurement and point-of-care testing.

Humidity-Induced Self-Oscillating and Self-Healing Hypercrosslinked Metal-Organic Polyhedra Membranes.

Designing autonomously oscillating materials is highly desirable for emerging smart material fields but challenging. Herein, a type of hypercrosslinked metal-organic polyhedra (HCMOPs) membranes formed by covalent crosslinking of boronic acid-modified Zr-based MOPs with polyvinyl alcohol (PVA) are rationally designed. In these membranes, MOPs serve as high-connectivity nodes and provide dynamic borate bonds with PVA in hypercrosslinked networks, which can be broken/formed reversibly upon the stimulus of water vapor. The humidity response characteristic of HCMOPs promotes their self-oscillating and self-healing properties. HCMOP membranes can realize a self-oscillating property above the water surface even after loading a cargo that is 1.5 times the weight of the membrane due to the fast adsorption and desorption kinetics. Finally, the HCMOP actuator can realize energy conversion from mechanical energy into electricity when coupled with a piezoelectric membrane. This work not only paves a new avenue to construct MOP-polymer hybrid materials but also expands the application scopes of MOPs for smart actuation devices.

Study on the Efficacy and Potential Mechanism of Topical Shen Bai Hair Growing Decoction against Androgenetic Alopecia Based on Ultrahigh Performance Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometry and RNA-seq.

Androgenetic alopecia (AGA) is a major problem that can happen to people of all ages, leading to psychological problems, such as anxiety and depression. Topical Shen Bai hair growing decoction (TSBHGD) is based on the pathogenesis of AGA, combined with Traditional Chinese Medicine theory, improved by the Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital according to its clinical treatment experience. This study was designed to demonstrate the therapeutic efficacy of TSBHGD against AGA, analyze the chemical components of TSBHGD as well as the skin-retained and blood-retained components in mice after topical administration of TSBHGD, and clarify the mechanism of its therapeutic efficacy. It was demonstrated that TSBHGD could suppress TNF-α and IL-6 levels and improve pathological phenomena such as hair loss, reduced follicle density, and dermal thickness caused by testosterone solution. Totally 35 components were identified in TSBHGD extracts, 12 skin-retained components were identified in drug-containing skin, and 7 blood-retained components were identified in drug-containing plasma, according to ultrahigh performance liquid chromatography quadrupole time-of-flight mass spectrometry. Transcriptomic sequencing revealed that some of the genes in AGA mice had altered expression patterns, which could be reversed by TSBHGD. Through network pharmacology analysis, it was found that TSBHGD mainly regulated eight signaling pathways, among which the apoptosis signaling pathway ranked first with a significance of 0.00149. Finally, both Bcl-2 and Caspase family proteins in the apoptosis signaling pathway were examined by Western blot. It was confirmed that TSBHGD could inhibit the apoptosis level in AGA mice's skin tissue to exert an anti-AGA effect. This will facilitate the development of new-generation herbal compound formulas with precise efficacy and provide novel ideas for AGA therapy.

First-in-human phase I study of BEBT-109 in previously treated EGFR exon 20 insertion-mutated advanced non-small cell lung cancer.

BACKGROUND: BEBT-109 is an oral pan-mutant-selective inhibitor of epidermal growth factor receptor (EGFR) that demonstrated promising antitumor potency in preclinical models. METHODS: This first-in-human study was a single-arm, open-label, two-stage study. Phase Ia dose-escalation study evaluated the safety and pharmacokinetics of BEBT-109 in 11 patients with EGFR T790M-mutated advanced non-small cell lung cancer (aNSCLC). Phase Ib dose-expansion study evaluated the safety and efficacy of BEBT-109 in 18 patients with EGFR exon 20 insertion (ex20ins)-mutated treatment-refractory aNSCLC. The primary outcomes were adverse events and antitumor activity. Clinical trial registration number CTR20192575. FINDINGS: The phase Ia study demonstrated no dose-limiting toxicity, no observation of the maximum tolerated dose, and no new safety signals with BEBT-109 in the dose range of 20-180 mg/d, suggesting that BEBT-109 had an acceptable safety profile among patients with EGFR T790M-mutated aNSCLC. Plasma pharmacokinetics of BEBT-109 showed a dose-proportional increase in the area under the curve and maximal concentration, with no significant drug accumulation. The dose-expansion study demonstrated that BEBT-109 treatment was tolerable across the three dose levels. The three most common treatment-related adverse events were diarrhea (100%; 22.2% ≥Grade 3), rash (66.7%; 5.6% ≥Grade 3), and anemia (61.1%; 0% ≥Grade 3). The objective response rate was 44.4% (8 of 18). Median progression-free survival was 8.0 months (95% confidence intervals, 1.33-14.67). CONCLUSION: Preliminary findings showed that BEBT-109 had an acceptable safety profile and favorable antitumor activity in patients with refractory EGFR ex20ins-mutated aNSCLC. FUNDING: National Natural Science Foundation of China.

Clinical treatment patterns, molecular characteristics and survival outcomes of ROS1-rearranged non-small cell lung cancer: A large multicenter retrospective study.

BACKGROUND: Non-small cell lung cancer (NSCLC) harboring ROS1 rearrangements is a molecular subset that exhibits favorable responses to tyrosine kinase inhibitor (TKI) treatment than chemotherapy. This study investigated real-world treatment patterns and survival outcomes among patients with ROS1-rearranged advanced NSCLC. METHODS: We conducted a retrospective analysis of patients with ROS1-rearranged advanced NSCLC treated in four different hospitals in China from August 2018 to March 2022. The study analyzed gene fusion distribution, resistance patterns, and survival outcomes. RESULTS: ROS1 rearrangement occurs in 1.8 % (550/31,225) of our study cohort. CD74 was the most common ROS1 fusion partner, accounting for 45.8 %. Crizotinib was used in 73.9 % of patients in the first-line treatment, and an increased use of chemotherapy, ceritinib, and lorlatinib was seen in the second-line setting. Lung (43.2 %) and brain (27.6 %) were the most common sites of progression in first-line setting, while brain progression (39.2 %) was the most common site of progression in second-line. Median overall survival was 46 months (95 % confidence intervals: 39.6-52.4). First-line crizotinib use yielded significantly superior survival outcomes over chemotherapy in terms of progression-free (18.5 vs. 6.0; p < 0.001) and overall survival (49.8 vs. 37; p = 0.024). The choice of treatment in the latter line also had survival implications, wherein survival outcomes were better when first-line crizotinib was followed by sequential TKI therapy than first-line chemotherapy followed by TKI therapy. CONCLUSIONS: Our study provided insights into the real-world treatment, drug resistance patterns, and survival outcomes among patients with ROS1-rearranged NSCLC. This information serves as a valuable reference for guiding the treatment of this molecular subset of NSCLC.

Mesenchymal Stem Cells in Heterotopic Ossification in Ankylosing Spondylitis: A Bibliometric Study Based on CiteSpace and VOSViewer.

Background: Heterotopic ossification is a complication in the late stage of ankylosing spondylitis (AS), and involves abnormal osteogenesis by mesenchymal stem cells (MSC). Research activity in this area has been rapidly expanding, but there is a lack of bibliometric studies that summarize the progresses. Methods: We searched the Web of Science (WoS) for articles pertaining to the role of MSCs in heterotopic ossification in AS from the database inception to December 2022 and visualized the countries, authors, institutions, references, and keywords using CiteSpace 6.1.R6 and VOSViewer. Results: A total of 127 publications from 188 institutions were identified, with a trend for increasing number of articles per year. China published the largest number of literature, followed by the United States and France. There were 47 core authors. The most recent research in this area mainly focused on "osteogenic differentiation", "gene expression", "inflammation", "TNF-α" and "bone formation". Current research can be broadly summarized into two topics: abnormalities in the inflammatory microenvironment and abnormalities in the MSCs. Aberrant expression of a variety of surface proteins in MSCs predisposes these cells to undergo osteogenic differentiation, and pro-inflammatory cytokines in the inflammatory milieu stimulate osteogenic differentiation of MSCs. Conclusion: MSCs in heterotopic ossification in AS is a relatively new area of research. Research activities primarily consist abnormalities in the inflammatory microenvironment and abnormalities in the MSCs.

B cells intervention in inflammatory mechanism of ankylosing spondylitis: A visualization analysis for the past 20 years.

Ankylosing spondylitis (AS) is an autoimmune disease with complex inflammatory mechanism. The aim of this study is to apply the methods of bibliometrics and knowledge mapping to analyze the research trends and hot spots of B cells intervention in inflammatory mechanism of AS. Global published articles on B-cells intervention in inflammatory mechanism of AS were retrieved from the Web of Science (WOS) database from 2004 to 2023. CiteSpace 6.1.R6 software was used to conduct the visualization analysis of countries, authors, institutions, references and keywords in this field. A total of 359 related articles were collected. Since 2004, the number of articles published in the field of B cells intervention in inflammatory mechanism of AS has shown a fluctuating upward trend. The 29 core authors are part of a research group centered on Bowness, Paul and Breban, Maxime. The main research institutions are Anhui Med Univ and Charite. Co-citation analysis reveals that research in this field is currently focused on "intergenic region" and "bone mineral density." Keyword analysis shows that the current research hotspots and trends in this field mainly focus on the cellular immune mechanism, humoral immune mechanism and clinical application value of B cells intervention in inflammatory mechanism of AS. In the past 20 years, the research on the mechanism of B cells intervention in AS inflammation has focused on B cells intervention in AS inflammation through humoral and cellular immune mechanisms. The future research focus may tend to use B cells as a new therapeutic target for AS.

Reducing Interface Defects and Porosity of Adhesive Bonded Aluminum Alloy Joints via Ultrasonic Vibration.

The surface microstructure formed by physical or chemical modification is essential for the desired joint strength. However, defects in the bonding interface and adhesive can be found. Such defects decrease shear strength and durability. In this study, ultrasonic vibration was applied to liquid adhesive on the sandblasted aluminum alloy plates. With ultrasonic treatment, the joints obtained the compact bonding interfaces and lower porosity of the adhesive layer. The treatment improved the shear strength by 9.1%. After two weeks of hydrothermal aging, the shear strength of joints only sandblasted decreased drastically by 48.9%, while it was 14% for the joints with ultrasonic vibration. The cavitation effect in the adhesive was detected by the aluminum foil erosion method. The result showed that a great number of micro-jets generated by the cavitation effect have intensive impact on the bonding interface which provide the adhesive with powerful force to fill the micro-grooves. Another finding in this work is that bubbles were gathered in the adhesive away from the vibration area. This mechanism was successfully used to reduce the porosity of the adhesive layer of joints.

Integrating network pharmacology and experimental verification to explore the mechanism of Tripterygium wilfordii in ankylosing spondylitis.

OBJECTIVE: This study aimed to validate the mechanism of triptolide in treating ankylosing spondylitis (AS) through network pharmacology, molecular docking, and in vitro experiments. METHODS: We gathered AS-related genes using databases including DrugBank, OMIM, GeneCards, TTD and DisGeNET. TCMSP database was used to collect Tripterygium wilfordii (TWHF)-related data. Additionally, the potential targets of TWHF in treating AS were predicted by consulting databases such as Venny, String, Cytoscape, and Cytohubba. Subsequently, a protein-protein interaction network was created and the gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed by metascape database. After selecting the most active ingredient of TWHF, molecular docking was performed to confirm the predicted results. Furthermore, we explore the potential mechanism of the most active ingredient of TWHF in the treatment of AS in vitro. RESULT: By integrating the results of network pharmacological analysis, 62 genes were found to be strongly associated with AS, such as STAT3, TNF, MMP9, VEGFA, CXCL8, PTGS2, etc. Triptolide (TP) is one of the most active ingredients in TWHF. The enrichment analysis indicated that 292 biological processes and 132 signaling pathways were involved, with the T helper 17 cells cell differentiation pathway as the key pathway. TP was selected for molecular docking and in vitro experiments. The molecular docking results indicated that TP had excellent affinity with 6 key targets. Further, flow cytometry, cell counting assay, and ELISA demonstrated that the serum level of IL-17 was higher in AS patients compared to XXX, and 25 µg/mL TP was the optimal intervention concentration. RT-qPCR and Western blotting further verified that TP could inhibit the activation of RORγt and the JAK2/STAT3 signaling pathway. CONCLUSION: In conclusion, based on network pharmacology, molecular docking, and experimental verification in vitro, we proposed that the TP can inhibit the activation of RORγt and the JAK2/STAT3 signaling pathway and inhibit the differentiation of T helper 17 cells cells. The article provide a theoretical basis for further development and utilization of TWHF in AS management.

Integrated analysis of tumor microenvironment features to establish a diagnostic model for papillary thyroid cancer using bulk and single-cell RNA sequencing technology.

BACKGROUND: Characterizing tumor microenvironment using single-cell RNA sequencing has been a promising strategy for cancer diagnosis and treatment. However, a few studies have focused on diagnosing papillary thyroid cancer (PTC) through this technology. Therefore, our study explored tumor microenvironment (TME) features and identified potential biomarkers to establish a diagnostic model for papillary thyroid cancer. METHODS: The cell types were identified using the markers from the CellMarker database and published research. The CellChat package was conducted to analyze the cell-cell interaction. The SCEVAN package was used to identify malignant thyroid cells. The SCP package was used to perform multiple single-cell downstream analyses, such as GSEA analysis, enrichment analysis, pseudotime trajectory analysis, and differential expression analysis. The diagnostic model of PTC was estimated using the calibration curves, receiver operating characteristic curves, and decision curve analysis. RT-qPCR was performed to validate the expression of candidate genes in human papillary thyroid samples. RESULTS: Eight cell types were identified in the scRNA-seq dataset by published cell markers. Extensive cell-cell interactions like FN1/ITGB1 existed in PTC tissues. We identified 26 critical genes related to PTC progression. Further, eight subgroups of PTC tumor cells were identified and exhibited high heterogeneity. The MDK/LRP1, MDK/ALK, GAS6/MERTK, and GAS6/AXL were identified as potential ligand-receptor pairs involved in the interactions between fibroblasts/endothelial cells and tumor cells. Eventually, the diagnostic model constructed by TRPC5, TENM1, NELL2, DMD, SLC35F3, and AUTS2 showed a good efficiency for distinguishing the PTC and normal tissues. CONCLUSIONS: Our study comprehensively characterized the tumor microenvironment in papillary thyroid cancer. Through combined analysis with bulk RNA-seq, six potential diagnostic biomarkers were identified and validated. The diagnostic model we constructed was a promising tool for PTC diagnosis. Our findings provide new insights into the heterogeneity of thyroid cancer and the theoretical basis for diagnosing thyroid cancer.