Design, synthesis and biological evaluation of sulfonylurea derivatives as NLRP3 inflammasome inhibitors.

The NLRP3 inflammasome has been extensively studied in recent years and its aberrant activation can exacerbate inflammatory responses, contributing to various diseases. MCC950, a sulfonylurea drug, is a potent selective inhibitor of the NLRP3 inflammasome. However, its clinical development was halted due to hepatotoxicity, and studies have indicated significant reduction in activity among its metabolites. Building upon MCC950, we referenced substitution sites of NP3-146 for structural modifications aimed at addressing potential metabolism-related issues. Consequently, we synthesized a series of sulfonylurea derivatives. Ultimately, the optimized compound C4 exhibited a remarkable 80.39 % inhibition of IL-1ß at 2 µM, with an IC50 value of 0.805 µM. In conclusion, compound C4 shows potential as a lead compound and warrants further development as an anti-inflammatory NLRP3 inhibitor.

Effect of topical antibiotics on the prevention and management of wound infections: A meta-analysis.

A meta-analysis research was implemented to appraise the effect of topical antibiotics (TAs) on the prevention and management of wound infections (WIs). Inclusive literature research was performed until April 2023, and 765 interconnected researches were reviewed. The 11 selected researches included 6500 persons with uncomplicated wounds at the starting point of the research: 2724 of them were utilising TAs, 3318 were utilising placebo and 458 were utilising antiseptics. Odds ratio (OR) and 95% confidence intervals (CIs) were utilised to appraise the consequence of TAs on the prevention and management of WIs by the dichotomous approach and a fixed or random model. TAs had significantly lower WI compared with placebo (OR, 0.59; 95% CI, 0.38-0.92, p = 0.02) and compared with antiseptics (OR, 0.52; 95% CI, 0.31-0.88, p = 0.01) in persons with uncomplicated wounds (UWs). TAs had significantly lower WIs compared with placebo and antiseptics in persons with UWs. However, caution needs to be taken when interacting with their values because of the low sample size of some of the chosen researches and low number of researches found for the comparisons in the meta-analysis.

Mechanistic modelling of relative biological effectiveness of carbon ion beams and comparison with experiments.

Objective.Relative biological effectiveness (RBE) plays a vital role in carbon ion radiotherapy, which is a promising treatment method for reducing toxic effects on normal tissues and improving treatment efficacy. It is important to have an effective and precise way of obtaining RBE values to support clinical decisions. A method of calculating RBE from a mechanistic perspective is reported.Approach.Ratio of dose to obtain the same number of double strand breaks (DSBs) between different radiation types was used to evaluate RBE. Package gMicroMC was used to simulate DSB yields. The DSB inductions were then analyzed to calculate RBE. The RBE values were compared with experimental results.Main results.Furusawa's experiment yielded RBE values of 1.27, 2.22, 3.00 and 3.37 for carbon ion beam with dose-averaged LET of 30.3 keVµm-1, 54.5 keVµm-1, 88 keVµm-1and 137 keVµm-1, respectively. RBE values computed from gMicroMC simulations were 1.75, 2.22, 2.87 and 2.97. When it came to a more sophisticated carbon ion beam with 6 cm spread-out Bragg peak, RBE values were 1.61, 1.63, 2.19 and 2.36 for proximal, middle, distal and distal end part, respectively. Values simulated by gMicroMC were 1.50, 1.87, 2.19 and 2.34. The simulated results were in reasonable agreement with the experimental data.Significance.As a mechanistic way for the evaluation of RBE for carbon ion radiotherapy by combining the macroscopic simulation of energy spectrum and microscopic simulation of DNA damages, this work provides a promising tool for RBE calculation supporting clinical applications such as treatment planning.

A Three-Dimensional Surface-Adaptive Stretchable Sensor for Online Monitoring of Composite Materials Curing.

Recently, rigid sensors have been commonly applied to online monitoring of the core curing processes of composite materials to prevent both overcuring and under-curing. However, conventional rigid sensors are prone to causing cracks and bubbles in composite materials during the curing process, thereby affecting both the mechanical performance and the overall reliability of the materials. Herein, stretchable interdigital dielectric sensors with flexible substrates and electrodes are designed to conform to complex 3D surfaces, thus enabling embedded nondestructive monitoring of composite curing processes. The sensors obtained can endure 1000 cycles of bending from 0° to 180° and 1000 cycles of stretching at 30% strain while still conforming perfectly to complex 3D surfaces, thus overcoming the inability of traditional curing monitoring sensors to bend. Additionally, sensor integration with an electronic circuit enables real-time data collection and transmission, which makes the device more portable, compact, and lightweight. Moreover, after atmospheric exposure for 5 months, the unit sensitivity of the sensor decreased by only 0.1%, thus demonstrating its excellent reliability and stability. Furthermore, during curing monitoring of the complex three-dimensional surfaces of the Fendouzhe deep-sea submersible, the unit's sensitivity is close to that of conventional planar monitoring equipment, decreasing by only 0.4%. The proposed online nondestructive monitoring technology demonstrates high sensitivity, high monitoring accuracy, and high reliability during surface monitoring, thus enabling long-term curing monitoring under complex nonplanar conditions.

Study on Printability Evaluation of Alginate/Silk Fibroin/Collagen Double-Cross-Linked Inks and the Properties of 3D Printed Constructs.

In recent years, biological 3D printing has garnered increasing attention for tissue and organ repair. The challenge with 3D-printing inks is to combine mechanical properties as well as biocompatibility. Proteins serve as vital structural components in living systems, and utilizing protein-based inks can ensure that the materials maintain the necessary biological activity. In this study, we incorporated two natural biomaterials, silk fibroin (SF) and collagen (COL), into a low-concentration sodium alginate (SA) solution to create novel composite inks. SF and COL were modified with glycidyl methacrylate (GMA) to impart photo-cross-linking properties. The UV light test and 1H NMR results demonstrated successful curing of silk fibroin (SF) and collagen (COL) after modification and grafting. Subsequently, the printability of modified silk fibroin (RSFMA)/SA with varying concentration gradients was assessed using a set of three consecutive printing models, and the material's properties were tested. The research results prove that the addition of RSFMA and ColMA enhances the printability of low-concentration SA solutions, with the Pr values increasing from 0.85 ± 0.02 to 0.90 ± 0.03 and 0.92 ± 0.02, respectively, and the mechanical strength increasing from 0.19 ± 0.01 to 0.28 ± 0.01 and 0.38 ± 0.01 MPa; cytocompatibility has also been improved. Furthermore, rheological tests indicated that all of the inks exhibited shear thinning properties. CCK-8 experiments demonstrated that the addition of ColMA increased the cytocompatibility of the ink system. Overall, the utilization of SF and COL-modified SA materials as inks represents a promising advancement in 3D-printed ink technology.

Harnessing oriented arrangement of collagen fibers by 3D printing for enhancing mechanical and osteogenic properties of mineralized collagen scaffolds.

As the structural basis of connective and load-bearing tissues, collagen fibers with orientation play an important role in the mechanical properties and physiological and biochemical functions of the tissues, but viable methods for preparing scaffolds with highly oriented collagenous structure still need to be further studied. In this study, pure collagen was used as printing ink to 3D printing. Harnessing oriented collagen fiber structure by 3D printing for promoting mechanical and osteogenic properties of scaffolds. The scaffolds with different printed angles and thicknesses were prepared to fit the bone defect site and realize personalized customization. The orientation assembly of collagen fibers was promoted by shear force action of 3D printing, the regular arrangement of collagen fibers and stabilization of fiber structure were promoted by pH adjustment and glutaraldehyde cross-linking, and the collagen fibers were mineralized by cyclic mineralization method. The microscopic morphology of fiber arrangement in the scaffolds were investigated by scanning electron microscopy. Results demonstrated that collagen fibers were changed from non-oriented to oriented after 3D printing. And the tensile modulus of the scaffolds with oriented collagen fibers was nine times higher than that of the scaffolds with non-oriented fibers. Moreover, the effects of oriented collagen fibers on the proliferation, differentiation and mineralization of MC3T3-E1 cells were studied by CCK-8 assay, live/dead cell staining, alkaline phosphatase activity test, and Alizarin red staining. The results indicated that cell proliferation, differentiation and mineralization were significantly promoted by oriented collagen fibers, and the cells proliferated directionally in the direction of the fibers. Taken together, mineralized collagen fiber scaffolds with oriented collagen fibers have great potential in bone tissue engineering applications.

Benchmarking DNA Foundation Models for Genomic Sequence Classification.

The rapid advancement of DNA foundation language models has revolutionized the field of genomics, enabling the decoding of complex patterns and regulatory mechanisms within DNA sequences. However, the current evaluation of these models often relies on fine-tuning and limited datasets, which introduces biases and limits the assessment of their true potential. Here, we present a benchmarking study of three recent DNA foundation language models, including DNABERT-2, Nucleotide Transformer version-2 (NT-v2), and HyenaDNA, focusing on the quality of their zero-shot embeddings across a diverse range of genomic tasks and species through analyses of 57 real datasets. We found that DNABERT-2 exhibits the most consistent performance across human genome-related tasks, while NT-v2 excels in epigenetic modification detection. HyenaDNA stands out for its exceptional runtime scalability and ability to handle long input sequences. Importantly, we demonstrate that using mean token embedding consistently improves the performance of all three models compared to the default setting of sentence-level summary token embedding, with average AUC improvements ranging from 4.3% to 9.7% for different DNA foundation models. Furthermore, the performance differences between these models are significantly reduced when using mean token embedding. Our findings provide a framework for selecting and optimizing DNA language models, guiding researchers in applying these tools effectively in genomic studies.

LINC00511, a future star for the diagnosis and therapy of digestive system malignant tumors.

The digestive system malignant tumors (DSMTs), mainly consist of digestive tract and digestive gland tumors, become an inescapable culprit to hazard human health worldwide. Due to the huge hysteresis in the cognitive theories of DSMTs occurrence and progression, advances in medical technology have not improved the prognosis. Therefore, more studies on a variety of tumor-associated molecular biomarkers and more detailed disclosure on potential regulatory networks are urgently needed to facilitate the diagnostic and therapeutic strategies of DSMTs. With the development of cancer bioinformatics, a special type of endogenous RNA involved in multi-level cellular function regulation rather than encoding protein, is categorized as non-coding RNAs (ncRNAs) and becomes a hotspot issue in oncology. Among them, long non-coding RNAs (lncRNAs), transcription length > 200 nt, show obvious superiority in both research quantity and dimension compared to microRNAs (miRNAs) and circular RNAs (circRNAs). As a recently discovered lncRNA, LINC00511 has been confirmed to be closely associated with DSMTs and might be exploited as a novel biomarker. In the present review, the comprehensive studies of LINC00511 in DSMTs are summarized, as well as the underlying molecular regulatory networks. In addition, deficiencies in researches are point out and discussed. The Cumulative oncology studies provide a fully credible theoretical basis for identifying the regulatory role of LINC00511 in human DSMTs. LINC00511, proved to be an oncogene in DSMTs, might be defined as a potential biomarker for diagnosis and prognosis evaluation, as well as a rare therapeutic target.

NIMCE: A Gene Regulatory Network Inference Approach Based on Multi Time Delays Causal Entropy.

Gene regulatory networks (GRNs)are involved in various biological processes, such as cell cycle, differentiation and apoptosis. The existing large amount of expression data, especially the time-series expression data, provide a chance to infer GRNs by computational methods. These data can reveal the dynamics of gene expression and imply the regulatory relationships among genes. However, identify the indirect regulatory links is still a big challenge as most studies treat time points as independent observations, while ignoring the influences of time delays. In this study, we propose a GRN inference method based on information-theory measure, called NIMCE. NIMCE incorporates the transfer entropy to measure the regulatory links between each pair of genes, then applies the causation entropy to filter indirect relationships. In addition, NIMCE applies multi time delays to identify indirect regulatory relationships from candidate genes. Experiments on simulated and colorectal cancer data show NIMCE outperforms than other competing methods. All data and codes used in this study are publicly available at https://github.com/CSUBioGroup/NIMCE.

Expression and Significance of Cyclin-Dependent Protein Kinase 6 in Diffuse Large B-Cell Lymphoma.

Objective: To study the relationship between cyclin-dependent protein kinase 6 (CDK6) expression in diffuse large B-cell lymphoma (DLBCL) and the clinical biological behavior and prognosis. Methods: Data mining was performed using the Oncomine and The Cancer Genome Atlas (TCGA) databases to analyze the expression level of CDK6 in DLBCL. CDK6 alterations in DLBCL and related functional networks were analyzed with c-BioPortal and the Gene Set Enrichment Analysis was performed by using DAVID and FunRich software. In addition, screening for differential gene expression of CDK6 was done and enriched by using LinkedOmics. Finally, formalin-fixed and paraffin-embedded (FFPE) tissue samples from 102 patients with DLBCL were collected from the Department of Pathology, Shanxi Cancer Hospital (Taiyuan, Shanxi, China) from January 2015 through December 2020. All cases had complete clinical course records. Thirty cases of lymph node reactive hyperplasia tissues were used as controls. The expression of CDK6 in DLBCL tissues was detected by qRT­PCR and immunohistochemistry. Results: Bioinformatics analysis: The data showed that mRNA expression level and DNA copy number variations (CNVs) of CDK6 were significantly higher in DLBCL as compared to normal tissue (P ˂ 0.05). Based on C-BioPortal analysis, we speculated that amplification was the most common copy of CDK6 CNV in DLBCL. Through Gene Ontology (GO) analysis of these genes, it was found that the proteins were mainly located in the nucleus and cytoplasm. The biological interaction network of CDK6 alterations were found to participate primarily in the G1-S phase of the process. Analysis of LinkedOmics mRNA sequencing data showed that three genes were positively correlated with CDK6 expression: PSMD1, C2orf29 and ASB1. Through experimental verification, we found that CDK6 was overexpressed in DLBCL, and the expression of CDK6 mRNA and protein in DLBCL were positively correlated with Ann Arbor staging and IPI score (P<0.05), and negatively correlated with overall survival (P<0.001). Conclusion: Data mining results and experiments revealed and confirmed multi-level evidence for the importance of CDK6 in DLBCL; hence, CDK6 may be a potential marker in DLBCL. Thus, our study will perhaps lay the foundation for further research on the role of CDK6 in the genesis and development of DLBCL.

Deoxyelephantopin Suppresses Pancreatic Cancer Progression In Vitro and In Vivo by Targeting linc00511/miR-370-5p/p21 Promoter Axis.

Objectives: Deoxyelephantopin (DET) is a kind of natural active ingredient extracted from the Chinese herbal medicine Elephantopus scaber L. Many studies have revealed the potential antitumor effect on multiple malignancies. However, the detailed mechanism of its antitumor effect in pancreatic cancer remains unclear. Recently, studies have confirmed that noncoding RNA (ncRNA) plays an important regulatory role in malignancies. This research was performed to explore the relationship between ncRNA and DET-induced tumor inhibition in pancreatic cancer. Methods: Microarray profiling was applied to identify the candidate ncRNAs associated with DET-induced tumor inhibition. Quantitative real-time PCR was used to evaluate the expression of linc00511 in pancreatic cancer cells and tissues. The influence of DET on the cell proliferation, migration, and invasion was assessed by CCK-8, colony formation, wound healing, and Transwell assays. The relationship between lncRNAs, miRNAs, and p21 promoter region was analyzed by bioinformatics and verified by luciferase reporter gene and western blotting. The effect of linc00511 on nuclear translocation of miR-370-5p was explored by cytoplasmic and nuclear RNA purification. Moreover, the effect of DET on tumor growth and metastasis, and the prophylactic effect were investigated by establishing subcutaneous and lung metastatic tumor models. Results: Microarray assay indicated linc00511 was a potential target gene. The antitumor effect of DET in pancreatic cancer depended on downregulating linc00511 expression, and linc00511 might be an oncogene in pancreatic cancer. Silencing linc00511 enhanced the antitumor function of DET; conversely, linc00511 overexpression antagonized the DET cytotoxic effect. Additionally, miR-370-5p could bind to p21 promoter to exert the RNA activation and then promote p21 expression. P21 was a downstream gene of linc00511 and associated with pancreatic cancer progression. Linc00511 regulated p21 expression by blocking miR-370-5p nuclear translocation. Conclusions: To sum up, the present finding confirmed that DET suppressed the malignant biological behavior of pancreatic cancer via linc00511/miR-370-5p/p21 promoter axis.

[Clinical observation of acupotomy combined with warm needling for cervical spondylotic radiculopathy of qi and blood stagnation syndrome].

OBJECTIVE: To observe the clinical effect of acupotomy combined with warm needling on cervical spondylotic radiculopathy (CSR) of qi and blood stagnation syndrome. METHODS: A total of 90 CSR patients were randomly divided into an acupotomy group, a warm needling group and a combined treatment group, with 30 cases in each group. The patients in the acupotomy group were treated with acupotomy, once every 7 days, consecutively for 3 times. The patients in the warm needling group received warm needling, once daily, at the interval of 2 days after consecutive treatments for 5 days, 7 days as one session of treatment and 3 consecutive sessions were required. The patients in the combined treatment group were treated with acupotomy and warm needling, and the methods and the treatment session were same as the the previous two groups. Before and after the treatment, the pain rating index (PRI) of McGill pain questionnaire (MPQ) and the 20-point scale of CSR developed by Yasuhisa Tanaka (CSR20) were adopted in the assessment. The changes of clinical symptoms and functions of patients were observed and the clinical efficacy was assessed in each group. RESULTS: After the treatment, the PRI score was decreased (P<0.05) and the CSR20 score was increased (P<0.05) in the 3 treatment groups when compared with those before the treatment. After the treatment, compared with the acupotomy group and the warm needling group, the PRI score was decreased (P<0.05) and the CSR20 score was increased (P<0.05) in the combined treatment group. The total effective rate was 83.3% (25/30) in the acupotomy group, 76.7% (23/30) in the warm needling group and 93.3% (28/30) in the combined treatment group. The total effective rate in the combined treatment group was higher than those in the acupotomy group and the warm needling group (P<0.05). CONCLUSION: The combined treatment with acupotomy and warm needling may obviously improve the clinical symptoms and physical signs, e.g. pain and numbness in the patients with CSR of qi and blood stagnation syndrome. Its efficacy is remarkably higher than that of the simple application of acupotomy or warm needling.