High-Dimensional Unbalanced Binary Classification by Genetic Programming with Multi-Criterion Fitness Evaluation and Selection.

High-dimensional unbalanced classification is challenging because of the joint effects of high dimensionality and class imbalance. Genetic programming (GP) has the potential benefits for use in high-dimensional classification due to its built-in capability to select informative features. However, once data are not evenly distributed, GP tends to develop biased classifiers which achieve a high accuracy on the majority class but a low accuracy on the minority class. Unfortunately, the minority class is often at least as important as the majority class. It is of importance to investigate how GP can be effectively utilized for high-dimensional unbalanced classification. In this article, to address the performance bias issue of GP, a new two-criterion fitness function is developed, which considers two criteria, that is, the approximation of area under the curve (AUC) and the classification clarity (i.e., how well a program can separate two classes). The obtained values on the two criteria are combined in pairs, instead of summing them together. Furthermore, this article designs a three-criterion tournament selection to effectively identify and select good programs to be used by genetic operators for generating offspring during the evolutionary learning process. The experimental results show that the proposed method achieves better classification performance than other compared methods.

A comprehensive analysis of single-cell RNA transcriptome reveals unique SPP1+ chondrocytes in human osteoarthritis.

Osteoarthritis (OA) has become the most common degenerative disease in the world, which brings a serious economic burden to society and the country. Although epidemiological studies have shown that the occurrence of osteoarthritis is associated with obesity, sex, and trauma, the biomolecular mechanisms for the development and progression of osteoarthritis remain ambiguous. Several studies have drawn a connection between SPP1 and osteoarthritis. SPP1 was first found to be highly expressed in osteoarthritic cartilage, and later more studies have shown that SPP1 is also highly expressed in subchondral bone and synovial in OA patients. However, the biological function of SPP1 remains unclear. Single-cell RNA sequencing (scRNA-seq) is a novel technique that reflects gene expression at the cellular level, making it better depict the state of different cells than ordinary transcriptome data. However, most of the existing chondrocyte scRNA-seq studies focus on the occurrence and development of OA chondrocytes and lack analysis of normal chondrocyte development. Therefore, to better understand the mechanism of OA, scRNA-seq analysis of a larger cell volume containing normal and osteoarthritic cartilage is of great importance. Our study identifies a unique cluster of chondrocytes characterized by high SPP1 expression. The metabolic and biological characteristics of these clusters were further investigated. Besides, in animal models, we found that the expression of SPP1 is spatially heterogeneous in cartilage. Overall, our work provides novel insight into the potential role of SPP1 in OA, which sheds light on understanding the role of SPP1 in OA, promoting the progress of the treatment and prevention in the field of OA.

Infiltration of LPAR5+ macrophages in osteosarcoma tumor microenvironment predicts better outcomes.

Introduction: Tumor microenvironment (TME) has been shown to be extensively involved in tumor development. However, the dynamic change of TME components and their effects are still unclear. Here, we attempted to identify TME-related genes that could help predict survival and may be potential therapeutic targets. Methods: Data was collected from UCSC Xena and GEO database. ESTIMATE and CIBERSORT algorithms were applied to estimate the components and the proportions of TIICs in TME. We analyzed the gene expression differences of immune components and stromal components, respectively, and finally got the overlapped DEGs. Through protein-protein interaction (PPI) network and univariate Cox regression analysis based on shared DEGs, we screened out and validated the TME-related genes. Focusing on this gene, we analyzed the expression and prognostic value of this gene, and investigated its relationship with immune cells by correlation analysis, single cell analysis, immunohistochemistry and immunofluorescence analysis. Results: Through a series analysis, we found that the proportion of immune and stromal components was an important prognostic factor, and screened out a key gene, LPAR5, which was highly correlated with prognosis and metastasis. And the expression of LPAR5 was positively correlated with immune cells, especially macrophages, indicating LPAR5+ macrophages played an important role in tumor microenvironment of osteosarcoma. Meanwhile, the genes in LPAR5 high expression group were enriched in immune-related activities and pathways, and differentially expressed genes between LPAR5+ macrophages and LPAR5- macrophages were enriched in the biological processes associated with phagocytosis and antigen presentation. What' more, we found that LPAR5 was mainly expressed in TME, and high LPAR5 expression predicting a better prognosis. Conclusion: We identified a TME-related gene, LPAR5, which is a promising indicator for TME remodeling in osteosarcoma. Particularly, LPAR5+ macrophages might have great potential to be a prognostic factor and therapeutic target for osteosarcoma.

Chondroprotective and antiarthritic effects of galangin in osteoarthritis: An in vitro and in vivo study.

Osteoarthritis (OA) is a common degenerative joint disease blamed for pain and disability in the elderly. Galangin (GAL) is a natural flavonoid that exhibits anti-inflammatory properties in various inflammation diseases. However, the role of GAL in OA remains unclear. In this study, we investigate the role of GAL in the progress and development of OA in vitro and vivo. The results showed that IL-1ß exposure resulted in increased expression of iNOS, COX-2, MMP1, MMP3, MMP13 and ADAMTS5 in rat chondrocytes. However, co-treatment with GAL significantly decreased theses inflammatory cytokines and catabolic factors expression. In addition, GAL reduced IL-1ß-induced degradation of collagen II and aggrecan in chondrocytes. Furthermore, GAL significantly suppressed IL-1ß-induced Akt phosphorylation and NF-κB activation in rat chondrocytes. In vivo, intra-articular injection of GAL could also reduce the cartilage degradation in the ACLT rat model. This study reveals galangin may act as a promising novel agent in the treatment of OA.

Selective STAT3 Inhibitor Alantolactone Ameliorates Osteoarthritis via Regulating Chondrocyte Autophagy and Cartilage Homeostasis.

Osteoarthritis (OA), which is identified by chronic pain, impacts the quality of life. Cartilage degradation and inflammation are the most relevant aspects involved in its development. Signal transducer and activator of transcription 3(STAT3), a member of the STATs protein family, is associated with inflammation. Alantolactone (ALT), a sesquiterpene lactone compound, can selectively suppress the phosphorylation of STAT3. However, the pharmacological effect of ALT on OA is still imprecise. In this study, IL-1ß (10 ng/ml) was applied to cartilage chondrocytes, which were treated with different concentrations of Alantolactone for 24 h. The expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2(COX2), matrix metalloproteinases (MMPs) and thrombospondin motifs-5 (ADAMTS5) were detected by western blot. Protein expression of Collagen Ⅱ was observed by western blot, safranin O staining and immunofluorescence. Manifestation of autophagy related proteins such as autophagy-related gene-5 (ATG5), P62, LC3Ⅱ/Ⅰ and PI3K/AKT/mTOR-related signaling molecules were measured by western blot and autophagic flux monitored by confocal microscopy. Expression of STAT3 and NF-κB-related signaling molecules were evaluated by western blot and immunofluorescence. In vivo, 2 mg/kg ALT or equal bulk of vehicle was engaged in the destabilization of medial meniscus (DMM) mouse models by intra-articular injection, the degree of cartilage destruction was classified by Safranin O/Fast green staining. Our findings reported that the enhance of inflammatory factors containing iNOS, COX2, MMPs and ADAMTS5 induced by IL-1ß could be ameliorated by ALT. Additionally, the diminish of Collagen Ⅱ and autophagy which was stimulated by IL-1ß could be alleviated by ALT. Mechanistically, STAT3, NF-κB and PI3K/AKT/mTOR signal pathways might be involved in the effect of ALT on IL-1ß-induced mouse chondrocytes. In vivo, ALT protected cartilage in the DMM mouse model. Overall, this study illustrated that ALT attenuated IL-1ß-induced inflammatory responses, relieved cartilage degeneration and promoted impaired autophagy via restraining of STAT3 and NF-κB signal pathways, implying its auspicious therapeutical effect for OA.

MCC950, the NLRP3 Inhibitor, Protects against Cartilage Degradation in a Mouse Model of Osteoarthritis.

Osteoarthritis (OA), characterized by chronic systemic low-level inflammation and cartilage degeneration, is a type of arthritis closely associated with aging. Inflammation and aging play a pivotal role in the occurrence and progression of OA. NLRP3 inflammasome is involved in many inflammatory and aging diseases, and NLRP3 inhibitor MCC950 has anti-inflammatory and antisenescence effects on some diseases such as Alzheimer's disease. In the present study, we found that NLRP3 protein was upregulated in human and mouse OA cartilage. Moreover, NLRP3 and Caspase1 expression induced by IL-1ß in chondrocytes was blocked by MCC950. In addition, MCC950 inhibited the expression of inflammatory mediators, matrix-degrading enzymes, senescence marker protein P16 (INK4A), and ß-galactosidase, as well as excessive production of ROS. Meanwhile, MCC950 promoted autophagy-related protein expression and autophagy flux under the inflammatory condition. However, autophagy inhibitor 3-MA reversed anti-inflammatory and anticatabolic effects of MCC950. In in vivo experiments, intra-articular administration of MCC950 further showed its protective effect on cartilage degeneration. Bioinformatic analysis and in vitro experimental results revealed that MCC950 might play a protective role in cartilage by regulating Nrf2/HO-1/NQO1, PI3k/Akt/mTOR, P38/MAPK, and JNK/MAPK pathways. In conclusion, our work demonstrated that NLRP3 inhibitor MCC950 might serve as a promising strategy for OA treatment.

Measurement of the sound velocity of shock compressed water.

The sound velocities of water in the Hugoniot states are investigated by laser shock compression of precompressed water in a diamond anvil cell. The obtained sound velocities in the off-Hugoniot region of liquid water at precompressed conditions are used to test the predictions of quantum molecular dynamics (QMD) simulations and the SESAME equation-of-state (EOS) library. It is found that the prediction of QMD simulations agrees with the experimental data while the prediction of SESAME EOS library underestimates the sound velocities probably due to its improper accounting for the ionization processes.