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Abstract Background Hepatocellular carcinoma (HCC) is the fifth most frequently diagnosed malignancy and the third leading cause of cancer death globally. T cells are significantly correlated with the progression, therapy and prognosis of cancer. Limited systematic studies regarding the role of T-cell-related markers in HCC have been performed. Methods T-cell markers were identified with single-cell RNA sequencing (scRNA-seq) data from the GEO database. A prognostic signature was developed with the LASSO algorithm in the TCGA cohort and verified in the GSE14520 cohort. Another three eligible immunotherapy datasets, GSE91061, PRJEB25780 and IMigor210, were used to verify the role of the risk score in the immunotherapy response. Results With 181 T-cell markers identified by scRNA-seq analysis, a 13 T-cell-related gene-based prognostic signature (TRPS) was developed for prognostic prediction, which divided HCC patients into high-risk and low-risk groups according to overall survival, with AUCs of 1 year, 3 years, and 5 years of 0.807, 0.752, and 0.708, respectively. TRPS had the highest C-index compared with the other 10 established prognostic signatures, suggesting a better performance of TRPS in predicting the prognosis of HCC. More importantly, the TRPS risk score was closely correlated with the TIDE score and immunophenoscore. The high-risk score patients had a higher percentage of SD/PD, and CR/PR occurred more frequently in patients with low TRPS-related risk scores in the IMigor210, PRJEB25780 and GSE91061 cohorts. We also constructed a nomogram based on the TRPS, which had high potential for clinical application. Conclusion Our study proposed a novel TRPS for HCC patients, and the TRPS could effectively indicate the prognosis of HCC. It also served as a predictor for immunotherapy.

Abstract Background The actin filament-associated protein (AFAP) family genes include AFAP1/AFAP-110, AFAP1L1 and AFAP1L2/XB130. Increasing evidence indicates these three AFAP family members participate in tumor progression, but their clinical significance and molecular mechanisms in gastric cancer (GC) remain unclear. Methods We first analyzed expression of AFAP family genes using public datasets and verified the results. The clinical significance of AFAP family genes in GC patients was also analyzed. In vitro and in vivo experiments were applied to explore the function of AFAP1L1. Enrichment analysis was used to explore potential molecular mechanisms. We then performed additional experiments, such as cell adhesion assay, co-immunoprecipitation and so on to confirm the downstream molecular mechanisms of AFAP1L1. Results Public data analyses and our verification both showed AFAP1L1 was the only AFAP family members that was significantly upregulated in GC compared with normal gastric tissues. Besides, only AFAP1L1 could predict poor prognosis and act as an independent risk factor for GC patients. In addition, AFAP1L1 promotes GC cells proliferation, migration, invasion in vitro and tumor growth, metastasis in vivo by inducing epithelial-to-mesenchymal transition (EMT). In terms of mechanism, AFAP1L1 interacts with VAV guanine nucleotide exchange factor 2 (VAV2) to activate Rho family GTPases CDC42, which finally promotes expression of integrin subunit alpha 5 (ITGA5) and activation of integrin signaling pathway. Conclusion AFAP1L1 promotes GC progression by inducing EMT through VAV2-mediated activation of CDC42 and ITGA5 signaling pathway, indicating AFAP1L1 may be a promising prognostic biomarker and therapeutic target for GC patients.

The transpalatal arch (TPA) is widely used in clinical orthodontics for various purposes. This article reviews the versatile clinical uses and mechanics of TPAs for clinical reference. Traditionally, TPA is conceived as an anchorage reinforcement device. However, the literature does not support the sole use of TPA for anchorage control. TPA, combined with other conventional anchorage means, can only provide sufficient anchorage in certain cases. As an adjunct to fixed appliance treatment, TPA can be applied for arch width maintenance, tooth alignment and habit braking to improve treatment efficiency and reduce side effects. Meanwhile, TPA can be used to provide active orthodontic forces for maxillary molars to move or rotate bilaterally and unilaterally in all three planes of space, especially on occasions where molar rotation and transverse discrepancy exist. A two-couple system is formed with a TPA connecting bilateral maxillary first molars, the mechanical analysis of which can improve the understanding of treatment mechanics and make tooth movement more predictable. In recent years, TPA has also been used in combination with temporary anchorage devices for maxillary molar intrusion and full arch mesialization or distalization. The combined use of TPA with TADs and maxillary skeletal expanders could be further investigated in the future.

Root position plays an important role in healthy, stable, and aesthetic orthodontic treatment. In the past, two-dimensional radiographic images were used to assess the accuracy and precision of tooth root positions. In recent years, the use of cone beam CT (CBCT) and its reconstructed images to measure the three-dimensional spatial position and angle of root position has become mainstream. The root position is mainly described by measuring the relationship between the root and adjacent structures in the buccolingual, vertical, and mesiodistal directions as well as the root angle. The thickness of the alveolar bone on the buccolingual side of the root represents the buccolingual position, the vertical height in the alveolar bone and the relationship between apex and maxillary sinus represents the vertical position, the interroot alveolar bone thickness represents the mesiodistal position of the root, and the root angle is mostly based on incisal mandibular plane angle, angulation, torque, and other angles in the traditional two-dimensional measurement. Fitting CBCT and digital model data can be used to monitor the relationship between root and alveolar bone during orthodontic treatment, but a more comprehensive, standardized three-dimensional tooth root position measurement method is required to make full use of the root data provided by CBCT to study the relative optimal position of the tooth root at different anatomical levels, which combines with computer technology to optimize the digital design of orthodontic diagnosis and treatment.

In recent years, artificial intelligence technology has developed rapidly and has been gradually applied to the fields of clinical image data processing, auxiliary diagnosis and prognosis evaluation. Research has shown that it can simplify doctors’ clinical tasks, quickly provide analysis and processing results, and has high accuracy. In terms of orthodontic diagnosis and treatment, artificial intelligence can assist in the rapid fixation of two-dimensional and three-dimensional cephalometric measurements. In addition, it is also widely used in the efficient processing and analysis of three-dimensional dental molds data, and shows considerable advantages in determining deciding whether orthodontic treatment needs tooth extraction, thus assisting in judging the stage of growth and development, orthodontic prognosis and aesthetic evaluation. Although the application of artificial intelligence technology is limited by the quantity and quality of training data, combining it with orthodontic clinical diagnosis and treatment can provide faster and more effective analysis and diagnosis and support more accurate diagnosis and treatment decisions. This paper reviews the current application of artificial intelligence technology in orthodontic diagnosis and treatment in the hope that orthodontists can rationally treat and use artificial intelligence technology in the clinic, and make artificial intelligence better serve orthodontic clinical diagnosis and treatment, so as to promote the further development of intelligent orthodontic diagnosis and treatment processes.

Deferred diabetic skin healing is an ever‐growing complication owing to the hyperglycemic microenvironment, which accelerates the generation of advanced glycated end products (AGEs) and provides a hotbed for pathogenic infection. Here, the H2S‐evolving bio‐heterojunction enzyme (BioHJzyme), which is consisted by MXene/FeS2 and glucose oxidase (GOx) is devised. It presents glutathione peroxidase (GPx)‐ and peroxidase (POD)‐mimetic antibacterial activity for anti‐pathogens and wound regeneration by AGEs depression. The GOx catalyzes glucose, resulting in reducing the bacterial nutrient and supplying H2O2. The POD‐mimetic activity of the BioHJzyme catalyzes the H2O2 to hydroxyl radical (•OH) with a turnover number of 4.45 × 10−1 s−1, while the GPx‐mimetic activity of it consumes glutathione for further •OH accumulation. The anti‐pathogens can be enhanced by near infrared laser (NIR) irradiation owing to the efficient separation of electron‐hole pairs originated from the heterostructure, which presents NIR‐activatable •OH and 1O2 production. Moreover, the BioHJzyme evolves H2S in acidic environment, acting as an H2S donor, which protects cells around the wound from oxidative damage and AGEs, rescues mitochondrial respiration, improves the extracellular matrix deposition and ameliorates dysfunction of fibroblasts for diabetic skin regeneration through TGF‐β/Smad pathway. The work provides a proof‐of‐concept for bacteria‐invaded diabetic wound regeneration via H2S‐evolving BioHJzyme. [ABSTRACT FROM AUTHOR]

Fibrous dysplasia (FD) is a disease caused by postzygotic activating mutations of GNAS (R201C and R201H) that encode the α-subunit of the Gs stimulatory protein. FD is characterized by the development of areas of abnormal fibroosseous tissue in the bones, resulting in skeletal deformities, fractures, and pain. Despite the well-defined genetic alterations underlying FD, whether GNAS activation is sufficient for FD initiation and the molecular and cellular consequences of GNAS mutations remains largely unresolved, and there are no currently available targeted therapeutic options for FD. Here, we have developed a conditional tetracycline (Tet)-inducible animal model expressing the GαsR201C in the skeletal stem cell (SSC) lineage (Tet-GαsR201C/Prrx1-Cre/LSL-rtTA-IRES-GFP mice), which develops typical FD bone lesions in both embryos and adult mice in less than 2 weeks following doxycycline (Dox) administration. Conditional GαsR201C expression promoted PKA activation and proliferation of SSCs along the osteogenic lineage but halted their differentiation to mature osteoblasts. Rather, as is seen clinically, areas of woven bone admixed with fibrous tissue were formed. GαsR201C caused the concomitant expression of receptor activator of nuclear factor kappa-B ligand (Rankl) that led to marked osteoclastogenesis and bone resorption. GαsR201C expression ablation by Dox withdrawal resulted in FD-like lesion regression, supporting the rationale for Gαs-targeted drugs to attempt FD cure. This model, which develops FD-like lesions that can form rapidly and revert on cessation of mutant Gαs expression, provides an opportunity to identify the molecular mechanism underlying FD initiation and progression and accelerate the development of new treatment options.

Motivation Genetic perturbations (e.g. knockouts, variants) have laid the foundation for our understanding of many diseases, implicating pathogenic mechanisms and indicating therapeutic targets. However, experimental assays are fundamentally limited by the number of measurable perturbations. Computational methods can fill this gap by predicting perturbation effects under novel conditions, but accurately predicting the transcriptional responses of cells to unseen perturbations remains a significant challenge. Results We address this by developing a novel attention-based neural network, AttentionPert, which accurately predicts gene expression under multiplexed perturbations and generalizes to unseen conditions. AttentionPert integrates global and local effects in a multi-scale model, representing both the nonuniform system-wide impact of the genetic perturbation and the localized disturbance in a network of gene–gene similarities, enhancing its ability to predict nuanced transcriptional responses to both single and multi-gene perturbations. In comprehensive experiments, AttentionPert demonstrates superior performance across multiple datasets outperforming the state-of-the-art method in predicting differential gene expressions and revealing novel gene regulations. AttentionPert marks a significant improvement over current methods, particularly in handling the diversity of gene perturbations and in predicting out-of-distribution scenarios. Availability and implementation Code is available at https://github.com/BaiDing1234/AttentionPert. [ABSTRACT FROM AUTHOR]

Objectives: Abnormal mechanical stress is the pivotal risk factor of temporomandibular joint osteoarthritis (TMJOA). This study investigated the pathogenic mechanism by which abnormal mechanical stress induced chondrocyte senescence. Materials and Methods: Cellular senescence was investigated in the rodent model of unilateral anterior crossbite and in the chondrocytes subjected to mechanical overloading in vitro. The effects of Yes‐associated protein (YAP) in chondrocyte senescence and its correlation with methyltransferase‐like 3 (METTL3) and N6‐methyladenosine (m6A) modification were evaluated. The role of m6A modification in chondrocyte senescence was determined. The therapeutic effects of m6A inhibition in TMJOA were investigated. Results: Senescent chondrocytes were accumulated in the mechanically induced TMJOA lesions in rats and mechanical overloading could trigger chondrocyte senescence in vitro. This mechanical stress‐induced cellular senescence was revealed to be mediated by YAP deficiency that promoted METTL3‐dependent m6A modification. Moreover, inhibition of m6A modification rescued chondrocyte senescence in vitro and in vivo, and suppressed TMJOA progression in rats. Conclusions: This study uncovered the underlying mechanism of mechanically induced senescence in TMJOA from the perspective of epitranscriptomics and revealed the therapeutic potential of m6A inhibition in TMJOA. [ABSTRACT FROM AUTHOR]