Longitudinal Dynamic Relationships Between Videogame Use and Symptoms of Gaming Disorder and Depression Among Chinese Children and Adolescents.

Although previous studies have shown a close relationship between gaming disorder and depressive symptoms, few have measured normal videogame use, symptoms of gaming disorder, and depressive symptoms concurrently. The longitudinal dynamics between these variables remain unclear. This study used two demographic cohorts to examine the longitudinal relationship between gaming and depressive symptoms: children (n = 1513, 46.9% girls, Mage ± SD = 9.63 ± 0.58 years) and adolescents (n = 1757, 48.5% girls, Mage ± SD = 12.55 ± 0.70 years). Random intercept cross-lagged panel models (RI-CLPMs) were employed to distinguish between within- and between-person levels of gaming and depressive symptoms. The RI-CLPM results showed a stable link between symptoms of gaming disorder and depression at the between-person level for both children and adolescents. At the within-person level, among children, depressive symptoms positively predicted subsequent gaming disorder symptoms, but gaming disorder symptoms were not a significant predictor of depressive symptoms at this level. Among adolescents, there was no significant cross-lagged effect between symptoms of gaming disorder and depression at the within-person level. Additionally, there was no significant cross-lagged effect between normal videogame use and depressive symptoms in either cohort. These results highlight the different effects of normal videogame use and gaming disorder symptoms associated with depressive symptoms. The different effects on children and adolescents underscore the importance of considering the different developmental stages in the study of gaming and mental health outcomes.

BRCA1 secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance.

PARP inhibitor (PARPi) therapy has transformed outcomes for patients with homologous recombination DNA repair (HRR) deficient ovarian cancers, for example those with BRCA1 or BRCA2 gene defects. Unfortunately, PARPi resistance is common. Multiple resistance mechanisms have been described, including secondary mutations that restore the HR gene reading frame. BRCA1 splice isoforms △11 and △11q can contribute to PARPi resistance by splicing out the mutation-containing exon, producing truncated, partially functional proteins. However, the clinical impacts and underlying drivers of BRCA1 exon skipping are not fully understood.We analyzed nine ovarian and breast cancer patient derived xenografts (PDX) with BRCA1 exon 11 frameshift mutations for exon skipping and therapy response, including a matched PDX pair derived from a patient pre- and post-chemotherapy/PARPi. BRCA1 exon 11 skipping was elevated in PARPi resistant PDX tumors. Two independent PDX models acquired secondary BRCA1 splice site mutations (SSMs) that drive exon skipping, confirmed using qRT-PCR, RNA sequencing, immunoblotting and minigene modelling. CRISPR/Cas9-mediated disruption of splicing functionally validated exon skipping as a mechanism of PARPi resistance. SSMs were also enriched in post-PARPi ovarian cancer patient cohorts from the ARIEL2 and ARIEL4 clinical trials.Few PARPi resistance mechanisms have been confirmed in the clinical setting. While secondary/reversion mutations typically restore a gene's reading frame, we have identified secondary mutations in patient cohorts that hijack splice sites to enhance mutation-containing exon skipping, resulting in the overexpression of BRCA1 hypomorphs, which in turn promote PARPi resistance. Thus, BRCA1 SSMs can and should be clinically monitored, along with frame-restoring secondary mutations.

Mitochondria Transplantation to Bone Marrow Stromal Cells Promotes Angiogenesis During Bone Repair.

Angiogenesis is crucial for successful bone defect repair. Co-transplanting Bone Marrow Stromal Cells (BMSCs) and Endothelial Cells (ECs) has shown promise for vascular augmentation, but it face challenges in hostile tissue microenvironments, including poor cell survival and limited efficacy. In this study, the mitochondria of human BMSCs are isolated and transplanted to BMSCs from the same batch and passage number (BMSCsmito). The transplanted mitochondria significantly boosted the ability of BMSCsmito-ECs to promote angiogenesis, as assessed by in vitro tube formation and spheroid sprouting assays, as well as in vivo transplantation experiments in balb/c mouse and SD rat models. The Dll4-Notch1 signaling pathway is found to play a key role in BMSCsmito-induced endothelial tube formation. Co-transplanting BMSCsmito with ECs in a rat cranial bone defect significantly improves functional vascular network formation, and improve bone repair outcomes. These findings thus highlight that mitochondrial transplantation, by acting through the DLL4-Notch1 signaling pathway, represents a promising therapeutic strategy for enhancing angiogenesis and improving bone repair. Hence, mitochondrial transplantation to BMSCS as a therapeutic approach for promoting angiogenesis offers valuable insights and holds much promise for innovative regenerative medicine therapies.

JrPPO1/2 play distinct roles in regulating walnut fruit browning by different spatiotemporal expression and enzymatic characteristics.

Polyphenol oxidase (PPO) activity drives walnut fruit browning, but the roles of its only two-family genes, JrPPO1 and JrPPO2, remain unclear. This study explores the spatiotemporal expression and enzymatic characteristics of JrPPO1 and JrPPO2 in walnut. Treatment with the PPO activator CuSO4 and H2O2 accelerated fruit browning and up-regulated JrPPO1/2 expression, whereas treatment with the PPO inhibitor ascorbic acid delayed browning, down-regulating JrPPO1 and up-regulating JrPPO2 expression. Compared to mJrPPO1, mJrPPO2 can exhibited better enzyme activity at higher temperatures (47 °C) and in more acidic environments (pH 4.25). mJrPPO2 exhibited a higher substrate specificity over mJrPPO1, and the preferred substrates are catechol, chlorogenic acid, and epicatechin. Additionally, mJrPPO2 adapted better to low concentration of oxygen (as low as 1.0% O2) and slightly elevated CO2 levels compared to mJrPPO1. Subcellular localization and spatiotemporal expression patterns showed that JrPPO1 is only expressed in green tissues and located in chloroplasts, while JrPPO2 is also located in chloroplasts, partly associated with membranes, and is expressed in both green and non-green tissues. Silencing JrPPO1/2 with virus-induced gene silencing (VIGS) reduced fruit browning, maintained higher total phenols, and decreased MDA production. Notably, silencing JrPPO1 had a greater impact on browning than JrPPO2, indicating JrPPO1's greater contribution to PPO activity and fruit browning in walnut fruits. Consequently, JrPPO1 can be effectively regulated both at the molecular level and by manipulating environmental conditions, to achieve the objective of controlling fruit browning.

Hyaluronan Mediates Cold-Induced Adipose Tissue Beiging.

Adipose tissue beiging refers to the process by which beige adipocytes emerge in classical white adipose tissue depots. Beige adipocytes dissipate chemical energy and secrete adipokines, such as classical brown adipocytes, to improve systemic metabolism, which is beneficial for people with obesity and metabolic diseases. Cold exposure and ß3-adrenergic receptor (AR) agonist treatment are two commonly used stimuli for increasing beige adipocytes in mice; however, their underlying biological processes are different. Transcriptional analysis of inguinal white adipose tissue (iWAT) has revealed that changes in extracellular matrix (ECM) pathway genes are specific to cold exposure. Hyaluronic acid (HA), a non-sulfated linear polysaccharide produced by nearly all cells, is one of the most common components of ECM. We found that cold exposure significantly increased iWAT HA levels, whereas the ß3-AR agonist CL316,243 did not. Increasing HA levels in iWAT by Has2 overexpression significantly increases cold-induced adipose tissue beiging; in contrast, decreasing HA by Spam1 overexpression, which encodes a hyaluronidase that digests HA, significantly decreases cold-induced iWAT beiging. All these data implicate a role of HA in promoting adipose tissue beiging, which is unique to cold exposure. Given the failure of ß3-AR agonists in clinical trials for obesity and metabolic diseases, increasing HA could serve as a new approach for recruiting more beige adipocytes to combat metabolic diseases.

Study of liquid-phase mass transfer and residual stress in jet electrodeposition process with coaxial megasonic agitation.

The electrodeposition process confronts significant challenges arising from mass transfer limitation and residual stress. To address these issues, an innovative method, combining megasonic agitation with coaxial jet electrodeposition, is introduced. This approach aims to enhance mass transfer and mitigate residual stress. First, an electrodeposition nozzle device was designed, and the liquid-phase mass transfer during electrodeposition was analyzed through finite element simulation. Simulation results indicate that the mass transfer coefficient increases with rising megasonic power density. Notably, when the megasonic power density reached 20 W/cm2, the mass transfer coefficient increased from 0.45 × 10-7 m/s to 18.63 × 10-7 m/s, compared to electrodeposition without megasonic agitation. Secondly, electrodeposition experiments were conducted both with and without megasonic assistance. X-ray diffraction (XRD) was employed to measure the residual stress values of the electrodeposited layers. The results reveal that samples processed with megasonic assistance exhibit lower residual stress values compared to those without. Specifically, at a megasonic power density of 10 W/cm2, the residual stress was 94.3 MPa, representing a 37.7 % reduction compared to the residual stress of 151.5 MPa observed in samples without megasonic agitation. Overall, the findings demonstrate that coaxial megasonic agitation can effectively enhance the liquid-phase mass transfer capability during electrodeposition and reduce the residual stress of the electroplated layer. This innovative method presents a promising avenue for improving electrodeposition processes and achieving superior material properties.

Relationship between bullying victimization and murderous behaviors and impulsivity's mediating role: Evidence from Chinese early adolescents.

BACKGROUND: Evidence suggests a robust relationship between experiencing bullying victimization (BV) and engaging in murderous behaviors among adolescents. However, the potential mediating effect of impulsivity on the relationship between BV and murderous behaviors in early adolescents remains underexplored. METHODS: A total of 5724 adolescents, with a mean age of 13.5 years, were enrolled from three middle schools in Anhui Province, China. Participants completed self-report questionnaires detailing their experiences with bullying, impulsiveness, and murderous behaviors. To assess the relationship between BV and murderous behaviors, multivariate logistic regression and Poisson regression analyses were conducted. Mediation analysis was performed using structural equation modeling. RESULTS: After controlling for confounding factors, a positive association was found between experiencing BV and engaging in murderous behaviors (p < 0.05). Mediation analysis revealed a significant indirect effect of BV on the occurrence of murderous behaviors through impulsivity (indirect effect = 0.027, 95 % CI: 0.021, 0.033). BV appears to heighten levels of impulsivity, which in turn increases the likelihood of murderous behaviors. Additionally, sex-specific analysis indicated that impulsivity played a greater mediating role in the link between verbal and relational BV and murderous behaviors in females, while physical and cyber BV were more significant in males. CONCLUSIONS: Our findings underscore the necessity of early targeted interventions for adolescents experiencing BV and exhibiting high levels of impulsivity to mitigate their risk of engaging in murderous behaviors.

Effective amendment of cadmium in water and soil before and after aging of nitrogen-doped biochar: Preparation optimization, removal efficiency and mechanism.

Nitrogen-doped biochar (NBC) is a green material for remediating heavy metal pollution, but it undergoes aging under natural conditions, affecting its interaction with heavy metals. The preparation conditions of NBC were optimized using response surface methodology (RSM), and NBC was subjected to five different aging treatments to analyze the removal efficiency of Cd(II) and soil remediation capability before and after aging. The results indicated that NBC achieved optimal performance with a mass ratio of 5:2.43, an immersion time of 10.66 h, and a pyrolysis temperature of 900 °C. Aging diminished NBC's adsorption capacity for Cd(II) but did not change the main removal mechanism of monolayer chemical adsorption. Freeze-thaw cycles (FT), UV aging (L), and composite aging (U) treatments increased the proportion of bioavailable-Cd, and all aging treatments facilitated the conversion of potentially bioavailable-Cd to non-bioavailable-Cd. The application of NBC and five aged NBCs reduced the proportion of bioavailable-Cd in the soil through precipitation and complexation, increasing the proportion of non-bioavailable-Cd. Aging modifies the physicochemical properties of NBC, thus influencing soil characteristics and ultimately diminishing NBC's ability to passivate Cd in the soil. This study provides reference for the long-term application of biochar in heavy metal-contaminated environments.

Anaerobic degradation of pesticide wastewater: Improving sludge characteristics and reducing membrane fouling with combined tandem UASB+membrane system with high velocity settlers.

In this pilot study, a combined tandem UASB+membrane reactor (R2) with high velocity settlers was proposed for the treatment of pesticide wastewater at different hydraulic retention times (HRT) and compared with a control reactor (R1). The average COD removal efficiencies of the R2 at HRTs of 96, 72, and 48 h were 83.7 %, 82.8 %, and 74.2 %, which are 14 %, 17 %, and 21 % higher than those of the R1, respectively. Throughout the operation, the biogas production of R2 was 33 %, 19 % and 28 % higher than that of R1 at the same stage, respectively, and the methane yield of R2 (0.19-0.26 L CH4/gCODremoved) was improved by 10-17 % compared to that of R1. Mean α values (VFA/ALK) of 0.13∼0.22 indicated that R2 did not undergo acidification. R2 reduced the extracellular polymers (EPS) content in the attached sludge by 56-62 % compared to R1. It also successfully delayed membrane fouling rate by 19-22 %. The results demonstrate that the R2 has a high treatment capacity, stability, and methane recovery, while also effectively reducing membrane fouling.

DisenSemi: Semi-Supervised Graph Classification via Disentangled Representation Learning.

Graph classification is a critical task in numerous multimedia applications, where graphs are employed to represent diverse types of multimedia data, including images, videos, and social networks. Nevertheless, in the real world, labeled graph data are always limited or scarce. To address this issue, we focus on the semi-supervised graph classification task, which involves both supervised and unsupervised models learning from labeled and unlabeled data. In contrast to recent approaches that transfer the entire knowledge from the unsupervised model to the supervised one, we argue that an effective transfer should only retain the relevant semantics that align well with the supervised task. We introduce a novel framework termed in this article, which learns disentangled representation for semi-supervised graph classification. Specifically, a disentangled graph encoder is proposed to generate factorwise graph representations for both supervised and unsupervised models. Then, we train two models via supervised objective and mutual information (MI)-based constraints, respectively. To ensure the meaningful transfer of knowledge from the unsupervised encoder to the supervised one, we further define an MI-based disentangled consistency regularization between two models and identify the corresponding rationale that aligns well with the current graph classification task. Experiments conducted on various publicly available datasets demonstrate the effectiveness of our .

The Link Between Temporomandibular Disorders and Jaw Functional Limitations Among Chinese Adolescents.

BACKGROUND: Currently, there is still controversy surrounding the relationship between temporomandibular disorders (TMDs) symptoms and jaw functional limitations. We investigated the distribution of TMDs in senior high school students, including both the number and types of symptoms, and assessed their association with jaw functional limitations. Furthermore, we explored sex differences in these associations. METHODS: This study was conducted at a public high school in Hefei, Anhui Province, China, with data collected from September to October 2022. All subjects completed questionnaires assessing the anamnestic symptoms of TMDs and the Jaw Functional Limitation Scale (JFLS), and examinations were performed by trained dentists according to the Diagnostic Criteria for TMD. Data were analysed using the Kruskal-Wallis, Mann-Whitney U, and Chi-square tests. RESULTS: The mean age of the participants (N = 2890) was 17.2 ± 0.14 years and 38.9% were females (61.1% were males). Limitations in self-assessed jaw function were associated with the presence of TMDs (P < .05). Participants with more symptoms reported significantly high levels of functional limitations (P < .05). Compared to male adolescents, female adolescents more commonly experienced TMDs pain and tended to have more symptoms (P < .05). However, no sex differences were observed in most associations between TMDs and jaw functional limitations. CONCLUSION: TMDs-positive symptoms are common in adolescents. Female adolescents were more affected by TMDs symptoms than male adolescents. Individuals with more TMDs symptoms have greater jaw functional limitations.

Prediabetes and the risk of peripheral artery disease: a meta-analysis.

BACKGROUND: Peripheral artery disease (PAD) is a significant vascular condition that can lead to severe complications, including limb ischemia and cardiovascular events. This meta-analysis aims to evaluate the association between prediabetes, an intermediate state between normoglycemia and diabetes, and the risk of developing PAD. METHODS: A comprehensive search of PubMed, EMBASE, and Web of Science databases was conducted to identify relevant cohort studies up to April 12, 2024. Data extraction was performed independently by two reviewers, and any discrepancies were resolved by consensus. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated using a random-effects model to account for heterogeneity among studies. RESULTS: A total of eight cohort studies comprising 90133 participants were included in the meta-analysis. The pooled analysis revealed that individuals with prediabetes had a significantly higher risk of PAD compared to those with normoglycemia (RR = 1.27, 95% CI: 1.13-1.42, p < 0.001; I2 = 55%). Subgroup analyses indicated that the association was stronger in prediabetes defined by mildly elevated hemoglobin A1c (RR: 1.47) compared to those defined by impaired fasting glucose (RR: 1.21) or impaired glucose tolerance (RR: 1.17, p for subgroup difference < 0.001). In addition, a stronger association was observed for studies reporting clinically diagnosed PAD compared to studies that included asymptomatic PAD (RR: 1.32 versus 0.92, p for subgroup difference = 0.02). CONCLUSIONS: This meta-analysis demonstrates a significant association between prediabetes and an increased risk of PAD in generally community-derived population.

Recent research progress on tumour-specific responsive hydrogels.

Most existing hydrogels, even recently developed injectable hydrogels that undergo a reversible sol-gel phase transition in response to external stimuli, are designed to gel immediately before or after implantation/injection to prevent the free diffusion of materials and drugs; however, the property of immediate gelation leads to a very weak tumour-targeting ability, limiting their application in anticancer therapy. Therefore, the development of tumour-specific responsive hydrogels for anticancer therapy is imperative because tumour-specific responses improve their tumour-targeting efficacy, increase therapeutic effects, and decrease toxicity and side effects. In this review, we introduce the following three types of tumour-responsive hydrogels: (1) hydrogels that gel specifically at the tumour site; (2) hydrogels that decompose specifically at the tumour site; and (3) hydrogels that react specifically with tumours. For each type, their compositions, the mechanisms of tumour-specific responsiveness and their applications in anticancer treatment are comprehensively discussed.

The Characteristics of Coronary Artery Lesions in COVID-19 Infected Patients With Coronary Artery Disease: An Optical Coherence Tomography Study.

COVID-19 may predispose patients to cardiac injuries but whether COVID-19 infection affects the morphological features of coronary plaques to potentially influence the outcome of patients with coronary artery disease (CAD) remains unknown. By using optical coherence tomography (OCT), this study compared the characteristics of coronary plaque in patients with CAD with/without COVID-19 infection. The 206 patients were divided into 2 groups. The COVID-19 group had 113 patients between December 7, 2022, and March 31, 2023, who received OCT assessment after China decided to lift the restriction on COVID-19 and had a history of COVID-19 infection. The non-COVID-19 group had 93 patients without COVID-19 infection who underwent OCT before December 7, 2022. The COVID-19 group demonstrated a higher incidence of plaque ruptures (53.1% vs 38.7%, p = 0.039), erosions (28.3% vs 11.8%, p = 0.004), fibrous (96.5% vs 89.2%, p = 0.041) and diffuse lesions (73.5% vs 50.5%, p <0.001) compared with the non-COVID-19 group, whereas non-COVID-19 group exhibited a higher frequency of cholesterol crystals (83.9% vs 70.8%, p = 0.027), deep calcifications (65.6% vs 51.3%, p = 0.039) and solitary lesions (57.0% vs 34.5%, p = 0.001). Kaplan-Meier survival analysis revealed a significantly lower major adverse cardiac events-free probability in the COVID-19 group (91.6% vs 95.5%, p = 0.006) than in the non-COVID-19 group. In conclusion, OCT demonstrated that COVID-19 infection is associated with coronary pathological changes such as more plaque ruptures, erosions, fibrosis, and diffuse lesions. Further, COVID-19 infection is associated with a higher propensity for acute coronary events and a higher risk of major adverse cardiac events in patients with CAD.

Advances in biomaterials for oral-maxillofacial bone regeneration: spotlight on periodontal and alveolar bone strategies.

The intricate nature of oral-maxillofacial structure and function, coupled with the dynamic oral bacterial environment, presents formidable obstacles in addressing the repair and regeneration of oral-maxillofacial bone defects. Numerous characteristics should be noticed in oral-maxillofacial bone repair, such as irregular morphology of bone defects, homeostasis between hosts and microorganisms in the oral cavity and complex periodontal structures that facilitate epithelial ingrowth. Therefore, oral-maxillofacial bone repair necessitates restoration materials that adhere to stringent and specific demands. This review starts with exploring these particular requirements by introducing the particular characteristics of oral-maxillofacial bones and then summarizes the classifications of current bone repair materials in respect of composition and structure. Additionally, we discuss the modifications in current bone repair materials including improving mechanical properties, optimizing surface topography and pore structure and adding bioactive components such as elements, compounds, cells and their derivatives. Ultimately, we organize a range of potential optimization strategies and future perspectives for enhancing oral-maxillofacial bone repair materials, including physical environment manipulation, oral microbial homeostasis modulation, osteo-immune regulation, smart stimuli-responsive strategies and multifaceted approach for poly-pathic treatment, in the hope of providing some insights for researchers in this field. In summary, this review analyzes the complex demands of oral-maxillofacial bone repair, especially for periodontal and alveolar bone, concludes multifaceted strategies for corresponding biomaterials and aims to inspire future research in the pursuit of more effective treatment outcomes.

Novel identification of mixed infection of Lactococcus garvieae and Cryptocaryon irritans isolated from cultured Trachinotus ovatus in China.

Lactococcus garvieae has recently been identified and listed as one of the causative agents of hyperacute hemorrhagic sepsis in fish. In intensive recirculating aquaculture systems where there are high fish densities and minimal water changes, not only will it be conducive to the growth of bacteria, but Cryptocaryon irritans as a marine protozoan fish parasite is also prone to appear. This study reports the disease status of Trachinotus ovatus in an aquaculture area in Yangjiang City, Guangdong Province. Through the diagnosis of clinical symptoms of the diseased fish, identification of specific primers, 16s rRNA sequences phylogenetic tree analysis, physiological and biochemical identification, and observation of histopathological sections, the result of the experiment is that the mass death of T. ovatus is caused by a mixture of L. garvieae and C. irritants infections. Subsequently, regression infection experiments were performed to verify Koch's law. It was confirmed that the pathogen had strong virulence to T. ovatus. This is the first time that the co-infection of L. garvieae and C. irritans to T. ovatus was found in South China. The research results of this experiment have certain enlightenment significance for the epidemic trend of fish diseases in relevant sea areas.

Additive manufacturing of degradable metallic scaffolds for material-structure-driven diabetic maxillofacial bone regeneration.

The regeneration of maxillofacial bone defects associated with diabetes mellitus remains challenging due to the occlusal loading and hyperglycemia microenvironment. Herein, we propose a material-structure-driven strategy through the additive manufacturing of degradable Zn-Mg-Cu gradient scaffolds. The in situ alloying of Mg and Cu endows Zn alloy with admirable compressive strength for mechanical support and uniform degradation mode for preventing localized rupture. The scaffolds manifest favorable antibacterial, angiogenic, and osteogenic modulation capacity in mimicked hyperglycemic microenvironment, and Mg and Cu promote osteogenic differentiation in the early and late stages, respectively. In addition, the scaffolds expedite diabetic maxillofacial bone ingrowth and regeneration by combining the metabolic regulation effect of divalent metal cations and the hyperboloid and suitable permeability of the gradient structure. RNA sequencing further reveals that RAC1 might be involved in bone formation by regulating the transport and uptake of glucose related to GLUT1 in osteoblasts, contributing to cell function recovery. Inspired by bone healing and structural cues, this study offers an essential understanding of the designation and underlying mechanisms of the material-structure-driven strategy for diabetic maxillofacial bone regeneration.

Understanding nanoparticle-liver interactions in nanomedicine.

INTRODUCTION: Understanding the interactions between administered nanoparticles and the liver is crucial for developing safe and effective nanomedicines. As the liver can sequester up to 99% of these particles due to its major phagocytic role, understanding these interactions is vital for clinical translation. AREAS COVERED: This review highlights recent studies on nanoparticle-liver interactions, including the influence of nanoparticle physicochemical properties on delivery, strategies to enhance delivery efficiency by modulating liver Kupffer cells, and their potential for treating certain hepatic diseases. Additionally, we discuss how aging impacts the liver's phagocytic functions. EXPERT OPINION: While liver accumulation can hinder nanomedicine safety and effectiveness, it also presents opportunities for treating certain liver diseases. A thorough understanding of nanoparticle-liver interactions is essential for advancing the clinical application of nanomedicines.

3D-QSAR, Scaffold Hopping, Virtual Screening, and Molecular Dynamics Simulations of Pyridin-2-one as mIDH1 Inhibitors.

Isocitrate dehydrogenase 1 (IDH1) is a necessary enzyme for cellular respiration in the tricarboxylic acid cycle. Mutant isocitrate dehydrogenase 1 (mIDH1) has been detected overexpressed in a variety of cancers. mIDH1 inhibitor ivosidenib (AG-120) was only approved by the Food and Drug Administration (FDA) for marketing, nevertheless, a range of resistance has been frequently reported. In this study, several mIDH1 inhibitors with the common backbone pyridin-2-one were explored using the three-dimensional structure-activity relationship (3D-QSAR), scaffold hopping, absorption, distribution, metabolism, excretion (ADME) prediction, and molecular dynamics (MD) simulations. Comparative molecular field analysis (CoMFA, R2 = 0.980, Q2 = 0.765) and comparative molecular similarity index analysis (CoMSIA, R2 = 0.997, Q2 = 0.770) were used to build 3D-QSAR models, which yielded notably decent predictive ability. A series of novel structures was designed through scaffold hopping. The predicted pIC50 values of C3, C6, and C9 were higher in the model of 3D-QSAR. Additionally, MD simulations culminated in the identification of potent mIDH1 inhibitors, exhibiting strong binding interactions, while the analyzed parameters were free energy landscape (FEL), radius of gyration (Rg), solvent accessible surface area (SASA), and polar surface area (PSA). Binding free energy demonstrated that C2 exhibited the highest binding free energy with IDH1, which was -93.25 ± 5.20 kcal/mol. This research offers theoretical guidance for the rational design of novel mIDH1 inhibitors.

SLGA-YOLO: A Lightweight Castings Surface Defect Detection Method Based on Fusion-Enhanced Attention Mechanism and Self-Architecture.

Castings' surface-defect detection is a crucial machine vision-based automation technology. This paper proposes a fusion-enhanced attention mechanism and efficient self-architecture lightweight YOLO (SLGA-YOLO) to overcome the existing target detection algorithms' poor computational efficiency and low defect-detection accuracy. We used the SlimNeck module to improve the neck module and reduce redundant information interference. The integration of simplified attention module (SimAM) and Large Separable Kernel Attention (LSKA) fusion strengthens the attention mechanism, improving the detection performance, while significantly reducing computational complexity and memory usage. To enhance the generalization ability of the model's feature extraction, we replaced part of the basic convolutional blocks with the self-designed GhostConvML (GCML) module, based on the addition of p2 detection. We also constructed the Alpha-EIoU loss function to accelerate model convergence. The experimental results demonstrate that the enhanced algorithm increases the average detection accuracy (mAP@0.5) by 3% and the average detection accuracy (mAP@0.5:0.95) by 1.6% in the castings' surface defects dataset.