Membrane protein degradation is a cutting-edge field in targeted protein degradation (TPD). Herein, we developed glypican-3 (GPC3)-mediated lysosome-targeting chimeras (GLTACs) as a novel strategy for the targeted degradation of tumor-specific membrane proteins. GLTACs utilize tumor-specific expression and endocytosis properties of GPC3 to degrade membrane proteins. By conjugating a GPC3-targeting peptide with the ligand of protein of interest (POI), GLTACs induce the formation of a ternary complex that is internalized into lysosomes, leading to the degradation of the POI. The effectiveness and specificity of GLTACs were validated by designing PD-L1, c-Met, and FGFR1 degraders. In particular, GLTAC WP0 potently degraded PD-L1 and induced T-cell-mediated tumor killing against HepG2 cells, highlighting the potential therapeutic applications. The development of GLTAC technology expands the scope of TPD strategies and opens new avenues for discovering novel therapeutic modalities against challenging protein targets.

Loss-of-function variants in CSDE1 have been strongly linked to neuropsychiatric disorders, yet the precise role of CSDE1 in neurogenesis remains elusive. In this study, we demonstrate that knockout of Csde1 during cortical development in mice results in impaired neural progenitor proliferation, leading to abnormal cortical lamination and embryonic lethality. Transcriptomic analysis revealed that Csde1 upregulates the transcription of genes involved in the cell cycle network. Applying a dual thymidine-labelling approach, we further revealed prolonged cell cycle durations of neuronal progenitors in Csde1-knockout mice, with a notable extension of the G1 phase. Intersection with CLIP-seq data demonstrated that Csde1 binds to the 3' untranslated region (UTR) of mRNA transcripts encoding cell cycle genes. Particularly, we uncovered that Csde1 directly binds to the 3' UTR of mRNA transcripts encoding Cdk6, a pivotal gene in regulating the transition from the G1 to S phases of the cell cycle, thereby maintaining its stability. Collectively, this study elucidates Csde1 as a novel regulator of Cdk6, sheds new light on its critical roles in orchestrating brain development, and underscores how mutations in Csde1 may contribute to the pathogenesis of neuropsychiatric disorders.
Animals ; Neurogenesis/genetics* ; Cell Cycle/genetics* ; Mice, Knockout ; Mice ; Neural Stem Cells/metabolism* ; DNA-Binding Proteins/metabolism* ; Cyclin-Dependent Kinase 6/genetics* ; Cell Proliferation ; 3' Untranslated Regions ; Cerebral Cortex/embryology* ; RNA-Binding Proteins ; Mice, Inbred C57BL

Kirsten rat sarcoma viral oncogene homolog (KRAS) protein inhibitors are a promising class of therapeutics, but research on molecules that effectively penetrate the blood-brain barrier (BBB) remains limited, which is crucial for treating central nervous system (CNS) malignancies. Although molecular generation models have recently advanced drug discovery, they often overlook the complexity of biological and chemical factors, leaving room for improvement. In this study, we present a structure-constrained molecular generation workflow designed to optimize lead compounds for both drug efficacy and drug absorption properties. Our approach utilizes a variational autoencoder (VAE) generative model integrated with reinforcement learning for multi-objective optimization. This method specifically aims to enhance BBB permeability (BBBp) while maintaining high-affinity substructures of KRAS inhibitors. To support this, we incorporate a specialized KRAS BBB predictor based on active learning and an affinity predictor employing comparative learning models. Additionally, we introduce two novel metrics, the knowledge-integrated reproduction score (KIRS) and the composite diversity score (CDS), to assess structural performance and biological relevance. Retrospective validation with KRAS inhibitors, AMG510 and MRTX849, demonstrates the framework's effectiveness in optimizing BBBp and highlights its potential for real-world drug development applications. This study provides a robust framework for accelerating the structural enhancement of lead compounds, advancing the drug development process across diverse targets.

Objective:To evaluate the role of histogram analysis based on amide proton transfer weighted (APTw) and apparent diffusion coefficient (ADC) imaging in predicting alpha-thalassemia/mental retardation syndrome X-linked ( ATRX) mutation in isocitrate dehydrogenase ( IDH)-mutant WHO grading 2/3 gliomas. Methods:Seventy-eight patients with IDH-mutant WHO grading 2/3 gliomas, admitted to and confirmed by surgical pathology in Department of Functional Neurosurgery, Neurosurgery Center, Zhujiang Hospital, Southern Medical University from June 2017 to October 2023, including 52 with ATRX wild and 26 with ATRX mutant-type, were selected. Preoperative 3D-APTw and ADC imaging data were collected; after post-processing, the lesions were segmented using lesion outlining method based on inclusion of peri-tumor edema and lesion outlining method based on tumor entity, respectively; after that, the histogram features (the 10 th percentile, 90 th percentile, maximum, mean, median, minimum, skewness, kurtosis, entropy, range, uniformity, and variance) were extracted from 3D-APTw and ADC imaging, respectively. Univariate Logistic regression was used to compare the differences in histogram features between patients in the ATRX mutant group and ATRX wild-type group, and multivariate Logistic regression was used to screen the independent predictors for ATRX mutation (a Logistic regression prediction model was constructed). Predictive values of independent predictors and Logistic regression prediction models in ATRX mutation were evaluated by receiver operating characteristic (ROC) curve. Results:(1) With lesion outlining method based on inclusion of peri-tumor edema, univariate analysis indicated significant difference between ATRX mutant group and ATRX wild-type group in 9 histogram features: relative 3D-APTw minimum, 3D-APTw skewness, relative ADC 90 th percentile, relative ADC mean, relative ADC median, ADC kurtosis, ADC skewness, ADC uniformity, and ADC entropy ( P<0.05). With lesion outlining method based on tumor entity, univariate analysis indicated significant difference between ATRX mutant group and ATRX wild-type group in 9 histogram features: relative 3D-APTw 90 th percentile, 3D-APTw skewness, relative ADC 90 th percentile, relative ADC mean, relative ADC median, ADC kurtosis, ADC skewness, ADC uniformity and ADC entropy ( P<0.05). (2) With lesion outlining method based on inclusion of peri-tumor edema, multivariate Logistic regression showed that 3D-APTw skewness and ADC kurtosis were the independent predictor for ATRX mutation in IDH mutant WHO grading 2/3 glioma patients ( OR=0.168, 95% CI: 0.034-0.800, P=0.025; OR=0.508, 95% CI: 0.319-0.807, P=0.004). The constructed Logistic regression prediction model was P(Y=1|X)=1/1+e -(1.827-1.785×3D-APTw skewness-0.678×ADC kurtosis). With lesion outlining method based on tumor entity, multivariate Logistic regression showed that 3D-APTw skewness and ADC kurtosis were independent predictors for ATRX mutation in IDH mutant WHO grading 2/3 glioma patients ( OR=0.164, 95% CI: 0.034-0.791, P=0.024; OR=0.496, 95% CI: 0.312-0.788, P=0.003); the constructed Logistic regression prediction model was P(Y=1|X)=1/1+e -(1.585-1.810×3D-APTw skewness-0.702×ADC kurtosis). (3) ROC curve analysis showed that, with lesion outlining method based on inclusion of peri-tumor edema, area under ROC curve (AUC) of 3D-APTw skewness and ADC kurtosis was 0.725 (95% CI: 0.608-0.842, P=0.001) and 0.794 (95% CI: 0.685-0.904), respectively ( P<0.001); AUC of Logistic regression prediction model was 0.836 (95% CI: 0.729-0.942, P<0.001), and its sensitivity and specificity were 73.10% and 90.40% when the best threshold was 0.505. ROC curve showed that, with lesion outlining method based on tumor entity, AUC of 3D-APTw skewness and ADC kurtosis was 0.705 (95% CI: 0.587-0.823, P=0.003) and 0.808 (95% CI: 0.704-0.913), respectively ( P<0.001); AUC of Logistic regression prediction model was 0.844 (95% CI: 0.739-0.949, P<0.001), and its sensitivity and specificity were 84.60% and 80.80% when the best threshold was 0.399. Conclusion:Histogram analysis based on 3D-APTw and ADC imaging can predict ATRX mutation in IDH mutant WHO grading 2/3 gliomas to a certain extent.

Objective:To discuss the protective effect of ginsenoside Rh1(G-Rh1)on kidney injury in the diabetic mellitus(DM)mice,and to clarify its mechanism.Methods:The diabetic kidney disease(DKD)model was prepared by using the high-fat,high-sugar diet combined with intraperitoneal injection of streptozotocin(STZ).A total of 48 C57/BL6 model mice were randomly divided into model group,nuclear factor erythroid 2-related factor 2(Nrf2)inhibitor ML385 group(ML385 group)(30 mg·kg-1),G-Rh1 group(30 mg·kg-1),and G-Rh1+ML385 group(30 mg·kg-1 G-Rh1+30 mg·kg-1 ML385),and there were 12 mice in each group.Additionally,12 C57/BL6 mice were selected as control group.After treated for 8 weeks,automatic analyzer was used to detect the levels of fasting blood glucose(FBG),blood urea nitrogen(BUN),and serum creatinine(Scr)in serum of the mice in various groups,as well as 24 h urinary protein(24 h UP)levels in urine,and the kidney index was calculated;kits were used to detect the activities of superoxide dismutase(SOD)and lactate dehydrogenase(LDH),and the levels of malondialdehyde(MDA)in kidney tissue of the mice in various groups;Western blotting method was used to detect the expression levels of Nrf2 and heme oxygenase-1(HO-1)proteins in kidney tissue of the mice in various groups.Results:Compared with control group,the levels of FBG and kidney indexes in serum of the mice in model group,ML385 group,and G-Rh1+ML385 group were significantly increased(P<0.01),and the level of FBG in serum of the mice in G-Rh1 group was significantly increased(P<0.01);compared with model group,the kidney index of the mice in ML385 group was significantly increased(P<0.05),while the levels of FBG and kidney index of the mice in G-Rh1 group were significantly decreased(P<0.05 or P<0.01);compared with G-Rh1 group,the level of FBG and kidney index of the mice in G-Rh1+ML385 group were significantly increased(P<0.01).Compared with control group,the levels of BUN and Scr in serum,and 24 h UP in urine of the mice in model group,ML385 group,G-Rh1 group,and G-Rh1+ML385 group were significantly increased(P<0.01);compared with model group,the level of BUN in serum and 24 h UP in urine of the mice in ML385 group were significantly increased(P<0.05),while the levels of BUN and Scr in serum,and 24 h UP in urine of the mice in G-Rh1 group were significantly decreased(P<0.01);compared with G-Rh1 group,the levels of BUN and Scr in serum,and 24 h UP in urine of the mice in G-Rh1+ML385 group were significantly increased(P<0.01).Compared with control group,the activities of SOD in kidney tissue of the mice in model group,ML385 group,G-Rh1 group,and G-Rh1+ML385 group were significantly decreased(P<0.01),while the levels of MDA and LDH activities were significantly increased(P<0.01);compared with model group,the activity of SOD in kidney tissue of the mice in ML385 group was significantly decreased(P<0.05),and the level of MDA was significantly increased(P<0.05);the activity of SOD in kidney tissue of the mice in of G-Rh1 group was significantly increased(P<0.01),and the level of MDA and activity of LDH were significantly decreased(P<0.01);compared with G-Rh1 group,the activity of SOD in kidney tissue of the mice in G-Rh1+ML385 group was significantly decreased(P<0.01),and the level of MDA and activity of LDH were significantly increased(P<0.01).Compared with control group,the expression levels of Nrf2 and HO-1 proteins in kidney tissue of the mice in model group,ML385 group,G-Rh1 group,and G-Rh1+ML385 group were significantly decreased(P<0.05 or P<0.01);compared with model group,the expression levels of Nrf2 and HO-1 proteins in kidney tissue of the mice in ML385 group and G-Rh1+ML385 group were significantly decreased(P<0.05),while the expression levels of Nrf2 and HO-1 proteins in kidney tissue of the mice in G-Rh1 group were significantly increased(P<0.01);compared with G-Rh1 group,the expression levels of Nrf2 and HO-1 proteins in kidney tissue of the mice in G-Rh1+ML385 group were significantly decreased(P<0.01).Conclusion:Ginsenoside Rh1 reduces the oxidative stress and improves the kidney function,providing protective effects on kidney injury in the DM mice,and its mechanism may be related to the activation of the Nrf2/HO-1 signaling pathway.

Objective:To understand the current status of fear of falling in patients receiving maintenance hemodialysis and analyze the influencing factors.Methods:The convenient sampling method was used to select maintenance hemodialysis patients admitted to BenQ Hospital Affiliated to Nanjing Medical University from August to October 2022 as the research objects. A survey was conducted on patients using the general information questionnaire, modified falls efficacy scale (MFES), fatigue, resistance, ambulation, illness, loss of weight (FRAIL), and Braden Mobility Subscale.Results:A total of 219 questionnaires were sent out, and 219 were effectively collected, with an effective recovery rate of 100.00%. Among 219 patients with maintenance hemodialysis, 96 had fear of falling, and the incidence of fear of falling was 43.84%. Binary logistic regression analysis showed that age, type of kidney disease, fall history, and score of FRAIL were the influencing factors of fear of falling in patients with maintenance hemodialysis ( P< 0.05) . Conclusions:The incidence of fear of falling in patients with maintenance hemodialysis is relatively high. Age, diabetic nephropathy, history of falls, and frailty are the risk factors for fear of falling in patients with maintenance hemodialysis. Medical staff can develop targeted intervention measures for maintenance hemodialysis patients based on risk factors to reduce their fear of falling.

Schistosomiasis is a neglected zoonotic parasitic disease. Currently, praziquantel is the drug of choice for the treatment of schistosomiasis, and is the only effective chemical for treatment of schistosomiasis japonica. Since its introduction in the 1970s, praziquantel has been used for large-scale chemotherapy of schistosomiasis for over 40 years. However, there have been reports pertaining to the resistance to praziquantel in schistosomes. Therefore, development of novel antischistosomal agents as alternatives of praziquantel, is of great need. Histone deacetylases and histone acetyltransferases have been recently reported to play critical roles in the growth, development and reproduction of schistosomes, and are considered as potential drug targets for the treatment of schistosomiasis. This review summarizes the latest advances of histone deacetylase and histone acetyltransferase inhibitors in the research on antischistosomal drugs, so as to provide insights into research and development of novelantischistosomal agents.

Radiotherapy can cause functional and morphological changes in the brain tissues of patients with primary or metastatic malignant brain tumors, leading to radiation-induced brain injury. However, the pathogenesis of radiation-induced brain injury has not yet been unanimously determined, and its research advances and treatment protocols are yet to be elucidated and improved. In this study, we explore the pathogenesis of radiation-induced brain injury from the perspective of vascular injury, inflammatory reactions, neuronal dysfunction, glial cell injury, and gut microbiota and reviewed the advances in research on its treatment and prevention. The purpose is to provide a reference and theoretical basis for the research and clinical diagnosis and treatment of radiation-induced brain injury.

Objective To investigate the association between chewing ability and frailty in elderly adults in communities of China. Methods A total of 12, 678 elderly people in community were selected from data of Chinese Longitudinal Healthy Longevity and Happy Family Study(CLHLS-HF) as the study subjects. Multivariate Logistic regression analysis was used to explore the relationship between chewing ability and frailty of elderly people in community, and restricted cubic spline (RCS) based on Logistic regression analysis was used to analyze the dose-response relationship between the number of teeth and frailty risk in elderly people in community of China. Results Of the 12, 678 community-dwelling older adults, the mean age was (83.62±11.16) years, with an age ranging from 65 to 117 years; there were 5, 848 (46.1%) men and 6, 830 (53.9%) women. The Results of the multifactorial Logistic regression analysis showed that after adjusting for the covariates including gender, age, marital status, place of residence, ethnicity, living arrangement, years of education, healthcare availability and occupation before age of 60, self-rated economic status, body mass index (BMI), smoking status, alcohol consumption status, exercise status, self-rating health status variables, and participation in the annual medical check-ups or not, the Results showed that the chewing ability of community-dwelling older adults was associated with the risk of frailty (P < 0.05). The RCS plot showed a linear correlation between the number of natural teeth and the risk of frailty, with the risk of frailty increasing when the number of natural teeth was less than 10, and the risk of frailty gradually increased as the number of teeth decreased. Conclusion Chewing ability is associated with the risk of frailty in Chinese older adults, and the number of natural teeth and the use of dentures are important for the development of frailty in older adults.

Objective To analyze the dose distribution of induced radiation in fixed proton beam therapy room and the influence of shielding materials, and to provide a basis for radiation protection and shielding material selection in proton therapy. Methods FLUKA was used to simulate the dose distribution of induced radiation in fixed proton beam therapy room, the dose over time, and the influence of different concrete materials. Results The dose of induced radiation was mainly concentrated around the target, and the dose rapidly decreased to 1/5-1/10 of the value at the time of stopping irradiation after cooling for 3-5 min. The induced radiation in concrete formed a slightly higher dose area at the end of the main beam near the inner side of the shield. The content of Fe, O, and H in concrete had significant effects on induced radiation (P < 0.01), and the dose was negatively correlated with the content of Fe. Conclusion The patients after proton therapy as well as the induced radiation in air and shielding materials are the main sources of external radiation dose for workers, and waiting for a period of time is the most effective way to protect the staff. Without considering the difficulty in construction and based on the analysis of shielding materials in protection against external irradiation and their influence on induced radiation, heavy concrete with a relatively high level of Fe is the best choice of the shielding material for proton therapy room.