3CL protease (3CLpro) of SARS-CoV-2 is a pivotal enzyme required in coronavirus replication and transcription. Its highly conserved structure and the absence of homologous proteins in the host make it an ideal target for broad-spectrum anti-coronavirus drug development. In this work, we systematically investigated and compared the binding modes and dynamic properties of the four stereoisomers of a pyridyl-urea diyne ester (PyDU) molecule with two chiral centers within the 3CLpro active site. Through molecular docking, MD simulations, MM/GBSA binding free-energy calculations, and DCCM analysis, all four stereoisomers were stabilized primarily by hydrophobic packing. Among them, the (R,S) isomer exhibited the best overall performance, including docking score, binding free-energy components, and key residue interactions. The (R,S) and (S,R) isomers also enhanced the cooperative motions around the binding pocket, while the (R,S) isomer further modulated the flexibility of domain III, which may influence 3CLpro dimerization. Conversely, the (S,S) isomer exhibited the weakest affinity due to insufficient hydrophobic contact. By innovatively integrating chirality, binding energy and protein dynamical features, we revealed the dual role of chirality in modulating affinity and dynamic responses, which provides a theoretical basis for the chiral-guided design of coronavirus inhibitors.

Diabetic tendinopathy is a common and disabling musculoskeletal complication of diabetes, clinically characterized by tendon thickening, pain, impaired healing capacity and compromised biomechanical performance, collectively undermining joint function and quality of life. Its pathogenesis is multifactorial. On the one hand, chronic hyperglycaemia promotes the abnormal accumulation of advanced glycation end products (AGEs) within tendon collagen, leading to non-enzymatic crosslinking and engagement of the receptor for AGEs (RAGE), which in turn triggers inflammasome activation and sustains inflammatory responses. On the other hand, the diabetic milieu disrupts collagen metabolic homeostasis, impairs microvascular function and induces peripheral neuropathy; together, these alterations drive extracellular matrix degeneration and weaken the mechanical properties of tendon. Exercise, as a non-pharmacological intervention, can ameliorate these pathological changes through multiple integrated mechanisms. First, exercise attenuates tendon inflammation and restores microenvironmental homeostasis. Regular physical activity reduces AGE-RAGE signalling, thereby suppressing downstream expression of tumour necrosis factor (TNF) and interleukin-1β (IL-1β), while upregulating the anti-inflammatory cytokine interleukin-10 (IL-10). This shift from a pro-inflammatory to a pro-resolving milieu not only restrains chronic inflammation but may also limit excessive inflammasome activation in tenocytes and tissue-resident immune cells. Second, exercise enhances local expression of insulin-like growth factor 1 (IGF-1), thereby activating the phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt) signalling pathway. This axis stimulates tenocyte proliferation, augments synthesis of type I collagen —— the principal load-bearing component of tendon —— and thereby promotes tissue repair, preserves tensile strength and supports matrix synthesis and structural integrity. In addition, exercise improves blood supply and nutrient delivery to tendon by increasing the expression of vascular endothelial growth factor (VEGF), connective tissue growth factor (CTGF) and the small leucine-rich proteoglycan decorin (DCN), thereby enhancing capillary growth, coordinating collagen fibrillogenesis and actively suppressing pathological vascular calcification. Exercise also increases the expression of angiopoietin-like 4 (ANGPTL4), fibroblast growth factor 2 (FGF-2) and CD34. Through the concerted actions of these factors, exercise promotes angiogenesis, restores the microvascular network and ensures adequate oxygen and nutrient supply to relatively ischaemic tendon tissue. Finally, exercise elevates levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), supporting neuronal survival, axonal growth and the function of sensory and sympathetic nerve endings within tendon, thereby exerting neurotrophic and neuromodulatory effects and improving tendon innervation and neuromuscular control. Moreover, exercise upregulates collapsin response mediator protein 2 (CRMP-2), a molecule involved in axonal guidance and regeneration, and moderately increases the activity of substance P (SP), thereby helping to regulate neurogenic inflammation, pain perception and trophic support for tenocytes. Drawing together current evidence, this review systematically summarizes the mechanisms underlying diabetic tendinopathy and examines the mechanistic basis of exercise intervention, with the aim of providing a theoretical framework for the development of precise exercise strategies for affected individuals. However, several key issues remain unresolved: the therapeutic efficacy and mechanistic specificity of different exercise modalities in diabetic tendinopathy have yet to be defined, and early diagnostic biomarkers remain insufficiently characterized. Future studies should apply multi-omics approaches to profile AGE subtypes, miRNA signatures and collagen metabolic products, and should also clarify the adverse effects and underlying mechanisms of excessive exercise or mechanical overloading in diabetic tendinopathy. Such efforts will further elucidate the therapeutic effects and mechanisms of exercise in diabetic tendinopathy and provide a stronger basis for precision exercise prescription and fitness guidance in patients with diabetes.

Objective To explore the correlation of bilateral knee joint strength asymmetry with balance,walking ability,and motor function in hemiplegic stroke patients,providing a reference for clinical assessment of stroke patients.Methods A total of 46 hemiplegic stroke patients admitted to the Rehabilitation Medicine Department of People's Hospital of Shijiazhuang from February to December 2023 were selected.According to the Berg Balance Scale(BBS)scores,patients were divided into Group A(BBS score≤20,n=23)and Group B(BBS score>20,n=23).The peak torque and differences of bilateral knee flexors and extensors were compared between two groups.Isokinetic technology was used to assess the differences in peak torque of bilateral knee joints at 60°/s and 120°/s.BBS,Functional Ambulation Classification(FAC),and Fugl-Meyer Assessment of Lower Extremity(FMA-LE)were used to evaluate patients'balance,walking ability,and lower limb motor function.The correlation between bilateral knee joint peak torque and its difference with the scores of three functional scales was analyzed.Results The peak torque of knee flexors and extensors at 60°/s in group A was significantly lower than that in group B(P<0.05).At both 60°/s and 120°/s the differences in peak torque between the healthy and affected sides of knee flexors and extensors were greater than those in group B(P<0.05).At 60°/s,the difference in peak torque of bilateral knee extensors in hemiplegic stroke patients was negatively correlated with the scores of BBS,FAC,and FMA-LE(r=-0.569,-0.582,-0.606,P<0.01),as did the knee flexors(r=-0.534,-0.386,-0.458,P<0.05).At 120°/s,similar negative correlations were observed for both knee extensors(r=-0.304,-0.304,-0.443,P<0.05)and flexors(r=-0.337,-0.349,-0.370,P<0.05).Conclusions Bilateral knee joint strength asymmetry in hemiplegic stroke patients is negatively correlated with balance and walking ability.The difference in strength between the two sides of knee joint may be one of the clinical indicators for evaluating the motor function of stroke patients.

Pancreatic cancer is characterized by significant drug resistance,and despite continuous advancements in treatment regimens,the 5-year survival rate of patients remains low.The nuclear factor-κB(NF-κB)signaling pathway,frequently mutated in tumors,has been identified as a critical factor in triggering drug resistance.Multiple studies have demonstrated that strategies targeting NF-κB signaling transduction exhibit promising outcomes in pancreatic cancer treatment.Therefore,exploring the relationship between the NF-κB signaling pathway and drug resistance in pancreatic cancer has become a research hotspot in pancreatic cancer treatment.This review summarizes recent advances in the relationship between NF-κB signaling pathway and tumor drug resistance,as well as its role in pancreatic cancer treatment.Specifically,the mechanisms by which the NF-κB signaling pathway mediates drug resistance in pancreatic cancer are elaborated from two perspectives:chemotherapy and immunotherapy,aiming to provide insights for pancreatic cancer treatment and future research.

Lung cancer has the highest incidence and mortality among malignant tumors in China.Persistent subsolid nodules(SSNs)are closely associated with early-stage lung adenocarcinoma.Artificial intelligence(AI),as an emerging technology,is capable of performing in-depth analysis of large-scale imaging data through autonomous learning and possesses the ability to predict outcomes from new data,demonstrating great potential and application prospects in the assessment of SSNs.AI can not only effectively assist radiologists in diagnosis and treatment,but also improve work efficiency while reducing misdiagnosis and missed diagnosis rates.This review summarizes the recent applications and research progress of AI in the assessment of SSNs,to provide new insights for the diagnosis and treatment of SSNs.

A mounting body of research suggests that circRNAs significantly contribute to the develop-ment of myocardial fibrosis.The microarray results of human circular RNA expression profile indicated that circHERC4_041 expression increased in the myocardium of patients with heart failure,RT-qPCR a-nalysis confirmed that the myocardial expression level of circHERC4_041 in individuals with heart failure were considerably elevated compared to that in healthy organ donors.Fluorescence in situ hybridization(FISH)confirmed that circHERC4_041 was abundant in the cytoplasm of human cardiomyocyte AC16.Overexpression of circHERC4_041 in mouse myocardial fibroblasts(mCFs)mediated by adenovirus in-hibited the expression of fibrosis-related proteins in mCFs.Experiments involving cell proliferation,wound healing,and Transwell assays demonstrated that overexpression of circHERC4_041 suppressed the growth and mobility of mCFs(P＜0.001).Sequence analysis results suggested that circHERC4_041 con-tains potential ribosome entry sequence(IRES)and open reading frame(ORF).Western blot confirmed that circHERC4_041 could translate the 516 amino acid HERC4-516aa protein,which was mainly located in the cytoplasm of the cell.Cell functional experiments confirmed that circHERC4_041 inhibited the fi-brotic phenotype of mCFs by specifically translating HERC4-516aa(P＜0.05).The specific interaction between HERC4-516aa and transglutaminase 2(TGM2)was confirmed by IP-MS screening and Co-IP i-dentification.Further results found that the degradation of TGM2 was promoted through proteasome path-way.The overexpression of TGM2 in mCFs facilitated by adenoviral vectors could counteract the suppres-sive effects of HERC4-516aa on the fibrotic phenotype of mCFs.Therefore,this study confirmed that the HERC4-516aa protein translated by circHERC4_041 can specifically bind to TGM2 to inhibit the fibrotic phenotype of myocardial fibroblasts.

Objective:To investigate the role of SiHa cell-derived exosomal hsa-miR-29c-3p in the angiogenesis of cervical cancer(CC).Methods:Cancer tissue specimens from 45 patients with cervical squamous cell carcinoma(CSCC)and normal cervical tissue specimens from 15 controls were collected from Department of Gynecology,Hengyang Central Hospital from January 2019 to December 2021.CSCC SiHa cells and human umbilical vein endothelial cells(HUVECs)were routinely cultured.miRNA-NC,hsa-miR-29c-3p,si-miRNA-NC,and si-hsa-miR-29c-3p were transfected into SiHa cells with Lipofectamine 2000,grouped as miRNA-NC group,hsa-miR-29c-3p group,si-miRNA-NC group and si-hsa-miR-29c-3p group,respectively.HUVECs were transfected with mimic-NC,miR-29c-3p-mimic,pCMV-NC,and pCMV-ATAD2B(ATPase family protein 2B with AAA domain)using Lipofectamine 2000,grouped as the mimic-NC group,miR-29c-3p-mimic group,pCMV-NC group,pCMV-ATAD2B group,and pCMV-ATAD2B+miR-29c-3p-mimic group.The expression of hsa-miR-29c-3p in CSCC tissues was detected by in situ hybridization(ISH),and CD31-positive blood vessels in CSCC tissues and xenograft tissues were detected by immunohistochemistry(IHC).Exosomes from SiHa and C33a cells were isolated and characterized using transmission electron microscopy(TEM)and western blotting(WB).The uptake of exosomes by HUVECs was examined.The expression of hsa-miR-29c-3p and ATAD2B mRNA in SiHa and C33a cells,as well as in their derived exosomes,was detected using qPCR.Tube-forming assay,Transwell assay,and scratch healing assay were performed to detect the effect of exosomes on the ability of HUVEC migration and tube formation.Dual luciferase reporter gene assay verified the interaction between hsa-miR-29c-3p and ATAD2B.Xenograft experiments examined the effects of SiHa cell-derived exosomes on transplanted tumor growth and angiogenesis in each group.Results:hsa-miR-29c-3p was highly expressed in CSCC tissues and was positively correlated with microvessel density(MVD)(all P<0.05).Exosomes derived from SiHa and C33a cells exhibited typical exosomal morphology and protein expression patterns.Exosomal hsa-miR-29c-3p from SiHa and C33a cells were efficiently taken up by HUVECs in vitro.The SiHa cell-derived exosomal hsa-miR-29c-3p promoted not only the tube-forming and migration of HUVECs in vitro but also the xenograft growth and angiogenesis in vivo(all P<0.05).hsa-miR-29c-3p directly targeted ATAD2B and regulated its expression(P<0.05).Overexpression of ATAD2B reversed the promotive effect of hsa-miR-29c-3p on tube-formation,migration,and scratch-healing in HUVECs(all P<0.05).Conclusion:SiHa cell-derived exosomal hsa-miR-29c-3p regulates angiogenesis in CSCC tissues by targeting ATAD2B.Exosomal hsa-miR-29c-3p may be a potential diagnostic marker and therapeutic target for CC diagnosis and treatment.

Aim To explore the mechanisms of PM2.5 exposure exacerbating bleomycin(BLM)-induced idio-pathic pulmonary fibrosis(IFP)by regulating ferropto-sis via nuclear factor 2 related factor 2(Nrf2)/solute carrier family 7 member 11(SLC7A11)/glutathione peroxidase(GPX)4 axis.Methods Forty C57BL/6J mice were randomized into the control,BLM,PM2.5,BLM+PM2.5 and sulforaphane(SFN,Nrf2 agonist)groups,with eight mice in each group.PM2.5 expo-sures were conducted to the BLM-induced IPF mice for two weeks.The lung function was measured,and the content of hydroxyproline(HYP)in lung tissue and the pathomorphology of lungs were observed.Reactive oxygen species(ROS),malondialdehyde(MDA),ferrous ion(Fe2+)and glutathione(GSH)of the lung tissue were measured by ELISA.The mRNA and pro-teins levels of Nrf2,SLC7A11,GPX4,collagen typeⅠ(COL-1),α-smooth muscle actin(α-SMA)were measured by quantitative polymerase chain reaction(qPCR)and Western blot.Results Compared with the control group,the lung function of mice was signif-icantly reduced(P＜0.01)in the BLM and PM2.5 groups,while lung tissue showed the characteristic pathological changes of pulmonary fibrosis such as a large number of inflammatory cell infiltration,alveolar wall fracture,thickening,collagen deposition,and sig-nificantly increased HYP,Fe2+,ROS,MDA(P＜0.05,P＜0.01),genes and proteins of COL-1,α-SMA(P＜0.01);and decreased GSH,Nrf2,SLC7A11,GPX4 genes and proteins(P＜0.05,P＜0.01).The above-mentioned lesions were markedly aggravated in the BLM+PM2.5 group compared with the BLM(P＜0.05)and PM2.5 groups(P＜0.01),and were also improved in the SFN group(P＜0.05,P＜0.01).Conclusions PM2.5 exposures can exac-erbate IPF-induced IPF in mice,and the regulating of Nrf2/SLC7 A1 1/GPX4 axis and ferroptosis might be in-volved in the related mechanisms.

After the wooden shipwreck was recovered from the marine underwater environment,the wooden components undergo varying degrees of degradation,therefore,accurately determining the extent of degradation is a fundamental scientific issue for implementing effective preservation strategies.In this work,the wooden remains of Pinus massoniana excavated from the"Nanhai No.1"shipwreck(Southern Song Dynasty)were investigated and compared with the modern wood to discriminate the degradation levels of archaeological wood using attenuated total reflection Fourier transform infrared(ATR-FTIR)spectroscopy.The residual sugar content within wood cell walls was determined using a non-invasive automated microscale ATR-FTIR method to extract chemical information from the wood tangential section.Microstructural characterization of wood samples was conducted by super depth of field microscopy and scanning electron microscopy.FTIR spectral analysis was performed to evaluate the degradation state and elucidate changes in cellulose crystallinity.Finally,the combination of FTIR spectroscopy with the sparse partial least squares discriminant analysis(sPLS-DA)model facilitated the rapid discrimination of degradation levels in shipwreck archaeological wood,and the performance of the model was evaluated using receiver operating characteristic(ROC)curves and area under the curve(AUC).The results showed that the higher the degree of wood degradation,the lower the residual sugar content in the wood cell wall,and the residual glucose content of highly degraded wood was only 4.7％.Significant differences were observed in both the tangential section microstructure and FTIR characteristic absorption patterns across degradation levels,and as the degradation advanced,progressive cell wall loosening occurred alongside selective removal of polysaccharide components,and the relative lignin content was increased,resulting in an elevated A1509/A1370 ratio in FTIR spectra.The sPLS-DA model achieved excellent discrimination performance with AUC values exceeding 0.9,confirming that the combination of FTIR spectroscopy with sPLS-DA enabled accurate assessment of degradation levels in shipwreck archaeological wood.This study developed a rapid and accurate methodology for assessing degradation levels in shipwreck archaeological wood based on microscale ATR-FTIR spectroscopy,which would help to promote the accurate assessment of the preservation state of waterlogged wooden artifacts.