Decline and fall of aging astrocytes:the human perspective

“Last scene of all that ends this strange,eventful history,is second childishness and mere oblivion.I am sans teeth,sans eyes,sans taste,sans everything.”William Shakespeare‘As You Like It'Act 2,Sc.7,l.139Aging of the human brain is characterized by a progressive decline of its functional capacity;this decline however varies widely,and cognitive longevity differs substantially between individuals.

Microstructural evolution during the progressive transformation-induced plasticity effect in a Fe-0.1C-5Mnmedium manganese steel

The microstructural evolution of a cold-rolled and intercritical annealed medium-Mn steel(Fe-0.10C-5Mn)was investigated during uniaxial tensile testing.In-situ observations under scanning electron microscopy,transmission electron microscopy,and X-ray diffraction analysis were conducted to characterize the progressive transformation-induced plasticity process and associated fracture initiation mechanisms.These findings were discussed with the local strain measurements via digital image correlation.The results indicated that Lüders band formation in the steel was limited to 1.5%strain,which was mainly due to the early-stage martensitic phase transformation of a very small amount of the less stable large-sized retained austenite(RA),which led to localized stress concentrations and strain hardening and further retardation of yielding.The small-sized RA exhibited high stability and progressively transformed into martensite and contributed to a stably extended Portevin-Le Chatelier effect.The volume fraction of RA gradually decreased from 26.8%to 8.2%prior to fracture.In the late deformation stage,fracture initiation primarily occurred at the austenite/martensite and ferrite/martensite interfaces and the ferrite phase.

The impact of alpha-fetoprotein(AFP),child-turcotte-pugh(CTP)score and disease staging on the survival of hepatocellular carcinoma(HCC)patients:a retrospective cohort from single oncology center

Background:Hepatocellular carcinoma(HCC)is the most common cause of cancer-related death in Saudi Arabia.Our study aimed to investigate the patterns of HCC and the effect of TNM staging,Alfa-fetoprotein(AFP),and Child-Turcotte Pugh(CTP)on patients’overall survival(OS).Methods:A retrospective analysis was conducted on 43 HCC patients at a single oncology center in Saudi Arabia from 2015 to 2020.All patients had to fulfill one of the following criteria:(a)a liver lesion reported as definitive HCC on dynamic imaging and/or(b)a biopsy-confirmed diagnosis.Results:The mean patient age of all HCC cases was 66.8 with a male-to-female ratio of 3.3:1.All patients were stratified into two groups:viral HCC(n=22,51%)and non-viral HCC(n=21,49%).Among viral-HCC patients,55%were due to HBV and 45%due to HCV.Cirrhosis was diagnosed in 79%of cases.Age and sex did not significantly statistically differ in OS among viral and non-viral HCC patients(p-value>0.05).About 65%of patients had tumor size>5 cm during the diagnosis,with a significant statistical difference in OS(p-value=0.027).AFP was>400 ng/ml in 45%of the patients.There was a statistically significant difference in the OS in terms of AFP levels(p-value=0.021).A statistically significant difference was also observed between the CTP score and OS(p-value=0.02).CTP class B had the longest survival.BSC was the most common treatment provided to HCC patients followed by sorafenib therapy.There was a significant statistical difference in OS among viral and non-viral HCC patients(p-value=0.008).Conclusions:The most common predictors for OS were the underlying cause of HCC,AFP,and tumor size.Being having non-viral etiology,a tumor size>5 cm,an AFP>400 ng/mL,and a CTP score class C were all negatively associated with OS.

Insights into spinal muscular atrophy from molecular biomarkers

Spinal muscular atrophy is a devastating motor neuron disease characterized by severe cases of fatal muscle weakness.It is one of the most common genetic causes of mortality among infants aged less than 2 years.Biomarker research is currently receiving more attention,and new candidate biomarkers are constantly being discovered.This review initially discusses the evaluation methods commonly used in clinical practice while briefly outlining their respective pros and cons.We also describe recent advancements in research and the clinical significance of molecular biomarkers for spinal muscular atrophy,which are classified as either specific or non-specific biomarkers.This review provides new insights into the pathogenesis of spinal muscular atrophy,the mechanism of biomarkers in response to drug-modified therapies,the selection of biomarker candidates,and would promote the development of future research.Furthermore,the successful utilization of biomarkers may facilitate the implementation of gene-targeting treatments for patients with spinal muscular atrophy.

Return to work in young and middle-aged colorectal cancer survivors:Factors influencing self-efficacy,fear,resilience,and financial toxicity

BACKGROUND Return to work(RTW)serves as an indication for young and middle-aged colorectal cancer(CRC)survivors to resume their normal social lives.However,these survivors encounter significant challenges during their RTW process.Hence,scientific research is necessary to explore the barriers and facilitating factors of returning to work for young and middle-aged CRC survivors.AIM To examine the current RTW status among young and middle-aged CRC survivors and to analyze the impact of RTW self-efficacy(RTW-SE),fear of progression(FoP),eHealth literacy(eHL),family resilience(FR),and financial toxicity(FT)on their RTW outcomes.METHODS A cross-sectional investigation was adopted in this study.From September 2022 to February 2023,a total of 209 participants were recruited through a convenience sampling method from the gastrointestinal surgery department of a class A tertiary hospital in Chongqing.The investigation utilized a general information questionnaire alongside scales assessing RTW-SE,FoP,eHL,FR,and FT.To analyze the factors that influence RTW outcomes among young and middle-aged CRC survivors,Cox regression modeling and Kaplan-Meier survival analysis were used.RESULTS A total of 43.54%of the participants successfully returned to work,with an average RTW time of 100 days.Cox regression univariate analysis revealed that RTW-SE,FoP,eHL,FR,and FT were significantly different between the non-RTW and RTW groups(P<0.05).Furthermore,Cox regression multivariate analysis identified per capita family monthly income,job type,RTW-SE,and FR as independent influencing factors for RTW(P<0.05).CONCLUSION The RTW rate requires further improvement.Elevated levels of RTW-SE and FR were found to significantly increase RTW among young and middle-aged CRC survivors.Health professionals should focus on modifiable factors,such as RTW-SE and FR,to design targeted RTW support programs,thereby facilitating their timely reintegration into mainstream society.

Glaucomatous retinal ganglion cells:death and protection

Glaucoma is a group of diseases characterized by progressive optic nerve degeneration,with the characteristic pathological change being death of retinal ganglion cells(RGCs),which ultimately causes visual field loss and irreversible blindness.Elevated intraocular pressure(IOP)remains the most important risk factor for glaucoma,but the exact mechanism responsible for the death of RGCs is currently unknown.Neurotrophic factor deficiency,impaired mitochondrial structure and function,disrupted axonal transport,disturbed Ca2+homeostasis,and activation of apoptotic and autophagic pathways play important roles in RGC death in glaucoma.This review was conducted using Web of Science,PubMed,Project,and other databases to summarize the relevant mechanisms of death of RGCs in glaucoma,in addition to outlining protective treatments to improve the degradation of RGCs.

Kinked Rebar and Engineering Structures Applying Kinked Materials:State-ofthe-Art Review

Kinked rebar is a special type of steel material,which is installed in beam column nodes and frame beams.It effectively enhances the blast resilience,seismic collapse resistance,and progressive collapse resistance of reinforced concrete(RC)structures without imposing substantial cost burdens,thereby emerging as a focal point of recent research endeavors.On the basis of explaining the working principle of kinked rebars,this paper reviews the research status of kinked rebars at home and abroad from three core domains:the tensile mechanical properties of kinked rebars,beam column nodes with kinked rebars,and concrete frame structures with kinked rebars.The analysis underscores that the straightening process of kinked rebars does not compromise their ultimate strength but significantly bolsters structural ductility and enhances energy dissipation capabilities.In beam-column joints,the incorporation of kinked rebars facilitates the seamless transfer of plastic hinges,adhering to the design principle of“strong columns and weak beams.”In addition,kinked rebars can greatly improve the resistance of the beam;The seismic resistance,internal explosion resistance,and progressive collapse resistance of reinforced concrete frame structures with kinked rebar have significantly improved.Beyond its primary application,the principle of kinked rebar was extended to other applications of kinked materials such as corrugated steel plates and origami structures,and the stress characteristics of related components and structures were studied.Intriguingly,this paper also proposes the application of kinked rebars in bridge engineering,aiming to address the challenges of localized damage concentration and excessive residual displacement in RC bridge piers.The introduction of kinked rebars in piers is envisioned to mitigate these issues,with the paper outlining its advantages and feasibility,thereby offering valuable insights for future research on kinked reinforcement and seismic design strategies for bridges.

Landscape of four different stages of human gastric cancer revealed by single-cell sequencing

BACKGROUND Gastric cancer(GC)poses a substantial risk to human health due to its high prevalence and mortality rates.Nevertheless,current therapeutic strategies remain insufficient.Single-cell RNA sequencing(scRNA-seq)offers the potential to provide comprehensive insights into GC pathogenesis.AIM To explore the distribution and dynamic changes of cell populations in the GC tumor microenvironment using scRNA-seq techniques.METHODS Cancerous tissues and paracancerous tissues were obtained from patients diagnosed with GC at various stages(I,II,III,and IV).Single-cell suspensions were prepared and analyzed using scRNA-seq to examine transcriptome profiles and cell-cell interactions.Additionally,quantitative real-time polymerase chain reaction(qRT-PCR)and flow cytometry were applied for measuring the expression of cluster of differentiation(CD)2,CD3D,CD3E,cytokeratin 19,cytokeratin 8,and epithelial cell adhesion molecules.RESULTS Transcriptome data from 73645 single cells across eight tissues of four patients were categorized into 25 distinct cell clusters,representing 10 different cell types.Variations were observed in these cell type distribution.The adjacent epithelial cells in stages II and III exhibited a degenerative trend.Additionally,the quantity of CD4 T cells and CD8 T cells were evidently elevated in cancerous tissues.Interaction analysis displayed a remarkable increase in interaction between B cells and other mast cells in stages II,III,and IV of GC.These findings were further validated through qRT-PCR and flow cytometry,demonstrating elevated T cells and declined epithelial cells within the cancerous tissues.CONCLUSION This study provides a comprehensive analysis of cell dynamics across GC stages,highlighting key interactions within the tumor microenvironment.These findings offer valuable insights for developing novel therapeutic strategies.

Internal biliary diversion using appendix during liver transplantation for progressive familial intrahepatic cholestasis type 1:A case report

BACKGROUND Progressive familial intrahepatic cholestasis type 1(PFIC-1)is a genetic cholestatic disease causing end-stage liver disease,which needs liver transplantation(LT).Simultaneous biliary diversion(BD)was recommended to prevent allograft steatosis after transplantation,while increasing the risk of infection.Here,an attempt was made to perform BD using appendix to prevent bacterial translocation after LT.CASE SUMMARY An 11-month-old boy diagnosed with PFIC-1 received ABO compatible living donor LT due to refractory jaundice and pruritus.His mother donated her left lateral segment with a graft-to-recipient weight ratio of 2.9%.Internal BD was constructed during LT using the appendix by connecting its proximal end with the intrahepatic biliary duct and the distal end with colon.Biliary leakage was suspected on the 5th day after transplantation and exploratory laparotomy indicated biliary leakage at the cutting surface of liver.The liver function returned to normal on the 9th day post-operation and maintained normal during the 15-month follow-up.Cholangiography at 10 months after transplantation confirmed the direct secretion of bile into colon.Computerized tomography scan(4 months and 10 months)and liver biopsy(10 months)indicated no steatosis in the allograft.No complaint of recurrent diarrhea,infection or growth retardation was reported during follow-up.CONCLUSION Internal BD using appendix during LT is effective in preventing allograft steatosis and post-transplant infection in PFIC-1 recipients.

Characterizing large deformation of soft rock tunnel using microseismic monitoring and numerical simulation

Surrounding rock deterioration and large deformation have always been a significant difficulty in designing and constructing tunnels in soft rock.The key lies in real-time perception and quantitative assessment of the damaged area around the tunnel.An in situ microseismic(MS)monitoring system is established in the plateau soft tock tunnel.This technique facilitates spatiotemporal monitoring of the rock mass's fracturing expansion and squeezing deformation,which agree well with field convergence deformation results.The formation mechanisms of progressive failure evolution of soft rock tunnels were discussed and analyzed with MS data and numerical results.The results demonstrate that:(1)Localized stress concentration and layered rock result in significant asymmetry in micro-fractures propagation in the tunnel radial section.As excavation continues,the fracture extension area extends into the deep surrounding rockmass on the east side affected by the weak bedding;(2)Tunnel excavation and long-term deformation can induce tensile shear action on the rock mass,vertical tension fractures(account for 45%)exist in deep rockmass,which play a crucial role in controlling the macroscopic failure of surrounding rock;and(3)Based on the radiated MS energy,a three-dimensional model was created to visualize the damage zone of the tunnel surrounding rock.The model depicted varying degrees of damage,and three high damage zones were identified.Generally,the depth of high damage zone ranged from 4 m to 12 m.This study may be a valuable reference for the warning and controlling of large deformations in similar projects.

Lipid metabolism analysis in esophageal cancer and associated drug discovery

Esophageal cancer is an upper gastrointestinal malignancy with a bleak prognosis.It is still being explored in depth due to its complex molecular mechanisms of occurrence and development.Lipids play a crucial role in cells by participating in energy supply,biofilm formation,and signal transduction processes,and lipid metabolic reprogramming also constitutes a significant characteristic of malignant tumors.More and more studies have found esophageal cancer has obvious lipid metabolism abnormalities throughout its beginning,progress,and treatment resistance.The inhibition of tumor growth and the enhancement of antitumor therapy efficacy can be achieved through the regulation of lipid metabolism.Therefore,we reviewed and analyzed the research results and latest findings for lipid metabolism and associated analysis techniques in esophageal cancer,and comprehensively proved the value of lipid metabolic reprogramming in the evolution and treatment resistance of esophageal cancer,as well as its significance in exploring potential therapeutic targets and biomarkers.

Progress in the generation of spinal cord organoids over the past decade and future perspectives

Spinal cord organoids are three-dimensional tissues derived from stem cells that recapitulate the primary morphological and functional characteristics of the spinal cord in vivo.As emerging bioengineering methods have led to the optimization of cell culture protocols,spinal cord organoids technology has made remarkable advancements in the past decade.Our literature search found that current spinal cord organoids do not only dynamically simulate neural tube formation but also exhibit diverse cytoarchitecture along the dorsal-ventral and rostral-caudal axes.Moreover,fused organoids that integrate motor neurons and other regionally specific organoids exhibit intricate neural circuits that allows for functional assessment.These qualities make spinal cord organoids valuable tools for disease modeling,drug screening,and tissue regeneration.By utilizing this emergent technology,researchers have made significant progress in investigating the pathogenesis and potential therapeutic targets of spinal cord diseases.However,at present,spinal cord organoid technology remains in its infancy and has not been widely applied in translational medicine.Establishment of the next generation of spinal cord organoids will depend on good manufacturing practice standards and needs to focus on diverse cell phenotypes and electrophysiological functionality evaluation.

Role of exosomal circular RNAs as microRNA sponges and potential targeting for suppressing hepatocellular carcinoma growth and progression

In this editorial,we comment on the article by Lyu et al published in the recent issue of the World Journal of Gastroenterology(2023;2219-2840).Hepatocellular carcinoma(HCC)is a frequently encountered and highly aggressive primary liver cancer,which remains the third-commonest cause of cancer-related death despite the current therapeutic modalities.There is urgency in developing novel thera-peutic approaches,such as by manipulating extracellular vesicles,which con-stitute a highly heterogeneous nanoparticle population that contains various cargoes.These cargoes have a pivotal role in cell-to-cell communication and can modify the functional level of the recipient cells via their uptake by other recipient cells.Exosomal non-coding RNAs have particular evolving significance in HCC,such as circular RNAs,which have been found differentially expressed in normal hepatic and HCC tissues.The aberrations in their expression levels have a key role in the HCC development and progression and the overall prognosis.In this editorial,we will shed light on the emerging role of exosomal circular RNAs in HCC development and progression,focusing on the oncogenic or potentially tumor suppressive effect of mesenchymal stem cells-derived exosomal non-coding RNAs.

Overview of the immunological mechanisms in hepatitis B virus reactivation:Implications for disease progression and management strategies

Hepatitis B virus(HBV)reactivation is a clinically significant challenge in disease management.This review explores the immunological mechanisms underlying HBV reactivation,emphasizing disease progression and management.It delves into host immune responses and reactivation’s delicate balance,spanning innate and adaptive immunity.Viral factors’disruption of this balance,as are interac-tions between viral antigens,immune cells,cytokine networks,and immune checkpoint pathways,are examined.Notably,the roles of T cells,natural killer cells,and antigen-presenting cells are discussed,highlighting their influence on disease progression.HBV reactivation’s impact on disease severity,hepatic flares,liver fibrosis progression,and hepatocellular carcinoma is detailed.Management strategies,including anti-viral and immunomodulatory approaches,are critically analyzed.The role of prophylactic anti-viral therapy during immunosuppressive treatments is explored alongside novel immunotherapeutic interventions to restore immune control and prevent reactivation.In conclusion,this compre-hensive review furnishes a holistic view of the immunological mechanisms that propel HBV reactivation.With a dedicated focus on understanding its implic-ations for disease progression and the prospects of efficient management stra-tegies,this article contributes significantly to the knowledge base.The more profound insights into the intricate interactions between viral elements and the immune system will inform evidence-based approaches,ultimately enhancing disease management and elevating patient outcomes.The dynamic landscape of management strategies is critically scrutinized,spanning anti-viral and immunomodulatory approaches.The role of prophylactic anti-viral therapy in preventing reactivation during immunosuppressive treatments and the potential of innovative immunotherapeutic interventions to restore immune control and proactively deter reactivation.

Pressure stimulated current in progressive failure process of combined coal-rock under uniaxial compression:Response and mechanism

Effective monitoring of the structural health of combined coal-rock under complex geological conditions by pressure stimulated currents(PSCs)has great potential for the understanding of dynamic disasters in underground engineering.To reveal the effect of this way,the uniaxial compression experiments with PSC monitoring were conducted on three types of coal-rock combination samples with different strength combinations.The mechanism explanation of PSCs are investigated by resistivity test,atomic force microscopy(AFM)and computed tomography(CT)methods,and a PSC flow model based on progressive failure process is proposed.The influence of strength combinations on PSCs in the progressive failure process are emphasized.The results show the PSC responses between rock part,coal part and the two components are different,which are affected by multi-scale fracture characteristics and electrical properties.As the rock strength decreases,the progressive failure process changes obviously with the influence range of interface constraint effect decreasing,resulting in the different responses of PSC strength and direction in different parts to fracture behaviors.The PSC flow model is initially validated by the relationship between the accumulated charges of different parts.The results are expected to provide a new reference and method for mining design and roadway quality assessment.

A Comparative Study on the Post-Buckling Behavior of Reinforced Thermoplastic Pipes(RTPs)Under External Pressure Considering Progressive Failure

The collapse pressure is a key parameter when RTPs are applied in harsh deep-water environments.To investigate the collapse of RTPs,numerical simulations and hydrostatic pressure tests are conducted.For the numerical simulations,the eigenvalue analysis and Riks analysis are combined,in which the Hashin failure criterion and fracture energy stiffness degradation model are used to simulate the progressive failure of composites,and the“infinite”boundary conditions are applied to eliminate the boundary effects.As for the hydrostatic pressure tests,RTP specimens were placed in a hydrostatic chamber after filled with water.It has been observed that the cross-section of the middle part collapses when it reaches the maximum pressure.The collapse pressure obtained from the numerical simulations agrees well with that in the experiment.Meanwhile,the applicability of NASA SP-8007 formula on the collapse pressure prediction was also discussed.It has a relatively greater difference because of the ignorance of the progressive failure of composites.For the parametric study,it is found that RTPs have much higher first-ply-failure pressure when the winding angles are between 50°and 70°.Besides,the effect of debonding and initial ovality,and the contribution of the liner and coating are also discussed.

Glucocorticoids-based prodrug design:Current strategies and research progress

Attributing to their broad pharmacological effects encompassing anti-inflammation,antitoxin,and immunosuppression,glucocorticoids(GCs)are extensively utilized in the clinic for the treatment of diverse diseases such as lupus erythematosus,nephritis,arthritis,ulcerative colitis,asthma,keratitis,macular edema,and leukemia.However,longterm use often causes undesirable side effects,including metabolic disorders-induced Cushing's syndrome(buffalo back,full moon face,hyperglycemia,etc.),osteoporosis,aggravated infection,psychosis,glaucoma,and cataract.These notorious side effects seriously compromise patients'quality of life,especially in patients with chronic diseases.Therefore,glucocorticoid-based advanced drug delivery systems for reducing adverse effects have received extensive attention.Among them,prodrugs have the advantages of low investment,low risk,and high success rate,making them a promising strategy.In this review,we propose the strategies for the design and summarize current research progress of glucocorticoid-based prodrugs in recent decades,including polymer-based prodrugs,dendrimer-based prodrugs,antibody-drug conjugates,peptide-drug conjugates,carbohydrate-based prodrugs,aliphatic acid-based prodrugs and so on.Besides,we also raise issues that need to be focused on during the development of glucocorticoid-based prodrugs.This review is expected to be helpful for the research and development of novel GCs and prodrugs.

Ethanol changes Nestin-promoter induced neural stem cells to disturb newborn dendritic spine remodeling in the hippocampus of mice

Adolescent binge drinking leads to long-lasting disorders of the adult central nervous system,particularly aberrant hippocampal neurogenesis.In this study,we applied in vivo fluorescent tracing using NestinCreERT2::Rosa26-tdTomato mice and analyzed the endogenous neurogenesis lineage progression of neural stem cells(NSCs)and dendritic spine formation of newborn neurons in the subgranular zone of the dentate gyrus.We found abnormal orientation of tamoxifen-induced tdTomato+(tdTom^(+))NSCs in adult mice 2 months after treatment with EtOH(5.0 g/kg,i.p.)for 7 consecutive days.EtOH markedly inhibited tdTom^(+)NSCs activation and hippocampal neurogenesis in mouse dentate gyrus from adolescence to adulthood.EtOH(100 mM)also significantly inhibited the proliferation to 39.2%and differentiation of primary NSCs in vitro.Adult mice exposed to EtOH also exhibited marked inhibitions in dendritic spine growth and newborn neuron maturation in the dentate gyrus,which was partially reversed by voluntary running or inhibition of the mammalian target of rapamycinenhancer of zeste homolog 2 pathway.In vivo tracing revealed that EtOH induced abnormal orientation of tdTom+NSCs and spatial misposition defects of newborn neurons,thus causing the disturbance of hippocampal neurogenesis and dendritic spine remodeling in mice.

Imbalance of Circulating Follicular Regulatory and Follicular Helper T Cell Subpopulations Is Associated with Disease Progression and Serum CYFRA 21-1 Levels in Patients with Non-small Cell Lung Cancer

Objective This study aimed to investigate the changes of follicular helper T(TFH)and follicular regulatory T(TFR)cell subpopulations in patients with non-small cell lung cancer(NSCLC)and their significance.Methods Peripheral blood was collected from 58 NSCLC patients at different stages and 38 healthy controls.Flow cytometry was used to detect TFH cell subpopulation based on programmed death 1(PD-1)and inducible co-stimulator(ICOS),and TFR cell subpopulation based on cluster determinant 45RA(CD45RA)and forkhead box protein P3(FoxP3).The levels of interleukin-10(IL-10),interleukin-17a(IL-17a),interleukin-21(IL-21),and transforming growth factor-β(TGF-β)in the plasma were measured,and changes in circulating B cell subsets and plasma IgG levels were also analyzed.The correlation between serum cytokeratin fragment antigen 21-1(CYFRA 21-1)levels and TFH,TFR,or B cell subpopulations was further explored.Results The TFR/TFH ratio increased significantly in NSCLC patients.The CD45RA^(+)FoxP3^(int) TFR subsets were increased,with their proportions increasing in stages Ⅱ to Ⅲ and decreasing in stage IV.PD-1^(+)ICOS+TFH cells showed a downward trend with increasing stages.Plasma IL-21 and TGF-β concentrations were increased in NSCLC patients compared with healthy controls.Plasmablasts,plasma IgG levels,and CD45RA^(+)FoxP3^(int) TFR cells showed similar trends.TFH numbers and plasmablasts were positively correlated with CYFRA 21-1 in stages Ⅰ-Ⅲ and negatively correlated with CYFRA 21-1 in stage IV.Conclusion Circulating TFH and TFR cell subpopulations and plasmablasts dynamically change in different stages of NSCLC,which is associated with serum CYFRA 21-1 levels and reflects disease progression.

Numerical analysis of downward progressive landslides in long natural slopes with sensitive clay

Landslides occurring in sensitive clay often result in widespread destruction,posing a significant risk to human lives and property due to the substantial decrease in undrained shear strength during deformation.Assessing the consequences of these landslides is challenging and necessitates robust numerical methods to comprehensively investigate their failure mechanisms.While studies have extensively explored upward progressive landslides in sensitive clays,understanding downward progressive cases remains limited.In this study,we utilised the nodal integration-based particle finite element method(NPFEM)with a nonlinear strain-softening model to analyse downward progressive landslides in sensitive clay on elongated slopes,induced by surcharge loads near the crest.We focused on elucidating the underlying failure mechanisms and evaluating the effects of different soil parameters and strainsoftening characteristics.The simulation results revealed the typical pattern for downward landslides,which typically start with a localised failure in proximity to the surcharge loads,followed by a combination of different types of failure mechanisms,including single flow slides,translational progressive landslides,progressive flow slides,and spread failures.Additionally,inclined shear bands occur within spread failures,often adopting distinctive ploughing patterns characterised by triangular shapes.The sensitive clay thickness at the base,the clay strength gradient,the sensitivity,and the softening rate significantly influence the failure mechanisms and the extent of diffused displacement.Remarkably,some of these effects mirror those observed in upward progressive landslides,underscoring the interconnectedness of these phenomena.This study contributes valuable insights into the complex dynamics of sensitive clay landslides,shedding light on the intricate interplay of factors governing their behaviour and progression.