AGK2 pre-treatment protects against thioacetamide-induced acute liver failure via regulating the MFN2-PERK axis and ferroptosis signaling pathway

Background:Acute liver failure(ALF)is an unpredictable and life-threatening critical illness.The pathological characteristic of ALF is massive necrosis of hepatocytes and lots of inflammatory cells infiltration which may lead to multiple organ failure.Methods:Animals were divided into 3 groups,normal,thioacetamide(TAA,ALF model)and TAA+AGK2.Cultured L02 cells were divided into 5 groups,normal,TAA,TAA+mitofusin 2(MFN2)-siRNA,TAA+AGK2,and TAA+AGK2+MFN2-siRNA groups.The liver histology was evaluated with hematoxylin and eosin staining,inositol-requiring enzyme 1(IRE1),activating transcription factor 6β(ATF6β),protein kinase R(PKR)-like endoplasmic reticulum kinase(PERK)and phosphorylated-PERK(p-PERK).C/EBP homologous protein(CHOP),reactive oxygen species(ROS),MFN2 and glutathione peroxidase 4(GPX4)were measured with Western blotting,and cell viability and liver chemistry were also measured.Mitochondriaassociated endoplasmic reticulum membranes(MAMs)were measured by immunofluorescence.Results:The liver tissue in the ALF group had massive inflammatory cell infiltration and hepatocytes necrosis,which were reduced by AGK2 pre-treatment.In comparison to the normal group,apoptosis rate and levels of IRE1,ATF6β,p-PERK,CHOP,ROS and Fe2+in the TAA-induced ALF model group were significantly increased,which were decreased by AGK2 pre-treatment.The levels of MFN2 and GPX4 were decreased in TAA-induced mice compared with the normal group,which were enhanced by AGK2 pretreatment.Compared with the TAA-induced L02 cell,apoptosis rate and levels of IRE1,ATF6β,p-PERK,CHOP,ROS and Fe2+were further increased and levels of MFN2 and GPX4 were decreased in the MFN2-siRNA group.AGK2 pre-treatment decreased the apoptosis rate and levels of IRE1,ATF6β,p-PERK,CHOP,ROS and Fe2+and enhanced the protein expression of MFN2 and GPX4 in MFN2-siRNA treated L02 cell.Immunofluorescence observation showed that level of MAMs was promoted in the AGK2 pre-treatment group when compared with the TAA-induced group in both mice and L02 cells.Conclusions:The data suggested that AGK2 pre-treatment had hepatoprotective role in TAA-induced ALF via upregulating the expression of MFN2 and then inhibiting PERK and ferroptosis pathway in ALF.

Left bundle branch pacing vs biventricular pacing in heart failure patients with left bundle branch block:A systematic review and meta-analysis

BACKGROUND Left bundle branch pacing(LBBP)is a novel pacing modality of cardiac resynchronization therapy(CRT)that achieves more physiologic native ventricular activation than biventricular pacing(BiVP).AIM To explore the validity of electromechanical resynchronization,clinical and echocardiographic response of LBBP-CRT.METHODS Systematic review and Meta-analysis were conducted in accordance with the standard guidelines as mentioned in detail in the methodology section.RESULTS In our analysis,the success rate of LBBP-CRT was determined to be 91.1%.LBBP CRT significantly shortened QRS duration,with significant improvement in echocardiographic parameters,including left ventricular ejection fraction,left ventricular end-diastolic diameter and left ventricular end-systolic diameter in comparison with BiVP-CRT.CONCLUSION A significant reduction in New York Heart Association class and B-type natriuretic peptide levels was also observed in the LBBP-CRT group vs BiVP-CRT group.Lastly,the LBBP-CRT cohort had a reduced pacing threshold at follow-up as compared to BiVP-CRT.

Predictive value of NLR, Fib4, and APRI in the occurrence of liver failure after hepatectomy in patients with hepatocellular carcinoma

BACKGROUND Neutrophil-lymphocyte ratio(NLR),fibrosis index based on four factors(Fib4),aspartate aminotransferase-to-platelet ratio index(APRI)can be used for prognostic evaluation of hepatocellular carcinoma.However,no study has established an individualized prediction model for the prognosis of hepatocellular carcinoma based on these factors.AIM To screen the factors that affect the prognosis of hepatocellular carcinoma and establish a nomogram model that predicts postoperative liver failure after hepatic resection in patients with hepatocellular carcinoma.METHODS In total,220 patients with hepatocellular carcinoma treated in our hospital from January 2022 to January 2023 were selected.They were divided into 154 participants in the modeling cohort,and 66 in the validation cohort.Comparative analysis of the changes in NLR,Fib4,and APRI levels in 154 patients with hepatocellular carcinoma before liver resection and at 3 mo,6 mo,and 12 mo postoperatively was conducted.Binary logistic regression to analyze the influencing factors on the occurrence of liver failure in hepatocellular carcinoma patients,roadmap prediction modeling,and validation,patient work characteristic curves(ROCs)to evaluate the predictive efficacy of the model,calibration curves to assess the consistency,and decision curve analysis(DCA)to evaluate the model’s validity were also conducted.RESULTS Binary logistic regression showed that Child-Pugh grading,Surgical site,NLR,Fib4,and APRI were all risk factors for liver failure after hepatic resection in patients with hepatocellular carcinoma.The modeling cohort built a column-line graph model,and the area under the ROC curve was 0.986[95%confidence in terval(CI):0.963-1.000].The patients in the validation cohort utilized the column-line graph to predict the probability of survival in the validation cohort and plotted the ROC curve with an area under the curve of the model of 0.692(95%CI:0.548-0.837).The deviation of the actual outcome curves from the calibration curves of the column-line plots generated by the modeling and validation cohorts was small,and the DCA confirmed the validity.CONCLUSION NLR,Fib4,and APRI independently influence posthepatectomy liver failure in patients with hepatocellular carcinoma.The column-line graph prediction model exhibited strong prognostic capability,with substantial concordance between predicted and actual events.

A Chinese Multi-Specialty Delphi Consensus to Optimize RAASi Usage and Hyperkalaemia Management in Patients with Chronic Kidney Disease and Heart Failure

Objective Variations are present in common clinical practices regarding best practice in managing hyperkalaemia(HK),there is therefore a need to establish a multi-specialty approach to optimal renin angiotension-aldosterone system inhibitors(RAASi)usage and HK management in patients with chronic kidney disease(CKD)&heart failure(HF).This study aimed to establish a multi-speciality approach to the optimal use of RAASi and the management of HK in patients with CKD and HF.Methods A steering expert group of cardiology and nephrology experts across China were convened to discuss challenges to HK management through a nominal group technique.The group then created a list of 41 statements for a consensus questionnaire,which was distributed for a further survey in extended panel group of cardiologists and nephrologists across China.Consensus was assessed using a modified Delphi technique,with agreement defined as"strong"(≥75%and<90%)and"very strong"(≥90%).The steering group,data collection,and analysis were aided by an independent facilitator.Results A total of 150 responses from 21 provinces across China were recruited in the survey.Respondents were comprised of an even split(n=75,50%)between cardiologists and nephrologists.All 41 statements achieved the 75%consensus agreement threshold,of which 27 statements attained very strong consensus(≥90%agreement)and 14 attained strong consensus(agreement between 75%and 90%).Conclusion Based on the agreement levels from respondents,the steering group agreed a set of recommendations intended to improve patient outcomes in the use of RAASi therapy and HK management in China.

Seismic-induced surficial failure of cohesive slopes using three-dimensional limit analysis:A case study of the Wangjiayan landslide in Beichuan, China

A seismic-induced landslide is a common geological catastrophe that occurs in nature.The Wangjiayan landslide,which was triggered by the Wenchuan earthquake,is a typical case in point.The Wanjiayan landslide caused many casualties and resulted in enormous property loss.This study constructs a simple surficial failure model based on the upper bound approach of three-dimensional(3D)limit analysis to evaluate the slope stability of the Wangjiayan case,while a traditional two-dimensional(2D)analysis is also conducted as a reference for comparison with the results of the 3D analysis.A quasi-static calculation is used to study the effect of the earthquake in terms of horizontal ground acceleration,while a parametric study is conducted to evaluate the critical cohesion of slopes.Rather than employing a 3D analysis,using the 2D analysis yields an underestimation regarding the safety factor.In the Wangjiayan landslide,the difference in the factors of safety between the 3D and 2D analyses can reach 20%.The sliding surface morphology as determined by the 3D method is similar to actual morphology,and the parameters of both are also compared to analyze the reliability of the proposed 3D method.

Failure mechanism and infrared radiation characteristic of hard siltstone induced by stratification effect

The deformation in sedimentary rock induced by train loads has potential threat to the safe operation of tunnels. This study investigated the influence of stratification structure on the infrared radiation and temporal damage mechanism of hard siltstone. The uniaxial compression tests, coupled with acoustic emission(AE) and infrared radiation temperature(IRT) were conducted on siltstones with different stratification effects. The results revealed that the stratigraphic structure significantly affects the stress-strain response and strength degradation characteristics. The mechanical parameters exhibit anisotropy characteristics, and the stratification effect exhibits a negative correlation with the cracking stress and peak stress. The failure modes caused by the stratification effect show remarkable anisotropic features, including splitting failure(Ⅰ: 0°-22.50°, Ⅱ: 90°), composite failure(45°), and shearing failure(67.50°). The AE temporal sequences demonstrate a stepwise response characteristic to the loading stress level. The AE intensity indicates that the stress sensitivity of shearing failure and composite failure is generally greater than that of splitting failure. The IRT field has spatiotemporal migration and progressive dissimilation with stress loading and its dissimilation degree increases under higher stress levels. The stronger the stratification effect, the greater the dissimilation degree of the IRT field. The abnormal characteristic points of average infrared radiation temperature(AIRT) variance at local stress drop and peak stress can be used as early and late precursors to identify fracture instability. Theoretical analysis shows that the competitive relationship between compaction strengthening and fracturing damage intensifies the dissimilation of the infrared thermal field for an increasing stress level. The present study provides a theoretical reference for disaster warnings in hard sedimentary rock mass.

Effect of Interface Form on Creep Failure and Life of Dissimilar Metal Welds Involving Nickel-Based Weld Metal and Ferritic Base Metal

For dissimilar metal welds(DMWs)involving nickel-based weld metal(WM)and ferritic heat resistant steel base metal(BM)in power plants,there must be an interface between WM and BM,and this interface suffers mechanical and microstructure mismatches and is often the rupture location of premature failure.In this study,a new form of WM/BM interface form,namely double Y-type interface was designed for the DMWs.Creep behaviors and life of DMWs containing double Y-type interface and conventional I-type interface were compared by finite element analysis and creep tests,and creep failure mechanisms were investigated by stress-strain analysis and microstructure characterization.By applying double Y-type interface instead of conventional I-type interface,failure location of DMW could be shifted from the WM/ferritic heat-affected zone(HAZ)interface into the ferritic HAZ or even the ferritic BM,and the failure mode change improved the creep life of DMW.The interface premature failure of I-type interface DMW was related to the coupling effect of microstructure degradation,stress and strain concentrations,and oxide notch on the WM/HAZ interface.The creep failure of double Y-type interface DMW was the result of Type IV fracture due to the creep voids and micro-cracks on fine-grain boundaries in HAZ,which was a result of the matrix softening of HAZ and lack of precipitate pinning at fine-grain boundaries.The double Y-type interface form separated the stress and strain concentrations in DMW from the WM/HAZ interface,preventing the trigger effect of oxide notch on interface failure and inhibiting the interfacial microstructure cracking.It is a novel scheme to prolong creep life and enhance reliability of DMW,by means of optimizing the interface form,decoupling the damage factors from WM/HAZ interface,and then changing the failure mechanism and shifting the failure location.

Local failure mechanism of sand-blocking fence in latticed dune along desert roads

The latticed dunes in the Tengger Desert are widely distributed,and the sand-blocking fence placed here are highly susceptible to local failure due to complex wind-sand activities,posing a serious threat to the safe operation of the highway.To explore the local failure mechanism of sand-blocking fence in the latticed dune area,the local failure of sand-blocking fence in the latticed dune areas along the Wuhai-Maqin Highway in China was observed.Taking the first main ridge of the latticed dune as the placement location,the structure of the wind-sand flow field of sand-blocking fence placed at top,the bottom and the middle of windward slope was analyzed by Computational Fluid Dynamics(CFD).The results show that when placed at top of the first main ridge,the wind speed near the sand-blocking fence is the highest,up to 15.23 m/s.Therefore,the wind load strength on the sand barrier is correspondingly larger,up to 232.61 N∙m-2.As the strength of material continues to decrease,the nylon net is prone to breakage.The roots of the angle steel posts are susceptible to hollowing by vortex action,which can cause sand-blocking fence to fall over in strong wind conditions.When placed at the bottom of windward slope,wind speed drop near sand-blocking fence is greatest,with the decrease of 12.48-14.32 m/s compared to the original wind speed.This is highly likely to lead to large-scale deposition of sand particles and burial of the sand-blocking fence.When placed in the middle of windward slope,sand-blocking fence is subjected to less wind load strength(168.61N∙m-2)and sand particles are mostly deposited at the bottom of windward slope,with only a small amount of sand accumulating at the root of sand-blocking fence.Based on field observations and numerical modelling results,when the sand-blocking fence is placed in latticed dune area,it should be placed in the middle of the windward slope of the first main ridge as a matter of priority.Besides the sand-blocking fence should be placed at the top of the first main ridge,and sand fixing measures should be added.

Roughness characterization and shearing dislocation failure for rock-backfill interface

Shearing dislocation is a common failure type for rock–backfill interfaces because of backfill sedimentation and rock strata movement in backfill mining goaf.This paper designed a test method for rock–backfill shearing dislocation.Using digital image techno-logy and three-dimensional(3D)laser morphology scanning techniques,a set of 3D models with rough joint surfaces was established.Further,the mechanical behavior of rock–backfill shearing dislocation was investigated using a direct shear test.The effects of interface roughness on the shear–displacement curve and failure characteristics of rock–backfill specimens were considered.The 3D fractal dimen-sion,profile line joint roughness coefficient(JRC),profile line two-dimensional fractal dimension,and the surface curvature of the frac-tures were obtained.The correlation characterization of surface roughness was then analyzed,and the shear strength could be measured and calculated using JRC.The results showed the following:there were three failure threshold value points in rock–backfill shearing dis-location:30%–50%displacement before the peak,70%–90%displacement before the peak,and 100%displacement before the peak to post-peak,which could be a sign for rock–backfill shearing dislocation failure.The surface JRC could be used to judge the rock–backfill shearing dislocation failure,including post-peak sliding,uniform variations,and gradient change,corresponding to rock–backfill disloca-tion failure on the field site.The research reveals the damage mechanism for rock–backfill complexes based on the free joint surface,fills the gap of existing shearing theoretical systems for isomerism complexes,and provides a theoretical basis for the prevention and control of possible disasters in backfill mining.

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.

Three‑dimensional numerical simulation of dynamic strength and failure mode of a rock mass with cross joints

To study the dynamic mechanical properties and failure characteristics of intersecting jointed rock masses with different joint distributions under confining pressure,considering the cross angleαand joint persistence ratioη,a numerical model of the biaxial Hopkinson bar test system was established using the finite element method–discrete-element model coupling method.The validity of the model was verified by comparing and analyzing it in conjunction with laboratory test results.Dynamics-static combined impact tests were conducted on specimens under various conditions to investigate the strength characteristics and patterns of crack initiation and expansion.The study revealed the predominant factors influencing intersecting joints with different angles and penetrations under impact loading.The results show that the peak stress of the specimens decreases first and then increases with the increase of the cross angle.Whenα<60°,regardless of the value ofη,the dynamic stress of the specimens is controlled by the main joint.Whenα≥60°,the peak stress borne by the specimens decreases with increasingη.Whenα<60°,the initiation and propagation of cracks in the cross-jointed specimens are mainly controlled by the main joint,and the final failure surface of the specimens is composed of the main joint and wing cracks.Whenα≥60°orη≥0.67,the secondary joint guides the expansion of the wing cracks,and multiple failure surfaces composed of main and secondary joints,wing cracks,and co-planar cracks are formed.Increasing lateral confinement significantly increases the dynamic peak stress able to be borne by the specimens.Under triaxial conditions,the degree of failure of the intersecting jointed specimens is much lower than that under uniaxial and biaxial conditions.

Energy evolution and structural health monitoring of coal under different failure modes:An experimental study

Structural instability in underground engineering,especially in coal-rock structures,poses significant safety risks.Thus,the development of an accurate monitoring method for the health of coal-rock bodies is crucial.The focus of this work is on understanding energy evolution patterns in coal-rock bodies under complex conditions by using shear,splitting,and uniaxial compression tests.We examine the changes in energy parameters during various loading stages and the effects of various failure modes,resulting in an innovative energy dissipation-based health evaluation technique for coal.Key results show that coal bodies go through transitions between strain hardening and softening mechanisms during loading,indicated by fluctuations in elastic energy and dissipation energy density.For tensile failure,the energy profile of coal shows a pattern of “high dissipation and low accumulation” before peak stress.On the other hand,shear failure is described by “high accumulation and low dissipation” in energy trends.Different failure modes correlate with an accelerated increase in the dissipation energy before destabilization,and a significant positive correlation is present between the energy dissipation rate and the stress state of the coal samples.A novel mathematical and statistical approach is developed,establishing a dissipation energy anomaly index,W,which categorizes the structural health of coal into different danger levels.This method provides a quantitative standard for early warning systems and is adaptable for monitoring structural health in complex underground engineering environments,contributing to the development of structural health monitoring technology.

Dynamic response and failure process of horizontal-layered fractured structure rock slope under strong earthquake

Rock slope with horizontal-layered fractured structure(HLFS)has high stability in its natural state.However,a strong earthquake can induce rock fissure expansion,ultimately leading to slope failure.In this study,the dynamic response,failure mode,and spectral characteristics of rock slope with HLFS under strong earthquake conditions were investigated based on the large-scale shaking table model test.On this basis,multiple sets of numerical calculation models were further established by UDEC discrete element program.Five influencing factors were considered in the parametric study of numerical simulations,including slope height,slope angle,bedding-plane spacing and secondary joint spacing as well as bedrock dip angle.The results showed that the failure process of rock slope with HLFS under earthquake action is mainly divided into four phases,i.e.,the tensile crack of the slope shoulder joints and shear dislocation at the top bedding plane,the extension of vertical joint cracks and increase of shear displacement,the formation of step-through sliding surfaces and the instability,and finally collapse of fractured rock mass.The acceleration response of slopes exhibits elevation amplification effect and surface effect.Numerical simulations indicate that the seismic stability of slopes with HLFS exhibits a negative correlation with slope height and angle,but a positive correlation with bedding-plane spacing,joint spacing,and bedrock dip angle.The results of this study can provide a reference for seismic stability evaluation of weathered rock slopes.

Development and validation of a new prognostic model for patients with acute-on-chronic liver failure in intensive care unit

BACKGROUND Cirrhotic patients with acute-on-chronic liver failure(ACLF)in the intensive care unit(ICU)have a poor but variable prognoses.Accurate prognosis evaluation can guide the rational management of patients with ACLF.However,existing prognostic scores for ACLF in the ICU environment lack sufficient accuracy.AIM To develop a new prognostic model for patients with ACLF in ICU.METHODS Data from 938 ACLF patients in the Medical Information Mart for Intensive Care(MIMIC)database were used to develop a new prognostic model(MIMIC ACLF)for ACLF.Discrimination,calibration and clinical utility of MIMIC ACLF were assessed by area under receiver operating characteristic curve(AUROC),calibration curve and decision curve analysis(DCA),respectively.MIMIC ACLF was then externally validated in a multiple-center cohort,the Electronic Intensive Care Collaborative Research Database and a single-center cohort from the Second Hospital of Hebei Medical University in China.RESULTS The MIMIC ACLF score was determined using nine variables:ln(age)×2.2+ln(white blood cell count)×0.22-ln(mean arterial pressure)×2.7+respiratory failure×0.6+renal failure×0.51+cerebral failure×0.31+ln(total bilirubin)×0.44+ln(internationalized normal ratio)×0.59+ln(serum potassium)×0.59.In MIMIC cohort,the AUROC(0.81/0.79)for MIMIC ACLF for 28/90-day ACLF mortality were significantly greater than those of Chronic Liver Failure Consortium ACLF(0.76/0.74),Model for End-stage Liver Disease(MELD;0.73/0.71)and MELD-Na(0.72/0.70)(all P<0.001).The consistency between actual and predicted 28/90-day survival rates of patients according to MIMIC ACLF score was excellent and superior to that of existing scores.The net benefit of MIMIC ACLF was greater than that achieved using existing scores within the 50%threshold probability.The superior predictive accuracy and clinical utility of MIMIC ACLF were validated in the external cohorts.CONCLUSION We developed and validated a new prognostic model with satisfactory accuracy for cirrhotic patients with ACLF hospitalized in the ICU.The model-based risk stratification and online calculator might facilitate the rational management of patients with ACLF.

Evolution model and failure mechanisms of rainfall-induced cracked red clay slopes:insights from Xinshao County,China

Red clay landslides are widely distributed worldwide,resulting in severe loss of life and property.Although rainfall-induced red clay slopes have received extensive attention,the role of cracks in the evolutionary process of red clay slopes and their connection to failure mechanisms is still poorly understood.A comprehensive approach integrating field investigation,laboratory tests,and numerical simulations was conducted to study the 168 red clay landslides in Xinshao County,China.The results show that red clay is prone to forming cracks at high moisture content due to its low swelling and high shrinkage properties.The failure mode of red clay slopes can be summarized in three stages:crack generation,slope excavation,and slope failure.Furthermore,the retrospective analysis and numerical simulations of the typical landslide in Guanchong indicated that intense rainfall primarily impacts the shallow layer of soil within approximately 0.5 m on the intact slope.However,cracks change the pattern of rainfall infiltration in the slope.Rainwater infiltrates rapidly through the preferential channels induced by the cracks rather than uniformly and slowly from the slope surface.This results in a significant increase in both the depth of infiltration and the saturated zone area of the cracked slope,reaching 3.8 m and 36.2 m^(2),respectively.Consequently,the factor of safety of the slope decreases by 13.4%compared to the intact slope,ultimately triggering landslides.This study can provide valuable insights into understanding the failure mechanisms of red clay slopes in China and other regions with similar geological settings.

Recent advances in quantifying the inactive lithium and failure mechanism of Li anodes in rechargeable lithium metal batteries

Lithium metal is considered as the ultimate anode material for the next generation of high-energy density batteries.However,non-uniform lithium dendrite growth,serious electrolyte consumption,and significant volume changes during lithium deposition/stripping processes lead to sustained accumulation of inactive lithium and poor cycling reversibility.Quantifying the formation and evolution of inactive lithium under different conditions and fully evaluating the complex failure modes are the key issues in this challenging field.This article comprehensively reviews recent research progress on the quantification of formation and evolution of inactive lithium detected by different quantitative techniques in rechargeable lithium metal batteries.The key research challenges such as failure mechanism,modification strategies and operando characterization of lithium metal anodes are systematically summarized and prospected.This review provides a new angle of view to understand failure mechanism of lithium metal anodes and inspiration and guidance for the future development of rechargeable lithium metal batteries.

Disturbance failure mechanism of highly stressed rock in deep excavation:Current status and prospects

This article reviews the current status on the dynamic behavior of highly stressed rocks under disturbances.Firstly,the experimental apparatus,methods,and theories related to the disturbance dynamics of deep,high-stress rock are reviewed,followed by the introduction of scholars’research on deep rock deformation and failure from an energy perspective.Subsequently,with a backdrop of highstress phenomena in deep hard rock,such as rock bursts and core disking,we delve into the current state of research on rock microstructure analysis and residual stresses from the perspective of studying the energy storage mechanisms in rocks.Thereafter,the current state of research on the mechanical response and the energy dissipation of highly stressed rock formations is briefly retrospected.Finally,the insufficient aspects in the current research on the disturbance and failure mechanisms in deep,highly stressed rock formations are summarized,and prospects for future research are provided.This work provides new avenues for the research on the mechanical response and damage-fracture mechanisms of rocks under high-stress conditions.

Numerical and theoretical study of load transfer behavior during cascading pillar failure

To further study the load transfer mechanism of roofemulti-pillarefloor system during cascading pillar failure(CPF),numerical simulation and theoretical analysis were carried out to study the three CPF modes according to the previous experimental study on treble-pillar specimens,e.g.successive failure mode(SFM),domino failure mode(DFM)and compound failure mode(CFM).Based on the finite element code rock failure process analysis(RFPA^(2D)),numerical models of treble-pillar specimen with different mechanical properties were established to reproduce and verify the experimental results of the three CPF modes.Numerical results show that the elastic rebound of roofefloor system induced by pillar instability causes dynamic disturbance to adjacent pillars,resulting in sudden load increases and sudden jump displacement of adjacent pillars.The phenomena of load transfer in the roofemulti-pillarefloor system,as well as the induced accelerated damage behavior in adjacent pillars,were discovered and studied.In addition,based on the catastrophe theory and the proposed mechanical model of treble-pillar specimen edisc spring group system,a potential function that characterizes the evolution characteristics of roof emulti-pillarefloor system was established.The analytical expressions of sudden jump and energy release of treble-pillar specimenedisc spring group system of the three CPF modes were derived according to the potential function.The numerical and theoretical results show good agreement with the experimental results.This study further reveals the physical essence of load transfer during CPF of roof emulti-pillarefloor system,which provides references for mine design,construction and disaster prevention.

Mitochondrial dysfunction affects hepatic immune and metabolic remodeling in patients with hepatitis B virus-related acute-onchronic liver failure

BACKGROUND Immune dysregulation and metabolic derangement have been recognized as key factors that contribute to the progression of hepatitis B virus(HBV)-related acute-on-chronic liver failure(ACLF).However,the mechanisms underlying immune and metabolic derangement in patients with advanced HBV-ACLF are unclear.AIM To identify the bioenergetic alterations in the liver of patients with HBV-ACLF causing hepatic immune dysregulation and metabolic disorders.METHODS Liver samples were collected from 16 healthy donors(HDs)and 17 advanced HBV-ACLF patients who were eligible for liver transplantation.The mitochondrial ultrastructure,metabolic characteristics,and immune microenvironment of the liver were assessed.More focus was given to organic acid metabolism as well as the function and subpopulations of macrophages in patients with HBV-ACLF.RESULTS Compared with HDs,there was extensive hepatocyte necrosis,immune cell infiltration,and ductular reaction in patients with ACLF.In patients,the liver suffered severe hypoxia,as evidenced by increased expression of hypoxia-inducible factor-1α.Swollen mitochondria and cristae were observed in the liver of patients.The number,length,width,and area of mitochondria were adaptively increased in hepatocytes.Targeted metabolomics analysis revealed that mitochondrial oxidative phosphorylation decreased,while anaerobic glycolysis was enhanced in patients with HBV-ACLF.These findings suggested that,to a greater extent,hepa-tocytes used the extra-mitochondrial glycolytic pathway as an energy source.Patients with HBV-ACLF had elevated levels of chemokine C-C motif ligand 2 in the liver homogenate,which stimulates peripheral monocyte infiltration into the liver.Characterization and functional analysis of macrophage subsets revealed that patients with ACLF had a high abundance of CD68^(+)HLA-DR^(+)macrophages and elevated levels of both interleukin-1βand transforming growth factor-β1 in their livers.The abundance of CD206^(+)CD163^(+)macrophages and expression of interleukin-10 decreased.The correlation analysis revealed that hepatic organic acid metabolites were closely associated with macrophage-derived cytokines/chemokines.CONCLUSION The results indicated that bioenergetic alteration driven by hypoxia and mitochondrial dysfunction affects hepatic immune and metabolic remodeling,leading to advanced HBV-ACLF.These findings highlight a new therapeutic target for improving the treatment of HBV-ACLF.

Validation and performance of three scoring systems for predicting primary non-function and early allograft failure after liver transplantation

Background: Primary non-function(PNF) and early allograft failure(EAF) after liver transplantation(LT) seriously affect patient outcomes. In clinical practice, effective prognostic tools for early identifying recipients at high risk of PNF and EAF were urgently needed. Recently, the Model for Early Allograft Function(MEAF), PNF score by King's College(King-PNF) and Balance-and-Risk-Lactate(BAR-Lac) score were developed to assess the risks of PNF and EAF. This study aimed to externally validate and compare the prognostic performance of these three scores for predicting PNF and EAF. Methods: A retrospective study included 720 patients with primary LT between January 2015 and December 2020. MEAF, King-PNF and BAR-Lac scores were compared using receiver operating characteristic(ROC) and the net reclassification improvement(NRI) and integrated discrimination improvement(IDI) analyses. Results: Of all 720 patients, 28(3.9%) developed PNF and 67(9.3%) developed EAF in 3 months. The overall early allograft dysfunction(EAD) rate was 39.0%. The 3-month patient mortality was 8.6% while 1-year graft-failure-free survival was 89.2%. The median MEAF, King-PNF and BAR-Lac scores were 5.0(3.5–6.3),-2.1(-2.6 to-1.2), and 5.0(2.0–11.0), respectively. For predicting PNF, MEAF and King-PNF scores had excellent area under curves(AUCs) of 0.872 and 0.891, superior to BAR-Lac(AUC = 0.830). The NRI and IDI analyses confirmed that King-PNF score had the best performance in predicting PNF while MEAF served as a better predictor of EAD. The EAF risk curve and 1-year graft-failure-free survival curve showed that King-PNF was superior to MEAF and BAR-Lac scores for stratifying the risk of EAF. Conclusions: MEAF, King-PNF and BAR-Lac were validated as practical and effective risk assessment tools of PNF. King-PNF score outperformed MEAF and BAR-Lac in predicting PNF and EAF within 6 months. BAR-Lac score had a huge advantage in the prediction for PNF without post-transplant variables. Proper use of these scores will help early identify PNF, standardize grading of EAF and reasonably select clinical endpoints in relative studies.