Aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorders:progress of experimental models based on disease pathogenesis

Neuromyelitis optica spectrum disorders are neuroinflammatory demyelinating disorders that lead to permanent visual loss and motor dysfunction.To date,no effective treatment exists as the exact causative mechanism remains unknown.Therefore,experimental models of neuromyelitis optica spectrum disorders are essential for exploring its pathogenesis and in screening for therapeutic targets.Since most patients with neuromyelitis optica spectrum disorders are seropositive for IgG autoantibodies against aquaporin-4,which is highly expressed on the membrane of astrocyte endfeet,most current experimental models are based on aquaporin-4-IgG that initially targets astrocytes.These experimental models have successfully simulated many pathological features of neuromyelitis optica spectrum disorders,such as aquaporin-4 loss,astrocytopathy,granulocyte and macrophage infiltration,complement activation,demyelination,and neuronal loss;however,they do not fully capture the pathological process of human neuromyelitis optica spectrum disorders.In this review,we summarize the currently known pathogenic mechanisms and the development of associated experimental models in vitro,ex vivo,and in vivo for neuromyelitis optica spectrum disorders,suggest potential pathogenic mechanisms for further investigation,and provide guidance on experimental model choices.In addition,this review summarizes the latest information on pathologies and therapies for neuromyelitis optica spectrum disorders based on experimental models of aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorders,offering further therapeutic targets and a theoretical basis for clinical trials.

Comparative transcriptomic analysis reveals the molecular changes of acute pancreatitis in experimental models

BACKGROUND Acute pancreatitis(AP)encompasses a spectrum of pancreatic inflammatory conditions,ranging from mild inflammation to severe pancreatic necrosis and multisystem organ failure.Given the challenges associated with obtaining human pancreatic samples,research on AP predominantly relies on animal models.In this study,we aimed to elucidate the fundamental molecular mechanisms underlying AP using various AP models.AIM To investigate the shared molecular changes underlying the development of AP across varying severity levels.METHODS AP was induced in animal models through treatment with caerulein alone or in combination with lipopolysaccharide(LPS).Additionally,using Ptf1αto drive the specific expression of the hM3 promoter in pancreatic acinar cells transgenic C57BL/6J-hM3/Ptf1α(cre)mice were administered Clozapine N-oxide to induce AP.Subsequently,we conducted RNA sequencing of pancreatic tissues and validated the expression of significantly different genes using the Gene Expression Omnibus(GEO)database.RESULTS Caerulein-induced AP showed severe inflammation and edema,which were exacerbated when combined with LPS and accompanied by partial pancreatic tissue necrosis.Compared with the control group,RNA sequencing analysis revealed 880 significantly differentially expressed genes in the caerulein model and 885 in the caerulein combined with the LPS model.Kyoto Encyclopedia of Genes and Genomes enrichment analysis and Gene Set Enrichment Analysis indicated substantial enrichment of the TLR and NOD-like receptor signaling pathway,TLR signaling pathway,and NF-κB signaling pathway,alongside elevated levels of apoptosis-related pathways,such as apoptosis,P53 pathway,and phagosome pathway.The significantly elevated genes in the TLR and NOD-like receptor signaling pathways,as well as in the apoptosis pathway,were validated through quantitative real-time PCR experiments in animal models.Validation from the GEO database revealed that only MYD88 concurred in both mouse pancreatic tissue and human AP peripheral blood,while TLR1,TLR7,RIPK3,and OAS2 genes exhibited marked elevation in human AP.The genes TUBA1A and GADD45A played significant roles in apoptosis within human AP.The transgenic mouse model hM3/Ptf1α(cre)successfully validated significant differential genes in the TLR and NOD-like receptor signaling pathways as well as the apoptosis pathway,indicating that these pathways represent shared pathological processes in AP across different models.CONCLUSION The TLR and NOD receptor signaling pathways play crucial roles in the inflammatory progression of AP,notably the MYD88 gene.Apoptosis holds a central position in the necrotic processes of AP,with TUBA1A and GADD45A genes exhibiting prominence in human AP.

Experimental models of high-risk bowel anastomosis in rats:A systematic review

BACKGROUND Anastomotic leaks remain one of the most dreaded complications in gastrointestinal surgery causing significant morbidity,that negatively affect the patients’quality of life.Experimental studies play an important role in understanding the pathophysiological background of anastomotic healing and there are still many fields that require further investigation.Knowledge drawn from these studies can lead to interventions or techniques that can reduce the risk of anastomotic leak in patients with high-risk features.Despite the advances in experimental protocols and techniques,designing a high-quality study is still challenging for the investigators as there is a plethora of different models used.AIM To review current state of the art for experimental protocols in high-risk anastomosis in rats.METHODS This systematic review was performed according to The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.To identify eligible studies,a comprehensive literature search was performed in the electronic databases PubMed(MEDLINE)and Scopus,covering the period from conception until 18 October 2023.RESULTS From our search strategy 102 studies were included and were categorized based on the mechanism used to create a high-risk anastomosis.Methods of assessing anastomotic healing were extracted and were individually appraised.CONCLUSION Anastomotic healing studies have evolved over the last decades,but the findings are yet to be translated into human studies.There is a need for high-quality,well-designed studies that will help to the better understanding of the pathophysiology of anastomotic healing and the effects of various interventions.

Dynamic Modeling and Experimental Verification of an RPR Type Compliant Paralle Mechanism with Low Orders

Efficiency of calculating a dynamic response is an important point of the compliant mechanism for posture adjustment.Dynamic modeling with low orders of a 2R1T compliant parallel mechanism is studied in the paper.The mechanism with two out-of-plane rotational and one lifting degrees of freedom(DoFs)plays an important role in posture adjustment.Based on elastic beam theory,the stiffness matrix and mass matrix of the beam element are established where the moment of inertia is considered.To improve solving efficiency,a dynamic model with low orders of the mechanism is established based on a modified modal synthesis method.Firstly,each branch of the RPR type mechanism is divided into a substructure.Subsequently,a set of hypothetical modes of each substructure is obtained based on the C-B method.Finally,dynamic equation of the whole mechanism is established by the substructure assembly.A dynamic experiment is conducted to verify the dynamic characteristics of the compliant mechanism.

Genome-edited rabbits:Unleashing the potential of a promising experimental animal model across diverse diseases

Animal models are extensively used in all aspects of biomedical research,with substantial contributions to our understanding of diseases,the development of pharmaceuticals,and the exploration of gene functions.The field of genome modification in rabbits has progressed slowly.However,recent advancements,particularly in CRISPR/Cas9-related technologies,have catalyzed the successful development of various genome-edited rabbit models to mimic diverse diseases,including cardiovascular disorders,immunodeficiencies,agingrelated ailments,neurological diseases,and ophthalmic pathologies.These models hold great promise in advancing biomedical research due to their closer physiological and biochemical resemblance to humans compared to mice.This review aims to summarize the novel gene-editing approaches currently available for rabbits and present the applications and prospects of such models in biomedicine,underscoring their impact and future potential in translational medicine.

Progress in experimental models to investigate the in vivo and in vitro antidiabetic activity of drugs

Diabetes mellitus is one of the world's most prevalent and complex metabolic disorders,and it is a rapidly growing global public health issue.It is characterized by hyperglycemia,a condition involving a high blood glucose level brought on by deficiencies in insulin secretion,decreased activity of insulin,or both.Prolonged effects of diabetes include cardiovascular problems,retinopathy,neuropathy,nephropathy,and vascular alterations in both macro-and micro-blood vessels.In vivo and in vitro models have always been important for investigating and characterizing disease pathogenesis,identifying targets,and reviewing novel treatment options and medications.Fully understanding these models is crucial for the researchers so this review summarizes the different experimental in vivo and in vitro model options used to study diabetes and its consequences.The most popular in vivo studies involves the small animal models,such as rodent models,chemically induced diabetogens like streptozotocin and alloxan,and the possibility of deleting or overexpressing a specific gene by knockout and transgenic technologies on these animals.Other models include virally induced models,diet/nutrition induced diabetic animals,surgically induced models or pancreatectomy models,and non-obese models.Large animals or non-rodent models like porcine(pig),canine(dog),nonhuman primate,and Zebrafish models are also outlined.The in vitro models discussed are murine and human beta-cell lines and pancreatic islets,human stem cells,and organoid cultures.The other enzymatic in vitro tests to assess diabetes include assay of amylase inhibition and inhibition ofα-glucosidase activity.

An internal ballistic model of electromagnetic railgun based on PFN coupled with multi-physical field and experimental validation

To accelerate the practicality of electromagnetic railguns,it is necessary to use a combination of threedimensional numerical simulation and experiments to study the mechanism of bore damage.In this paper,a three-dimensional numerical model of the augmented railgun with four parallel unconventional rails is introduced to simulate the internal ballistic process and realize the multi-physics field coupling calculation of the rail gun,and a test experiment of a medium-caliber electromagnetic launcher powered by pulse formation network(PFN)is carried out.Various test methods such as spectrometer,fiber grating and high-speed camera are used to test several parameters such as muzzle initial velocity,transient magnetic field strength and stress-strain of rail.Combining the simulation results and experimental data,the damage condition of the contact surface is analyzed.

Fine Sand and Clay Sediment Acoustic Properties of the Novel Sediment Sample from the Arabian Sea:Experimental Investigations and Biot−Stoll Model Validation

The present study explores the physical and acoustic characteristics of fine sand and clay in novel seabed marine sediments from of Pakistan coastline of the Arabian Sea.The measured physical parameters included mean grain size,mass density,bulk density,salinity,porosity,permeability,pore size and mineralogical composition.Acoustic properties,including sound speed and attenuation,in the high frequency range of 90-170 kHz were analyzed.A controlled laboratory setup with the acoustic transmission method and Fourier transform techniques was utilized to examine the sound propagation and absorption of novel seabed sediments.The standard deviation of mean sound speed in fresh water was 0.75 m/s,and attenuation was observed in the range of 0.43 to 0.61 dB/m.The mean sound velocity in sand and clay varied from 1706 to 1709 m/s and 1602 to 1608 m/s,respectively.Corresponding average attenuation was observed at 80 to 93 dB/m in sandy sediments and from 31.8 to 38.6 dB/m in clayey sediments.Sound velocity variation within sandy sediment is low,consistent with expected results,and smaller than the predicted uncertainty.However,clay sediment exhibited a positive linear correlation and low sound speed variation.Attenuation increased linearly with frequency for both sediments.Finally,the laboratory results were validated by using the Biot−Stoll model.The dispersion of sound speed in sandy and clayey sediments was consistent with the predictions of the Biot−Stoll model.Measured attenuation aligned more with Biot−Stoll model predictions due to improved permeability,tortuosity and pore size parameter fitting.

Static-to-kinematic modeling and experimental validation of tendon-driven quasi continuum manipulators with nonconstant subsegment stiffness

Continuum robots with high flexibility and compliance have the capability to operate in confined and cluttered environments. To enhance the load capacity while maintaining robot dexterity, we propose a novel non-constant subsegment stiffness structure for tendon-driven quasi continuum robots(TDQCRs) comprising rigid-flexible coupling subsegments.Aiming at real-time control applications, we present a novel static-to-kinematic modeling approach to gain a comprehensive understanding of the TDQCR model. The analytical subsegment-based kinematics for the multisection manipulator is derived based on screw theory and product of exponentials formula, and the static model considering gravity loading,actuation loading, and robot constitutive laws is established. Additionally, the effect of tension attenuation caused by routing channel friction is considered in the robot statics, resulting in improved model accuracy. The root-mean-square error between the outputs of the static model and the experimental system is less than 1.63% of the arm length(0.5 m). By employing the proposed static model, a mapping of bending angles between the configuration space and the subsegment space is established. Furthermore, motion control experiments are conducted on our TDQCR system, and the results demonstrate the effectiveness of the static-to-kinematic model.

Growth and inhibition of zinc anode dendrites in Zn-air batteries:Model and experiment

Zinc(Zn)-air batteries are widely used in secondary battery research owing to their high theoretical energy density,good electrochemical reversibility,stable discharge performance,and low cost of the anode active material Zn.However,the Zn anode also leads to many challenges,including dendrite growth,deformation,and hydrogen precipitation self-corrosion.In this context,Zn dendrite growth has a greater impact on the cycle lives.In this dissertation,a dendrite growth model for a Zn-air battery was established based on electrochemical phase field theory,and the effects of the charging time,anisotropy strength,and electrolyte temperature on the morphology and growth height of Zn dendrites were studied.A series of experiments was designed with different gradient influencing factors in subsequent experiments to verify the theoretical simulations,including elevated electrolyte temperatures,flowing electrolytes,and pulsed charging.The simulation results show that the growth of Zn dendrites is controlled mainly by diffusion and mass transfer processes,whereas the electrolyte temperature,flow rate,and interfacial energy anisotropy intensity are the main factors.The experimental results show that an optimal electrolyte temperature of 343.15 K,an optimal electrolyte flow rate of 40 ml·min^(-1),and an effective pulse charging mode.

Auto-parametric resonance of a continuous-beam-bridge model under two-point periodic excitation:an experimental investigation and stability analysis

The auto-parametric resonance of a continuous-beam bridge model subjected to a two-point periodic excitation is experimentally and numerically investigated in this study.An auto-parametric resonance experiment of the test model is conducted to observe and measure the auto-parametric resonance of a continuous beam under a two-point excitation on columns.The parametric vibration equation is established for the test model using the finite-element method.The auto-parametric resonance stability of the structure is analyzed by using Newmark's method and the energy-growth exponent method.The effects of the phase difference of the two-point excitation on the stability boundaries of auto-parametric resonance are studied for the test model.Compared with the experiment,the numerical instability predictions of auto-parametric resonance are consistent with the test phenomena,and the numerical stability boundaries of auto-parametric resonance agree with the experimental ones.For a continuous beam bridge,when the ratio of multipoint excitation frequency(applied to the columns)to natural frequency of the continuous girder is approximately equal to 2,the continuous beam may undergo a strong auto-parametric resonance.Combined with the present experiment and analysis,a hypothesis of Volgograd Bridge's serpentine vibration is discussed.

Shock Initiation Experiments with Modeling on a DNAN Based MeltCast Insensitive Explosive

2,4-dinitroanisole(DNAN)is a good replacement for 2,4,6-trinitrotoluene(TNT)in melt-cast explosives due to its superior insensitivity.With the increasing use of DNAN-based melt-cast explosives,the prediction of reaction violence and hazard assessment of the explosives subjected to shock is of great significance.This study investigated the shock initiation characteristics for a DNAN-based melt-cast explosive,DHFA,using the one-dimensional Lagrangian apparatus.The embedded manganin gauges in the apparatus record the pressure histories at four Lagrangian positions and show that shock-todetonation transition in DHFA needs a high input shock pressure.The experimental data are analyzed to calibrate the Ignition and Growth model.The calibration is performed using an objective function based on both pressure history and the arrival time of shock.Good agreement between experimental and calculated pressure histories indicates the high accuracy of the calibrated parameters with the optimization method.

Effect of dry-wet cycles on dynamic properties and microstructures of sandstone:Experiments and modelling

Underground pumped storage power plant(UPSP)is an innovative concept for space recycling of abandoned mines.Its realization requires better understanding of the dynamic performance and durability of reservoir rock.This paper conducted ultrasonic detection,split Hopkinson pressure bar(SHPB)impact,mercury intrusion porosimetry(MIP),and backscatter electron observation(BSE)tests to investigate the dynamical behaviour and microstructure of sandstone with cyclical dry-wet damage.A coupling FEM-DEM model was constructed for reappearing mesoscopic structure damage.The results show that dry-wet cycles decrease the dynamic compressive strength(DCS)with a maximum reduction of 39.40%,the elastic limit strength is reduced from 41.75 to 25.62 MPa.The sieved fragments obtain the highest crack growth rate during the 23rd dry-wet cycle with a predictable life of 25 cycles for each rock particle.The pore fractal features of the macropores and micro-meso pores show great differences between the early and late cycles,which verifies the computational statistics analysis of particle deterioration.The numerical results show that the failure patterns are governed by the strain in pre-peak stage and the shear cracks are dominant.The dry-wet cycles reduce the energy transfer efficiency and lead to the discretization of force chain and crack fields.

Utilization of Logistical Regression to the Modified Sine-Gordon Model in the MST Experiment

In this paper, a logistical regression statistical analysis (LR) is presented for a set of variables used in experimental measurements in reversed field pinch (RFP) machines, commonly known as “slinky mode” (SM), observed to travel around the torus in Madison Symmetric Torus (MST). The LR analysis is used to utilize the modified Sine-Gordon dynamic equation model to predict with high confidence whether the slinky mode will lock or not lock when compared to the experimentally measured motion of the slinky mode. It is observed that under certain conditions, the slinky mode “locks” at or near the intersection of poloidal and/or toroidal gaps in MST. However, locked mode cease to travel around the torus;while unlocked mode keeps traveling without a change in the energy, making it hard to determine an exact set of conditions to predict locking/unlocking behaviour. The significant key model parameters determined by LR analysis are shown to improve the Sine-Gordon model’s ability to determine the locking/unlocking of magnetohydrodyamic (MHD) modes. The LR analysis of measured variables provides high confidence in anticipating locking versus unlocking of slinky mode proven by relational comparisons between simulations and the experimentally measured motion of the slinky mode in MST.

采用STAMP-24Model的多组织事故分析

安全生产事故往往由多组织交互、多因素耦合造成,事故原因涉及多个组织。为预防和遏制多组织生产安全事故的发生,基于系统理论事故建模与过程模型(Systems-Theory Accident Modeling and Process,STAMP)、24Model,构建一种用于多组织事故分析的方法,并以青岛石油爆炸事故为例进行事故原因分析。结果显示:STAMP-24Model可以分组织,分层次且有效、全面、详细地分析涉及多个组织的事故原因,探究多组织之间的交互关系;对事故进行动态演化分析,可得到各组织不安全动作耦合关系与形成的事故失效链及管控失效路径,进而为预防多组织事故提供思路和参考。

MicroRNAs in mouse and rat models of experimental epilepsy and potential therapeutic targets

Epilepsy is a common and serious neurological disease that causes recurrent seizures. The brain damage caused by seizures can lead to depression, anxiety, cognitive impairment, or disability. In almost all cases chronic seizures are difficult to cure. MicroRNAs are widely expressed in the central nervous system and play important roles in the pathogenesis of several neurological disorders, including epilepsy. A variety of animals(mostly mice and rats) have been used to induce experimental epilepsy using different protocols and miRNA profiling performed. Most of the recent studies reviewed had performed miRNA profiling in hippocampal tissues and a large number of microRNAs were dysregulated when compared to controls. Most notably, miR-132-3p,-146a-5p,-10a-5p,-21a-3p,-27a-3p,-142a-5p,-212-3p,-431-5p, and-155 were upregulated in both the mouse and rat studies. Overexpression of miR-137 and miR-219 decreased seizure severity in a mouse epileptic model, and suppression of miR-451,-10a-5p,-21a-5p,-27a-5p,-142a-5p,-431-5p,-155, and-134 had a positive influence on seizure behavior. In the rat studies, overexpression of miR-139-5p decreased neuronal damage in drug-resistant rats and inhibition of miR-129-2-3p,-27a-3p,-155,-134,-181a, and-146a had a positive effect on seizure behavior and/or reduced the loss of neuronal cells. Further studies are warranted using adult female and immature male and female animals. It would also be helpful to test the ability of specific agomirs and antagomirs to control seizure activity in a subhuman primate model of epilepsy such as adult marmosets injected intraperitoneally with pilocarpine or cynomolgus monkeys given intrahippocampal injections of kainic acid.

Advances in viral encephalitis:Viral transmission,host immunity,and experimental animal models

Viral infections have led to many public health crises and pandemics in the last few centuries.Neurotropic virus infection-induced viral encephalitis(VE),especially the symptomatic inflammation of the meninges and brain parenchyma,has attracted growing attention due to its high mortality and disability rates.Understanding the infectious routes of neurotropic viruses and the mechanism underlying the host immune response is critical to reduce viral spread and improve antiviral therapy outcomes.In this review,we summarize the common categories of neurotropic viruses,viral transmission routes in the body,host immune responses,and experimental animal models used for VE study to gain a deeper understanding of recent progress in the pathogenic and immunological mechanisms under neurotropic viral infection.This review should provide valuable resources and perspectives on how to cope with pandemic infections.

基于改进24Model-ISM-SNA建筑工人不安全行为关联路径研究

建筑施工现场环境复杂,为有效控制不安全行为发生,基于行为安全“2-4”模型对360份具有代表性的建筑安全事故调查报告进行分析,提取出22个不安全行为的主要影响因素。利用灰色关联分析方法(GRA)改进的集成ISM-SNA模型,将不安全行为风险因素划分为表层、过渡层与深层,然后对风险因素进行可视化分析、中心度分析及凝聚子群分析,揭示了各致因因素间的关联关系和传导路径。结果表明,建筑工人不安全行为影响因素可划分成7级3阶的多级递阶结构,安全意识、现场监管、外部环境是建筑工人不安全行为的关键影响因素,同时现场监管和隐患排查到位能有效降低不安全行为的发生。

基于24Model-D-ISM的地铁站火灾疏散影响因素研究

为预防地铁站火灾事故,深入了解地铁站火灾人员疏散影响因素间的内在联系与层次结构,基于第6版“2-4”模型(24Model)分析63起地铁站火灾疏散事故,充分考虑各个因素之间的交互作用,提取19个影响地铁站人员疏散的关键因素,建立地铁站火灾人员疏散影响因素指标体系;采用算子客观赋权法(C-OWA)改进决策试验与评价实验法(DEMATEL),确定地铁站火灾人员疏散的重要影响因素;在此基础上,采用解释结构模型(ISM)分析各个因素间的层次结构及相互作用路径,构建地铁站火灾人员疏散影响因素的多级递阶结构模型。研究结果表明:疏散引导、恐慌从众行为、人员拥挤为地铁站火灾人员疏散的关键影响因素;地铁站火灾人员疏散受表层因素、中间层因素、深层因素共同作用的影响,其中,疏散教育与培训、设施维护与检查、疏散预案等因素是根源影响因素,重视根源影响因素的改善有利于从本质上预防和控制事故的发生。

Computational Experiments for Complex Social Systems:Experiment Design and Generative Explanation

Powered by advanced information technology,more and more complex systems are exhibiting characteristics of the cyber-physical-social systems(CPSS).In this context,computational experiments method has emerged as a novel approach for the design,analysis,management,control,and integration of CPSS,which can realize the causal analysis of complex systems by means of“algorithmization”of“counterfactuals”.However,because CPSS involve human and social factors(e.g.,autonomy,initiative,and sociality),it is difficult for traditional design of experiment(DOE)methods to achieve the generative explanation of system emergence.To address this challenge,this paper proposes an integrated approach to the design of computational experiments,incorporating three key modules:1)Descriptive module:Determining the influencing factors and response variables of the system by means of the modeling of an artificial society;2)Interpretative module:Selecting factorial experimental design solution to identify the relationship between influencing factors and macro phenomena;3)Predictive module:Building a meta-model that is equivalent to artificial society to explore its operating laws.Finally,a case study of crowd-sourcing platforms is presented to illustrate the application process and effectiveness of the proposed approach,which can reveal the social impact of algorithmic behavior on“rider race”.