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.

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.

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.

Animal models for anti-neutrophil cytoplasmic antibody-associated vasculitis:Are current models good enough?

Antineutrophil cytoplasmic autoantibody(ANCA)-associated vasculitis(AAV)is a rare and severe systemic autoimmune disease characterized by pauci-immune necrotizing inflammation of small blood vessels.AAV involves multiple organ systems throughout the body.Our knowledge of the pathogenesis of AAV has increased considerably in recent years,involving cellular,molecular and genetic factors.Because of the controlled environment with no other confounding factors,animal models are beneficial for studying the mechanistic details of disease development and for providing novel therapeutic targets with fewer toxic side effects.However,the complexity and heterogeneity of AAV make it very difficult to establish a single animal model that can fully represent the entire clinical spectrum found in patients.The aim of this review is to overview the current status of animal models for AAV,outline the pros and cons of methods,and propose potential directions for future research.

Water Modeling of Optimizing Tundish Flow Field

In the water modeling experiments, three cases were considered, i. e, , a bare tundish, a tundish equipped with a turbulence inhibitor, and a rectangular tundish equipped with weirs （dams） and a turbulence inhibitor. Comparing the RTD curves, inclusion separation, and the result of the streamline experiment, it can be found that the tundish equipped with weirs （dams） and a turbulence inhibitor has a great effect on the flow field and the inclusion separation when compared with the sole use or no use of the turbulent inhibitor or weirs （dams）. In addition, the enlargement of the distance between the weir and dam will result in a better effect when the tundish equipped with weirs （dam） and a turbulence inhibitor was used.

Spatiotemporal evolution rule of rocks fracture surrounding gob-side roadway with model experiments

A series of plane-strain physical model experiments are carried out to study the spatiotemporal evolution rule of rocks fracture surrounding gob-side roadway, which is subjected to the pressure induced by the mining process. The digital photogrammetry technology and large deformation analysis method are applied to measure the deformation and fracture of surrounding rocks. The experimental results indicate that the deformation and fracture of coal pillars are the cause to the instability and failure of the surrounding rocks. The spatiotemporal evolution rule of the rock deformation and fracture surrounding gob-side roadway is obtained. The coal pillar and the roof near coal pillar should be strengthened in support design. The engineering application results also can provide a useful guide that the combined support with wire meshes, beam, anchor bolt and cable is an effective method.

The Selection and Breeding of a Novel Microorganism Strain I and Investigation of Core Model Experiment for MEOR

This paper introduces the results of selecting and breeding a micro-organism, Strain I, and its core model experiment investigation for microbial enhanced oil recovery (MEOR). Strain I was separated from the formation water of the Dagang oil field, with analytical results showing that Strain I is a gram-positive bacillus. A further study revealed that this strain has an excellent tolerance of environmental stresses: It can survive in conditions of 70℃, 30 wt% salinity and pH3.5-9.4. Strain I can metabolize biosurfactants that could increase the oil recovery ratio, use crude oil as the single carbon source, and decompose long-chain paraffin with a large molecular weight into short-chain paraffin with a small molecular weight. The core model experiment shows that Strain I enhances oil recovery well. Using 2 vol% of the fermentation solution of Strain I to displace the crude oil in the synthetic plastic bonding core could increase the recovery ratio by 21.6%.

Mechanism of progressive failure of a slope with a steep joint under the action of freezing and thawing:model test

The stability of slope rock masses is influenced by freeze-thaw cycles in cold region,and the mechanism of stability deterioration is not clear.In order to understand the damage and progressive failure characteristics of rock masses under the action of freezing and thawing,a model test was conducted on slope with steep joint in this study.The temperature,frost heaving pressure and deformation of slope rock mass were monitored in real-time during the test and the progressive failure mode was studied.The experimental results show that the temperature variations of cracking and the rock mass of a slope are different.There are obvious latent heat stages in the temperature-change plot in the crack,but not in the slope rock masses.The frost heaving effect in the fracture is closely related to the constraint conditions,which change with the deformation of the fracture.The frost heaving pressure fluctuates periodically during freezing and continues to decrease during thawing.The surface deformation of the rock mass increases during freezing,and the deformation is restored when it thaws.Freeze-thaw cycling results in residual deformation of the rock mass which cannot be fully restored.Analysis shows that the rock mass at the free side of the steep-dip joint rotates slightly under the frost heaving effect,causing fracture propagation.The fracture propagation pattern is a circular arc at the beginning,then extends to the possible sliding direction of the rock mass.Frost heaving force and fracture water pressure are the key factors for the failure of the slope,which can cause the crack to penetrate the rock mass,and a landslide ensues when the overall anti-sliding resistance of the rock mass is overcome.

Classic mechanisms and experimental models for the anti-inflammatory effect of traditional Chinese medicine

Inflammation is a common disease involved in the pathogenesis,complications,and sequelae of a large number of related diseases,and therefore considerable research has been directed toward developing anti-inflammatory drugs for the prevention and treatment of these diseases.Traditional Chinese medicine(TCM)has been used to treat inflammatory and related diseases since ancient times.According to the re-view of abundant modern scientific researches,it is suggested that TCM exhibit anti-inflammatory effects at different levels,and via multiple pathways with various targets,and recently a series of in vitro and in vivo anti-inflammatory models have been developed for anti-inflammation research in TCM.Currently,the reported classic mechanisms of TCM and experimental models of its anti-inflammatory effects pro-vide reference points and guidance for further research and development of TCM.Importantly,the research clearly confirms that TCM is now and will continue to be an effective form of treatment for many types of inflammation and inflammation-related diseases.

Evaluation of a Micro-scale Wind Model's Performance over Realistic Building Clusters Using Wind Tunnel Experiments

The simulation performance over complex building clusters of a wind simulation model（Wind Information Field Fast Analysis model, WIFFA） in a micro-scale air pollutant dispersion model system（Urban Microscale Air Pollution dispersion Simulation model, UMAPS） is evaluated using various wind tunnel experimental data including the CEDVAL（Compilation of Experimental Data for Validation of Micro-Scale Dispersion Models） wind tunnel experiment data and the NJU-FZ experiment data（Nanjing University-Fang Zhuang neighborhood wind tunnel experiment data）. The results show that the wind model can reproduce the vortexes triggered by urban buildings well, and the flow patterns in urban street canyons and building clusters can also be represented. Due to the complex shapes of buildings and their distributions, the simulation deviations/discrepancies from the measurements are usually caused by the simplification of the building shapes and the determination of the key zone sizes. The computational efficiencies of different cases are also discussed in this paper. The model has a high computational efficiency compared to traditional numerical models that solve the Navier–Stokes equations, and can produce very high-resolution（1–5 m） wind fields of a complex neighborhood scale urban building canopy（～ 1 km ×1km） in less than 3 min when run on a personal computer.

Establishing an experimental model of photodynamic induced anterior ischemic optic neuropathy

BACKGROUND： Scholars have supposed to establish animal models of optic neuropathy by pressing and partially amputating optic nerve, increasing intraocular pressure and injecting vasoconstrictor, etc., but the models are greatly different from anterior ischemia optic neuropathy. Therefore, a more ideal method is needed to establish animal model of anterior ischemic optic neuropathy （AION）. OBJECTIVE ： To establish AION models in rats, observe the functional changes of fundus, fundus fluorescein angiography （FFA）, optical coherence tomography （OCT）, flash visual evoked potential （F-VEP）, and histopathologically confirm its reliability. DESIGN： A randomized control tria SETTINGS ： Department of Ophthalmology, Xi＇an Fourth Hospital; Xi＇an Institute of Ocular Fundus Diseases MATERIALS ： The experiments were carried out in the research room of Xi＇an Institute of Ocular Fundus Diseases from February 2005 to May 2006. Thirty healthy male SD rats of 4-5 weeks old, weighing 140-160 g, were provided by the animal experimental center of the Fourth Military Medical University of Chinese PLA [SCXK （Military）2002-005], and those without eye disease examined by slit lamp and direct ophthalmoscope after mydriasis were enrolled. The conditions for feeding mice without special pathogen were strictly followed. The rats were randomly divided into blank control group （n =5）, laser group （n =5）, hematoporphyrin derivative （HPD） group and AION group （n =15）, each group was numbered randomly. For each rat, the right eye was taken as the experimental eye, and the left one as the control one. METHODS： In the AION group, the rats were injected with HPD （10 mg/kg） via caudal vein, and then the optic discs were exposed to krypton red （647 nm, 80 mV） for 120 s, and the rats were in avoidance of light for 2 weeks postoperatively. Rats in the laser group were only exposed to krypton red （647 rim, 80 mV） for 120 s, and in avoidance of light for 2 weeks postoperatively; Those in the HPD group were only injected with HPD （10 mg/kg） via caudal vein; Those in the blank control group were untouched. （1） Visual electrophysiological test： The F-VEP was used to evaluate the function of visual nerve. （2） FFA： After mydriasis and anesthesia as describe above, the fluorescein sodium parenteral solution （1 mL/kg） was injected v/a caudal vein and finished within about 3 s, the time of FFA was recorded from the beginning of injection, the video sight aimed at the optic disc and the surrounding area. （3） After mydriasis and anesthesia as describe above, the rats were examined with OCT. （4） Histological observation： After hematoxylin and eosin （HE） staining, the optic disc and surrounding blood vessels of retina were observed under light microscope at high power field. MAIN OUTCOME MEASURES： The results of fundus, FFA, visual electrophysiological test and OCT detection within 90 days after model establishment were observed. RESULTS： Of the 30 rats, 1 died after anesthesia in the laser group and 2 died in the AION group respectively, and finally 27 rats were involved in the analysis of results. （1） Changes in fundus： In the AION group, there was edema in upper optic disc and unclear boundary at 1 day after establishment, edema still could be observed at 6 days, and upper optic disc atrophied and appeared as pale at 90 days. （2） FFA results： In the AION group, early ＂low fluorescence＂, middle and late ＂high fluorescence＂ were observed in upper optic disc 1 day after model establishment, and there was ＂low fluorescence＂ at 6 days, and the low fluorescence could be observed all the time at 23 days. （3） Visual electrophysiological changes： In the AION group as compared with the control eyes, the experimental ones had prolonged F-VEP P100 latency [（71.65±8.81）, （57.58±8.38） ms, t =3.148, P =0.012], and decreased wave amplitude [（4.77±1.90）, （10.06±3.66） μV, t =4.082, P =0.003], and these changes lasted to 35 days after model establishment. （4） OCT results： In the AION group, the reflection surface of part nerve fiber layer was higher than the retina plane, the surface was rough and the thickness was increased at 6 days after model establishment. （5） Histopathological results： At 1 day after model establishment, part optic discs had highly edema, edema of nerve fibers, and loose tissue, also accompanied by the displacement of surrounding retina; At 23 days, the optic disc and surrounding nerve fiber layers became thinner, and the numbers of ganglion nuclei in the retina tissue sections were obviously decreased. These changes were not observed in the laser group, HPD group and blank control group. CONCLUSION ： The changes of fundus, FFA, OCT, visual electrophysiology and histopathology confirmed that the krypton red laser irradiation （647 nm） at 2 hours after HPD was injected via caudal vein can establish more ideal animal models of AION.

Establishment of Bacterial Lobular Pneumonia Model in Mice

In this study cortisol and cyclophosphamide were injected into abdominal cavities of mice to keep them in an immunosuppressive state. Then the pathogen Klebsiella pneumoniae was given to infect the lungs and the experimental modcl of lobular pneumonia in the mice was thus established successfully.The experimental animal model has typical pathologic manifestation and good replication and can be used to to study the effect of drugs.

A Nine-layer Atmospheric General Circulation Model and Its Performance

Different versions of a new nine-layer general circulation model which is rhomboidally truncated at zonal wavenumber 15(L9R15)are introduced in this paper.On using the observed global monthly sea surfaCe temperature(SST)and sea ice(SI)data from 1979 to 1988 offered by the internahonal Atmospheric Model Iute-comparison Program(AMIP),these different model versions were integrated for the ten-year AMIP period. Results show that the model iscapable of simulating the basic states of the atmosphere and its interannual variability,and in performing reasonablesensitivity experiments.

Evaluating the Amount of Erodability and Sedimentation by Comparing Sediment Weight Model and PSIAC Experimental Model (Case Study: Lali Water Catchment, Khuzestan, Iran)

The upstream water catchments are the main source providing sediments in rivers and sedimentary basins. The balance between the erosion phenomenon and the amount of sediment entering into the basin relies on the geometrical specifications and the morphology of the river along the water catchment direction and the amount and type of the sediments. The sedimentary feed of rivers and basins are changed for the sake of natural factors or human disturbances. The river and basin react against this change in that their shape, morphology, plan and profile get changed due to the increase or decrease of the input sediment into the basin. It is essential to know the sediment amount produced by erodability and sedimentation of upstream basins and effects of projects and also to evaluate the amount of sedimentary load in base studies, civil projects, optimizing rivers and dam construction studies specially calculating the amount of sediment amount entering into the dams’ reservoirs in order to take engineering decisions and related alternatives. Sediment Weight Model and PSIAC Experimental Model are recognized as two common methods calculating the amount of the produced sediment caused by erosion applied in this research. Holistically, these methods have been used and compared. Although the results are almost close to one another, more sediment load has been produced in PSIAC method. As more affective parameters are used to cause erosion and produce sediment in PSIAC experimental model, it is recommended to refer to the results of this method because they are closer to reality.

Physical Model of Drying Shrinkage of Recycled Aggregate Concrete

We prepared concretes（RC0, RC30, and RC100） with three different mixes. The poresize distribution parameters of RAC were examined by high-precision mercury intrusion method（MIM） and nuclear magnetic resonance（NMR） imaging. A capillary-bundle physical model with random-distribution pores（improved model, IM） was established according to the parameters, and dry-shrinkage strain values were calculated and verified. Results show that in all pore types, capillary pores, and gel pores have the greatest impacts on concrete shrinkage, especially for pores 2.5-50 and 50-100 nm in size. The median radii are 34.2, 31, and 34 nm for RC0, RC30, and RC100, respectively. Moreover, the internal micropore size distribution of RC0 differs from that of RC30 and RC100, and the pore descriptions of MIM and NMR are consistent both in theory and in practice. Compared with the traditional capillary-bundle model, the calculated results of IM have higher accuracy as demonstrated by experimental verifi cation.

Discrete optimization models and methods for management systems of pavement maintenance and rehabilitation

With the rapid development of highway construction and formation of the highway network in China,the man- agement of pavement maintenance and rehabilitation （MR） activities has become important.In this paper,four discrete optimization models are proposed for different parties involved in the management system： government,highway agent,con- tractor and the common users.These four optimal decision models are formulated as linear integer programming problems with binary decision variables.The objective function and constraints are based on the pavement performance and prediction model using the pavement condition index （PCI）.Numerical experiments are carried out with the data from a highway system in Sichuan Province which show the feasibility and effectiveness of the proposed models.

Effects of diesel oil on the polychaete Annelida in model benthic ecosystem

An experiment about the effect of diesel oil pollution on the model benthic ecosystem was conducted inthe land-based tank at the 3rd Institute of Oceanography, State Oceanic Administration, in Xiamen, added with No.0 diesel oil at concentrations of 5, 25, 125, 625 mg/dm3 in water of series sub-tanks for 16 h. The changes in polychaete community were studied in the period of two weeks with results that though all concentrations did not basically altered the population structure and composition, the total biomass decreased significantly and individualstended to be smaller in size. The average weight of individual decreased with the increase of diesel pollutant stress.

Research on the optimization of tundish by water model

Based on the principle of similarity, water was used to simulate the flow of molten steel to analyze the flow field in a tundish. Several schemes of the tundish＇ s tracer shape were designed and corresponding water model experiments were conducted. During the experiments, a computer automatically collected data. The comparison of the residence time distribution（ RTD ） curves drawn according to the computer-collected data optimized the scheme and photographs originated from the experiments with ink as its tracer. It indicates that the water model can optimize the flow field of the tundish.