Effects of mesenchymal stem cell on dopaminergic neurons,motor and memory functions in animal models of Parkinson's disease:a systematic review and meta-analysis

Parkinson’s disease is chara cterized by the loss of dopaminergic neurons in the substantia nigra pars com pacta,and although restoring striatal dopamine levels may improve symptoms,no treatment can cure or reve rse the disease itself.Stem cell therapy has a regenerative effect and is being actively studied as a candidate for the treatment of Parkinson’s disease.Mesenchymal stem cells are considered a promising option due to fewer ethical concerns,a lower risk of immune rejection,and a lower risk of teratogenicity.We performed a meta-analysis to evaluate the therapeutic effects of mesenchymal stem cells and their derivatives on motor function,memory,and preservation of dopamine rgic neurons in a Parkinson’s disease animal model.We searched bibliographic databases(PubMed/MEDLINE,Embase,CENTRAL,Scopus,and Web of Science)to identify articles and included only pee r-reviewed in vivo interve ntional animal studies published in any language through J une 28,2023.The study utilized the random-effect model to estimate the 95%confidence intervals(CI)of the standard mean differences(SMD)between the treatment and control groups.We use the systematic review center for laboratory animal expe rimentation’s risk of bias tool and the collaborative approach to meta-analysis and review of animal studies checklist for study quality assessment.A total of 33studies with data from 840 Parkinson’s disease model animals were included in the meta-analysis.Treatment with mesenchymal stem cells significantly improved motor function as assessed by the amphetamine-induced rotational test.Among the stem cell types,the bone marrow MSCs with neurotrophic factor group showed la rgest effect size(SMD[95%CI]=-6.21[-9.50 to-2.93],P=0.0001,I^(2)=0.0%).The stem cell treatment group had significantly more tyrosine hydroxylase positive dopamine rgic neurons in the striatum([95%CI]=1.04[0.59 to 1.49],P=0.0001,I^(2)=65.1%)and substantia nigra(SMD[95%CI]=1.38[0.89 to 1.87],P=0.0001,I^(2)=75.3%),indicating a protective effect on dopaminergic neurons.Subgroup analysis of the amphetamine-induced rotation test showed a significant reduction only in the intracranial-striatum route(SMD[95%CI]=-2.59[-3.25 to-1.94],P=0.0001,I^(2)=74.4%).The memory test showed significant improvement only in the intravenous route(SMD[95%CI]=4.80[1.84 to 7.76],P=0.027,I^(2)=79.6%).Mesenchymal stem cells have been shown to positively impact motor function and memory function and protect dopaminergic neurons in preclinical models of Parkinson’s disease.Further research is required to determine the optimal stem cell types,modifications,transplanted cell numbe rs,and delivery methods for these protocols.

Immunobiology of COVID-19: Mechanistic and therapeutic insights from animal models

The distribution of the immune system throughout the body complicates in vitro assessments of coronavirus disease 2019(COVID-19)immunobiology,often resulting in a lack of reproducibility when extrapolated to the whole organism.Consequently,developing animal models is imperative for a comprehensive understanding of the pathology and immunology of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.This review summarizes current progress related to COVID-19 animal models,including non-human primates(NHPs),mice,and hamsters,with a focus on their roles in exploring the mechanisms of immunopathology,immune protection,and long-term effects of SARS-CoV-2 infection,as well as their application in immunoprevention and immunotherapy of SARS-CoV-2 infection.Differences among these animal models and their specific applications are also highlighted,as no single model can fully encapsulate all aspects of COVID-19.To effectively address the challenges posed by COVID-19,it is essential to select appropriate animal models that can accurately replicate both fatal and non-fatal infections with varying courses and severities.Optimizing animal model libraries and associated research tools is key to resolving the global COVID-19 pandemic,serving as a robust resource for future emerging infectious diseases.

Genetically modified pigs:Emerging animal models for hereditary hearing loss

Hereditary hearing loss(HHL),a genetic disorder that impairs auditory function,significantly affects quality of life and incurs substantial economic losses for society.To investigate the underlying causes of HHL and evaluate therapeutic outcomes,appropriate animal models are necessary.Pigs have been extensively used as valuable large animal models in biomedical research.In this review,we highlight the advantages of pig models in terms of ear anatomy,inner ear morphology,and electrophysiological characteristics,as well as recent advancements in the development of distinct genetically modified porcine models of hearing loss.Additionally,we discuss the prospects,challenges,and recommendations regarding the use pig models in HHL research.Overall,this review provides insights and perspectives for future studies on HHL using porcine models.

Large animal models for Huntington's disease research

Huntington'sdisease(HD)isahereditary neurodegenerative disorder for which there is currently no effectivetreatmentavailable.Consequently,the development of appropriate disease models is critical to thoroughly investigate disease progression.The genetic basis of HD involves the abnormal expansion of CAG repeats in the huntingtin(HTT)gene,leading to the expansion of a polyglutamine repeat in the HTT protein.Mutant HTT carrying the expanded polyglutamine repeat undergoes misfolding and forms aggregates in the brain,which precipitate selective neuronal loss in specific brain regions.Animal models play an important role in elucidating the pathogenesis of neurodegenerative disorders such as HD and in identifying potential therapeutic targets.Due to the marked species differences between rodents and larger animals,substantial efforts have been directed toward establishing large animal models for HD research.These models are pivotal for advancing the discovery of novel therapeutic targets,enhancing effective drug delivery methods,and improving treatment outcomes.We have explored the advantages of utilizing large animal models,particularly pigs,in previous reviews.Since then,however,significant progress has been made in developing more sophisticated animal models that faithfully replicate the typical pathology of HD.In the current review,we provide a comprehensive overview of large animal models of HD,incorporating recent findings regarding the establishment of HD knock-in(KI)pigs and their genetic therapy.We also explore the utilization of large animal models in HD research,with a focus on sheep,non-human primates(NHPs),and pigs.Our objective is to provide valuable insights into the application of these large animal models for the investigation and treatment of neurodegenerative disorders.

Neurophysiological, histological, and behavioral characterization of animal models of distraction spinal cord injury: a systematic review

Distraction spinal cord injury is caused by some degree of distraction or longitudinal tension on the spinal cord and commonly occurs in patients who undergo corrective operation for severe spinal deformity.With the increased degree and duration of distraction,spinal cord injuries become more serious in terms of their neurophysiology,histology,and behavior.Very few studies have been published on the specific characteristics of distraction spinal cord injury.In this study,we systematically review 22 related studies involving animal models of distraction spinal cord injury,focusing particularly on the neurophysiological,histological,and behavioral characteristics of this disease.In addition,we summarize the mechanisms underlying primary and secondary injuries caused by distraction spinal cord injury and clarify the effects of different degrees and durations of distraction on the primary injuries associated with spinal cord injury.We provide new concepts for the establishment of a model of distraction spinal cord injury and related basic research,and provide reference guidelines for the clinical diagnosis and treatment of this disease.

Knee osteoarthritis:A review of animal models and intervention of traditional Chinese medicine

Background:Knee osteoarthritis(KOA)characterized by degeneration of knee cartilage and subsequent bone hyperplasia is a prevalent joint condition primarily affecting aging adults.The pathophysiology of KOA remains poorly understood,as it involves complex mechanisms that result in the same outcome.Consequently,researchers are interested in studying KOA and require appropriate animal models for basic research.Chinese herbal compounds,which consist of multiple herbs with diverse pharmacological properties,possess characteristics such as multicomponent,multipathway,and multitarget effects.The potential benefits in the treatment of KOA continue to attract attention.Purpose:This study aims to provide a comprehensive overview of the advantages,limitations,and specific considerations in selecting different species and methods for KOA animal models.This will help researchers make informed decisions when choosing an animal model.Methods:Online academic databases(e.g.,PubMed,Google Scholar,Web of Science,and CNKI)were searched using the search terms“knee osteoarthritis,”“animal models,”“traditional Chinese medicine,”and their combinations,primarily including KOA studies published from 2010 to 2023.Results:Based on literature retrieval,this review provides a comprehensive overview of the methods of establishing KOA animal models;introduces the current status of advantages and disadvantages of various animal models,including mice,rats,rabbits,dogs,and sheep/goats;and presents the current status of methods used to establish KOA animal models.Conclusion:This study provides a review of the animal models used in recent KOA research,discusses the common modeling methods,and emphasizes the role of traditional Chinese medicine compounds in the treatment of KOA.

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.

Animal models of eosinophilic esophagitis,review and perspectives

Eosinophilic oesophagitis(EoE)is an allergen/immune-mediated chronic esophageal disease characterized by esophageal mucosal eosinophilic infiltration and esophageal dysfunction.Although the disease was originally attributed to a delayed allergic reaction to allergens and a Th2-type immune response,the exact pathogenesis is complex,and the efficacy of existing treatments is unsatisfactory.Therefore,the study of the pathophysiological process of EOE has received increasing attention.Animal models have been used extensively to study the molecular mechanism of EOE pathogenesis and also provide a preclinical platform for human clinical intervention studies of novel therapeutic agents.To maximize the use of existing animal models of EOE,it is important to understand the advantages or limitations of each modeling approach.This paper systematically describes the selection of experimental animals,types of allergens,and methods of sensitization and excitation during the preparation of animal models of EoE.It also discusses the utility and shortcomings of each model with the aim of providing the latest perspectives on EoE models and leading to better choices of animal models.

Animal models of hepatitis E infection: Advances and challenges

Hepatitis E virus(HEV)is one of the leading causes of acute viral hepatitis worldwide.Although most of HEV infections are asymptomatic,some patients will develop the symptoms,especially pregnant women,the elderly,and patients with preexisting liver diseases,who often experience anorexia,nausea,vom-iting,malaise,abdominal pain,and jaundice.HEV infection may become chronic in immunosuppressed individuals.In addition,HEV infection can also cause several extrahepatic manifestations.HEV exists in a wide range of hosts in nature and can be transmitted across species.Hence,animals susceptible to HEV can be used as models.The establishment of animal models is of great significance for studying HEV transmission,clinical symptoms,extrahepatic manifestations,and therapeutic strategies,which will help us understand the pathogenesis,prevention,and treatment of hepatitis E.This review summarized the animal models of HEV,including pigs,monkeys,rabbits,mice,rats,and other animals.For each animal species,we provided a concise summary of the HEV genotypes that they can be infected with,the cross-species transmission pathways,as well as their role in studying extrahepatic manifestations,prevention,and treatment of HEV infection.The advantages and disadvantages of these animal models were also emphasized.This review offers new perspectives to enhance the current understanding of the research landscape surrounding HEV animal models.

Animal models of tendon calcification:Past,present,and future

Tendon calcification is a common clinical condition that frequently occurs as a complication after tendon injury and surgery,or as an expression of fibrodysplasia ossificans progressiva.This condition can be referred to by various names in clinical practice and literature,including tendon ossification,tendon mineralization,heterotopic ossification,and calcific tendonitis.The exact pathogenesis of tendon calcification remains uncertain,but current mainstream research suggests that calcification is mostly cell mediated.To further elucidate the pathogenesis of tendon calcification and to better simulate the overall process,selecting appropriate experimental animal models is important.Numerous animal models have been utilized in various clinical studies,each with its own set of advantages and limitations.In this review,we have discussed the advancements made in research on animal models of tendon calcification,with a focus on the selection of experimental animals,the sites of injury in these models,and the methods employed for modeling.

Applications and advancements in animal models for antiviral research on mosquito-borne arboviruses

Vector-borne diseases caused by arthropod-borne viruses(arboviruses) are a considerable challenge to public health globally. Mosquito-borne arboviruses, such as Chikungunya, Dengue, and Zika viruses, cause a range of human illnesses and may be fatal. Currently, efforts to control these diseases still face challenges due to growing vector resistance towards insecticides, urbanization, and limited effective antiviral treatments and vaccines. Animal models are crucial in antiviral research on mosquito-borne arboviruses, playing a role in understanding disease mechanisms,vaccine development, and toxicity testing, but the application of animal models still faces the challenges of ethical considerations and animal-to-human translational success. Genetically engineered mouse models, hamster models and non-human primate(NHP) are currently used in arbovirus research, but new models such as tree shrews and novel humanized mice are emerging. In the context of Malaysian research, the use of long-tailed macaques as potential NHP models for arbovirus research is possible;however, it faces the ethical dilemma of using an endangered species for scientific purposes. Overall, animal models play a crucial role in advancing infectious disease research, but a balance between medical research and species conservation must be upheld.

How can we establish animal models of HIV-associated lymphoma?

Human immunodeficiency virus(HIV)infection is strongly associated with a height-ened incidence of lymphomas.To mirror the natural course of human HIV infection,animal models have been developed.These models serve as valuable tools to inves-tigate disease pathobiology,assess antiretroviral and immunomodulatory drugs,ex-plore viral reservoirs,and develop eradication strategies.However,there are currently no validated in vivo models of HIV-associated lymphoma(HAL),hampering progress in this crucial domain,and scant attention has been given to developing animal models dedicated to studying HAL,despite their pivotal role in advancing knowledge.This re-view provides a comprehensive overview of the existing animal models of HAL,which may enhance our understanding of the underlying pathogenesis and approaches for malignancies linked to HIV infection.

Animal models of cochlear implant: Classification and update

Cochlear implantation(CI)is currently recognized as the most effective treatment for severe to profound sensorineural deafness and is considered one of the most successful neural prostheses.Since its inception in 1961,cochlear implantation has expanded its range of applications to encompass younger newborns,older people,and individuals with unilateral hearing loss.In addition,it has improved its surgical methods to minimize the occurrence of complications.Furthermore,notable advancements have been made in the design of electrodes,techniques for speech processing,and software for programming.Nevertheless,inflammation,fibrosis,and even ossification are observed in the cochlea of nearly all cochlear implant(CI)patients.These tissue responses might have a negative impact on the performance of the implants,residual hearing,and the results of post-operative CI rehabilitation.Animal models are significant translational tools that offer essential preclinical data for possible therapeutics.Thus,this study concentrates on the existing animal models used for cochlear implantation,highlights the advancements made in research,and offers insights into potential future research areas.

Exploiting fly models to investigate rare human neurological disorders

Rare neurological diseases,while individually are rare,collectively impact millions globally,leading to diverse and often severe neurological symptoms.Often attributed to genetic mutations that disrupt protein function or structure,understanding their genetic basis is crucial for accurate diagnosis and targeted therapies.To investigate the underlying pathogenesis of these conditions,researchers often use non-mammalian model organisms,such as Drosophila(fruit flies),which is valued for their genetic manipulability,cost-efficiency,and preservation of genes and biological functions across evolutionary time.Genetic tools available in Drosophila,including CRISPR-Cas9,offer a means to manipulate gene expression,allowing for a deep exploration of the genetic underpinnings of rare neurological diseases.Drosophila boasts a versatile genetic toolkit,rapid generation turnover,and ease of large-scale experimentation,making it an invaluable resource for identifying potential drug candidates.Researchers can expose flies carrying disease-associated mutations to various compounds,rapidly pinpointing promising therapeutic agents for further investigation in mammalian models and,ultimately,clinical trials.In this comprehensive review,we explore rare neurological diseases where fly research has significantly contributed to our understanding of their genetic basis,pathophysiology,and potential therapeutic implications.We discuss rare diseases associated with both neuron-expressed and glial-expressed genes.Specific cases include mutations in CDK19 resulting in epilepsy and developmental delay,mutations in TIAM1 leading to a neurodevelopmental disorder with seizures and language delay,and mutations in IRF2BPL causing seizures,a neurodevelopmental disorder with regression,loss of speech,and abnormal movements.And we explore mutations in EMC1 related to cerebellar atrophy,visual impairment,psychomotor retardation,and gain-of-function mutations in ACOX1 causing Mitchell syndrome.Loss-of-function mutations in ACOX1 result in ACOX1 deficiency,characterized by very-long-chain fatty acid accumulation and glial degeneration.Notably,this review highlights how modeling these diseases in Drosophila has provided valuable insights into their pathophysiology,offering a platform for the rapid identification of potential therapeutic interventions.Rare neurological diseases involve a wide range of expression systems,and sometimes common phenotypes can be found among different genes that cause abnormalities in neurons or glia.Furthermore,mutations within the same gene may result in varying functional outcomes,such as complete loss of function,partial loss of function,or gain-of-function mutations.The phenotypes observed in patients can differ significantly,underscoring the complexity of these conditions.In conclusion,Drosophila represents an indispensable and cost-effective tool for investigating rare neurological diseases.By facilitating the modeling of these conditions,Drosophila contributes to a deeper understanding of their genetic basis,pathophysiology,and potential therapies.This approach accelerates the discovery of promising drug candidates,ultimately benefiting patients affected by these complex and understudied diseases.

Preliminary exploration of animal models of congenital choledochal cysts

BACKGROUND Various animal models have been used to explore the pathogenesis of choledochal cysts(CCs),but with little convincing results.Current surgical techniques can achieve satisfactory outcomes for treatment of CCs.Consequently,recent studies have focused more on clinical issues rather than basic research.Therefore,we need appropriate animal models to further basic research.AIM To establish an appropriate animal model that may contribute to the investigation of the pathogenesis of CCs.METHODS Eighty-four specific pathogen-free female Sprague-Dawley rats were randomly allocated to a surgical group,sham surgical group,or control group.A rat model of CC was established by partial ligation of the bile duct.The reliability of the model was confirmed by measurements of serum biochemical indices,morpho-logy of common bile ducts of the rats as well as molecular biology experiments in rat and human tissues.RESULTS Dilation classified as mild(diameter,≥1 mm to<3 mm),moderate(≥3 mm to<10 mm),and severe(≥10 mm)was observed in 17,17,and 2 rats in the surgical group,respectively,while no dilation was observed in the control and sham surgical groups.Serum levels of alanine aminotransferase,aspartate aminotrans-ferase,total bilirubin,direct bilirubin,and total bile acids were significantly elevated in the surgical group as compared to the control group 7 d after surgery,while direct bilirubin,total bilirubin,and gamma-glutamyltransferase were further increased 14 d after surgery.Most of the biochemical indices gradually decreased to normal ranges 28 d after surgery.The protein expression trend of signal transducer and activator of transcription 3 in rat model was consistent with the human CC tissues.CONCLUSION The model of partial ligation of the bile duct of juvenile rats could morphologically simulate the cystic or fusiform CC,which may contribute to investigating the pathogenesis of CC.

Protective Effects of Oral Fructose-1, 6-diphosphate on Liver Injury in Animal Models

Aim To investigate the effects of FDP on different liver injury models to explore the possibility of FDP used as an oral liver protective agent. Methods Chronic liver injury model in rats was induced by carbon tetrachloride （ CCl4 ） ; Acute liver injury model in mice was induced by aminogalactose （GAIN） or lipopolysaccharide （LPS）. Results In CCl4-induced chronic liver injury model, FDP （1 , 4 g·kg^-1·d^-1, q.d., for 10 weeks） significantly lowered ALT, AST,γ-glutamyl transpeptidase （γ-GT）, alkaline phosphatase （ALP）, and total bilirubin （T-BIL） in serum compared with vehicle; simultaneously it evidently elevated abnormal total protein （TP）, albumin （ALB） and total cholesterol （ T-CHO ） levels in serum; it also dose-dependently reduced hydroxyproline contents in hepatic tissue. 4 g·kg^-1·d^-1 of FDP apparently decreased incidence of hepatic cirrhosis, and alleviated pathological changes of liver tissue. In GaiN-induced model, 1.0 - 4. 0 g·kg^-1·d^-1 of FDP （ bid, for 3 d ） significantly lowered alanine aminotransferase （ ALT ） and aspartate aminotransferase （ AST ） levels in serum ; it also decreased liver coefficient. 4. 0 g·kg^-1·d^-1 of FDP significantly alleviated pathological changes of cell ultra-structures. In LPS-induced model, only high dose of FDP （4. 0 g·kg^-1·d^-1, bid, for 12 d） significantly decreased ALT level in serum. Conclusion This study first demonstrated the protective effect of oral FDP on chronic liver injury caused by CCl4, and confirmed its effect on acute liver injury at the same time, suggesting that Long-term oral FDP is efficacious against liver injury induced by different factors and can be used as an oral liver protective agent in clinic.

Genetically modified non-human primate models for research on neurodegenerative diseases

Neurodegenerative diseases(NDs)are a group of debilitating neurological disorders that primarily affect elderly populations and include Alzheimer's disease(AD),Parkinson's disease(PD),Huntington's disease(HD),and amyotrophic lateral sclerosis(ALS).Currently,there are no therapies available that can delay,stop,or reverse the pathological progression of NDs in clinical settings.As the population ages,NDs are imposing a huge burden on public health systems and affected families.Animal models are important tools for preclinical investigations to understand disease pathogenesis and test potential treatments.While numerous rodent models of NDs have been developed to enhance our understanding of disease mechanisms,the limited success of translating findings from animal models to clinical practice suggests that there is still a need to bridge this translation gap.Old World nonhuman primates(NHPs),such as rhesus,cynomolgus,and vervet monkeys,are phylogenetically,physiologically,biochemically,and behaviorally most relevant to humans.This is particularly evident in the similarity of the structure and function of their central nervous systems,rendering such species uniquely valuable for neuroscience research.Recently,the development of several genetically modified NHP models of NDs has successfully recapitulated key pathologies and revealed novel mechanisms.This review focuses on the efficacy of NHPs in modeling NDs and the novel pathological insights gained,as well as the challenges associated with the generation of such models and the complexities involved in their subsequent analysis.

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.

Creating animal models, why not use the Chinese tree shrew ( Tupaia belangeri chinensis)？

The Chinese tree shrew （Tupaia belangeri chinensis） a squirrel-like and rat-sized mammal, has a wide distribution in Southeast Asia, South and Southwest China and has many unique characteristics that make it suitable for use as an experimental animal. There have been many studies using the tree shrew （Tupaia belangeri） aimed at increasing our understanding of fundamental biological mechanisms and for the modeling of human diseases and therapeutic responses. The recent release of a publicly available annotated genome sequence of the Chinese tree shrew and its genome database （www.treeshrewdb.org） has offered a solid base from which it is possible to elucidate the basic biological properties and create animal models using this species. The extensive characterization of key factors and signaling pathways in the immune and nervous systems has shown that tree shrews possess both conserved and unique features relative to primates. Hitherto, the tree shrew has been successfully used to create animal models for myopia, depression, breast cancer, alcohol-induced or non-alcoholic fatty liver diseases, herpes simplex virus type 1 （HSV-1） and hepatitis C virus （HCV） infections, to name a few. The recent successful genetic manipulation of the tree shrew has opened a new avenue for the wider usage of this animal in biomedical research. In this opinion paper, I attempt to summarize the recent research advances that have used the Chinese tree shrew, with a focus on the new knowledge obtained by using the biological properties identified using the tree shrew genome, a proposal for the genome-based approach for creating animal models, and the genetic manipulation of the tree shrew. With more studies using this species and the application of cutting-edge gene editing techniques, the tree shrew will continue to be under the spot light as a viable animal model for investigating the basis of many different human diseases.

Anisotropic time-dependent behaviors of shale under direct shearing and associated empirical creep models

Understanding the anisotropic creep behaviors of shale under direct shearing is a challenging issue.In this context,we conducted shear-creep and steady-creep tests on shale with five bedding orientations (i.e.0°,30°,45°,60°,and 90°),under multiple levels of direct shearing for the first time.The results show that the anisotropic creep of shale exhibits a significant stress-dependent behavior.Under a low shear stress,the creep compliance of shale increases linearly with the logarithm of time at all bedding orientations,and the increase depends on the bedding orientation and creep time.Under high shear stress conditions,the creep compliance of shale is minimal when the bedding orientation is 0°,and the steady-creep rate of shale increases significantly with increasing bedding orientations of 30°,45°,60°,and 90°.The stress-strain values corresponding to the inception of the accelerated creep stage show an increasing and then decreasing trend with the bedding orientation.A semilogarithmic model that could reflect the stress dependence of the steady-creep rate while considering the hardening and damage process is proposed.The model minimizes the deviation of the calculated steady-state creep rate from the observed value and reveals the behavior of the bedding orientation's influence on the steady-creep rate.The applicability of the five classical empirical creep models is quantitatively evaluated.It shows that the logarithmic model can well explain the experimental creep strain and creep rate,and it can accurately predict long-term shear creep deformation.Based on an improved logarithmic model,the variations in creep parameters with shear stress and bedding orientations are discussed.With abovementioned findings,a mathematical method for constructing an anisotropic shear creep model of shale is proposed,which can characterize the nonlinear dependence of the anisotropic shear creep behavior of shale on the bedding orientation.