Ji Xiao, Rong Liu, Ce-Shi Chen,*

1Medical Faculty of Kunming University of Science and Technology,Kunming Yunnan650500,China

2Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province,Kunming Institute of Zoology,Chinese Academy of Sciences,Kunming Yunnan650223,China

ZOOLOGICAL RESEARCH

Tree shrew (Tupaia belangeri) as a novel laboratory disease animal model

Ji Xiao1,2, Rong Liu2, Ce-Shi Chen2,*

1Medical Faculty of Kunming University of Science and Technology,Kunming Yunnan650500,China

2Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province,Kunming Institute of Zoology,Chinese Academy of Sciences,Kunming Yunnan650223,China

The tree shrew (Tupaia belangeri) is a promising laboratory animal that possesses a closer genetic relationship to primates than to rodents. In addition, advantages such as small size, easy breeding, and rapid reproduction make the tree shrew an ideal subject for the study of human disease. Numerous tree shrew disease models have been generated in biological and medical studies in recent years. Here we summarize current tree shrew disease models, including models of infectious diseases, cancers, depressive disorders, drug addiction, myopia, metabolic diseases, and immune-related diseases. With the success of tree shrew transgenic technology, this species will be increasingly used in biological and medical studies in the future.

Tree shrew (Tupaia belangeri); Animal model; Transgenic; Disease

INTRODUCTION

Animal models are used to simulate complex biological phenomena and human disease characteristics. Laboratory animal models are essential for addressing complicated biological problems, understanding the mechanisms of human diseases, and testing the efficacies of therapeutics. To date,Drosophila, zebrafish (Brachydanio rerio), frog (Xenopus laevis), mouse (Mus musculus), rat (Rattus norvegicus), rabbit (Oryctolagus cuniculus), dog (Canis lupus familiaris), pig (Sus scrofa domesticus), and rhesus macaque (Macaca mulatta) have been applied as animal models in the simulation of human cancers, as well as cardiovascular, neurological, metabolic, infectious, and autoimmune diseases (Buchholz, 2015; Jiang et al., 2011; Kazama, 2016; Xu, 2011; Xue et al., 2014). While mature animal models have propelled medical research considerably, no perfect model for human disease currently exists. Each animal model has its own unique advantages and disadvantages. Mice, e.g., have been widely applied due to their small size and clear genetic background; however, the significant genetic differences between rodents and humans mean that such models are unsatisfactory for certain diseases, such as hepatitis and AIDS (Glebe & Bremer, 2013). Compared with other experimental animals, non-human primates are genetically close to humans, allowing for the relatively accurate simulation of human pathology and physiology. However, their high cost and low reproductivity severely limit their use as experimental models. Therefore, the development of novel animal models to balance the advantages and disadvantages for specific disease research is critical.1

The tree shrew (Tupaia belangeri) belongs to Mammalia, Scandentia, and Tupaiidae (Wang, 1987). It lives mainly in Southeast Asia and is characterized by short reproductive and life cycles, high reproductivity (4–6 months from birth to adulthood, with 2–6 offspring born each time), moderate size (adult weight 120–150 g), and easy feeding. The physiological features of the tree shrew, such as anatomy, neurodevelopment, and psychological stress, are highly similar to those of primates, including humans. For example, based on their mixed insectivorous and frugivorous diets, tree shrews are adept at climbing and moving with ease. Furthermore, tree shrews have a relatively well developed and arranged visual thalamus, resulting in acute visual and color discrimination abilities (Ranc et al., 2012). The primary visual cortex branch of the tree shrew is similar to that of primates, but not of rats, indicating that their visual system is closer to that of primates than that of rodents (Caspi et al., 2003; Veit et al., 2011, 2014; Wang et al., 2013b). The amygdaloid nucleus/hippocampus rate of tree shrews is much greater than that of rodents, allowing tree shrews to more easily accomplish memory tasks (Khani & Rainer, 2012; Nair et al., 2014; Wang et al., 2013b). Because of these advantages, agrowing number of tree shrew disease models have been created (Xu et al., 2013). In 2012, the Kunming Institute of Zoology of the Chinese Academy of Sciences (KIZ, CAS) completed genome sequencing of the Chinese tree shrew, which showed that the nervous, immune, and metabolic systems of the tree shrew were very close to those of humans (Fan et al., 2013). The tree shrew database website (http://www.treeshrewdb.org/) was built based on the tree shrew genome sequence data (Fan et al., 2014). In addition, 3 482 tree shrew proteins have been predicted to be drug targets for cancer chemotherapy, depression, and cardiovascular diseases (Zhao et al., 2014). These studies have greatly facilitated the application of the Chinese tree shrew as an animal model in biomedical research. To date, 1 136 papers related to the tree shrew have been published.

INFECTIOUS DISEASES MODELS

Hepatitis virus infection models

Hepatitis is a serious health problem worldwide (Gravitz, 2011; Thun et al., 2010; Yan et al., 2012). However, it is difficult to identify suitable animal models for hepatitis research. In recent decades, studies have shown the tree shrew to be a practical small-animal model for experimental studies on the hepatitis virus, including hepatitis B, C, D, and E. Su (1987) and Pang et al. (1981) inoculated HBV into wild tree shrews and were able to detect the integrated HBV DNA, suggesting that HBV infection could be established in tree shrew models. Walter et al. (1996) also detected HBV DNA replication and viral protein expression in HBV-infected tree shrew liver. Experimental chronic hepatitis B infection in neonatal tree shrews further improved the efficiency of infection and more accurately simulated human chronic HBV infection (Liang et al., 2006; Wang et al., 2012a; Yang et al., 2009). Neonatal tree shrews can be persistently infected with HBV, and hepatic histopathological changes observed in chronically HBV-infected animals are similar to those observed in HBV-infected humans (Ruan et al., 2013). Additionally, chronic HBV infection combined with aflatoxin B1 has been shown to induce liver cancer in tree shrews (Li et al., 1999b; Yang et al., 2015). Furthermore, tumor necrosis factor α (TNFα) can inhibit hepatitis B virus replication inTupaiahepatocytes (Xu et al., 2011). Sodium taurocholate co-transporting polypeptide (NTCP) has also been identified as a functional receptor for HBV and HDV based on a tree shrew model (Yan et al., 2012; Zhong et al., 2013).

Hepatitis C virus (HCV) is responsible for 150–200 million chronic infections and more than 350 000 deaths worldwide every year (Gravitz, 2011). Although chimpanzees and monkeys are considered natural infection hosts (Li et al., 2011), HCV has also been shown in tree shrews, with infected animals exhibiting intermittent viremia, high levels of ALT during the acute phase of infection, chronic hepatitis, liver steatosis, cirrhotic nodules, and accompanying tumorigenesis in the late stage (Amako et al., 2010). Irradiation has also been shown to increase the proportion of HCV infection in tree shrews (Xie et al., 1998). In addition, HCV can infect the primary hepatocytes of tree shrews (Amako et al., 2010; Zhao et al., 2002), with HCV receptors CD81, scavenger receptor BI (SR-BI), claudin-1, and occludin found to be essential factors for HCV entry and infection cycle in the primary hepatocytes ofTupaia belangeri(Tong et al., 2011).

Previous research successfully established HDV/HBV double infection in adult tree shrews to study virus pathogenesis and treatment (Li et al., 1995). In addition, tree shrews have been found to be susceptible to HEV when intravenously injected with swine genotype 4 HEV, with HEV RNA subsequently detected in the feces, liver, spleen, kidneys, and bile of infected tree shrews (Yu et al., 2016).

As one of only a few hepatitis susceptible animals, tree shrews can be infected with almost all hepatitis viruses, and can exhibit symptoms similar to those observed in humans. This makes the tree shrew an ideal animal for hepatitis disease research.

Bacterial infection models

Pathogenic bacteria, such asStaphylococcus aureus,Escherichia coli, andPseudomonas aeruginosa, can cause hundreds of thousands of deaths every year. Li et al. (2012) found that tree shrews are susceptible toStaphylococcus aureusandPseudomonas aeruginosa. Zhan et al. (2014) infected Chinese tree shrews withMycobacterium tuberculosisand found that infected animals developed serious symptoms similar to the clinical signs of active tuberculosis observed in humans. These studies indicate that tree shrews can be used to establish bacterial infection models.

Other virus infection models

Other human viruses can also infect tree shrews. Herpes Simplex Virus type I (HSV-1) and type 2 (HSV-2) can latently infect peripheral nervous system sensory neurons, and their reactivation can lead to recurring cold sores in tree shrews (Han et al., 2011). HSV-1 infection in the tree shrew trigeminal ganglion following ocular inoculation differs significantly from mice in the expression of key HSV-1 genes, including ICP0, ICP4, and latency-associated transcript (LAT), providing a valuable alternative model to study HSV-1 infection and pathogenesis (Han et al., 2011; Li et al., 2016a, b). As an important human pathogen of hand-foot-mouth disease (HFMD), Coxsackie virus A16 (CA16) has been successfully used to infect tree shrews to investigate its pathogenesis (Li et al., 2014). Foamy virus can naturally infectTupaia belangeri chinensisand is highly related to simian foamy virus inMacaca mulatta(Huang et al., 2013a). Human H1N1 influenza-infected tree shrews have been shown to display mild to moderate systemic and respiratory symptoms and pathological changes in respiratory tracts (Yang et al., 2013).Tupaia belangeri chinensishas also been positively infected with enterovirus 71 (EV71) via oral administration, nasal dripping, and tail intravenous injection (Wang et al., 2012b).

Immune-related disease models

Tree shrews can be used as an alternative to primates for studying immune-related diseases. The homology of the interleukin-2 (IL-2) protein sequence between tree shrews andhumans is reportedly as high as 80% (Huang et al., 2013b). Although retinoic acid induction gene protein I (RIG-I) has been lost in the Chinese tree shrew lineage, melanoma differentiation-associated protein 5 (MDA5) replaces its role in innate antiviral activity (Xu et al., 2016). In addition, chemokines in tree shrews might play similar roles as those in humans (Chen et al., 2014). Intraperitoneal injection of pristane and LPS (lipopolysaccharide) can induce systemic lupus erythematosus (SLE) (Ruan et al., 2016). Major histocompatibility complex (MHC) class I and II cell surface proteins are crucial for the self/non-self-discrimination of the adaptive immune system, with the MHC class I gene recently characterized in the tree shrew successfully (Zhang et al., 2013).

CANCER MODELS

Hepatocellular carcinoma (HCC) models

Hepatocellular carcinoma is one of the most common malignancies worldwide (Raphael et al., 2012). Tree shrews can develop spontaneous HCC (Hofmann et al., 1981), but it can also be induced by aflatoxin B1 application (Reddy et al., 1976). The incidence of HCC has also been found to significantly increase when animals are infected with HBV and exposed to AFB1 (52.94%) compared with those solely infected with HBV (11.11%) or solely exposed to AFB1 (12.50%) (Yan et al., 1996). Alterations inp53andp21genes have also been detected in tree shrew HCCs induced by human HBV and/or AFB1 (Park et al., 2000; Su et al., 2003, 2004).

Breast cancer models

Breast cancer is a common malignant tumor in women (Tong et al., 2014). Elliot et al. (1966) reported the first observed spontaneous breast cancer in tree shrew in the 1960s. Xia et al. (2012) further characterized a second case of spontaneous breast papillary tumor, with additional research showing that 50% of female tree shrews developed mammary tumors with long latency (about 7 months) following oral administration of carcinogens 7,12-dimethylbenz(a)anthracene plus medroxyprogesterone acetate (DMBA and MPA). Interestingly, thePTEN/PIK3CAgenes, but not theTP53gene, were frequently mutated in both the spontaneous and DMBA plus MPA-induced tree shrew mammary tumors (Xia et al., 2014; Xu et al., 2015). Overexpression of thePyMToncogene by lentivirus can also efficiently induce mammary tumors in tree shrews within a month (Ge et al., 2016). Furthermore, KLF5, an important transcription factor in breast cancer initiation and development, is reported to be highly conserved between tree shrews and humans (Shao et al., 2017).

Lung cancer models

Pulmonary cancer has the highest incidence and mortality in the world (Torre et al., 2016). The first spontaneous lung tumor in the tree shrew was reported in 1996 (Brack et al., 1996). The administration of DHPN (2,2'-dihydroxy-di-n-propylnitrosamine) at a weekly dose of 250 mg/kg body weight subcutaneous for 80 weeks resulted in 78%–89% of animals developing pulmonary adenomas between 65 and 102 weeks (Rao & Reddy, 1980). In 2013, we administered a single dose of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, 100 mg/kg) via intraperitoneal injection to induce lung cancer in tree shrews, but did not find any lesions in the lungs after one year (unpublished data). Furthermore, PM10 (particulate matter with diameters of 10 μm or less) from Xuanwei bituminous coal dust was found to induce bronchial epithelial hyperplasia in tree shrews, although animals died within a week of prefusion (Chen et al., 2015). Most recently, tree shrews receiving iodized oil suspensions of 3-methylcholanthrene (3-MC) and diethylnitrosamine (DEN) via endotracheal instillation for 11 weeks developed bronchial epithelial atypical hyperplasia and carcinomain situ, although all experimental animals died (Ye et al., 2016).

Other tumor models

Spontaneous lymphoma was first observed in tree shrews in 1996 (Brack et al., 1996). Overexpression of H-Ras (human) and shP53 (tree shrew) by lentivirus for 139 days was shown to induce glioma tumors in tree shrews (Tong et al., 2017). Compared with corresponding mouse gliomas, tree shrew gliomas are more similar to human glioblastomas in terms of gene expression profile (Tong et al., 2017).

METABOLIC DISEASE MODELS

Diabetes models

Diabetes along with hyperglycemia is a metabolic disease. There are about 285 million diabetic patients worldwide (Shaw et al., 2010). Rabb et al. (1966) reported that spontaneous diabetes with the same ketosis, alopecia, and cataract phenotypes as observed in human diabetes was also found in the Philippine tree shrews (Urogale everetti). Several research groups have successfully induced type 1 diabetes in tree shrews using streptozotocin (STZ) (Ishiko et al., 1997; Xian et al., 2000), which is widely used to establish diabetic animal models by selectively killing β cells (Srinivasan & Ramarao, 2007). Li et al. (2010) used a high-glucose-fat-diet in combination with dexamethasone to induce type 2 diabetes in tree shrews (Li et al., 2010). Wu et al. (2013) also established similar type 2 diabetes in tree shrews using different doses of STZ (60, 70, and 80 mg/kg). Furthermore, a diabetic nephropathy tree shrew model was successfully induced by a high-sugar and high-fat diet and four injections of STZ, with bone-marrow mesenchymal stem cell transplantation also demonstrated to improve insulin resistance (Pan et al., 2014).

Fatty liver disease models

With economic development and an increase in the standard of living, fatty liver disease has become increasingly common (Qian et al., 2007). Tree shrews treated with alcohol solutions (10% and 20%) for two weeks were found to develop fatty liverlike pathological changes and alterations (Xing et al., 2015), while Meng et al. (2003) found that Rosiglitazone could prevent fatty liver development in the tree shrew. Using a high fat, cholesterol, and cholate diet, Zhang et al. (2015, 2016) successfully established non-alcoholic non-obese fatty liver disease (NAFLD) in tree shrews; interestingly, the inhibition oflipoprotein lipase by Poloxamer 407 improved the severity of steatosis and reduced inflammation (Zhang et al., 2015). Additionally, 20% sucrose and 1% cholesterol added to their standard diet resulted in massive gallstones in the tree shrew (Schwaier, 1979). Compared with the mouse fatty liver disease model, the tree shrew model shows a shorter onset time and more obvious symptoms (Zhang et al., 2015).

Blood vascular disease models

Tree shrews are regarded as an animal model resistant to atherosclerosis. Liu et al. (2010) showed that tree shrews are resistant to atherosclerosis because of low cholesteryl ester transfer protein expression and low phospholipid transfer protein activities. Li et al. (1999a) induced thrombotic cerebral ischemia in tree shrews using a photochemical approach, with Feng et al. (2011) showing that cerebral ischemia caused a predominant increase in TLR4 protein expression in the tree shrew hippocampus. A blood stasis syndrome model was also successfully established in tree shrews with high-dose carrageen glue (Zhang et al., 2016)

MENTAL DISEASE MODELS

Depression models

Depression, a common mental disease, influences about 20% of people worldwide (Nestler et al., 2002). Tree shrews are diurnal animals, which can be advantageous in certain research compared with using nocturnal animals such as rodents. Previous studies have shown a variety of physiological changes, such as constantly elevated levels of urinary cortisol and norepinephrine and reduced body weight, in subordinate, but not dominant males (Fuchs et al., 1995; Magari?os et al., 1996). Fuchs & Flügge (2002) described the physiology, brain function, and behaviors of subordinate tree shrews. Coexistence of two males with visual and olfactory contact led to a stable dominant/subordinate relationship, with the subordinate showing obvious changes in behavior, neuroendocrine, and central nervous activity similar to the symptoms observed in depression patients (Van Kampen et al., 2002). Clomipramine treatment has also been shown to counteract the behavioral and endocrine effects of chronic psychosocial stress in tree shrews (Fuchs, 2005; Fuchs et al., 1996), whereas diazepam has no beneficial effects on stress-induced behavioral and endocrine changes in male tree shrews (Van Kampen et al., 2000). Wang et al. (2011) examined two male tree shrews for one hour of direct conflict (fighting) and 23 hours of indirect influence (e.g., smell, visual cues) per day for 21 days and found that the subordinate tree shrews showed alterations in body weight, locomotion, avoidance behavior, and urinary cortisol levels in the final week of social conflict. Schmelting et al. (2014) reported that agomelatine normalized the core body temperature in psychosocially stressed male tree shrews. Moreover, chronic clomipramine treatment reversed symptoms of depression, such as weight loss, anhedonia, fluctuations in locomotor activity, sustained urinary cortisol elevation, irregular cortisol rhythms, and deficient hippocampal long-term potentiation (LTP) in subordinate tree shrews (Wang et al., 2013a). These findings all suggest that tree shrews are suitable for studying depression.

Drug addiction models

Drug addiction is a chronic and relapsing brain disease. Tree shrews are useful animal models for the study of human drug addiction pathogenesis due to their well-developed central nervous system. Opitz & Weischer (1988) observed that nondeprived, unstressed tree shrews preferred nicotine solution over water in a free-choice situation. In addition, Wiens et al. (2008) revealed that wild tree shrews naturally preferred alcohol. Morphine, an effective analgesic, induces tolerance and addiction in animals. Sun et al. (2012) injected tree shrews with morphine for 7 days and induced conditioned place aversion (CPA) along with withdrawal symptoms. Intramuscular injection of morphine (5 or 10 mg/kg) has been shown to significantly increase the locomotor activity of tree shrews, with morphineconditioned tree shrews exhibiting place preference in the morphine-paired chamber and naloxone-precipitated withdrawal inducing place aversion in chronic morphine-dependent tree shrews (Wang et al., 2012a). Cocaine and amphetamine regulated transcript peptides are also reported to show similar expression patterns in tree shrews and primates (ábrahám et al., 2005). These findings suggest that tree shrews are suitable for studying human drug addiction.

NERVE RELATED DISEASES

Myopia models

Chickens and monkeys are the most commonly used animal models for myopia study; however, tree shrews might be better candidates due to their low cost, short experiment cycle, small size, and similar eye development to humans. Axial myopia has been reliably produced in tree shrews raised with eyelid closure (Marsh-Tootle & Norton, 1989) and following the application of agents to block collagen crosslinking (McBrien & Norton, 1994). Dark treatment has also resulted in a shift toward myopia in tree shrews (Norton et al., 2006). Tree shrews demonstrated significant scleral thinning and tissue loss, particularly at the posterior pole of the eye, after monocular deprivation of pattern vision (McBrien et al., 2001). The scleral gene expression levels are regulated by the visual environment during the development of myopia and recovery (Guo et al., 2014; He et al., 2014; Siegwart & Norton, 2002). The use of positive lenses has been shown to inhibit myopia in tree shrews, suggesting that daily intermittent positive lens wear might effectively prevent myopia progression in children (McBrien et al., 2012; Siegwart & Norton, 2010). Taken together, tree shrews appear to be ideal animal models for studying myopia.

Alzheimer's disease (AD) models

Alzheimer’s disease is one of the most common neurodegenerative diseases. The central pathological feature of AD is the profuse deposition of amyloid-β protein (Aβ) in the brain parenchyma and vessel walls. The sequence of the tree shrew Aβ protein has very high homology (92% identity) with the human Aβ protein (Pawlik et al., 1999). Fan et al. (2013) revealed that genes related to AD in tree shrews share a high degree of homology with human beings. Yamashita et al. (2012) observedsenile plaque-like structures in the frontal cortex and nucleus accumbens of aged tree shrews. He et al. (2013) induced AD in tree shrews by intracerebroventricular injection of Aβ. Lin et al. (2016) injected Aβ1-40 into the tree shrew hippocampus and induced cognitive lesions associated with neuronal apoptosis. Thus, tree shrews are a potentially effective animal for studying AD.

Transgenic tree shrews

Transgenesis is an important technology for the establishment of disease models. To date, site-directed gene editing has been applied to generate transgenic animals (Capecchi, 2005). Additionally, the development of CRISPR/Cas9 technology has made transgenesis more extensively applicable (Mali et al., 2013). Li et al. (2017) found a culture system for the long-term expansion of tree shrew spermatogonial stem cells without the loss of stem cell properties and successfully generated transgenic offspring by transplanting enhanced green fl uorescent protein (EGFP) into sterilized adult male tree shrew testes. Such research has greatly consolidated the position of the tree shrew in the field of disease animal models.

CONCLUSIONS AND PERSPECTIVES

The tree shrew is more closely related to humans than to rodents in evolution and offers distinct advantages in breeding (Fan et al., 2013). This species has garnered increasing attention in China and worldwide in terms of its use as a novel animal model for a variety of human diseases. To date, tree shrews have shown unique advantages in the study of hepatitis, depression, drug addiction, and myopia. The successful application of transgenic techniques in tree shrews (Li et al., 2017) will broaden the choices for researchers in selecting appropriate animal models for studying human diseases.

However, several hurdles still exist in this field. To date, there are no tree shrew strains with a pure genetic background. Scientists at KIZ, CAS have worked very hard to establish tree shrew strains in recent years, but have only obtained fourth generation offspring by inbreeding so far. Additionally, gene knockout techniques have yet to be applied in tree shrews. Moreover, physiological research tools and materials for the tree shrew remain relatively underdeveloped. This includes tree shrew specific antibodies, although most antibodies against human proteins are suitable for detecting tree shrew proteins. Current tree shrew disease models need to be optimized and studied in depth, and, as such, we to need exhibit patience before adopting the tree shrew in the study of all human diseases. There is, however, no doubt that the tree shrew will play an increasingly important role in the biomedical field.

REFERENCES

ábrahám H, Czéh B, Fuchs E, Seress L. 2005. Mossy cells and different subpopulations of pyramidal neurons are immunoreactive for cocaine- and amphetamine-regulated transcript peptide in the hippocampal formation of non-human primates and tree shrew (Tupaia belangeri).Neuroscience,136(1): 231-240.

Amako Y, Tsukiyama-Kohara K, Katsume A, Hirata Y, Sekiguchi S, Tobita Y, Hayashi Y, Hishima T, Funata N, Yonekawa H, Kohara M. 2010. Pathogenesis of hepatitis C virus infection inTupaia belangeri.Journal of Virology,84(1): 303-311.

Brack M, Schwartz P, Heinrichs T, Schultz M, Fuchs E. 1996. Tumors of the respiratory tract observed at the German Primate Center, 1978-1994.Journal of Medical Primatology,25(6): 424-434.

Buchholz DR. 2015. More similar than you think: frog metamorphosis as a model of human perinatal endocrinology.Developmental Biology,408(2): 188-195.

Capecchi MR. 2005. Gene targeting in mice: functional analysis of the mammalian genome for the twenty-first century.Nature ReviewsGenetics,6(6): 507-512.

Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R. 2003. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene.Science,301(5631): 386-389.

Chen B, Huang JL,Guo XX, Feng XT, Guo EC, Zhang SR, Chen WY, Hu YL, Zhong ZG. 2016. Study on tree shrews model of blood stasis induced by different dose of carrageen glue.World Chinese Medicine,11(11): 2219-2222. (in Chinese)

Chen GY, Wang W, Meng SK, Zhang LC, Wang WX, Jiang ZM, Yu M, Cui QH, Li MZ. 2014. CXC chemokine CXCL12 and its receptor CXCR4 in tree shrews (Tupaia belangeri): structure, expression and function.PLoS One,9(5): e98231.

Chen XB, He M, Li GJ, Zhou YC, Zhao GQ, Lei YJ, Yang KY, Tian LW, Huang YC. 2015. Study of the changes on tree shrew bronchial epithelium induced by xuanwei bituminous coal dust.Chinese Journal of Lung Cancer,18(8): 469-474. (in Chinese)

Elliot OS, Elliot MW, Lisco H. 1966. Breast cancer in a tree shrew (Tupaia glis).Nature,211(5053): 1105.

Fan Y, Huang ZY, Cao CC, Chen CS, Chen YX, Fan DD, He J, Hou HL, Hu L, Hu XT, Jiang XT, Lai R, Lang YS, Liang B, Liao SG, Mu D, Ma YY, Niu YY, Sun XQ, Xia JQ, Xiao J, Xiong ZQ, Xu L, Yang L, Zhang Y, Zhao W, Zhao XD, Zheng YT, Zhou JM, Zhu YB, Zhang GJ, Wang J, Yao YG. 2013. Genome of the Chinese tree shrew.Nature Communications,4: 1426.

Fan Y, Yu DD, Yao YG. 2014. Tree shrew database (TreeshrewDB): a genomic knowledge base for the Chinese tree shrew.Scientific Reports,4: 7145.

Feng R, Li SQ, Li F. 2011. Toll-like receptor 4 is involved in ischemic tolerance of postconditioning in hippocampus of tree shrews to thrombotic cerebral ischemia.Brain Research,1384: 118-127.

Fuchs E, Uno H, Flügge G. 1995. Chronic psychosocial stress induces morphological alterations in hippocampal pyramidal neurons of the tree shrew.Brain Research,673(2): 275-282.

Fuchs E, Kramer M, Hermes B, Netter P, Hiemke C. 1996. Psychosocial stress in tree shrews: clomipramine counteracts behavioral and endocrine changes.Pharmacology Biochemistry and Behavior,54(1): 219-228.

Fuchs E, Flügge G. 2002. Social stress in tree shrews: effects on physiology, brain function, and behavior of subordinate individuals.Pharmacology Biochemistry and Behavior,73(1): 247-258.

Fuchs E. 2005. Social stress in tree shrews as an animal model of depression: an example of a behavioral model of a CNS disorder.CNS Spectrums,10(3): 182-190.

Ge GZ, Xia HJ, He BL, Zhang HL, Liu WJ, Shao M, Wang CY, Xiao J, Ge F, Li FB, Li Y, Chen CS. 2016. Generation and characterization of a breast carcinoma model by PyMT overexpression in mammary epithelial cells of tree shrew, an animal close to primates in evolution.International Journal of Cancer,138(3): 642-651.

Glebe D, Bremer CM. 2013. The molecular virology of hepatitis B virus.Seminars in Liver Disease,33(2): 103-112.

Gravitz L. 2011. Introduction: a smouldering public-health crisis.Nature,474(7350): S2-S4.

Guo L, Frost MR, Siegwart JT, Jr., Norton TT. 2014. Scleral gene expression during recovery from myopia compared with expression during myopia development in tree shrew.Molecular Vision,20: 1643-1659.

Han JB, Zhang GH, Duan Y, Ma JP, Zhang XH, Luo RH, Lü LB, Zheng YT. 2011. Sero-epidemiology of six viruses natural infection inTupaia belangeri chinensis.Zoological Research,32(1): 11-16. (in Chinese)

He BL, Jiao JL, Li B, Wang JT, Wang LM. 2013. Effects of Gastrodin on BDNF Expression in AD Tree Shrew.Journal of Kunming Medical University,34(9): 29-30, 37.

He L, Frost MR, Siegwart JT, Jr., Norton TT. 2014. Gene expression signatures in tree shrew choroid during lens-induced myopia and recovery.Experimental Eye Research,123: 56-71.

Hofmann W, M?ller P, Schwaier A, Flügel RM, Z?ller L, Darai G. 1981. Malignant tumours in Tupaia (tree shrew).Journal of Medical Primatology,10(2-3): 155-163.

Huang F, Yu WH, He ZL. 2013a. Foamy virus in the tree shrewTupaia belangeriis highly related to simian foamy virus inMacaca mulatta.AIDS Research and Human Retroviruses,29(8): 1177-1178.

Huang XY, Li ML, Xu J, Gao YD, Wang WG, Yin AG, Li XF, Sun XM, Xia XS, Dai JJ. 2013b. Analysis of the molecular characteristics and cloning of fulllength coding sequence ofinterleukin-2in tree shrews.Zoological Research,34(2): 121-126. (in Chinese)

Ishiko S, Yoshida A, Mori F, Abiko T, Kitaya N, Kojima M, Saito K. 1997. Early ocular changes in a tree shrew model of diabetes.Nippon Ganka Gakkai Zasshi,101(1): 19-23. (in Japanese)

Jiang HJ, Feng F, Dong ED. 2011. Model animals and animal models of human diseases.Chinese Bulletin of Life Sciences,23(3): 234-238. (in Chinese)

Kazama I. 2016. Burn-induced subepicardial injury in frog heart: a simple model mimicking ST segment changes in ischemic heart disease.Journal of Veterinary Medical Science,78(2): 313-316.

Khani A, Rainer G. 2012. Recognition memory in tree shrew (Tupaia belangeri) after repeated familiarization sessions.Behavioural Processes,90(3): 364-371.

Li CH, Yan LZ, Ban WZ, Tu Q, Wu Y, Wang L, Bi R, Ji S, Ma YH, Nie WH, Lv LB, Yao YG, Zhao XD, Zheng P. 2017. Long-term propagation of tree shrew spermatogonial stem cells in culture and successful generation of transgenic offspring.Cell Research,27(2): 241-252.

Li HY, Li JM, Li JX, Wang XX, Dai JJ, Sun XM. 2010. Insulin-resistance tree shrew model induced by high-glucose-fat-diet with dexamethasone.Laboratory Animal and Comparative Medicine,30(3): 197-200, 204. (in Chinese)

Li JP, Liao Y, Zhang Y, Wang JJ, Wang LC, Feng K, Li QH, Liu LD. 2014. Experimental infection of tree shrews (Tupaia belangeri) with Coxsackie virus A16.Zoological Research,35(6): 485-491.

Li LH, Li ZR, Li X, Wang EL, Lang FC, Xia YJ, Fraser NW, Gao F, Zhou JM. 2016a. Reactivation of HSV-1 following explant of tree shrew brain.Journal of Neurovirology,22(3): 293-306.

Li LH, Li ZR, Wang EL, Yang R, Xiao Y, Han HB, Lang FC, Li X, Xia YJ, Gao F, Li QH, Fraser NW, Zhou JM. 2016b. Herpes simplex virus 1 infection of tree shrews differs from that of mice in the severity of acute infection and viral transcription in the peripheral nervous system.Journal of Virology,90(2): 790-804.

Li QF, Ding MQ, Wang H, Mao Q, Wu CQ, Zheng H, Gu CH, Wang YM. 1995. The infection of hepatitis D virus in adult tupaia.National Medical Journal of China,75(10): 611-613, 639-641. (in Chinese)

Li SA, Lee WH, Zhang Y. 2012. Two bacterial infection models in tree shrew for evaluating the efficacy of antimicrobial agents.Zoological Research,33(1): 1-6.

Li SQ, Meng Q, Zhang L. 1999a. Experimental therapy of a plateletactivating factor antagonist (ginkgolide B) on photochemically induced thrombotic cerebral ischaemia in tree shrews.Clinical and Experimental Pharmacology and Physiology,26(10): 824-825.

Li Y, Su JJ, Qin LL, Yang C, Ban KC, Yan RQ. 1999b. Synergistic effect of hepatitis B virus and aflatoxin B1 in hepatocarcinogenesis in tree shrews.Annals of the Academy of Medicine, Singapore, 28(1): 67-71.

Li Y, Dai JJ, Sun XM, Xia XS. 2011. Progress in studies on HCV receptor of Tupaia as a potential hepatitis C animal model.Zoological Research,32(1): 97-103. (in Chinese)

Liang L, Li Y, Yang C, Cao J, Su JJ, Chen MW, Ban KC, Ou C, Duan XX, Yue HF. 2006. Preliminary study of using the artificially fed and young tree shrews as the infection model for human Hepatitis B virus.Chinese Journal of Zoonoses,22(8): 792-795. (in Chinese)

Lin N, Xiong LL, Zhang RP, Zheng H, Wang L, Qian ZY, Zhang P, Chen ZW, Gao FB, Wang TH. 2016. Erratum to: injection of Aβ1-40 into hippocampus induced cognitive lesion associated with neuronal apoptosis and multiple gene expressions in the tree shrew.Apoptosis,21(5): 641.

Liu HR, Wu G, Zhou B, Chen BS. 2010. Low cholesteryl ester transfer protein and phospholipid transfer protein activities are the factors making tree shrew and beijing duck resistant to atherosclerosis.Lipids in Health and Disease,9: 114.

Magari?os AM, McEwen BS, Fl ü gge G, Fuchs E. 1996. Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews.The Journal of Neuroscience,16(10): 3534-3540.

Mali P, Aach J, Stranges PB, Esvelt KM, Moosburner M, Kosuri S, Yang LH, Church GM. 2013. CAS9 transcriptional activators for target specificity screening and paired nickases for cooperative genome engineering.Nature Biotechnology,31(9): 833-838.

Marsh-Tootle WL, Norton TT. 1989. Refractive and structural measures of lid-suture myopia in tree shrew.Investigative Ophthalmology & Visual Science,30(10): 2245-2257.

McBrien NA, Norton TT. 1994. Prevention of collagen crosslinking increases form-deprivation myopia in tree shrew.Experimental Eye Research,59(4): 475-486.

McBrien NA, Cornell LM, Gentle A. 2001. Structural and ultrastructural changes to the sclera in a mammalian model of high myopia.Investigative Ophthalmology & Visual Science,42(10): 2179-2187.

McBrien NA, Arumugam B, Metlapally S. 2012. The effect of daily transient +4 D positive lens wear on the inhibition of myopia in the tree shrew.Investigative Ophthalmology & Visual Science,53(3): 1593-1601.

Meng BH, Liang SK, Huang S, Xian S, Shu CD. 2003. The protective effects of rosiglitazone on tree shrew's fatty liver.Chinese Journal of Digestion,23(12): 718-722. (in Chinese)

Nair J, Topka M, Khani A, Isenschmid M, Rainer G. 2014. Tree shrews (Tupaia belangeri) exhibit novelty preference in the novel location memory task with 24-h retention periods.Frontiers in Psychology,5: 303.

Nestler EJ, Barrot M, Dileone RJ, Eisch AJ, Gold SJ, Monteggia LM. 2002.Neurobiology of Depression.Neuron,34(1): 13-25.

Norton TT, Amedo AO, Siegwart JT, Jr. 2006. Darkness causes myopia in visually experienced tree shrews.Investigative Ophthalmology & Visual Science,47(11): 4700-4707.

Opitz K, Weischer ML. 1988. Volitional oral intake of nicotine in tupaias: drug-induced alterations.Drug and Alcohol Dependence,21(2): 99-104.

Pan XH, Yang XY, Yao X, Sun XM, Zhu L, Wang JX, Pang RQ, Cai XM, Dai JJ, Ruan GP. 2014. Bone-marrow mesenchymal stem cell transplantation to treat diabetic nephropathy in tree shrews.Cell Biochemistry & Function,32(5): 453-463.

Pang QF, Wu XB, Xu AY, Wang ZM, Wang GX, Zhu BY, Zhang XS. 1981. Hepatitis b virus (HBV) infection in tree shrews experimental research (abstract).Journal of Medical Research,(9): 11-12. (in Chinese)

Park US, Su JJ, Ban KC, Qin LL, Lee EH, Lee YI. 2000. Mutations in the p53 tumor suppressor gene in tree shrew hepatocellular carcinoma associated with hepatitis B virus infection and intake of aflatoxin B1.Gene,251(1): 73-80.

Pawlik M, Fuchs E, Walker LC, Levy E. 1999. Primate-like amyloid-β sequence but no cerebral amyloidosis in aged tree shrews.Neurobiology of Aging,20(1): 47-51.

Qian BC, Shi H, Lü YP. 2007. Development of model of nonalcoholic fatty liver disease and steatohepatitis.Chinese Journal of Comparative Medicine,17(7): 426-430. (in Chinese)

Rabb GB, Getty RE, Williamson WM, Lombard LS. 1966. Spontaneous diabetes mellitus in tree shrews,Urogale everetti.Diabetes,15(5): 327-330.

Ranc V, Petruzziello F, Kretz R, Argando?a EG, Zhang XZ, Rainer G. 2012. Broad characterization of endogenous peptides in the tree shrew visual system.Journal of Proteomics,75(9): 2526-2535.

Rao MS, Reddy JK. 1980. Carcinogenicity of 2,2'-dihydroxy-di-npropylnitrosamine in the tree shrew (Tupaia glis): light and electron microscopic features of pulmonary adenomas.Journal of the National Cancer Institute,65(4): 835-840.

Raphael SW, Zhang YD, Chen YX. 2012. Hepatocellular carcinoma: focus on different aspects of management.ISRN Oncology,2012: 421673.

Reddy JK, Svoboda DJ, Rao MS. 1976. Induction of liver tumors by aflatoxin B1 in the tree shrew (Tupaia glis), a nonhuman primate.Cancer Research,36(1): 151-160.

Ruan GP, Yao X, Liu JF, He J, Li ZA, Yang JY, Pang RQ, Pan XH. 2016. Establishing a tree shrew model of systemic lupus erythematosus and cell transplantation treatment.Stem Cell Research & Therapy,7(1): 121.

Ruan P, Yang C, Su JJ, Cao J, Ou C, Luo CP, Tang YP, Wang Q, Yang F, Shi JL, Lu XX, Zhu LQ, Qin H, Sun W, Lao YZ, Li Y. 2013. Histopathological changes in the liver of tree shrew (Tupaia belangeri chinensis) persistently infected with hepatitis B virus.Virology Journal,10(1): 333.

Schmelting B, Corbach-S?hle S, Kohlhause S, Schlumbohm C, Flügge G, Fuchs E. 2014. Agomelatine in the tree shrew model of depression: effects on stress-induced nocturnal hyperthermia and hormonal status.European Neuropsychopharmacology,24(3): 437-447.

Schwaier A. 1979. Tupaias (tree shrews)—a new animal model for gallstone research.Research in Experimental Medicine,176(1): 15-24.

Shao M, Ge GZ, Liu WJ, Xiao J, Xia HJ, Fan Y, Zhao F, He BL, Chen CS. 2017. Characterization and phylogenetic analysis of Kruppel-like transcription factor (KLF) gene family in tree shrews (Tupaia belangeri chinensis).Oncotarget,7(10): 16325-16339.

Shaw JE, Sicree RA, Zimmet PZ. 2010. Global estimates of the prevalence of diabetes for 2010 and 2030.Diabetes Research and Clinical Practice,87(1): 4-14.

Siegwart JT, Jr., Norton TT. 2002. The time course of changes in mRNA levels in tree shrew sclera during induced myopia and recovery.Investigative Ophthalmology & Visual Science,43(7): 2067-2075.

Siegwart JT, Jr., Norton TT. 2010. Binocular lens treatment in tree shrews: effect of age and comparison of plus lens wear with recovery from minus lens-induced myopia.Experimental Eye Research,91(5): 660-669.

Srinivasan K, Ramarao P. 2007. Animal models in type 2 diabetes research: an overview.The Indian Journal of Medical Research,125(3): 451-472.

Su JJ. 1987. Experimental infection of human hepatitis B virus (HBV) in adult tree shrews.Chinese Journal of Pathology,16(2): 103-106, 22. (in Chinese)

Su JJ, Li Y, Ban KC, Qin LL, Wang HY, Yang C, Ou C, Duan XX, Lee YY, Yan RQ. 2003. Alteration of the p53 gene during tree shrews' hepatocarcinogenesis.Hepatobiliary & Pancreatic Diseases International,2(4): 612-616.

Su JJ, Ban KC, Li Y, Qin LL, Wang HY, Yang C, Ou C, Duan XX, Lee YL, Yang RQ. 2004. Alteration ofp53andp21during hepatocarcinogenesis in tree shrews.World Journal Of Gastroenterology,10(24): 3559-3563.

Sun YM, Yang JZ, Sun HY, Ma YY, Wang JH. 2012. Establishment of tree shrew chronic morphine dependent model.Zoological Research,33(1): 14-18.

Thun MJ, Delancey JO, Center MM, Jemal A, Ward EM. 2010. The global burden of cancer: priorities for prevention.Carcinogenesis,31(1): 100-110.

Tong YH, Zhou X, Zhao XD. 2014. Tree shrew glioma tumor model.In: Zheng YT, Yao YG, Xu L. Basic Biology and Disease Models of Tree Shrews. Kunming: Yunnan Science and Technology Press, 427-437. (in Chinese)

Tong YH, Hao JJ, Tu Q, Yu HL, Yan LZ, Li Y, Lv LB, Wang F, Iavarone A, Zhao XD. 2017. A tree shrew glioblastoma model recapitulates features of human glioblastoma.Oncotarget,8(11): 17897-17907.

Tong YM, Zhu YZ, Xia XS, Liu Y, Feng Y, Hua X, Chen ZH, Ding H, Gao L, Wang YZ, Feitelson MA, Zhao P, Qi ZT. 2011. Tupaia CD81, SR-BI, claudin-1, and occludin support hepatitis C virus infection.Journal of Virology,85(6): 2793-2802.

Torre LA, Siegel RL, Jemal A. 2016. Lung Cancer Statistics.Advances in Experimental Medicine and Biology, 893: 1-19.

Van Kampen M, Schmitt U, Hiemke C, Fuchs E. 2000. Diazepam has no beneficial effects on stress-induced behavioural and endocrine changes in male tree shrews.Pharmacology Biochemistry and Behavior,65(3): 539-546.

Van Kampen M, Kramer M, Hiemke C, Flügge G, Fuchs E. 2002. The chronic psychosocial stress paradigm in male tree shrews: evaluation of a novel animal model for depressive disorders.Stress,5(1): 37-46.

Veit J, Bhattacharyya A, Kretz R, Rainer G. 2011. Neural response dynamics of spiking and local field potential activity depend on CRT monitor refresh rate in the tree shrew primary visual cortex.Journal of Neurophysiology,106(5): 2303-2313.

Veit J, Bhattacharyya A, Kretz R, Rainer G. 2014. On the relation between receptive field structure and stimulus selectivity in the tree shrew primary visual cortex.Cerebral Cortex,24(10): 2761-2771.

Walter E, Keist R, Nieder?st B, Pult I, Blum HE. 1996. Hepatitis B virusinfection of tupaia hepatocytesin vitroandin vivo.Hepatology,24(1): 1-5.

Wang J, Zhou QX, Tian M, Yang YX, Xu L. 2011. Tree shrew models: a chronic social defeat model of depression and a one-trial captive conditioning model of learning and memory.Zoological Research,32(1): 24-30.

Wang J, Chai AP, Zhou QX, Lv LB, Wang LP, Yang YX, Xu L. 2013a. Chronic clomipramine treatment reverses core symptom of depression in subordinate tree shrews.PLoS One,8(12): e80980.

Wang Q, Schwarzenberger P, Yang F, Zhang JJ, Su JJ, Yang C, Cao J, Ou C, Liang L, Shi JL, Yang F, Wang DP, Wang J, Wang XJ, Ruan P, Li Y. 2012a. Experimental chronic hepatitis B infection of neonatal tree shrews (Tupaia belangeri chinensis): a model to study molecular causes for susceptibility and disease progression to chronic hepatitis in humans.Virology Journal,9(1): 170.

Wang SX, Shan D, Dai JK, Niu HC, Ma YY, Lin FC, Lei H. 2013b. Anatomical MRI templates of tree shrew brain for volumetric analysis and voxel-based morphometry.Journal of Neuroscience Methods,220(1): 9-17.

Wang WG, Huang XY, Xu J, Sun XM, Dai JJ, Li QH. 2012b. Experimental studies on infant Tupaia belangeri chineses with EV71 infection.Zoological Research,33(1): 7-13. (in Chinese)

Wang YX. 1987. Taxonomic research on Burma-Chinese tree shrew, Tupaia belangeri (Wagner), from Southern China.Zoological Research,8(3): 213-230. (in Chinese)

Wiens F, Zitzmann A, Lachance MA, Yegles M, Pragst F, Wurst FM, Von Holst D, Guan SL, Spanagel R. 2008. Chronic intake of fermented floral nectar by wild treeshrews.Proceedings of the National Academy of Sciences of the United States of America,105(30): 10426-10431.

Wu XY, Li YH, Chang Q, Zhang LQ, Liao SS, Liang B. 2013. Streptozotocin induction of type 2 diabetes in tree shrew.Zoological Research,34(2): 108-115. (in Chinese)

Xia HJ, Wang CY, Zhang HL, He BL, Jiao JL, Chen CS. 2012. Characterization of spontaneous breast tumor in tree shrews (Tupaia belangeri chinenesis).Zoological Research,33(1): 55-59.

Xia HJ, He BL, Wang CY, Zhang HL, Ge GZ, Zhang YX, Lv LB, Jiao JL, Chen CS. 2014.PTEN/PIK3CAgenes are frequently mutated in spontaneous and medroxyprogesterone acetate-accelerated 7,12-dimethylbenz (a)anthracene-induced mammary tumours of tree shrews.European Journal of Cancer,50(18): 3230-3242.

Xian S, Huang S, Su JJ, Qin YF, Ou C, Luo ZJ, Wei MY. 2000. A study on experimental diabetes animal models in tree shrews induced by streptozotocin.Journal of Guangxi Medical University,17(6): 945-948. (in Chinese)

Xie ZC, Riezu-Boj JI, Lasarte JJ, Guillen J, Su JH, Civeira MP, Prieto J. 1998. Transmission of hepatitis C virus infection to tree shrews.Virology,244(2): 513-520.

Xing HJ, Jia K, He J, Shi CZ, Fang MX, Song LL, Zhang P, Zhao Y, Fu JN, Li SJ. 2015. Establishment of the tree shrew as an alcohol-induced Fatty liver model for the study of alcoholic liver diseases.PLoS One,10(6): e0128253.

Xu L. 2011. Animal models of human diseases.Zoological Research,32(1): 1-3. (in Chinese)

Xu L, Zhang Y, Liang B, Lü LB, Chen CS, Chen YB, Zhou JM, Yao YG. 2013. Tree shrews under the spot light: emerging model of human diseases.Zoological Research, 34(2): 59-69.

Xu L, Yu DD, Fan Y, Peng L, Wu Y, Yao YG. 2016. Loss of RIG-I leads to a functional replacement with MDA5 in the Chinese tree shrew.Proceedings of the National Academy of Sciences of the United States of America,113(39): 10950-10955.

Xu XS, Hou XM, Wang W, Hao PQ, Zhu KL, Yan HK, Huang QS, Yang SH. 2015. DMBA induced breast tumors in tree shrews (Tupaia Belangeri Chinese).Progress in Modern Biomedicine,15(2): 228-232.

Xu Y, K?ck J, Lu YP, Yang DL, Lu MJ, Zhao XP. 2011. Suppression of hepatitis B virus replication inTupaiahepatocytes by tumor necrosis factor alpha ofTupaia belangeri.Comparative Immunology, Microbiology and Infectious Diseases,34(4): 361-368.

Xue LX, Zhang FZ, Sun RJ, Dong ED. 2014. Research status and perspective of disease animal models in China.Scientia Sinica Vitae,44(9): 851-860.

Yamashita A, Fuchs E, Taira M, Yamamoto T, Hayashi M. 2012. Somatostatin-immunoreactive senile plaque-like structures in the frontal cortex and nucleus accumbens of aged tree shrews and Japanese macaques.Journal of Medical Primatology,41(3): 147-157.

Yan H, Zhong GC, Xu GW, He WH, Jing ZY, Gao ZC, Huang Y, Qi YH, Peng B, Wang HM, Fu LR, Song M, Chen P, Gao WQ, Ren BJ, Sun YY, Cai T, Feng XF, Sui JH, Li WH. 2012. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus.eLife,1: e00049.

Yan RQ, Su JJ, Huang DR, Gan YC, Yang C, Huang GH. 1996. Human hepatitis B virus and hepatocellular carcinoma. II. Experimental induction of hepatocellular carcinoma in tree shrews exposed to hepatitis B virus and aflatoxin B1.Journal of Cancer Research and Clinical Oncology,122(5): 289-295.

Yang C, Ruan P, Ou C, Su JJ, Cao J, Luo CP, Tang YP, Wang Q, Qin H, Sun W, Li Y. 2015. Chronic hepatitis B virus infection and occurrence of hepatocellular carcinoma in tree shrews (Tupaia belangeri chinensis).Virology Journal,12: 26.

Yang F, Cao J, Zhang JJ, Wang Q, Su JJ, Yang C, Ou C, Shi JL, Wang DP, Li Y. 2009. Long-term observation of hepatitis B virus (HBV) replication in new-born tree shrews inoculated with HBV.Chinese Journal of Hepatology,17(8): 580-584.

Yang ZF, Zhao J, Zhu YT, Wang YT, Liu R, Zhao SS, Li RF, Yang CG, Li JQ, Zhong NS. 2013. The tree shrew provides a useful alternative model for the study of influenza H1N1 virus.Virology Journal,10(1): 111.

Ye LH, He M, Huang YC, Zhao GQ, Lei YJ, Zhou YC, Chen XB. 2016. Tree shrew as a new animal model for the study of lung cancer.Oncology Letters,11(3): 2091-2095.

Yu WH, Yang CC, Bi YH, Long FY, Li YL, Wang J, Huang F. 2016. Characterization of hepatitis E virus infection in tree shrew (Tupaia belangeri chinensis).BMC Infectious Diseases,16(1): 80.

Zhan LJ, Ding HR, Lin SZ, Tang J, Deng W, Xu YF, Xu YH, Qin C. 2014. Experimental Mycobacterium tuberculosis infection in the Chinese tree shrew.FEMS Microbiology Letters360(1):23-32.

Zhang LQ, Zhang ZG, Li YH, Liao SS, Wu XY, Chang Q, Liang B. 2015. Cholesterol induces lipoprotein lipase expression in a tree shrew (Tupaia belangeri chinensis) model of non-alcoholic fatty liver disease.Scientific Reports,5: 15970.

Zhang LQ, Wu XY, Liao SS, Li YH, Zhang ZG, Chang Q, Xiao RY, Liang B. 2016. Tree shrew (Tupaia belangeri chinensis), a novel non-obese animal model of non-alcoholic fatty liver disease.Biology Open,5(10): 1545-1552.

Zhang XH, Dai ZX, Zhang GH, Han JB, Zheng YT. 2013. Molecular characterization, balancing selection, and genomic organization of the tree shrew (Tupaia belangeri) MHC class I gene.Gene,522(2): 147-155.

Zhao F, Guo XL, Wang YJ, Liu J, Lee WH, Zhang Y. 2014. Drug target mining and analysis of the Chinese tree shrew for pharmacological testing.PLoS One,9(8): e104191.

Zhao XP, Tang ZY, Klumpp B, Wolff-Vorbeck G, Barth H, Levy S, Von Weizs?cker F, Blum HE, Baumert TF. 2002. Primary hepatocytes of Tupaia belangeri as a potential model for hepatitis C virus infection.The Journal of Clinical Investigation,109(2): 221-232.

Zhong GC, Yan H, Wang HM, He WH, Jing ZY, Qi YH, Fu LR, Gao ZC, Huang Y, Xu GW, Feng XF, Sui JH, Li WH. 2013. Sodium taurocholate cotransporting polypeptide mediates woolly monkey hepatitis B virus infection ofTupaia hepatocytes.Journal of Virology,87(12): 7176-7184.

Received: 14 March 2017; Accepted: 03 May 2017

s: This study was supported by the National Nature Science Foundation of China (81325016, U1602221, 81322038 and U1502222)

*Corresponding author, E-mail: chenc@mail.kiz.ac.cn

10.24272/j.issn.2095-8137.2017.033