Taking central nervous system regenerative therapies to the clinic: curing rodents versus nonhuman primates versus humans

The central nervous system is known to have limited regenerative capacity.Not only does this halt the human body’s reparative processes after central nervous system lesions,but it also impedes the establishment of effective and safe therapeutic options for such patients.Despite the high prevalence of stroke and spinal cord injury in the general population,these conditions remain incurable and place a heavy burden on patients’families and on society more broadly.Neuroregeneration and neural engineering are diverse biomedical fields that attempt reparative treatments,utilizing stem cells-based strategies,biologically active molecules,nanotechnology,exosomes and highly tunable biodegradable systems(e.g.,certain hydrogels).Although there are studies demonstrating promising preclinical results,safe clinical translation has not yet been accomplished.A key gap in clinical translation is the absence of an ideal animal or ex vivo model that can perfectly simulate the human microenvironment,and also correspond to all the complex pathophysiological and neuroanatomical factors that affect functional outcomes in humans after central nervous system injury.Such an ideal model does not currently exist,but it seems that the nonhuman primate model is uniquely qualified for this role,given its close resemblance to humans.This review considers some regenerative therapies for central nervous system repair that hold promise for future clinical translation.In addition,it attempts to uncover some of the main reasons why clinical translation might fail without the implementation of nonhuman primate models in the research pipeline.

Nonhuman primate models of focal cerebral ischemia

Rodents have been widely used in the production of cerebral ischemia models. However, successful therapies have been proven on experimental rodent stroke model, and they have often failed to be effective when tested clinically. Therefore, nonhuman primates were recommended as the ideal alternatives, owing to their similarities with the human cerebrovascular system, brain metabolism, grey to white matter ratio and even their rich behavioral repertoire. The present review is a thorough summary of ten methods that establish nonhuman primate models of focal cerebral ischemia; electrocoagulation, endothelin-1-induced occlusion, microvascular clip occlusion, autologous blood clot embolization, balloon inflation, microcatheter embolization, coil embolization, surgical suture embolization, suture, and photochemical induction methods. This review addresses the advantages and disadvantages of each method, as well as precautions for each model, compared nonhuman primates with rodents, different species of nonhuman primates and different modeling methods. Finally it discusses various factors that need to be considered when modelling and the method of evaluation after modelling. These are critical for understanding their respective strengths and weaknesses and underlie the selection of the optimum model.

Local transgene expression and whole-body transgenesis to model brain diseases in nonhuman primate

Animal model is an essential tool in the life sciences research, notably in understanding the pathogenesis of the diseases and for further therapeutic intervention success. Rodents have been the most frequently used animals to model human disease since the establishment of gene manipulation technique. However, they remain inadequate to fully mimic the pathophysiology of human brain disease, partially due to huge differences between rodents and humans in terms of anatomy, brain function, and social behaviors. Nonhuman primates are more suitable in translational perspective. Thus, genetically modified animals have been generated to investigate neurologic and psychiatric disorders. The classical transgenesis technique is not efficient in that model; so, viral vector-mediated transgene delivery and the new genome-editing technologies have been promoted. In this review, we summarize some of the technical progress in the generation of an ad hoc animal model of brain diseases by gene delivery and real transgenic nonhuman primate.

Endovascular middle cerebral arterial occlusion in a nonhuman primate model of chronic stroke

No study has reported the safety, effectiveness, and consistency of endovascular middle cerebral artery occlusion in a chronic cerebral ischemia model. Nor have studies verified the safest and most effective segment, or branch, in the embolic middle cerebral artery. In this experiment, cerebral infarction models were established at M1, and on the upper and lower trunks on the contralateral side of the handedness of rhesus monkeys by using endovascular intervention. The results confirmed a high animal survival rate in stroke models of middle cerebral artery upper trunk occlusion. There was pronounced paralysis at the acute phase, long-term upper extremity dysfunction at the chronic phase, and the models showed good repeatability and consistency. Thus, this study describes a safe and effective model of chronic stroke.

Comparative evaluation of acute phase proteins by C-reactive protein(CRP)and serum amyloid A(SAA)in nonhuman primates and feline carnivores

The feasibility of a commercially available assay for C-reactive protein(CRP,CRP for humans:hCRP,and CRP for dogs:vCRP)and a trial reagent of serum amyloid A(SAA,vSAA for animals)were applied to the measurement of acute phase proteins in zoo animals,particularly in nonhuman primates and feline carnivores was evaluate.Results showed that hCRP and vSAA methods were applicable to measure CRP and SAA in Haplorhini.There was a highly signifcant correlation between both parameters with remarkably high correlation coefcient.A higher proportion of Bonnet macaques in Haplorhini,and the linear regression with good correlation between hCRP and vSAA levels were observed.Reference values in healthy Bonnet macaques were hCRP(46.86±30.97 nmol/L)and vSAA(9.06±1.95μg/mL).Although Ring-tailed lemur,which belonging to Strepsirrhini,showed low vSAA concentrations(reference values:1.08±0.47μg/mL),vSAA in patients was apparently elevated.The vCRP and vSAA methods were applicable to measurements of CRP and SAA in feline carnivores for highly signifcant correlation between both parameters.Theses two methods were also been deteded in lions,tigers and cheetahs.vSAA assays can be applied to measure SAA levels in other carnivores and herbivores.In conclusion,vSAA systems have potential utility as diagnostic tools for health screening and prediction in zoo animals.

Comparative transcriptome analysis between rhesus macaques(Macaca mulatta) and crab-eating macaques(M. fascicularis)

Understanding gene expression variations between species is pivotal for deciphering the evolutionary diversity in phenotypes. Rhesus macaques(Macaca mulatta, MMU)and crab-eating macaques(M. fascicularis, MFA) serve as crucial nonhuman primate biomedical models with different phenotypes. To date, however, large-scale comparative transcriptome research between these two species has not yet been fully explored. Here, we conducted systematic comparisons utilizing newly sequenced RNA-seq data from84 samples(41 MFA samples and 43 MMU samples)encompassing 14 common tissues. Our findings revealed a small fraction of genes(3.7%) with differential expression between the two species, as well as 36.5% of genes with tissue-specific expression in both macaques. Comparison of gene expression between macaques and humans indicated that 22.6% of orthologous genes displayed differential expression in at least two tissues. Moreover,19.41% of genes that overlapped with macaque-specific structural variants showed differential expression between humans and macaques. Of these, the FAM220A gene exhibited elevated expression in humans compared to macaques due to lineage-specific duplication. In summary,this study presents a large-scale transcriptomic comparison between MMU and MFA and between macaques and humans. The discovery of gene expression variations not only enhances the biomedical utility of macaque models but also contributes to the wider field of primate genomics.

Transgenic Nonhuman Primate Models for Human Diseases:Approaches and Contributing Factors

Nonhuman primates （NHPs） provide powerful experimental models to study human development, cognitive functions and disturbances as well as complex behavior, because of their genetic and physiological similarities to humans. Therefore, NHPs are appropriate models for the study of human diseases, such as neurodegenerative diseases including Parkinson＇s, Alzheimer＇s and Huntington＇s diseases, which occur as a result of genetic mutations. However, such diseases afflicting humans do not occur naturally in NHPs. So transgenic NHPs need to be established to understand the etiology of disease pathology and pathogenesis. Compared to rodent genetic models, the generation of transgenic NHPs for human diseases is inefficient, and only a transgenic monkey model for Huntington＇s disease has been reported. This review focuses on potential approaches and contributing factors for generating transgenic NHPs to study human diseases.

Generation of nonhuman primate retinitis pigmentosa model by in situ knockout of RHO in rhesus macaque retina

Retinitis pigmentosa(RP)is a form of inherited retinal degenerative diseases that ultimately involves the macula,which is present in primates but not in the rodents.Therefore,creating nonhuman primate(NHP)models of RP is of critical importance to study its mechanism of pathogenesis and to evaluate potential therapeutic options in the future.Here we applied adeno-associated virus(AAV)-delivered CRISPR/SaCas9 technology to knockout the RHO gene in the retinae of the adult rhesus macaque(Macaca mulatta)to investigate the hypothesis whether non-germline mutation of the RHO gene is sufficient to recapitulate RP.Through a series of studies,we were able to demonstrate successful somatic editing of the RHO gene and reduced RHO protein expression.More importantly,the mutant macaque retinae displayed clinical RP phenotypes,including photoreceptor degeneration,retinal thinning,abnormal rod subcellular structures,and reduced photoresponse.Therefore,we suggest somatic editing of the RHO gene is able to phenocopy RP,and the reduced time span in generating NHP mutant accelerates RP research and expands the utility of NHP model for human disease study.

Technology advancing the study of animalcognition： using virtual reality to presentvirtually simulated environments to investigatenonhuman primate spatial cognition

Virtual simulated environments provide multiple ways of testing cognitive function and evaluatingproblem solving with humans （e.g., Woollett et al. 2009）. The use of such interactive technologyhas increasingly become an essential part of modern life （e.g., autonomously driving vehicles, glo-bal positioning systems （GPS）, and touchscreen computers; Chinn and Fairlie 2007; Brown 2011）.While many nonhuman animals have their own forms of technology, such as chimpanzees whocreate and use tools, in captive animal environments the opportunity to actively participate withinteractive technology is not often made available. Exceptions can be found in some state-of-the-art zoos and laboratory facilities （e.g., Mallavarapu and Kuhar 2005）. When interactive technologyis available, captive animals often selectively choose to engage with it. This enhances the animal＇ssense of control over their immediate surroundings （e.g., Clay et al. 2011; Ackerman 2012）. Suchself-efficacy may help to fulfill basic requirements in a species＇ daily activities using problem solv-ing that can involve foraging and other goal-oriented behaviors. It also assists in fulfilling thestrong underlying motivation for contrafreeloading and exploration expressed behaviorally bymany species in captivity （Young 1999）. Moreover, being able to present nonhuman primates vir-tual reality environments under experimental conditions provides the opportunity to gain insightinto their navigational abilities and spatial cognition. It allows for insight into the generation andapplication of internal mental representations of landmarks and environments under multiple con-ditions （e.g., small- and large-scale space） and subsequent spatial behavior. This paper reviewsmethods using virtual reality developed to investigate the spatial cognitive abilities of nonhumanprimates, and great apes in particular, in comparison with that of humans of multiple age groups.We make recommendations about training, best practices, and also pitfalls to avoid.

Assessing the nonhuman primate reservoir of Schistosoma mansoni in Africa:a systematic review

Background:Reports of natural infections of Schistosoma mansoni in a number of species of nonhuman primates(NHPs)in Africa,coupled with the substantial overlap of NHP habitats and human schistosomiasis endemic areas,has led to concerns about the role of NHPs in the transmission of human schistosomiasis.We conducted a systematic review of the literature to describe the current scope of knowledge for Africa,for the NHP species implicated,their geographical distribution,infection rates with 5.mansoni,and to discuss the implications for public health and conservation.Main text:A systematic search of the literature was performed using PubMed,Web of Science,Google Scholar,the World Health Organization(WHO)library database,World Cat,and ScienceDirect without any language restriction.Studies examining 5.monsoni infeaion of any African NHP species were included.Study types,primate species,their geographical distribution,and parasite diagnostic techniques reported in the studies were qualitatively summarized.Data for species with sample sizes>10 were included in the meta-analysis.We assessed the reported infection rate,and used a random-effeas model to estimate the summary infeaion rates and 95%confidence intervals(C/s).We assessed heterogeneity among studies using the I2 statistics.Twenty-nine publications,from 1960 to 2018,were identified and included in the review.The studies examined a total of 2962 primates belonging to 22 species in 11 genera across ten countries(Cameroon,Eritrea,Ethiopia,Gabon,Kenya,Nigeria,Senegal,Tanzania,Uganda,and Zimbabwe),and 5.mansoni infeaions were found in nine species of five genera in all countries.When we excluded studies with sample sizes<10,data from 24 studies on 11 species of primates in three genera in ten countries remained in the meta-analysis.The overall pooled estimate of infection rate was 10%(95%Cl:6-16%)with high heterogeneity(I^2=9477%)across countries and species/genera.Among the three genera,Pan had the highest infection rate of 15%(95%CI:0-55%),followed by Popio at 11%(95%Cl:6-18%),and Cercopithecus at 5%(95%CI:0-14%).The association between NHP and human infections was positive,but not significant,due to low study sample matches and high variation.Conclusions:Our findings suggest that 5.mansoni infection rate is high in African NHPs,with substantial heterogeneities across spedes/genera and countries in Africa.Given the evidence for potential spillover and spillback of S.mansoni between African NHPs and humans,further research is urgently needed to understand ecology and mechanisms of transmission of the parasite between NHP and human hosts,in order to inform control strategies of this important neglected tropical disease.

非人灵长类和非灵长类糖尿病动物模型构建方法的研究进展

关于糖尿病动物模型的研究,国内外均主要集中于大鼠、小鼠、兔,其方法涉及自发性动物模型、转基因、高脂高糖饲料诱导和化学诱导等。虽然兔和啮齿动物模型对糖尿病机制的研究做出了重要贡献,但其生理结构和遗传背景与人类仍有较大区别,无法很好的模拟人类糖尿病发生发展过程。非人灵长类动物(NHP)与人类具有重要的代谢相似性,这使其成为研究糖尿病机制研究和临床前试验的理想模型。本综述简述了目前主要的NHP和非灵长类糖尿病模型构建方法和研究进展。

Artifacts of Technoculture:Excommunication in the Nonhuman Theatre

The aim of this article is to form a conceptual framework for analyzing and understanding the latest intermedial practice within the field of new technologies.In order to achieve this,it suggests two converging theoretical strategies.Firstly,the introduction emphasizes on concept of"excommunication,"coined by Alexander R.Galloway in his 2013 book,in order to provide a better understanding of the scenic mediation that encompasses a great number of contemporary productions.More specifically,by both following and criticizing Galloway’s stance on three different media modalities,a fourth mediation vector will be isolated—The Water Principle—incorporated in the mythology of Neptune.Such a theoretical orientation is primarily guided by an ambition to associate intermedial theory with watery elements that appear in two different stage examples analyzed within this paper.Secondly,two different performances will be analyzed:Romeo Castellucci’s"M.#10 Marseille"(2002)and"Fontaine Boréale"(2018).Prompted by intermedial issues,these two productions question the ontological claims of the human presence on stage by establishing digital stage simulation as a para-performative phenomenon.By analyzing these plays,I will demonstrate that in both examples,the Water Principle delivers a privileged media model through which aesthetic force is achieved.Finally,on a broader level,the paper suggests that the artistic trajectory of these productions calls for a new perspective on the nature of performance;a perspective emphasizing an aesthetics of disappearance and nonhuman structural impact.

恒河猴H5N1禽流感病毒性肺炎模型建立及其发病机制

目的：探讨H5N1病毒（AF148678/ACGoose/Guangdong/11961H5N1）感染恒河猴诱发自初期至恢复期过程肺炎的机制。方法以 H5N1病毒液经鼻滴入恒河猴，染毒后第0h、12h、1d、2d、3d、4d、6d、10d、12d和14d采血作血液学和流感特异抗体检测。染毒后第1、3、6、14 d分别剖杀1只恒河猴，取气管支气管淋巴结、肺、心、肝、肾、大脑及小脑进行病毒分离、滴定、病理及免疫组化检测并观察感染后临床表现。结果猴感染后出现发热、呼吸困难，食欲下降等。病毒仅在肺组织复制，主要侵犯下呼吸道的肺泡上皮细胞和肺巨噬细胞。感染后第1～3d引起暂时性的严重肺炎，主要为中性粒细胞浸润；第6 d后逐渐恢复，以巨噬细胞浸润为主；第14 d后以 T 淋巴细胞浸润为主，肺组织呈恢复期状态。结论下呼吸道是H5N1病毒感染主要攻击的对象，这可能是H5N1病毒在人与人之间传递的障碍之一，其发病可能经过病毒侵入、复制阶段及免疫损伤阶段。

灵长类动物模型在抗艾滋病毒药物研究中的应用

艾滋病(AIDS)灵长类动物模型广泛用于艾滋病毒(HIV)研究。较为常用的有猴免疫缺陷病毒(SIV)/猕猴模型和猴/人免疫缺陷嵌合病毒(SHIV)/猕猴模型,除了在发病机制和抗HIV疫苗研究中的重要作用外,这2种模型在抗HIV药物研究中同样显示出优越性和实用性,体现在药物疗效的研究、新药的开发、耐药性研究、机体免疫反应在药物治疗作用的研究中。通过这些体内抗病毒活性及机制的研究,可进一步揭示药物的抗HIV疗效,对AIDS的临床用药具有重要的指导作用,将使人们重新考虑抗HIV药物的用药原则和药效评价标准。

非人灵长类糖尿病动物模型研究进展

糖尿病是继心血管疾病和肿瘤之后的另一种严重危害人类健康的重要慢性疾病,据世界卫生组织(WHO)报道,2009年全世界约有2.2亿糖尿病患者。对糖尿病发病机理的研究、预防和诊断、治疗药物的筛选和评价都需要合适的动物模型。在已报道的糖尿病动物模型中,非人灵长类动物糖尿病病程、病症与人类的糖尿病最为相似。该文从糖尿病动物模型的来源归纳了目前报道的主要的非人灵长类糖尿病模型,重点介绍了猕猴、食蟹猴和树鼩糖尿病模型及其特征,并对该领域的发展提出了一些思考。

非人类灵长类恒河猴衰老与热量限制抗衰老研究进展

非人类灵长类恒河猴是研究人类衰老和热量限制抗衰老的理想模型。与人类衰老一样,恒河猴由于增龄性神经内分泌、免疫、神经系统、心血管系统等衰老,出现相应的老年病。热量限制能有效地延缓恒河猴原发性衰老和继发性衰老。其机制可能是调节代谢相关的信号通路,抑制氧化应激-炎性衰老-DNA损伤;同时激活DNA损伤修复。然而,不同的实验设计、饲养环境、饮食组成和遗传背景等可能对热量限制抗长生命周期恒河猴原发性衰老和继发性衰老作用存在不同的影响。优化实验设计,控制这些变量,缩短实验周期将更有利于明确CR抗衰老的作用及其机制。

非人灵长类动物模型在医学研究中的应用概况

1非人灵长类动物的生物学特点 1.1动物分类学位置 猕猴（Macaca mulatta）属于哺乳纲、灵长目、猴科、猕猴属动物。猕猴实际上是猕猴属猴的总称,共有12个种、46个亚种。分布于我国的有5个种,包括恒河猴、熊猴、红面断尾猴、台湾岩猴和平顶猴。

非人灵长类的体外受精和胚胎移植

非人灵长类的体外受精和胚胎移植是了解人类生殖机制,如卵的成熟调控,受精卵的成熟与分化,胚胎着床,控制某些遗传疾病以及保护珍稀灵长类和提高实验灵长类质量的有效途径。本文从非人灵长类卵的获取(包括超数排卵,非激素刺激动物取卵),精子处理(精液采集,冻存和精子获能),体外受精和胚胎移植、胚胎的冻存等方面介绍了有关研究概况和发展动态。

非人灵长类动物主要免疫器官及免疫细胞的研究进展

免疫毒性是生物技术药物临床前安全性评价中最常见的毒副作用。免疫系统是由多个器官、多种细胞和多种分子组成的一个复杂的系统,其结构和功能与遗传背景、年龄、性别和环境等因素有关,其正常的生理变异范围较大,这对于评估药物所致的免疫毒性是一个巨大的挑战。非人灵长类动物是药物临床前安全性评价中较常用的实验动物。了解和熟悉非人灵长类动物免疫系统的特点,有助于正确、客观地评价药物所致的免疫毒性。本文从非人灵长类动物主要的免疫器官(胸腺、脾和淋巴结)及免疫细胞(T和B淋巴细胞)的发育、形态特征和功能特征等方面进行了详细的论述。

品牌拟人化理论最新研究进展及启示

品牌拟人化通过对特定品牌注入人的特质、动机、主观意图、行为和情感,进一步延伸发展消费者与品牌的特殊关系。品牌拟人化作为一种品牌营销策略,对品牌建设与传播具有非常重要的作用。系统梳理品牌拟人化概念内涵、内在机理及消费者行为影响结果相关文献发现,目前有关品牌拟人化内在机理的研究主要从认知动机和图示匹配两大视角展开,其中前者更充分地将品牌视作完整的人,后者侧重非人载体所呈现出的外显特征与消费者内在特定类别图示的一致性,但二者的实质均在于探讨人们为何以及何时倾向于对包括品牌在内的非人载体进行拟人。一旦消费者把品牌视作一个完整的人,必然会将复杂的人际关系特征引入人与品牌的互动过程,进而导致品牌拟人化结果高度依赖于人的特征、人与拟人化品牌关系的特征、情境特征三者间的交互,使品牌拟人化影响结果呈现出正反两面的"双刃"效应,使企业对品牌拟人实践持有更加审慎的态度。目前,品牌拟人化研究正处于从有限拟人向完整拟人,从关心结果到注重与消费者特质交互,从单一角色到多个角色并行过渡的阶段,未来可基于跨文化情境、角色差异、关系类型的不同侧面进行更加深入的研究。