Spinal cord injury results in the loss of sensory,motor,and autonomic functions,which almost always produces permanent physical disability.Thus,in the search for more effective treatments than those already applied fo...Spinal cord injury results in the loss of sensory,motor,and autonomic functions,which almost always produces permanent physical disability.Thus,in the search for more effective treatments than those already applied for years,which are not entirely efficient,researches have been able to demonstrate the potential of biological strategies using biomaterials to tissue manufacturing through bioengineering and stem cell therapy as a neuroregenerative approach,seeking to promote neuronal recovery after spinal cord injury.Each of these strategies has been developed and meticulously evaluated in several animal models with the aim of analyzing the potential of interventions for neuronal repair and,consequently,boosting functional recovery.Although the majority of experimental research has been conducted in rodents,there is increasing recognition of the importance,and need,of evaluating the safety and efficacy of these interventions in non-human primates before moving to clinical trials involving therapies potentially promising in humans.This article is a literature review from databases(PubMed,Science Direct,Elsevier,Scielo,Redalyc,Cochrane,and NCBI)from 10 years ago to date,using keywords(spinal cord injury,cell therapy,non-human primates,humans,and bioengineering in spinal cord injury).From 110 retrieved articles,after two selection rounds based on inclusion and exclusion criteria,21 articles were analyzed.Thus,this review arises from the need to recognize the experimental therapeutic advances applied in non-human primates and even humans,aimed at deepening these strategies and identifying the advantages and influence of the results on extrapolation for clinical applicability in humans.展开更多
Selective regulation of gene expression across distinct brain regions is crucial for establishing and maintaining subdivision identities.DNA methylation,a key regulator of gene transcription,modulates transcriptional ...Selective regulation of gene expression across distinct brain regions is crucial for establishing and maintaining subdivision identities.DNA methylation,a key regulator of gene transcription,modulates transcriptional activity through the conversion of 5-methylcytosine(5mC)to 5-hydroxymethylcytosine(5hmC).While DNA methylation is hypothesized to play an essential role in shaping brain identity by influencing gene expression patterns,its direct contribution,especially in primates,remains largely unexplored.This study examined DNA methylation landscapes and transcriptional profiles across four brain regions,including the cortex,cerebellum,striatum,and hippocampus,using samples from 12 rhesus monkeys.The cerebellum exhibited distinct epigenetic and transcriptional signatures,with differentially methylated regions(DMRs)significantly enriched in metabolic pathways.Notably,genes harboring clustered differentially hydroxymethylated regions(DhMRs)overlapped with those implicated in schizophrenia.Moreover,5mC located1 kb upstream of the ATG start codon was correlated with gene expression and exhibited region-specific associations with 5hmC.These findings provide insights into the coordinated regulation of cerebellum-specific 5mC and5hmC,highlighting their potential roles in defining cerebellar identity and contributing to neuropsychiatric diseases.展开更多
Alzheimer's disease(AD),the most prevalent form of dementia,disproportionately affects the elderly population.While aging is widely recognized as a major risk factor for AD,the precise mechanisms by which aging co...Alzheimer's disease(AD),the most prevalent form of dementia,disproportionately affects the elderly population.While aging is widely recognized as a major risk factor for AD,the precise mechanisms by which aging contributes to the pathogenesis of AD remain poorly understood.In our previous work,the neuropathological changes in the brains of aged cynomolgus monkeys(≥18 years old)following parenchymal cerebral injection of amyloid-β oligomers(AβOs)have been characterized.Here,we extend our investigation to middle-aged cynomolgus monkeys(≤15 years old)to establish an AD model.Surprisingly,immunohistochemical analysis reveals no detectable AD-related pathology in the brains of middle-aged monkeys,even after AβOs injection.In a comprehensive pathological analysis of 38 monkeys,we observe that the amyloid-β(Aβ)burden increases significantly with advancing age.Notably,the density of Aβ plaques is markedly higher in the ventral regions compared with the dorsal regions of aged monkey brains.Furthermore,we demonstrate that tau phosphorylation coincides with the accumulation of extensive Aβplaques and exhibits a positive correlation with Aβ burden in aged monkeys.Collectively,these findings underscore the critical role of the aged brain in providing the necessary conditions for AβO-induced AD pathologies in cynomolgus monkeys.展开更多
Demyelination and remyelination play key roles in spinal cord injury(SCI),affecting the recovery of motor and sensory functions.Research in rodent models is extensive,but the study of these processes in non-human prim...Demyelination and remyelination play key roles in spinal cord injury(SCI),affecting the recovery of motor and sensory functions.Research in rodent models is extensive,but the study of these processes in non-human primates is limited.Therefore,our goal was to thoroughly study the histological features of demyelination and remyelination after contusion injury of the cervical spinal cord in Macaca fascicularis.In a previous study,we created an SCI model in M.fascicularis by controlling the contusion displacement.We used Eriochrome Cyanine staining,immunohistochemical analysis,and toluidine blue staining to evaluate demyelination and remyelination.The results showed demyelination ipsilateral to the injury epicenter both rostrally and caudally,the former mainly impacting sensory pathways,while the latter primarily affected motor pathways.Toluidine blue staining showed myelin loss and axonal distension at the injury site.Schwann cell-derived myelin sheaths were only found at the center,while thinner myelin sheaths from oligodendrocytes were seen at the center and surrounding areas.Our study showed that long-lasting demyelination occurs in the spinal cord of M.fascicularis after SCI,with oligodendrocytes and Schwann cells playing a significant role in myelin sheath formation at the injury site.展开更多
Dear Editor,Traumatic optic neuropathy(TON)is a severe vision-threatening condition,with an incidence rate ranging from 0.7% to 2.5%[1].The limited regenerative capacity of the optic nerve and the challenges of nerve ...Dear Editor,Traumatic optic neuropathy(TON)is a severe vision-threatening condition,with an incidence rate ranging from 0.7% to 2.5%[1].The limited regenerative capacity of the optic nerve and the challenges of nerve transplantation result in substantial and irreversible visual loss in patients with TON.展开更多
In the past three years, RNA-guided Cas9 nuclease from the microbial clustered regularly interspaced short palindromic repeats （CRISPR） adaptive immune system has been used to facilitate efficient genome editing in ...In the past three years, RNA-guided Cas9 nuclease from the microbial clustered regularly interspaced short palindromic repeats （CRISPR） adaptive immune system has been used to facilitate efficient genome editing in many model and non-model animals. However, its application in nonhuman primates is still at the early stage, though in view of the similarities in anatomy, physiology, behavior and genetics, closely related nonhuman primates serve as optimal models for human biology and disease studies. In this review, we summarize the current proceedings of gene editing using CRISPR/Cas9 in nonhuman primates.展开更多
Strategies to fill the huge gap in supply versus demand of human organs include bioartificial organs, growing humanized organs in animals, cell therapy, and implantable bioengineered constructs. Reproducing the comple...Strategies to fill the huge gap in supply versus demand of human organs include bioartificial organs, growing humanized organs in animals, cell therapy, and implantable bioengineered constructs. Reproducing the complex relations between different cell types, generation of adequate vasculature, and immunological complications are road blocks in generation of bioengineered organs, while immunological complications limit the use of humanized organs produced in animals. Recent developments in induced pluripotent stem cell (iPSC) biology offer a possibility of generating human, patient-specific organs in non-human primates (NHP) using patient-derived iPSC and NHP-derived iPSC lacking the critical developmental genes for the organ of interest complementing a NHP tetraploid embryo. The organ derived in this way will have the same human leukocyte antigen (HLA) profile as the patient. This approach can be curative in genetic disorders as this offers the possibility of gene manipulation and correction of the patient's genome at the iPSC stage before tetraploid complementation. The process of generation of patient-specific organs such as the liver in this way has the great advantage of making use of the natural signaling cascades in the natural milieu probably resulting in organs of great quality for transplantation. However, the inexorable scientific developments in this direction involve several social issues and hence we need to educate and prepare society in advance to accept the revolutionary consequences, good, bad and ugly.展开更多
In order to understand the fundamental questions of the biology of life and to duplicate the pathogenesis of human diseases, animal models using different experimental animals, such as rodents, Drosophila, Caenorhabdi...In order to understand the fundamental questions of the biology of life and to duplicate the pathogenesis of human diseases, animal models using different experimental animals, such as rodents, Drosophila, Caenorhabditis elegans, and zebrafish, have been established and used widely for many decades. The controllability of environmental conditions, the high reproducibility, the ease of scale and the comparability of results, as well as the ability to use different standards for ethical protocols, all make an animal model the ideal tool for carrying out studies on human diseases and the development of novel pharmaceuticals and new therapies （Xue et al., 2014）. An ideal animal model should reflect the complete spectra of a specific human disease, with similar features on the following key issues： （1） genetic basis; （2） anatomy and physiology; （3） pathological response（s） and underlying mechanism（s）; （4） phenotypic endpoints as clinical studies; （5） responsiveness to known drugs with clinical efficacy; and （6） prediction of clinical efficacy （McGonigle and Ruggeri, 2014）.展开更多
Strabismus and amblyopia are common ophthalmologic developmental diseases caused by abnormal visual experiences. However, the underlying pathogenesis and visual defects are still not fully understood. Most studies hav...Strabismus and amblyopia are common ophthalmologic developmental diseases caused by abnormal visual experiences. However, the underlying pathogenesis and visual defects are still not fully understood. Most studies have used experimental interference to establish diseaseassociated animal models, while ignoring the natural pathophysiological mechanisms. This study was designed to investigate whether natural strabismus and amblyopia are associated with abnormal neurological defects. We screened one natural strabismic monkey(Macaca fascicularis) and one natural amblyopic monkey from hundreds of monkeys, and retrospectively analyzed one human strabismus case. Neuroimaging, behavioral,neurophysiological, neurostructural, and genovariation features were systematically evaluated using magnetic resonance imaging(MRI), behavioral tasks, flash visual evoked potentials(FVEP),electroretinogram(ERG), optical coherence tomography(OCT), and whole-genome sequencing(WGS), respectively. Results showed that the strabismic patient and natural strabismic and amblyopic monkeys exhibited similar abnormal asymmetries in brain structure, i.e., ipsilateral impaired right hemisphere. Visual behavior, visual function, retinal structure, and fundus of the monkeys were impaired. Aberrant asymmetry in binocular visual function and structure between the strabismic and amblyopic monkeys was closely related, with greater impairment of the left visual pathway.Several similar known mutant genes for strabismus and amblyopia were also identified. In conclusion,natural strabismus and amblyopia are accompanied by abnormal asymmetries of the visual system,especially visual neurophysiological and neurostructural defects. Our results suggest that future therapeutic and mechanistic studies should consider defects and asymmetries throughout the entire visual system.展开更多
Spinal cord injury results in significant sensorimotor deficits,currently,there is no curative treatment for the symptoms induced by spinal cord injury.Basic and pre-clinical research on spinal cord injury relies on t...Spinal cord injury results in significant sensorimotor deficits,currently,there is no curative treatment for the symptoms induced by spinal cord injury.Basic and pre-clinical research on spinal cord injury relies on the development and characterization of appropriate animal models.These models should replicate the symptoms observed in human,allowing for the exploration of functional deficits and investigation into various aspects of physiopathology of spinal cord injury.Non-human primates,due to their close phylogenetic association with humans,share more neuroanatomical,genetic,and physiological similarities with humans than rodents.Therefore,the responses to spinal cord injury in nonhuman primates most likely resemble the responses to traumatism in humans.In this review,we will discuss nonhuman primate models of spinal cord injury,focusing on in vivo assessments,including behavioral tests,magnetic resonance imaging,and electrical activity recordings,as well as ex vivo histological analyses.Additionally,we will present therapeutic strategies developed in non-human primates and discuss the unique specificities of non-human primate models of spinal cord injury.展开更多
Optical-neural stimulation,which encompasses cutting-edge techniques such as optogenetics and infrared neurostimulation,employs distinct mechanisms to modulate brain function and behavior.These advanced neuromodulatio...Optical-neural stimulation,which encompasses cutting-edge techniques such as optogenetics and infrared neurostimulation,employs distinct mechanisms to modulate brain function and behavior.These advanced neuromodulation techniques offer accurate manipulation of targeted areas,even selectively modulating specific neurons,in the brain.This makes it possible to investigate the cause-and-effect connections between neural activity and behavior,allowing for a better comprehension of the intricate brain dynamics towards complex environments.Non-human primates serve as an essential animal model for investigating these complex functions in brain research,bridging the gap between the basic research and clinical applications.One of the earliest optical studies utilizing optogenetic neuromodulation in monkeys was conducted in 2009.Since then,the optical-neural stimulations have been effectively applied in non-human primates.This review summarises recent research that employed optogenetics or infrared neurostimulation techniques to regulate brain function and behavior in non-human primates.The current state of optical-neural stimulations discussed here demonstrates their efficacy in advancing the understanding of brain systems.Nevertheless,there are still challenges that need to be addressed before they can fully achieve their potential.展开更多
Twenty five monkeys were used in this experiment. They were divided into 5 groups with 5 animals as the replicates in each group and were adapted for two weeks to the environment before the data were collected. The an...Twenty five monkeys were used in this experiment. They were divided into 5 groups with 5 animals as the replicates in each group and were adapted for two weeks to the environment before the data were collected. The animals were subjected to 5 experimental diets, i.e. T1 (Basal diet); T2 (Basal diet + palm oil); T3 (Basal diet + palm oil + soybean hull); T4 (Basal diet + cholesterol) and T5 (Basal diet + cholesterol + soybean hull). The diets were given for a period of 8 months and water were given ad lib. Blood serum was taken before and during the experiment. The cholesterol, triglycerides, LDL and HDL were measured using the spectrophotometric method. At the end of the experiment thorax surgery was performed on the animals under general anesthesia. The aorta was removed surgicalIy for histopathological observation stained with hematoxylin and eosine.The results showed that the soybean hull decreased the serum cholesterol level in the groups given palm oil (T2 vs T3) and the groups given cholesterol (T4 vs T5) i.e.: 163.4 vs 124.7 mg/dl and 359 vs 288.5 mg/dl respectively. The soybean hull did not significantly affect the serum triglyceride nor the LDL level when palm oil was given in the diet, but it significantly decreased the two parameters where cholesterol was given in the diet (102.5 vs 98.6 mg/dl triglyceride) and (231 .9 vs 183 mg/dl LDL). The soybean hull did not seem to affect the HDL level.Histopathological observation of the aorta indicated that given T1, T2, T3, T4 and T5 caused 45%, 41 .67%, 31.25%, 86.25% and 53.38% lesion (Atheroma arteriale) resPectively.It was concluded that the soybean hull given in the diet has the ability to prevent the development of atherosclerosis in the aorta of the experimental animals展开更多
From 2 to 4 November, 2016, the 4th Symposium on Animal Models of Non-Human Primates （NHP） was held in Kunming, Yunnan, China. This meeting was organized by the Key Laboratory of Animal Models and Human Disease Mech...From 2 to 4 November, 2016, the 4th Symposium on Animal Models of Non-Human Primates （NHP） was held in Kunming, Yunnan, China. This meeting was organized by the Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences （CAS） ＆ Yunnan Province Kunming Primate Research Center （KPRC）, Zoological Research, and Kunming Institute of Zoology （KIZ）, CAS.展开更多
Cryptosporidium is an emerging single-cell zoonotic pathogen.By invading human and animal small intestinal epithelial cells,the host produces a variety of clinical symptoms,mainly diarrhea.Spores of Cryptosporidium ca...Cryptosporidium is an emerging single-cell zoonotic pathogen.By invading human and animal small intestinal epithelial cells,the host produces a variety of clinical symptoms,mainly diarrhea.Spores of Cryptosporidium can be transmitted through water-borne,food-borne,and mutual transmission between hosts,which has important public health significance.Studies have shown that non-human primates can be infected with multiple Cryptosporidium genotypes.Moreover,this species has a high genetic similarity with humans,so it needs to be taken seriously.This article reviews the infection rates,genotypes,and zoonotic risk of Cryptosporidium in non-human primates.展开更多
Human functional MRI studies in acute and various chronic pain conditions have revolutionized how we view pain, and have led to a new theory that complex multi-dimensional pain experience （sensory-discriminative, aff...Human functional MRI studies in acute and various chronic pain conditions have revolutionized how we view pain, and have led to a new theory that complex multi-dimensional pain experience （sensory-discriminative, affective/motivational, and cognitive） is represented by concurrent activity in widely-distributed brain regions （termed a network or pain matrix）. Despite these break- through discoveries, the specific functions proposed for these regions remain elusive, because detailed electrophys- iological characterizations of these regions in the primate brain are lacking. To fill in this knowledge gap, we have studied the cortical areas around the central and lateral sulci of the non-human primate brain with combined submillimeter resolution functional imaging （optical imaging and fMRI） and intracranial electrophysiological recording. In this mini-review, I summarize and present data showing that the cortical circuitry engaged in nociceptive processing is much more complex than previously recognized. Electrophysiological evidence supports the engage- ment of a distinct nociceptive-processing network within SI （i.e., areas 3a, 3b, 1 and 2）, SII, and other areas along the lateral sulcus. Deafferentation caused by spinal cord injury profoundly alters the relationships between fMRI and electrophysiological signals. This finding has significant implications for using fMRI to study chronic pain conditions involving deafferentation in humans.展开更多
The ongoing coronavirus disease 2019(COVID-19)pandemic caused more than 96 million infections and over 2 million deaths worldwide so far.However,there is no approved vaccine available for severe acute respiratory synd...The ongoing coronavirus disease 2019(COVID-19)pandemic caused more than 96 million infections and over 2 million deaths worldwide so far.However,there is no approved vaccine available for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the disease causative agent.Vaccine is the most effective approach to eradicate a pathogen.The tests of safety and efficacy in animals are pivotal for developing a vaccine and before the vaccine is applied to human populations.Here we evaluated the safety,immunogenicity,and efficacy of an inactivated vaccine based on the whole viral particles in human ACE2 transgenic mouse and in non-human primates.Our data showed that the inactivated vaccine successfully induced SARS-CoV-2-specific neutralizing antibodies in mice and non-human primates,and subsequently provided partial(in low dose)or full(in high dose)protection of challenge in the tested animals.In addition,passive serum transferred from vaccine-immunized mice could also provide full protection from SARS-CoV-2 infection in mice.These results warranted positive outcomes in future clinical trials in humans.展开更多
Transplantation therapy for diabetes in humans is limited by the low availability of human donor whole pancreas or islets. Outcomes are complicated by immunosuppressive drug toxicity. Xenotransplantation is a strategy...Transplantation therapy for diabetes in humans is limited by the low availability of human donor whole pancreas or islets. Outcomes are complicated by immunosuppressive drug toxicity. Xenotransplantation is a strategy to overcome supply problems. Implantation of tissue obtained early during embryogenesis is a way to reduce transplant immunogenicity. Pig insulin is biologically active in humans. In that regard the pig is an appropriate xenogeneic organ donor. Insulin-producing cells originating from embryonic pig pancreas obtained very early following pancreatic primordium formation [embryonic day 28 (E28)] engraft long-term in rhesus macaques. Endocrine cells originating from embryonic pig pancreas transplanted in host mesentery migrate to mesenteric lymph nodes, engraft, differentiate and improve glucose tolerance in rhesus macaques without the need for immune suppression. Transplantation of embryonic pig pancreas is a novel approach towards beta cell replacement therapy that could be applicable to humans.展开更多
Viruses can be transmitted from animals to humans(and vice versa)and across animal species.As such,host-virus interactions and transmission have attracted considerable attention.Non-human primates(NHPs),our closest ev...Viruses can be transmitted from animals to humans(and vice versa)and across animal species.As such,host-virus interactions and transmission have attracted considerable attention.Non-human primates(NHPs),our closest evolutionary relatives,are susceptible to human viruses and certain pathogens are known to circulate between humans and NHPs.Here,we generated global statistics on virus infections in NHPs(VI-NHPs)based on a literature search and public data mining.In total,140 NHP species from 12 families are reported to be infected by 186 DNA and RNA virus species,68.8%of which are also found in humans,indicating high potential for crossing species boundaries.展开更多
Active exploratory behaviors have often been associated with theta oscillations in rodents,while theta oscillations during active exploration in non-human primates are still not well understood.We recorded neural acti...Active exploratory behaviors have often been associated with theta oscillations in rodents,while theta oscillations during active exploration in non-human primates are still not well understood.We recorded neural activities in the frontal eye field(FEF)and V4 simultaneously when monkeys performed a free-gaze visual search task.Saccades were strongly phase-locked to theta oscillations of V4 and FEF local field potentials,and the phase-locking was dependent on saccade direction.The spiking probability of V4 and FEF units was significantly modulated by the theta phase in addition to the time-locked modulation associated with the evoked response.V4 and FEF units showed significantly stronger responses following saccades initiated at their preferred phases.Granger causality and ridge regression analysis showed modulatory effects of theta oscillations on saccade timing.Together,our study suggests phase-locking of saccades to the theta modulation of neural activity in visual and oculomotor cortical areas,in addition to the theta phase locking caused by saccade-triggered responses.展开更多
Genetic tools,which can be used for the morphology study of specific neurons,pathway-selective connectome mapping,neuronal activity monitoring,and manipulation with a spatiotemporal resolution,have been widely applied...Genetic tools,which can be used for the morphology study of specific neurons,pathway-selective connectome mapping,neuronal activity monitoring,and manipulation with a spatiotemporal resolution,have been widely applied to the understanding of complex neural circuit formation,interactions,and functions in rodents.Recently,similar genetic approaches have been tried in non-human primates(NHPs)in neuroscience studies for dissecting the neural circuits involved in sophisticated behaviors and clinical brain disorders,although they are still very preliminary.In this review,we introduce the progress made in the development and application of genetic tools for brain studies on NHPs.We also discuss the advantages and limitations of each approach and provide a perspective for using genetic tools to study the neural circuits of NHPs.展开更多
文摘Spinal cord injury results in the loss of sensory,motor,and autonomic functions,which almost always produces permanent physical disability.Thus,in the search for more effective treatments than those already applied for years,which are not entirely efficient,researches have been able to demonstrate the potential of biological strategies using biomaterials to tissue manufacturing through bioengineering and stem cell therapy as a neuroregenerative approach,seeking to promote neuronal recovery after spinal cord injury.Each of these strategies has been developed and meticulously evaluated in several animal models with the aim of analyzing the potential of interventions for neuronal repair and,consequently,boosting functional recovery.Although the majority of experimental research has been conducted in rodents,there is increasing recognition of the importance,and need,of evaluating the safety and efficacy of these interventions in non-human primates before moving to clinical trials involving therapies potentially promising in humans.This article is a literature review from databases(PubMed,Science Direct,Elsevier,Scielo,Redalyc,Cochrane,and NCBI)from 10 years ago to date,using keywords(spinal cord injury,cell therapy,non-human primates,humans,and bioengineering in spinal cord injury).From 110 retrieved articles,after two selection rounds based on inclusion and exclusion criteria,21 articles were analyzed.Thus,this review arises from the need to recognize the experimental therapeutic advances applied in non-human primates and even humans,aimed at deepening these strategies and identifying the advantages and influence of the results on extrapolation for clinical applicability in humans.
基金supported by the Natural Science Foundation of Guangdong Province(2022A1515010689)National Natural Science Foundation of China(82394422,82371874,82071421,82271902)Department of Science and Technology of Guangdong Province(2021ZT09Y007,2020B121201006)。
文摘Selective regulation of gene expression across distinct brain regions is crucial for establishing and maintaining subdivision identities.DNA methylation,a key regulator of gene transcription,modulates transcriptional activity through the conversion of 5-methylcytosine(5mC)to 5-hydroxymethylcytosine(5hmC).While DNA methylation is hypothesized to play an essential role in shaping brain identity by influencing gene expression patterns,its direct contribution,especially in primates,remains largely unexplored.This study examined DNA methylation landscapes and transcriptional profiles across four brain regions,including the cortex,cerebellum,striatum,and hippocampus,using samples from 12 rhesus monkeys.The cerebellum exhibited distinct epigenetic and transcriptional signatures,with differentially methylated regions(DMRs)significantly enriched in metabolic pathways.Notably,genes harboring clustered differentially hydroxymethylated regions(DhMRs)overlapped with those implicated in schizophrenia.Moreover,5mC located1 kb upstream of the ATG start codon was correlated with gene expression and exhibited region-specific associations with 5hmC.These findings provide insights into the coordinated regulation of cerebellum-specific 5mC and5hmC,highlighting their potential roles in defining cerebellar identity and contributing to neuropsychiatric diseases.
基金supported in part by the National Key Basic Research and Development Program of China(2019YFA0801402,2018YFA0107200,2018YFA0801402,2018YFA0800100)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16020501 and XDA16020404)the National Natural Science Foundation of China(32130030,31900454,32470866,32471010,32100800)。
文摘Alzheimer's disease(AD),the most prevalent form of dementia,disproportionately affects the elderly population.While aging is widely recognized as a major risk factor for AD,the precise mechanisms by which aging contributes to the pathogenesis of AD remain poorly understood.In our previous work,the neuropathological changes in the brains of aged cynomolgus monkeys(≥18 years old)following parenchymal cerebral injection of amyloid-β oligomers(AβOs)have been characterized.Here,we extend our investigation to middle-aged cynomolgus monkeys(≤15 years old)to establish an AD model.Surprisingly,immunohistochemical analysis reveals no detectable AD-related pathology in the brains of middle-aged monkeys,even after AβOs injection.In a comprehensive pathological analysis of 38 monkeys,we observe that the amyloid-β(Aβ)burden increases significantly with advancing age.Notably,the density of Aβ plaques is markedly higher in the ventral regions compared with the dorsal regions of aged monkey brains.Furthermore,we demonstrate that tau phosphorylation coincides with the accumulation of extensive Aβplaques and exhibits a positive correlation with Aβ burden in aged monkeys.Collectively,these findings underscore the critical role of the aged brain in providing the necessary conditions for AβO-induced AD pathologies in cynomolgus monkeys.
基金supported by the National Natural Science Foundation of China(81972064)the Guangdong Basic and Applied Basic Research Foundation(2021A1515111117,2020A1515011415).
文摘Demyelination and remyelination play key roles in spinal cord injury(SCI),affecting the recovery of motor and sensory functions.Research in rodent models is extensive,but the study of these processes in non-human primates is limited.Therefore,our goal was to thoroughly study the histological features of demyelination and remyelination after contusion injury of the cervical spinal cord in Macaca fascicularis.In a previous study,we created an SCI model in M.fascicularis by controlling the contusion displacement.We used Eriochrome Cyanine staining,immunohistochemical analysis,and toluidine blue staining to evaluate demyelination and remyelination.The results showed demyelination ipsilateral to the injury epicenter both rostrally and caudally,the former mainly impacting sensory pathways,while the latter primarily affected motor pathways.Toluidine blue staining showed myelin loss and axonal distension at the injury site.Schwann cell-derived myelin sheaths were only found at the center,while thinner myelin sheaths from oligodendrocytes were seen at the center and surrounding areas.Our study showed that long-lasting demyelination occurs in the spinal cord of M.fascicularis after SCI,with oligodendrocytes and Schwann cells playing a significant role in myelin sheath formation at the injury site.
基金supported by Guangzhou Key Projects of Brain Science and Brain-Like Intelligence Technology(20200730009)the National Natural Science Foundation of China(81870656)the Natural Science Foundation of Guangdong Province of China(2017A030313610 and 2023A1515012397).
文摘Dear Editor,Traumatic optic neuropathy(TON)is a severe vision-threatening condition,with an incidence rate ranging from 0.7% to 2.5%[1].The limited regenerative capacity of the optic nerve and the challenges of nerve transplantation result in substantial and irreversible visual loss in patients with TON.
基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB13010000)the National Natural Science Foundation of China(31130051)
文摘In the past three years, RNA-guided Cas9 nuclease from the microbial clustered regularly interspaced short palindromic repeats （CRISPR） adaptive immune system has been used to facilitate efficient genome editing in many model and non-model animals. However, its application in nonhuman primates is still at the early stage, though in view of the similarities in anatomy, physiology, behavior and genetics, closely related nonhuman primates serve as optimal models for human biology and disease studies. In this review, we summarize the current proceedings of gene editing using CRISPR/Cas9 in nonhuman primates.
文摘Strategies to fill the huge gap in supply versus demand of human organs include bioartificial organs, growing humanized organs in animals, cell therapy, and implantable bioengineered constructs. Reproducing the complex relations between different cell types, generation of adequate vasculature, and immunological complications are road blocks in generation of bioengineered organs, while immunological complications limit the use of humanized organs produced in animals. Recent developments in induced pluripotent stem cell (iPSC) biology offer a possibility of generating human, patient-specific organs in non-human primates (NHP) using patient-derived iPSC and NHP-derived iPSC lacking the critical developmental genes for the organ of interest complementing a NHP tetraploid embryo. The organ derived in this way will have the same human leukocyte antigen (HLA) profile as the patient. This approach can be curative in genetic disorders as this offers the possibility of gene manipulation and correction of the patient's genome at the iPSC stage before tetraploid complementation. The process of generation of patient-specific organs such as the liver in this way has the great advantage of making use of the natural signaling cascades in the natural milieu probably resulting in organs of great quality for transplantation. However, the inexorable scientific developments in this direction involve several social issues and hence we need to educate and prepare society in advance to accept the revolutionary consequences, good, bad and ugly.
文摘In order to understand the fundamental questions of the biology of life and to duplicate the pathogenesis of human diseases, animal models using different experimental animals, such as rodents, Drosophila, Caenorhabditis elegans, and zebrafish, have been established and used widely for many decades. The controllability of environmental conditions, the high reproducibility, the ease of scale and the comparability of results, as well as the ability to use different standards for ethical protocols, all make an animal model the ideal tool for carrying out studies on human diseases and the development of novel pharmaceuticals and new therapies （Xue et al., 2014）. An ideal animal model should reflect the complete spectra of a specific human disease, with similar features on the following key issues： （1） genetic basis; （2） anatomy and physiology; （3） pathological response（s） and underlying mechanism（s）; （4） phenotypic endpoints as clinical studies; （5） responsiveness to known drugs with clinical efficacy; and （6） prediction of clinical efficacy （McGonigle and Ruggeri, 2014）.
基金supported by the National Natural Science Foundation of China(81870682,81961128021,81670885)National Key R&D Program of China(2022YEF0203200,2021ZD0200103,2018YFA0108300)+2 种基金Guangdong Provincial Key R&D Programs(2018B030335001,2018B030337001)Local Innovative and Research Teams Project of Guangdong(2017BT01S138)Science and Technology Program of Guangzhou(202007030011,202007030010)。
文摘Strabismus and amblyopia are common ophthalmologic developmental diseases caused by abnormal visual experiences. However, the underlying pathogenesis and visual defects are still not fully understood. Most studies have used experimental interference to establish diseaseassociated animal models, while ignoring the natural pathophysiological mechanisms. This study was designed to investigate whether natural strabismus and amblyopia are associated with abnormal neurological defects. We screened one natural strabismic monkey(Macaca fascicularis) and one natural amblyopic monkey from hundreds of monkeys, and retrospectively analyzed one human strabismus case. Neuroimaging, behavioral,neurophysiological, neurostructural, and genovariation features were systematically evaluated using magnetic resonance imaging(MRI), behavioral tasks, flash visual evoked potentials(FVEP),electroretinogram(ERG), optical coherence tomography(OCT), and whole-genome sequencing(WGS), respectively. Results showed that the strabismic patient and natural strabismic and amblyopic monkeys exhibited similar abnormal asymmetries in brain structure, i.e., ipsilateral impaired right hemisphere. Visual behavior, visual function, retinal structure, and fundus of the monkeys were impaired. Aberrant asymmetry in binocular visual function and structure between the strabismic and amblyopic monkeys was closely related, with greater impairment of the left visual pathway.Several similar known mutant genes for strabismus and amblyopia were also identified. In conclusion,natural strabismus and amblyopia are accompanied by abnormal asymmetries of the visual system,especially visual neurophysiological and neurostructural defects. Our results suggest that future therapeutic and mechanistic studies should consider defects and asymmetries throughout the entire visual system.
基金supported by the patient organizations“Verticale”(to FEP).
文摘Spinal cord injury results in significant sensorimotor deficits,currently,there is no curative treatment for the symptoms induced by spinal cord injury.Basic and pre-clinical research on spinal cord injury relies on the development and characterization of appropriate animal models.These models should replicate the symptoms observed in human,allowing for the exploration of functional deficits and investigation into various aspects of physiopathology of spinal cord injury.Non-human primates,due to their close phylogenetic association with humans,share more neuroanatomical,genetic,and physiological similarities with humans than rodents.Therefore,the responses to spinal cord injury in nonhuman primates most likely resemble the responses to traumatism in humans.In this review,we will discuss nonhuman primate models of spinal cord injury,focusing on in vivo assessments,including behavioral tests,magnetic resonance imaging,and electrical activity recordings,as well as ex vivo histological analyses.Additionally,we will present therapeutic strategies developed in non-human primates and discuss the unique specificities of non-human primate models of spinal cord injury.
文摘Optical-neural stimulation,which encompasses cutting-edge techniques such as optogenetics and infrared neurostimulation,employs distinct mechanisms to modulate brain function and behavior.These advanced neuromodulation techniques offer accurate manipulation of targeted areas,even selectively modulating specific neurons,in the brain.This makes it possible to investigate the cause-and-effect connections between neural activity and behavior,allowing for a better comprehension of the intricate brain dynamics towards complex environments.Non-human primates serve as an essential animal model for investigating these complex functions in brain research,bridging the gap between the basic research and clinical applications.One of the earliest optical studies utilizing optogenetic neuromodulation in monkeys was conducted in 2009.Since then,the optical-neural stimulations have been effectively applied in non-human primates.This review summarises recent research that employed optogenetics or infrared neurostimulation techniques to regulate brain function and behavior in non-human primates.The current state of optical-neural stimulations discussed here demonstrates their efficacy in advancing the understanding of brain systems.Nevertheless,there are still challenges that need to be addressed before they can fully achieve their potential.
文摘Twenty five monkeys were used in this experiment. They were divided into 5 groups with 5 animals as the replicates in each group and were adapted for two weeks to the environment before the data were collected. The animals were subjected to 5 experimental diets, i.e. T1 (Basal diet); T2 (Basal diet + palm oil); T3 (Basal diet + palm oil + soybean hull); T4 (Basal diet + cholesterol) and T5 (Basal diet + cholesterol + soybean hull). The diets were given for a period of 8 months and water were given ad lib. Blood serum was taken before and during the experiment. The cholesterol, triglycerides, LDL and HDL were measured using the spectrophotometric method. At the end of the experiment thorax surgery was performed on the animals under general anesthesia. The aorta was removed surgicalIy for histopathological observation stained with hematoxylin and eosine.The results showed that the soybean hull decreased the serum cholesterol level in the groups given palm oil (T2 vs T3) and the groups given cholesterol (T4 vs T5) i.e.: 163.4 vs 124.7 mg/dl and 359 vs 288.5 mg/dl respectively. The soybean hull did not significantly affect the serum triglyceride nor the LDL level when palm oil was given in the diet, but it significantly decreased the two parameters where cholesterol was given in the diet (102.5 vs 98.6 mg/dl triglyceride) and (231 .9 vs 183 mg/dl LDL). The soybean hull did not seem to affect the HDL level.Histopathological observation of the aorta indicated that given T1, T2, T3, T4 and T5 caused 45%, 41 .67%, 31.25%, 86.25% and 53.38% lesion (Atheroma arteriale) resPectively.It was concluded that the soybean hull given in the diet has the ability to prevent the development of atherosclerosis in the aorta of the experimental animals
基金supported by the Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province,KPRC,KIZ,CAS,and Zoology Research
文摘From 2 to 4 November, 2016, the 4th Symposium on Animal Models of Non-Human Primates （NHP） was held in Kunming, Yunnan, China. This meeting was organized by the Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences （CAS） ＆ Yunnan Province Kunming Primate Research Center （KPRC）, Zoological Research, and Kunming Institute of Zoology （KIZ）, CAS.
基金Innovation Research Team Project of Natural Science Foundation of Hainan Province(No.2018CXTD340)National Natural Science Foundation of China(No.81760378)National Natural Science Foundation of China(No.82060375)。
文摘Cryptosporidium is an emerging single-cell zoonotic pathogen.By invading human and animal small intestinal epithelial cells,the host produces a variety of clinical symptoms,mainly diarrhea.Spores of Cryptosporidium can be transmitted through water-borne,food-borne,and mutual transmission between hosts,which has important public health significance.Studies have shown that non-human primates can be infected with multiple Cryptosporidium genotypes.Moreover,this species has a high genetic similarity with humans,so it needs to be taken seriously.This article reviews the infection rates,genotypes,and zoonotic risk of Cryptosporidium in non-human primates.
基金supported by NIH Grant R01 NS069909an imaging track Grant from the Dana Foundation
文摘Human functional MRI studies in acute and various chronic pain conditions have revolutionized how we view pain, and have led to a new theory that complex multi-dimensional pain experience （sensory-discriminative, affective/motivational, and cognitive） is represented by concurrent activity in widely-distributed brain regions （termed a network or pain matrix）. Despite these break- through discoveries, the specific functions proposed for these regions remain elusive, because detailed electrophys- iological characterizations of these regions in the primate brain are lacking. To fill in this knowledge gap, we have studied the cortical areas around the central and lateral sulci of the non-human primate brain with combined submillimeter resolution functional imaging （optical imaging and fMRI） and intracranial electrophysiological recording. In this mini-review, I summarize and present data showing that the cortical circuitry engaged in nociceptive processing is much more complex than previously recognized. Electrophysiological evidence supports the engage- ment of a distinct nociceptive-processing network within SI （i.e., areas 3a, 3b, 1 and 2）, SII, and other areas along the lateral sulcus. Deafferentation caused by spinal cord injury profoundly alters the relationships between fMRI and electrophysiological signals. This finding has significant implications for using fMRI to study chronic pain conditions involving deafferentation in humans.
基金supported by the National Key R&D Program of China(2020YFC0842000 to Z.M.Yuan and 2020YFC0842100 to C.Shan)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB29010101 to Z.L.Shi)+1 种基金the China Natural Science Foundation(82041013 to P.Zhou)the Youth Innovation Promotion Association of the Chinese Academy of Sciences(CAS)(2019328 to X.L.Yang)。
文摘The ongoing coronavirus disease 2019(COVID-19)pandemic caused more than 96 million infections and over 2 million deaths worldwide so far.However,there is no approved vaccine available for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the disease causative agent.Vaccine is the most effective approach to eradicate a pathogen.The tests of safety and efficacy in animals are pivotal for developing a vaccine and before the vaccine is applied to human populations.Here we evaluated the safety,immunogenicity,and efficacy of an inactivated vaccine based on the whole viral particles in human ACE2 transgenic mouse and in non-human primates.Our data showed that the inactivated vaccine successfully induced SARS-CoV-2-specific neutralizing antibodies in mice and non-human primates,and subsequently provided partial(in low dose)or full(in high dose)protection of challenge in the tested animals.In addition,passive serum transferred from vaccine-immunized mice could also provide full protection from SARS-CoV-2 infection in mice.These results warranted positive outcomes in future clinical trials in humans.
文摘Transplantation therapy for diabetes in humans is limited by the low availability of human donor whole pancreas or islets. Outcomes are complicated by immunosuppressive drug toxicity. Xenotransplantation is a strategy to overcome supply problems. Implantation of tissue obtained early during embryogenesis is a way to reduce transplant immunogenicity. Pig insulin is biologically active in humans. In that regard the pig is an appropriate xenogeneic organ donor. Insulin-producing cells originating from embryonic pig pancreas obtained very early following pancreatic primordium formation [embryonic day 28 (E28)] engraft long-term in rhesus macaques. Endocrine cells originating from embryonic pig pancreas transplanted in host mesentery migrate to mesenteric lymph nodes, engraft, differentiate and improve glucose tolerance in rhesus macaques without the need for immune suppression. Transplantation of embryonic pig pancreas is a novel approach towards beta cell replacement therapy that could be applicable to humans.
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA23080201,XDA19050202)National Natural Science Foundation of China(31821001)+1 种基金National Key R&D Program of China(2016YFC0503200)。
文摘Viruses can be transmitted from animals to humans(and vice versa)and across animal species.As such,host-virus interactions and transmission have attracted considerable attention.Non-human primates(NHPs),our closest evolutionary relatives,are susceptible to human viruses and certain pathogens are known to circulate between humans and NHPs.Here,we generated global statistics on virus infections in NHPs(VI-NHPs)based on a literature search and public data mining.In total,140 NHP species from 12 families are reported to be infected by 186 DNA and RNA virus species,68.8%of which are also found in humans,indicating high potential for crossing species boundaries.
基金We are grateful for the financial support from the National Natural Science Foundation of China(31671108 and 31800900)the National Key R&D Program of China(2017YFC1307500)+1 种基金the Shenzhen Science and Technology Innovation Commission(JCYJ20180508152240368)the Shenzhen Basic Research Program(JCYJ20200109114805984).
文摘Active exploratory behaviors have often been associated with theta oscillations in rodents,while theta oscillations during active exploration in non-human primates are still not well understood.We recorded neural activities in the frontal eye field(FEF)and V4 simultaneously when monkeys performed a free-gaze visual search task.Saccades were strongly phase-locked to theta oscillations of V4 and FEF local field potentials,and the phase-locking was dependent on saccade direction.The spiking probability of V4 and FEF units was significantly modulated by the theta phase in addition to the time-locked modulation associated with the evoked response.V4 and FEF units showed significantly stronger responses following saccades initiated at their preferred phases.Granger causality and ridge regression analysis showed modulatory effects of theta oscillations on saccade timing.Together,our study suggests phase-locking of saccades to the theta modulation of neural activity in visual and oculomotor cortical areas,in addition to the theta phase locking caused by saccade-triggered responses.
基金This review was supported by grants from the Shanghai Municipal Science and Technology Major Project,the Strategic Priority Research Program of the Chinese Academy of Sciences,and the Lingang National Laboratory Key Project.
文摘Genetic tools,which can be used for the morphology study of specific neurons,pathway-selective connectome mapping,neuronal activity monitoring,and manipulation with a spatiotemporal resolution,have been widely applied to the understanding of complex neural circuit formation,interactions,and functions in rodents.Recently,similar genetic approaches have been tried in non-human primates(NHPs)in neuroscience studies for dissecting the neural circuits involved in sophisticated behaviors and clinical brain disorders,although they are still very preliminary.In this review,we introduce the progress made in the development and application of genetic tools for brain studies on NHPs.We also discuss the advantages and limitations of each approach and provide a perspective for using genetic tools to study the neural circuits of NHPs.
