Background:Non-human primates(NPHs),such as rhesus macaques,cynomol-gus monkeys,and Assamese macaques,play a crucial role in biomedical research.However,baseline cytokine and electrolyte data for these three species,p...Background:Non-human primates(NPHs),such as rhesus macaques,cynomol-gus monkeys,and Assamese macaques,play a crucial role in biomedical research.However,baseline cytokine and electrolyte data for these three species,particularly data stratified by age and sex,are limited.Therefore,the aim of this study was to establish and analyze age-and sex-specific cytokine and electrolyte profiles in these three species.Methods:This study included 40 rhesus macaques(21 males,19 females),33 cyn-omolgus monkeys(17 males,16 females),and 45 Assamese macaques(25 males,20 females)classified by age(1-5 years,6-12 years,>13 years)and sex.The levels of 23 immune function indicators and 5 electrolyte indicators were measured.Results:Among the three monkey species,the levels of sCD40L,IL-18,MCP-1,MIP-1β,TGFa,K^(+),Na^(+),and Cl^(-)exhibited species-,sex-,and age-related differences.Comparison within the same species,sex had no significant impact on cytokine levels in NHPs but did affect electrolyte levels,particularly Cl^(-)and Na^(+)levels,in cynomol-gus monkeys and Assamese macaques.Electrolyte levels in NHPs were not affected by age,whereas the levels of certain cytokines,particularly sCD40L,GM-CSF,and IL-10,varied with age.The remaining 21 cytokines demonstrated no significant age-related changes.Conclusions:Significant variations in cytokine and electrolyte levels exist among dif-ferent monkey species,sexes,and age groups.This research provides valuable re-sources for NHP researchers and sets the stage for further exploring the impacts of sex and age on NHP physiology and immune function.展开更多
While viral infections can disturb the host gut microbiome,the dynamic alterations in microbial composition following infection remain poorly characterized.This study identified SRV-8-infected monkeys and classified t...While viral infections can disturb the host gut microbiome,the dynamic alterations in microbial composition following infection remain poorly characterized.This study identified SRV-8-infected monkeys and classified them into five groups based on infection progression.16S rRNA amplicon sequencing revealed significant alterations in the relative and inferred absolute abundance of bacterial genera UCG-002,Agathobacter,Coprococcus,and Holdemanella during the early stage of SRV-8 infection,coinciding with provirus formation.These microbial shifts were accompanied by functional modifications in bacterial communities at the same stage.In contrast,ITS amplicon sequencing indicated no significant differences in fungal composition between healthy wild-type and SRV-8-infected monkeys.Spearman correlation analyses demonstrated close interactions between intestinal bacteria and fungi following SRV-8 infection.Additionally,SRV-8 seropositive groups exhibited significantly elevated mRNA expression levels of pro-inflammatory(TNF-α,IFN-γ,IL-1β,and IL-6)and anti-inflammatory(IL-10)cytokine genes,highlighting close associations between inflammatory cytokines and immune responses.Overall,these findings provide a comprehensive characterization of bacterial and fungal microbiota dynamics and inflammatory cytokine responses associated with SRV-8 infection,clarifying the pathobiological mechanisms underlying SRV-8 infection from the perspective of the gut microbiome.展开更多
Neural tube defects(NTDs)are severe congenital neurodevelopmental disorders arising from incomplete neural tube closure.Although folate supplementation has been shown to mitigate the incidence of NTDs,some cases,often...Neural tube defects(NTDs)are severe congenital neurodevelopmental disorders arising from incomplete neural tube closure.Although folate supplementation has been shown to mitigate the incidence of NTDs,some cases,often attributable to genetic factors,remain unpreventable.The SHROOM3 gene has been implicated in NTD cases that are unresponsive to folate supplementation;at present,however,the underlying mechanism remains unclear.Neural tube morphogenesis is a complex process involving the folding of the planar epithelium of the neural plate.To determine the role of SHROOM3 in early developmental morphogenesis,we established a neuroepithelial organoid culture system derived from cynomolgus monkeys to closely mimic the in vivo neural plate phase.Loss of SHROOM3 resulted in shorter neuroepithelial cells and smaller nuclei.These morphological changes were attributed to the insufficient recruitment of cytoskeletal proteins,namely fibrous actin(F-actin),myosin II,and phospho-myosin light chain(PMLC),to the apical side of the neuroepithelial cells.Notably,these defects were not rescued by folate supplementation.RNA sequencing revealed that differentially expressed genes were enriched in biological processes associated with cellular and organ morphogenesis.In summary,we established an authentic in vitro system to study NTDs and identified a novel mechanism for NTDs that are unresponsive to folate supplementation.展开更多
Complex brain diseases seriously endanger human health,and early diagnostic biomarkers and effective treatments are currently lacking.Due to ethical constraints on human research,establishing monkey models is crucial ...Complex brain diseases seriously endanger human health,and early diagnostic biomarkers and effective treatments are currently lacking.Due to ethical constraints on human research,establishing monkey models is crucial to address these issues.With the rapid development of technology,transgenic monkey models of a range of brain diseases,especially autism spectrum disorder(ASD),have been successfully established.However,to establish practical and effective brain disease models and subsequently apply them to disease mechanism and treatment studies,there is still a lack of a standard tool,i.e.,a system for collecting and analyzing the daily behaviors of brain disease model monkeys.Therefore,with the goal of undertaking a comprehensive and quantitative study of behavioral phenotypes,we established a standard daily behavior collection and analysis system,including behavioral data collection protocols and a monkey daily behavior ethogram(MDBE)for rhesus and cynomolgus monkeys,which are the most commonly used non-human primates in model construction.Then,we used ASD as an application example after referring to the Diagnostic and Statistical Manual of Mental Disorders,Fifth Edition,Text Revision(DSM-5-TR),which is widely used in clinical disease diagnosis to obtain ASD core clinical symptoms.We then established a sub-ethogram(ASD monkey core behavior ethogram(MCBE-ASD))specifically for quantitative assessment of the core clinical symptoms of an ASD monkey model based on MDBE.Subsequently,we demonstrated the high reproducibility of the system.展开更多
Hypobaric hypoxia (HH) exposure can cause serious brain injury as well as life-threatening cerebral edema in severe cases. Previous studies on the mechanisms of HH-induced brain injury have been conducted primarily us...Hypobaric hypoxia (HH) exposure can cause serious brain injury as well as life-threatening cerebral edema in severe cases. Previous studies on the mechanisms of HH-induced brain injury have been conducted primarily using non-primate animal models that are genetically distant to humans, thus hindering the development of disease treatment. Here, we report that cynomolgus monkeys (Macaca fascicularis) exposed to acute HH developed human-like HH syndrome involving severe brain injury and abnormal behavior. Transcriptome profiling of white blood cells and brain tissue from monkeys exposed to increasing altitude revealed the central role of the HIF-1 and other novel signaling pathways, such as the vitamin D receptor (VDR) signaling pathway, in co-regulating HH-induced inflammation processes. We also observed profound transcriptomic alterations in brains after exposure to acute HH, including the activation of angiogenesis and impairment of aerobic respiration and protein folding processes, which likely underlie the pathological effects of HH-induced brain injury. Administration of progesterone (PROG) and steroid neuroprotectant 5α-androst-3β,5,6β-triol (TRIOL) significantly attenuated brain injuries and rescued the transcriptomic changes induced by acute HH. Functional investigation of the affected genes suggested that these two neuroprotectants protect the brain by targeting different pathways, with PROG enhancing erythropoiesis and TRIOL suppressing glutamate-induced excitotoxicity. Thus, this study advances our understanding of the pathology induced by acute HH and provides potential compounds for the development of neuroprotectant drugs for therapeutic treatment.展开更多
Postpartum depression （PPD） is a modified form of major depressive disorders （MDD） that can exert profound negative effects on both mothers and infants than MDD. Within the postpartum period, both mothers and infa...Postpartum depression （PPD） is a modified form of major depressive disorders （MDD） that can exert profound negative effects on both mothers and infants than MDD. Within the postpartum period, both mothers and infants are susceptible; but because PPD typically occurs for short durations and has moderate symptoms, there exists challenges in exploring and addressing the underlying cause of the depression. This fact highlights the need for relevant animal models. In the present study, postpartum adult female cynomolgus monkeys （Macaca fascicularis） living in breeding groups were observed for typical depressive behavior. The huddle posture behavior was utilized as an indicator of behavioral depression postpartum （BDP） as it has been established as the core depressive-like behavior in primates. Monkeys were divided into two groups： A t3DP group （n=6）, which were found to spend more time huddling over the first two weeks postpartum than other individuals that formed a non-depression control group （n=4）. The two groups were then further analyzed for locomotive activity, stressful events, hair cortisol levels and for maternal interactive behaviors. No differences were found between the BDP and control groups in locomotive activity, in the frequencies of stressful events experienced and in hair cortisol levels. These findings suggested that the postpartum depression witnessed in the monkeys was not related to external factors other than puerperium period. Interestingly, the BDP monkeys displayed an abnormal maternal relationship consisting of increased infant grooming. Taken together, these findings suggest that the adult female cynomolgus monkeys provide a natural model of behavioral postpartum depression that holds a number of advantages over commonly used rodent systems in PPD modeling. The cynomolgus monkeys have a highly-organized social hierarchy and reproductive characteristics without seasonal restriction--similar to humans--as well as much greater homology to humans than rodents. As such, this model may provide a greater translational efficiency and research platform for systematically investigating the etiology, treatment, prevention of PPD.展开更多
AIM To establish a simplified, reproducible D-galactosamineinduced cynomolgus monkey model of acute liver failure having an appropriate treatment window. METHODS Sixteen cynomolgus monkeys were randomly dividedinto fo...AIM To establish a simplified, reproducible D-galactosamineinduced cynomolgus monkey model of acute liver failure having an appropriate treatment window. METHODS Sixteen cynomolgus monkeys were randomly dividedinto four groups(A, B, C and D) after intracranial pressure(ICP) sensor implantation. D-galactosamine at 0.3, 0.25, 0.20 + 0.05(24 h interval), and 0.20 g/kg body weight, respectively, was injected via the small saphenous vein. Vital signs, ICP, biochemical indices, and inflammatory factors were recorded at 0, 12, 24, 36, 48, 72, 96, and 120 h after D-galactosamine administration. Progression of clinical manifestations, survival times, and results of H&E staining, TUNEL, and Masson staining were recorded. RESULTS Cynomolgus monkeys developed different degrees of debilitation, loss of appetite, and jaundice after D-galactosamine administration. Survival times of groups A, B, and C were 56 ± 8.7 h, 95 ± 5.5 h, and 99 ± 2.2 h, respectively, and in group D all monkeys survived the 144-h observation period except for one, which died at 136 h. Blood levels of ALT, AST, CK, LDH, TBi L, Cr, BUN, and ammonia, prothrombin time, ICP, endotoxin, and inflammatory markers [(tumor necrosis factor(TNF)-α, interleukin(IL)-1β, and IL-6)] significantly increased compared with baseline values in different groups(P < 0.05). Pathological results showed obvious liver cell necrosis that was positively correlated with the dose of D-galactosamine.CONCLUSION We successfully established a simplified, reproducible D-galactosamine-induced cynomolgus monkey model of acute liver failure, and the single or divided dosage of 0.25 g/kg is optimal for creating this model.展开更多
In this study, we developed a systemic PD model in middle-aged cynomolgus monkeys using individualized low-dose MPTP, to explore effective indicators for the early prediction of clinical outcomes. MPTP was not stopped...In this study, we developed a systemic PD model in middle-aged cynomolgus monkeys using individualized low-dose MPTP, to explore effective indicators for the early prediction of clinical outcomes. MPTP was not stopped until the animals showed typical PD motor symptoms on days 10 to 13 after MPTP administration when the Kurlan score reached 10; this abrogated the dif- ferences in individual susceptibility to MPTP. The clinical symptoms persisted, peaking on days 3 to 12 after MPTP withdrawal （rapid progress stage）, and then the Kurlan score plateaued. A Kurlan score at the end of the rapid progress stage 〉15 reflected stable or slowly-progressive PD, while a score 〈15 indicated spontaneous recovery. The entire clinical evolution and outcome of the systemic PD model was characterized in this study, thus providing options for therapeutic and translational research.展开更多
Stress from dominance ranks in human societies, or that of other social animals, especially nonhuman primates, can have negative influences on health. Individuals holding different social status may be burdened with v...Stress from dominance ranks in human societies, or that of other social animals, especially nonhuman primates, can have negative influences on health. Individuals holding different social status may be burdened with various stress levels. The middle class experiences a special stress situation within the dominance hierarchy due to its position between the higher and lower classes. Behaviorally, questions about where middle-class stress comes from and how individuals adapt to middle-class stress remain poorly understood in nonhuman primates. In the present study, social interactions, including aggression, avoidance, grooming and mounting behaviors, between beta males, as well as among group members holding higher or lower social status, were analyzed in captive male-only cynomolgus monkey groups. We found that aggressive tension from the higher hierarchy members was the main origin of stress for middle- class individuals. However, behaviors such as attacking lower hierarchy members immediately after being the recipient of aggression, as well as increased avoidance, grooming and mounting toward both higher and lower hierarchy members helped alleviate middle-class stress and were particular adaptations to middle-class social status.展开更多
Juvenile （2-3 years old） cynomolgus monkeys are frequently used as recipients in non-human primate islet transplantation studies. The aim of this study was to examine the effects of different doses of streptozotocin...Juvenile （2-3 years old） cynomolgus monkeys are frequently used as recipients in non-human primate islet transplantation studies. The aim of this study was to examine the effects of different doses of streptozotocin （STZ）, and find the optimal dose for inducing diabetes in these monkeys. Fifteen juvenile （2-3 years old） cynomolgus monkeys were separated into three groups and administered with different doses of STZ （100, 68 or 60 mg kg-l）. Basal and glucose-stimulated blood glucose, in- sulin, and C-peptide levels, as well as body weights were monitored. Hepatic and renal function tests and pancreatic immuno- histochemistry were performed before and after STZ treatment. Monkeys treated with both 100 and 68 mg kg-1 of STZ exhib- ited continuous hyperglycemia, which coincided with a nearly complete loss of islet 13-cells. Two monkeys received 60 mg kg-1 of STZ, but only one became completely diabetic. During the first week following STZ treatment, hepatic and renal func- tion slightly increased in these three groups. However. 24 hours post-STZ, serum total bile acid levels were significantly in- creased in monkeys treated with 100 mg kg-1 than those treated with 68 mg kg-I of STZ （P〈0.05）. These data suggest that 100 mg kg-1 and 68 mg kg-1 of STZ can safely induce diabetes in cynomolgus monkeys aged 2-3 years, but 68 mg kg-1 of STZ, rather than 100 mg kg-1 of STZ, may be more appropriate for inducing diabetes in these monkeys. Furthermore, body surface area, rather than body weight, was a more reliable determinant of dosage, where 700 mg m-2 of STZ should be the lower limit for inducing diabetes in juvenile monkeys.展开更多
Subject Code:H09With the support by the National Natural Science Foundation of China,a collaborative study by the research group led by Prof.Chen Yongchang(陈永昌)and Ji Weizhi from the Yunnan Key Laboratory of Primat...Subject Code:H09With the support by the National Natural Science Foundation of China,a collaborative study by the research group led by Prof.Chen Yongchang(陈永昌)and Ji Weizhi from the Yunnan Key Laboratory of Primate Biomedicine Research&Institute of Primate Translational Medicine,Kunming University展开更多
AIM：To determine acute and chronic choroidal vascular changes after vortex vein occlusion in monkeys.METHODS：One or two temporal vortex veins were occluded in 8 cynomolgus monkeys.Fluorescein angiography（FA）,indoc...AIM：To determine acute and chronic choroidal vascular changes after vortex vein occlusion in monkeys.METHODS：One or two temporal vortex veins were occluded in 8 cynomolgus monkeys.Fluorescein angiography（FA）,indocyanine green angiogram（ICGA）,and enhanced-depth imaging optical coherence tomography（EDI-OCT）were performed preoperatively and at 1d,1,4,8 and 12wk after occlusion.EDI-OCT images were binarized to calculate the choroid vascular index（CVI）.RESULTS：ICGA showed delayed filling of choroidal arteries in occluded quadrants in eyes with two occluded temporal vortex veins within 1wk.The thickness of the superotemporal choroid increased 1d and 4wk after occlusion,the thickness of the superonasal and inferonasal choroid increased 12wk after occlusion,and the CVI of the superonasal quadrant increased 8wk after occlusion in eyes with 2 occluded vortex veins. CONCLUSION：Occlusion of two vortex veins leads to hemodynamic and structural changes in choroidal layers in the acute phase,while autoregulation may play the main role in the long term.Occlusion of one vortex vein has little influence on the hemodynamic and structural status of the choroid.展开更多
Controlling the immune response with only clinically approved immunosuppressant drugs is difficult in renal heterotra ns plantation from pigs to nonhuman primates.Moreover,to the best of our knowledge,no reports exist...Controlling the immune response with only clinically approved immunosuppressant drugs is difficult in renal heterotra ns plantation from pigs to nonhuman primates.Moreover,to the best of our knowledge,no reports exist on the use of fetal pigs as kidney donors.This study aimed to compare the degree of transplant rejection between neonatal and fetal kidneys,with genetically unmodified pigs as donors and cynomolgus monkeys as recipients.The left kidneys of the recipient monkeys were removed,followed by transplantation of neonatal as well as fetal pig kidneys,which had undergone vascular anastomosis at the same site,into the retroperitoneum.Immunosuppression was performed with only US Food and Drug Administration-approved drugs.The fetal kidneys were transplanted into the omentum and paraaortic regions of cynomolgus monkeys.Consequently,the engraftment and development of the transplanted tissues were pathologically examined by sampling over time(twice in each experiment).An acute rejection was observed after a few weeks in neonatal renal grafts with vascular anastomosis.However,fetal pig kidneys were spared from rejection despite the administration of the same immunosuppressive protocol to the monkeys and the recipient blood vessels flowing into the fetal kidneys.The immunogenicity of fetal kidneys in pig-monkey renal heterotransplantation was lower than that of neonatal kidneys.展开更多
To characterize recombinant AAV2 （rAAV2）-mediated expression of L 132C/T 159C ChR2 mutant in retinal ganglion cells （RGCs） of young adult cynomolgus monkeys, rAAV2 vectors carrying a fusion construct of the ChR2 m...To characterize recombinant AAV2 （rAAV2）-mediated expression of L 132C/T 159C ChR2 mutant in retinal ganglion cells （RGCs） of young adult cynomolgus monkeys, rAAV2 vectors carrying a fusion construct of the ChR2 mutant and GFP （ChR2-GFP） were delivered to the vitreous chamber by intravitreal injection. Expression patterns of the ChR2 mutant in RGCs were examined by immunohistochemical methods three months after injection. The RNA-binding protein with multiple splicing （RBPMS） was used as an RGC specific marker to differentiate RGCs from other retinal neurons and non-neuronal cells. The numbers of RBPMS＋ and GFP＋ double-labeled RGCs in the central foveal varied with the eccentricity. The expression peaked within 100 p.m from the edge of the foveola and drastically decreased to a single superficial RGC layer approximately 300 ~tm from the edge. On average, the ratio of the double-labeled RGCs versus RBPMS＋ RGCs approached 0.324-0.15 （n=14 fields） at the central foveal region （0.1 to 0.53 mm）. We observed that the ratio reached 0.784-0.16 （n=21 fields） at peripheral retinal locations （eccentricity 〉7 mm）. This investigation demonstrates that RBPMS could serve as a valuable RGC specific marker for future investigations in this field.展开更多
Advanced atherosclerotic lesions and vascular calcification substantially increase the risk of cardiovascular events.However,effective strategies for preventing or treating advanced atherosclerosis and calcification a...Advanced atherosclerotic lesions and vascular calcification substantially increase the risk of cardiovascular events.However,effective strategies for preventing or treating advanced atherosclerosis and calcification are currently lacking.This study investigated the efficacy of DT-109(Gly-Gly-Leu)in attenuating atherosclerosis and calcification in nonhuman primates,exploring its broader therapeutic potential.In this study,twenty male cynomolgus monkeys were administered a cholesterol-rich diet ad libitum for 10 months.Then,the animals were treated either orally with DT-109(150 mg/kg/day)or a vehicle(H2O)for 5 months while continuing on the same diet.Plasma lipid levels were measured monthly and at the end of the experiment,pathological examinations of the aortas and coronary arteries and RNA sequencing of the coronary arteries were performed.To explore possible molecular mechanisms,the effects of DT-109 on smooth muscle cells(SMCs)were examined in vitro.We found that DT-109 administration significantly suppressed atherosclerotic lesion formation in both the aorta and coronary arteries.Pathological examinations revealed that DT-109 treatment reduced lesional macrophage content and calcification.RNA sequencing analysis showed that DT-109 treatment significantly downregulated the pro-inflammatory factors NLRP3,AIM2,and CASP1,the oxidative stress factors NCF2 and NCF4,and the osteogenic factors RUNX2,COL1A1,MMP2,and MMP9,while simultaneously upregulating the expression of the SMCs contraction markers ACTA2,CNN1,and TAGLN.Furthermore,DT-109 inhibited SMC calcification and NLRP3 inflammasome activation in vitro.These results demonstrate that DT-109 effectively suppresses both atherosclerosis and calcification.These findings,in conjunction with insights from our previous studies,position DT-109 as a novel multifaceted therapeutic agent for cardiovascular diseases.展开更多
基金National Resources Center for Non Human PrimatesNational Key R&D Project of China,Grant/Award Number:2021YFF0702804。
文摘Background:Non-human primates(NPHs),such as rhesus macaques,cynomol-gus monkeys,and Assamese macaques,play a crucial role in biomedical research.However,baseline cytokine and electrolyte data for these three species,particularly data stratified by age and sex,are limited.Therefore,the aim of this study was to establish and analyze age-and sex-specific cytokine and electrolyte profiles in these three species.Methods:This study included 40 rhesus macaques(21 males,19 females),33 cyn-omolgus monkeys(17 males,16 females),and 45 Assamese macaques(25 males,20 females)classified by age(1-5 years,6-12 years,>13 years)and sex.The levels of 23 immune function indicators and 5 electrolyte indicators were measured.Results:Among the three monkey species,the levels of sCD40L,IL-18,MCP-1,MIP-1β,TGFa,K^(+),Na^(+),and Cl^(-)exhibited species-,sex-,and age-related differences.Comparison within the same species,sex had no significant impact on cytokine levels in NHPs but did affect electrolyte levels,particularly Cl^(-)and Na^(+)levels,in cynomol-gus monkeys and Assamese macaques.Electrolyte levels in NHPs were not affected by age,whereas the levels of certain cytokines,particularly sCD40L,GM-CSF,and IL-10,varied with age.The remaining 21 cytokines demonstrated no significant age-related changes.Conclusions:Significant variations in cytokine and electrolyte levels exist among dif-ferent monkey species,sexes,and age groups.This research provides valuable re-sources for NHP researchers and sets the stage for further exploring the impacts of sex and age on NHP physiology and immune function.
基金supported by the National Science and Technology Innovation 2030 Major Program(2021ZD0200900)National Key Research and Development Program of China(2022YFF0710901)+3 种基金National Natural Science Foundation of China(82021001,31825018)Biological Resources Program of the Chinese Academy of Sciences(KFJBRP-005)111 Project D18007a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)。
文摘While viral infections can disturb the host gut microbiome,the dynamic alterations in microbial composition following infection remain poorly characterized.This study identified SRV-8-infected monkeys and classified them into five groups based on infection progression.16S rRNA amplicon sequencing revealed significant alterations in the relative and inferred absolute abundance of bacterial genera UCG-002,Agathobacter,Coprococcus,and Holdemanella during the early stage of SRV-8 infection,coinciding with provirus formation.These microbial shifts were accompanied by functional modifications in bacterial communities at the same stage.In contrast,ITS amplicon sequencing indicated no significant differences in fungal composition between healthy wild-type and SRV-8-infected monkeys.Spearman correlation analyses demonstrated close interactions between intestinal bacteria and fungi following SRV-8 infection.Additionally,SRV-8 seropositive groups exhibited significantly elevated mRNA expression levels of pro-inflammatory(TNF-α,IFN-γ,IL-1β,and IL-6)and anti-inflammatory(IL-10)cytokine genes,highlighting close associations between inflammatory cytokines and immune responses.Overall,these findings provide a comprehensive characterization of bacterial and fungal microbiota dynamics and inflammatory cytokine responses associated with SRV-8 infection,clarifying the pathobiological mechanisms underlying SRV-8 infection from the perspective of the gut microbiome.
基金supported by the National Natural Science Foundation of China (81930121,82125008 to Y.C.C.)National Key Research and Development Program of China (2018YFA0107902 to Y.C.C.and 2018YFA0801403 to Z.B.W.)+1 种基金Major Basic Research Project of Science and Technology of Yunnan (202001BC070001 to Y.C.C.)Natural Science Foundation of Yunnan Province (202102AA100053 to Y.C.C.)。
文摘Neural tube defects(NTDs)are severe congenital neurodevelopmental disorders arising from incomplete neural tube closure.Although folate supplementation has been shown to mitigate the incidence of NTDs,some cases,often attributable to genetic factors,remain unpreventable.The SHROOM3 gene has been implicated in NTD cases that are unresponsive to folate supplementation;at present,however,the underlying mechanism remains unclear.Neural tube morphogenesis is a complex process involving the folding of the planar epithelium of the neural plate.To determine the role of SHROOM3 in early developmental morphogenesis,we established a neuroepithelial organoid culture system derived from cynomolgus monkeys to closely mimic the in vivo neural plate phase.Loss of SHROOM3 resulted in shorter neuroepithelial cells and smaller nuclei.These morphological changes were attributed to the insufficient recruitment of cytoskeletal proteins,namely fibrous actin(F-actin),myosin II,and phospho-myosin light chain(PMLC),to the apical side of the neuroepithelial cells.Notably,these defects were not rescued by folate supplementation.RNA sequencing revealed that differentially expressed genes were enriched in biological processes associated with cellular and organ morphogenesis.In summary,we established an authentic in vitro system to study NTDs and identified a novel mechanism for NTDs that are unresponsive to folate supplementation.
基金supported by the Key-Area Research and Development Program of Guangdong Province(No.2019B030335001)the STI2030-Major Projects(No.2021ZD0200900)+9 种基金the National Key Research and Development Program of China(Nos.2021YFF0702700 and 2018YFA0801403)the National Natural Science Foundation of China(Nos.81960422,32100801,82101241,82360226,82160923,82260929,82374425,and 32460194)the Strategic Priority Research Program of the Chinese Academy of Sciences(CAS)(No.XDB32060200)the STI2030-Major Projects(Nos.2022ZD0205200 and 2022ZD0212700)the Science and Technology Department of Yunnan Province(Nos.202305AH340006 and 202305AH340007)the Yunnan Fundamental Research Projects(Nos.202201AT070153 and 202201AT070139)the Science and Technology Project of Yunnan Province(No.202101AY070001-001)the Yunnan Revitalization Talent Support Program(No.YNWR-QNBJ2019-043)the CAS“Light of West China”Programthe Yunnan Revitalization Talents Support Plan。
文摘Complex brain diseases seriously endanger human health,and early diagnostic biomarkers and effective treatments are currently lacking.Due to ethical constraints on human research,establishing monkey models is crucial to address these issues.With the rapid development of technology,transgenic monkey models of a range of brain diseases,especially autism spectrum disorder(ASD),have been successfully established.However,to establish practical and effective brain disease models and subsequently apply them to disease mechanism and treatment studies,there is still a lack of a standard tool,i.e.,a system for collecting and analyzing the daily behaviors of brain disease model monkeys.Therefore,with the goal of undertaking a comprehensive and quantitative study of behavioral phenotypes,we established a standard daily behavior collection and analysis system,including behavioral data collection protocols and a monkey daily behavior ethogram(MDBE)for rhesus and cynomolgus monkeys,which are the most commonly used non-human primates in model construction.Then,we used ASD as an application example after referring to the Diagnostic and Statistical Manual of Mental Disorders,Fifth Edition,Text Revision(DSM-5-TR),which is widely used in clinical disease diagnosis to obtain ASD core clinical symptoms.We then established a sub-ethogram(ASD monkey core behavior ethogram(MCBE-ASD))specifically for quantitative assessment of the core clinical symptoms of an ASD monkey model based on MDBE.Subsequently,we demonstrated the high reproducibility of the system.
基金Supported by National High Technology Research and Development Program of China 863 Programs No.2006AA02A141 and No.2012AA020505the Medical Research Fund of Guangdong Province No.2009164
文摘AIM: To evaluate a hybrid bioartificial liver support system (HBALSS) in cynomolgus monkeys with acute liver failure.
基金supported by the National Natural Science Foundation of China(81773711)to W.Y.Strategic Priority Research Program of the Chinese Academy of Sciences(XDB13000000)+6 种基金Lundbeck Foundation Grant(R190-2014-2827)Carlsberg Foundation Grant(CF16-0663)to G.J.Z.Science and Technology Program of Guangzhou,China(201704020103)to W.Y.Introduction of Innovative R&D Team Program of Guangdong Province(2013Y104)Leading Talent Project in Science and Technology of Guangzhou Development District(2019-L002)National Major Scientific and Technological Special Project for “Significant New Drugs Development”(2016ZX09101026)to S.Z.L.Key Projects of the Military Science and Technology PLA(AWS14C007 and AWS16J023)to Y.Q.G
文摘Hypobaric hypoxia (HH) exposure can cause serious brain injury as well as life-threatening cerebral edema in severe cases. Previous studies on the mechanisms of HH-induced brain injury have been conducted primarily using non-primate animal models that are genetically distant to humans, thus hindering the development of disease treatment. Here, we report that cynomolgus monkeys (Macaca fascicularis) exposed to acute HH developed human-like HH syndrome involving severe brain injury and abnormal behavior. Transcriptome profiling of white blood cells and brain tissue from monkeys exposed to increasing altitude revealed the central role of the HIF-1 and other novel signaling pathways, such as the vitamin D receptor (VDR) signaling pathway, in co-regulating HH-induced inflammation processes. We also observed profound transcriptomic alterations in brains after exposure to acute HH, including the activation of angiogenesis and impairment of aerobic respiration and protein folding processes, which likely underlie the pathological effects of HH-induced brain injury. Administration of progesterone (PROG) and steroid neuroprotectant 5α-androst-3β,5,6β-triol (TRIOL) significantly attenuated brain injuries and rescued the transcriptomic changes induced by acute HH. Functional investigation of the affected genes suggested that these two neuroprotectants protect the brain by targeting different pathways, with PROG enhancing erythropoiesis and TRIOL suppressing glutamate-induced excitotoxicity. Thus, this study advances our understanding of the pathology induced by acute HH and provides potential compounds for the development of neuroprotectant drugs for therapeutic treatment.
基金supported by National Natural Science Foundation of China(31271167,81271495,31070963,30921064)the Yunnan Provincial Project to attract ore-hundred exceptional talents from Overseas
文摘Postpartum depression （PPD） is a modified form of major depressive disorders （MDD） that can exert profound negative effects on both mothers and infants than MDD. Within the postpartum period, both mothers and infants are susceptible; but because PPD typically occurs for short durations and has moderate symptoms, there exists challenges in exploring and addressing the underlying cause of the depression. This fact highlights the need for relevant animal models. In the present study, postpartum adult female cynomolgus monkeys （Macaca fascicularis） living in breeding groups were observed for typical depressive behavior. The huddle posture behavior was utilized as an indicator of behavioral depression postpartum （BDP） as it has been established as the core depressive-like behavior in primates. Monkeys were divided into two groups： A t3DP group （n=6）, which were found to spend more time huddling over the first two weeks postpartum than other individuals that formed a non-depression control group （n=4）. The two groups were then further analyzed for locomotive activity, stressful events, hair cortisol levels and for maternal interactive behaviors. No differences were found between the BDP and control groups in locomotive activity, in the frequencies of stressful events experienced and in hair cortisol levels. These findings suggested that the postpartum depression witnessed in the monkeys was not related to external factors other than puerperium period. Interestingly, the BDP monkeys displayed an abnormal maternal relationship consisting of increased infant grooming. Taken together, these findings suggest that the adult female cynomolgus monkeys provide a natural model of behavioral postpartum depression that holds a number of advantages over commonly used rodent systems in PPD modeling. The cynomolgus monkeys have a highly-organized social hierarchy and reproductive characteristics without seasonal restriction--similar to humans--as well as much greater homology to humans than rodents. As such, this model may provide a greater translational efficiency and research platform for systematically investigating the etiology, treatment, prevention of PPD.
基金Supported by The National Natural Science Foundation of China,No.81470875The Natural Science Foundation of Guangdong Province,China,No.2014A030312013+1 种基金The Science and Technology Planning Project of Guangdong Province,China,No.2014B020227002,No.2015B090903069,and No.2015B020229002The Science and Technology Program of Guangzhou,China,No.201604020002
文摘AIM To establish a simplified, reproducible D-galactosamineinduced cynomolgus monkey model of acute liver failure having an appropriate treatment window. METHODS Sixteen cynomolgus monkeys were randomly dividedinto four groups(A, B, C and D) after intracranial pressure(ICP) sensor implantation. D-galactosamine at 0.3, 0.25, 0.20 + 0.05(24 h interval), and 0.20 g/kg body weight, respectively, was injected via the small saphenous vein. Vital signs, ICP, biochemical indices, and inflammatory factors were recorded at 0, 12, 24, 36, 48, 72, 96, and 120 h after D-galactosamine administration. Progression of clinical manifestations, survival times, and results of H&E staining, TUNEL, and Masson staining were recorded. RESULTS Cynomolgus monkeys developed different degrees of debilitation, loss of appetite, and jaundice after D-galactosamine administration. Survival times of groups A, B, and C were 56 ± 8.7 h, 95 ± 5.5 h, and 99 ± 2.2 h, respectively, and in group D all monkeys survived the 144-h observation period except for one, which died at 136 h. Blood levels of ALT, AST, CK, LDH, TBi L, Cr, BUN, and ammonia, prothrombin time, ICP, endotoxin, and inflammatory markers [(tumor necrosis factor(TNF)-α, interleukin(IL)-1β, and IL-6)] significantly increased compared with baseline values in different groups(P < 0.05). Pathological results showed obvious liver cell necrosis that was positively correlated with the dose of D-galactosamine.CONCLUSION We successfully established a simplified, reproducible D-galactosamine-induced cynomolgus monkey model of acute liver failure, and the single or divided dosage of 0.25 g/kg is optimal for creating this model.
基金supported by grants from the National High-Tech Development Project of Ministry of Sciences and Technology of China(2012AA020703)the National Natural Science Foundation of China(31472056)+1 种基金Scientific Project of the Science and Technology Department of Guangxi Zhuang Autonomous Region,China(1598025-31)Scientific Project of the Science and Technology Bureau of Nanning Municipality,Guangxi Zhuang Autonomous Region,China(20145194,20155192)
文摘In this study, we developed a systemic PD model in middle-aged cynomolgus monkeys using individualized low-dose MPTP, to explore effective indicators for the early prediction of clinical outcomes. MPTP was not stopped until the animals showed typical PD motor symptoms on days 10 to 13 after MPTP administration when the Kurlan score reached 10; this abrogated the dif- ferences in individual susceptibility to MPTP. The clinical symptoms persisted, peaking on days 3 to 12 after MPTP withdrawal （rapid progress stage）, and then the Kurlan score plateaued. A Kurlan score at the end of the rapid progress stage 〉15 reflected stable or slowly-progressive PD, while a score 〈15 indicated spontaneous recovery. The entire clinical evolution and outcome of the systemic PD model was characterized in this study, thus providing options for therapeutic and translational research.
基金Foundation items： This study was supported by the Ministry of Science and Technology of China Grant （2012CB825500） and the Youth Innovation Promotion Association of Chinese Academy of Sciences （2012075）
文摘Stress from dominance ranks in human societies, or that of other social animals, especially nonhuman primates, can have negative influences on health. Individuals holding different social status may be burdened with various stress levels. The middle class experiences a special stress situation within the dominance hierarchy due to its position between the higher and lower classes. Behaviorally, questions about where middle-class stress comes from and how individuals adapt to middle-class stress remain poorly understood in nonhuman primates. In the present study, social interactions, including aggression, avoidance, grooming and mounting behaviors, between beta males, as well as among group members holding higher or lower social status, were analyzed in captive male-only cynomolgus monkey groups. We found that aggressive tension from the higher hierarchy members was the main origin of stress for middle- class individuals. However, behaviors such as attacking lower hierarchy members immediately after being the recipient of aggression, as well as increased avoidance, grooming and mounting toward both higher and lower hierarchy members helped alleviate middle-class stress and were particular adaptations to middle-class social status.
基金supported by the National Basic Research Program of China(Grant No.2007CB947704)the National High Technology Research and Development Program of China(Grant Nos. 2006AA02A112 and 2006AA02A116)High Level Talent Fund of the Beijing Healthcare System(Grant No.2009-2-14)
文摘Juvenile （2-3 years old） cynomolgus monkeys are frequently used as recipients in non-human primate islet transplantation studies. The aim of this study was to examine the effects of different doses of streptozotocin （STZ）, and find the optimal dose for inducing diabetes in these monkeys. Fifteen juvenile （2-3 years old） cynomolgus monkeys were separated into three groups and administered with different doses of STZ （100, 68 or 60 mg kg-l）. Basal and glucose-stimulated blood glucose, in- sulin, and C-peptide levels, as well as body weights were monitored. Hepatic and renal function tests and pancreatic immuno- histochemistry were performed before and after STZ treatment. Monkeys treated with both 100 and 68 mg kg-1 of STZ exhib- ited continuous hyperglycemia, which coincided with a nearly complete loss of islet 13-cells. Two monkeys received 60 mg kg-1 of STZ, but only one became completely diabetic. During the first week following STZ treatment, hepatic and renal func- tion slightly increased in these three groups. However. 24 hours post-STZ, serum total bile acid levels were significantly in- creased in monkeys treated with 100 mg kg-1 than those treated with 68 mg kg-I of STZ （P〈0.05）. These data suggest that 100 mg kg-1 and 68 mg kg-1 of STZ can safely induce diabetes in cynomolgus monkeys aged 2-3 years, but 68 mg kg-1 of STZ, rather than 100 mg kg-1 of STZ, may be more appropriate for inducing diabetes in these monkeys. Furthermore, body surface area, rather than body weight, was a more reliable determinant of dosage, where 700 mg m-2 of STZ should be the lower limit for inducing diabetes in juvenile monkeys.
文摘Subject Code:H09With the support by the National Natural Science Foundation of China,a collaborative study by the research group led by Prof.Chen Yongchang(陈永昌)and Ji Weizhi from the Yunnan Key Laboratory of Primate Biomedicine Research&Institute of Primate Translational Medicine,Kunming University
基金Supported by National Natural Science Foundation of China(No.81670879)
文摘AIM：To determine acute and chronic choroidal vascular changes after vortex vein occlusion in monkeys.METHODS：One or two temporal vortex veins were occluded in 8 cynomolgus monkeys.Fluorescein angiography（FA）,indocyanine green angiogram（ICGA）,and enhanced-depth imaging optical coherence tomography（EDI-OCT）were performed preoperatively and at 1d,1,4,8 and 12wk after occlusion.EDI-OCT images were binarized to calculate the choroid vascular index（CVI）.RESULTS：ICGA showed delayed filling of choroidal arteries in occluded quadrants in eyes with two occluded temporal vortex veins within 1wk.The thickness of the superotemporal choroid increased 1d and 4wk after occlusion,the thickness of the superonasal and inferonasal choroid increased 12wk after occlusion,and the CVI of the superonasal quadrant increased 8wk after occlusion in eyes with 2 occluded vortex veins. CONCLUSION：Occlusion of two vortex veins leads to hemodynamic and structural changes in choroidal layers in the acute phase,while autoregulation may play the main role in the long term.Occlusion of one vortex vein has little influence on the hemodynamic and structural status of the choroid.
基金supported by the Japan Agency for Medical Research and Development(AMED21bk0104094h0003)a grant from Sumitomo Dainippon Pharma Co.,Ltd。
文摘Controlling the immune response with only clinically approved immunosuppressant drugs is difficult in renal heterotra ns plantation from pigs to nonhuman primates.Moreover,to the best of our knowledge,no reports exist on the use of fetal pigs as kidney donors.This study aimed to compare the degree of transplant rejection between neonatal and fetal kidneys,with genetically unmodified pigs as donors and cynomolgus monkeys as recipients.The left kidneys of the recipient monkeys were removed,followed by transplantation of neonatal as well as fetal pig kidneys,which had undergone vascular anastomosis at the same site,into the retroperitoneum.Immunosuppression was performed with only US Food and Drug Administration-approved drugs.The fetal kidneys were transplanted into the omentum and paraaortic regions of cynomolgus monkeys.Consequently,the engraftment and development of the transplanted tissues were pathologically examined by sampling over time(twice in each experiment).An acute rejection was observed after a few weeks in neonatal renal grafts with vascular anastomosis.However,fetal pig kidneys were spared from rejection despite the administration of the same immunosuppressive protocol to the monkeys and the recipient blood vessels flowing into the fetal kidneys.The immunogenicity of fetal kidneys in pig-monkey renal heterotransplantation was lower than that of neonatal kidneys.
基金supported by National Science Foundation of China(31571091 to Mingliang Pu),National Basic Research Program of China (2015CB351806 to Mingliang Pu)National Institutes of Health Grant (NIH) (EY17130 to Zhuo-Hua Pan)Dryer Foundation, the Ligon Research Center of Vision, and Research to Prevent Blindness to Department of Ophthalmology at Wayne State University
文摘To characterize recombinant AAV2 （rAAV2）-mediated expression of L 132C/T 159C ChR2 mutant in retinal ganglion cells （RGCs） of young adult cynomolgus monkeys, rAAV2 vectors carrying a fusion construct of the ChR2 mutant and GFP （ChR2-GFP） were delivered to the vitreous chamber by intravitreal injection. Expression patterns of the ChR2 mutant in RGCs were examined by immunohistochemical methods three months after injection. The RNA-binding protein with multiple splicing （RBPMS） was used as an RGC specific marker to differentiate RGCs from other retinal neurons and non-neuronal cells. The numbers of RBPMS＋ and GFP＋ double-labeled RGCs in the central foveal varied with the eccentricity. The expression peaked within 100 p.m from the edge of the foveola and drastically decreased to a single superficial RGC layer approximately 300 ~tm from the edge. On average, the ratio of the double-labeled RGCs versus RBPMS＋ RGCs approached 0.324-0.15 （n=14 fields） at the central foveal region （0.1 to 0.53 mm）. We observed that the ratio reached 0.784-0.16 （n=21 fields） at peripheral retinal locations （eccentricity 〉7 mm）. This investigation demonstrates that RBPMS could serve as a valuable RGC specific marker for future investigations in this field.
基金partially supported by the National Key R&D Program of China(No.2020YFA0803700)National Natural Science Foundation of China(No.81970425 and No.81941001)+6 种基金Natural Science Foundation of Shaanxi Province(No.2020PT-001)Innovation team program supported by Guangdong Province(2020KCXTD038)Guangdong Province Key Program of Discipline(2021ZDJS091)National Key Research and Development Program of China(2022YFA1105403)Science and Technology Planning Project of Guangdong Province(2021A1515110916)the Hong Kong-Macao Joint Research and Development Fund of Wuyi UniversityFrederick G.L.Huetwell Endowed Professor of Cardiovascular Medicine at University of Michigan(Y.E.C.).
文摘Advanced atherosclerotic lesions and vascular calcification substantially increase the risk of cardiovascular events.However,effective strategies for preventing or treating advanced atherosclerosis and calcification are currently lacking.This study investigated the efficacy of DT-109(Gly-Gly-Leu)in attenuating atherosclerosis and calcification in nonhuman primates,exploring its broader therapeutic potential.In this study,twenty male cynomolgus monkeys were administered a cholesterol-rich diet ad libitum for 10 months.Then,the animals were treated either orally with DT-109(150 mg/kg/day)or a vehicle(H2O)for 5 months while continuing on the same diet.Plasma lipid levels were measured monthly and at the end of the experiment,pathological examinations of the aortas and coronary arteries and RNA sequencing of the coronary arteries were performed.To explore possible molecular mechanisms,the effects of DT-109 on smooth muscle cells(SMCs)were examined in vitro.We found that DT-109 administration significantly suppressed atherosclerotic lesion formation in both the aorta and coronary arteries.Pathological examinations revealed that DT-109 treatment reduced lesional macrophage content and calcification.RNA sequencing analysis showed that DT-109 treatment significantly downregulated the pro-inflammatory factors NLRP3,AIM2,and CASP1,the oxidative stress factors NCF2 and NCF4,and the osteogenic factors RUNX2,COL1A1,MMP2,and MMP9,while simultaneously upregulating the expression of the SMCs contraction markers ACTA2,CNN1,and TAGLN.Furthermore,DT-109 inhibited SMC calcification and NLRP3 inflammasome activation in vitro.These results demonstrate that DT-109 effectively suppresses both atherosclerosis and calcification.These findings,in conjunction with insights from our previous studies,position DT-109 as a novel multifaceted therapeutic agent for cardiovascular diseases.
