Understanding gene expression variations between species is pivotal for deciphering the evolutionary diversity in phenotypes. Rhesus macaques(Macaca mulatta, MMU)and crab-eating macaques(M. fascicularis, MFA) serve as...Understanding gene expression variations between species is pivotal for deciphering the evolutionary diversity in phenotypes. Rhesus macaques(Macaca mulatta, MMU)and crab-eating macaques(M. fascicularis, MFA) serve as crucial nonhuman primate biomedical models with different phenotypes. To date, however, large-scale comparative transcriptome research between these two species has not yet been fully explored. Here, we conducted systematic comparisons utilizing newly sequenced RNA-seq data from84 samples(41 MFA samples and 43 MMU samples)encompassing 14 common tissues. Our findings revealed a small fraction of genes(3.7%) with differential expression between the two species, as well as 36.5% of genes with tissue-specific expression in both macaques. Comparison of gene expression between macaques and humans indicated that 22.6% of orthologous genes displayed differential expression in at least two tissues. Moreover,19.41% of genes that overlapped with macaque-specific structural variants showed differential expression between humans and macaques. Of these, the FAM220A gene exhibited elevated expression in humans compared to macaques due to lineage-specific duplication. In summary,this study presents a large-scale transcriptomic comparison between MMU and MFA and between macaques and humans. The discovery of gene expression variations not only enhances the biomedical utility of macaque models but also contributes to the wider field of primate genomics.展开更多
Fluoxetine(Prozac^(TM))is the only antidepressant approved by the US Food and Drug Administration(FDA)for the treatment of major depressive disorder(MDD)in children.Despite its considerable efficacy as a selective ser...Fluoxetine(Prozac^(TM))is the only antidepressant approved by the US Food and Drug Administration(FDA)for the treatment of major depressive disorder(MDD)in children.Despite its considerable efficacy as a selective serotonin reuptake inhibitor,the possible long-term effects of fluoxetine on brain development in children are poorly understood.In the current study,we aimed to delineate molecular mechanisms and protein biomarkers in the brains of juvenile rhesus macaques(Macaca mulatta)one year after the discontinuation of fluoxetine treatment using proteomic and phosphoproteomic profiling.We identified several differences in protein expression and phosphorylation in the dorsolateral prefrontal cortex(DLPFC)and cingulate cortex(CC)that correlated with impulsivity in animals,suggesting that the GABAergic synapse pathway may be affected by fluoxetine treatment.Biomarkers in combination with the identified pathways contribute to a better understanding of the mechanisms underlying the chronic effects of fluoxetine after discontinuation in children.展开更多
Viral vector transfection systems are among the simplest of biological agents with the ability to transfer genes into the central nervous system.In brain research,a series of powerful and novel gene editing technologi...Viral vector transfection systems are among the simplest of biological agents with the ability to transfer genes into the central nervous system.In brain research,a series of powerful and novel gene editing technologies are based on these systems.Although many viral vectors are used in rodents,their full application has been limited in non-human primates.To identify viral vectors that can stably and effectively express exogenous genes within nonhuman primates,eleven commonly used recombinant adeno-associated viral and lentiviral vectors,each carrying a gene to express green or red fluorescence,were injected into the parietal cortex of four rhesus monkeys.The expression of fluorescent cells was used to quantify transfection efficiency.Histological results revealed that recombinant adeno-associated viral vectors,especially the serotype 2/9 coupled with the cytomegalovirus,human synapsin I,or Ca2+/calmodulin-dependentproteinkinaseII promoters,and lentiviral vector coupled with the human ubiquitin C promoter,induced higher expression of fluorescent cells,representing high transfection efficiency.This is the first comparison of transfection efficiencies of different viral vectors carrying different promoters and serotypes in non-human primates(NHPs).These results can be used as an aid to select optimal vectors to transfer exogenous genes into the central nervous system of non-human primates.展开更多
Background:Since December 2019,an outbreak of the Corona Virus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus(SARS-CoV-2)in Wuhan,China,has become a public health emergency of internatio...Background:Since December 2019,an outbreak of the Corona Virus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus(SARS-CoV-2)in Wuhan,China,has become a public health emergency of international concern.The high fatality of aged cases caused by SARS-CoV-2 was a need to explore the possible age-related phenomena with non-human primate models.Methods:Three 3-5 years old and two 15 years old rhesus macaques were intratracheally infected with SARS-CoV-2,and then analyzed by clinical signs,viral replication,chest X-ray,histopathological changes and immune response.Results:Viral replication of nasopharyngeal swabs,anal swabs and lung in old monkeys was more active than that in young monkeys for 14 days after SARS-CoV-2 challenge.Monkeys developed typical interstitial pneumonia characterized by thickened alveolar septum accompanied with inflammation and edema,notably,old monkeys exhibited diffuse severe interstitial pneumonia.Viral antigens were detected mainly in alveolar epithelial cells and macrophages.Conclusion:SARS-CoV-2 caused more severe interstitial pneumonia in old monkeys than that in young monkeys.Rhesus macaque models infected with SARS-CoV-2 provided insight into the pathogenic mechanism and facilitated the development of vaccines and therapeutics against SARS-CoV-2 infection.展开更多
AIM To establish a rotavirus(RV)-induced diarrhea model using RV SA11 in neonatal rhesus monkeys for the study of the pathogenic and immune mechanisms of RV infection and evaluation of candidate vaccines.METHODS Neona...AIM To establish a rotavirus(RV)-induced diarrhea model using RV SA11 in neonatal rhesus monkeys for the study of the pathogenic and immune mechanisms of RV infection and evaluation of candidate vaccines.METHODS Neonatal rhesus monkeys with an average age of 15-20 d and an average weight of 500 g ± 150 g received intragastric administration of varying doses of SA11 RV( 107 PFUs/mL, 106 PFUs/mL, or 105 PFUs/mL, 10 mL/animal) to determine whether the SA11 strain can effectively infect these animals by observing their clinical symptoms, fecal shedding of virus antigen by ELISA, distribution of RV antigen in the organs by immunofluorescence, variations of viral RNA load in the organs by qRT-PCR, histopathological changes in the small intestine by HE staining, and apoptosis of small intestinal epithelial cells by TUNEL assay.RESULTS The RV monkey model showed typical clinical diarrhea symptoms in the 108 PFUs SA11 group, where we observed diarrhea 1-4 d post infection(dpi) and viral antigen shed in the feces from 1-7 dpi. RV was found in jejunal epithelial cells. We observed a viral load of approximately 5.85 × 103 copies per 100 mg in the jejunum at 2 dpi, which was increased to 1.09 × 105 copies per 100 mg at 3 dpi. A relatively high viral load was also seen in mesenteric lymph nodes at 2 dpi and 3 dpi. The following histopathological changes were observed in the small intestine following intragastric administration of SA11 RV: vacuolization, edema, and atrophy. Apoptosis in the jejunal villus epithelium was also detectable at 3 dpi.CONCLUSION Our results indicate that we have successfully established a RV SA11 strain diarrhea model in neonatal rhesus monkeys. Future studies will elucidate the mechanisms underlying the pathogenesis of RV infection, and we will use the model to evaluate the protective effect of candidate vaccines.展开更多
AIM:In order to improve the biocompatibility of intraocular lenses(IOL),the polymethylmethacrylate(PMMA)IOL was modified with F-heparin. METHODS:The PMMA IOL was modified with F ions and heparin by the technique of io...AIM:In order to improve the biocompatibility of intraocular lenses(IOL),the polymethylmethacrylate(PMMA)IOL was modified with F-heparin. METHODS:The PMMA IOL was modified with F ions and heparin by the technique of ion beam combined with low temperature and low pressure plasma.The monkeys(20 eyes)with cataract partly were randomly classified into 2 groups and implanted with PMMA IOL and modified IOL respectively for 180 days.All of the eyes were examined by slit-lamp microscope at postoperative 15,30,60,90,180 days.The extracted IOL was analyzed with computer image analysis,light microscope(LM)and scanning electron microscope(SEM)at postoperative 180 days. RESULTS:The early inflammatory reactions postoperatively include anterior chamber exudation and aqueous cell count. The modified IOL group showed less than the non-modified IOL group.The late foreign body cell reaction that adhered to the surface of non-modified IOL was more predominant.The morphologic and pathological changes of posterior capsule opacification(PCO)in monkeys’ eyes included fibrosis-type, pearl-type and soemmerring’s ring.There was a significant difference between the two groups. CONCLUSION:F-heparin modified IOL has good uveal and capsular biocompatibility.展开更多
DEAR EDITOR,Major depressive disorder (MDD), commonly known as depression, is a mental disease characterized by a core symptom of low mood. It lasts at least two weeks (Badamasi et al., 2019;Wang et al., 2019) and is ...DEAR EDITOR,Major depressive disorder (MDD), commonly known as depression, is a mental disease characterized by a core symptom of low mood. It lasts at least two weeks (Badamasi et al., 2019;Wang et al., 2019) and is frequently accompanied by low self-esteem, loss of interest in routinely enjoyable activities, low energy, and unexplained pain (Huey et al., 2018;Park et al., 2012;Post & Warden, 2018;Rice et al., 2019;Xiao et al., 2018). Approximately 2%–8% of adults with MDD commit suicide (Richards & O'Hara, 2014;Strakowski & Nelson, 2015), and around half of suicidal individuals suffer depression or other mood disorders (Bachmann, 2018).展开更多
Rhesus monkey neural stem cells are capable of differentiating into neurons and glial cells.Therefore,neural stem cell transplantation can be used to promote functional recovery of the nervous system.Rhesus monkey neu...Rhesus monkey neural stem cells are capable of differentiating into neurons and glial cells.Therefore,neural stem cell transplantation can be used to promote functional recovery of the nervous system.Rhesus monkey neural stem cells(1×105 cells/μL) were injected into bilateral hippocampi of rats with hippocampal lesions.Confocal laser scanning microscopy demonstrated that green fluorescent protein-labeled transplanted cells survived and grew well.Transplanted cells were detected at the lesion site,but also in the nerve fiber-rich region of the cerebral cortex and corpus callosum.Some transplanted cells differentiated into neurons and glial cells clustering along the ventricular wall,and integrated into the recipient brain.Behavioral tests revealed that spatial learning and memory ability improved,indicating that rhesus monkey neural stem cells noticeably improve spatial learning and memory abilities in rats with hippocampal lesions.展开更多
Rhesus macaques(Macaca mulatta) and cynomolgus macaques(Macaca fascicularis) are frequently used in establishing animal models for human diseases. To determine the differences in gut microbiota between these species, ...Rhesus macaques(Macaca mulatta) and cynomolgus macaques(Macaca fascicularis) are frequently used in establishing animal models for human diseases. To determine the differences in gut microbiota between these species, rectal swabs from 20 rhesus macaques and 21 cynomolgus macaques were collected, and the microbial composition was examined by deep sequencing of the 16 S rR NA gene. We found that the rectal microbiota of cynomolgus macaques exhibited significantly higher alpha diversity than that of rhesus macaques, although the observed number of operational taxonomic units(OTUs) was almost the same. The dominant taxa at both the phylum and genus levels were similar between the two species, although the relative abundances of these dominant taxa were significantly different between them. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States(PICRUSt) showed significant differences in the functional components between the microbiota of the two species, in particular the lipopolysaccharide(LPS) synthesis proteins. The above data indicated significant differences in microbial composition and function between these two closely related macaque species, which should be taken into consideration in the future selection of these animals for disease models.展开更多
Infection with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) causes diverse clinical manifestations and tissue injuries in multiple organs.However, cellular and molecular understanding of SARS-CoV-2 infe...Infection with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) causes diverse clinical manifestations and tissue injuries in multiple organs.However, cellular and molecular understanding of SARS-CoV-2 infection-associated pathology and immune defense features in different organs remains incomplete. Here, we profiled approximately 77 000single-nucleus transcriptomes of the lung, liver,kidney, and cerebral cortex in rhesus macaques(Macaca mulatta) infected with SARS-CoV-2 and healthy controls. Integrated analysis of the multiorgan dataset suggested that the liver harbored the strongest global transcriptional alterations. We observed prominent impairment in lung epithelial cells, especially in AT2 and ciliated cells, and evident signs of fibrosis in fibroblasts. These lung injury characteristics are similar to those reported in patients with coronavirus disease 2019(COVID-19).Furthermore, we found suppressed MHC class I/II molecular activity in the lung, inflammatory response in the liver, and activation of the kynurenine pathway,which induced the development of an immunosuppressive microenvironment. Analysis of the kidney dataset highlighted tropism of tubule cells to SARS-CoV-2, and we found membranous nephropathy(an autoimmune disease) caused by podocyte dysregulation. In addition, we identified the pathological states of astrocytes and oligodendrocytes in the cerebral cortex, providing molecular insights into COVID-19-related neurological implications. Overall, our multi-organ single-nucleus transcriptomic survey of SARS-CoV-2-infected rhesus macaques broadens our understanding of disease features and antiviral immune defects caused by SARS-CoV-2 infection,which may facilitate the development of therapeutic interventions for COVID-19.展开更多
There is a growing appreciation for the specific health benefits conferred by commensal microbiota on their hosts.Clinical microbiota analysis and animal studies in germ-free or antibiotic-treated mice have been cruci...There is a growing appreciation for the specific health benefits conferred by commensal microbiota on their hosts.Clinical microbiota analysis and animal studies in germ-free or antibiotic-treated mice have been crucial for improving our understanding of the role of the microbiome on the host mucosal surface;however,studies on the mechanisms involved in microbiome-host interactions remain limited to small animal models.Here,we demonstrated that rhesus monkeys under short-term broad-spectrum antibiotic treatment could be used as a model to study the gut mucosal host-microbiome niche and immune balance with steady health status.Results showed that the diversity and community structure of the gut commensal bacteria in rhesus monkeys were both disrupted after antibiotic treatment.Furthermore,the 16S rDNA amplicon sequencing results indicated that Escherichia-Shigella were predominant in stool samples 9 d of treatment,and the abundances of bacterial functional genes and predicted KEGG pathways were significantly changed.In addition to inducing aberrant morphology of small intestinal villi,the depletion of gut commensal bacteria led to increased proportions of CD3+T,CD4+T,and CD16+NK cells in peripheral blood mononuclear cells(PBMCs),but decreased numbers of Treg and CD20+B cells.The transcriptome of PBMCs from antibiotic-treated monkeys showed that the immune balance was affected by modulation of the expression of many functional genes,including IL-13,VCAM1,and LGR4.展开更多
Taihang Mountain area, a high Incidence area of human esophageal cancer in Northern China. 124 Rhesus monkeys (Macacs Mulatta) were caught in the area in January 1989. Among them, two monkeys died of esophageal carcin...Taihang Mountain area, a high Incidence area of human esophageal cancer in Northern China. 124 Rhesus monkeys (Macacs Mulatta) were caught in the area in January 1989. Among them, two monkeys died of esophageal carcinoma in 1990. Case 1, a male monkey about 6. 5 yean old and weighing 14. 5 kg, had symptoms of salivation, vomiting and dysphagia in Fabruary 1990. The symptoms became gradually more serious and died in march 1990. Postmortem examination revealed a huge tumor in the distal segment of esophagus, causing severe structure of the organ. The tumor was classified as medullary type and histopathologically diagnosed as a well differentiated squamous cell carcinoma, with metastases to mediastinum and lymph nodes of right gastric group. Case 2, a female monkey ablut 11-year-old and weighing 10. 0 kg, showed loss of appetite, tiredness, somnolence, caughing and vomiting in September and died in December 1990. Autopsy revealed an annular tumor involving the whole clcumference of lower portion of the展开更多
In animal societies,some stressful events can lead to higher levels of physiological stress.Such stressors,like social rank,also predict an increased vulnerability to an array of diseases.However,the physiological rel...In animal societies,some stressful events can lead to higher levels of physiological stress.Such stressors,like social rank,also predict an increased vulnerability to an array of diseases.However,the physiological relationship between social rank and stress varies between different species,as well as within groups of a single species.For example,dominant individuals are more socially stressed at times,while at other times it is the subordinate ones who experience this stress.Together,these variations make it difficult to assess disease vulnerability as connected to social interactions.In order to learn more about how physiological rank relationships vary between groups of a single species,cortisol measurements from hair samples were used to evaluate the effects of dominance rank on long-term stress levels in despotic and less stringent female rhesus macaque hierarchal groups.In despotic groups,cortisol levels were found not to be correlated with social rank,but a negative correlation was found between social rank and cortisol levels in less stringent hierarchies.Low ranking monkeys in less stringent groups secreted elevated levels of cortisol compared to higher ranking animals.These data suggest that variations in the strictness of the dominance hierarchy are determining factors in rank related stress physiology.The further consideration of nonhuman primate social system diversity and the linear degree of their hierarchies may allow for the development of valid rank-related stress models that will help increase our understanding and guide the development of new therapeutics for diseases related to human socioeconomic status.展开更多
BACKGROUND:Pig islet xenotransplantation has the potential to overcome the shortage of donated human islets for islet cell transplantation in type 1 diabetes.Testing in nonhuman primate models is necessary before clin...BACKGROUND:Pig islet xenotransplantation has the potential to overcome the shortage of donated human islets for islet cell transplantation in type 1 diabetes.Testing in nonhuman primate models is necessary before clinical application in humans.Intraportal islet transplantation in monkeys is usually performed by surgical infusion during laparotomy or laparoscopy.In this paper,we describe a new method of percutaneous transhepatic portal catheterization(PTPC) as an alternative to current methods of islet transplantation in rhesus monkeys.METHODS:We performed ultrasound-guided PTPC in five adult rhesus monkeys weighing 7-8 kg,with portal vein catheterization confirmed by digital subtraction angiography.We monitored for complications in the thoracic and abdominal cavity.To evaluate the safety of ultrasound-guided PTPC,we recorded the changes in portal pressure throughout the microbead transplantation procedure.RESULTS:Ultrasound-guided PTPC and infusion of 16 000 microbeads/kg body weight into the portal vein was successful in all five monkeys.Differences in the hepatobiliary anatomy of rhesus monkeys compared to humans led to a higher initial complication rate.The first monkey died of abdominal hemorrhage 10 hours post-transplantation.The second suffered from a mild pneumothorax but recovered fully after taking only conservative measures.After gaining experience with the first two monkeys,we decreased both the hepatic puncture time and the number of puncture attempts required,with the remaining three monkeys experiencing no complications.Portal pressures initially increased proportional to the number of transplanted microbeads but returned to preinfusion levels at 30 minutes post-transplantation.The changes in portal pressures occurring during the procedure were not significantly different.CONCLUSIONS:Ultrasound-guided PTPC is an effective,convenient,and minimally invasive method suitable for use in non-human primate models of islet cell transplantation provided that care is taken with hepatic puncture.Its advantages must be weighed against the risks of procedure-related complications.展开更多
AIM: To determine the progression of parameters from optical coherence tomography(OCT) in chronic elevated intraocular pressure(IOP) monkeys.METHODS: A chronic elevated IOP model of rhesus monkeys was induced by laser...AIM: To determine the progression of parameters from optical coherence tomography(OCT) in chronic elevated intraocular pressure(IOP) monkeys.METHODS: A chronic elevated IOP model of rhesus monkeys was induced by laser photocoagulation. Representative OCT parameters, including the average and four-quadrant retinal nerve fiber layer(RNFL) thickness, and parameters from optic nerve head(ONH) analysis were collected before and after laser treatments biweekly for up to 28 wk. The performance of each parameter for early progression detection was analyzed. The progressive trends toward elevated IOP were analyzed using a linear mixed-effects model.RESULTS: There were 10 successfully maintained high IOP eyes in 7 monkeys. The follow-up time was 24±5.37 wk. With cumulative IOP elevation, the cup area, rim area and C/D area ratio were statistically significantly changed as early as 2 wk after elevated IOP induction(P<0.05). The quadrant RNFL thickness changed at 6wk after high IOP induction, and the superior and inferior RNFL thicknesses exhibited more obvious reductions than other quadrants. The average RNFL thickness was the last one to show a significant decrease at 8wk.CONCLUSION: The parameters of ONH are most sensitive to elevated IOP in a primate glaucomatous model. These findings suggest that we should focus on those parameters instead of RNFL thickness in patients with elevated IOP, as they might present with earlier glaucomatous changes.展开更多
基金supported by the National Natural Science Foundation of China (82021001 and 31825018 to Q.S., 32370658 to Y.M.,82001372 to X.Y.)National Key Research and Development Program of China (2022YFF0710901)+2 种基金National Science and Technology Innovation2030 Major Program (2021ZD0200900) to Q.S.Shanghai Pujiang Program (22PJ1407300)Shanghai Jiao Tong University 2030 Initiative (WH510363001-7) to Y.M。
文摘Understanding gene expression variations between species is pivotal for deciphering the evolutionary diversity in phenotypes. Rhesus macaques(Macaca mulatta, MMU)and crab-eating macaques(M. fascicularis, MFA) serve as crucial nonhuman primate biomedical models with different phenotypes. To date, however, large-scale comparative transcriptome research between these two species has not yet been fully explored. Here, we conducted systematic comparisons utilizing newly sequenced RNA-seq data from84 samples(41 MFA samples and 43 MMU samples)encompassing 14 common tissues. Our findings revealed a small fraction of genes(3.7%) with differential expression between the two species, as well as 36.5% of genes with tissue-specific expression in both macaques. Comparison of gene expression between macaques and humans indicated that 22.6% of orthologous genes displayed differential expression in at least two tissues. Moreover,19.41% of genes that overlapped with macaque-specific structural variants showed differential expression between humans and macaques. Of these, the FAM220A gene exhibited elevated expression in humans compared to macaques due to lineage-specific duplication. In summary,this study presents a large-scale transcriptomic comparison between MMU and MFA and between macaques and humans. The discovery of gene expression variations not only enhances the biomedical utility of macaque models but also contributes to the wider field of primate genomics.
基金supported by the Max Planck Society to C.W.T.and National Institutes of Health USDHHS(R01-HD065826to M.G.,OD011107 to Harris Lewin)。
文摘Fluoxetine(Prozac^(TM))is the only antidepressant approved by the US Food and Drug Administration(FDA)for the treatment of major depressive disorder(MDD)in children.Despite its considerable efficacy as a selective serotonin reuptake inhibitor,the possible long-term effects of fluoxetine on brain development in children are poorly understood.In the current study,we aimed to delineate molecular mechanisms and protein biomarkers in the brains of juvenile rhesus macaques(Macaca mulatta)one year after the discontinuation of fluoxetine treatment using proteomic and phosphoproteomic profiling.We identified several differences in protein expression and phosphorylation in the dorsolateral prefrontal cortex(DLPFC)and cingulate cortex(CC)that correlated with impulsivity in animals,suggesting that the GABAergic synapse pathway may be affected by fluoxetine treatment.Biomarkers in combination with the identified pathways contribute to a better understanding of the mechanisms underlying the chronic effects of fluoxetine after discontinuation in children.
基金supported by the National Program on Key Basic Research Project(973 Programs 2015CB755605)the National Natural Science Foundation of China(81471312)
文摘Viral vector transfection systems are among the simplest of biological agents with the ability to transfer genes into the central nervous system.In brain research,a series of powerful and novel gene editing technologies are based on these systems.Although many viral vectors are used in rodents,their full application has been limited in non-human primates.To identify viral vectors that can stably and effectively express exogenous genes within nonhuman primates,eleven commonly used recombinant adeno-associated viral and lentiviral vectors,each carrying a gene to express green or red fluorescence,were injected into the parietal cortex of four rhesus monkeys.The expression of fluorescent cells was used to quantify transfection efficiency.Histological results revealed that recombinant adeno-associated viral vectors,especially the serotype 2/9 coupled with the cytomegalovirus,human synapsin I,or Ca2+/calmodulin-dependentproteinkinaseII promoters,and lentiviral vector coupled with the human ubiquitin C promoter,induced higher expression of fluorescent cells,representing high transfection efficiency.This is the first comparison of transfection efficiencies of different viral vectors carrying different promoters and serotypes in non-human primates(NHPs).These results can be used as an aid to select optimal vectors to transfer exogenous genes into the central nervous system of non-human primates.
基金This work was supported by the National Research and Development Project of China(Grant No.2020YFC0841100)Fundamental Research Funds for CAMS of China(Grant No.2020HY320001)+3 种基金National Key Research and Development Project of China(Grant No.2016YFD0500304)CAMS initiative for Innovative Medicine of China(Grant No.2016-I2M-2-006)National Mega projects of China for Major Infectious Diseases(Grant No.2017ZX10304402)and National Key Research and Development Programme of China(2016YFD0500301,2020YFC0840800,2020YFC0840900).
文摘Background:Since December 2019,an outbreak of the Corona Virus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus(SARS-CoV-2)in Wuhan,China,has become a public health emergency of international concern.The high fatality of aged cases caused by SARS-CoV-2 was a need to explore the possible age-related phenomena with non-human primate models.Methods:Three 3-5 years old and two 15 years old rhesus macaques were intratracheally infected with SARS-CoV-2,and then analyzed by clinical signs,viral replication,chest X-ray,histopathological changes and immune response.Results:Viral replication of nasopharyngeal swabs,anal swabs and lung in old monkeys was more active than that in young monkeys for 14 days after SARS-CoV-2 challenge.Monkeys developed typical interstitial pneumonia characterized by thickened alveolar septum accompanied with inflammation and edema,notably,old monkeys exhibited diffuse severe interstitial pneumonia.Viral antigens were detected mainly in alveolar epithelial cells and macrophages.Conclusion:SARS-CoV-2 caused more severe interstitial pneumonia in old monkeys than that in young monkeys.Rhesus macaque models infected with SARS-CoV-2 provided insight into the pathogenic mechanism and facilitated the development of vaccines and therapeutics against SARS-CoV-2 infection.
基金the CAMS Initiative for Innovative Medicine,No.2016-I2M-1-019National Natural Science Foundation of China,No.31700154+4 种基金Major Science and Technology Special Project of Yunnan Province(Biomedicine),No.2018ZF006Science and Technology Project of Yunnan Province-general program,No.2016FB034Science and Technology Innovation Team Project of Kunming,No.2016-2-R-07674the Project of National Nonprofit Scientific Institutes Basic Scientific Service Fee,No.2016ZX310179-4Science and Technology Project of Yunnan Province,Key New Product Development,No.2014BC008
文摘AIM To establish a rotavirus(RV)-induced diarrhea model using RV SA11 in neonatal rhesus monkeys for the study of the pathogenic and immune mechanisms of RV infection and evaluation of candidate vaccines.METHODS Neonatal rhesus monkeys with an average age of 15-20 d and an average weight of 500 g ± 150 g received intragastric administration of varying doses of SA11 RV( 107 PFUs/mL, 106 PFUs/mL, or 105 PFUs/mL, 10 mL/animal) to determine whether the SA11 strain can effectively infect these animals by observing their clinical symptoms, fecal shedding of virus antigen by ELISA, distribution of RV antigen in the organs by immunofluorescence, variations of viral RNA load in the organs by qRT-PCR, histopathological changes in the small intestine by HE staining, and apoptosis of small intestinal epithelial cells by TUNEL assay.RESULTS The RV monkey model showed typical clinical diarrhea symptoms in the 108 PFUs SA11 group, where we observed diarrhea 1-4 d post infection(dpi) and viral antigen shed in the feces from 1-7 dpi. RV was found in jejunal epithelial cells. We observed a viral load of approximately 5.85 × 103 copies per 100 mg in the jejunum at 2 dpi, which was increased to 1.09 × 105 copies per 100 mg at 3 dpi. A relatively high viral load was also seen in mesenteric lymph nodes at 2 dpi and 3 dpi. The following histopathological changes were observed in the small intestine following intragastric administration of SA11 RV: vacuolization, edema, and atrophy. Apoptosis in the jejunal villus epithelium was also detectable at 3 dpi.CONCLUSION Our results indicate that we have successfully established a RV SA11 strain diarrhea model in neonatal rhesus monkeys. Future studies will elucidate the mechanisms underlying the pathogenesis of RV infection, and we will use the model to evaluate the protective effect of candidate vaccines.
文摘AIM:In order to improve the biocompatibility of intraocular lenses(IOL),the polymethylmethacrylate(PMMA)IOL was modified with F-heparin. METHODS:The PMMA IOL was modified with F ions and heparin by the technique of ion beam combined with low temperature and low pressure plasma.The monkeys(20 eyes)with cataract partly were randomly classified into 2 groups and implanted with PMMA IOL and modified IOL respectively for 180 days.All of the eyes were examined by slit-lamp microscope at postoperative 15,30,60,90,180 days.The extracted IOL was analyzed with computer image analysis,light microscope(LM)and scanning electron microscope(SEM)at postoperative 180 days. RESULTS:The early inflammatory reactions postoperatively include anterior chamber exudation and aqueous cell count. The modified IOL group showed less than the non-modified IOL group.The late foreign body cell reaction that adhered to the surface of non-modified IOL was more predominant.The morphologic and pathological changes of posterior capsule opacification(PCO)in monkeys’ eyes included fibrosis-type, pearl-type and soemmerring’s ring.There was a significant difference between the two groups. CONCLUSION:F-heparin modified IOL has good uveal and capsular biocompatibility.
基金supported by the National Natural Science Foundation of China(31700910)Applied Basic Research Programs of Science and Technology Commission Foundation of Yunnan Province(2017FB109)
文摘DEAR EDITOR,Major depressive disorder (MDD), commonly known as depression, is a mental disease characterized by a core symptom of low mood. It lasts at least two weeks (Badamasi et al., 2019;Wang et al., 2019) and is frequently accompanied by low self-esteem, loss of interest in routinely enjoyable activities, low energy, and unexplained pain (Huey et al., 2018;Park et al., 2012;Post & Warden, 2018;Rice et al., 2019;Xiao et al., 2018). Approximately 2%–8% of adults with MDD commit suicide (Richards & O'Hara, 2014;Strakowski & Nelson, 2015), and around half of suicidal individuals suffer depression or other mood disorders (Bachmann, 2018).
基金supported by the National Natural Science Foundation of China,No.31571109,81460261the Chinese-Finnish Joint Project Fund,No.813111172+2 种基金a grant from the Yunnan Key Program of Science and Technology of China,No.2014FC005the Key Science and Technology Research Project Fund of Hainan Province of China,No.ZDYF2016156the National Clinical Key Subject Construction Project Fund of China
文摘Rhesus monkey neural stem cells are capable of differentiating into neurons and glial cells.Therefore,neural stem cell transplantation can be used to promote functional recovery of the nervous system.Rhesus monkey neural stem cells(1×105 cells/μL) were injected into bilateral hippocampi of rats with hippocampal lesions.Confocal laser scanning microscopy demonstrated that green fluorescent protein-labeled transplanted cells survived and grew well.Transplanted cells were detected at the lesion site,but also in the nerve fiber-rich region of the cerebral cortex and corpus callosum.Some transplanted cells differentiated into neurons and glial cells clustering along the ventricular wall,and integrated into the recipient brain.Behavioral tests revealed that spatial learning and memory ability improved,indicating that rhesus monkey neural stem cells noticeably improve spatial learning and memory abilities in rats with hippocampal lesions.
基金supported by the National Natural Science Foundation of China(81571607)Beijing Natural Science Foundation(7162136)Ministry of Science and Technology(2017ZX10202102003005,2015BAI08B03)of China
文摘Rhesus macaques(Macaca mulatta) and cynomolgus macaques(Macaca fascicularis) are frequently used in establishing animal models for human diseases. To determine the differences in gut microbiota between these species, rectal swabs from 20 rhesus macaques and 21 cynomolgus macaques were collected, and the microbial composition was examined by deep sequencing of the 16 S rR NA gene. We found that the rectal microbiota of cynomolgus macaques exhibited significantly higher alpha diversity than that of rhesus macaques, although the observed number of operational taxonomic units(OTUs) was almost the same. The dominant taxa at both the phylum and genus levels were similar between the two species, although the relative abundances of these dominant taxa were significantly different between them. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States(PICRUSt) showed significant differences in the functional components between the microbiota of the two species, in particular the lipopolysaccharide(LPS) synthesis proteins. The above data indicated significant differences in microbial composition and function between these two closely related macaque species, which should be taken into consideration in the future selection of these animals for disease models.
基金supported by the National Basic Research Program of China(2020YFA0804000,2020YFC0842000,2020YFA0112200,2021YFC2301703)Strategic Priority Research Program of the Chinese Academy of Sciences(XDB32010100)+6 种基金Special Associate Research Program of the Chinese Academy of Sciences(E1290601)National Natural Science Foundation of China(32122037,81891001,32192411,32100512,U1902215)Collaborative Research Fund of the Chinese Institute for Brain Research,Beijing(2020-NKX-PT-03)CAS Project for Young Scientists in Basic Research(YSBR-013)Young Elite Scientist Sponsorship Program by the China Association for Science and Technology(2020QNRC001)National Resource Center for Non-Human Primates。
文摘Infection with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) causes diverse clinical manifestations and tissue injuries in multiple organs.However, cellular and molecular understanding of SARS-CoV-2 infection-associated pathology and immune defense features in different organs remains incomplete. Here, we profiled approximately 77 000single-nucleus transcriptomes of the lung, liver,kidney, and cerebral cortex in rhesus macaques(Macaca mulatta) infected with SARS-CoV-2 and healthy controls. Integrated analysis of the multiorgan dataset suggested that the liver harbored the strongest global transcriptional alterations. We observed prominent impairment in lung epithelial cells, especially in AT2 and ciliated cells, and evident signs of fibrosis in fibroblasts. These lung injury characteristics are similar to those reported in patients with coronavirus disease 2019(COVID-19).Furthermore, we found suppressed MHC class I/II molecular activity in the lung, inflammatory response in the liver, and activation of the kynurenine pathway,which induced the development of an immunosuppressive microenvironment. Analysis of the kidney dataset highlighted tropism of tubule cells to SARS-CoV-2, and we found membranous nephropathy(an autoimmune disease) caused by podocyte dysregulation. In addition, we identified the pathological states of astrocytes and oligodendrocytes in the cerebral cortex, providing molecular insights into COVID-19-related neurological implications. Overall, our multi-organ single-nucleus transcriptomic survey of SARS-CoV-2-infected rhesus macaques broadens our understanding of disease features and antiviral immune defects caused by SARS-CoV-2 infection,which may facilitate the development of therapeutic interventions for COVID-19.
基金supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2016-I2M-1-014)
文摘There is a growing appreciation for the specific health benefits conferred by commensal microbiota on their hosts.Clinical microbiota analysis and animal studies in germ-free or antibiotic-treated mice have been crucial for improving our understanding of the role of the microbiome on the host mucosal surface;however,studies on the mechanisms involved in microbiome-host interactions remain limited to small animal models.Here,we demonstrated that rhesus monkeys under short-term broad-spectrum antibiotic treatment could be used as a model to study the gut mucosal host-microbiome niche and immune balance with steady health status.Results showed that the diversity and community structure of the gut commensal bacteria in rhesus monkeys were both disrupted after antibiotic treatment.Furthermore,the 16S rDNA amplicon sequencing results indicated that Escherichia-Shigella were predominant in stool samples 9 d of treatment,and the abundances of bacterial functional genes and predicted KEGG pathways were significantly changed.In addition to inducing aberrant morphology of small intestinal villi,the depletion of gut commensal bacteria led to increased proportions of CD3+T,CD4+T,and CD16+NK cells in peripheral blood mononuclear cells(PBMCs),but decreased numbers of Treg and CD20+B cells.The transcriptome of PBMCs from antibiotic-treated monkeys showed that the immune balance was affected by modulation of the expression of many functional genes,including IL-13,VCAM1,and LGR4.
文摘Taihang Mountain area, a high Incidence area of human esophageal cancer in Northern China. 124 Rhesus monkeys (Macacs Mulatta) were caught in the area in January 1989. Among them, two monkeys died of esophageal carcinoma in 1990. Case 1, a male monkey about 6. 5 yean old and weighing 14. 5 kg, had symptoms of salivation, vomiting and dysphagia in Fabruary 1990. The symptoms became gradually more serious and died in march 1990. Postmortem examination revealed a huge tumor in the distal segment of esophagus, causing severe structure of the organ. The tumor was classified as medullary type and histopathologically diagnosed as a well differentiated squamous cell carcinoma, with metastases to mediastinum and lymph nodes of right gastric group. Case 2, a female monkey ablut 11-year-old and weighing 10. 0 kg, showed loss of appetite, tiredness, somnolence, caughing and vomiting in September and died in December 1990. Autopsy revealed an annular tumor involving the whole clcumference of lower portion of the
基金This study was funded by the National Science Foundation of China(NSFC 31271167,and 31070963)the 973 program(2007CB947703 and 2011CB707800)the Key Program of the Chinese Academy of Sciences,China(KSCX2-EW-R-13)。
文摘In animal societies,some stressful events can lead to higher levels of physiological stress.Such stressors,like social rank,also predict an increased vulnerability to an array of diseases.However,the physiological relationship between social rank and stress varies between different species,as well as within groups of a single species.For example,dominant individuals are more socially stressed at times,while at other times it is the subordinate ones who experience this stress.Together,these variations make it difficult to assess disease vulnerability as connected to social interactions.In order to learn more about how physiological rank relationships vary between groups of a single species,cortisol measurements from hair samples were used to evaluate the effects of dominance rank on long-term stress levels in despotic and less stringent female rhesus macaque hierarchal groups.In despotic groups,cortisol levels were found not to be correlated with social rank,but a negative correlation was found between social rank and cortisol levels in less stringent hierarchies.Low ranking monkeys in less stringent groups secreted elevated levels of cortisol compared to higher ranking animals.These data suggest that variations in the strictness of the dominance hierarchy are determining factors in rank related stress physiology.The further consideration of nonhuman primate social system diversity and the linear degree of their hierarchies may allow for the development of valid rank-related stress models that will help increase our understanding and guide the development of new therapeutics for diseases related to human socioeconomic status.
基金supported by grants from the Natural Science Foundation of Hunan Province(11JJ4078)the National Natural Science Foundation of China(30900359 and 30900377)
文摘BACKGROUND:Pig islet xenotransplantation has the potential to overcome the shortage of donated human islets for islet cell transplantation in type 1 diabetes.Testing in nonhuman primate models is necessary before clinical application in humans.Intraportal islet transplantation in monkeys is usually performed by surgical infusion during laparotomy or laparoscopy.In this paper,we describe a new method of percutaneous transhepatic portal catheterization(PTPC) as an alternative to current methods of islet transplantation in rhesus monkeys.METHODS:We performed ultrasound-guided PTPC in five adult rhesus monkeys weighing 7-8 kg,with portal vein catheterization confirmed by digital subtraction angiography.We monitored for complications in the thoracic and abdominal cavity.To evaluate the safety of ultrasound-guided PTPC,we recorded the changes in portal pressure throughout the microbead transplantation procedure.RESULTS:Ultrasound-guided PTPC and infusion of 16 000 microbeads/kg body weight into the portal vein was successful in all five monkeys.Differences in the hepatobiliary anatomy of rhesus monkeys compared to humans led to a higher initial complication rate.The first monkey died of abdominal hemorrhage 10 hours post-transplantation.The second suffered from a mild pneumothorax but recovered fully after taking only conservative measures.After gaining experience with the first two monkeys,we decreased both the hepatic puncture time and the number of puncture attempts required,with the remaining three monkeys experiencing no complications.Portal pressures initially increased proportional to the number of transplanted microbeads but returned to preinfusion levels at 30 minutes post-transplantation.The changes in portal pressures occurring during the procedure were not significantly different.CONCLUSIONS:Ultrasound-guided PTPC is an effective,convenient,and minimally invasive method suitable for use in non-human primate models of islet cell transplantation provided that care is taken with hepatic puncture.Its advantages must be weighed against the risks of procedure-related complications.
基金Supported by National Natural Science Foundation of China(No.81470627 No.81600726)+2 种基金Shandong Province Natural Science Foundation(No.ZR2016HB53)Natural Science Foundation of Guangdong Province(No.2018A030310185)the Research Funding of Guangzhou Medical University(No.2016C21)
文摘AIM: To determine the progression of parameters from optical coherence tomography(OCT) in chronic elevated intraocular pressure(IOP) monkeys.METHODS: A chronic elevated IOP model of rhesus monkeys was induced by laser photocoagulation. Representative OCT parameters, including the average and four-quadrant retinal nerve fiber layer(RNFL) thickness, and parameters from optic nerve head(ONH) analysis were collected before and after laser treatments biweekly for up to 28 wk. The performance of each parameter for early progression detection was analyzed. The progressive trends toward elevated IOP were analyzed using a linear mixed-effects model.RESULTS: There were 10 successfully maintained high IOP eyes in 7 monkeys. The follow-up time was 24±5.37 wk. With cumulative IOP elevation, the cup area, rim area and C/D area ratio were statistically significantly changed as early as 2 wk after elevated IOP induction(P<0.05). The quadrant RNFL thickness changed at 6wk after high IOP induction, and the superior and inferior RNFL thicknesses exhibited more obvious reductions than other quadrants. The average RNFL thickness was the last one to show a significant decrease at 8wk.CONCLUSION: The parameters of ONH are most sensitive to elevated IOP in a primate glaucomatous model. These findings suggest that we should focus on those parameters instead of RNFL thickness in patients with elevated IOP, as they might present with earlier glaucomatous changes.
