Some 10 years ago, in early 2012, we started discussing the establishment of the National Research Facility for Phenotypic and Genetic Analysis of Model Animals(Primate Facility).Even though the Primate Facility is st...Some 10 years ago, in early 2012, we started discussing the establishment of the National Research Facility for Phenotypic and Genetic Analysis of Model Animals(Primate Facility).Even though the Primate Facility is still under construction, the rapid passing of a decade is a good excuse to look back and reflect for a moment.展开更多
Primates are highly successful mammals with significant morphological,behavioral,and physiological diversity.Studying the genomes of non-human primates,as the closest relative of humans,can provide insights into human...Primates are highly successful mammals with significant morphological,behavioral,and physiological diversity.Studying the genomes of non-human primates,as the closest relative of humans,can provide insights into human evolution,genetic structure,and potential drug targets relevant to human health,thus making important contributions to medical research.Additionally,primate genome research can support ecological balance and resource conservation and promote sustainable development and human well-being.Despite the existence of more than 500 primate species belonging to 80 genera and 16 families worldwide,with new species still being discovered in recent years(Fan et al.,2017;Khanal et al.,2021;Roos et al.,2020),genome sequencing efforts have been limited to a relatively small number of species from only 22 genera(Ensembl v103).Notably,approximately 72%of primate genera remain unsequenced,leading to significant knowledge gaps in our understanding of their evolutionary history.This situation presents considerable challenges for the development,utilization,and protection of primate genetic resources.It is for these compelling reasons that we initiated the Primate Genome Project(PGP)(Wu et al.,2022).展开更多
A crucial step for understanding human evolution is to identify the genomic changes that occurred during primate evolution,thus allowing investigators to reconstruct the ancestral states preceding the human condition....A crucial step for understanding human evolution is to identify the genomic changes that occurred during primate evolution,thus allowing investigators to reconstruct the ancestral states preceding the human condition.In the past several decades,the primate clade has been a research focus in genome sequencing due to its unique phylogenetic position and key importance.展开更多
The Chinese tree shrew has gained prominence as a model organism due to its phylogenetic proximity to primates,offering distinct advantages over traditional rodent models in biomedical research.However,the neuroanatom...The Chinese tree shrew has gained prominence as a model organism due to its phylogenetic proximity to primates,offering distinct advantages over traditional rodent models in biomedical research.However,the neuroanatomy of this species remains insufficiently defined,limiting its utility in neurophysiological and neuropathological studies.In this study,immunofluorescence microscopy was employed to comprehensively map the distribution of three calciumbinding proteins,parvalbumin,calbindin D-28k,and calretinin,across the tree shrew cerebrum.Serial brain sections in sagittal,coronal,and horizontal planes from 12 individuals generated a dataset of 3638 cellular-resolution images.This dataset,accessible via Science Data Bank(https://doi.org/10.57760/sciencedb.23471),provides detailed region-and laminar-selective distributions of calcium-binding proteins valuable for the cyto-and chemoarchitectural characterization of the tree shrew cerebrum.This resource will not only advance our understanding of brain organization and facilitate basic and translational neuroscience research in tree shrews but also enhance comparative and evolutionary analyses across species.展开更多
Automated behavior monitoring of macaques offers transformative potential for advancing biomedical research and animal welfare.However,reliably identifying individual macaques in group environments remains a significa...Automated behavior monitoring of macaques offers transformative potential for advancing biomedical research and animal welfare.However,reliably identifying individual macaques in group environments remains a significant challenge.This study introduces ACE-YOLOX,a lightweight facial recognition model tailored for captive macaques.ACE-YOLOX incorporates Efficient Channel Attention(ECA),Complete Intersection over Union loss(CIoU),and Adaptive Spatial Feature Fusion(ASFF)into the YOLOX framework,enhancing prediction accuracy while reducing computational complexity.These integrated approaches enable effective multiscale feature extraction.Using a dataset comprising 179400 labeled facial images from 1196 macaques,ACE-YOLOX surpassed the performance of classical object detection models,demonstrating superior accuracy and real-time processing capabilities.An Android application was also developed to deploy ACE-YOLOX on smartphones,enabling on-device,real-time macaque recognition.Our experimental results highlight the potential of ACE-YOLOX as a non-invasive identification tool,offering an important foundation for future studies in macaque facial expression recognition,cognitive psychology,and social behavior.展开更多
The DNA replication stress(RS)response is crucial for maintaining cellular homeostasis and promoting physiological longevity.However,the mechanisms by which long-lived species,such as bats,regulate RS to maintain geno...The DNA replication stress(RS)response is crucial for maintaining cellular homeostasis and promoting physiological longevity.However,the mechanisms by which long-lived species,such as bats,regulate RS to maintain genomic stability remain unclear.Also,recent studies have uncovered noncanonical roles of ribosome-associated factors in maintaining genomic stability.In this study,somatic skin fibroblasts from the long-lived big-footed bat(Myotis pilosus)were examined,with results showing that bat cells exhibited enhanced RS tolerance compared to mouse cells.Comparative transcriptome analysis under RS conditions revealed pronounced species-specific transcriptional differences,including robust up-regulation of ribosome biogenesis genes in bat cells and a markedly reduced activation of the P53 signaling pathway.These features emphasize a distinct homeostatic strategy in bat cells.Nuclear fragile X mental retardation-interacting protein 1(Nufip1),a ribosome-associated factor highly expressed in bat fibroblasts,was identified as a potential integrator of ribosomal and P53 signaling via its association with ribosomal protein S27-like(Rps27l).These findings provide direct cellular and molecular evidence for a noncanonical RS response in bats,highlighting a deeper understanding of the biological characteristics and genomic maintenance mechanisms of long-lived species.展开更多
As of June 2020, Coronavirus Disease 2019(COVID-19) has killed an estimated 440 000 people worldwide, 74% of whom were aged ≥65 years,making age the most significant risk factor for death caused by severe acute respi...As of June 2020, Coronavirus Disease 2019(COVID-19) has killed an estimated 440 000 people worldwide, 74% of whom were aged ≥65 years,making age the most significant risk factor for death caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) infection. To examine the effect of age on death, we established a SARSCoV-2 infection model in Chinese rhesus macaques(Macaca mulatta) of varied ages. Results indicated that infected young macaques manifested impaired respiratory function, active viral replication, severe lung damage, and infiltration of CD11b^+ and CD8^+ cells in lungs at one-week post infection(wpi), but also recovered rapidly at 2 wpi. In contrast, aged macaques demonstrated delayed immune responses with a more severe cytokine storm, increased infiltration of CD11b^+ cells, and persistent infiltration of CD8^+ cells in the lungs at 2 wpi. In addition,peripheral blood T cells from aged macaques showed greater inflammation and chemotaxis, but weaker antiviral functions than that in cells from young macaques. Thus, the delayed but more severe cytokine storm and higher immune cell infiltration may explain the poorer prognosis of older aged patients suffering SARS-CoV-2 infection.展开更多
The Chinese tree shrew(Tupaia belangeri chinensis)is emerging as an important experimental animal in multiple fields of biomedical research.Comprehensive reference genome annotation for both mRNA and long non-coding R...The Chinese tree shrew(Tupaia belangeri chinensis)is emerging as an important experimental animal in multiple fields of biomedical research.Comprehensive reference genome annotation for both mRNA and long non-coding RNA(lncRNA)is crucial for developing animal models using this species.In the current study,we collected a total of 234 high-quality RNA sequencing(RNA-seq)datasets and two long-read isoform sequencing(ISO-seq)datasets and improved the annotation of our previously assembled high-quality chromosomelevel tree shrew genome.We obtained a total of 3514 newly annotated coding genes and 50576 lncRNA genes.We also characterized the tissuespecific expression patterns and alternative splicing patterns of mRNAs and lncRNAs and mapped the orthologous relationships among 11 mammalian species using the current annotated genome.We identified 144 tree shrew-specific gene families,including interleukin 6(IL6)and STT3 oligosaccharyltransferase complex catalytic subunit B(STT3B),which underwent significant changes in size.Comparison of the overall expression patterns in tissues and pathways across four species(human,rhesus monkey,tree shrew,and mouse)indicated that tree shrews are more similar to primates than to mice at the tissue-transcriptome level.Notably,the newly annotated purine rich element binding protein A(PURA)gene and the STT3B gene family showed dysregulation upon viral infection.The updated version of the tree shrew genome annotation(KIZ version 3:TS_3.0)is available at http://www.treeshrewdb.org and provides an essential reference for basic and biomedical studies using tree shrew animal models.展开更多
Thecoronavirusdisease2019(COVID-19)pandemic continues to pose a global threat to the human population. Identifying animal species susceptible to infection with the SARS-CoV-2/HCoV-19 pathogen is essential for controll...Thecoronavirusdisease2019(COVID-19)pandemic continues to pose a global threat to the human population. Identifying animal species susceptible to infection with the SARS-CoV-2/HCoV-19 pathogen is essential for controlling the outbreak and for testing valid prophylactics or therapeutics based on animal model studies. Here,different aged Chinese tree shrews(adult group, 1 year old;old group, 5–6 years old), which are close relatives to primates, were infected with SARS-CoV-2. X-ray, viral shedding, laboratory, and histological analyses were performed on different days postinoculation(dpi). Results showed that Chinese tree shrews could be infected by SARS-CoV-2. Lung infiltrates were visible in X-ray radiographs in most infected animals. Viral RNA was consistently detected in lung tissues from infected animals at 3,5, and 7 dpi, along with alterations in related parameters from routine blood tests and serum biochemistry, including increased levels of aspartate aminotransferase(AST) and blood urea nitrogen(BUN). Histological analysis of lung tissues from animals at 3 dpi(adult group) and 7 dpi(old group) showed thickened alveolar septa and interstitial hemorrhage. Several differences were found between the two different aged groups in regard to viral shedding peak. Our results indicate that Chinese tree shrews have the potential to be used as animal models for SARS-CoV-2 infection.展开更多
We recently identified a cynomolgus monkey with naturally occurring Parkinson's disease(PD), indicating that PD may not be a uniquely human disease(Li et al., 2020). In our previous study, four lines of evidence, ...We recently identified a cynomolgus monkey with naturally occurring Parkinson's disease(PD), indicating that PD may not be a uniquely human disease(Li et al., 2020). In our previous study, four lines of evidence, including typical PD clinical symptoms, pharmacological responses, pathological hallmarks, and genetic mutations, strongly supported the identification of a monkey with spontaneous PD(Figure 1).展开更多
The recalcitrance of pathogens to traditional antibiotics has made treating and eradicating bacterial infections more difficult.In this regard,developing new antimicrobial agents to combat antibiotic-resistant strains...The recalcitrance of pathogens to traditional antibiotics has made treating and eradicating bacterial infections more difficult.In this regard,developing new antimicrobial agents to combat antibiotic-resistant strains has become a top priority.Antimicrobial peptides(AMPs),a ubiquitous class of naturally occurring compounds with broadspectrum antipathogenic activity,hold significant promise as an effective solution to the current antimicrobial resistance(AMR)crisis.Several AMPs have been identified and evaluated for their therapeutic application,with many already in the drug development pipeline.Their distinct properties,such as high target specificity,potency,and ability to bypass microbial resistance mechanisms,make AMPs a promising alternative to traditional antibiotics.Nonetheless,several challenges,such as high toxicity,lability to proteolytic degradation,low stability,poor pharmacokinetics,and high production costs,continue to hamper their clinical applicability.Therefore,recent research has focused on optimizing the properties of AMPs to improve their performance.By understanding the physicochemical properties of AMPs that correspond to their activity,such as amphipathicity,hydrophobicity,structural conformation,amino acid distribution,and composition,researchers can design AMPs with desired and improved performance.In this review,we highlight some of the key strategies used to optimize the performance of AMPs,including rational design and de novo synthesis.We also discuss the growing role of predictive computational tools,utilizing artificial intelligence and machine learning,in the design and synthesis of highly efficacious lead drug candidates.展开更多
DEAR EDITOR,Rhesus monkeys(Macaca mulatta)are valuable experimental animals for studies on neurodegenerative diseases due to their evolutionarily close relationship to humans(Zhang et al.,2014).Rhesus monkeys also dis...DEAR EDITOR,Rhesus monkeys(Macaca mulatta)are valuable experimental animals for studies on neurodegenerative diseases due to their evolutionarily close relationship to humans(Zhang et al.,2014).Rhesus monkeys also display similar hallmarks of aging and neurodegeneration as humans,including formation of senile plaques in the brain(Beckman et al.,2019;Paspalas et al.,2018).展开更多
Whether direct manipulation of Parkinson’s disease(PD)risk genes in the adult monkey brain can elicit a Parkinsonian phenotype remains an unsolved issue.Here,we used an adeno-associated virus serotype 9(AAV9)-deliver...Whether direct manipulation of Parkinson’s disease(PD)risk genes in the adult monkey brain can elicit a Parkinsonian phenotype remains an unsolved issue.Here,we used an adeno-associated virus serotype 9(AAV9)-delivered CRISPR/Cas9 system to directly co-edit PINK1 and DJ-1 genes in the substantia nigras(SNs)of two monkey groups:an old group and a middle-aged group.After the operation,the old group exhibited all the classic PD symptoms,including bradykinesia,tremor,and postural instability,accompanied by key pathological hallmarks of PD,such as severe nigral dopaminergic neuron loss(>64%)and evidentα-synuclein pathology in the gene-edited SN.In contrast,the phenotype of their middle-aged counterparts,which also showed clear PD symptoms and pathological hallmarks,were less severe.In addition to the higher final total PD scores and more severe pathological changes,the old group were also more susceptible to gene editing by showing a faster process of PD progression.These results suggested that both genetic and aging factors played important roles in the development of PD in the monkeys.Taken together,this system can effectively develop a large number of genetically-edited PD monkeys in a short time(6–10 months),and thus provides a practical transgenic monkey model for future PD studies.展开更多
Tree shrews(Tupaia belangeri chinensis)share a close relationship to primates and have been widely used in biomedical research.We previously established a spermatogonial stem cell(SSC)-based gene editing platform to g...Tree shrews(Tupaia belangeri chinensis)share a close relationship to primates and have been widely used in biomedical research.We previously established a spermatogonial stem cell(SSC)-based gene editing platform to generate transgenic tree shrews.However,the influences of long-term expansion on tree shrew SSC spermatogenesis potential remain unclear.Here,we examined the in vivo spermatogenesis potential of tree shrew SSCs cultured across different passages.We found that SSCs lost spermatogenesis ability after long-term expansion(>50 passages),as indicated by the failure to colonize the seminiferous epithelium and generate donor spermatogonia(SPG)-derivedspermatocytesor spermatids marking spermatogenesis.RNA sequencing(RNA-seq)analysis of undifferentiated SPGs across different passages revealed significant gene expression changes after sub-culturing primary SPG lines for more than 40 passages on feeder layers.Specifically,DNA damage response and repair genes(e.g.,MRE11,SMC3,BLM,and GEN1)were down-regulated,whereas genes associated with mitochondrial function(e.g.,NDUFA9,NDUFA8,NDUFA13,and NDUFB8)were up-regulated after expansion.The DNA damage accumulation and mitochondrial dysfunction were experimentally validated in high-passage cells.Supplementation with nicotinamide adenine dinucleotide(NAD+)precursor nicotinamide riboside(NR)exhibited beneficial effects by reducing DNA damage accumulation and mitochondrial dysfunction in SPG elicited by long-term culture.Our research presents a comprehensive analysis of the genetic and physiological attributes critical for the sustained expansion of undifferentiated SSCs in tree shrews and proposes an effective strategy for extended in vitro maintenance.展开更多
Coronavirus disease 2019(COVID-19),which is caused by severe acute respiratory syndrome coronavirus(SARS-CoV-2),has become an unprecedented global health emergency.At present,SARS-CoV-2-infected nonhuman primates are ...Coronavirus disease 2019(COVID-19),which is caused by severe acute respiratory syndrome coronavirus(SARS-CoV-2),has become an unprecedented global health emergency.At present,SARS-CoV-2-infected nonhuman primates are considered the gold standard animal model for COVID-19 research.Here,we showed that northern pig-tailed macaques(Macaca leonina,NPMs)supported SARS-CoV-2 replication.Furthermore,compared with rhesus macaques,NPMs showed rapid viral clearance in lung tissues,nose swabs,throat swabs,and rectal swabs,which may be due to higher expression of interferon(IFN)-αin lung tissue.However,the rapid viral clearance was not associated with good outcome.In the second week post infection,NPMs developed persistent or even more severe inflammation and body injury compared with rhesus macaques.These results suggest that viral clearance may have no relationship with COVID-19 progression and SARS-CoV-2-infected NPMs could be considered as a critically ill animal model in COVID-19 research.展开更多
The incidence of myopia has increased rapidly in recent decades, suggesting that environmental factors, such as light,may be an important cause. Correlated color temperature(CCT) is a commonly used index to quantify t...The incidence of myopia has increased rapidly in recent decades, suggesting that environmental factors, such as light,may be an important cause. Correlated color temperature(CCT) is a commonly used index to quantify the spectral composition of light. Here, we used 32 juvenile monkeys(16 females and 16 males) and selected four kinds of light with typical but different CCTs to study the relationship between CCT and ocular axial elongation.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
The use of tree shrews as experimental animals for biomedical research is a new practice.Several recent studies suggest that tree shrews are suitable for studying cancers,including breast cancer,glioblastoma,lung canc...The use of tree shrews as experimental animals for biomedical research is a new practice.Several recent studies suggest that tree shrews are suitable for studying cancers,including breast cancer,glioblastoma,lung cancer,and hepatocellular carcinoma.However,the telomeres and the telomerase of tree shrews have not been studied to date.Here,we characterize telomeres and telomerase in tree shrews.The telomere length of tree shrews is approximately 23 kb,which is longer than that of primates and shorter than that of mice,and it is extended in breast tumor tissues according to Southern blot and flow-fluorescence in situ hybridization(FISH)analyses.Tree shrew spleen,bone marrow,testis,ovary,and uterus show high telomerase activities,which are increased in breast tumor tissues by telomeric repeat amplification protocol assays.The telomere length becomes shorter,and telomerase activity decreases with age.The tree shrew TERT and TERC are more highly similar to primates than to rodents.These findings lay a solid foundation for using tree shrews to study aging and cancers.展开更多
Although it first appeared almost two years ago,the COVID-19 pandemic continues to have an impact on a global scale,in part due to newly emerging SARS-CoV-2 variants such as Delta and Lambda.The B.1.621 variant,first ...Although it first appeared almost two years ago,the COVID-19 pandemic continues to have an impact on a global scale,in part due to newly emerging SARS-CoV-2 variants such as Delta and Lambda.The B.1.621 variant,first identified in Colombia in January 2021,was classified as a variant of interest(VOI)and designated as Mu by the World Health Organization(WHO)in August 2021.However,its infectivity and resistance to neutralizing antibodies remain largely unknown.Here,in comparison to Delta,the Mu variant showed an unexpectedly enhanced immune resistance to inactivated vaccine-elicited antibodies.Nevertheless,Mu demonstrated less infectivity than Delta,implying a biological trade-off between viral transmission and immune escape.This study strongly calls for urgent evaluation of the protective efficacy of current COVID-19 vaccines against the Mu variant.Variants of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)are of concern regarding control of the global COVID-19 pandemic(Wang et al.,2021).The SARS-CoV-2 B.1.621 variant was first identified in Colombia in January 2021.Considering its epidemiological prevalence,the WHO defined B.1.621(named Mu)as a VOI on 30 August 2021.As of September 2021,the WHO has classified four variants of concern(VOC),i.e.,Alpha(B.1.1.7),Beta(B.1.351),Gamma(P.1),and Delta(B.1.617.2),and two VOI,i.e.,Lambda(C.37)and Mu(B.1.621)(Supplementary Figure S1A).展开更多
The distribution of the immune system throughout the body complicates in vitro assessments of coronavirus disease 2019(COVID-19)immunobiology,often resulting in a lack of reproducibility when extrapolated to the whole...The distribution of the immune system throughout the body complicates in vitro assessments of coronavirus disease 2019(COVID-19)immunobiology,often resulting in a lack of reproducibility when extrapolated to the whole organism.Consequently,developing animal models is imperative for a comprehensive understanding of the pathology and immunology of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.This review summarizes current progress related to COVID-19 animal models,including non-human primates(NHPs),mice,and hamsters,with a focus on their roles in exploring the mechanisms of immunopathology,immune protection,and long-term effects of SARS-CoV-2 infection,as well as their application in immunoprevention and immunotherapy of SARS-CoV-2 infection.Differences among these animal models and their specific applications are also highlighted,as no single model can fully encapsulate all aspects of COVID-19.To effectively address the challenges posed by COVID-19,it is essential to select appropriate animal models that can accurately replicate both fatal and non-fatal infections with varying courses and severities.Optimizing animal model libraries and associated research tools is key to resolving the global COVID-19 pandemic,serving as a robust resource for future emerging infectious diseases.展开更多
文摘Some 10 years ago, in early 2012, we started discussing the establishment of the National Research Facility for Phenotypic and Genetic Analysis of Model Animals(Primate Facility).Even though the Primate Facility is still under construction, the rapid passing of a decade is a good excuse to look back and reflect for a moment.
文摘Primates are highly successful mammals with significant morphological,behavioral,and physiological diversity.Studying the genomes of non-human primates,as the closest relative of humans,can provide insights into human evolution,genetic structure,and potential drug targets relevant to human health,thus making important contributions to medical research.Additionally,primate genome research can support ecological balance and resource conservation and promote sustainable development and human well-being.Despite the existence of more than 500 primate species belonging to 80 genera and 16 families worldwide,with new species still being discovered in recent years(Fan et al.,2017;Khanal et al.,2021;Roos et al.,2020),genome sequencing efforts have been limited to a relatively small number of species from only 22 genera(Ensembl v103).Notably,approximately 72%of primate genera remain unsequenced,leading to significant knowledge gaps in our understanding of their evolutionary history.This situation presents considerable challenges for the development,utilization,and protection of primate genetic resources.It is for these compelling reasons that we initiated the Primate Genome Project(PGP)(Wu et al.,2022).
基金supported by the National Natural Science Foundation of China(31822048)Strategic Priority Research Program of the Chinese Academy of Sciences(XDPB17)。
文摘A crucial step for understanding human evolution is to identify the genomic changes that occurred during primate evolution,thus allowing investigators to reconstruct the ancestral states preceding the human condition.In the past several decades,the primate clade has been a research focus in genome sequencing due to its unique phylogenetic position and key importance.
基金supported by the Science and Technology Innovation(STI)2030-Major Projects(2022ZD0205000 to L.L.)CAS“Light of West China”Program(xbzg-zdsys-202404 to L.L.)+1 种基金Yunnan Revitalization Talent Support Program Yunling Scholar Project(to L.L.)Yunnan Fundamental Research Projects(202305AH340006,202301AS070060 to L.L.,202401AT070206 to X.C.)。
文摘The Chinese tree shrew has gained prominence as a model organism due to its phylogenetic proximity to primates,offering distinct advantages over traditional rodent models in biomedical research.However,the neuroanatomy of this species remains insufficiently defined,limiting its utility in neurophysiological and neuropathological studies.In this study,immunofluorescence microscopy was employed to comprehensively map the distribution of three calciumbinding proteins,parvalbumin,calbindin D-28k,and calretinin,across the tree shrew cerebrum.Serial brain sections in sagittal,coronal,and horizontal planes from 12 individuals generated a dataset of 3638 cellular-resolution images.This dataset,accessible via Science Data Bank(https://doi.org/10.57760/sciencedb.23471),provides detailed region-and laminar-selective distributions of calcium-binding proteins valuable for the cyto-and chemoarchitectural characterization of the tree shrew cerebrum.This resource will not only advance our understanding of brain organization and facilitate basic and translational neuroscience research in tree shrews but also enhance comparative and evolutionary analyses across species.
基金supported by the grants from Yunnan Province(202305AH340006,202305AH340007)CAS Light of West China Program(xbzg-zdsys-202213)。
文摘Automated behavior monitoring of macaques offers transformative potential for advancing biomedical research and animal welfare.However,reliably identifying individual macaques in group environments remains a significant challenge.This study introduces ACE-YOLOX,a lightweight facial recognition model tailored for captive macaques.ACE-YOLOX incorporates Efficient Channel Attention(ECA),Complete Intersection over Union loss(CIoU),and Adaptive Spatial Feature Fusion(ASFF)into the YOLOX framework,enhancing prediction accuracy while reducing computational complexity.These integrated approaches enable effective multiscale feature extraction.Using a dataset comprising 179400 labeled facial images from 1196 macaques,ACE-YOLOX surpassed the performance of classical object detection models,demonstrating superior accuracy and real-time processing capabilities.An Android application was also developed to deploy ACE-YOLOX on smartphones,enabling on-device,real-time macaque recognition.Our experimental results highlight the potential of ACE-YOLOX as a non-invasive identification tool,offering an important foundation for future studies in macaque facial expression recognition,cognitive psychology,and social behavior.
基金supported by the Applied Basic Research Programs of Science and Technology Commission Foundation of Yunnan Province(202401AT070186 to K.Q.L.,202201AS070044 to B.Z.)Yunnan Province(202305AH340006 to B.Z.)Kunming Science and Technology Bureau(2022SCP007 to B.Z.)。
文摘The DNA replication stress(RS)response is crucial for maintaining cellular homeostasis and promoting physiological longevity.However,the mechanisms by which long-lived species,such as bats,regulate RS to maintain genomic stability remain unclear.Also,recent studies have uncovered noncanonical roles of ribosome-associated factors in maintaining genomic stability.In this study,somatic skin fibroblasts from the long-lived big-footed bat(Myotis pilosus)were examined,with results showing that bat cells exhibited enhanced RS tolerance compared to mouse cells.Comparative transcriptome analysis under RS conditions revealed pronounced species-specific transcriptional differences,including robust up-regulation of ribosome biogenesis genes in bat cells and a markedly reduced activation of the P53 signaling pathway.These features emphasize a distinct homeostatic strategy in bat cells.Nuclear fragile X mental retardation-interacting protein 1(Nufip1),a ribosome-associated factor highly expressed in bat fibroblasts,was identified as a potential integrator of ribosomal and P53 signaling via its association with ribosomal protein S27-like(Rps27l).These findings provide direct cellular and molecular evidence for a noncanonical RS response in bats,highlighting a deeper understanding of the biological characteristics and genomic maintenance mechanisms of long-lived species.
基金This work was supported by the National Key Research and Development Program of China(2020YFC0842000)。
文摘As of June 2020, Coronavirus Disease 2019(COVID-19) has killed an estimated 440 000 people worldwide, 74% of whom were aged ≥65 years,making age the most significant risk factor for death caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) infection. To examine the effect of age on death, we established a SARSCoV-2 infection model in Chinese rhesus macaques(Macaca mulatta) of varied ages. Results indicated that infected young macaques manifested impaired respiratory function, active viral replication, severe lung damage, and infiltration of CD11b^+ and CD8^+ cells in lungs at one-week post infection(wpi), but also recovered rapidly at 2 wpi. In contrast, aged macaques demonstrated delayed immune responses with a more severe cytokine storm, increased infiltration of CD11b^+ cells, and persistent infiltration of CD8^+ cells in the lungs at 2 wpi. In addition,peripheral blood T cells from aged macaques showed greater inflammation and chemotaxis, but weaker antiviral functions than that in cells from young macaques. Thus, the delayed but more severe cytokine storm and higher immune cell infiltration may explain the poorer prognosis of older aged patients suffering SARS-CoV-2 infection.
基金This study was supported by the National Natural Science Foundation of China(U1902215 to Y.G.Y.and 31970542 to Y.F.)Chinese Academy of Sciences(Light of West China Program xbzg-zdsys-201909 to Y.G.Y.)Yunnan Province(202001AS070023 and 2018FB046 to D.D.Y.and 202002AA100007 to Y.G.Y.)。
文摘The Chinese tree shrew(Tupaia belangeri chinensis)is emerging as an important experimental animal in multiple fields of biomedical research.Comprehensive reference genome annotation for both mRNA and long non-coding RNA(lncRNA)is crucial for developing animal models using this species.In the current study,we collected a total of 234 high-quality RNA sequencing(RNA-seq)datasets and two long-read isoform sequencing(ISO-seq)datasets and improved the annotation of our previously assembled high-quality chromosomelevel tree shrew genome.We obtained a total of 3514 newly annotated coding genes and 50576 lncRNA genes.We also characterized the tissuespecific expression patterns and alternative splicing patterns of mRNAs and lncRNAs and mapped the orthologous relationships among 11 mammalian species using the current annotated genome.We identified 144 tree shrew-specific gene families,including interleukin 6(IL6)and STT3 oligosaccharyltransferase complex catalytic subunit B(STT3B),which underwent significant changes in size.Comparison of the overall expression patterns in tissues and pathways across four species(human,rhesus monkey,tree shrew,and mouse)indicated that tree shrews are more similar to primates than to mice at the tissue-transcriptome level.Notably,the newly annotated purine rich element binding protein A(PURA)gene and the STT3B gene family showed dysregulation upon viral infection.The updated version of the tree shrew genome annotation(KIZ version 3:TS_3.0)is available at http://www.treeshrewdb.org and provides an essential reference for basic and biomedical studies using tree shrew animal models.
基金partly supported by the National Key R&D Program of China(2020YFC0842000 to Y.T.Z.)National Natural Science Foundation of China(U1902215 to Y.G.Y.)+2 种基金National Science and Technology Major Projects of Infectious Disease Funds(2017ZX10304402 to Y.T.Z.)Yunnan Province(2018FB046 to D.D.Y.)CAS“Light of West China”Program(xbzg-zdsys-201909to Y.G.Y.and Y.T.Z.)。
文摘Thecoronavirusdisease2019(COVID-19)pandemic continues to pose a global threat to the human population. Identifying animal species susceptible to infection with the SARS-CoV-2/HCoV-19 pathogen is essential for controlling the outbreak and for testing valid prophylactics or therapeutics based on animal model studies. Here,different aged Chinese tree shrews(adult group, 1 year old;old group, 5–6 years old), which are close relatives to primates, were infected with SARS-CoV-2. X-ray, viral shedding, laboratory, and histological analyses were performed on different days postinoculation(dpi). Results showed that Chinese tree shrews could be infected by SARS-CoV-2. Lung infiltrates were visible in X-ray radiographs in most infected animals. Viral RNA was consistently detected in lung tissues from infected animals at 3,5, and 7 dpi, along with alterations in related parameters from routine blood tests and serum biochemistry, including increased levels of aspartate aminotransferase(AST) and blood urea nitrogen(BUN). Histological analysis of lung tissues from animals at 3 dpi(adult group) and 7 dpi(old group) showed thickened alveolar septa and interstitial hemorrhage. Several differences were found between the two different aged groups in regard to viral shedding peak. Our results indicate that Chinese tree shrews have the potential to be used as animal models for SARS-CoV-2 infection.
基金supported by the Key-Area Research and Development Program of Guangdong Province(2019B030335001)National Key R&D Program of China(2018YFA0801403)Strategic Priority Research Program of the Chinese Academy of Sciences (XDB32060200 and XDB32020200)。
文摘We recently identified a cynomolgus monkey with naturally occurring Parkinson's disease(PD), indicating that PD may not be a uniquely human disease(Li et al., 2020). In our previous study, four lines of evidence, including typical PD clinical symptoms, pharmacological responses, pathological hallmarks, and genetic mutations, strongly supported the identification of a monkey with spontaneous PD(Figure 1).
基金This work was supported by the National Natural Science Foundation of China(31930015,32200397)Ministry of Science and Technology of China(2018YFA0801403)+3 种基金Chinese Academy of Sciences(XDB31000000,KFJ-BRP-008-003)Yunnan Province Grant(202003AD150008,202002AA100007)Kunming Science and Technology Bureau(2023SCP001)New Cornerstone Investigator Program。
文摘The recalcitrance of pathogens to traditional antibiotics has made treating and eradicating bacterial infections more difficult.In this regard,developing new antimicrobial agents to combat antibiotic-resistant strains has become a top priority.Antimicrobial peptides(AMPs),a ubiquitous class of naturally occurring compounds with broadspectrum antipathogenic activity,hold significant promise as an effective solution to the current antimicrobial resistance(AMR)crisis.Several AMPs have been identified and evaluated for their therapeutic application,with many already in the drug development pipeline.Their distinct properties,such as high target specificity,potency,and ability to bypass microbial resistance mechanisms,make AMPs a promising alternative to traditional antibiotics.Nonetheless,several challenges,such as high toxicity,lability to proteolytic degradation,low stability,poor pharmacokinetics,and high production costs,continue to hamper their clinical applicability.Therefore,recent research has focused on optimizing the properties of AMPs to improve their performance.By understanding the physicochemical properties of AMPs that correspond to their activity,such as amphipathicity,hydrophobicity,structural conformation,amino acid distribution,and composition,researchers can design AMPs with desired and improved performance.In this review,we highlight some of the key strategies used to optimize the performance of AMPs,including rational design and de novo synthesis.We also discuss the growing role of predictive computational tools,utilizing artificial intelligence and machine learning,in the design and synthesis of highly efficacious lead drug candidates.
基金This study was supported by the National Key R&D Program of China(2018YFA0801403)Key Realm R&D Program of GuangDong Province(2019B030335001)+3 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB32060200)the National Natural Science Foundation of China(81941014,81471312,81771387,81460352,81500983,31700897,31700910,31800901,31960178,91732302)the Applied Basic Research Programs of Science and Technology Commission Foundation of Yunnan Province(2017FB109,2018FB052,2018FB053,2019FA007)China Postdoctoral Science Foundation(2018M631105)and CAS"Light of West China"Program。
文摘DEAR EDITOR,Rhesus monkeys(Macaca mulatta)are valuable experimental animals for studies on neurodegenerative diseases due to their evolutionarily close relationship to humans(Zhang et al.,2014).Rhesus monkeys also display similar hallmarks of aging and neurodegeneration as humans,including formation of senile plaques in the brain(Beckman et al.,2019;Paspalas et al.,2018).
基金This work was supported by the National Key R&D Program of China(2018YFA0801403)the Key-Area Research and Development Program of Guangdong Province(2019B030335001)+6 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB32060200)the National Program for Key Basic Research Projects(973 Program:2015CB755605)the National Natural Science Foundation of China(81471312,81771387,81460352,81500983,31700897,31700910,31800901,31625013,and 91732302)the Applied Basic Research Programs of Science and Technology Commission Foundation of Yunnan Province(2017FB109,2018FB052,2018FB053,2019FA007,and 202001AT070130)Chinese Academy of Sciences"Light of West China"Program,Shanghai Brain-Intelligence Project from Science and Technology Commission of Shanghai Municipality(16JC1420501)Shanghai Municipal Science and Technology Major Project(2018SHZDZX05)Open Large Infrastructure Research of Chinese Academy of Sciences,and China Postdoctoral Science Foundation(2018M631105).
文摘Whether direct manipulation of Parkinson’s disease(PD)risk genes in the adult monkey brain can elicit a Parkinsonian phenotype remains an unsolved issue.Here,we used an adeno-associated virus serotype 9(AAV9)-delivered CRISPR/Cas9 system to directly co-edit PINK1 and DJ-1 genes in the substantia nigras(SNs)of two monkey groups:an old group and a middle-aged group.After the operation,the old group exhibited all the classic PD symptoms,including bradykinesia,tremor,and postural instability,accompanied by key pathological hallmarks of PD,such as severe nigral dopaminergic neuron loss(>64%)and evidentα-synuclein pathology in the gene-edited SN.In contrast,the phenotype of their middle-aged counterparts,which also showed clear PD symptoms and pathological hallmarks,were less severe.In addition to the higher final total PD scores and more severe pathological changes,the old group were also more susceptible to gene editing by showing a faster process of PD progression.These results suggested that both genetic and aging factors played important roles in the development of PD in the monkeys.Taken together,this system can effectively develop a large number of genetically-edited PD monkeys in a short time(6–10 months),and thus provides a practical transgenic monkey model for future PD studies.
基金supported by the Ministry of Science and Technology of China (2021YFF0702700,STI2030-Major Project2021ZD0200900)National Natural Science Foundation of China (U2102202,U1702284)Yunnan Province (202305AH340006)。
文摘Tree shrews(Tupaia belangeri chinensis)share a close relationship to primates and have been widely used in biomedical research.We previously established a spermatogonial stem cell(SSC)-based gene editing platform to generate transgenic tree shrews.However,the influences of long-term expansion on tree shrew SSC spermatogenesis potential remain unclear.Here,we examined the in vivo spermatogenesis potential of tree shrew SSCs cultured across different passages.We found that SSCs lost spermatogenesis ability after long-term expansion(>50 passages),as indicated by the failure to colonize the seminiferous epithelium and generate donor spermatogonia(SPG)-derivedspermatocytesor spermatids marking spermatogenesis.RNA sequencing(RNA-seq)analysis of undifferentiated SPGs across different passages revealed significant gene expression changes after sub-culturing primary SPG lines for more than 40 passages on feeder layers.Specifically,DNA damage response and repair genes(e.g.,MRE11,SMC3,BLM,and GEN1)were down-regulated,whereas genes associated with mitochondrial function(e.g.,NDUFA9,NDUFA8,NDUFA13,and NDUFB8)were up-regulated after expansion.The DNA damage accumulation and mitochondrial dysfunction were experimentally validated in high-passage cells.Supplementation with nicotinamide adenine dinucleotide(NAD+)precursor nicotinamide riboside(NR)exhibited beneficial effects by reducing DNA damage accumulation and mitochondrial dysfunction in SPG elicited by long-term culture.Our research presents a comprehensive analysis of the genetic and physiological attributes critical for the sustained expansion of undifferentiated SSCs in tree shrews and proposes an effective strategy for extended in vitro maintenance.
基金This work was partly supported by the National Key R&D Program of China(2020YFC0842000)National Science and Technology Major Projects of Infectious Disease Funds(2017ZX10304402,2018ZX10301406-003)+1 种基金the National Natural Science Foundation of China(U1802284,U1902210)National Resource Center for Non-Human Primates。
文摘Coronavirus disease 2019(COVID-19),which is caused by severe acute respiratory syndrome coronavirus(SARS-CoV-2),has become an unprecedented global health emergency.At present,SARS-CoV-2-infected nonhuman primates are considered the gold standard animal model for COVID-19 research.Here,we showed that northern pig-tailed macaques(Macaca leonina,NPMs)supported SARS-CoV-2 replication.Furthermore,compared with rhesus macaques,NPMs showed rapid viral clearance in lung tissues,nose swabs,throat swabs,and rectal swabs,which may be due to higher expression of interferon(IFN)-αin lung tissue.However,the rapid viral clearance was not associated with good outcome.In the second week post infection,NPMs developed persistent or even more severe inflammation and body injury compared with rhesus macaques.These results suggest that viral clearance may have no relationship with COVID-19 progression and SARS-CoV-2-infected NPMs could be considered as a critically ill animal model in COVID-19 research.
基金supported by the Key-Area Research and Development Program of Guangdong Province(2019B030335001)Science and Technology Service Network Initiative(STS)Project of Chinese Academy of Sciences(E02E1801)+6 种基金National Key R&D Program of China(2018YFA0801403)Scientific Instrument Developing Project of the Chinese Academy of Sciences(CAS)(022006)Strategic Priority Research Program of the Chinese Academy of Sciences(XDB32060200)National Natural Science Foundation of China(81941014,81771387,31800901,31960178)CAS“Light of West China”ProgramApplied Basic Research Programs of Science and Technology Commission Foundation of Yunnan Province(202001AT070130)National Research Facility for Phenotypic and Genetic Analysis of Model Animals,Kunming Institute of Zoology,Chinese Academy of Sciences。
文摘The incidence of myopia has increased rapidly in recent decades, suggesting that environmental factors, such as light,may be an important cause. Correlated color temperature(CCT) is a commonly used index to quantify the spectral composition of light. Here, we used 32 juvenile monkeys(16 females and 16 males) and selected four kinds of light with typical but different CCTs to study the relationship between CCT and ocular axial elongation.
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 National Key Research and Development Program of China(2018YFC2000400,2020YFA0112300 to C.Chen)National Natural Science Foundation of China(81830087,31771516 to C.Chen)+1 种基金project of Innovative Research Team of Yunnan Province(2019HC005)CAS“light of West China”Program(xbzg-zdsys-201909)。
文摘The use of tree shrews as experimental animals for biomedical research is a new practice.Several recent studies suggest that tree shrews are suitable for studying cancers,including breast cancer,glioblastoma,lung cancer,and hepatocellular carcinoma.However,the telomeres and the telomerase of tree shrews have not been studied to date.Here,we characterize telomeres and telomerase in tree shrews.The telomere length of tree shrews is approximately 23 kb,which is longer than that of primates and shorter than that of mice,and it is extended in breast tumor tissues according to Southern blot and flow-fluorescence in situ hybridization(FISH)analyses.Tree shrew spleen,bone marrow,testis,ovary,and uterus show high telomerase activities,which are increased in breast tumor tissues by telomeric repeat amplification protocol assays.The telomere length becomes shorter,and telomerase activity decreases with age.The tree shrew TERT and TERC are more highly similar to primates than to rodents.These findings lay a solid foundation for using tree shrews to study aging and cancers.
基金This work was supported by start-up funding from the Kunming Institute of Zoology,Chinese Academy of Sciences to J.X.Z.
文摘Although it first appeared almost two years ago,the COVID-19 pandemic continues to have an impact on a global scale,in part due to newly emerging SARS-CoV-2 variants such as Delta and Lambda.The B.1.621 variant,first identified in Colombia in January 2021,was classified as a variant of interest(VOI)and designated as Mu by the World Health Organization(WHO)in August 2021.However,its infectivity and resistance to neutralizing antibodies remain largely unknown.Here,in comparison to Delta,the Mu variant showed an unexpectedly enhanced immune resistance to inactivated vaccine-elicited antibodies.Nevertheless,Mu demonstrated less infectivity than Delta,implying a biological trade-off between viral transmission and immune escape.This study strongly calls for urgent evaluation of the protective efficacy of current COVID-19 vaccines against the Mu variant.Variants of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)are of concern regarding control of the global COVID-19 pandemic(Wang et al.,2021).The SARS-CoV-2 B.1.621 variant was first identified in Colombia in January 2021.Considering its epidemiological prevalence,the WHO defined B.1.621(named Mu)as a VOI on 30 August 2021.As of September 2021,the WHO has classified four variants of concern(VOC),i.e.,Alpha(B.1.1.7),Beta(B.1.351),Gamma(P.1),and Delta(B.1.617.2),and two VOI,i.e.,Lambda(C.37)and Mu(B.1.621)(Supplementary Figure S1A).
基金National Key Research and Development Program of China(2022YFC2303700,2021YFC2301300)Yunnan Key Research and Development Program(202303AC100026)+2 种基金National Natural Science Foundation of China(82302002,82341069)Yunnan Fundamental Research Project(202201AS070047)Strategic Priority Research Program of the Chinese Academy of Sciences(XDB0490000)。
文摘The distribution of the immune system throughout the body complicates in vitro assessments of coronavirus disease 2019(COVID-19)immunobiology,often resulting in a lack of reproducibility when extrapolated to the whole organism.Consequently,developing animal models is imperative for a comprehensive understanding of the pathology and immunology of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.This review summarizes current progress related to COVID-19 animal models,including non-human primates(NHPs),mice,and hamsters,with a focus on their roles in exploring the mechanisms of immunopathology,immune protection,and long-term effects of SARS-CoV-2 infection,as well as their application in immunoprevention and immunotherapy of SARS-CoV-2 infection.Differences among these animal models and their specific applications are also highlighted,as no single model can fully encapsulate all aspects of COVID-19.To effectively address the challenges posed by COVID-19,it is essential to select appropriate animal models that can accurately replicate both fatal and non-fatal infections with varying courses and severities.Optimizing animal model libraries and associated research tools is key to resolving the global COVID-19 pandemic,serving as a robust resource for future emerging infectious diseases.
