Attempts have been made to use cell transplantation and biomaterials to promote cell proliferation,differentiation,migration,and survival,as well as angiogenesis,in the context of brain injury.However,whether bioactiv...Attempts have been made to use cell transplantation and biomaterials to promote cell proliferation,differentiation,migration,and survival,as well as angiogenesis,in the context of brain injury.However,whether bioactive materials can repair the damage caused by ischemic stroke by activating endogenous neurogenesis and angiogenesis is still unknown.In this study,we applied chitosan gel loaded with basic fibroblast growth factor to the stroke cavity 7 days after ischemic stroke in rats.The gel slowly released basic fibroblast growth factor,which improved the local microenvironment,activated endogenous neural stem/progenitor cells,and recruited these cells to migrate toward the penumbra and stroke cavity and subsequently differentiate into neurons,while enhancing angiogenesis in the penumbra and stroke cavity and ultimately leading to partial functional recovery.This study revealed the mechanism by which bioactive materials repair ischemic strokes,thus providing a new strategy for the clinical application of bioactive materials in the treatment of ischemic stroke.展开更多
It has long been asserted that failure to recover from central nervous system diseases is due to the system's intricate structure and the regenerative incapacity of adult neurons.Yet over recent decades,numerous s...It has long been asserted that failure to recover from central nervous system diseases is due to the system's intricate structure and the regenerative incapacity of adult neurons.Yet over recent decades,numerous studies have established that endogenous neurogenesis occurs in the adult central nervous system,including humans'.This has challenged the long-held scientific consensus that the number of adult neurons remains constant,and that new central nervous system neurons cannot be created or renewed.Herein,we present a comprehensive overview of the alterations and regulatory mechanisms of endogenous neurogenesis following central nervous system injury,and describe novel treatment strategies that to rget endogenous neurogenesis and newborn neurons in the treatment of central nervous system injury.Central nervous system injury frequently results in alterations of endogenous neurogenesis,encompassing the activation,proliferation,ectopic migration,diffe rentiation,and functional integration of endogenous neural stem cells.Because of the unfavorable local microenvironment,most activated neural stem cells diffe rentiate into glial cells rather than neurons.Consequently,the injury-induced endogenous neurogenesis response is inadequate for repairing impaired neural function.Scientists have attempted to enhance endogenous neurogenesis using various strategies,including using neurotrophic factors,bioactive materials,and cell reprogramming techniques.Used alone or in combination,these therapeutic strategies can promote targeted migration of neural stem cells to an injured area,ensure their survival and diffe rentiation into mature functional neurons,and facilitate their integration into the neural circuit.Thus can integration re plenish lost neurons after central nervous system injury,by improving the local microenvironment.By regulating each phase of endogenous neurogenesis,endogenous neural stem cells can be harnessed to promote effective regeneration of newborn neurons.This offers a novel approach for treating central nervous system injury.展开更多
Neurotrophic keratopathy is a persistent defect of the corneal epithelium,with or without stromal ulceration,due to corneal nerve deficiency caused by a variety of etiologies.The treatment options for neurotrophic ker...Neurotrophic keratopathy is a persistent defect of the corneal epithelium,with or without stromal ulceration,due to corneal nerve deficiency caused by a variety of etiologies.The treatment options for neurotrophic keratopathy are limited.In this study,an ophthalmic solution was constructed from a chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor(CTH-mNGF).Its effectiveness was evaluated in corneal denervation(CD)mice and patients with neurotrophic keratopathy.In the preclinical setting,CTH-mNGF was assessed in a murine corneal denervation model.CTH-mNGF was transparent,thermosensitive,and ensured sustained release of mNGF for over 20 hours on the ocular surface,maintaining the local mNGF concentration around 1300 pg/mL in vivo.Corneal denervation mice treated with CTH-mNGF for 10 days showed a significant increase in corneal nerve area and total corneal nerve length compared with non-treated and CTH treated mice.A subsequent clinical trial of CTH-mNGF was conducted in patients with stage 2 or 3 neurotrophic keratopathy.Patients received topical CTH-mNGF twice daily for 8 weeks.Fluorescein sodium images,Schirmer’s test,intraocular pressure,Cochet-Bonnet corneal perception test,and best corrected visual acuity were evaluated.In total,six patients(total of seven eyes)diagnosed with neurotrophic keratopathy were enrolled.After 8 weeks of CTH-mNGF treatment,all participants showed a decreased area of corneal epithelial defect,as stained by fluorescence.Overall,six out of seven eyes had fluorescence staining scores<5.Moreover,best corrected visual acuity,intraocular pressure,Schirmer’s test and Cochet-Bonnet corneal perception test results showed no significant improvement.An increase in corneal nerve density was observed by in vivo confocal microscopy after 8 weeks of CTH-mNGF treatment in three out of seven eyes.This study demonstrates that CTH-mNGF is transparent,thermosensitive,and has sustained-release properties.Its effectiveness in healing corneal epithelial defects in all eyes with neurotrophic keratopathy suggests CTH-mNGF has promising application prospects in the treatment of neurotrophic keratopathy,being convenient and cost effective.展开更多
Wallerian degeneration,the progressive disintegration of distal axons and myelin that occurs after peripheral nerve injury,is essential for creating a permissive microenvironment for nerve regeneration,and involves cy...Wallerian degeneration,the progressive disintegration of distal axons and myelin that occurs after peripheral nerve injury,is essential for creating a permissive microenvironment for nerve regeneration,and involves cytoskeletal reconstruction.However,it is unclear whether microtubule dynamics play a role in this process.To address this,we treated cultured sciatic nerve explants,an in vitro model of Wallerian degeneration,with the microtubule-targeting agents paclitaxel and nocodazole.We found that paclitaxel-induced microtubule stabilization promoted axon and myelin degeneration and Schwann cell dedifferentiation,whereas nocodazole-induced microtubule destabilization inhibited these processes.Evaluation of an in vivo model of peripheral nerve injury showed that treatment with paclitaxel or nocodazole accelerated or attenuated axonal regeneration,as well as functional recovery of nerve conduction and target muscle and motor behavior,respectively.These results suggest that microtubule dynamics participate in peripheral nerve regeneration after injury by affecting Wallerian degeneration.This study was approved by the Animal Care and Use Committee of Southern Medical University,China(approval No.SMUL2015081) on October 15,2015.展开更多
The presence of endogenous neural stem/progenitor cells in the adult mammalian brain suggests that the central nervous system can be repaired and regenerated after injury.However,whether it is possible to stimulate ne...The presence of endogenous neural stem/progenitor cells in the adult mammalian brain suggests that the central nervous system can be repaired and regenerated after injury.However,whether it is possible to stimulate neurogenesis and reconstruct cortical layers II to VI in non-neurogenic regions,such as the cortex,remains unknown.In this study,we implanted a hyaluronic acid collagen gel loaded with basic fibroblast growth factor into the motor cortex immediately following traumatic injury.Our findings reveal that this gel effectively stimulated the proliferation and migration of endogenous neural stem/progenitor cells,as well as their differentiation into mature and functionally integrated neurons.Importantly,these new neurons reconstructed the architecture of cortical layers II to VI,integrated into the existing neural circuitry,and ultimately led to improved brain function.These findings offer novel insight into potential clinical treatments for traumatic cerebral cortex injuries.展开更多
Previous studies have shown that Lycium barbarum polysaccharide,the main active component of Lycium barbarum,exhibits antiinflammatory and antioxidant effects in treating neurological diseases.However,the therapeutic ...Previous studies have shown that Lycium barbarum polysaccharide,the main active component of Lycium barbarum,exhibits antiinflammatory and antioxidant effects in treating neurological diseases.However,the therapeutic action of Lycium barbarum polysaccharide on depression has not been studied.In this investigation,we established mouse models of depression using aversive stimuli including exposure to fox urine,air puff and foot shock and physical restraint.Concurrently,we administered 5 mg/kg per day Lycium barbarum polysaccharide-glycoprotein to each mouse intragastrically for the 28 days.Our results showed that long-term exposure to aversive stimuli significantly enhanced depressive-like behavior evaluated by the sucrose preference test and the forced swimming test and increased anxietylike behaviors evaluated using the open field test.In addition,aversive stimuli-induced depressed mice exhibited aberrant neuronal activity in the lateral habenula.Importantly,concurrent Lycium barbarum polysaccharide-glycoprotein treatment significantly reduced these changes.These findings suggest that Lycium barbarum polysaccharide-glycoprotein is a potential preventative intervention for depression and may act by preventing aberrant neuronal activity and microglial activation in the lateral habenula.The study was approved by the Jinan University Institutional Animal Care and Use Committee(approval No.20170301003)on March 1,2017.展开更多
Age-related neurodegenerative disorders such as Alzheimer’s disease(AD)have become a critical public health issue due to the significantly extended human lifespan,leading to considerable economic and social burdens.T...Age-related neurodegenerative disorders such as Alzheimer’s disease(AD)have become a critical public health issue due to the significantly extended human lifespan,leading to considerable economic and social burdens.Traditional therapies for AD such as medicine and surgery remain ineffective,impractical,and expensive.Many studies have shown that a variety of bioactive substances released by physical exercise(called“exerkines”)help to maintain and improve the normal functions of the brain in terms of cognition,emotion,and psychomotor coordination.Increasing evidence suggests that exerkines may exert beneficial effects in AD as well.This review summarizes the neuroprotective effects of exerkines in AD,focusing on the underlying molecular mechanism and the dynamic expression of exerkines after physical exercise.The findings described in this review will help direct research into novel targets for the treatment of AD and develop customized exercise therapy for individuals of different ages,genders,and health conditions.展开更多
Microtubule networks support many cellular processes and exhibit a highly ordered architecture.However,due to the limited axial resolution of conventional light microscopy,the structural features of these networks can...Microtubule networks support many cellular processes and exhibit a highly ordered architecture.However,due to the limited axial resolution of conventional light microscopy,the structural features of these networks cannot be resolved in three-dimensional(3D)space.Here,we used customized ultra-high-resolution interferometric single-molecule localization microscopy to characterize the microtubule networks in Caco2 cells.We found that the calmodulin-regulated spectrin-associated proteins(CAMSAPs)localize at a portion of microtubule intersections.Further investigation showed that depletion of CAMSAP2 and CAMSAP3 leads to the narrowing of the inter-microtubule distance.Mechanistically,CAMSAPs recognize microtubule defects,which often occur near microtubule intersections,and then recruit katanin to remove the damaged microtubules.Therefore,the CAMSAP–katanin complex is a regulatory module for the distance between microtubules.Taken together,our results characterize the architecture of cellular microtubule networks in high resolution and provide molecular insights into how the 3D structure of microtubule networks is controlled.展开更多
Molecular knowledge of human gastric corpus epithelium remains incomplete.Here,by integrated analyses using single-cell RNA sequencing(scRNA-seq),spatial transcriptomics,and single-cell assay for transposase accessibl...Molecular knowledge of human gastric corpus epithelium remains incomplete.Here,by integrated analyses using single-cell RNA sequencing(scRNA-seq),spatial transcriptomics,and single-cell assay for transposase accessible chromatin sequencing(scATAC-seq)techniques,we uncovered the spatially resolved expression landscape and gene-regulatory network of human gastric corpus epithelium.Specifically,we identified a stem/progenitor cell population in the isthmus of human gastric corpus,where EGF and WNT signaling pathways were activated.Meanwhile,LGR4,but not LGR5,was responsible for the activation of WNT signaling pathway.Importantly,FABP5 and NME1 were identified and validated as crucial for both normal gastric stem/progenitor cells and gastric cancer cells.Finally,we explored the epigenetic regulation of critical genes for gastric corpus epithelium at chromatin state level,and identified several important cell-type-specific transcription factors.In summary,our work provides novel insights to systematically understand the cellular diversity and homeostasis of human gastric corpus epithelium in vivo.展开更多
Although somatic cells can be reprogrammed to pluripotent stem cells(PsCs)with pure chemicals,authentic pluripotency of chemically induced pluripotent stem celis(CipsCs)has never been achieved through tetraploid compl...Although somatic cells can be reprogrammed to pluripotent stem cells(PsCs)with pure chemicals,authentic pluripotency of chemically induced pluripotent stem celis(CipsCs)has never been achieved through tetraploid complementation assay.Spontaneous reprogramming of spermatogonial stem cells(ssCs)was another non-transgenic way to obtain PsCs,but this process lacks mechanistic explanation.Here,we reconstructed the trajectory of mouse SsC reprogramming and developed a five-chemical combination,boosting the reprogramming effciency by nearly 80-to 100-folds.More importantly,chemical induced germline-derived PsCs(5C-gPSCs),but not gpsCs and chemical induced pluripotent stem cells,had authentic pluripotency,as determined by tetraploid complementation.Mechanistically,ssCs traversed through an inverted pathway of in vivo germ ceil development,exhibiting the expression signatures and DNA methylation dynamics from spermatogonia to primordial germ cells and further to epiblasts.Besides,ssC-specific imprinting control regions switched from biallelic methylated states to monoallelic methylated states by imprinting demethylation and then re-methylation on one of the two alleles in 5c-gPsCs,which was apparently distinct with the imprinting reprogramming in vivo as DNA methylation simultaneously occurred on both alleles.Our work sheds ight on the unique regulatory network underpinning SsC reprogramming,providing insights to understand generic mechanisms for cell-fate decision and epigenetic-relateddisorders in regenerative medicine.展开更多
Dear Editor,The optic nerve,which belongs to the central nervous system(CNS),cannot regenerate when injured in adult mammals.1 Up to now,no readily translatable measures are available for repairing a severely injured ...Dear Editor,The optic nerve,which belongs to the central nervous system(CNS),cannot regenerate when injured in adult mammals.1 Up to now,no readily translatable measures are available for repairing a severely injured optic nerve.Herein we demonstrated that ciliary neurotrophic factor(CNTF)-chitosan enabled the reconstruction and functional recovery of the adult rat visual system,thus shedding light on the clinical potential for repairing the severely injured optic nerve.展开更多
The coronavirus disease 2019(COVID-19)pandemic is caused by infection with the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which is spread primary via respiratory droplets and infects the lungs.Current...The coronavirus disease 2019(COVID-19)pandemic is caused by infection with the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which is spread primary via respiratory droplets and infects the lungs.Currently widely used cell lines and animals are unable to accurately mimic human physiological conditions because of the abnormal status of cell lines(transformed or cancer cells)and species differences between animals and humans.Organoids are stem cell-derived selforganized three-dimensional culture in vitro and model the physiological conditions of natural organs.Here we showed that SARS-CoV-2 infected and extensively replicated in human embryonic stem cells(hESCs)-derived lung organoids,including airway and alveolar organoids which covered the complete infection and spread route for SARS-CoV-2 within lungs.The infected ceils were ciliated,club,and alveolar type 2(AT2)cells,which were sequentially located from the proximal to the distal airway and terminal alveoli,respectively.Additionally,RNA-seq revealed early cell response to virus infection including an unexpected downregulation of the metabolic processes,especially lipid metabolism,in addition to the well-known upregulation of immune response.Further,Remdesivir and a human neutralizing antibody potently inhibited SARS-CoV-2 replication in lung organoids.Therefore,human lung organoids can serve as a pathophysiological model to investigate the underlying mechanism of SARS-CoV-2 infection and to discover and test therapeutic drugs for COVID-19.展开更多
Inducible expression systems are indispensable for precise regulation and in-depth analysis of biological process.Binary Tet-On system has been widely employed to regulate transgenic expression by doxycycline.Previous...Inducible expression systems are indispensable for precise regulation and in-depth analysis of biological process.Binary Tet-On system has been widely employed to regulate transgenic expression by doxycycline.Previous pig models with tetracycline regulatory elements were generated through random integration.This process often resulted in uncertain expression and unpredictable phenotypes,thus hindering their applications.Here,by precise knock-in of binary Tet-On 3G elements into Rosa26 and Hipp11 locus,respectively,a double knock-in reporter pig model was generated.We characterized excellent properties of this system for controllable transgenic expression both in vitro and in vivo.Two att P sites were arranged to flank the td Tomato to switch reporter gene.Single or multiple gene replacement was efficiently and faithfully achieved in fetal fibroblasts and nuclear transfer embryos.To display the flexible application of this system,we generated a pig strain with Dox-inducing h KRASexpression through phiC31 integrase-mediated cassette exchange.After eight months of Dox administration,squamous cell carcinoma developed in the nose,mouth,and scrotum,which indicated this pig strain could serve as an ideal large animal model to study tumorigenesis.Overall,the established pig models with controllable and switchable transgene expression system will provide a facilitating platform for transgenic and biomedical research.展开更多
Calcium phosphate bio-ceramics are osteo-conductive,but it remains a challenge to promote the induction of bone augmentation and capillary formation.The surface micro/nano-topography of materials can be recognized by ...Calcium phosphate bio-ceramics are osteo-conductive,but it remains a challenge to promote the induction of bone augmentation and capillary formation.The surface micro/nano-topography of materials can be recognized by cells and then the cell fate are mediated.Traditional regulation methods of carving surface structures on bio-ceramics employ mineral reagents and organic additives,which might introduce impurity phases and affect the biological results.In a previous study,a facile and novel method was utilized with ultrapure water as the unique reagent for hydrothermal treatment,and a uniform hydroxyapatite(HAp)surface layer was constructed on composite ceramics(β-TCP/CaSiO_(3))in situ.Further combined with 3D printing technology,biomimetic hierarchical structure scaffolds were fabricated with interconnected porous composite ceramic scaffolds as the architecture and micro/nano-rod hybrid HAp as the surface layer.The obtained HAp surface layer favoured cell adhesion,alleviated the cytotoxicity of precursor scaffolds,and upregulated the cellular differentiation of mBMSCs and gene expression of HUVECs in vitro.In vivo studies showed that capillary formation,bone augmentation and new bone matrix formation were upregulated after the HAp surface layer was obtained,and the results confirmed that the fabricated biomimetic hierarchical structure scaffold could be an effective candidate for bone regeneration.展开更多
Fibronectin(Fn)is significant to the performance of biomaterials,and the chemistry of biomaterial surface play important roles in Fn adsorption and subsequent cell behavior.However,the“molecular scale”mechanism is s...Fibronectin(Fn)is significant to the performance of biomaterials,and the chemistry of biomaterial surface play important roles in Fn adsorption and subsequent cell behavior.However,the“molecular scale”mechanism is still unclear.Herein,we combined experimental strategies with molecular simulations to solve this problem.We prepared self-assembled monolayers with varying chemistries,i.e.,SAMs-CH3,SAMs-NH2,SAMs-COOH and SAMs-OH,and characterized Fn adsorption and cell behaviors on them.Next,Monte Carlo method and all-atom molecular dynamics simulations were employed to reveal the orientation/conformation of Fn on surfaces.We found that SAMs-CH3 strongly adsorbed Fn via hydrophobic interactions,but show poor bioactivity as the low exposure of RGD/PHSRN motifs and the deformation of Fn.SAMs-NH2 and SAMs-COOH could adsorb Fn efficiently via vdW interactions,electrostatic interactions,hydrogen bonds and salt bridges.Fn exhibited excellent bioactivity for cell adhesion,proliferation and osteogenic differentiation as high exposure of bioactive motifs on SAMs-NH2,or as the activation of other inferior cell-binding motifs on SAMs-COOH.SAMs-OH showed poor Fn adsorption as the water film.However,the adsorbed Fn displayed non-negligible bioactivity due to high exposure of PHSRN motif and large degree of protein flexibility.We believe that the revealed mechanism presents great potential to rationally design Fn-activating biomaterials.展开更多
Genomic reassortment is an important evolutionary mechanism for influenza viruses.In this process,the novel viruses acquire new characteristics by the exchange of the intact gene segments among multiple influenza viru...Genomic reassortment is an important evolutionary mechanism for influenza viruses.In this process,the novel viruses acquire new characteristics by the exchange of the intact gene segments among multiple influenza virus genomes,which may cause flu endemics and epidemics within or even across hosts.Due to the safety and ethical limitations of the experimental studies on influenza virus reassortment,numerous computational researches on the influenza virus reassortment have been done with the explosion of the influenza virus genomic data.A great amount of computational methods and bioinformatics databases were developed to facilitate the identification of influenza virus reassortments.In this review,we summarized the progress and challenge of the bioinformatics research on influenza virus reassortment,which can guide the researchers to investigate the influenza virus reassortment events reasonably and provide valuable insight to develop the related computational identification tools.展开更多
Central to the core principle of cell theory,depicting cells'history,state and fate is a fundamental goal in modern biology.By leveraging clonal analysis and sin-gle-cell RNA-seq technologies,single-cell lineage t...Central to the core principle of cell theory,depicting cells'history,state and fate is a fundamental goal in modern biology.By leveraging clonal analysis and sin-gle-cell RNA-seq technologies,single-cell lineage trac-ing provides new opportunities to interrogate both cell states and lineage histories.During the past few years,many strategies to achieve lineage tracing at single-cell resolution have been developed,and three of them(in-tegration barcodes,polylox barcodes,and CRISPR barcodes)are noteworthy as they are amenable in experimentally tractable systems.Although the above strategies have been demonstrated in animal develop-ment and stem cell research,much care and effort are still required to implement these methods.Here we review the development of single-cell lineage tracing,major characteristics of the cell barcoding strategies,applications,as well as technical considerations and limitations,providing a guide to choose or improve the single-cell barcoding lineage tracing.展开更多
Understanding the pathological features of severe acute respiratory syn drome coronavirus 2(SARS-CoV-2)infect io n in an animal model is crucial for the treatment of coronavirus disease 2019(COVID-19).Here,we compared...Understanding the pathological features of severe acute respiratory syn drome coronavirus 2(SARS-CoV-2)infect io n in an animal model is crucial for the treatment of coronavirus disease 2019(COVID-19).Here,we compared imnnunopathological changes in young and old rhesus macaques(RMs)before and after SARS-CoV-2 infection at the tissue level.Quantitative analysis of multiplex immunofluoresce nee staining images of formali n-fixed paraffi n-embedded(FFPE)sections showed that SARS-CoV-2 infectio n specifically induced elevated levels of apoptosis,autophagy,and nuclear factor kappa-B(NF-kB)activation of angiotensirv convert!ng enzyme 2(ACE2)+cells,and increased interferon a(IFN-a)-and interleukin 6(IL-6)-secreting cells and C-X-C motif chemokine receptor 3(CXCR3)+cells in lung tissue of old RMs.This pathological pattern,which may be related to the age-related pro-inflammatory microenvironment in both lungs and spleens,was significantly correlated with the systemic accumulation of CXCR3+cells in lungs,spleens,and peripheral blood.Furthermore,the ratio of CXCR3+to T-box protein expression in T cell(T-bet)+(CXCR3+/T-bet+ratio)in CD8+cells may be used as a predictor of severe COVID-19.These findings uncovered the impact of aging on the immunopathology of early SARS-CoV-2 infection and demonstrated the potential application of CXCR3+cells in predicting severe COVID-19.展开更多
The COVID-19 pandemic poses a global threat to public health and economy.The continuously emerging SARS-CoV-2 variants present a major challenge to the development of antiviral agents and vaccines.In this study,we ide...The COVID-19 pandemic poses a global threat to public health and economy.The continuously emerging SARS-CoV-2 variants present a major challenge to the development of antiviral agents and vaccines.In this study,we identified that EK1 and cholesterol-coupled derivative of EK1,EK1C4,as pan-CoV fusion inhibitors,exhibit potent antiviral activity against SARS-CoV-2 infection in both lung-and intestine-derived cell lines(Calu-3 and Caco2,respectively).They are also effective against infection of pseudotyped SARS-CoV-2 variants B.1.1.7(Alpha)and B.l.1.248(Gamma)as well as those with mutations in S protein,including N417T,E484K,N501Y,and D614G,which are common in South African and Brazilian variants.Crystal structure revealed that EK1 targets the HR1 domain in the SARS-CoV-2 S protein to block virus-cell fusion and provide mechanistic insights into its broad and effective antiviral activity.Nasal administration of EK1 peptides to hACE2 transgenic mice significantly reduced viral titers in lung and intestinal tissues.EK1 showed good safety profiles in various animal models,supporting further clinical development of EK1-based pan-CoV fusion inhibitors against SARS-CoV-2 and its variants.展开更多
Background:Epigenetic modifications,namely non-coding RNAs,DNA methylation,and histone modifications such as methylation,phosphorylation,acetylation,ubiquitylation,and sumoylation play a significant role in brain deve...Background:Epigenetic modifications,namely non-coding RNAs,DNA methylation,and histone modifications such as methylation,phosphorylation,acetylation,ubiquitylation,and sumoylation play a significant role in brain development.DNA methyltransferases,methyl-CpG binding proteins,and ten-eleven translocation proteins facilitate the maintenance,interpretation,and removal of DNA methylation,respectively.Different forms of methylation,including 5-methylcytosine,5-hydroxymethylcytosine,and other oxidized forms,have been detected by recently developed sequencing technologies.Emerging evidence suggests that the diversity of DNA methylation patterns in the brain plays a key role in fine-tuning and coordinating gene expression in the development,plasticity,and disorders of the mammalian central nervous system.Neural stem cells(NSCs),originating from the neuroepithelium,generate neurons and glial cells in the central nervous system and contribute to brain plasticity in the adult mammalian brain.Main body:Here,we summarized recent research in proteins responsible for the establishment,maintenance,interpretation,and removal of DNA methylation and those involved in the regulation of the proliferation and differentiation of NSCs.In addition,we discussed the interactions of chemicals with epigenetic pathways to regulate NSCs as well as the connections between proteins involved in DNA methylation and human diseases.Conclusion:Understanding the interplay between DNA methylation and NSCs in a broad biological context can facilitate the related studies and reduce potential misunderstanding.展开更多
基金supported by the National Natural Science Foundation of China,Nos.81941011(to XL),31771053(to HD),31730030(to XL),31971279(to ZY),31900749(to PH),31650001(to XL),31320103903(to XL),31670988(to ZY)the Natural Science Foundation of Beijing,Nos.7222004(to HD)+1 种基金a grant from Ministry of Science and Technology of China,Nos.2017YFC1104002(to ZY),2017YFC1104001(to XL)a grant from Beihang University,No.JKF-YG-22-B001(to FH)。
文摘Attempts have been made to use cell transplantation and biomaterials to promote cell proliferation,differentiation,migration,and survival,as well as angiogenesis,in the context of brain injury.However,whether bioactive materials can repair the damage caused by ischemic stroke by activating endogenous neurogenesis and angiogenesis is still unknown.In this study,we applied chitosan gel loaded with basic fibroblast growth factor to the stroke cavity 7 days after ischemic stroke in rats.The gel slowly released basic fibroblast growth factor,which improved the local microenvironment,activated endogenous neural stem/progenitor cells,and recruited these cells to migrate toward the penumbra and stroke cavity and subsequently differentiate into neurons,while enhancing angiogenesis in the penumbra and stroke cavity and ultimately leading to partial functional recovery.This study revealed the mechanism by which bioactive materials repair ischemic strokes,thus providing a new strategy for the clinical application of bioactive materials in the treatment of ischemic stroke.
基金supported by the National Natural Science Foundation of ChinaNos.82272171 (to ZY),82271403 (to XL),31971279 (to ZY),81941011 (to XL),31730030 (to XL)。
文摘It has long been asserted that failure to recover from central nervous system diseases is due to the system's intricate structure and the regenerative incapacity of adult neurons.Yet over recent decades,numerous studies have established that endogenous neurogenesis occurs in the adult central nervous system,including humans'.This has challenged the long-held scientific consensus that the number of adult neurons remains constant,and that new central nervous system neurons cannot be created or renewed.Herein,we present a comprehensive overview of the alterations and regulatory mechanisms of endogenous neurogenesis following central nervous system injury,and describe novel treatment strategies that to rget endogenous neurogenesis and newborn neurons in the treatment of central nervous system injury.Central nervous system injury frequently results in alterations of endogenous neurogenesis,encompassing the activation,proliferation,ectopic migration,diffe rentiation,and functional integration of endogenous neural stem cells.Because of the unfavorable local microenvironment,most activated neural stem cells diffe rentiate into glial cells rather than neurons.Consequently,the injury-induced endogenous neurogenesis response is inadequate for repairing impaired neural function.Scientists have attempted to enhance endogenous neurogenesis using various strategies,including using neurotrophic factors,bioactive materials,and cell reprogramming techniques.Used alone or in combination,these therapeutic strategies can promote targeted migration of neural stem cells to an injured area,ensure their survival and diffe rentiation into mature functional neurons,and facilitate their integration into the neural circuit.Thus can integration re plenish lost neurons after central nervous system injury,by improving the local microenvironment.By regulating each phase of endogenous neurogenesis,endogenous neural stem cells can be harnessed to promote effective regeneration of newborn neurons.This offers a novel approach for treating central nervous system injury.
基金supported by PLA General Hospital Program,No.LB20201A010024(to LW).
文摘Neurotrophic keratopathy is a persistent defect of the corneal epithelium,with or without stromal ulceration,due to corneal nerve deficiency caused by a variety of etiologies.The treatment options for neurotrophic keratopathy are limited.In this study,an ophthalmic solution was constructed from a chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor(CTH-mNGF).Its effectiveness was evaluated in corneal denervation(CD)mice and patients with neurotrophic keratopathy.In the preclinical setting,CTH-mNGF was assessed in a murine corneal denervation model.CTH-mNGF was transparent,thermosensitive,and ensured sustained release of mNGF for over 20 hours on the ocular surface,maintaining the local mNGF concentration around 1300 pg/mL in vivo.Corneal denervation mice treated with CTH-mNGF for 10 days showed a significant increase in corneal nerve area and total corneal nerve length compared with non-treated and CTH treated mice.A subsequent clinical trial of CTH-mNGF was conducted in patients with stage 2 or 3 neurotrophic keratopathy.Patients received topical CTH-mNGF twice daily for 8 weeks.Fluorescein sodium images,Schirmer’s test,intraocular pressure,Cochet-Bonnet corneal perception test,and best corrected visual acuity were evaluated.In total,six patients(total of seven eyes)diagnosed with neurotrophic keratopathy were enrolled.After 8 weeks of CTH-mNGF treatment,all participants showed a decreased area of corneal epithelial defect,as stained by fluorescence.Overall,six out of seven eyes had fluorescence staining scores<5.Moreover,best corrected visual acuity,intraocular pressure,Schirmer’s test and Cochet-Bonnet corneal perception test results showed no significant improvement.An increase in corneal nerve density was observed by in vivo confocal microscopy after 8 weeks of CTH-mNGF treatment in three out of seven eyes.This study demonstrates that CTH-mNGF is transparent,thermosensitive,and has sustained-release properties.Its effectiveness in healing corneal epithelial defects in all eyes with neurotrophic keratopathy suggests CTH-mNGF has promising application prospects in the treatment of neurotrophic keratopathy,being convenient and cost effective.
基金supported by the National Natural Science Foundation of China,Nos.82071386 (to JS),81870982 (to JS)&81571182 (to JS)the National Key Basic Research Program of China,No.2014CB542202 (to JS)+3 种基金the Program for Changjiang Scholars and Innovative Research Team in University of China,No.IRT-16R37 (to JS)Key Research&Development Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory of China,No.2018GZR110104008 (to HZ)Research Grant of Guangdong Province Key Laboratory of Psychiatric Disorders of China,No.N201904 (to JS)Natural Science Foundation of Guangdong Province of China,No.2017A030312009 (to JS)。
文摘Wallerian degeneration,the progressive disintegration of distal axons and myelin that occurs after peripheral nerve injury,is essential for creating a permissive microenvironment for nerve regeneration,and involves cytoskeletal reconstruction.However,it is unclear whether microtubule dynamics play a role in this process.To address this,we treated cultured sciatic nerve explants,an in vitro model of Wallerian degeneration,with the microtubule-targeting agents paclitaxel and nocodazole.We found that paclitaxel-induced microtubule stabilization promoted axon and myelin degeneration and Schwann cell dedifferentiation,whereas nocodazole-induced microtubule destabilization inhibited these processes.Evaluation of an in vivo model of peripheral nerve injury showed that treatment with paclitaxel or nocodazole accelerated or attenuated axonal regeneration,as well as functional recovery of nerve conduction and target muscle and motor behavior,respectively.These results suggest that microtubule dynamics participate in peripheral nerve regeneration after injury by affecting Wallerian degeneration.This study was approved by the Animal Care and Use Committee of Southern Medical University,China(approval No.SMUL2015081) on October 15,2015.
基金supported by the National Natural Science Foundation of China,Nos.82272171(to ZY),82271403(to XL),81941011(to XL),31971279(to ZY),31730030(to XL)the Natural Science Foundation of Beijing,No.7222004(to HD).
文摘The presence of endogenous neural stem/progenitor cells in the adult mammalian brain suggests that the central nervous system can be repaired and regenerated after injury.However,whether it is possible to stimulate neurogenesis and reconstruct cortical layers II to VI in non-neurogenic regions,such as the cortex,remains unknown.In this study,we implanted a hyaluronic acid collagen gel loaded with basic fibroblast growth factor into the motor cortex immediately following traumatic injury.Our findings reveal that this gel effectively stimulated the proliferation and migration of endogenous neural stem/progenitor cells,as well as their differentiation into mature and functionally integrated neurons.Importantly,these new neurons reconstructed the architecture of cortical layers II to VI,integrated into the existing neural circuitry,and ultimately led to improved brain function.These findings offer novel insight into potential clinical treatments for traumatic cerebral cortex injuries.
基金supported by the National Natural Science Foundation of China,Nos.31900825(to SL),31922030(to CRR),31771170(to CRR)Science and Technology Program of Guangdong Province of China,No.2018B030334001(to CRR)+3 种基金Science and Techology of Guangzhou of China,No.202007030012(to CRR)Guangdong Special Support Program of China,No.2017TQ04R173(to CRR)Pearl River S&T Nova Program of Guangzhou Province of China,No.201806010198(to CRR)Outstanding Scholar Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory of China,No.2018GZR110102002(to KFS)。
文摘Previous studies have shown that Lycium barbarum polysaccharide,the main active component of Lycium barbarum,exhibits antiinflammatory and antioxidant effects in treating neurological diseases.However,the therapeutic action of Lycium barbarum polysaccharide on depression has not been studied.In this investigation,we established mouse models of depression using aversive stimuli including exposure to fox urine,air puff and foot shock and physical restraint.Concurrently,we administered 5 mg/kg per day Lycium barbarum polysaccharide-glycoprotein to each mouse intragastrically for the 28 days.Our results showed that long-term exposure to aversive stimuli significantly enhanced depressive-like behavior evaluated by the sucrose preference test and the forced swimming test and increased anxietylike behaviors evaluated using the open field test.In addition,aversive stimuli-induced depressed mice exhibited aberrant neuronal activity in the lateral habenula.Importantly,concurrent Lycium barbarum polysaccharide-glycoprotein treatment significantly reduced these changes.These findings suggest that Lycium barbarum polysaccharide-glycoprotein is a potential preventative intervention for depression and may act by preventing aberrant neuronal activity and microglial activation in the lateral habenula.The study was approved by the Jinan University Institutional Animal Care and Use Committee(approval No.20170301003)on March 1,2017.
基金the National Natural Science Foundation of China,No.82071372(to AL)the Natural Science Foundation of Guangdong Province of China,No.2021A1515011231(to AL)+1 种基金Outstanding Scholar Program of Bioland Laboratory(Guangzhou Regenerative Medicine and Health Guangdong Laboratory)of China,No.2018GZR110102002(to KFS and AL)Science and Technology Program of Guangzhou of China,No.202007030012(to KFS and AL).
文摘Age-related neurodegenerative disorders such as Alzheimer’s disease(AD)have become a critical public health issue due to the significantly extended human lifespan,leading to considerable economic and social burdens.Traditional therapies for AD such as medicine and surgery remain ineffective,impractical,and expensive.Many studies have shown that a variety of bioactive substances released by physical exercise(called“exerkines”)help to maintain and improve the normal functions of the brain in terms of cognition,emotion,and psychomotor coordination.Increasing evidence suggests that exerkines may exert beneficial effects in AD as well.This review summarizes the neuroprotective effects of exerkines in AD,focusing on the underlying molecular mechanism and the dynamic expression of exerkines after physical exercise.The findings described in this review will help direct research into novel targets for the treatment of AD and develop customized exercise therapy for individuals of different ages,genders,and health conditions.
基金funded by the National Natural Science Foundation of China(31930025,31922018,and 3227073)the National Key Research and Development Program of China(2021YFA0804802 and 2018YFA0801104)X.L.was supported by the IDG/McGovern Institute for Brain Research at Tsinghua University.
文摘Microtubule networks support many cellular processes and exhibit a highly ordered architecture.However,due to the limited axial resolution of conventional light microscopy,the structural features of these networks cannot be resolved in three-dimensional(3D)space.Here,we used customized ultra-high-resolution interferometric single-molecule localization microscopy to characterize the microtubule networks in Caco2 cells.We found that the calmodulin-regulated spectrin-associated proteins(CAMSAPs)localize at a portion of microtubule intersections.Further investigation showed that depletion of CAMSAP2 and CAMSAP3 leads to the narrowing of the inter-microtubule distance.Mechanistically,CAMSAPs recognize microtubule defects,which often occur near microtubule intersections,and then recruit katanin to remove the damaged microtubules.Therefore,the CAMSAP–katanin complex is a regulatory module for the distance between microtubules.Taken together,our results characterize the architecture of cellular microtubule networks in high resolution and provide molecular insights into how the 3D structure of microtubule networks is controlled.
基金supported by grants from Beijing Advanced Innovation Center for Genomics(ICG),supported by grants from the National Natural Science Foundation of China(No.81672361)supported by grants from the National Natural Science Foundation of China(No.32100672).
文摘Molecular knowledge of human gastric corpus epithelium remains incomplete.Here,by integrated analyses using single-cell RNA sequencing(scRNA-seq),spatial transcriptomics,and single-cell assay for transposase accessible chromatin sequencing(scATAC-seq)techniques,we uncovered the spatially resolved expression landscape and gene-regulatory network of human gastric corpus epithelium.Specifically,we identified a stem/progenitor cell population in the isthmus of human gastric corpus,where EGF and WNT signaling pathways were activated.Meanwhile,LGR4,but not LGR5,was responsible for the activation of WNT signaling pathway.Importantly,FABP5 and NME1 were identified and validated as crucial for both normal gastric stem/progenitor cells and gastric cancer cells.Finally,we explored the epigenetic regulation of critical genes for gastric corpus epithelium at chromatin state level,and identified several important cell-type-specific transcription factors.In summary,our work provides novel insights to systematically understand the cellular diversity and homeostasis of human gastric corpus epithelium in vivo.
基金supported by grants from the National Key R&D Program of China(2020YFA0113300 to M.W.,2018YFA0107601 to F.T.,2019YFA0801802 to M.W.,2022YFA0806300 to X.-Y.Z.)the National Natural Science Foundation of China(82071711 to X.-Y.Z.,32170866 to M.W.,U22A20278 to X.-Y.Z.)+2 种基金Key Research&Development Program of Bioland Laboratory(Guangzhou Regenerative Medicine and Health Guangdong Laboratory)(2018GZR110104002 to X.-Y.Z.)Guangdong Basic and Applied Basic Research Foundation(2021A1515010802 to M.W.)National Demonstration Center for Experimental Education of Basic Medical Sciences(Southerm Medical University).
文摘Although somatic cells can be reprogrammed to pluripotent stem cells(PsCs)with pure chemicals,authentic pluripotency of chemically induced pluripotent stem celis(CipsCs)has never been achieved through tetraploid complementation assay.Spontaneous reprogramming of spermatogonial stem cells(ssCs)was another non-transgenic way to obtain PsCs,but this process lacks mechanistic explanation.Here,we reconstructed the trajectory of mouse SsC reprogramming and developed a five-chemical combination,boosting the reprogramming effciency by nearly 80-to 100-folds.More importantly,chemical induced germline-derived PsCs(5C-gPSCs),but not gpsCs and chemical induced pluripotent stem cells,had authentic pluripotency,as determined by tetraploid complementation.Mechanistically,ssCs traversed through an inverted pathway of in vivo germ ceil development,exhibiting the expression signatures and DNA methylation dynamics from spermatogonia to primordial germ cells and further to epiblasts.Besides,ssC-specific imprinting control regions switched from biallelic methylated states to monoallelic methylated states by imprinting demethylation and then re-methylation on one of the two alleles in 5c-gPsCs,which was apparently distinct with the imprinting reprogramming in vivo as DNA methylation simultaneously occurred on both alleles.Our work sheds ight on the unique regulatory network underpinning SsC reprogramming,providing insights to understand generic mechanisms for cell-fate decision and epigenetic-relateddisorders in regenerative medicine.
基金We thank for Beijing Key Laboratory of Ophthalmology and Visual Science,School of Ophthalmology,Capital Medical University for measuring F-VEP.We thank technicians in the Core Facility Center of Capital Medical University.This work was supported by the National Natural Science Foundation of China(Grants 81941011,31730030,31971279,31900749,31771053)and Ministry of Science and Technology of China(Grants 2017YFC1104002,2017YFC1104001)+2 种基金Beijing Science and Technology Program(Grant Z181100001818007)National Natural Science Foundation of China(Grants 31650001,31320103903,31670988)Beijing Natural Science Foundation(Grant 7214301).
文摘Dear Editor,The optic nerve,which belongs to the central nervous system(CNS),cannot regenerate when injured in adult mammals.1 Up to now,no readily translatable measures are available for repairing a severely injured optic nerve.Herein we demonstrated that ciliary neurotrophic factor(CNTF)-chitosan enabled the reconstruction and functional recovery of the adult rat visual system,thus shedding light on the clinical potential for repairing the severely injured optic nerve.
基金This work was supported by grants from National Natural Science Foundation of China(Grant Nos.82070002,82072329,81872511,and 81670093)Frontier Research Program of Bioland Laboratory(Guangzhou Regenerative Medicine and Health Guangdong Laboratory)(2018GZR110105005)+6 种基金National Science and Technology Major Project(2018ZX10301101)the Natural Science Foundation of Guangdong Province(2018A030313455)the Program of Department of Science and Technology of Guangdong Province(2014B020212018)National Key Research and Development Project(2018YFA0507201)the special project for COVID-19 of Guangzhou Regenerative Medicine and Health Guangdong Labo・ratory(2020GZR110106006)the emergency grants for prevention and control of SARS-CoV-2 of Guangdong province(2020B111108001)National Postdoctoral Program for Innovative Talent(BX20190089).
文摘The coronavirus disease 2019(COVID-19)pandemic is caused by infection with the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which is spread primary via respiratory droplets and infects the lungs.Currently widely used cell lines and animals are unable to accurately mimic human physiological conditions because of the abnormal status of cell lines(transformed or cancer cells)and species differences between animals and humans.Organoids are stem cell-derived selforganized three-dimensional culture in vitro and model the physiological conditions of natural organs.Here we showed that SARS-CoV-2 infected and extensively replicated in human embryonic stem cells(hESCs)-derived lung organoids,including airway and alveolar organoids which covered the complete infection and spread route for SARS-CoV-2 within lungs.The infected ceils were ciliated,club,and alveolar type 2(AT2)cells,which were sequentially located from the proximal to the distal airway and terminal alveoli,respectively.Additionally,RNA-seq revealed early cell response to virus infection including an unexpected downregulation of the metabolic processes,especially lipid metabolism,in addition to the well-known upregulation of immune response.Further,Remdesivir and a human neutralizing antibody potently inhibited SARS-CoV-2 replication in lung organoids.Therefore,human lung organoids can serve as a pathophysiological model to investigate the underlying mechanism of SARS-CoV-2 infection and to discover and test therapeutic drugs for COVID-19.
基金the National Key Research and Development Program of China(2017YFA0105103,2021YFA0805903)the National Natural Science Foundation of China(81941004,32170542)+10 种基金2020 Research Program of Sanya Yazhou Bay Science and Technology City(202002011)Major Science and Technology Projects of Hainan Province(ZDKJ2021030)Key Research&Development Program of Hainan Province(ZDYF2021SHFZ052)Youth Innovation Promotion Association of the Chinese Academy of Sciences(2019347)Young Elite Scientist Sponsorship Program by CAST(YESS20200024)Biological Resources Progaramme,Chinese Academy of Sciences(KFJBRP-017-57)Key Research&Development Program of Bioland Laboratory(Guangzhou Regenerative Medicine and Health Guangdong Laboratory)(2018GZR110104004)China Postdoctoral Science Foundation(2020M682943)Science and Technology Planning Project of Guangdong Province,China(2019A030317010,2020B1212060052,2021B1212040016,2021A1515011110)Science and Technology Program of Guangzhou,China(202007030003)Research Unit of Generation of Large Animal Disease Models,Chinese Academy of Medical Sciences(2019-I2M-5-025)。
文摘Inducible expression systems are indispensable for precise regulation and in-depth analysis of biological process.Binary Tet-On system has been widely employed to regulate transgenic expression by doxycycline.Previous pig models with tetracycline regulatory elements were generated through random integration.This process often resulted in uncertain expression and unpredictable phenotypes,thus hindering their applications.Here,by precise knock-in of binary Tet-On 3G elements into Rosa26 and Hipp11 locus,respectively,a double knock-in reporter pig model was generated.We characterized excellent properties of this system for controllable transgenic expression both in vitro and in vivo.Two att P sites were arranged to flank the td Tomato to switch reporter gene.Single or multiple gene replacement was efficiently and faithfully achieved in fetal fibroblasts and nuclear transfer embryos.To display the flexible application of this system,we generated a pig strain with Dox-inducing h KRASexpression through phiC31 integrase-mediated cassette exchange.After eight months of Dox administration,squamous cell carcinoma developed in the nose,mouth,and scrotum,which indicated this pig strain could serve as an ideal large animal model to study tumorigenesis.Overall,the established pig models with controllable and switchable transgene expression system will provide a facilitating platform for transgenic and biomedical research.
基金financially supported by the National key research and development plan(Grant No.2017YFC1105000,Grant No.2017YFA0205600)Outstanding Scholar Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory(2018GZR110102001)+4 种基金the Science and Technology Program of Guangdong Province(Grant No.2019B010941002)the Science and Technology Program of Guangzhou(Grant No.201804020060,Grant No.202007020002)Natural Science Foundation of Guangdong Province(Grant No.2021A1515011741,2020A1515011354)the National Nature Science Foundation of China(Grants U1801252),National Natural Science Foundation of China(31700823)Guangzhou Science and Technology Planning Project(202102020005).
文摘Calcium phosphate bio-ceramics are osteo-conductive,but it remains a challenge to promote the induction of bone augmentation and capillary formation.The surface micro/nano-topography of materials can be recognized by cells and then the cell fate are mediated.Traditional regulation methods of carving surface structures on bio-ceramics employ mineral reagents and organic additives,which might introduce impurity phases and affect the biological results.In a previous study,a facile and novel method was utilized with ultrapure water as the unique reagent for hydrothermal treatment,and a uniform hydroxyapatite(HAp)surface layer was constructed on composite ceramics(β-TCP/CaSiO_(3))in situ.Further combined with 3D printing technology,biomimetic hierarchical structure scaffolds were fabricated with interconnected porous composite ceramic scaffolds as the architecture and micro/nano-rod hybrid HAp as the surface layer.The obtained HAp surface layer favoured cell adhesion,alleviated the cytotoxicity of precursor scaffolds,and upregulated the cellular differentiation of mBMSCs and gene expression of HUVECs in vitro.In vivo studies showed that capillary formation,bone augmentation and new bone matrix formation were upregulated after the HAp surface layer was obtained,and the results confirmed that the fabricated biomimetic hierarchical structure scaffold could be an effective candidate for bone regeneration.
基金This work was financially supported by National key R&D Program of China(2018YFC1105402,2017YFC1104402,2017YFC1105000)National Natural Science Foundation of China(31700823,U1801252,31771027)+6 种基金Natural Science Foundation of Guangdong Province of China(2020A1515011354,2017A030310335)Science and Technology Program of Guangzhou(201804020060)the Guangdong Natural Science Funds for Distinguished Young Scholars(2019B151502029)the Pearl River Nova Program of Guangzhou(201806010156)Outstanding Scholar Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory(2018GZR110102001)the Fundamental Research Funds for the Central UniversitiesL.W.thanks the Funds for Young Pearl River Scholars.
文摘Fibronectin(Fn)is significant to the performance of biomaterials,and the chemistry of biomaterial surface play important roles in Fn adsorption and subsequent cell behavior.However,the“molecular scale”mechanism is still unclear.Herein,we combined experimental strategies with molecular simulations to solve this problem.We prepared self-assembled monolayers with varying chemistries,i.e.,SAMs-CH3,SAMs-NH2,SAMs-COOH and SAMs-OH,and characterized Fn adsorption and cell behaviors on them.Next,Monte Carlo method and all-atom molecular dynamics simulations were employed to reveal the orientation/conformation of Fn on surfaces.We found that SAMs-CH3 strongly adsorbed Fn via hydrophobic interactions,but show poor bioactivity as the low exposure of RGD/PHSRN motifs and the deformation of Fn.SAMs-NH2 and SAMs-COOH could adsorb Fn efficiently via vdW interactions,electrostatic interactions,hydrogen bonds and salt bridges.Fn exhibited excellent bioactivity for cell adhesion,proliferation and osteogenic differentiation as high exposure of bioactive motifs on SAMs-NH2,or as the activation of other inferior cell-binding motifs on SAMs-COOH.SAMs-OH showed poor Fn adsorption as the water film.However,the adsorbed Fn displayed non-negligible bioactivity due to high exposure of PHSRN motif and large degree of protein flexibility.We believe that the revealed mechanism presents great potential to rationally design Fn-activating biomaterials.
基金This work was supported by the National Natural Science Foundation of China(31801101 to X.D.,31671371,32070678 to T.J.)the CAMS Initiative for Innovative Medicine(CAMS-I2M,2016-I2M-1-005,2020-I2M-2-003 to T.J.)。
文摘Genomic reassortment is an important evolutionary mechanism for influenza viruses.In this process,the novel viruses acquire new characteristics by the exchange of the intact gene segments among multiple influenza virus genomes,which may cause flu endemics and epidemics within or even across hosts.Due to the safety and ethical limitations of the experimental studies on influenza virus reassortment,numerous computational researches on the influenza virus reassortment have been done with the explosion of the influenza virus genomic data.A great amount of computational methods and bioinformatics databases were developed to facilitate the identification of influenza virus reassortments.In this review,we summarized the progress and challenge of the bioinformatics research on influenza virus reassortment,which can guide the researchers to investigate the influenza virus reassortment events reasonably and provide valuable insight to develop the related computational identification tools.
基金supported in part by National Key R&D Program of China(2018YFA0801402,2018YFA0107200)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16020404)+3 种基金Guangdong Basic and Applied Basic Research Foundation(2019B151502054)Frontier Research Program of Bioland Laboratory(Guangzhou Regenerative Medicine and Health Guangdong Laboratory,2018GZR110105013)Jiazi Research Innovative Project of Bioland Laboratory(2019GZR110108001)Science and Technology Planning Project of Guangdong Province(2020B1212060052).
文摘Central to the core principle of cell theory,depicting cells'history,state and fate is a fundamental goal in modern biology.By leveraging clonal analysis and sin-gle-cell RNA-seq technologies,single-cell lineage trac-ing provides new opportunities to interrogate both cell states and lineage histories.During the past few years,many strategies to achieve lineage tracing at single-cell resolution have been developed,and three of them(in-tegration barcodes,polylox barcodes,and CRISPR barcodes)are noteworthy as they are amenable in experimentally tractable systems.Although the above strategies have been demonstrated in animal develop-ment and stem cell research,much care and effort are still required to implement these methods.Here we review the development of single-cell lineage tracing,major characteristics of the cell barcoding strategies,applications,as well as technical considerations and limitations,providing a guide to choose or improve the single-cell barcoding lineage tracing.
基金supported by the National Key Research and Development Program of China(2020YFC0842000,2020YFC0847000).
文摘Understanding the pathological features of severe acute respiratory syn drome coronavirus 2(SARS-CoV-2)infect io n in an animal model is crucial for the treatment of coronavirus disease 2019(COVID-19).Here,we compared imnnunopathological changes in young and old rhesus macaques(RMs)before and after SARS-CoV-2 infection at the tissue level.Quantitative analysis of multiplex immunofluoresce nee staining images of formali n-fixed paraffi n-embedded(FFPE)sections showed that SARS-CoV-2 infectio n specifically induced elevated levels of apoptosis,autophagy,and nuclear factor kappa-B(NF-kB)activation of angiotensirv convert!ng enzyme 2(ACE2)+cells,and increased interferon a(IFN-a)-and interleukin 6(IL-6)-secreting cells and C-X-C motif chemokine receptor 3(CXCR3)+cells in lung tissue of old RMs.This pathological pattern,which may be related to the age-related pro-inflammatory microenvironment in both lungs and spleens,was significantly correlated with the systemic accumulation of CXCR3+cells in lungs,spleens,and peripheral blood.Furthermore,the ratio of CXCR3+to T-box protein expression in T cell(T-bet)+(CXCR3+/T-bet+ratio)in CD8+cells may be used as a predictor of severe COVID-19.These findings uncovered the impact of aging on the immunopathology of early SARS-CoV-2 infection and demonstrated the potential application of CXCR3+cells in predicting severe COVID-19.
基金This work was supported by the National Natural Science Foundation of China(81822045 and 82041036 to L.L.,82041025 and 81630090 to SJ.,32071187 to Y.Z.,21877127 to C.W.,82002142 to S.X.)Strategic Priority Research Program of Chinese Academy of Sciences(XDB 37040102 to F.S.)+3 种基金National Key Project for Infectious Diseases of China(2017ZX10202202,2018ZX10301208 to Y.X.)Program of Shanghai Academic/Technology Research Leader(20XD1420300 to L.L.)Shanghai Municipal Education Commission(2017-01-07-00-07-E00057 to Y.X)F.K.and J.M.are supported by the German Research Foundation(CRC 1279).
文摘The COVID-19 pandemic poses a global threat to public health and economy.The continuously emerging SARS-CoV-2 variants present a major challenge to the development of antiviral agents and vaccines.In this study,we identified that EK1 and cholesterol-coupled derivative of EK1,EK1C4,as pan-CoV fusion inhibitors,exhibit potent antiviral activity against SARS-CoV-2 infection in both lung-and intestine-derived cell lines(Calu-3 and Caco2,respectively).They are also effective against infection of pseudotyped SARS-CoV-2 variants B.1.1.7(Alpha)and B.l.1.248(Gamma)as well as those with mutations in S protein,including N417T,E484K,N501Y,and D614G,which are common in South African and Brazilian variants.Crystal structure revealed that EK1 targets the HR1 domain in the SARS-CoV-2 S protein to block virus-cell fusion and provide mechanistic insights into its broad and effective antiviral activity.Nasal administration of EK1 peptides to hACE2 transgenic mice significantly reduced viral titers in lung and intestinal tissues.EK1 showed good safety profiles in various animal models,supporting further clinical development of EK1-based pan-CoV fusion inhibitors against SARS-CoV-2 and its variants.
基金This work was supported by the Guangzhou Key Area Research and Development Project,No.202007030003the National Natural Science Foundation of China,No.U1601228,81901288 and 31671475+5 种基金the Strategic Priority Research Program of Chinese Academy of Sciences,No.XDA16010305the Natural Science Foundation of Guangdong Province,No.2017A030313786the Key Research Program of Frontier Sciences of Chinese Academy of Sciences,No.QYZDB-SSW-SMC031the International Partnership Program of Chinese Academy of Sciences,No.154144KYSB20190034the Key Research&Development Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory,No.2018GZR110104008the Science and Technology Planning Project of Guangdong Province,No.2017B030314056.
文摘Background:Epigenetic modifications,namely non-coding RNAs,DNA methylation,and histone modifications such as methylation,phosphorylation,acetylation,ubiquitylation,and sumoylation play a significant role in brain development.DNA methyltransferases,methyl-CpG binding proteins,and ten-eleven translocation proteins facilitate the maintenance,interpretation,and removal of DNA methylation,respectively.Different forms of methylation,including 5-methylcytosine,5-hydroxymethylcytosine,and other oxidized forms,have been detected by recently developed sequencing technologies.Emerging evidence suggests that the diversity of DNA methylation patterns in the brain plays a key role in fine-tuning and coordinating gene expression in the development,plasticity,and disorders of the mammalian central nervous system.Neural stem cells(NSCs),originating from the neuroepithelium,generate neurons and glial cells in the central nervous system and contribute to brain plasticity in the adult mammalian brain.Main body:Here,we summarized recent research in proteins responsible for the establishment,maintenance,interpretation,and removal of DNA methylation and those involved in the regulation of the proliferation and differentiation of NSCs.In addition,we discussed the interactions of chemicals with epigenetic pathways to regulate NSCs as well as the connections between proteins involved in DNA methylation and human diseases.Conclusion:Understanding the interplay between DNA methylation and NSCs in a broad biological context can facilitate the related studies and reduce potential misunderstanding.
