Major depressive disorder(MDD)is a prevalent psychiatric disease that involves malfunctions of different cell types in the brain.Accumulating studies started to reveal that microglia,the primary resident immune cells,...Major depressive disorder(MDD)is a prevalent psychiatric disease that involves malfunctions of different cell types in the brain.Accumulating studies started to reveal that microglia,the primary resident immune cells,play an important role in the development and progression of depression.Microglia respond to stress-triggered neuroinflammation,and through the release of proinflammatory cytokines and their metabolic products,microglia may modulate the function of neurons and astrocytes to regulate depression.In this review,we focused on the role of microglia in the etiology of depression.We discussed the dynamic states of microglia;the correlative and causal evidence of microglial abnormalities in depression;possible mechanisms of how microglia sense depression-related stress and modulate depression state;and how antidepressive therapies affect microglia.Understanding the role of microglia in depression may shed light on developing new treatment strategies to fight against this devastating mental illness.展开更多
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
Reproductive biology is a uniquely important topic since it is about germ cells, which are central for transmitting genetic information from generation to generation. In this review, we discuss recent advances in mamm...Reproductive biology is a uniquely important topic since it is about germ cells, which are central for transmitting genetic information from generation to generation. In this review, we discuss recent advances in mammalian germ cell development,including preimplantation development, fetal germ cell development and postnatal development of oocytes and sperm. We also discuss the etiologies of female and male infertility and describe the emerging technologies for studying reproductive biology such as gene editing and single-cell technologies.展开更多
With the current limited drug therapy for the core symptoms of autism spectrum disorder(ASD),we herein report a randomized,double-blind,placebo-controlled trial to investigate the efficacy,safety,and potential neural ...With the current limited drug therapy for the core symptoms of autism spectrum disorder(ASD),we herein report a randomized,double-blind,placebo-controlled trial to investigate the efficacy,safety,and potential neural mechanism of bumetanide in children with ASD aged 3-6 years old.A total of 120 children were enrolled into the study and randomly assigned to either 0.5 mg bumetanide or placebo.In the final sample,119 children received at least one dose of bumetanide(59 children) or placebo(60 children) were included in the final analysis.The primary outcome was a reduction in the Childhood Autism Rating Scale(CARS) score,and the secondary outcomes were the Clinical Global Impressions Scale(CGI)-Global Improvement(CGI-I) score at 3 months and the change from baseline to 3-month in the Autism Diagnostic Observation Schedule(ADOS).Magnetic resonance spectroscopy(MRS) was used to measure y-aminobutyric acid(GABA) and glutamate neurotransmitter concentrations in the insular cortex(IC) before and after the treatment.As compared with the placebo,bumetanide treatment was significantly better in reducing the severity.No patient withdrew from the trial due to adverse events.The superiority of bumetanide to placebo in reducing insular GABA,measured using MRS,was demonstrated.The clinical improvement was associated with a decrease in insular GABA in the bumetanide group.In conclusion,this trial in a large group of young children with predominantly moderate and severe ASD demonstrated that bumetanide is safe and effective in improving the core symptoms of ASD.However,the clinical significance remains uncertain,and future multi-center clinical trials are required to replicate these findings and confirm the clinical significance using a variety of outcome measures.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
An electroencephalographic(EEG)signature of auditory hallucinations(AHs)is important for facilitating the diagnosis and treatment of AHs in schizophrenia.We recorded EEG from 25 schizophrenia patients with recurrent A...An electroencephalographic(EEG)signature of auditory hallucinations(AHs)is important for facilitating the diagnosis and treatment of AHs in schizophrenia.We recorded EEG from 25 schizophrenia patients with recurrent AHs.During the period of AHs,EEG recordings exhibited significantly elevated beta2-band power in the temporal region,as compared to those recorded in the absence of AHs or during stimulation with verbal sounds.We further generated methamphetamine-treated rhesus monkeys exhibiting psychosis-like behaviors,including repetitive sudden searching actions in the absence of external intrusion,suggesting the occurrence of AHs.Epidural EEG beta2-band power in the temporal region of these monkeys was enhanced immediately after methamphetamine treatment and positively correlated with the frequency of sudden searching actions.Thus,the enhancement of temporal beta2-band oscillations represents a signature for AHs in both patients and a monkey model of psychosis,and this monkey model can be used for developing closed-loop neuromodulation approaches for the treatment of refractory AHs in schizophrenia.展开更多
Hearing loss is one of the most common sensory disorders worldwide,affecting approximately 466 million people,including 34 million children[1].Genetic mutations accounts for approximately 60%of inherited hearing loss ...Hearing loss is one of the most common sensory disorders worldwide,affecting approximately 466 million people,including 34 million children[1].Genetic mutations accounts for approximately 60%of inherited hearing loss cases[2,3].These genetic changes result in a wide variety of clinical manifestations,ranging from nonsyndromic hearing loss(NSHL)to over 400 syndromes involving hearing loss and from mild adult-onset hearing loss to profound congenital deafness,covering the entire spectrum of Mendelian inheritance.展开更多
All animals possess a plethora of innate behaviors that do not require extensive learning and are fundamental for their survival and propagation.With the advent of newly-developed techniques such as viral tracing and ...All animals possess a plethora of innate behaviors that do not require extensive learning and are fundamental for their survival and propagation.With the advent of newly-developed techniques such as viral tracing and optogenetic and chemogenetic tools,recent studies are gradually unraveling neural circuits underlying different innate behaviors.Here,we summarize current development in our understanding of the neural circuits controlling predation,feeding,male-typical mating,and urination,highlighting the role of genetically defined neurons and their connections in sensory triggering,sensory to motor/motivation transformation,motor/motivation encoding during these different behaviors.Along the way,we discuss possible mechanisms underlying binge-eating disorder and the pro-social effects of the neuropeptide oxytocin,elucidating the clinical relevance of studying neural circuits underlying essential innate functions.Finally,we discuss some exciting brain structures recurrently appearing in the regulation of different behaviors,which suggests both divergence and convergence in the neural encoding of specific innate behaviors.Going forward,we emphasize the importance of multi-angle and cross-species dissections in delineating neural circuits that control innate behaviors.展开更多
Autism spectrum disorder(ASD)is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and repetitive behaviors.Although hundreds of ASD risk genes,implicated in synaptic forma...Autism spectrum disorder(ASD)is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and repetitive behaviors.Although hundreds of ASD risk genes,implicated in synaptic formation and transcriptional regulation,have been identified through human genetic studies,the East Asian ASD cohorts are still under-represented in genome-wide genetic studies.Here,we applied whole-exome sequencing to 369 ASD trios including probands and unaffected parents of Chinese origin.Using a joint-calling analytical pipeline based on GATK toolkits,we identified numerous de novo mutations including 55 high-impact variants and 165 moderate-impact variants,as well as de novo copy number variations containing known ASD-related genes.Importantly,combined with single-cell sequencing data from the developing human brain,we found that the expression of genes with de novo mutations was specifically enriched in the pre-,post-central gyrus(PRC,PC)and banks of the superior temporal(BST)regions in the human brain.By further analyzing the brain imaging data with ASD and healthy controls,we found that the gray volume of the right BST in ASD patients was significantly decreased compared to healthy controls,suggesting the potential structural deficits associated with ASD.Finally,we found a decrease in the seed-based functional connectivity between BST/PC/PRC and sensory areas,the insula,as well as the frontal lobes in ASD patients.This work indicated that combinatorial analysis with genome-wide screening,single-cell sequencing,and brain imaging data reveal the brain regions contributing to the etiology of ASD.展开更多
Defensive behaviors induced by innate fear or Pavlovian fear conditioning are crucial for animals to avoid threats and ensure survival.The zona incerta(ZI)has been demonstrated to play important roles in fear learning...Defensive behaviors induced by innate fear or Pavlovian fear conditioning are crucial for animals to avoid threats and ensure survival.The zona incerta(ZI)has been demonstrated to play important roles in fear learning and fear memory,as well as modulating auditory-induced innate defensive behavior.However,whether the neuronal subtypes in the ZI and specific circuits can mediate the innate fear response is largely unknown.Here,we found that somatostatin(SST)-positive neurons in the rostral ZI of mice were activated by a visual innate fear stimulus.Optogenetic inhibition of SST-positive neurons in the rostral ZI resulted in reduced flight responses to an overhead looming stimulus.Optogenetic activation of SST-positive neurons in the rostral ZI induced fear-like defensive behavior including increased immobility and bradycardia.In addition,we demonstrated that manipulation of the GABAergic projections from SST-positive neurons in the rostral ZI to the downstream nucleus reuniens(Re)mediated fear-like defensive behavior.Retrograde trans-synaptic tracing also revealed looming stimulus-activated neurons in the superior colliculus(SC)that projected to the Re-projecting SST-positive neurons in the rostral ZI(SC-ZIrSST-Re pathway).Together,our study elucidates the function of SST-positive neurons in the rostral ZI and the SC-ZIrSST-Re tri-synaptic circuit in mediating the innate fear response.展开更多
Understanding gene expression variations between species is pivotal for deciphering the evolutionary diversity in phenotypes. Rhesus macaques(Macaca mulatta, MMU)and crab-eating macaques(M. fascicularis, MFA) serve as...Understanding gene expression variations between species is pivotal for deciphering the evolutionary diversity in phenotypes. Rhesus macaques(Macaca mulatta, MMU)and crab-eating macaques(M. fascicularis, MFA) serve as crucial nonhuman primate biomedical models with different phenotypes. To date, however, large-scale comparative transcriptome research between these two species has not yet been fully explored. Here, we conducted systematic comparisons utilizing newly sequenced RNA-seq data from84 samples(41 MFA samples and 43 MMU samples)encompassing 14 common tissues. Our findings revealed a small fraction of genes(3.7%) with differential expression between the two species, as well as 36.5% of genes with tissue-specific expression in both macaques. Comparison of gene expression between macaques and humans indicated that 22.6% of orthologous genes displayed differential expression in at least two tissues. Moreover,19.41% of genes that overlapped with macaque-specific structural variants showed differential expression between humans and macaques. Of these, the FAM220A gene exhibited elevated expression in humans compared to macaques due to lineage-specific duplication. In summary,this study presents a large-scale transcriptomic comparison between MMU and MFA and between macaques and humans. The discovery of gene expression variations not only enhances the biomedical utility of macaque models but also contributes to the wider field of primate genomics.展开更多
Background Understanding the evolution of circadian rhythm dysfunction and psychopathology in the high-risk population has important implications for the prevention of bipolar disorder.Nevertheless,some of the previou...Background Understanding the evolution of circadian rhythm dysfunction and psychopathology in the high-risk population has important implications for the prevention of bipolar disorder.Nevertheless,some of the previous studies on the emergence of psychopathologies and circadian dysfunction among high-risk populations were inconsistent and limited.Aims To examine the prevalence rates of sleep and circadian dysfunctions,mental disorders and their symptoms in the offspring of parents with(O-BD)and without bipolar disorder(O-control).Methods The study included 191 O-BD and 202 O-control subjects aged 6-21 years from the Greater Bay Area,China.The diagnoses and symptoms of sleep/circadian rhythm and mental disorders were assessed by the Diagnostic Interview for Sleep Patterns and Disorders,and the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version,respectively.Generalised estimating equations and shared frailty proportional hazards models of survival analysis were applied to compare the outcomes in the offspring.Results Adjusting for age,sex and region of recruitment,there was a significantly higher risk of delayed sleep phase symptoms(9.55%vs 2.58%,adjusted OR:4.04)in O-BD than in O-control.O-BD had a nearly fivefold higher risk of mood disorders(11.70%vs 3.47%,adjusted OR:4.68)and social anxiety(6.28%vs 1.49%,adjusted OR:4.70),a fourfold higher risk of depressive disorders(11.17%vs 3.47%,adjusted OR:3.99)and a threefold higher risk of mood symptoms(20.74%vs 10.40%,adjusted OR:2.59)than O-control.Subgroup analysis revealed that O-BD children(aged under 12 years)had a nearly 2-fold higher risk of any mental and behavioural symptoms than O-control,while there was a nearly 4-fold higher risk of delayed sleep phase symptoms,a 7.5-fold higher risk of social anxiety and a 3-fold higher risk of mood symptoms in O-BD adolescents(aged 12 years and over).Conclusions There was an increase in delayed sleep phase symptoms in O-BD adolescents compared with their control counterp展开更多
Acquired drug resistance is the major reason why patients fail to respond to cancer therapies.It is a challenging task to deter.mine the tipping point of endocrine resistance and detect the associated molecules.Derive...Acquired drug resistance is the major reason why patients fail to respond to cancer therapies.It is a challenging task to deter.mine the tipping point of endocrine resistance and detect the associated molecules.Derived from new systems biology theory, the dynamic network biomarker (DNB) method is designed to quantitatively identify the tipping point of a drastic system transition and can theoretically identify DNB genes that play key roles in acquiring drug resistance.We analyzed time-course mRNA sequence data generated from the tamoxifen-treated estrogen receptor (ER)-positive MCF-7 cell line, and identified the tipping point of endocrine resistance with its leading molecules.The results show that there is interplay between gene mutations and DNB genes, in which the accumulated mutations eventually affect the DNB genes that subsequently cause the change of transcriptional landscape, enabling full-blown drug resistance. Survival analyses based on clinical datasets validated that the DNB genes were associated with the poor survival of breast cancer patients.The results provided the detection for the pre-resistance state or early signs of endocrine resistance.Our predictive method may greatly benefit the scheduling of treatments for complex diseases in which patients are exposed to considerably different drugs and may become drug resistant.展开更多
Major depressive disorder(MDD) is a common mood disorder that affects almost 20% of the global population.In addition,much evidence has implicated altered function of the gamma-aminobutyric acid(GABAergic) system in t...Major depressive disorder(MDD) is a common mood disorder that affects almost 20% of the global population.In addition,much evidence has implicated altered function of the gamma-aminobutyric acid(GABAergic) system in the pathophysiology of depression.Recent research has indicated that GABA_B receptors(GABA_BRs) are an emerging therapeutic target in the treatment of stress-related disorders such as MDD.However,which cell types with GABA_BRs are involved in this process is unknown.As hippocampal dysfunction is implicated in MDD,we knocked down GABA_BRs in the hippocampus and found that knocking down these receptors in astrocytes,but not in GABAergic or pyramidal neurons,caused a decrease in immobility in the forced swimming test(FST) without affecting other anxiety-and depression-related behaviors.We also generated astrocytespecific GABABR-knockout mice and found decreased immobility in the FST in these mice.Furthermore,the conditional knockout of GABA_BRs in astrocytes selectively increased the levels of brain-derived neurotrophic factor protein in hippocampal astrocytes,which controlled the decrease in immobility in the FST.Taken together,our findings contribute to the current understanding of which cell types expressing GABA_BRs modulate antidepressant activity in the FST,and they may provide new insights into the pathological mechanisms and potential targets for the treatment of depression.展开更多
When new information enters the brain,a human's prior knowledge of the world can change rapidly through a process referred to as"knowledge assembly".Recently,Nelli et al.investigated the neural correlate...When new information enters the brain,a human's prior knowledge of the world can change rapidly through a process referred to as"knowledge assembly".Recently,Nelli et al.investigated the neural correlates of knowledge assembly in the human brain using functional MRI.Further,inspired by the neural mechanism,the authors developed an artificial neural network algorithm to permit rapid knowledge assembly,improving the flexibility of the system[1].Once again,this research demonstrates that studying how the brain works can lead to better computational algorithms.展开更多
Acute administration of MK-801(dizocilpine),an N-methyl-D-aspartate receptor(NMDAR)antagonist,can establish animal models of psychiatric disorders.However,the roles of microglia and inflammation-related genes in these...Acute administration of MK-801(dizocilpine),an N-methyl-D-aspartate receptor(NMDAR)antagonist,can establish animal models of psychiatric disorders.However,the roles of microglia and inflammation-related genes in these animal models of psychiatric disorders remain unknown.Here,we found rapid elimination of microglia in the prefrontal cortex(PFC)and hippocampus(HPC)of mice following administration of the dual colony-stimulating factor 1 receptor(CSF1R)/c-Kit kinase inhibitor PLX3397(pexidartinib)in drinking water.Single administration of MK-801 induced hyperactivity in the open-field test(OFT).Importantly,PLX3397-induced depletion of microglia prevented the hyperactivity and schizophrenia-like behaviors induced by MK-801.However,neither repopulation of microglia nor inhibition of microglial activation by minocycline affected MK-801-induced hyperactivity.Importantly,microglial density in the PFC and HPC was significantly correlated with behavioral changes.In addition,common and distinct glutamate-,GABA-,and inflammation-related gene(116 genes)expression patterns were observed in the brains of PLX3397-and/or MK-801-treated mice.Moreover,10 common inflammation-related genes(CD68,CD163,CD206,TMEM119,CSF3R,CX3CR1,TREM2,CD11b,CSF1R,and F4/80)with very strong correlations were identified in the brain using hierarchical clustering analysis.Further correlation analysis demonstrated that the behavioral changes in the OFT were most significantly associated with the expression of inflammation-related genes(NLRP3,CD163,CD206,F4/80,TMEM119,and TMEM176a),but not glutamate-or GABA-related genes in PLX3397-and MK-801-treated mice.Thus,our results suggest that microglial depletion via a CSF1R/c-Kit kinase inhibitor can ameliorate the hyperactivity induced by an NMDAR antagonist,which is associated with modulation of immune-related genes in the brain.展开更多
Neurodegenerative diseases cause great medical and economic burdens for both patients and society;however, the complex molecular mechanisms thereof are not yet well understood. With the development of high-coverage se...Neurodegenerative diseases cause great medical and economic burdens for both patients and society;however, the complex molecular mechanisms thereof are not yet well understood. With the development of high-coverage sequencing technology, researchers have started to notice that genomic repeat regions, previously neglected in search of disease culprits, are active contributors to multiple neurodegenerative diseases. In this review, we describe the association between repeat element variants and multiple degenerative diseases through genome-wide association studies and targeted sequencing. We discuss the identification of disease-relevant repeat element variants, further powered by the advancement of long-read sequencing technologies and their related tools, and summarize recent findings in the molecular mechanisms of repeat element variants in brain degeneration, such as those causing transcriptional silencing or RNA-mediated gain of toxic function. Furthermore, we describe how in silico predictions using innovative computational models, such as deep learning language models, could enhance and accelerate our understanding of the functional impact of repeat element variants. Finally, we discuss future directions to advance current findings for a better understanding of neurodegenerative diseases and the clinical applications of genomic repeat elements.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展开更多
Radiation therapy is a standard treatment for head and neck tumors.However,patients often exhibit cognitive impairments following radiation therapy.Previous studies have revealed that hippocampal dysfunction,specifica...Radiation therapy is a standard treatment for head and neck tumors.However,patients often exhibit cognitive impairments following radiation therapy.Previous studies have revealed that hippocampal dysfunction,specifically abnormal hippocampal neurogenesis or neuroinflammation,plays a key role in radiation-induced cognitive impairment.However,the long-term effects of radiation with respect to the electrophysiological adaptation of hippocampal neurons remain poorly characterized.We found that mice exhibited cognitive impairment 3 months after undergoing 10 minutes of cranial irradiation at a dose rate of 3 Gy/min.Furthermore,we observed a remarkable reduction in spike firing and excitatory synaptic input,as well as greatly enhanced inhibitory inputs,in hippocampal CA1 pyramidal neurons.Corresponding to the electrophysiological adaptation,we found reduced expression of synaptic plasticity marker VGLUT1 and increased expression of VGAT.Furthermore,in irradiated mice,long-term potentiation in the hippocampus was weakened and GluR1 expression was inhibited.These findings suggest that radiation can impair intrinsic excitability and synaptic plasticity in hippocampal CA1 pyramidal neurons.展开更多
CRISPR-mediated genome editing is a revolutionary technology for genome manipulation that uses the CRISPR-Cas systems and base editors.Currently,poor efficiency and off-target problems have impeded the application of ...CRISPR-mediated genome editing is a revolutionary technology for genome manipulation that uses the CRISPR-Cas systems and base editors.Currently,poor efficiency and off-target problems have impeded the application of CRISPR systems.The on-target efficiency has been improved in several advanced versions of CRISPR systems,whereas the off-target detection still remains a key challenge.Here,we outline the different versions of CRISPR systems and off-target detection strategies,discuss the merits and limitations of off-target detection methods,and provide potential implications for further gene editing research.展开更多
基金supported by the National Natural Science Foundation of China(31830032,81527901,and 31671057)the non-profit Central Research Institute Fund of the Chinese Academy of Medical Sciences(2017PT31038,2018PT31041)+3 种基金the National Key Research and Development Program of China(2016YFA0501000)Key-Area Research and Development Program of Guangdong Province(2018B030334001,2018B030331001)the 111 Project(B13026)the Fountain-Valley Life Sciences Fund of University of Chinese Academy of Sciences Education Foundation and the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-057)。
文摘Major depressive disorder(MDD)is a prevalent psychiatric disease that involves malfunctions of different cell types in the brain.Accumulating studies started to reveal that microglia,the primary resident immune cells,play an important role in the development and progression of depression.Microglia respond to stress-triggered neuroinflammation,and through the release of proinflammatory cytokines and their metabolic products,microglia may modulate the function of neurons and astrocytes to regulate depression.In this review,we focused on the role of microglia in the etiology of depression.We discussed the dynamic states of microglia;the correlative and causal evidence of microglial abnormalities in depression;possible mechanisms of how microglia sense depression-related stress and modulate depression state;and how antidepressive therapies affect microglia.Understanding the role of microglia in depression may shed light on developing new treatment strategies to fight against this devastating mental illness.
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.
文摘Reproductive biology is a uniquely important topic since it is about germ cells, which are central for transmitting genetic information from generation to generation. In this review, we discuss recent advances in mammalian germ cell development,including preimplantation development, fetal germ cell development and postnatal development of oocytes and sperm. We also discuss the etiologies of female and male infertility and describe the emerging technologies for studying reproductive biology such as gene editing and single-cell technologies.
基金the Shanghai Municipal Commission of Health and Family Planning(2018BR33,2017EKHWYX-02,and GWV-10.1-XK07)the Shanghai Shenkang Hospital Development Center(16CR2025B)+9 种基金the Shanghai Clinical Key Subject Construction Project(shslczdzk02902)the National Natural Science Foundation of China(81761128035,81930095,81873909,82001771,and 31860306)the Shanghai Committee of Science and Technology(17XD1403200,20ZR1404900,and 19410713500)Xinhua Hospital of Shanghai Jiao Tong University School of Medicine(2018YJRC03)the National Human Genetic Resources Sharing Service Platform(2005DKA21300)the National Key Research and Development Program of China(2018YFC0910503)111 Project(B18015)the Shanghai Municipal Science and Technology Major Project(2018SHZDZX01)Guangdong Key Project in‘‘Development of New Tools for Diagnosis and Treatment of Autism”(2018B030335001)the Science and Technology Department of Yunnan Province(202001AV070010)。
文摘With the current limited drug therapy for the core symptoms of autism spectrum disorder(ASD),we herein report a randomized,double-blind,placebo-controlled trial to investigate the efficacy,safety,and potential neural mechanism of bumetanide in children with ASD aged 3-6 years old.A total of 120 children were enrolled into the study and randomly assigned to either 0.5 mg bumetanide or placebo.In the final sample,119 children received at least one dose of bumetanide(59 children) or placebo(60 children) were included in the final analysis.The primary outcome was a reduction in the Childhood Autism Rating Scale(CARS) score,and the secondary outcomes were the Clinical Global Impressions Scale(CGI)-Global Improvement(CGI-I) score at 3 months and the change from baseline to 3-month in the Autism Diagnostic Observation Schedule(ADOS).Magnetic resonance spectroscopy(MRS) was used to measure y-aminobutyric acid(GABA) and glutamate neurotransmitter concentrations in the insular cortex(IC) before and after the treatment.As compared with the placebo,bumetanide treatment was significantly better in reducing the severity.No patient withdrew from the trial due to adverse events.The superiority of bumetanide to placebo in reducing insular GABA,measured using MRS,was demonstrated.The clinical improvement was associated with a decrease in insular GABA in the bumetanide group.In conclusion,this trial in a large group of young children with predominantly moderate and severe ASD demonstrated that bumetanide is safe and effective in improving the core symptoms of ASD.However,the clinical significance remains uncertain,and future multi-center clinical trials are required to replicate these findings and confirm the clinical significance using a variety of outcome measures.
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supported by a Shanghai Municipal Science and Technology Major Project(2021SHZDZX,E154N41011)the Lingang Lab Program(LG2021050202 and LG2021060301)+1 种基金the National Nature Science Foundation(82130041)the Shanghai Rising-star Cultivation Program(22YF1439200).
文摘An electroencephalographic(EEG)signature of auditory hallucinations(AHs)is important for facilitating the diagnosis and treatment of AHs in schizophrenia.We recorded EEG from 25 schizophrenia patients with recurrent AHs.During the period of AHs,EEG recordings exhibited significantly elevated beta2-band power in the temporal region,as compared to those recorded in the absence of AHs or during stimulation with verbal sounds.We further generated methamphetamine-treated rhesus monkeys exhibiting psychosis-like behaviors,including repetitive sudden searching actions in the absence of external intrusion,suggesting the occurrence of AHs.Epidural EEG beta2-band power in the temporal region of these monkeys was enhanced immediately after methamphetamine treatment and positively correlated with the frequency of sudden searching actions.Thus,the enhancement of temporal beta2-band oscillations represents a signature for AHs in both patients and a monkey model of psychosis,and this monkey model can be used for developing closed-loop neuromodulation approaches for the treatment of refractory AHs in schizophrenia.
基金supported by the STI2030-Major Projects(2022ZD0205400)the National Natural Science Foundation of China(82192861,81922018,82271170,and 82101218)+3 种基金the Foundation from Science and Technology Commission of Shanghai Municipality(22140900800 and 20JC1419500)the Foundation from Shanghai Municipal Health Commission(20234Z0007)the China Postdoctoral Science Foundation(2021M700824 and 2022T150133)the Shanghai Super Postdoctoral Incentive Program.
文摘Hearing loss is one of the most common sensory disorders worldwide,affecting approximately 466 million people,including 34 million children[1].Genetic mutations accounts for approximately 60%of inherited hearing loss cases[2,3].These genetic changes result in a wide variety of clinical manifestations,ranging from nonsyndromic hearing loss(NSHL)to over 400 syndromes involving hearing loss and from mild adult-onset hearing loss to profound congenital deafness,covering the entire spectrum of Mendelian inheritance.
基金supported by the National Key Research and Development Program of China(2017YFA0104200)the National Natural Science Foundation of China(31871066,31922028,31900721 and 32122039)+2 种基金the Shanghai Municipal Science and Technology Major Project(2018SHZDZX05)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB32000000)the Shanghai Science and Technology Committee of Shanghai City(19140903800 and 21XD1422700)。
文摘All animals possess a plethora of innate behaviors that do not require extensive learning and are fundamental for their survival and propagation.With the advent of newly-developed techniques such as viral tracing and optogenetic and chemogenetic tools,recent studies are gradually unraveling neural circuits underlying different innate behaviors.Here,we summarize current development in our understanding of the neural circuits controlling predation,feeding,male-typical mating,and urination,highlighting the role of genetically defined neurons and their connections in sensory triggering,sensory to motor/motivation transformation,motor/motivation encoding during these different behaviors.Along the way,we discuss possible mechanisms underlying binge-eating disorder and the pro-social effects of the neuropeptide oxytocin,elucidating the clinical relevance of studying neural circuits underlying essential innate functions.Finally,we discuss some exciting brain structures recurrently appearing in the regulation of different behaviors,which suggests both divergence and convergence in the neural encoding of specific innate behaviors.Going forward,we emphasize the importance of multi-angle and cross-species dissections in delineating neural circuits that control innate behaviors.
基金This work was supported by the National Natural Science Foundation of China(31625013,81941015,32000726,and 61973086)the Shanghai Brain-Intelligence Project from STCSM(16JC1420501)+2 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDBS01060200)the Program of Shanghai Academic Research LeaderThe Open Large Infrastructure Research of the Chinese Academy of Sciences,and the Shanghai Municipal Science and Technology Major Project(2018SHZDZX01).
文摘Autism spectrum disorder(ASD)is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and repetitive behaviors.Although hundreds of ASD risk genes,implicated in synaptic formation and transcriptional regulation,have been identified through human genetic studies,the East Asian ASD cohorts are still under-represented in genome-wide genetic studies.Here,we applied whole-exome sequencing to 369 ASD trios including probands and unaffected parents of Chinese origin.Using a joint-calling analytical pipeline based on GATK toolkits,we identified numerous de novo mutations including 55 high-impact variants and 165 moderate-impact variants,as well as de novo copy number variations containing known ASD-related genes.Importantly,combined with single-cell sequencing data from the developing human brain,we found that the expression of genes with de novo mutations was specifically enriched in the pre-,post-central gyrus(PRC,PC)and banks of the superior temporal(BST)regions in the human brain.By further analyzing the brain imaging data with ASD and healthy controls,we found that the gray volume of the right BST in ASD patients was significantly decreased compared to healthy controls,suggesting the potential structural deficits associated with ASD.Finally,we found a decrease in the seed-based functional connectivity between BST/PC/PRC and sensory areas,the insula,as well as the frontal lobes in ASD patients.This work indicated that combinatorial analysis with genome-wide screening,single-cell sequencing,and brain imaging data reveal the brain regions contributing to the etiology of ASD.
基金supported by the Science and Technology Innovation 2030-Major Project of Brain Science and Brain-like Research(2021ZD0202700,2021ZD0202702)the Key-Area Research and Development Program of Guangdong Province(2019B030335001,2018B030334001)+6 种基金the Major Program of the National Natural Science Foundation of China(82090030,82090031)the CAMS Innovation Fund for Medical Sciences(2019-12M-5-057)the Ministry of Science and Technology(2019YFA0110103)the National Natural Science Foundation of China(81870898)the Fundamental Research Funds for the Central Universities(2021FZZX001-37)the Zhejiang Provincial Natural Science Foundation(LR18H090002)the Young Scientist Program of the National Natural Science Foundation of China(82001135).
文摘Defensive behaviors induced by innate fear or Pavlovian fear conditioning are crucial for animals to avoid threats and ensure survival.The zona incerta(ZI)has been demonstrated to play important roles in fear learning and fear memory,as well as modulating auditory-induced innate defensive behavior.However,whether the neuronal subtypes in the ZI and specific circuits can mediate the innate fear response is largely unknown.Here,we found that somatostatin(SST)-positive neurons in the rostral ZI of mice were activated by a visual innate fear stimulus.Optogenetic inhibition of SST-positive neurons in the rostral ZI resulted in reduced flight responses to an overhead looming stimulus.Optogenetic activation of SST-positive neurons in the rostral ZI induced fear-like defensive behavior including increased immobility and bradycardia.In addition,we demonstrated that manipulation of the GABAergic projections from SST-positive neurons in the rostral ZI to the downstream nucleus reuniens(Re)mediated fear-like defensive behavior.Retrograde trans-synaptic tracing also revealed looming stimulus-activated neurons in the superior colliculus(SC)that projected to the Re-projecting SST-positive neurons in the rostral ZI(SC-ZIrSST-Re pathway).Together,our study elucidates the function of SST-positive neurons in the rostral ZI and the SC-ZIrSST-Re tri-synaptic circuit in mediating the innate fear response.
基金supported by the National Natural Science Foundation of China (82021001 and 31825018 to Q.S., 32370658 to Y.M.,82001372 to X.Y.)National Key Research and Development Program of China (2022YFF0710901)+2 种基金National Science and Technology Innovation2030 Major Program (2021ZD0200900) to Q.S.Shanghai Pujiang Program (22PJ1407300)Shanghai Jiao Tong University 2030 Initiative (WH510363001-7) to Y.M。
文摘Understanding gene expression variations between species is pivotal for deciphering the evolutionary diversity in phenotypes. Rhesus macaques(Macaca mulatta, MMU)and crab-eating macaques(M. fascicularis, MFA) serve as crucial nonhuman primate biomedical models with different phenotypes. To date, however, large-scale comparative transcriptome research between these two species has not yet been fully explored. Here, we conducted systematic comparisons utilizing newly sequenced RNA-seq data from84 samples(41 MFA samples and 43 MMU samples)encompassing 14 common tissues. Our findings revealed a small fraction of genes(3.7%) with differential expression between the two species, as well as 36.5% of genes with tissue-specific expression in both macaques. Comparison of gene expression between macaques and humans indicated that 22.6% of orthologous genes displayed differential expression in at least two tissues. Moreover,19.41% of genes that overlapped with macaque-specific structural variants showed differential expression between humans and macaques. Of these, the FAM220A gene exhibited elevated expression in humans compared to macaques due to lineage-specific duplication. In summary,this study presents a large-scale transcriptomic comparison between MMU and MFA and between macaques and humans. The discovery of gene expression variations not only enhances the biomedical utility of macaque models but also contributes to the wider field of primate genomics.
基金supported by the Health and Medical Research Fund of the Food and Health Bureau of Hong Kong(03140636)and the donation fund from Mr Yip WT and Mrs Yip。
文摘Background Understanding the evolution of circadian rhythm dysfunction and psychopathology in the high-risk population has important implications for the prevention of bipolar disorder.Nevertheless,some of the previous studies on the emergence of psychopathologies and circadian dysfunction among high-risk populations were inconsistent and limited.Aims To examine the prevalence rates of sleep and circadian dysfunctions,mental disorders and their symptoms in the offspring of parents with(O-BD)and without bipolar disorder(O-control).Methods The study included 191 O-BD and 202 O-control subjects aged 6-21 years from the Greater Bay Area,China.The diagnoses and symptoms of sleep/circadian rhythm and mental disorders were assessed by the Diagnostic Interview for Sleep Patterns and Disorders,and the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version,respectively.Generalised estimating equations and shared frailty proportional hazards models of survival analysis were applied to compare the outcomes in the offspring.Results Adjusting for age,sex and region of recruitment,there was a significantly higher risk of delayed sleep phase symptoms(9.55%vs 2.58%,adjusted OR:4.04)in O-BD than in O-control.O-BD had a nearly fivefold higher risk of mood disorders(11.70%vs 3.47%,adjusted OR:4.68)and social anxiety(6.28%vs 1.49%,adjusted OR:4.70),a fourfold higher risk of depressive disorders(11.17%vs 3.47%,adjusted OR:3.99)and a threefold higher risk of mood symptoms(20.74%vs 10.40%,adjusted OR:2.59)than O-control.Subgroup analysis revealed that O-BD children(aged under 12 years)had a nearly 2-fold higher risk of any mental and behavioural symptoms than O-control,while there was a nearly 4-fold higher risk of delayed sleep phase symptoms,a 7.5-fold higher risk of social anxiety and a 3-fold higher risk of mood symptoms in O-BD adolescents(aged 12 years and over).Conclusions There was an increase in delayed sleep phase symptoms in O-BD adolescents compared with their control counterp
基金This work was supported by grants from the National Key R&D Program of China (2017YFA0505500)Strategic Priority Research Program of the Chinese Academy of Sciences (XDBl3040700)+6 种基金the National Natural Science Foundation of China (11771152,91529303,31771476,31571363,31771469,91530320,61134013,81573023,81501203,and 11326035)Pearl River Science and Technology Nova Program of Guangzhou (201610010029)FISRT,Aihara Innovative Mathematical Modeling Project from Cabinet Office,JapanFundamental Research Funds for the Central Universities (2017ZD095)JSPS KAKENHI (15H05707)Grant-in-Aid for Scientific Research on Innovative Areas (3901) and SPS KAKENHI (15KT0084,17H06299,17H06302,and 18H04031)RIKEN Epigenome and Single Cell Project Grants to M.O.-H.This work was performed in part under the International Cooperative Research Program of Institute for Protein Research,Osaka University (ICRa-17-01 to L.C.and M.O.-H.).
文摘Acquired drug resistance is the major reason why patients fail to respond to cancer therapies.It is a challenging task to deter.mine the tipping point of endocrine resistance and detect the associated molecules.Derived from new systems biology theory, the dynamic network biomarker (DNB) method is designed to quantitatively identify the tipping point of a drastic system transition and can theoretically identify DNB genes that play key roles in acquiring drug resistance.We analyzed time-course mRNA sequence data generated from the tamoxifen-treated estrogen receptor (ER)-positive MCF-7 cell line, and identified the tipping point of endocrine resistance with its leading molecules.The results show that there is interplay between gene mutations and DNB genes, in which the accumulated mutations eventually affect the DNB genes that subsequently cause the change of transcriptional landscape, enabling full-blown drug resistance. Survival analyses based on clinical datasets validated that the DNB genes were associated with the poor survival of breast cancer patients.The results provided the detection for the pre-resistance state or early signs of endocrine resistance.Our predictive method may greatly benefit the scheduling of treatments for complex diseases in which patients are exposed to considerably different drugs and may become drug resistant.
基金supported by grants from the National Natural Science Foundation of China (31430032,31830033, 81671356,and 31600864)the Program for Changjiang Scholars and Innovative Research Teams in University (IRT_16R37)+2 种基金the Science and Technology Program of Guangdong Province,China (2018B030334001)the Guangzhou Municipal Science and Technology Project (201707020027)the Postdoctoral Science Foundation of China (2018M633072)。
文摘Major depressive disorder(MDD) is a common mood disorder that affects almost 20% of the global population.In addition,much evidence has implicated altered function of the gamma-aminobutyric acid(GABAergic) system in the pathophysiology of depression.Recent research has indicated that GABA_B receptors(GABA_BRs) are an emerging therapeutic target in the treatment of stress-related disorders such as MDD.However,which cell types with GABA_BRs are involved in this process is unknown.As hippocampal dysfunction is implicated in MDD,we knocked down GABA_BRs in the hippocampus and found that knocking down these receptors in astrocytes,but not in GABAergic or pyramidal neurons,caused a decrease in immobility in the forced swimming test(FST) without affecting other anxiety-and depression-related behaviors.We also generated astrocytespecific GABABR-knockout mice and found decreased immobility in the FST in these mice.Furthermore,the conditional knockout of GABA_BRs in astrocytes selectively increased the levels of brain-derived neurotrophic factor protein in hippocampal astrocytes,which controlled the decrease in immobility in the FST.Taken together,our findings contribute to the current understanding of which cell types expressing GABA_BRs modulate antidepressant activity in the FST,and they may provide new insights into the pathological mechanisms and potential targets for the treatment of depression.
基金supported by STI2030-Major Projects 2021ZD0200201the Scientific Research and Equipment Development Project of the Chinese Academy of Sciences(YJKYYQ20190040)。
文摘When new information enters the brain,a human's prior knowledge of the world can change rapidly through a process referred to as"knowledge assembly".Recently,Nelli et al.investigated the neural correlates of knowledge assembly in the human brain using functional MRI.Further,inspired by the neural mechanism,the authors developed an artificial neural network algorithm to permit rapid knowledge assembly,improving the flexibility of the system[1].Once again,this research demonstrates that studying how the brain works can lead to better computational algorithms.
基金supported by the National Natural Science Foundation of China(81920108018,82230046,82001432)Ministry of Science and Technology of the People’s Republic of China(2022ZD0211700,2022ZD0205200)+5 种基金Natural Science Foundation of Sichuan Province(2022NSFSC1607)Key Research and Development Program of Science and Technology Department of Sichuan Province(22ZDYF1531,22ZDYF1696)Key R&D Program of Zhejiang(2022C03096)Special Foundation for Brain Research from Science and Technology Program of Guangdong(2018B030334001)China Postdoctoral Science Foundation(2020TQ0213,2020M683319)Sichuan University(2022SCUH0023)。
文摘Acute administration of MK-801(dizocilpine),an N-methyl-D-aspartate receptor(NMDAR)antagonist,can establish animal models of psychiatric disorders.However,the roles of microglia and inflammation-related genes in these animal models of psychiatric disorders remain unknown.Here,we found rapid elimination of microglia in the prefrontal cortex(PFC)and hippocampus(HPC)of mice following administration of the dual colony-stimulating factor 1 receptor(CSF1R)/c-Kit kinase inhibitor PLX3397(pexidartinib)in drinking water.Single administration of MK-801 induced hyperactivity in the open-field test(OFT).Importantly,PLX3397-induced depletion of microglia prevented the hyperactivity and schizophrenia-like behaviors induced by MK-801.However,neither repopulation of microglia nor inhibition of microglial activation by minocycline affected MK-801-induced hyperactivity.Importantly,microglial density in the PFC and HPC was significantly correlated with behavioral changes.In addition,common and distinct glutamate-,GABA-,and inflammation-related gene(116 genes)expression patterns were observed in the brains of PLX3397-and/or MK-801-treated mice.Moreover,10 common inflammation-related genes(CD68,CD163,CD206,TMEM119,CSF3R,CX3CR1,TREM2,CD11b,CSF1R,and F4/80)with very strong correlations were identified in the brain using hierarchical clustering analysis.Further correlation analysis demonstrated that the behavioral changes in the OFT were most significantly associated with the expression of inflammation-related genes(NLRP3,CD163,CD206,F4/80,TMEM119,and TMEM176a),but not glutamate-or GABA-related genes in PLX3397-and MK-801-treated mice.Thus,our results suggest that microglial depletion via a CSF1R/c-Kit kinase inhibitor can ameliorate the hyperactivity induced by an NMDAR antagonist,which is associated with modulation of immune-related genes in the brain.
基金supported by the National Natural Science Foundation of China, No.61932008Natural Science Foundation of Shanghai, No.21ZR1403200 (both to JC)。
文摘Neurodegenerative diseases cause great medical and economic burdens for both patients and society;however, the complex molecular mechanisms thereof are not yet well understood. With the development of high-coverage sequencing technology, researchers have started to notice that genomic repeat regions, previously neglected in search of disease culprits, are active contributors to multiple neurodegenerative diseases. In this review, we describe the association between repeat element variants and multiple degenerative diseases through genome-wide association studies and targeted sequencing. We discuss the identification of disease-relevant repeat element variants, further powered by the advancement of long-read sequencing technologies and their related tools, and summarize recent findings in the molecular mechanisms of repeat element variants in brain degeneration, such as those causing transcriptional silencing or RNA-mediated gain of toxic function. Furthermore, we describe how in silico predictions using innovative computational models, such as deep learning language models, could enhance and accelerate our understanding of the functional impact of repeat element variants. Finally, we discuss future directions to advance current findings for a better understanding of neurodegenerative diseases and the clinical applications of genomic repeat elements.
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
基金supported by the National Natural Science Foundation of China,Nos.81925031(to YT),81820108026(to YT),81972967(to WJL),81872549(to YL)the Youth Program of National Natural Science Foundation of China,No.81801229(to YTX)+3 种基金a grant from Guangdong Science and Technology Department of China,Nos.2020B1212060018(to WJL),2020B1212030004(to WJL)the Natural Science Foundation of Guangdong Province,No.2019A1515011754(to WJL)the Science and Technology Program of Guangzhou of China,No.202007030001(to YT)the Science and Technology Planning Project of Guangzhou of China,No.201704030033(to YL).
文摘Radiation therapy is a standard treatment for head and neck tumors.However,patients often exhibit cognitive impairments following radiation therapy.Previous studies have revealed that hippocampal dysfunction,specifically abnormal hippocampal neurogenesis or neuroinflammation,plays a key role in radiation-induced cognitive impairment.However,the long-term effects of radiation with respect to the electrophysiological adaptation of hippocampal neurons remain poorly characterized.We found that mice exhibited cognitive impairment 3 months after undergoing 10 minutes of cranial irradiation at a dose rate of 3 Gy/min.Furthermore,we observed a remarkable reduction in spike firing and excitatory synaptic input,as well as greatly enhanced inhibitory inputs,in hippocampal CA1 pyramidal neurons.Corresponding to the electrophysiological adaptation,we found reduced expression of synaptic plasticity marker VGLUT1 and increased expression of VGAT.Furthermore,in irradiated mice,long-term potentiation in the hippocampus was weakened and GluR1 expression was inhibited.These findings suggest that radiation can impair intrinsic excitability and synaptic plasticity in hippocampal CA1 pyramidal neurons.
基金supported by the grants 81771230(W.C.),31922048(E.Z.)and 31522037(H.Y.)from the National Natural Science Foundation of China.
文摘CRISPR-mediated genome editing is a revolutionary technology for genome manipulation that uses the CRISPR-Cas systems and base editors.Currently,poor efficiency and off-target problems have impeded the application of CRISPR systems.The on-target efficiency has been improved in several advanced versions of CRISPR systems,whereas the off-target detection still remains a key challenge.Here,we outline the different versions of CRISPR systems and off-target detection strategies,discuss the merits and limitations of off-target detection methods,and provide potential implications for further gene editing research.
