Huntington’s disease(HD)is a genetic disease characterized by the progressive degeneration of the striatum and cortex.Patients can present with a variety of symptoms that can broadly be classified into motor symptoms...Huntington’s disease(HD)is a genetic disease characterized by the progressive degeneration of the striatum and cortex.Patients can present with a variety of symptoms that can broadly be classified into motor symptoms,inclusive of choreatic movements and rigidity,mood and psychiatric symptoms,such as depression and apathy,and cognitive symptoms,such as cognitive decline.The causal mutation underlying HD results from an expansion of a CAG repeat sequence on the IT15 gene,resulting in the formation and accumulation of a mutant huntingtin protein.展开更多
In 1872, George Huntington presented his essay “On Chorea” to the Meigs and Mason Academy of Medicine and, in doing so, detailed a disease that would later bear his name. Huntington's disease(HD) is a genetic, n...In 1872, George Huntington presented his essay “On Chorea” to the Meigs and Mason Academy of Medicine and, in doing so, detailed a disease that would later bear his name. Huntington's disease(HD) is a genetic, neurodegenerative disease that manifests as the loss of motor control,cognitive impairment,and mood and psychiatric changes in paents.展开更多
Neural damage or degeneration is at the crux of many diseases,and treatment of these diseases will require the development of therapeutics to enhance and guide neural regeneration.Both intrinsic and extrinsic factors ...Neural damage or degeneration is at the crux of many diseases,and treatment of these diseases will require the development of therapeutics to enhance and guide neural regeneration.Both intrinsic and extrinsic factors dictate a neuron’s ability to regenerate,and the combination of these factors results in the great regenerative capacity of the peripheral nervous system(PNS)and the poor regenerative capacity of the central nervous system(CNS)following injury.At the core of a neuron’s function is its ability to relay electrochemical signals,and a neuron’s excitability is a key factor in its ability to regenerate.Recent works have focused on the changes in neuronal electrophysiological properties,firing patterns,and ion flux after injury,which differentially activate signaling pathways at the core of regeneration.The role of glia in neuron regeneration has long been studied.展开更多
Dorsal root ganglion neurons transmit peripheral somatic information to the central nervous system,and dorsal root ganglion neuron excitability affects pain perception.Dorsal root ganglion stimulation is a new approac...Dorsal root ganglion neurons transmit peripheral somatic information to the central nervous system,and dorsal root ganglion neuron excitability affects pain perception.Dorsal root ganglion stimulation is a new approach for managing pain sensation.Knowledge of the cell-cell communication among dorsal root ganglion cells may help in the development of new pain and itch management strategies.Here,we used the single-cell RNA-sequencing(scRNA-seq)database to investigate intercellular communication networks among dorsal root ganglion cells.We collected scRNA-seq data from six samples from three studies,yielding data on a total of 17,766 cells.Based on genetic profiles,we identified satellite glial cells,Schwann cells,neurons,vascular endothelial cells,immune cells,fibroblasts,and vascular smooth muscle cells.Further analysis revealed that eight types of dorsal root ganglion neurons mediated proprioceptive,itch,touch,mechanical,heat,and cold sensations.Moreover,we predicted several distinct forms of intercellular communication among dorsal root ganglion cells,including cell-cell contact,secreted signals,extracellular matrix,and neurotransmitter-mediated signals.The data mining predicted that Mrgpra3-positive neurons robustly express the genes encoding the adenosine Adora2b(A2B)receptor and glial cell line-derived neurotrophic factor family receptor alpha 1(GFRα-1).Our immunohistochemistry results confirmed the coexpression of the A2B receptor and GFRα-1.Intrathecal injection of the A2B receptor antagonist PSB-603 effectively prevented histamine-induced scratching behaviour in a dose-dependent manner.Our results demonstrate the involvement of the A2B receptor in the modulation of itch sensation.Furthermore,our findings provide insight into dorsal root ganglion cell-cell communication patterns and mechanisms.Our results should contribute to the development of new strategies for the regulation of dorsal root ganglion excitability.展开更多
Amyotrophic lateral sclerosis(ALS) is a devastating motoneuron disease,in which lower motoneurons lose control of skeletal muscles.Degeneration of neuromuscular junctions(NMJs) occurs at the initial stage of ALS.Dipep...Amyotrophic lateral sclerosis(ALS) is a devastating motoneuron disease,in which lower motoneurons lose control of skeletal muscles.Degeneration of neuromuscular junctions(NMJs) occurs at the initial stage of ALS.Dipeptide repeat proteins(DPRs) from G4C2repeat-associated non-ATG(RAN) translation are known to cause C9orf72-associated ALS(C9-ALS).However,DPR inclusion burdens are weakly correlated with neurodegenerative areas in C9-ALS patients,indicating that DPRs may exert cell non-autonomous effects,in addition to the known intracellular pathological mechanisms.Here,we report that poly-GA,the most abundant form of DPR in C9-ALS,is released from cells.Local administration of poly-GA proteins in peripheral synaptic regions causes muscle weakness and impaired neuromuscular transmission in vivo.The NMJ structure cannot be maintained,as evidenced by the fragmentation of postsynaptic acetylcholine receptor(AChR) clusters and distortion of presynaptic nerve terminals.Mechanistic study demonstrated that extracellular poly-GA sequesters soluble Agrin ligands and inhibits Agrin-MuSK signaling.Our findings provide a novel cell non-autonomous mechanism by which poly-GA impairs NMJs in C9-ALS.Thus,targeting NMJs could be an early therapeutic intervention for C9-ALS.展开更多
Pathological dry skin is a disturbing and intractable healthcare burden,characterized by epithelial hyperplasia and severe itch.Atopic dermatitis(AD)and psoriasis models with complications of dry skin have been studie...Pathological dry skin is a disturbing and intractable healthcare burden,characterized by epithelial hyperplasia and severe itch.Atopic dermatitis(AD)and psoriasis models with complications of dry skin have been studied using single-cell RNA sequencing(scRNA-seq).However,scRNA-seq analysis of the dry skin mouse model(acetone/ether/water(AEW)-treated model)is still lacking.Here,we used scRNA-seq and in situ hybridization to identify a novel proliferative basal cell(PBC)state that exclusively expresses transcription factor CUT-like homeobox 1(Cux1).Further in vitro study demonstrated that Cux1 is vital for keratinocyte proliferation by regulating a series of cyclin-dependent kinases(CDKs)and cyclins.Clinically,Cux1+PBCs were increased in patients with psoriasis,suggesting that Cux1+PBCs play an important part in epidermal hyperplasia.This study presents a systematic knowledge of the transcriptomic changes in a chronic dry skin mouse model,as well as a potential therapeutic target against dry skin-related dermatoses.展开更多
This was a single-arm,multicenter,open-label phase I trial.Lentiviral vectors(LV)carrying the ABCD1 gene(LV-ABCD1)was directly injected into the brain of patients with childhood cerebral adrenoleukodystrophy(CCALD),an...This was a single-arm,multicenter,open-label phase I trial.Lentiviral vectors(LV)carrying the ABCD1 gene(LV-ABCD1)was directly injected into the brain of patients with childhood cerebral adrenoleukodystrophy(CCALD),and multi-site injection was performed.The injection dose increased from 200 to 1600 lL(vector titer:1×10^(9) transduction units per mL(TU/mL)),and the average dose per kilogram body weight ranges from 8 to 63.6 lL/kg.The primary endpoint was safety,dose-exploration and immunogenicity and the secondary endpoint was initial evaluation of efficacy and the expression of ABCD1 protein.A total of 7 patients participated in this phase I study and were followed for 1 year.No injectionrelated serious adverse event or death occurred.Common adverse events associated with the injection were irritability(71%,5/7)and fever(37.2-38.5℃,57%,4/7).Adverse events were mild and selflimited,or resolved within 3 d of symptomatic treatment.The maximal tolerable dose is 1600 lL.In 5 cases(83.3%,5/6),no lentivirus associated antibodies were detected.The overall survival at 1-year was 100%.The ABCD1 protein expression was detected in neutrophils,monocytes and lymphocytes.This study suggests that the intracerebral injection of LV-ABCD1 for CCALD is safe and can achieve successful LV transduction in vivo;even the maximal dose did not increase the risk of adverse events.Furthermore,the direct LV-ABCD1 injection displayed low immunogenicity.In addition,the effectiveness of intracerebral LV-ABCD1 injection has been preliminarily demonstrated while further investigation is needed.This study has been registered in the Chinese Clinical Trial Registry(https://www.chictr.org.cn/,registration number:ChiCTR1900026649).展开更多
Resveratrol, a natural phenolic compound, has been shown to prevent cardiovascular diseases and cancer and exhibit neuroprotective effects. In this study, we examined the neuroprotective and antJoxJdant effects of res...Resveratrol, a natural phenolic compound, has been shown to prevent cardiovascular diseases and cancer and exhibit neuroprotective effects. In this study, we examined the neuroprotective and antJoxJdant effects of resveratrol against hydrogen peroxide in embryonic neural stem cells. Hydrogen peroxide treatment alone increased catalase and glutathione peroxidase activities but did not change superoxide dismutase levels compared with hydrogen peroxide ＋ resveratrol treatment. Nitric oxide synthase activity and concomitant nitric oxide levels increased in response to hydrogen peroxide treatment. Conversely, resveratrol treatment decreased nitric oxide synthase activity and nitric oxide levels. Resveratrol also attenuated hydrogen peroxide-induced nuclear or mitochondrial DNA damage. We propose that resveratrol may be a promising agent for protecting embryonic neural stem cells because of its potential to decrease oxidative stress by inducing higher activity of antioxidant enzymes, decreasing nitric oxide production and nitric oxide synthase activity, and alleviating both nuclear and mitochondrial DNA damage.展开更多
Glaucoma is closely related to elevation of intraocular pressure （IOP）. Many studies have done on the effect of chronic elevation of lOP on the retina and optic nerve, but less attention was paid to the effect of ac...Glaucoma is closely related to elevation of intraocular pressure （IOP）. Many studies have done on the effect of chronic elevation of lOP on the retina and optic nerve, but less attention was paid to the effect of acute elevated lOP. Here we briefly review experimental studies on functional changes of the visual system from the retina to the visual cortex under acute elevated lOP condition, which is similar to that of acute primary angle-closure glaucoma.展开更多
Importance:Infantile spasm(IS)is a kind of refractory epilepsy.The first-line treatments for IS are adrenocorticotropic hormone(ACTH),oral corticosteroids,and vigabatrin.Objective:This study aimed to evaluate the effi...Importance:Infantile spasm(IS)is a kind of refractory epilepsy.The first-line treatments for IS are adrenocorticotropic hormone(ACTH),oral corticosteroids,and vigabatrin.Objective:This study aimed to evaluate the efficacy of magnesium sulfate and ACTH(MgSO_(4)+ACTH)combination therapy in patients with IS who failed first-line treatments.Methods:In this retrospective study,the clinical data of patients with IS who failed first-line treatments were collected in the Chinese PLA General Hospital.Patients received MgSO_(4)+ACTH combination therapy after first-line treatments failed.The course of treatments was 2 weeks.The therapeutic dose of ACTH and MgSO_(4)was 2.5 U·kg^(-1)·d^(-1)and 0.25 g·kg^(-1)·d^(-1),respectively.Results:A total of 229 patients with IS who failed the first-line treatments were collected.At the end of the MgSO_(4)+ACTH combination treatment,the seizure-free rate was 48.5%(111/229),and the resolution of hypsarrhythmia on electroencephalogram(EEG)was 72.1%(165/229).About 21.4%(49/229)of patients showed side effects,including infectious diseases,hypokalemia,and diarrhea.Interpretation:For patients with IS who failed first-line treatments,in terms of the seizure-free rate and resolution of hypsarrhythmia on EEG,MgSO_(4)+ACTH combination therapy can be considered.展开更多
Fungal and bacterial diseases, directly infecting various parts of body, have received much attention in recent years. Bacterial infections, such as Tinea Pedis, Pityriasis versicolor and Mycetoma can secondarily occu...Fungal and bacterial diseases, directly infecting various parts of body, have received much attention in recent years. Bacterial infections, such as Tinea Pedis, Pityriasis versicolor and Mycetoma can secondarily occur in superficial fungal damaged skin. They often occur in immune compromised individuals including diabetics and patients with peripheral arterial diseases. Mycetoma infections can travel through the bloodstream affecting different organs. In this paper, we investigate the photo-inactivation of the pathogens causing Tinea Pedis, Pityriasis versicolor, and Mycetoma infections in three therapy resistant patients without photosensitizing drugs. We have used a combination of visible to near-infrared (VIS/NIR) laser beams in association with blue (B), red (R) and ultra-violet (UV) light emitted diodes (LEDs) with incident doses of 0.63 - 21.43 J/cm2. These beams have minimum side effects on the normal part of the skin. According to the physicians’ assessments, all case study patients achieved an observable progress such as decreases in inflammatory lesions, rapid process of wound healing and scars improvements. Side effects such as inflammation, crusting, or hypopigmentation were not observed. The presented irradiation protocol may be a valuable complementary treatment for patients suffering from fungal and bacterial skin infections.展开更多
The deformability and high degree of freedom of mollusks bring challenges in mathematical modeling and synthesis of motions.Traditional analytical and statistical models are limited by either rigid skeleton assumption...The deformability and high degree of freedom of mollusks bring challenges in mathematical modeling and synthesis of motions.Traditional analytical and statistical models are limited by either rigid skeleton assumptions or model capacity,and have difficulty in generating realistic and multi-pattern mollusk motions.In this work,we present a large-scale dynamic pose dataset of Drosophila larvae and propose a motion synthesis model named Path2Pose to generate a pose sequence given the initial poses and the subsequent guiding path.The Path2Pose model is further used to synthesize long pose sequences of various motion patterns through a recursive generation method.Evaluation analysis results demonstrate that our novel model synthesizes highly realistic mollusk motions and achieves state-of-the-art performance.Our work proves high performance of deep neural networks for mollusk motion synthesis and the feasibility of long pose sequence synthesis based on the customized body shape and guiding path.展开更多
While somatosensory over-reactivity is a common feature of autism spectrum disorders such as fragile X syndrome(FXS),the thalamic mechanisms underlying this remain unclear.Here,we found that the developmental eliminat...While somatosensory over-reactivity is a common feature of autism spectrum disorders such as fragile X syndrome(FXS),the thalamic mechanisms underlying this remain unclear.Here,we found that the developmental elimination of synapses formed between the principal nucleus of V(PrV)and the ventral posterior medial nucleus(VPm)of the somatosensory system was delayed in fragile X mental retardation 1 gene knockout(Fmr1 KO)mice,while the developmental strengthening of these synapses was disrupted.Immunohistochemistry showed excessive VGluT2 puncta in mutants at P12–13,but not at P7–8 or P15–16,confirming a delay in somatic pruning of PrV-VPm synapses.Impaired synaptic function was associated with a reduction in the frequency of quantal AMPA events,as well as developmental deficits in presynaptic vesicle size and density.Our results uncovered the developmental impairment of thalamic relay synapses in Fmr1 KO mice and suggest that a thalamic contribution to the somatosensory over-reactivity in FXS should be considered.展开更多
The Shack-Hartmann wavefront sensor(SHWS)is an essential tool for wavefront sensing in adaptive optical microscopes.However,the distorted spots induced by the complex wavefront challenge its detection performance.Here...The Shack-Hartmann wavefront sensor(SHWS)is an essential tool for wavefront sensing in adaptive optical microscopes.However,the distorted spots induced by the complex wavefront challenge its detection performance.Here,we propose a deep learning based wavefront detection method which combines point spread function image based Zernike coefficient estimation and wavefront stitching.Rather than using the centroid displacements of each micro-lens,this method first estimates the Zernike coefficients of local wavefront distribution over each micro-lens and then stitches the local wavefronts for reconstruction.The proposed method can offer low root mean square wavefront errors and high accuracy for complex wavefront detection,and has potential to be applied in adaptive optical microscopes.展开更多
Human cognition plays a crucial role in our daily life.It enables us to perceive a constant influx of inputs,to memorize the scenarios,and to reason or decide their outcomes(Thagard,2005).Abnormal cognitive function,w...Human cognition plays a crucial role in our daily life.It enables us to perceive a constant influx of inputs,to memorize the scenarios,and to reason or decide their outcomes(Thagard,2005).Abnormal cognitive function,which is usually involved in neurological and mental diseases,such as chronic pain,mood disorders,autism,dementia,often seriously deteriorates individuals’life quality and brings inexhaustible social problems.展开更多
The genetically engineered pig is regarded as an optimal source of organ transplantation for humans and an excellent model for human disease research,given its comparable physiology to human beings.A myriad of single-...The genetically engineered pig is regarded as an optimal source of organ transplantation for humans and an excellent model for human disease research,given its comparable physiology to human beings.A myriad of single-cell RNA sequencing(sc RNA-seq)data on humans has been reported,but such data on pigs are scarce.Here,we apply sc RNA-seq technology to study the cellular heterogeneity of 3-month-old pig lungs,generating the single-cell atlas of 13,580 cells covering 16 major cell types.Based on these data,we systematically characterize the similarities and differences in the cellular cross-talk and expression patterns of respiratory virus receptors in each cell type of pig lungs compared with human lungs.Furthermore,we analyze pig lung xenotransplantation barriers and reported the cell-type expression patterns of 10 genes associated with pig-to-human immunobiological incompatibility and coagulation dysregulation.We also investigate the conserved transcription factors(TFs)and their candidate target genes and constructed five conserved TF regulatory networks in the main cell types shared by pig and human lungs.Finally,we present a comprehensive and openly accessible online platform,Scdb Lung.Our sc RNA-seq atlas of the domestic pig lung and Scdb Lung database can guide pig lung research and clinical applicability.展开更多
Background:Parkinson’s disease(PD)is characterized by a chronic loss of dopaminergic neurons and the presence of proteinaceous inclusions(Lewy bodies)within some remaining neurons in the substantia nigra.Recently,ast...Background:Parkinson’s disease(PD)is characterized by a chronic loss of dopaminergic neurons and the presence of proteinaceous inclusions(Lewy bodies)within some remaining neurons in the substantia nigra.Recently,astroglial inclusion body has also been found in some neurodegenerative diseases including PD.However,the underlying molecular mechanisms of how astroglial protein aggregation forms remain largely unknown.Here,we investigated the contribution ofαB-crystallin(CRYAB),a small heat shock protein,inα-synuclein inclusion formation in astrocytes.Methods:Small interfering RNA(siRNA)-mediated CRYAB(siCRYAB)knockdown or CRYAB overexpression was performed to investigate the impact of CRYAB on the autophagy in human glioblastoma cell line U251 cells.Coimmunoprecipitation(co-IP)and immunoblotting were used to dissect the interaction among multiple proteins.The clearance ofα-synuclein in vitro was evaluated by immunocytochemistry.CRYAB transgenic mice and transgenic mice overexpressing A30P mutant form of humanα-synuclein were used to examine the influence of CRYAB toα-synuclein accumulation in vivo.Results:We found that knockdown of CRYAB in U251 cells or primary cultured astrocytes resulted in a marked augmentation of autophagy activity.In contrast,exogenous CRYAB disrupted the assembly of the BAG3-HSPB8-HSC70 complex via binding with BAG3,thereby suppressing the autophagy activity.Furthermore,CRYAB-regulated autophagy has relevance to PD pathogenesis.Knockdown of CRYAB remarkably promoted cytoplasmic clearance ofα-synuclein preformed fibrils(PFFs).Conversely,selective overexpression of CRYAB in astrocytes markedly suppressed autophagy leading to the accumulation of α-synuclein aggregates in the brain of transgenic mice expressing humanα-synuclein A30P mutant.Conclusions:This study reveals a novel function for CRYAB as a natural inhibitor of astrocytic autophagy and shows that knockdown of CYRAB may provide a therapeutic target against proteinopathies such as synucleinopathies.展开更多
CaMKII is essential for long-term potentiation(LTP),a process in which synaptic strength is increased following the acquisition of information.Among the four CaMKII isoforms,γCaMKII is the one that mediates the LTP o...CaMKII is essential for long-term potentiation(LTP),a process in which synaptic strength is increased following the acquisition of information.Among the four CaMKII isoforms,γCaMKII is the one that mediates the LTP of excitatory synapses onto inhibitory interneurons(LTPE→I).However,the molecular mechanism underlying howγCaMKII mediates LTPE→I remains unclear.Here,we show thatγCaMKII is highly enriched in cultured hippocampal inhibitory interneurons and opts to be activated by higher stimulating frequencies in the 10–30 Hz range.Following stimulation,γCaMKII is translocated to the synapse and becomes co-localized with the postsynaptic protein PSD-95.Knocking downγCaMKII prevents the chemical LTP-induced phosphorylation and trafficking of AMPA receptors(AMPARs)in putative inhibitory interneurons,which are restored by overexpression ofγCaMKII but not its kinase-dead form.Taken together,these data suggest thatγCaMKII decodes NMDAR-mediated signaling and in turn regulates AMPARs for expressing LTP in inhibitory interneurons.展开更多
Parkinson's disease(PD)is a neurodegenerative disease,leading to the impairment of movement execution.PD pathogenesis has been largely investigated,either limited to bulk transcriptomic levels or at certain cell t...Parkinson's disease(PD)is a neurodegenerative disease,leading to the impairment of movement execution.PD pathogenesis has been largely investigated,either limited to bulk transcriptomic levels or at certain cell types,which failed to capture the cellular heterogeneity and intrinsic interplays among distinct cell types.Here,we report the application of single-nucleus RNA-seq on midbrain,striatum,and cerebellum of theα-syn-A53 T mouse,a well-established PD mouse model,and matched controls,generating the first single cell transcriptomic atlas for the PD model mouse brain composed of 46,174 individual cells.Additionally,we comprehensively depicte the dysfunctions in PD pathology,covering the elevation of NF-k B activity,the alteration of ion channel components,the perturbation of protein homeostasis network,and the dysregulation of glutamatergic signaling.Notably,we identify a variety of cell types closely associated with PD risk genes.Taken together,our study provides valuable resources to systematically dissect the molecular mechanism of PD pathogenesis at the single-cell resolution,which facilitates the development of novel approaches for diagnosis and therapies against PD.展开更多
Moderate to severe perinatal hypoxic-ischemic encephalopathy occurs in~1 to 3/1000 live births in high-income countries and is associated with a significant risk of death or neurodevelopmental disability.Detailed asse...Moderate to severe perinatal hypoxic-ischemic encephalopathy occurs in~1 to 3/1000 live births in high-income countries and is associated with a significant risk of death or neurodevelopmental disability.Detailed assessment is important to help identify highrisk infants,to help families,and to support appropriate interventions.A wide range of monitoring tools is available to assess changes over time,including urine and blood biomarkers,neurological examination,and electroencephalography.At present,magnetic resonance imaging is unique as although it is expensive and not suited to monitoring the early evolution of hypoxic-ischemic encephalopathy by a week of life it can provide direct insight into the anatomical changes in the brain after hypoxic-ischemic encephalopathy and so offers strong prognostic information on the long-term outcome after hypoxic-ischemic encephalopathy.This review investigated the temporal dynamics of neonatal hypoxic-ischemic encephalopathy injuries,with a particular emphasis on exploring the correlation between the prognostic implications of magnetic resonance imaging scans in the first week of life and their relationship to long-term outcome prediction,particularly for infants treated with therapeutic hypothermia.A comprehensive literature search,from 2016 to 2024,identified 20 pertinent articles.This review highlights that while the optimal timing of magnetic resonance imaging scans is not clear,overall,it suggests that magnetic resonance imaging within the first week of life provides strong prognostic accuracy.Many challenges limit the timing consistency,particularly the need for intensive care and clinical monitoring.Conversely,although most reports examined the prognostic value of scans taken between 4 and 10 days after birth,there is evidence from small numbers of cases that,at times,brain injury may continue to evolve for weeks after birth.This suggests that in the future it will be important to explore a wider range of times after hypoxic-ischemic encephalopathy to fully understand the optimal timing for predicting long-term outcomes.展开更多
文摘Huntington’s disease(HD)is a genetic disease characterized by the progressive degeneration of the striatum and cortex.Patients can present with a variety of symptoms that can broadly be classified into motor symptoms,inclusive of choreatic movements and rigidity,mood and psychiatric symptoms,such as depression and apathy,and cognitive symptoms,such as cognitive decline.The causal mutation underlying HD results from an expansion of a CAG repeat sequence on the IT15 gene,resulting in the formation and accumulation of a mutant huntingtin protein.
文摘In 1872, George Huntington presented his essay “On Chorea” to the Meigs and Mason Academy of Medicine and, in doing so, detailed a disease that would later bear his name. Huntington's disease(HD) is a genetic, neurodegenerative disease that manifests as the loss of motor control,cognitive impairment,and mood and psychiatric changes in paents.
文摘Neural damage or degeneration is at the crux of many diseases,and treatment of these diseases will require the development of therapeutics to enhance and guide neural regeneration.Both intrinsic and extrinsic factors dictate a neuron’s ability to regenerate,and the combination of these factors results in the great regenerative capacity of the peripheral nervous system(PNS)and the poor regenerative capacity of the central nervous system(CNS)following injury.At the core of a neuron’s function is its ability to relay electrochemical signals,and a neuron’s excitability is a key factor in its ability to regenerate.Recent works have focused on the changes in neuronal electrophysiological properties,firing patterns,and ion flux after injury,which differentially activate signaling pathways at the core of regeneration.The role of glia in neuron regeneration has long been studied.
基金supported by the National Natural Science Foundation of China,Nos.32271042 and 31871062(to XL)。
文摘Dorsal root ganglion neurons transmit peripheral somatic information to the central nervous system,and dorsal root ganglion neuron excitability affects pain perception.Dorsal root ganglion stimulation is a new approach for managing pain sensation.Knowledge of the cell-cell communication among dorsal root ganglion cells may help in the development of new pain and itch management strategies.Here,we used the single-cell RNA-sequencing(scRNA-seq)database to investigate intercellular communication networks among dorsal root ganglion cells.We collected scRNA-seq data from six samples from three studies,yielding data on a total of 17,766 cells.Based on genetic profiles,we identified satellite glial cells,Schwann cells,neurons,vascular endothelial cells,immune cells,fibroblasts,and vascular smooth muscle cells.Further analysis revealed that eight types of dorsal root ganglion neurons mediated proprioceptive,itch,touch,mechanical,heat,and cold sensations.Moreover,we predicted several distinct forms of intercellular communication among dorsal root ganglion cells,including cell-cell contact,secreted signals,extracellular matrix,and neurotransmitter-mediated signals.The data mining predicted that Mrgpra3-positive neurons robustly express the genes encoding the adenosine Adora2b(A2B)receptor and glial cell line-derived neurotrophic factor family receptor alpha 1(GFRα-1).Our immunohistochemistry results confirmed the coexpression of the A2B receptor and GFRα-1.Intrathecal injection of the A2B receptor antagonist PSB-603 effectively prevented histamine-induced scratching behaviour in a dose-dependent manner.Our results demonstrate the involvement of the A2B receptor in the modulation of itch sensation.Furthermore,our findings provide insight into dorsal root ganglion cell-cell communication patterns and mechanisms.Our results should contribute to the development of new strategies for the regulation of dorsal root ganglion excitability.
基金supported by the National Key Research and Development Program of China (2022YFF1000500 to K.Z. and2021YFA1101100 to C.S.)Zhejiang Provincial Natural Science Foundation(LZ22C110002 to C.S.)National Natural Science Foundation of China(32271031 to K.Z. and 82230038, 31871203, and 32071032 to C.S.)。
文摘Amyotrophic lateral sclerosis(ALS) is a devastating motoneuron disease,in which lower motoneurons lose control of skeletal muscles.Degeneration of neuromuscular junctions(NMJs) occurs at the initial stage of ALS.Dipeptide repeat proteins(DPRs) from G4C2repeat-associated non-ATG(RAN) translation are known to cause C9orf72-associated ALS(C9-ALS).However,DPR inclusion burdens are weakly correlated with neurodegenerative areas in C9-ALS patients,indicating that DPRs may exert cell non-autonomous effects,in addition to the known intracellular pathological mechanisms.Here,we report that poly-GA,the most abundant form of DPR in C9-ALS,is released from cells.Local administration of poly-GA proteins in peripheral synaptic regions causes muscle weakness and impaired neuromuscular transmission in vivo.The NMJ structure cannot be maintained,as evidenced by the fragmentation of postsynaptic acetylcholine receptor(AChR) clusters and distortion of presynaptic nerve terminals.Mechanistic study demonstrated that extracellular poly-GA sequesters soluble Agrin ligands and inhibits Agrin-MuSK signaling.Our findings provide a novel cell non-autonomous mechanism by which poly-GA impairs NMJs in C9-ALS.Thus,targeting NMJs could be an early therapeutic intervention for C9-ALS.
基金supported by Technological Innovation 2030-Major Projects of Brain Science and Brain-like Research(Grant No.:2022zD0206200)the Natural Science Foundation of China(Grant Nos.:31872796,82030108 to W.Yang,32071102 to P.Yu)+3 种基金the National Major Special Project on New Drug Innovation of China(Grant No.:2018ZX09711001-004-005)the key research and development program of Ningxia Hui Autonomous Region(Grant No.:2019BFH02003)Fundamental Research Funds for the Central Universities of China(Grant No.:2016QNA7002 to P.Yu)Zhejiang Provincial Natural Science Foundation(Grant No.:LR16H090001 to W.Yang).
文摘Pathological dry skin is a disturbing and intractable healthcare burden,characterized by epithelial hyperplasia and severe itch.Atopic dermatitis(AD)and psoriasis models with complications of dry skin have been studied using single-cell RNA sequencing(scRNA-seq).However,scRNA-seq analysis of the dry skin mouse model(acetone/ether/water(AEW)-treated model)is still lacking.Here,we used scRNA-seq and in situ hybridization to identify a novel proliferative basal cell(PBC)state that exclusively expresses transcription factor CUT-like homeobox 1(Cux1).Further in vitro study demonstrated that Cux1 is vital for keratinocyte proliferation by regulating a series of cyclin-dependent kinases(CDKs)and cyclins.Clinically,Cux1+PBCs were increased in patients with psoriasis,suggesting that Cux1+PBCs play an important part in epidermal hyperplasia.This study presents a systematic knowledge of the transcriptomic changes in a chronic dry skin mouse model,as well as a potential therapeutic target against dry skin-related dermatoses.
基金supported by the Capital’s Funds for Health Improvement and Research(2022-1-5081)the National Key Research and Development Program of China(2023YFC2706304)+1 种基金Shenzhen Geno-Immune Medical InstituteBeijing Meikang Biotechnology Co.,LTD.
文摘This was a single-arm,multicenter,open-label phase I trial.Lentiviral vectors(LV)carrying the ABCD1 gene(LV-ABCD1)was directly injected into the brain of patients with childhood cerebral adrenoleukodystrophy(CCALD),and multi-site injection was performed.The injection dose increased from 200 to 1600 lL(vector titer:1×10^(9) transduction units per mL(TU/mL)),and the average dose per kilogram body weight ranges from 8 to 63.6 lL/kg.The primary endpoint was safety,dose-exploration and immunogenicity and the secondary endpoint was initial evaluation of efficacy and the expression of ABCD1 protein.A total of 7 patients participated in this phase I study and were followed for 1 year.No injectionrelated serious adverse event or death occurred.Common adverse events associated with the injection were irritability(71%,5/7)and fever(37.2-38.5℃,57%,4/7).Adverse events were mild and selflimited,or resolved within 3 d of symptomatic treatment.The maximal tolerable dose is 1600 lL.In 5 cases(83.3%,5/6),no lentivirus associated antibodies were detected.The overall survival at 1-year was 100%.The ABCD1 protein expression was detected in neutrophils,monocytes and lymphocytes.This study suggests that the intracerebral injection of LV-ABCD1 for CCALD is safe and can achieve successful LV transduction in vivo;even the maximal dose did not increase the risk of adverse events.Furthermore,the direct LV-ABCD1 injection displayed low immunogenicity.In addition,the effectiveness of intracerebral LV-ABCD1 injection has been preliminarily demonstrated while further investigation is needed.This study has been registered in the Chinese Clinical Trial Registry(https://www.chictr.org.cn/,registration number:ChiCTR1900026649).
基金funded by the Research Fund of Ege University,Project No. 05/ECZ/020
文摘Resveratrol, a natural phenolic compound, has been shown to prevent cardiovascular diseases and cancer and exhibit neuroprotective effects. In this study, we examined the neuroprotective and antJoxJdant effects of resveratrol against hydrogen peroxide in embryonic neural stem cells. Hydrogen peroxide treatment alone increased catalase and glutathione peroxidase activities but did not change superoxide dismutase levels compared with hydrogen peroxide ＋ resveratrol treatment. Nitric oxide synthase activity and concomitant nitric oxide levels increased in response to hydrogen peroxide treatment. Conversely, resveratrol treatment decreased nitric oxide synthase activity and nitric oxide levels. Resveratrol also attenuated hydrogen peroxide-induced nuclear or mitochondrial DNA damage. We propose that resveratrol may be a promising agent for protecting embryonic neural stem cells because of its potential to decrease oxidative stress by inducing higher activity of antioxidant enzymes, decreasing nitric oxide production and nitric oxide synthase activity, and alleviating both nuclear and mitochondrial DNA damage.
基金grants of the National Natural Science Foundation of China （No. 90208013, No. 30170249）.
文摘Glaucoma is closely related to elevation of intraocular pressure （IOP）. Many studies have done on the effect of chronic elevation of lOP on the retina and optic nerve, but less attention was paid to the effect of acute elevated lOP. Here we briefly review experimental studies on functional changes of the visual system from the retina to the visual cortex under acute elevated lOP condition, which is similar to that of acute primary angle-closure glaucoma.
基金The National Key Research and Development Program of China(2016YFC1000707)
文摘Importance:Infantile spasm(IS)is a kind of refractory epilepsy.The first-line treatments for IS are adrenocorticotropic hormone(ACTH),oral corticosteroids,and vigabatrin.Objective:This study aimed to evaluate the efficacy of magnesium sulfate and ACTH(MgSO_(4)+ACTH)combination therapy in patients with IS who failed first-line treatments.Methods:In this retrospective study,the clinical data of patients with IS who failed first-line treatments were collected in the Chinese PLA General Hospital.Patients received MgSO_(4)+ACTH combination therapy after first-line treatments failed.The course of treatments was 2 weeks.The therapeutic dose of ACTH and MgSO_(4)was 2.5 U·kg^(-1)·d^(-1)and 0.25 g·kg^(-1)·d^(-1),respectively.Results:A total of 229 patients with IS who failed the first-line treatments were collected.At the end of the MgSO_(4)+ACTH combination treatment,the seizure-free rate was 48.5%(111/229),and the resolution of hypsarrhythmia on electroencephalogram(EEG)was 72.1%(165/229).About 21.4%(49/229)of patients showed side effects,including infectious diseases,hypokalemia,and diarrhea.Interpretation:For patients with IS who failed first-line treatments,in terms of the seizure-free rate and resolution of hypsarrhythmia on EEG,MgSO_(4)+ACTH combination therapy can be considered.
文摘Fungal and bacterial diseases, directly infecting various parts of body, have received much attention in recent years. Bacterial infections, such as Tinea Pedis, Pityriasis versicolor and Mycetoma can secondarily occur in superficial fungal damaged skin. They often occur in immune compromised individuals including diabetics and patients with peripheral arterial diseases. Mycetoma infections can travel through the bloodstream affecting different organs. In this paper, we investigate the photo-inactivation of the pathogens causing Tinea Pedis, Pityriasis versicolor, and Mycetoma infections in three therapy resistant patients without photosensitizing drugs. We have used a combination of visible to near-infrared (VIS/NIR) laser beams in association with blue (B), red (R) and ultra-violet (UV) light emitted diodes (LEDs) with incident doses of 0.63 - 21.43 J/cm2. These beams have minimum side effects on the normal part of the skin. According to the physicians’ assessments, all case study patients achieved an observable progress such as decreases in inflammatory lesions, rapid process of wound healing and scars improvements. Side effects such as inflammation, crusting, or hypopigmentation were not observed. The presented irradiation protocol may be a valuable complementary treatment for patients suffering from fungal and bacterial skin infections.
基金supported by the Zhejiang Lab,China(No.2020KB0AC02)the Zhejiang Provincial Key R&D Program,China(Nos.2022C01022,2022C01119,and 2021C03003)+2 种基金the National Natural Science Foundation of China(Nos.T2293723 and 61972347)the Zhejiang Provincial Natural Science Foundation,China(No.LR19F020005)the Fundamental Research Funds for the Central Universities,China(No.226-2022-00051)。
文摘The deformability and high degree of freedom of mollusks bring challenges in mathematical modeling and synthesis of motions.Traditional analytical and statistical models are limited by either rigid skeleton assumptions or model capacity,and have difficulty in generating realistic and multi-pattern mollusk motions.In this work,we present a large-scale dynamic pose dataset of Drosophila larvae and propose a motion synthesis model named Path2Pose to generate a pose sequence given the initial poses and the subsequent guiding path.The Path2Pose model is further used to synthesize long pose sequences of various motion patterns through a recursive generation method.Evaluation analysis results demonstrate that our novel model synthesizes highly realistic mollusk motions and achieves state-of-the-art performance.Our work proves high performance of deep neural networks for mollusk motion synthesis and the feasibility of long pose sequence synthesis based on the customized body shape and guiding path.
基金supported by grants from the National Natural Science Foundation of China(32171014,31970940,31671100,31622027)the Zhejiang Provincial Natural Science Foundation of China(LR18H090001)+1 种基金the Non-profit Central Research Institute Fund of the Chinese Academy of Medical Sciences(2018PT31041)the Program for Introducing Talents in Discipline to Universities,the Fundamental Research Funds for Central Universities(2021FZZX001-37).
文摘While somatosensory over-reactivity is a common feature of autism spectrum disorders such as fragile X syndrome(FXS),the thalamic mechanisms underlying this remain unclear.Here,we found that the developmental elimination of synapses formed between the principal nucleus of V(PrV)and the ventral posterior medial nucleus(VPm)of the somatosensory system was delayed in fragile X mental retardation 1 gene knockout(Fmr1 KO)mice,while the developmental strengthening of these synapses was disrupted.Immunohistochemistry showed excessive VGluT2 puncta in mutants at P12–13,but not at P7–8 or P15–16,confirming a delay in somatic pruning of PrV-VPm synapses.Impaired synaptic function was associated with a reduction in the frequency of quantal AMPA events,as well as developmental deficits in presynaptic vesicle size and density.Our results uncovered the developmental impairment of thalamic relay synapses in Fmr1 KO mice and suggest that a thalamic contribution to the somatosensory over-reactivity in FXS should be considered.
基金Project supported by the National Natural Science Foundation of China(Nos.61735016,81771877,and 61975178)the Zhejiang Provincial Natural Science Foundation of China(No.LR20F050002)+2 种基金the Key R&D Program of Zhejiang Province,China(No.2021C03001)the CAMS Innovation Fund for Medical Sciences,China(No.2019-I2M-5-057)the Fundamental Research Funds for the Central Universities,China。
文摘The Shack-Hartmann wavefront sensor(SHWS)is an essential tool for wavefront sensing in adaptive optical microscopes.However,the distorted spots induced by the complex wavefront challenge its detection performance.Here,we propose a deep learning based wavefront detection method which combines point spread function image based Zernike coefficient estimation and wavefront stitching.Rather than using the centroid displacements of each micro-lens,this method first estimates the Zernike coefficients of local wavefront distribution over each micro-lens and then stitches the local wavefronts for reconstruction.The proposed method can offer low root mean square wavefront errors and high accuracy for complex wavefront detection,and has potential to be applied in adaptive optical microscopes.
文摘Human cognition plays a crucial role in our daily life.It enables us to perceive a constant influx of inputs,to memorize the scenarios,and to reason or decide their outcomes(Thagard,2005).Abnormal cognitive function,which is usually involved in neurological and mental diseases,such as chronic pain,mood disorders,autism,dementia,often seriously deteriorates individuals’life quality and brings inexhaustible social problems.
基金supported by China National Gene Bank(CNGB)financially supported by the National Natural Science Foundation of China(31670742)the Natural Science Foundation of Guangdong Province,China(2021A1515011109)。
文摘The genetically engineered pig is regarded as an optimal source of organ transplantation for humans and an excellent model for human disease research,given its comparable physiology to human beings.A myriad of single-cell RNA sequencing(sc RNA-seq)data on humans has been reported,but such data on pigs are scarce.Here,we apply sc RNA-seq technology to study the cellular heterogeneity of 3-month-old pig lungs,generating the single-cell atlas of 13,580 cells covering 16 major cell types.Based on these data,we systematically characterize the similarities and differences in the cellular cross-talk and expression patterns of respiratory virus receptors in each cell type of pig lungs compared with human lungs.Furthermore,we analyze pig lung xenotransplantation barriers and reported the cell-type expression patterns of 10 genes associated with pig-to-human immunobiological incompatibility and coagulation dysregulation.We also investigate the conserved transcription factors(TFs)and their candidate target genes and constructed five conserved TF regulatory networks in the main cell types shared by pig and human lungs.Finally,we present a comprehensive and openly accessible online platform,Scdb Lung.Our sc RNA-seq atlas of the domestic pig lung and Scdb Lung database can guide pig lung research and clinical applicability.
基金This work was supported by grants from the Natural Science Foundation of China(31430036,91742116,U1801681)National Key Basic Research Program of China(2015CB553500)+3 种基金Key Research Program of Frontier Sciences(QYZDJ-SSW-SMC002)Strategic Priority Research Program of Chinese Academy of Science(XDB32020100)Shanghai Municipal Science and Technology Major Project(2018SHZDZX05)the Shanghai Municipal Science and Technology Commission(17ZR1435300 to SZZ).
文摘Background:Parkinson’s disease(PD)is characterized by a chronic loss of dopaminergic neurons and the presence of proteinaceous inclusions(Lewy bodies)within some remaining neurons in the substantia nigra.Recently,astroglial inclusion body has also been found in some neurodegenerative diseases including PD.However,the underlying molecular mechanisms of how astroglial protein aggregation forms remain largely unknown.Here,we investigated the contribution ofαB-crystallin(CRYAB),a small heat shock protein,inα-synuclein inclusion formation in astrocytes.Methods:Small interfering RNA(siRNA)-mediated CRYAB(siCRYAB)knockdown or CRYAB overexpression was performed to investigate the impact of CRYAB on the autophagy in human glioblastoma cell line U251 cells.Coimmunoprecipitation(co-IP)and immunoblotting were used to dissect the interaction among multiple proteins.The clearance ofα-synuclein in vitro was evaluated by immunocytochemistry.CRYAB transgenic mice and transgenic mice overexpressing A30P mutant form of humanα-synuclein were used to examine the influence of CRYAB toα-synuclein accumulation in vivo.Results:We found that knockdown of CRYAB in U251 cells or primary cultured astrocytes resulted in a marked augmentation of autophagy activity.In contrast,exogenous CRYAB disrupted the assembly of the BAG3-HSPB8-HSC70 complex via binding with BAG3,thereby suppressing the autophagy activity.Furthermore,CRYAB-regulated autophagy has relevance to PD pathogenesis.Knockdown of CRYAB remarkably promoted cytoplasmic clearance ofα-synuclein preformed fibrils(PFFs).Conversely,selective overexpression of CRYAB in astrocytes markedly suppressed autophagy leading to the accumulation of α-synuclein aggregates in the brain of transgenic mice expressing humanα-synuclein A30P mutant.Conclusions:This study reveals a novel function for CRYAB as a natural inhibitor of astrocytic autophagy and shows that knockdown of CYRAB may provide a therapeutic target against proteinopathies such as synucleinopathies.
基金This work was supported by Science and Technology Innovation 2030-Major Project(2021ZD0203501)the National Natural Science Foundation of China(81930030,31771109,and 31722023)+5 种基金the National Key R&D Program of China(2019YFA0508603)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-057)Project for Hangzhou Medical Disciplines of ExcellenceKey Project for Hangzhou Medical Disciplinesthe Fundamental Research Funds for the Central Universities of China(2018XZZX002-02,2019XZZX001-01-04,and 2019FZA7009)the National Postdoctoral Program for Innovative Talents(BX2021263).
文摘CaMKII is essential for long-term potentiation(LTP),a process in which synaptic strength is increased following the acquisition of information.Among the four CaMKII isoforms,γCaMKII is the one that mediates the LTP of excitatory synapses onto inhibitory interneurons(LTPE→I).However,the molecular mechanism underlying howγCaMKII mediates LTPE→I remains unclear.Here,we show thatγCaMKII is highly enriched in cultured hippocampal inhibitory interneurons and opts to be activated by higher stimulating frequencies in the 10–30 Hz range.Following stimulation,γCaMKII is translocated to the synapse and becomes co-localized with the postsynaptic protein PSD-95.Knocking downγCaMKII prevents the chemical LTP-induced phosphorylation and trafficking of AMPA receptors(AMPARs)in putative inhibitory interneurons,which are restored by overexpression ofγCaMKII but not its kinase-dead form.Taken together,these data suggest thatγCaMKII decodes NMDAR-mediated signaling and in turn regulates AMPARs for expressing LTP in inhibitory interneurons.
基金supported by the National Natural Science Foundation of China(31702074 and 31872309)Sanming Project of Medicine in Shenzhen(SZSM202011012)Science,Technology and Innovation Commission of Shenzhen Municipality(JCYJ20170412153100794)。
文摘Parkinson's disease(PD)is a neurodegenerative disease,leading to the impairment of movement execution.PD pathogenesis has been largely investigated,either limited to bulk transcriptomic levels or at certain cell types,which failed to capture the cellular heterogeneity and intrinsic interplays among distinct cell types.Here,we report the application of single-nucleus RNA-seq on midbrain,striatum,and cerebellum of theα-syn-A53 T mouse,a well-established PD mouse model,and matched controls,generating the first single cell transcriptomic atlas for the PD model mouse brain composed of 46,174 individual cells.Additionally,we comprehensively depicte the dysfunctions in PD pathology,covering the elevation of NF-k B activity,the alteration of ion channel components,the perturbation of protein homeostasis network,and the dysregulation of glutamatergic signaling.Notably,we identify a variety of cell types closely associated with PD risk genes.Taken together,our study provides valuable resources to systematically dissect the molecular mechanism of PD pathogenesis at the single-cell resolution,which facilitates the development of novel approaches for diagnosis and therapies against PD.
基金supported by a grant from the Health Research New Zealand(HRC)22/559(to AJG and LB)。
文摘Moderate to severe perinatal hypoxic-ischemic encephalopathy occurs in~1 to 3/1000 live births in high-income countries and is associated with a significant risk of death or neurodevelopmental disability.Detailed assessment is important to help identify highrisk infants,to help families,and to support appropriate interventions.A wide range of monitoring tools is available to assess changes over time,including urine and blood biomarkers,neurological examination,and electroencephalography.At present,magnetic resonance imaging is unique as although it is expensive and not suited to monitoring the early evolution of hypoxic-ischemic encephalopathy by a week of life it can provide direct insight into the anatomical changes in the brain after hypoxic-ischemic encephalopathy and so offers strong prognostic information on the long-term outcome after hypoxic-ischemic encephalopathy.This review investigated the temporal dynamics of neonatal hypoxic-ischemic encephalopathy injuries,with a particular emphasis on exploring the correlation between the prognostic implications of magnetic resonance imaging scans in the first week of life and their relationship to long-term outcome prediction,particularly for infants treated with therapeutic hypothermia.A comprehensive literature search,from 2016 to 2024,identified 20 pertinent articles.This review highlights that while the optimal timing of magnetic resonance imaging scans is not clear,overall,it suggests that magnetic resonance imaging within the first week of life provides strong prognostic accuracy.Many challenges limit the timing consistency,particularly the need for intensive care and clinical monitoring.Conversely,although most reports examined the prognostic value of scans taken between 4 and 10 days after birth,there is evidence from small numbers of cases that,at times,brain injury may continue to evolve for weeks after birth.This suggests that in the future it will be important to explore a wider range of times after hypoxic-ischemic encephalopathy to fully understand the optimal timing for predicting long-term outcomes.
