Amyotrophic lateral sclerosis is a devastating neurodegenerative disease for which the current treatment approaches remain severely limited.The principal pathological alterations of the disease include the selective d...Amyotrophic lateral sclerosis is a devastating neurodegenerative disease for which the current treatment approaches remain severely limited.The principal pathological alterations of the disease include the selective degeneration of motor neurons in the brain,brainstem,and spinal cord,as well as abnormal protein deposition in the cytoplasm of neurons and glial cells.The biological markers under extensive scrutiny are predominantly located in the cerebrospinal fluid,blood,and even urine.Among these biomarke rs,neurofilament proteins and glial fibrillary acidic protein most accurately reflect the pathologic changes in the central nervous system,while creatinine and creatine kinase mainly indicate pathological alterations in the peripheral nerves and muscles.Neurofilament light chain levels serve as an indicator of neuronal axonal injury that remain stable throughout disease progression and are a promising diagnostic and prognostic biomarker with high specificity and sensitivity.However,there are challenges in using neurofilament light chain to diffe rentiate amyotrophic lateral sclerosis from other central nervous system diseases with axonal injury.Glial fibrillary acidic protein predominantly reflects the degree of neuronal demyelination and is linked to non-motor symptoms of amyotrophic lateral sclerosis such as cognitive impairment,oxygen saturation,and the glomerular filtration rate.TAR DNA-binding protein 43,a pathological protein associated with amyotrophic lateral sclerosis,is emerging as a promising biomarker,particularly with advancements in exosome-related research.Evidence is currently lacking for the value of creatinine and creatine kinase as diagnostic markers;however,they show potential in predicting disease prognosis.Despite the vigorous progress made in the identification of amyotrophic lateral sclerosis biomarkers in recent years,the quest for definitive diagnostic and prognostic biomarke rs remains a formidable challenge.This review summarizes the latest research achievements concerning blood biomarkers in amyotrophic lateral sclerosis that can provide a more direct basis for the differential diagnosis and prognostic assessment of the disease beyond a reliance on clinical manifestations and electromyography findings.展开更多
The period of infancy is important for the formation of social behaviors due to the rapid postnatal development of the brain functions underlying emotions and social skills.Ilustration of the neural circuits involved ...The period of infancy is important for the formation of social behaviors due to the rapid postnatal development of the brain functions underlying emotions and social skills.Ilustration of the neural circuits involved in the developmental process of infant social behaviors could foster new therapies for some social impairments occurring in the infant period.展开更多
Social behaviors are crucial for gregarious animals,including humans.In order to exhibit appropriate behaviors in a complex social context,such as mating,aggression,avoidance,and cooperation,individuals need to rememb...Social behaviors are crucial for gregarious animals,including humans.In order to exhibit appropriate behaviors in a complex social context,such as mating,aggression,avoidance,and cooperation,individuals need to remember their previous experiences with other members and accurately recognize them when they meet again.This ability is called“social memory”[1].Many psychiatric disorders in humans,such as autism spectrum disorder,attention deficit hyperactivity disorder,and schizophrenia,are characterized by social memory impairments.Patients with these disorders,along with corresponding animal models,often show defects associated with the thalamic reticular nucleus(TRN).The TRN,a thin layer of neurons surrounding the thalamus,mainly regulates and coordinates the transfer of information between the cortex and the thalamus,playing a role in higher brain functions such as consciousness,attention,and sensory processing.However,whether the TRN is involved in social memory remains unknown.展开更多
Hereditary spastic paraplegias(HSPs)refer to a genetically and clinically heterogeneous group of neurodegenerative disorders characterized by the degeneration of motor neurons.To date,a significant number of patients ...Hereditary spastic paraplegias(HSPs)refer to a genetically and clinically heterogeneous group of neurodegenerative disorders characterized by the degeneration of motor neurons.To date,a significant number of patients still have not received a definite genetic diagnosis.Therefore,identifying unreported causative genes continues to be of great importance.Here,we perform whole-exome sequencing in a cohort of Chinese HSP patients.Three homozygous variants(p.L604W,p.S517F,and p.T984A)within the sterol regulatory element-binding factor 2(SREBF2)gene are identified in one autosomal recessive family and two sporadic patients,respectively.Co-segregation is confirmed by Sanger sequencing in all available members.The three variants are rare in the public or in-house database and are predicted to be damaging.The biological impacts of variants in SREBF2 are examined by functional experiments in patient-derived fibroblasts and Drosophila.We find that the variants upregulate cellular cholesterol due to the overactivation of SREBP2,eventually impairing the autophagosomal and lysosomal functions.The overexpression of the mature form of SREBP2 leads to locomotion defects in Drosophila.Our findings identify SREBF2 as a causative gene for HSP and highlight the impairment of cholesterol as a critical pathway for HSP.展开更多
A growing interest in the comprehensive pathogenic mechanisms of psychiatric disorders from the perspective of the microbiome has been witnessed in recent decades;the intrinsic link between microbiota and brain functi...A growing interest in the comprehensive pathogenic mechanisms of psychiatric disorders from the perspective of the microbiome has been witnessed in recent decades;the intrinsic link between microbiota and brain function through the microbiota-gut-brain axis or other pathways has gradually been realized.However,little research has focused on viruses–entities characterized by smaller dimensions,simpler structures,greater diversity,and more intricate interactions with their surrounding milieu compared to bacteria.To date,alterations in several populations of bacteriophages and viruses have been documented in both mouse models and patients with psychiatric disorders,including schizophrenia,major depressive disorder,autism spectrum disorder,and Alzheimer’s disease,accompanied by metabolic disruptions that may directly or indirectly impact brain function.In addition,eukaryotic virus infection-mediated brain dysfunction provides insights into the psychiatric pathology involving viruses.Efforts towards virus-based diagnostic and therapeutic approaches have primarily been documented.However,limitations due to the lack of large-scale cohort studies,reliability,clinical applicability,and the unclear role of viruses in microbiota interactions pose a challenge for future studies.Nevertheless,it is conceivable that investigations into viruses herald a new era in the field of precise psychiatry.展开更多
Metal alloy anode materials with high specific capacity and low voltage have recently gained significant attention due to their excellent electrochemical performance and the ability to suppress dendrite growth.However...Metal alloy anode materials with high specific capacity and low voltage have recently gained significant attention due to their excellent electrochemical performance and the ability to suppress dendrite growth.However,experimental investigations of metal alloys can be time-consuming and expensive,often requiring extensive experimental design and effort.In this study,we developed a machine learning model based on the Crystal Graph Convolutional Neural Network(CGCNN)to screen alloy anode materials for seven battery systems,including lithium(Li),sodium(Na),potassium(K),zinc(Zn),magnesium(Mg),calcium(Ca),and aluminum(Al).We utilized data with tens of thousands of alloy materials from the Materials Project(MP)and Automatic FLOW for Materials Discovery(AFLOW)databases.Without any experimental voltage input,we identified over 30 alloy systems that have been experimentally validated with good precision.Additionally,we predicted over 100 alloy anodes with low potential and high specific capacity.We hope this work to spur further interest in employing advanced machine learning models for the design of battery materials.展开更多
Empathy is one of the most important abilities for social animals.In a world that is largely socially constructed,when encountering altered affective states of others,particularly negative states,individuals often exh...Empathy is one of the most important abilities for social animals.In a world that is largely socially constructed,when encountering altered affective states of others,particularly negative states,individuals often exhibit evolutionarily conserved empathic behaviors,such as mirroring,consolation,and helping[l,2].Appropriate empathic behaviors can foster the consolidation of social relationships.Previous studies have suggested that both male and female rodents show some empathic behaviors when facing affective conspecifics[1].However,the role of sex in different empathic behaviors remains largely unexplored.Therefore,there is a need to probe whether animals show sex-dependent empathic behavior and which neural circuits modulate these distinct behaviors.展开更多
Reward or stress,which exists extensively,causes resilient emotional fluctuations under common situations.However,reward or stress is a typical trigger for manic or depressive episodes of bipolar disorder(BD),which is...Reward or stress,which exists extensively,causes resilient emotional fluctuations under common situations.However,reward or stress is a typical trigger for manic or depressive episodes of bipolar disorder(BD),which is corroborated by psychological theory,biological findings,and psychosocial treatment approaches[1,2].During an episode of BD,the affective aberration can be persistent and switchable,accompanied by opposite constellations of cognitive and psychomotor symptoms.Characterized by uncontrollable mood ranging in severity,duration,and polarity,to disentangle the pathophysiology mechanism of BD is to delineate the mystery of affective fluctuations driven by reward or stress.展开更多
Objective:Whether vortioxetine has a utility as an adjuvant drug in the treatment of bipolar depression remains controversial.This study aimed to validate the efficacy and safety of vortioxetine in bipolar depression....Objective:Whether vortioxetine has a utility as an adjuvant drug in the treatment of bipolar depression remains controversial.This study aimed to validate the efficacy and safety of vortioxetine in bipolar depression.Methods:Patients with bipolarⅡdepression were enrolled in this prospective,two-center,randomized,12-week pilot trial.The main indicator for assessing treatment effectiveness was a Montgomery-Asberg Depression Rating Scale(MADRS)of≥50%.All eligible patients initially received four weeks of lurasidone monotherapy.Patients who responded well continued to receive this kind of monotherapy.However,no-response patients were randomly assigned to either valproate or vortioxetine treatment for eight weeks.By comprehensively comparing the results of MADRS over a period of 4-12 weeks,a systematic analysis was conducted to determine whether vortioxetine could be used as an adjuvant drug for treating bipolar depression.Results:Thirty-seven patients responded to lurasidone monotherapy,and 60 patients were randomly assigned to the valproate or vortioxetine group for eight weeks.After two weeks of combined valproate or vortioxetine treatment,the MADRS score in the vortioxetine group was significantly lower than that in the valproate group.There was no difference in the MADRS scores between the two groups at 8 and 12 weeks.The incidence of side effects did not significantly differ between the valproate and vortioxetine groups.Importantly,three patients in the vortioxetine group appeared to switch to mania or hypomania.Conclusions:This study suggested that lurasidone combination with vortioxetine might have potential benefits to bipolar II depression in the early stage,while disease progression should be monitored closely for the risk of switching to mania.展开更多
KCNA1 is the coding gene for Kv1.1 voltage-gated potassium-channelαsubunit.Three variants of KCNA1 have been reported to manifest as paroxysmal kinesigenic dyskinesia(PKD),but the correlation between them remains unc...KCNA1 is the coding gene for Kv1.1 voltage-gated potassium-channelαsubunit.Three variants of KCNA1 have been reported to manifest as paroxysmal kinesigenic dyskinesia(PKD),but the correlation between them remains unclear due to the phenotypic complexity of KCNA1 variants as well as the rarity of PKD cases.Using the whole exome sequencing followed by Sanger sequencing,we screen for potential pathogenic KCNA1 variants in patients clinically diagnosed with paroxysmal movement disorders and identify three previously unreported missense variants of KCNA1 in three unrelated Chinese families.The proband of one family(c.496G>A,p.A166T)manifests as episodic ataxia type 1,and the other two(c.877G>A,p.V293I and c.1112C>A,p.T371A)manifest as PKD.The pathogenicity of these variants is confirmed by functional studies,suggesting that p.A166T and p.T371A cause a loss-of-function of the channel,while p.V293I leads to a gain-of-function with the property of voltage-dependent gating and activation kinetic affected.By reviewing the locations of PKD-manifested KCNA1 variants in Kv1.1 protein,we find that these variants tend to cluster around the pore domain,which is similar to epilepsy.Thus,our study strengthens the correlation between KCNA1 variants and PKD and provides more information on genotype–phenotype correlations of KCNA1 channelopathy.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
Leukodystrophies represent a group of cerebral white matter disorders that mainly affect axon-glia units.The disorders are clinically diverse and display significant genetic variability.It is challenging to differenti...Leukodystrophies represent a group of cerebral white matter disorders that mainly affect axon-glia units.The disorders are clinically diverse and display significant genetic variability.It is challenging to differentiate hereditary leukodystrophies,particularly those that present in adulthood,from acquired leukodystrophies and other genetic disorders,such as multiple sclerosis(MS)or hereditary spastic paraplegia(HSP)(Wei et al.,2021).Over the past few decades,a series of causative genes associated with leukodystrophies have been identified(Kohler et al.,2018).Nevertheless,a significant proportion of patients still lack a precise molecular diagnosis.展开更多
Male sexual behavior is an innate social behavior crucial for reproduction[1].Previous studies have identified several brain regions crucial for the control of both sexual and aggressive behaviors in males.Yet,molecul...Male sexual behavior is an innate social behavior crucial for reproduction[1].Previous studies have identified several brain regions crucial for the control of both sexual and aggressive behaviors in males.Yet,molecularly specified neural circuits that specifically control male sexual behavior remain elusive.Consistent with the inherently rewarding nature of sexual behavior,previous research has implicated the role of the dopamine system in regulating sexual desire[2].However,the interaction between reward and copulation at the circuit level remains largely unexplored.Besides,it is unclear if the associated neural pathways are specific in modulating sexual reward.展开更多
Exhibiting appropriate social behavior toward conspecifics is crucial for survival within a social group.For instance,after a conflict,it is essential for the loser to stay away from the victor to avoid further harm[1...Exhibiting appropriate social behavior toward conspecifics is crucial for survival within a social group.For instance,after a conflict,it is essential for the loser to stay away from the victor to avoid further harm[1].Previous studies have indicated that the anterior ventrolateral part of the ventromedial hypothalamus(aVMHvl)plays a pivotal role in social fear and avoidance following a social defeat.However,the precise mechanisms through which the aVMHvl effectively transforms social defeat to subsequent behavioral changes in social interaction remain largely unknown.展开更多
Traditional ferroelectric materials,such as lead zirconate titanate(PZT)ceramics,exhibit positive strain when subjected to an electric field along the polarization direction.In contrast,the piezoelectric polymer polyv...Traditional ferroelectric materials,such as lead zirconate titanate(PZT)ceramics,exhibit positive strain when subjected to an electric field along the polarization direction.In contrast,the piezoelectric polymer polyvinylidene fluoride(PVDF)and its copolymer P(VDF-TrFE)display unique negative strain properties.While extensive research has focused on understanding the origin and mechanisms of this negative strain,limited efforts have been directed toward regulating these properties.This study optimizes the electro-strain and ferroelectric properties of P(VDF-TrFE)piezoelectric films through the synergistic effect of PbTiO_(3)nanosheets and an in-situ electrostatic field.Our results demonstrate that while the incorporation of PbTiO_(3)nanosheets does not notably enhance ferroelectricity,it significantly improves electro-strain properties,particularly negative strain,which increases from-0.097%to-0.185%,an enhancement of 91%.Moreover,the ferroelectric polarization and positive strain of P(VDF-TrFE)are further enhanced under the combined influence of PbTiO_(3)nanosheets and in-situ electrostatic field,increasing maximum polarization from 10.79μmC/cm^(2)to 13.16μmC/cm^(2),a 22%improvement,and positive strain from 0.213%to 0.267%,a 25%enhancement.We propose a possible mechanism for these improvements,attributed to the enhanced flexibility of the amorphous phase and increased content of polar b-phase in P(VDF-TrFE)films under this synergistic effect.This work highlights novel strategies for controlling the electro-strain and ferroelectric properties of P(VDF-TrFE)piezoelectric films.展开更多
Dendritic cells(DCs)serve as the primary antigen-presenting cells in autoimmune diseases,like rheumatoid arthritis(RA),and exhibit distinct signaling profiles due to antigenic diversity.Type II collagen(CII)has been r...Dendritic cells(DCs)serve as the primary antigen-presenting cells in autoimmune diseases,like rheumatoid arthritis(RA),and exhibit distinct signaling profiles due to antigenic diversity.Type II collagen(CII)has been recognized as an RA-specific antigen;however,little is known about CII-stimulated DCs,limiting the development of RA-specific therapeutic interventions.In this study,we show that CII-stimulated DCs display a preferential gene expression profile associated with migration,offering a new perspective for targeting DC migration in RA treatment.Then,saikosaponin D(SSD)was identified as a compound capable of blocking CII-induced DC migration and effectively ameliorating arthritis.Optineurin(OPTN)is further revealed as a potential SSD target,with Optn deletion impairing CII-pulsed DC migration without affecting maturation.Function analyses uncover that OPTN prevents the proteasomal transport and ubiquitin-dependent degradation of C-C chemokine receptor 7(CCR7),a pivotal chemokine receptor in DC migration.Optn-deficient DCs exhibit reduced CCR7 expression,leading to slower migration in CII-surrounded environment,thus alleviating arthritis progression.Our findings underscore the significance of antigen-specific DC activation in RA and suggest OPTN is a crucial regulator of CII-specific DC migration.OPTN emerges as a promising drug target for RA,potentially offering significant value for the therapeutic management of RA.展开更多
Disease-associated microglia(DAM)are observed in neurodegenerative diseases,demyelinating disorders,and aging.However,the spatiotemporal dynamics and evolutionary trajectory of DAM during the progression of amyotrophi...Disease-associated microglia(DAM)are observed in neurodegenerative diseases,demyelinating disorders,and aging.However,the spatiotemporal dynamics and evolutionary trajectory of DAM during the progression of amyotrophic lateral sclerosis(ALS)remain unclear.Using a mouse model of ALS that expresses a human SOD1 gene mutation,we found that the microglia subtype DAM begins to appear following motor neuron degeneration,primarily in the brain stem and spinal cord.Using reverse transcription quantitative polymerase chain reaction,RNAscope in situ hybridization,and flow cytometry,we found that DAM increased in number as the disease progressed,reaching their peak in the late disease stage.DAM responded to disease progression in both SOD1G93A mice and sporadic ALS and C9orf72-mutated patients.Motor neuron loss in SOD1G93A mice exhibited 2 accelerated phases:P90 to P110(early stage)and P130 to P150(late stage).Some markers were synchronized with the accelerated phase of motor neuron loss,suggesting that these proteins may be particularly responsive to disease progression.Through pseudotime trajectory analysis,we tracked the dynamic transition of homeostatic microglia into DAM and cluster 6 microglia.Interestingly,we used the colony-stimulating factor 1 receptor(CSF1R)inhibitor PLX5622 to deplete microglia in SOD1G93A mice and observed that DAM survival is independent of CSF1R.An in vitro phagocytosis assay directly confirmed that DAM could phagocytose more beads than other microglia subtypes.These findings reveal that the induction of the DAM phenotype is a shared cross-species and cross-subtype characteristic in ALS.Inducing the DAM phenotype and enhancing its function during the early phase of disease progression,or the time window between P130 and P150 where motor neuron loss slows,could serve as a neuroprotective strategy for ALS.展开更多
Adenosine(Ado)is significantly elevated in the tumor microenvironment(TME)compared to normal tissues.It binds to adenosine receptors(AdoRs),suppressing tumor antigen presentation and immune cell activation,thereby inh...Adenosine(Ado)is significantly elevated in the tumor microenvironment(TME)compared to normal tissues.It binds to adenosine receptors(AdoRs),suppressing tumor antigen presentation and immune cell activation,thereby inhibiting tumor adaptive immunity.Ado downregulates major histocompatibility complex II(MHC II)and co-stimulatory factors on dendritic cells(DCs)and macrophages,inhibiting antigen presentation.It suppresses anti-tumor cytokine secretion and T cell activation by disrupting T cell receptor(TCR)binding and signal transduction.Ado also inhibits chemokine secretion and KCa3.1 channel activity,impeding effector T cell trafficking and infiltration into the tumor site.Furthermore,Ado diminishes T cell cytotoxicity against tumor cells by promoting immune-suppressive cytokine secretion,upregulating immune checkpoint proteins,and enhancing immune-suppressive cell activity.Reducing Ado production in the TME can significantly enhance anti-tumor immune responses and improve the efficacy of other immunotherapies.Preclinical and clinical development of inhibitors targeting Ado generation or AdoRs is underway.Therefore,this article will summarize and analyze the inhibitory effects and molecular mechanisms of Ado on tumor adaptive immunity,as well as provide an overview of the latest advancements in targeting Ado pathways in anti-tumor immune responses.展开更多
Macrophage senescence,manifested by the special form of durable cell cycle arrest and chronic low-grade inflammation like senescence-associated secretory phenotype,has long been consid-ered harmful.Persistent senescen...Macrophage senescence,manifested by the special form of durable cell cycle arrest and chronic low-grade inflammation like senescence-associated secretory phenotype,has long been consid-ered harmful.Persistent senescence of macrophages may lead to maladaptation,immune dysfunction,and finally the development of age-related diseases,infections,autoimmune diseases,and malignancies.However,it is a ubiquitous,multi-factorial,and dynamic complex phenomenon that also plays roles in remodeled processes,including wound repair and embryogenesis.In this review,we summarize some general molecular changes and several specific biomarkers during macrophage senescence,which may bring new sight to recognize senescent macrophages in different conditions.Also,we take an in-depth look at the functional changes in senescent macrophages,including metabolism,autophagy,polarization,phagocytosis,antigen presentation,and infiltration or recruitment.Furthermore,some degenerations and diseases associated with senescent macrophages as well as the mechanisms or relevant genetic regulations of senescent macrophages are integrated,not only emphasizing the possibility of regulating macrophage senescence to benefit age-associated diseases but also has an implication on the finding of potential tar-gets ordrugs clinically.展开更多
Plant high-affinity K^(+) transporters(HKTs)mediate Na^(+) and K^(+) uptake,maintain Na^(+)/K^(+) homeostasis,and therefore play crucial roles in plant salt tolerance.In this study,we present cryoelectron microscopy s...Plant high-affinity K^(+) transporters(HKTs)mediate Na^(+) and K^(+) uptake,maintain Na^(+)/K^(+) homeostasis,and therefore play crucial roles in plant salt tolerance.In this study,we present cryoelectron microscopy structures of HKTs from two classes,classI HKT1;1 from Arabidopsis thaliana(AtHKT1;1)and class II HKT2;1 from Triticum aestivum(TaHKT2;1),in both Na^(+) -and K^(+) -bound states at 2.6-to 3.0-A resolutions.BothAtHKT1;1and TaHKT2;1function ashomodimers.Each HKT subunit consists of four tan-dem domain units(D1-D4)with a repeated K^(+) -channel-like M-P-M topology.In each subunit,D1-D4 assemble into an ion conduction pore with a pseudo-four-fold symmetry.Although both TaHKT2;1and AtHKT1;1 have only one putative Na^(+) ion bound in the selectivity filter with a similar coordination pattern,the two HKTs display different K^(+) binding modes in the filter.TaHKT2;1 has three K^(+) ions bound in the selec-tivity filter,but AtHKT1;1 has only two K^(+) ions bound in the filter,which has a narrowed external entrance due to the presence of a Ser residue in the first filter motif.These structures,along with compu-tational,mutational,and electrophysiological analyses,enable us to pinpoint key residues that are critical for the ion selectivity of HKTs.The findings provide new insights into the ion selectivity and ion transport mechanisms of plant HKTs and improve our understanding about how HKTs mediate plant salt tolerance and enhance crop growth.展开更多
文摘Amyotrophic lateral sclerosis is a devastating neurodegenerative disease for which the current treatment approaches remain severely limited.The principal pathological alterations of the disease include the selective degeneration of motor neurons in the brain,brainstem,and spinal cord,as well as abnormal protein deposition in the cytoplasm of neurons and glial cells.The biological markers under extensive scrutiny are predominantly located in the cerebrospinal fluid,blood,and even urine.Among these biomarke rs,neurofilament proteins and glial fibrillary acidic protein most accurately reflect the pathologic changes in the central nervous system,while creatinine and creatine kinase mainly indicate pathological alterations in the peripheral nerves and muscles.Neurofilament light chain levels serve as an indicator of neuronal axonal injury that remain stable throughout disease progression and are a promising diagnostic and prognostic biomarker with high specificity and sensitivity.However,there are challenges in using neurofilament light chain to diffe rentiate amyotrophic lateral sclerosis from other central nervous system diseases with axonal injury.Glial fibrillary acidic protein predominantly reflects the degree of neuronal demyelination and is linked to non-motor symptoms of amyotrophic lateral sclerosis such as cognitive impairment,oxygen saturation,and the glomerular filtration rate.TAR DNA-binding protein 43,a pathological protein associated with amyotrophic lateral sclerosis,is emerging as a promising biomarker,particularly with advancements in exosome-related research.Evidence is currently lacking for the value of creatinine and creatine kinase as diagnostic markers;however,they show potential in predicting disease prognosis.Despite the vigorous progress made in the identification of amyotrophic lateral sclerosis biomarkers in recent years,the quest for definitive diagnostic and prognostic biomarke rs remains a formidable challenge.This review summarizes the latest research achievements concerning blood biomarkers in amyotrophic lateral sclerosis that can provide a more direct basis for the differential diagnosis and prognostic assessment of the disease beyond a reliance on clinical manifestations and electromyography findings.
基金supported by grants from the National Natural Science Foundation of China(32125018,32071005,and 32171079)Zhejiang Provincial Natural Science Foundation of China(LD24H090002 and LZ24C090001)+2 种基金the Fundamental Research Funds for the Central Universities(226-2024-00133)the Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZDCX20211102)the MOE Frontiers Science Center for Brain Science&Brain-Machine Integration of Zhejiang University.
文摘The period of infancy is important for the formation of social behaviors due to the rapid postnatal development of the brain functions underlying emotions and social skills.Ilustration of the neural circuits involved in the developmental process of infant social behaviors could foster new therapies for some social impairments occurring in the infant period.
基金supported by grants from the National Natural Science Foundation of China(32125018 and 32071005)Zhejiang Provincial Natural Science Foundation of China(LD24H090002)+3 种基金Nanhu Brain-computer Interface Institute(010904008)Innovative Research Team of High-level Local Universities in Shanghai(SHSMUZDCX20211102)Fundamental Research Funds for the Central Universities(226-2024-00133)the MOE Frontiers Science Center for Brain Science&Brain-Machine Integration of Zhejiang University.
文摘Social behaviors are crucial for gregarious animals,including humans.In order to exhibit appropriate behaviors in a complex social context,such as mating,aggression,avoidance,and cooperation,individuals need to remember their previous experiences with other members and accurately recognize them when they meet again.This ability is called“social memory”[1].Many psychiatric disorders in humans,such as autism spectrum disorder,attention deficit hyperactivity disorder,and schizophrenia,are characterized by social memory impairments.Patients with these disorders,along with corresponding animal models,often show defects associated with the thalamic reticular nucleus(TRN).The TRN,a thin layer of neurons surrounding the thalamus,mainly regulates and coordinates the transfer of information between the cortex and the thalamus,playing a role in higher brain functions such as consciousness,attention,and sensory processing.However,whether the TRN is involved in social memory remains unknown.
基金supported by the grants from the National Natural Science Foundation of China to Zhi-Ying Wu(82230062,Beijing),Qiao Wei(82402156,Beijing),and Wanzhong Ge(31970668,Beijing)the research foundation for distinguished scholar of Zhejiang University(188020-193810101/089,Hangzhou)to Zhi-Ying Wu
文摘Hereditary spastic paraplegias(HSPs)refer to a genetically and clinically heterogeneous group of neurodegenerative disorders characterized by the degeneration of motor neurons.To date,a significant number of patients still have not received a definite genetic diagnosis.Therefore,identifying unreported causative genes continues to be of great importance.Here,we perform whole-exome sequencing in a cohort of Chinese HSP patients.Three homozygous variants(p.L604W,p.S517F,and p.T984A)within the sterol regulatory element-binding factor 2(SREBF2)gene are identified in one autosomal recessive family and two sporadic patients,respectively.Co-segregation is confirmed by Sanger sequencing in all available members.The three variants are rare in the public or in-house database and are predicted to be damaging.The biological impacts of variants in SREBF2 are examined by functional experiments in patient-derived fibroblasts and Drosophila.We find that the variants upregulate cellular cholesterol due to the overactivation of SREBP2,eventually impairing the autophagosomal and lysosomal functions.The overexpression of the mature form of SREBP2 leads to locomotion defects in Drosophila.Our findings identify SREBF2 as a causative gene for HSP and highlight the impairment of cholesterol as a critical pathway for HSP.
基金supported by The Research Project of Jinan Microecological Biomedicine Shandong Laboratory(JNL-2023001B)The National Key Research and Development Program of China(2023YFC2506200)+2 种基金The Zhejiang Provincial Key Research and Development Program(2021C03107)The Leading Talent of Scientific and Technological Innovation-“Ten Thousand Talents Program”of Zhejiang Province(2021R52016)The Fundamental Research Funds for the Central Universities(226-2022-00193,226-2022-00002,2023ZFJH01-01,and 2024ZFJH01-01).
文摘A growing interest in the comprehensive pathogenic mechanisms of psychiatric disorders from the perspective of the microbiome has been witnessed in recent decades;the intrinsic link between microbiota and brain function through the microbiota-gut-brain axis or other pathways has gradually been realized.However,little research has focused on viruses–entities characterized by smaller dimensions,simpler structures,greater diversity,and more intricate interactions with their surrounding milieu compared to bacteria.To date,alterations in several populations of bacteriophages and viruses have been documented in both mouse models and patients with psychiatric disorders,including schizophrenia,major depressive disorder,autism spectrum disorder,and Alzheimer’s disease,accompanied by metabolic disruptions that may directly or indirectly impact brain function.In addition,eukaryotic virus infection-mediated brain dysfunction provides insights into the psychiatric pathology involving viruses.Efforts towards virus-based diagnostic and therapeutic approaches have primarily been documented.However,limitations due to the lack of large-scale cohort studies,reliability,clinical applicability,and the unclear role of viruses in microbiota interactions pose a challenge for future studies.Nevertheless,it is conceivable that investigations into viruses herald a new era in the field of precise psychiatry.
基金supported by the National Key R&D Program of China(2023YFB2504000,YH)a start-up grant from Zhejiang University and the Fundamental Research Funds for the Central Universities(2021FZZX001,226-2024-00005)supported by Special Support Plan for High Level Talents in Zhejiang Province(2023R5231)。
文摘Metal alloy anode materials with high specific capacity and low voltage have recently gained significant attention due to their excellent electrochemical performance and the ability to suppress dendrite growth.However,experimental investigations of metal alloys can be time-consuming and expensive,often requiring extensive experimental design and effort.In this study,we developed a machine learning model based on the Crystal Graph Convolutional Neural Network(CGCNN)to screen alloy anode materials for seven battery systems,including lithium(Li),sodium(Na),potassium(K),zinc(Zn),magnesium(Mg),calcium(Ca),and aluminum(Al).We utilized data with tens of thousands of alloy materials from the Materials Project(MP)and Automatic FLOW for Materials Discovery(AFLOW)databases.Without any experimental voltage input,we identified over 30 alloy systems that have been experimentally validated with good precision.Additionally,we predicted over 100 alloy anodes with low potential and high specific capacity.We hope this work to spur further interest in employing advanced machine learning models for the design of battery materials.
基金supported by grants from the National Natural Science Foundation of China(32125018 and 32071005)the National Key Research and Development Program of China(2021YFA1101701)+5 种基金Zhejiang Provincial Natural Science Foundation of China(LD24H090002)the Nanhu Brain-computer Interface Institute(010904008)the Fundamental Research Funds for the Central Universities(226-2024-00133)the Key R&D Program of Zhejiang(2024SSYS0016)the Non-profit Central Research Institute Fund of the Chinese Academy of Medical Sciences(2023-PT310-01)the MOE Frontiers Science Center for Brain Science&Brain-Machine Integration of Zhejiang University.
文摘Empathy is one of the most important abilities for social animals.In a world that is largely socially constructed,when encountering altered affective states of others,particularly negative states,individuals often exhibit evolutionarily conserved empathic behaviors,such as mirroring,consolation,and helping[l,2].Appropriate empathic behaviors can foster the consolidation of social relationships.Previous studies have suggested that both male and female rodents show some empathic behaviors when facing affective conspecifics[1].However,the role of sex in different empathic behaviors remains largely unexplored.Therefore,there is a need to probe whether animals show sex-dependent empathic behavior and which neural circuits modulate these distinct behaviors.
基金supported by the National Key Research and Development Program of China(2023YFC2506200)the Leading Talent of Scientific and Technological Innovation-"Ten Thousand Talents Program"of Zhejiang Province(2021R52016).
文摘Reward or stress,which exists extensively,causes resilient emotional fluctuations under common situations.However,reward or stress is a typical trigger for manic or depressive episodes of bipolar disorder(BD),which is corroborated by psychological theory,biological findings,and psychosocial treatment approaches[1,2].During an episode of BD,the affective aberration can be persistent and switchable,accompanied by opposite constellations of cognitive and psychomotor symptoms.Characterized by uncontrollable mood ranging in severity,duration,and polarity,to disentangle the pathophysiology mechanism of BD is to delineate the mystery of affective fluctuations driven by reward or stress.
基金partially supported by the Construction Fund of Key Medical Disciplines of Hangzhou(No.OO2020491)the National Key Research and Development Program of China(No.2023YFC2506200)+4 种基金the Zhejiang Provincial Key Research and Development Program(No.2021C03107)the Research Project of Jinan Microecological Biomedicine Shandong Laboratory(No.JNL-2023001B)the Leading Talent of Scientific and Technological Innovation-“Ten Thousand Talents Program”of Zhejiang Province(No.2021R52016)the Innovation Team for Precision Diagnosis and Treatment of Major Brain Diseases(No.2020R01001)the Chinese Medical Education Association(No.2022KTZ004).
文摘Objective:Whether vortioxetine has a utility as an adjuvant drug in the treatment of bipolar depression remains controversial.This study aimed to validate the efficacy and safety of vortioxetine in bipolar depression.Methods:Patients with bipolarⅡdepression were enrolled in this prospective,two-center,randomized,12-week pilot trial.The main indicator for assessing treatment effectiveness was a Montgomery-Asberg Depression Rating Scale(MADRS)of≥50%.All eligible patients initially received four weeks of lurasidone monotherapy.Patients who responded well continued to receive this kind of monotherapy.However,no-response patients were randomly assigned to either valproate or vortioxetine treatment for eight weeks.By comprehensively comparing the results of MADRS over a period of 4-12 weeks,a systematic analysis was conducted to determine whether vortioxetine could be used as an adjuvant drug for treating bipolar depression.Results:Thirty-seven patients responded to lurasidone monotherapy,and 60 patients were randomly assigned to the valproate or vortioxetine group for eight weeks.After two weeks of combined valproate or vortioxetine treatment,the MADRS score in the vortioxetine group was significantly lower than that in the valproate group.There was no difference in the MADRS scores between the two groups at 8 and 12 weeks.The incidence of side effects did not significantly differ between the valproate and vortioxetine groups.Importantly,three patients in the vortioxetine group appeared to switch to mania or hypomania.Conclusions:This study suggested that lurasidone combination with vortioxetine might have potential benefits to bipolar II depression in the early stage,while disease progression should be monitored closely for the risk of switching to mania.
基金supported by grants from the National Natural Science Foundation of China(82101526,82171238,and 81330025)。
文摘KCNA1 is the coding gene for Kv1.1 voltage-gated potassium-channelαsubunit.Three variants of KCNA1 have been reported to manifest as paroxysmal kinesigenic dyskinesia(PKD),but the correlation between them remains unclear due to the phenotypic complexity of KCNA1 variants as well as the rarity of PKD cases.Using the whole exome sequencing followed by Sanger sequencing,we screen for potential pathogenic KCNA1 variants in patients clinically diagnosed with paroxysmal movement disorders and identify three previously unreported missense variants of KCNA1 in three unrelated Chinese families.The proband of one family(c.496G>A,p.A166T)manifests as episodic ataxia type 1,and the other two(c.877G>A,p.V293I and c.1112C>A,p.T371A)manifest as PKD.The pathogenicity of these variants is confirmed by functional studies,suggesting that p.A166T and p.T371A cause a loss-of-function of the channel,while p.V293I leads to a gain-of-function with the property of voltage-dependent gating and activation kinetic affected.By reviewing the locations of PKD-manifested KCNA1 variants in Kv1.1 protein,we find that these variants tend to cluster around the pore domain,which is similar to epilepsy.Thus,our study strengthens the correlation between KCNA1 variants and PKD and provides more information on genotype–phenotype correlations of KCNA1 channelopathy.
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supported by the grant(82230062)from the National Natural Science Foundation of China to Zhi-Ying Wu.
文摘Leukodystrophies represent a group of cerebral white matter disorders that mainly affect axon-glia units.The disorders are clinically diverse and display significant genetic variability.It is challenging to differentiate hereditary leukodystrophies,particularly those that present in adulthood,from acquired leukodystrophies and other genetic disorders,such as multiple sclerosis(MS)or hereditary spastic paraplegia(HSP)(Wei et al.,2021).Over the past few decades,a series of causative genes associated with leukodystrophies have been identified(Kohler et al.,2018).Nevertheless,a significant proportion of patients still lack a precise molecular diagnosis.
基金supported by grants from the National Natural Science Foundation of China(32125018 and 32071005)the National Key Research and Development Program of China(2021YFA1101701)+2 种基金the Fundamental Research Funds for the Central Universities,the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2023-PT310-01)the MOE Frontiers Science Center for Brain Science&Brain-Machine Integration of Zhejiang University,the Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZDCX20211102)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2023-PT310-01).
文摘Male sexual behavior is an innate social behavior crucial for reproduction[1].Previous studies have identified several brain regions crucial for the control of both sexual and aggressive behaviors in males.Yet,molecularly specified neural circuits that specifically control male sexual behavior remain elusive.Consistent with the inherently rewarding nature of sexual behavior,previous research has implicated the role of the dopamine system in regulating sexual desire[2].However,the interaction between reward and copulation at the circuit level remains largely unexplored.Besides,it is unclear if the associated neural pathways are specific in modulating sexual reward.
基金National Natural Science Foundation of China(32125018 and 32071005)Zhejiang Provincial Natural Science Foundation of China(LD24H090002)+3 种基金National Key Research and Development Program of China(2021YFA1101701)Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2023-PT310-01)Nanhu Brain-computer Interface Institute(010904008)MOE Frontiers Science Center for Brain Science&Brain-Machine Integration of Zhejiang University.
文摘Exhibiting appropriate social behavior toward conspecifics is crucial for survival within a social group.For instance,after a conflict,it is essential for the loser to stay away from the victor to avoid further harm[1].Previous studies have indicated that the anterior ventrolateral part of the ventromedial hypothalamus(aVMHvl)plays a pivotal role in social fear and avoidance following a social defeat.However,the precise mechanisms through which the aVMHvl effectively transforms social defeat to subsequent behavioral changes in social interaction remain largely unknown.
基金supported by the Zhejiang Provincial Natural Science Foundation(No.LD22E030005,LY22E020005)the“Leading Goose”R&D Program of Zhejiang Province(No.2022C01136)+2 种基金the Joint Funds of the National Science Foundation of China(No.U20A20172)the Fundamental Research Funds for the Central Universities(Grant No.226-2024-00120,226-2024-00188)the Open Research Project of Innovation Center of Yangtze River Delta of Zhejiang University.
文摘Traditional ferroelectric materials,such as lead zirconate titanate(PZT)ceramics,exhibit positive strain when subjected to an electric field along the polarization direction.In contrast,the piezoelectric polymer polyvinylidene fluoride(PVDF)and its copolymer P(VDF-TrFE)display unique negative strain properties.While extensive research has focused on understanding the origin and mechanisms of this negative strain,limited efforts have been directed toward regulating these properties.This study optimizes the electro-strain and ferroelectric properties of P(VDF-TrFE)piezoelectric films through the synergistic effect of PbTiO_(3)nanosheets and an in-situ electrostatic field.Our results demonstrate that while the incorporation of PbTiO_(3)nanosheets does not notably enhance ferroelectricity,it significantly improves electro-strain properties,particularly negative strain,which increases from-0.097%to-0.185%,an enhancement of 91%.Moreover,the ferroelectric polarization and positive strain of P(VDF-TrFE)are further enhanced under the combined influence of PbTiO_(3)nanosheets and in-situ electrostatic field,increasing maximum polarization from 10.79μmC/cm^(2)to 13.16μmC/cm^(2),a 22%improvement,and positive strain from 0.213%to 0.267%,a 25%enhancement.We propose a possible mechanism for these improvements,attributed to the enhanced flexibility of the amorphous phase and increased content of polar b-phase in P(VDF-TrFE)films under this synergistic effect.This work highlights novel strategies for controlling the electro-strain and ferroelectric properties of P(VDF-TrFE)piezoelectric films.
基金support by the National Natural Science Foundation of China(Nos.82222069,82273935,82104177,82073857 and 81872878)the Key R&D Program of Zhejiang(No.2022C03077,China)+1 种基金the Fundamental Research Funds for the Central Universities(No.226-2024-00094,China)the Opening Fund of Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province.
文摘Dendritic cells(DCs)serve as the primary antigen-presenting cells in autoimmune diseases,like rheumatoid arthritis(RA),and exhibit distinct signaling profiles due to antigenic diversity.Type II collagen(CII)has been recognized as an RA-specific antigen;however,little is known about CII-stimulated DCs,limiting the development of RA-specific therapeutic interventions.In this study,we show that CII-stimulated DCs display a preferential gene expression profile associated with migration,offering a new perspective for targeting DC migration in RA treatment.Then,saikosaponin D(SSD)was identified as a compound capable of blocking CII-induced DC migration and effectively ameliorating arthritis.Optineurin(OPTN)is further revealed as a potential SSD target,with Optn deletion impairing CII-pulsed DC migration without affecting maturation.Function analyses uncover that OPTN prevents the proteasomal transport and ubiquitin-dependent degradation of C-C chemokine receptor 7(CCR7),a pivotal chemokine receptor in DC migration.Optn-deficient DCs exhibit reduced CCR7 expression,leading to slower migration in CII-surrounded environment,thus alleviating arthritis progression.Our findings underscore the significance of antigen-specific DC activation in RA and suggest OPTN is a crucial regulator of CII-specific DC migration.OPTN emerges as a promising drug target for RA,potentially offering significant value for the therapeutic management of RA.
基金supported by grants from the National Natural Science Foundation to Zhi-Ying Wu(81671245)the Integrative Traditional Chinese and Western Medicine Innovation Team for Neurodegenerative Diseases of Zhejiang Province,and the Research Foundation for Distinguished Scholars of Zhejiang University to Zhi-Ying Wu(188020-193810101/089).
文摘Disease-associated microglia(DAM)are observed in neurodegenerative diseases,demyelinating disorders,and aging.However,the spatiotemporal dynamics and evolutionary trajectory of DAM during the progression of amyotrophic lateral sclerosis(ALS)remain unclear.Using a mouse model of ALS that expresses a human SOD1 gene mutation,we found that the microglia subtype DAM begins to appear following motor neuron degeneration,primarily in the brain stem and spinal cord.Using reverse transcription quantitative polymerase chain reaction,RNAscope in situ hybridization,and flow cytometry,we found that DAM increased in number as the disease progressed,reaching their peak in the late disease stage.DAM responded to disease progression in both SOD1G93A mice and sporadic ALS and C9orf72-mutated patients.Motor neuron loss in SOD1G93A mice exhibited 2 accelerated phases:P90 to P110(early stage)and P130 to P150(late stage).Some markers were synchronized with the accelerated phase of motor neuron loss,suggesting that these proteins may be particularly responsive to disease progression.Through pseudotime trajectory analysis,we tracked the dynamic transition of homeostatic microglia into DAM and cluster 6 microglia.Interestingly,we used the colony-stimulating factor 1 receptor(CSF1R)inhibitor PLX5622 to deplete microglia in SOD1G93A mice and observed that DAM survival is independent of CSF1R.An in vitro phagocytosis assay directly confirmed that DAM could phagocytose more beads than other microglia subtypes.These findings reveal that the induction of the DAM phenotype is a shared cross-species and cross-subtype characteristic in ALS.Inducing the DAM phenotype and enhancing its function during the early phase of disease progression,or the time window between P130 and P150 where motor neuron loss slows,could serve as a neuroprotective strategy for ALS.
基金This work was supported by the National Natural Science Foundation of China(No.81930102 to Bo Yang,No.82273949 to Ling Ding,No.82104196 to Xi Chen)Fundamental Research Funds for the Central Universities[grant number:2021FZZX001-48].
文摘Adenosine(Ado)is significantly elevated in the tumor microenvironment(TME)compared to normal tissues.It binds to adenosine receptors(AdoRs),suppressing tumor antigen presentation and immune cell activation,thereby inhibiting tumor adaptive immunity.Ado downregulates major histocompatibility complex II(MHC II)and co-stimulatory factors on dendritic cells(DCs)and macrophages,inhibiting antigen presentation.It suppresses anti-tumor cytokine secretion and T cell activation by disrupting T cell receptor(TCR)binding and signal transduction.Ado also inhibits chemokine secretion and KCa3.1 channel activity,impeding effector T cell trafficking and infiltration into the tumor site.Furthermore,Ado diminishes T cell cytotoxicity against tumor cells by promoting immune-suppressive cytokine secretion,upregulating immune checkpoint proteins,and enhancing immune-suppressive cell activity.Reducing Ado production in the TME can significantly enhance anti-tumor immune responses and improve the efficacy of other immunotherapies.Preclinical and clinical development of inhibitors targeting Ado generation or AdoRs is underway.Therefore,this article will summarize and analyze the inhibitory effects and molecular mechanisms of Ado on tumor adaptive immunity,as well as provide an overview of the latest advancements in targeting Ado pathways in anti-tumor immune responses.
基金This study was supported by the Fundamental Research Funds for the Central Universities(No.226-2023-00114,China)National Natural Science Foundation of China(Nos.82222069 and 82104181)+1 种基金the Key R&D Program of Zhejiang(No.2022C03143,China)the Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China(No.LHDMD22H310004).
文摘Macrophage senescence,manifested by the special form of durable cell cycle arrest and chronic low-grade inflammation like senescence-associated secretory phenotype,has long been consid-ered harmful.Persistent senescence of macrophages may lead to maladaptation,immune dysfunction,and finally the development of age-related diseases,infections,autoimmune diseases,and malignancies.However,it is a ubiquitous,multi-factorial,and dynamic complex phenomenon that also plays roles in remodeled processes,including wound repair and embryogenesis.In this review,we summarize some general molecular changes and several specific biomarkers during macrophage senescence,which may bring new sight to recognize senescent macrophages in different conditions.Also,we take an in-depth look at the functional changes in senescent macrophages,including metabolism,autophagy,polarization,phagocytosis,antigen presentation,and infiltration or recruitment.Furthermore,some degenerations and diseases associated with senescent macrophages as well as the mechanisms or relevant genetic regulations of senescent macrophages are integrated,not only emphasizing the possibility of regulating macrophage senescence to benefit age-associated diseases but also has an implication on the finding of potential tar-gets ordrugs clinically.
基金supported in part by the National Key Research and Development Program of China(2022YFA1303400 to S.J.Z.and S.Q.,2020YFA0908501 to J.G.,and 2021YFF1200404 to Y.W.)the National Natural Science Foundation of China(32371204 to J.G.,82030108 and 31872796 to W.Y.,and 32371300 to Y.W.)+2 种基金Zhejiang Provincial Natural Science Foundation(LR19C050002 to J.G.)the China Postdoctoral Science Foundation(no.74,2023M743044 to J.W.)the National Postdoctoral Researcher Program of China(GZB20230634 to J.W.).
文摘Plant high-affinity K^(+) transporters(HKTs)mediate Na^(+) and K^(+) uptake,maintain Na^(+)/K^(+) homeostasis,and therefore play crucial roles in plant salt tolerance.In this study,we present cryoelectron microscopy structures of HKTs from two classes,classI HKT1;1 from Arabidopsis thaliana(AtHKT1;1)and class II HKT2;1 from Triticum aestivum(TaHKT2;1),in both Na^(+) -and K^(+) -bound states at 2.6-to 3.0-A resolutions.BothAtHKT1;1and TaHKT2;1function ashomodimers.Each HKT subunit consists of four tan-dem domain units(D1-D4)with a repeated K^(+) -channel-like M-P-M topology.In each subunit,D1-D4 assemble into an ion conduction pore with a pseudo-four-fold symmetry.Although both TaHKT2;1and AtHKT1;1 have only one putative Na^(+) ion bound in the selectivity filter with a similar coordination pattern,the two HKTs display different K^(+) binding modes in the filter.TaHKT2;1 has three K^(+) ions bound in the selec-tivity filter,but AtHKT1;1 has only two K^(+) ions bound in the filter,which has a narrowed external entrance due to the presence of a Ser residue in the first filter motif.These structures,along with compu-tational,mutational,and electrophysiological analyses,enable us to pinpoint key residues that are critical for the ion selectivity of HKTs.The findings provide new insights into the ion selectivity and ion transport mechanisms of plant HKTs and improve our understanding about how HKTs mediate plant salt tolerance and enhance crop growth.
