Background:Choosing the appropriate antipsychotic drug(APD)treatment for patients with schizophrenia(SCZ)can be challenging,as the treatment response to APD is highly variable and difficult to predict due to the lack ...Background:Choosing the appropriate antipsychotic drug(APD)treatment for patients with schizophrenia(SCZ)can be challenging,as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers.Previous studies have indicated the association between treatment response and genetic and epigenetic factors,but no effective biomarkers have been identified.Hence,further research is imperative to enhance precision medicine in SCZ treatment.Methods:Participants with SCZ were recruited from two randomized trials.The discovery cohort was recruited from the CAPOC trial(n=2307)involved 6 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,Quetiapine,Aripiprazole,Ziprasidone,and Haloperidol/Perphenazine(subsequently equally assigned to one or the other)groups.The external validation cohort was recruited from the CAPEC trial(n=1379),which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,and Aripiprazole groups.Additionally,healthy controls(n=275)from the local community were utilized as a genetic/epigenetic reference.The genetic and epigenetic(DNA methylation)risks of SCZ were assessed using the polygenic risk score(PRS)and polymethylation score,respectively.The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis,methylation quantitative trait loci,colocalization,and promoteranchored chromatin interaction.Machine learning was used to develop a prediction model for treatment response,which was evaluated for accuracy and clinical benefit using the area under curve(AUC)for classification,R^(2) for regression,and decision curve analysis.Results:Six risk genes for SCZ(LINC01795,DDHD2,SBNO1,KCNG2,SEMA7A,and RUFY1)involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response.The developed and externally validated prediction model,which incorporated clinical information,PRS,genetic risk score(GRS),and proxy methylation level(proxyDNAm),demonstrated positive benefits for a wide range of patients receiving different APDs,regardless of sex[discovery cohort:AUC=0.874(95%CI 0.867-0.881),R^(2)=0.478;external validation cohort:AUC=0.851(95%CI 0.841-0.861),R^(2)=0.507].Conclusions:This study presents a promising precision medicine approach to evaluate treatment response,which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ.Trial registration Chinese Clinical Trial Registry(https://www.chictr.org.cn/),18 Aug 2009 retrospectively registered:CAPOC-ChiCTR-RNC-09000521(https://www.chictr.org.cn/showproj.aspx?proj=9014),CAPEC-ChiCTRRNC-09000522(https://www.chictr.org.cn/showproj.aspx?proj=9013).展开更多
Amyotrophic lateral sclerosis is a rare neurodegenerative disease characterized by the involvement of both upper and lower motor neurons.Early bilateral limb involvement significantly affects patients'daily lives ...Amyotrophic lateral sclerosis is a rare neurodegenerative disease characterized by the involvement of both upper and lower motor neurons.Early bilateral limb involvement significantly affects patients'daily lives and may lead them to be confined to bed.However,the effect of upper and lower motor neuron impairment and other risk factors on bilateral limb involvement is unclear.To address this issue,we retrospectively collected data from 586 amyotrophic lateral sclerosis patients with limb onset diagnosed at Peking University Third Hospital between January 2020 and May 2022.A univariate analysis revealed no significant differences in the time intervals of spread in different directions between individuals with upper motor neuron-dominant amyotrophic lateral sclerosis and those with classic amyotrophic lateral sclerosis.We used causal directed acyclic graphs for risk factor determination and Cox proportional hazards models to investigate the association between the duration of bilateral limb involvement and clinical baseline characteristics in amyotrophic lateral sclerosis patients.Multiple factor analyses revealed that higher upper motor neuron scores(hazard ratio[HR]=1.05,95%confidence interval[CI]=1.01–1.09,P=0.018),onset in the left limb(HR=0.72,95%CI=0.58–0.89,P=0.002),and a horizontal pattern of progression(HR=0.46,95%CI=0.37–0.58,P<0.001)were risk factors for a shorter interval until bilateral limb involvement.The results demonstrated that a greater degree of upper motor neuron involvement might cause contralateral limb involvement to progress more quickly in limb-onset amyotrophic lateral sclerosis patients.These findings may improve the management of amyotrophic lateral sclerosis patients with limb onset and the prediction of patient prognosis.展开更多
Previous studies have shown that ulnar nerve compound muscle action potential recorded by the conventional“belly-tendon”montage does not accurately and completely reflect the action potential of the ulnar nerve domi...Previous studies have shown that ulnar nerve compound muscle action potential recorded by the conventional“belly-tendon”montage does not accurately and completely reflect the action potential of the ulnar nerve dominating the abductor digiti minimi muscle due to the effects of far-field potentials of intrinsic hand muscles.A new method of ulnar nerve compound muscle action potential measurement was developed in 2020,which adjusts the E2 electrode from the distal tendon of the abductor digitorum to the middle of the back of the proximal wrist.This new method may reduce the influence of the reference electrode and better reflect the actual ulnar nerve compound muscle action potential.In this prospective cross-sectional study,we included 64 patients with amyotrophic lateral sclerosis and 64 age-and sex-matched controls who underwent conventional and novel ulnar nerve compound muscle action potential measurement between April 2020 and May 2021 in Peking University Third Hospital.The compound muscle action potential waveforms recorded by the new montage were unimodal and more uniform than those recorded by traditional montage.In the controls,no significant difference in the compound muscle action potential waveforms was found between the traditional montage and new montage recordings.In amyotrophic lateral sclerosis patients presenting with abductor digiti minimi spontaneous activity and muscular atrophy,the amplitude of compound muscle action potential-pE2 was significantly lower than that of compound muscle action potential-dE2(P<0.01).Using the new method,damaged axons were more likely to exhibit more severe amplitude decreases than those measured with the traditional method,in particular for patients in early stage amyotrophic lateral sclerosis.In addition,the decline in compound muscle action potential amplitude measured by the new method was correlated with a decrease in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale scores.These findings suggest that the new ulnar nerve compound muscle action potential measurement montage reduces the effects of the reference electrode through altering the E2 electrode position,and that this method is more suitable for monitoring disease progression than the traditional montage.This method may be useful as a biomarker for longitudinal follow-up and clinical trials in amyotrophic lateral sclerosis.展开更多
BACKGROUND Acupuncture promotes the recovery of gastrointestinal function and provides analgesia after major abdominal surgery.The effects of transcutaneous electrical acupoint stimulation(TEAS)remain unclear.AIM To e...BACKGROUND Acupuncture promotes the recovery of gastrointestinal function and provides analgesia after major abdominal surgery.The effects of transcutaneous electrical acupoint stimulation(TEAS)remain unclear.AIM To explore the potential effects of TEAS on the recovery of gastrointestinal function after gastrectomy and colorectal resection.METHODS Patients scheduled for gastrectomy or colorectal resection were randomized at a 2:3:3:2 ratio to receive:(1)TEAS at maximum tolerable current for 30 min immediately prior to anesthesia induction and for the entire duration of surgery,plus two 30-min daily sessions for 3 consecutive days after surgery(perioperative TEAS group);(2)Preoperative and intraoperative TEAS only;(3)Preoperative and postoperative TEAS only;or(4)Sham stimulation.The primary outcome was the time from the end of surgery to the first bowel sound.RESULTS In total,441 patients were randomized;405 patients(58.4±10.2 years of age;247 males)received the planned surgery.The time to the first bowel sounds did not differ among the four groups(P=0.90;log-rank test).On postoperative day 1,the rest pain scores differed significantly among the four groups(P=0.04;Kruskal–Wallis test).Post hoc comparison using the Bonferroni test showed lower pain scores in the perioperative TEAS group(1.4±1.2)than in the sham sti-mulation group(1.7±1.1;P=0.04).Surgical complications did not differ among the four groups.CONCLUSION TEAS provided analgesic effects in adult patients undergoing major abdominal surgery,and it can be added to clinical practice as a means of accelerating postoperative rehabilitation of these patients.展开更多
As a main structure of the limbic system,the hippocampus plays a critical role in pain perception and chronicity.The ventral hippocampal CA1(vCA1)is closely associated with negative emotions such as anxiety,stress,and...As a main structure of the limbic system,the hippocampus plays a critical role in pain perception and chronicity.The ventral hippocampal CA1(vCA1)is closely associated with negative emotions such as anxiety,stress,and fear,yet how vCA1 neurons encode nociceptive information remains unclear.Using in vivo electrophysiological recording,we characterized vCA1 pyramidal neuron subpopulations that exhibited inhibitory or excitatory responses to plantar stimuli and were implicated in encoding stimuli modalities in naïve rats.Functional heterogeneity of the vCA1 pyramidal neurons was further identified in neuropathic pain conditions:the proportion and magnitude of the inhibitory response neurons paralleled mechanical allodynia and contributed to the confounded encoding of innocuous and noxious stimuli,whereas the excitatory response neurons were still instrumental in the discrimination of stimulus properties.Increased theta power and theta-spike coupling in vCA1 correlated with nociceptive behaviors.Optogenetic inhibition of vCA1 pyramidal neurons induced mechanical allodynia in naïve rats,whereas chemogenetic reversal of the overall suppressed vCA1 activity had analgesic effects in rats with neuropathic pain.These results provide direct evidence for the representations of nociceptive information in vCA1.展开更多
As a result of evolution,our body has evolved into a sophisticated system in which various tissues and organs cooperate in a highly orchestrated manner.Few tissues or organs operate in isolation.The brain serves as th...As a result of evolution,our body has evolved into a sophisticated system in which various tissues and organs cooperate in a highly orchestrated manner.Few tissues or organs operate in isolation.The brain serves as the command center of our body and is relatively isolated from the peripheral system due to the presence of the blood-brain barrier(BBB).This barrier prevents direct and extensive interaction between blood cells,plasma molecules,and brain cells,contributing to the longstanding perception of the brain as an“immune-privileged”area.Consequently,neuroscientists and immunologists historically conducted separate research with minimal overlap between these two disciplines.However,this perspective has undergone reconsideration over the past few decades.展开更多
BACKGROUND: Induced differentiation strategies and cytochemical properties of human embryonic stem ceils (hESCs) have been investigated. However, the electrophysiological functions of tyrosine hydroxylase (TH)-po...BACKGROUND: Induced differentiation strategies and cytochemical properties of human embryonic stem ceils (hESCs) have been investigated. However, the electrophysiological functions of tyrosine hydroxylase (TH)-positive cells dedved from hESCs remain unclear. OBJECTIVE: To investigate the differentiation efficiency of TH-positive cells from hESCs in vitro using modified four-step culture methods, including embryoid body formation, and to examine the functional characteristics of the differentiated TH-positive cells using electrophysiological techniques. DESIGN, TIME AND SETTING: Neuroelectrophysiology was performed at the Reproductive Medicine Center and Stem Cell Research Center, Peking University Third Hospital, and the Neuroscience Research Institute and Department of Neurobiology, Peking University, from September 2004 to August 2008. MATERIALS: The hESC line, PKU-1.1, a monoclonal cell line derived from a pre-implantation human blastocyst in the Reproductive Medical Center of Peking University Third Hospital. The patch clamp recording system was provided by the Neuroscience Research Institute and Department of Neurobiology, Peking University. METHODS: The hESC line was induced to differentiate into TH-positive cells in vitro using a modified four-step culture method, including the formation of embryoid body, as well as the presence of sonic hedgehog and fibroblast growth factor 8. The cell karyotype was assessed by G-banding karyotype analysis techniques and specific markers were detected immunocytochemically. Whole-cell configuration was obtained after obtaining a tight seal of over 1 GΩ. Ionic currents were detected by holding the cells at -70 mV and stepping to test voltages between -80 and 40 mV in 10-mV increments in voltage-clamp configuration. MAIN OUTCOME MEASURES: We measured the cell karyotype, specific cell markers, and the electrophysiological properties of the voltage-gated ion channels on the cell membrane of TH-positive dopaminergic cells differentiated from our hESCs line in vitro. RESULTS: The differentiated cells had a consistent appearance, and the majority of cells (〉 90%) expressed TH and β-tubulion, as well as the neural progenitor marker, nestino Cell karyotype analysis demonstrated that all of the hESCs had a stable and normal karyotype (46, XX) after differentiation. In addition, patch clamp recording showed that the 10 recorded TH-positive cells exhibited a fast inward current when the test voltage depolarized to -30 mV, and a delayed outward current when the test voltage depolarized to -10 mV. The peak of inward current was obtained at voltage between 10 mV and 0 mV, while the peak of outward current was obtained at 40 mV. The average peak of inward current density was ( -50.05 ± 15.50) pA/pF, and the average peak of outward current density was (41.98 ± 13.55) pA/pE CONCLUSION: More than 90% of the differentiated hESC-derived cells induced by the modified four-step culture method exhibit dopaminergic neuronal properties, including general electrophysiological functional properties, such as functional potassium and sodium channels.展开更多
The input-output relationship of neuronal networks depends heavily on the intrinsic properties of their neuronal elements.Profound changes in intrinsic properties have been observed in various physiological and pathol...The input-output relationship of neuronal networks depends heavily on the intrinsic properties of their neuronal elements.Profound changes in intrinsic properties have been observed in various physiological and pathological processes,such as learning,memory and epilepsy.However,the cellular and molecular mechanisms underlying acquired changes in intrinsic excitability are still not fully understood.Here,we demonstrate that ERG3 channels are critically involved in the regulation of intrinsic excitability in hippocampal CA1 pyramidal neurons and DG granule cells.Knock-down of ERG3 channels significantly increases neuronal intrinsic excitability,which is mainly caused by decreased fast afterhyperpolarization,delayed time to the generation of an action potential and enhanced summation of somatic excitatory post-synaptic potentials.Interestingly,the expression level of ERG3 protein is significantly reduced in human and mouse brain tissues with temporal lobe epilepsy.Moreover,ERG3 channel knock-down in hippocampus significantly enhanced seizure susceptibility,while mice treated with ERG3 channel activator NS1643 were less prone to epileptogenesis.Taken together,our results suggest ERG3 channels play an important role in determining the excitability of hippocampal neurons and dysregulation of these channels may be involved in the generation of epilepsy.ERG3 channels may thus be a novel therapeutic target for the prevention of epilepsy.展开更多
Background:Autism spectrum disorder(ASD)is associated with altered brain development,but it is unclear which specific structural changes may serve as potential diagnostic markers,particularly in young children at the ...Background:Autism spectrum disorder(ASD)is associated with altered brain development,but it is unclear which specific structural changes may serve as potential diagnostic markers,particularly in young children at the age when symptoms become fully estab-lished.Furthermore,such brain markers need to meet the requirements of precision medicine and be accurate in aiding diagnosis at an individual rather than only a group level.Objective:This study aimed to identify and model brain-wide differences in structural connectivity using diffusion tensor imaging(DTI)in young ASD and typically developing(TD)children.Methods:A discovery cohort including 93 ASD and 26 TD children and two independent validation cohorts including 12 ASD and 9 TD children from three different cities in China were included.Brain-wide(294 regions)structural connectivity was measured using DTI(fractional anisotropy,FA)together with symptom severity and cognitive development.A connection matrix was constructed for each child for comparisons between ASD and TD groups.Pattern classification was performed on the discovery dataset and the resulting model was tested on the two independent validation datasets.Results:Thirty-three structural connections showed increased FA in ASD compared to TD children and associated with both autistic symptom severity and impaired general cognitive development.The majority(29/33)involved the frontal lobe and comprised five different networks with functional relevance to default mode,motor control,social recognition,language and reward.Overall,clas-sification achieved very high accuracy of 96.77%in the discovery dataset,and 91.67%and 88.89%in the two independent validation datasets.Conclusions:Identified structural connectivity differences primarily involving the frontal cortex can very accurately distinguish novel individual ASD from TD children and may therefore represent a robust early brain biomarker which can address the requirements of precision medicine.展开更多
The nervous system possesses bidirectional,sophisticated and delicate communications with the immune system.These neuroimmune interactions play a vitally important role in the initiation and development of many disord...The nervous system possesses bidirectional,sophisticated and delicate communications with the immune system.These neuroimmune interactions play a vitally important role in the initiation and development of many disorders,especially neurodegenerative diseases.Although scientific advancements have made tremendous progress in this field during the last few years,neuroimmune communications are still far from being elucidated.By organizing recent research,in this review,we discuss the local and intersystem neuroimmune interactions and their roles in Alzheimer’s disease,Parkinson’s disease and amyotrophic lateral sclerosis.Unveiling these will help us gain a better understanding of the process of interplay inside the body and how the organism maintains homeostasis.It will also facilitate a view of the diseases from a holistic,pluralistic and interconnected perspective,thus providing a basis of developing novel and effective methods to diagnose,intervene and treat diseases.展开更多
Background The PACS gene family has been demonstrated to be related to intracellular vesicular trafficking.The phenotypic manifestations caused by the pathogenic variants of PACS include epilepsy,intellectual disabili...Background The PACS gene family has been demonstrated to be related to intracellular vesicular trafficking.The phenotypic manifestations caused by the pathogenic variants of PACS include epilepsy,intellectual disability/developmental delay,and malformations,such as facial abnormalities.Methods We identified seven new cases with pathogenic or likely pathogenic PACS variants using next-generation sequencing.Detailed information obtained from these patients was analyzed along with that obtained from previously reported patients.Results With the inclusion of the newly diagnosed cases in this study,103 cases with PACS gene family-related neurological diseases were reported,of which 43 were PACS2-related cases and the remaining were PACSI-related cases.Most patients had seizures,which have been reported to be effectively controlled by several types of anti-seizure medications(ASMs).The most efficacious and frequently prescribed ASMs included sodium valproate(43.3%,13/30),oxcarbazepine/carbamazepine(26.7%,8/30),and levetiracetam(20%,6/30).Almost all patients had intellectual disability/developmental delay.The most common pathogenic missense variants were PACSI p.Arg203Trp and PACS2 p.Glu209Lys.In addition,we report a patient carrying a likely pathogenic copy number variation(CNV)(de novo heterozygous deletion of chr14:105821380-106107443,286 kilobase,destroyed part of the furin-binding region domain and the protein structure after it)with more severe and refractory late-onset epilepsy.Conclusions The clinical phenotypes of the different PACS heterozygous missense variants were similar.The pathogenic variant sites of PACSI and PACS2 were quite limited but located in different regions.A CNV destroying part of the PACS2 gene might also be pathogenic.These findings may provide an important clue for further functional studies on the pathogenic mechanism of neurological disorders related to the PACS gene family.展开更多
Abnormal hyperphosphorylation and accumulation of tau protein play a pivotal role in neurodegeneration in Alzheimer’s disease(AD)and many other tauopathies.Selective elimination of hyperphosphorylated tau is promisin...Abnormal hyperphosphorylation and accumulation of tau protein play a pivotal role in neurodegeneration in Alzheimer’s disease(AD)and many other tauopathies.Selective elimination of hyperphosphorylated tau is promising for the therapy of these diseases.We have conceptualized a strategy,named dephosphorylation-targeting chimeras(DEPTACs),for specifically hijacking phosphatases to tau to debilitate its hyperphosphorylation.Here,we conducted the step-by-step optimization of each constituent motif to generate DEPTACs with reasonable effectiveness in facilitating the dephosphorylation and subsequent clearance of pathological tau.Specifically,for one of the selected chimeras,D16,we demonstrated its significant efficiency in rescuing the neurodegeneration caused by neurotoxic K18-tau seeds in vitro.Moreover,intravenous administration of D16 also alleviated tau pathologies in the brain and improved memory deficits in AD mice.These results suggested DEPTACs as targeted modulators of tau phosphorylation,which hold therapeutic potential for AD and other tauopathies.展开更多
Infectious diseases,mostly caused by bacteria and viruses but also a result of fungal and parasitic infection,have been one of the most important public health concerns throughout human history.The first step in comba...Infectious diseases,mostly caused by bacteria and viruses but also a result of fungal and parasitic infection,have been one of the most important public health concerns throughout human history.The first step in combating these pathogens is to get a timely and accurate diagnosis at an affordable cost.Many kinds of diagnostics have been developed,such as pathogen culture,biochemical tests and serological tests,to help detect and fight against the causative agents of diseases.However,these diagnostic tests are generally unsatisfactory because they are not particularly sensitive and specific and are unable to deliver speedy results.Nucleic acid-based diagnostics,detecting pathogens through the identification of their genomic sequences,have shown promise to overcome the above limitations and become more widely adopted in clinical tests.Here we review some of the most popular nucleic acid-based diagnostics and focus on their adaptability and applicability to routine clinical usage.We also compare and contrast the characteristics of different types of nucleic acid-based diagnostics.展开更多
Objective Formaldehyde at high concentrations is a contributor to air pollution. It is also an endogenous metabolic product in cells, and when beyond physiological concentrations, has pathological effects on neurons. ...Objective Formaldehyde at high concentrations is a contributor to air pollution. It is also an endogenous metabolic product in cells, and when beyond physiological concentrations, has pathological effects on neurons. Formaldehyde induces mis-folding and aggregation of neuronal tau protein, hippocampal neuronal apoptosis, cognitive impairment and loss of memory functions, as well as excitation of peripheral nociceptive neurons in cancer pain models. Intracellular calcium ([Ca2+]i) is an important intracellular messenger, and plays a key role in many pathological processes. The present study aimed to investigate the effect of formaldehyde on [Ca2+]i and the possible involvement of N-methyl-D-aspartate receptors (NMDARs) and T-type Ca2+ channels on the cell membrane. Methods Using primary cultured hippocampal neurons as a model, changes of [Ca2+]i in the presence of formaldehyde at a low concentration were detected by confocal laser scanning microscopy. Results Formaldehyde at 1 mmol/L approximately doubled [Ca2+]i. (2R)-amino-5-phosphonopentanoate (AP5, 25 μmol/L, an NMDAR antagonist) and mibefradil (MIB, 1 μmol/L, a T-type Ca2+ channel blocker), given 5 min after formaldehyde perfusion, each partly inhibited the formaldehyde-induced increase of [Ca:+]i, and this inhibitory effect was reinforced by combined application of AP5 and MIB. When applied 3 min before formaldehyde perfusion, AP5 (even at 50μmol/L) did not inhibit the formaldehyde-induced increase of [Ca2+]i, but MIB (1 μmol/L) significantly inhibited this increase by 70%. Conclusion These results suggest that formaldehyde at a low concentration increases [Ca2+]i in cultured hippocampal neurons; NMDARs and T-type Ca2+ channels may be involved in this process.展开更多
Drug addiction is a chronic brain disorder characterized by withdrawal symptoms that occur during drug abstinence and a high tendency of relapse.Compared with the currently available pharmacological interventions,acup...Drug addiction is a chronic brain disorder characterized by withdrawal symptoms that occur during drug abstinence and a high tendency of relapse.Compared with the currently available pharmacological interventions,acupuncture therapy has the potential to help drug addicts stay away from drugs without major adverse side effects.It has taken decades of research to optimize the parameters of electrical acupoint stimulation for detoxification and for relapse prevention,as well as to establish a safe and easy procedure by which drug addicts can use it on themselves.The discovery that acupuncture can trigger the release of opioid substances from the brain in the 1970s provided the inspiration.Following this,basic research on animals made it possible to understand the mechanisms of action and establish the procedure for treating drug addictions.This article reviews the past,present,and foreseeable future regarding the use of acupuncture-related technique for the treatment of opiate addiction from the perspective of translational medicine.展开更多
The local field potential(LFP) is a signal reflecting the electrical activity of neurons surrounding the electrode tip. Synchronization between LFP signals provides important details about how neural networks are or...The local field potential(LFP) is a signal reflecting the electrical activity of neurons surrounding the electrode tip. Synchronization between LFP signals provides important details about how neural networks are organized. Synchronization between two distant brain regions is hard to detect using linear synchronization algorithms like correlation and coherence. Synchronization likelihood(SL) is a non-linear synchronization-detecting algorithm widely used in studies of neural signals from two distant brain areas. One drawback of non-linear algorithms is the heavy computational burden. In the present study, we proposed a graphic processing unit(GPU)-accelerated implementation of an SL algorithm with optional 2-dimensional time-shifting. We tested the algorithm with both artificial data and raw LFP data. The results showed that this method revealed detailed information from original data with the synchronization values of two temporal axes,delay time and onset time, and thus can be used to reconstruct the temporal structure of a neural network. Our results suggest that this GPU-accelerated method can be extended to other algorithms for processing time-series signals(like EEG and f MRI) using similar recording techniques.展开更多
Frontiers of Medicine 2011,5(2):141–150 A mistake appeared in the sentence on lines 4–6 on the right column of page 148.The sentence“Low frequency(represented by 2 Hz)EA is most effective for suppressing the withdr...Frontiers of Medicine 2011,5(2):141–150 A mistake appeared in the sentence on lines 4–6 on the right column of page 148.The sentence“Low frequency(represented by 2 Hz)EA is most effective for suppressing the withdrawal syndromes and high frequency(100 Hz)EA is best for alleviating craving.”should be changed to“Low frequency(represented by 2 Hz)EA is most effective for alleviating craving and high frequency(100 Hz)EA is best for suppressing the withdrawal syndromes.”展开更多
Background NR2F1 mutations are associated with Bosch-Boonstra-Schaaf optic atrophy syndrome(BBSOAS).Although~46.7%of BBSOAS patients present with epilepsy,which is always drug-resistant and associated with higher rate...Background NR2F1 mutations are associated with Bosch-Boonstra-Schaaf optic atrophy syndrome(BBSOAS).Although~46.7%of BBSOAS patients present with epilepsy,which is always drug-resistant and associated with higher rates of behavioral and cognitive problems,the treatment and outcomes of NR2F1-related epilepsy have rarely been described.Here,we present new cases of BBSOAS-related epilepsy and summarize all previously reported cases to explore the effective treatment for this type of epilepsy.Methods We identified six new Chinese cases of BBSOAS with epilepsy.Five different de novo heterozygous NR2F1 mutations were identified in these cases,including two novel mutations c.365G>T,p.Cys122Phe and c.449G>T,p.Gly150Val.By combining the six cases and 14 previously reported cases,we analyzed the characteristics and treatment outcomes of NR2F1-related epilepsy.Results Twelve of the 20 patients(60%)had infantile epileptic spasms,while the other patients had generalized tonic/tonic-clonic,focal,myoclonic,absence,or unclassified seizures.Several anti-seizure medications,steroids,and a ketogenic diet were administered in these cases.However,seizures were controlled in only 50%of previously reported cases,while all of the six new cases became seizure-free after perampanel as an add-on treatment.The average time from the addition of perampanel to seizure control was 7.33±4.59 months(range,1–12 months).The median time to seizure freedom was 14 months(1–32 months,>19 months in 3 cases).The average dosage of perampanel needed for epilepsy control was 0.22±0.17 mg/kg per day.Conclusions In this paper,we comprehensively summarized the clinical characteristics,treatments and outcomes of NR2F1-related epilepsy for the first time.Perampanel exhibits dramatic efficacy for NR2F1-related epilepsy.This will help optimize the treatment of this type of epilepsy and provide clues for its pathogenic mechanisms.The two novel mutations expand the genotype spectrum of this disease.展开更多
The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease(AD)and associated socioeconomic burdens.Abnormal metabolism of amyloid-β(Aβ)has been proposed as a s...The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease(AD)and associated socioeconomic burdens.Abnormal metabolism of amyloid-β(Aβ)has been proposed as a significant pathomechanism in AD,supported by results of recent clinical trials using anti-Aβantibodies.Nonetheless,the cognitive benefits of the current treatments are limited.The etiology of AD is multifactorial,encompassing Aβand tau accumulation,neuroinflammation,demyelination,vascular dysfunction,and comorbidities,which collectively lead to widespread neurodegeneration in the brain and cognitive impairment.Hence,solely removing Aβfrom the brain may be insufficient to combat neurodegeneration and preserve cognition.To attain effective treatment for AD,it is necessary to(1)conduct extensive research on various mechanisms that cause neurodegeneration,including advances in neuroimaging techniques for earlier detection and a more precise characterization of molecular events at scales ranging from cellular to the full system level;(2)identify neuroprotective intervention targets against different neurodegeneration mechanisms;and(3)discover novel and optimal combinations of neuroprotective intervention strategies to maintain cognitive function in AD patients.The Alzheimer's Disease Neuroprotection Research Initiative's objective is to facilitate coordinated,multidisciplinary efforts to develop systemic neuroprotective strategies to combat AD.The aim is to achieve mitigation of the full spectrum of pathological processes underlying AD,with the goal of halting or even reversing cognitive decline.展开更多
基金supported by the National Natural Science Foundation of China(81825009,82071505,81901358)the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2021-I2MC&T-B-099,2019-I2M-5–006)+2 种基金the Program of Chinese Institute for Brain Research Beijing(2020-NKX-XM-12)the King’s College London-Peking University Health Science Center Joint Institute for Medical Research(BMU2020KCL001,BMU2019LCKXJ012)the National Key R&D Program of China(2021YFF1201103,2016YFC1307000).
文摘Background:Choosing the appropriate antipsychotic drug(APD)treatment for patients with schizophrenia(SCZ)can be challenging,as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers.Previous studies have indicated the association between treatment response and genetic and epigenetic factors,but no effective biomarkers have been identified.Hence,further research is imperative to enhance precision medicine in SCZ treatment.Methods:Participants with SCZ were recruited from two randomized trials.The discovery cohort was recruited from the CAPOC trial(n=2307)involved 6 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,Quetiapine,Aripiprazole,Ziprasidone,and Haloperidol/Perphenazine(subsequently equally assigned to one or the other)groups.The external validation cohort was recruited from the CAPEC trial(n=1379),which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,and Aripiprazole groups.Additionally,healthy controls(n=275)from the local community were utilized as a genetic/epigenetic reference.The genetic and epigenetic(DNA methylation)risks of SCZ were assessed using the polygenic risk score(PRS)and polymethylation score,respectively.The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis,methylation quantitative trait loci,colocalization,and promoteranchored chromatin interaction.Machine learning was used to develop a prediction model for treatment response,which was evaluated for accuracy and clinical benefit using the area under curve(AUC)for classification,R^(2) for regression,and decision curve analysis.Results:Six risk genes for SCZ(LINC01795,DDHD2,SBNO1,KCNG2,SEMA7A,and RUFY1)involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response.The developed and externally validated prediction model,which incorporated clinical information,PRS,genetic risk score(GRS),and proxy methylation level(proxyDNAm),demonstrated positive benefits for a wide range of patients receiving different APDs,regardless of sex[discovery cohort:AUC=0.874(95%CI 0.867-0.881),R^(2)=0.478;external validation cohort:AUC=0.851(95%CI 0.841-0.861),R^(2)=0.507].Conclusions:This study presents a promising precision medicine approach to evaluate treatment response,which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ.Trial registration Chinese Clinical Trial Registry(https://www.chictr.org.cn/),18 Aug 2009 retrospectively registered:CAPOC-ChiCTR-RNC-09000521(https://www.chictr.org.cn/showproj.aspx?proj=9014),CAPEC-ChiCTRRNC-09000522(https://www.chictr.org.cn/showproj.aspx?proj=9013).
基金supported by the National Natural Science Foundation of China,Nos.82071426,81873784Clinical Cohort Construction Program of Peking University Third Hospital,No.BYSYDL2019002(all to DF)。
文摘Amyotrophic lateral sclerosis is a rare neurodegenerative disease characterized by the involvement of both upper and lower motor neurons.Early bilateral limb involvement significantly affects patients'daily lives and may lead them to be confined to bed.However,the effect of upper and lower motor neuron impairment and other risk factors on bilateral limb involvement is unclear.To address this issue,we retrospectively collected data from 586 amyotrophic lateral sclerosis patients with limb onset diagnosed at Peking University Third Hospital between January 2020 and May 2022.A univariate analysis revealed no significant differences in the time intervals of spread in different directions between individuals with upper motor neuron-dominant amyotrophic lateral sclerosis and those with classic amyotrophic lateral sclerosis.We used causal directed acyclic graphs for risk factor determination and Cox proportional hazards models to investigate the association between the duration of bilateral limb involvement and clinical baseline characteristics in amyotrophic lateral sclerosis patients.Multiple factor analyses revealed that higher upper motor neuron scores(hazard ratio[HR]=1.05,95%confidence interval[CI]=1.01–1.09,P=0.018),onset in the left limb(HR=0.72,95%CI=0.58–0.89,P=0.002),and a horizontal pattern of progression(HR=0.46,95%CI=0.37–0.58,P<0.001)were risk factors for a shorter interval until bilateral limb involvement.The results demonstrated that a greater degree of upper motor neuron involvement might cause contralateral limb involvement to progress more quickly in limb-onset amyotrophic lateral sclerosis patients.These findings may improve the management of amyotrophic lateral sclerosis patients with limb onset and the prediction of patient prognosis.
基金supported by the National Natural Science Foundation of China,Nos.81873784,82071426Clinical Cohort Construction Program of Peking University Third Hospital,No.BYSYDL2019002(all to DSF)。
文摘Previous studies have shown that ulnar nerve compound muscle action potential recorded by the conventional“belly-tendon”montage does not accurately and completely reflect the action potential of the ulnar nerve dominating the abductor digiti minimi muscle due to the effects of far-field potentials of intrinsic hand muscles.A new method of ulnar nerve compound muscle action potential measurement was developed in 2020,which adjusts the E2 electrode from the distal tendon of the abductor digitorum to the middle of the back of the proximal wrist.This new method may reduce the influence of the reference electrode and better reflect the actual ulnar nerve compound muscle action potential.In this prospective cross-sectional study,we included 64 patients with amyotrophic lateral sclerosis and 64 age-and sex-matched controls who underwent conventional and novel ulnar nerve compound muscle action potential measurement between April 2020 and May 2021 in Peking University Third Hospital.The compound muscle action potential waveforms recorded by the new montage were unimodal and more uniform than those recorded by traditional montage.In the controls,no significant difference in the compound muscle action potential waveforms was found between the traditional montage and new montage recordings.In amyotrophic lateral sclerosis patients presenting with abductor digiti minimi spontaneous activity and muscular atrophy,the amplitude of compound muscle action potential-pE2 was significantly lower than that of compound muscle action potential-dE2(P<0.01).Using the new method,damaged axons were more likely to exhibit more severe amplitude decreases than those measured with the traditional method,in particular for patients in early stage amyotrophic lateral sclerosis.In addition,the decline in compound muscle action potential amplitude measured by the new method was correlated with a decrease in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale scores.These findings suggest that the new ulnar nerve compound muscle action potential measurement montage reduces the effects of the reference electrode through altering the E2 electrode position,and that this method is more suitable for monitoring disease progression than the traditional montage.This method may be useful as a biomarker for longitudinal follow-up and clinical trials in amyotrophic lateral sclerosis.
基金National Basic Research Program of China(Project 973)from The Ministry of Science and Technology of the People's Republic of China,No.2013CB531900。
文摘BACKGROUND Acupuncture promotes the recovery of gastrointestinal function and provides analgesia after major abdominal surgery.The effects of transcutaneous electrical acupoint stimulation(TEAS)remain unclear.AIM To explore the potential effects of TEAS on the recovery of gastrointestinal function after gastrectomy and colorectal resection.METHODS Patients scheduled for gastrectomy or colorectal resection were randomized at a 2:3:3:2 ratio to receive:(1)TEAS at maximum tolerable current for 30 min immediately prior to anesthesia induction and for the entire duration of surgery,plus two 30-min daily sessions for 3 consecutive days after surgery(perioperative TEAS group);(2)Preoperative and intraoperative TEAS only;(3)Preoperative and postoperative TEAS only;or(4)Sham stimulation.The primary outcome was the time from the end of surgery to the first bowel sound.RESULTS In total,441 patients were randomized;405 patients(58.4±10.2 years of age;247 males)received the planned surgery.The time to the first bowel sounds did not differ among the four groups(P=0.90;log-rank test).On postoperative day 1,the rest pain scores differed significantly among the four groups(P=0.04;Kruskal–Wallis test).Post hoc comparison using the Bonferroni test showed lower pain scores in the perioperative TEAS group(1.4±1.2)than in the sham sti-mulation group(1.7±1.1;P=0.04).Surgical complications did not differ among the four groups.CONCLUSION TEAS provided analgesic effects in adult patients undergoing major abdominal surgery,and it can be added to clinical practice as a means of accelerating postoperative rehabilitation of these patients.
基金supported by the National Natural Science Foundation of China(81974166,32271053,and 31872774).
文摘As a main structure of the limbic system,the hippocampus plays a critical role in pain perception and chronicity.The ventral hippocampal CA1(vCA1)is closely associated with negative emotions such as anxiety,stress,and fear,yet how vCA1 neurons encode nociceptive information remains unclear.Using in vivo electrophysiological recording,we characterized vCA1 pyramidal neuron subpopulations that exhibited inhibitory or excitatory responses to plantar stimuli and were implicated in encoding stimuli modalities in naïve rats.Functional heterogeneity of the vCA1 pyramidal neurons was further identified in neuropathic pain conditions:the proportion and magnitude of the inhibitory response neurons paralleled mechanical allodynia and contributed to the confounded encoding of innocuous and noxious stimuli,whereas the excitatory response neurons were still instrumental in the discrimination of stimulus properties.Increased theta power and theta-spike coupling in vCA1 correlated with nociceptive behaviors.Optogenetic inhibition of vCA1 pyramidal neurons induced mechanical allodynia in naïve rats,whereas chemogenetic reversal of the overall suppressed vCA1 activity had analgesic effects in rats with neuropathic pain.These results provide direct evidence for the representations of nociceptive information in vCA1.
文摘As a result of evolution,our body has evolved into a sophisticated system in which various tissues and organs cooperate in a highly orchestrated manner.Few tissues or organs operate in isolation.The brain serves as the command center of our body and is relatively isolated from the peripheral system due to the presence of the blood-brain barrier(BBB).This barrier prevents direct and extensive interaction between blood cells,plasma molecules,and brain cells,contributing to the longstanding perception of the brain as an“immune-privileged”area.Consequently,neuroscientists and immunologists historically conducted separate research with minimal overlap between these two disciplines.However,this perspective has undergone reconsideration over the past few decades.
基金the National Natural Science Foundation of China, No. 30672239
文摘BACKGROUND: Induced differentiation strategies and cytochemical properties of human embryonic stem ceils (hESCs) have been investigated. However, the electrophysiological functions of tyrosine hydroxylase (TH)-positive cells dedved from hESCs remain unclear. OBJECTIVE: To investigate the differentiation efficiency of TH-positive cells from hESCs in vitro using modified four-step culture methods, including embryoid body formation, and to examine the functional characteristics of the differentiated TH-positive cells using electrophysiological techniques. DESIGN, TIME AND SETTING: Neuroelectrophysiology was performed at the Reproductive Medicine Center and Stem Cell Research Center, Peking University Third Hospital, and the Neuroscience Research Institute and Department of Neurobiology, Peking University, from September 2004 to August 2008. MATERIALS: The hESC line, PKU-1.1, a monoclonal cell line derived from a pre-implantation human blastocyst in the Reproductive Medical Center of Peking University Third Hospital. The patch clamp recording system was provided by the Neuroscience Research Institute and Department of Neurobiology, Peking University. METHODS: The hESC line was induced to differentiate into TH-positive cells in vitro using a modified four-step culture method, including the formation of embryoid body, as well as the presence of sonic hedgehog and fibroblast growth factor 8. The cell karyotype was assessed by G-banding karyotype analysis techniques and specific markers were detected immunocytochemically. Whole-cell configuration was obtained after obtaining a tight seal of over 1 GΩ. Ionic currents were detected by holding the cells at -70 mV and stepping to test voltages between -80 and 40 mV in 10-mV increments in voltage-clamp configuration. MAIN OUTCOME MEASURES: We measured the cell karyotype, specific cell markers, and the electrophysiological properties of the voltage-gated ion channels on the cell membrane of TH-positive dopaminergic cells differentiated from our hESCs line in vitro. RESULTS: The differentiated cells had a consistent appearance, and the majority of cells (〉 90%) expressed TH and β-tubulion, as well as the neural progenitor marker, nestino Cell karyotype analysis demonstrated that all of the hESCs had a stable and normal karyotype (46, XX) after differentiation. In addition, patch clamp recording showed that the 10 recorded TH-positive cells exhibited a fast inward current when the test voltage depolarized to -30 mV, and a delayed outward current when the test voltage depolarized to -10 mV. The peak of inward current was obtained at voltage between 10 mV and 0 mV, while the peak of outward current was obtained at 40 mV. The average peak of inward current density was ( -50.05 ± 15.50) pA/pF, and the average peak of outward current density was (41.98 ± 13.55) pA/pE CONCLUSION: More than 90% of the differentiated hESC-derived cells induced by the modified four-step culture method exhibit dopaminergic neuronal properties, including general electrophysiological functional properties, such as functional potassium and sodium channels.
文摘The input-output relationship of neuronal networks depends heavily on the intrinsic properties of their neuronal elements.Profound changes in intrinsic properties have been observed in various physiological and pathological processes,such as learning,memory and epilepsy.However,the cellular and molecular mechanisms underlying acquired changes in intrinsic excitability are still not fully understood.Here,we demonstrate that ERG3 channels are critically involved in the regulation of intrinsic excitability in hippocampal CA1 pyramidal neurons and DG granule cells.Knock-down of ERG3 channels significantly increases neuronal intrinsic excitability,which is mainly caused by decreased fast afterhyperpolarization,delayed time to the generation of an action potential and enhanced summation of somatic excitatory post-synaptic potentials.Interestingly,the expression level of ERG3 protein is significantly reduced in human and mouse brain tissues with temporal lobe epilepsy.Moreover,ERG3 channel knock-down in hippocampus significantly enhanced seizure susceptibility,while mice treated with ERG3 channel activator NS1643 were less prone to epileptogenesis.Taken together,our results suggest ERG3 channels play an important role in determining the excitability of hippocampal neurons and dysregulation of these channels may be involved in the generation of epilepsy.ERG3 channels may thus be a novel therapeutic target for the prevention of epilepsy.
文摘Background:Autism spectrum disorder(ASD)is associated with altered brain development,but it is unclear which specific structural changes may serve as potential diagnostic markers,particularly in young children at the age when symptoms become fully estab-lished.Furthermore,such brain markers need to meet the requirements of precision medicine and be accurate in aiding diagnosis at an individual rather than only a group level.Objective:This study aimed to identify and model brain-wide differences in structural connectivity using diffusion tensor imaging(DTI)in young ASD and typically developing(TD)children.Methods:A discovery cohort including 93 ASD and 26 TD children and two independent validation cohorts including 12 ASD and 9 TD children from three different cities in China were included.Brain-wide(294 regions)structural connectivity was measured using DTI(fractional anisotropy,FA)together with symptom severity and cognitive development.A connection matrix was constructed for each child for comparisons between ASD and TD groups.Pattern classification was performed on the discovery dataset and the resulting model was tested on the two independent validation datasets.Results:Thirty-three structural connections showed increased FA in ASD compared to TD children and associated with both autistic symptom severity and impaired general cognitive development.The majority(29/33)involved the frontal lobe and comprised five different networks with functional relevance to default mode,motor control,social recognition,language and reward.Overall,clas-sification achieved very high accuracy of 96.77%in the discovery dataset,and 91.67%and 88.89%in the two independent validation datasets.Conclusions:Identified structural connectivity differences primarily involving the frontal cortex can very accurately distinguish novel individual ASD from TD children and may therefore represent a robust early brain biomarker which can address the requirements of precision medicine.
基金supported by grants from the National Natural Science Foundation of China(32030052 and 31530028).
文摘The nervous system possesses bidirectional,sophisticated and delicate communications with the immune system.These neuroimmune interactions play a vitally important role in the initiation and development of many disorders,especially neurodegenerative diseases.Although scientific advancements have made tremendous progress in this field during the last few years,neuroimmune communications are still far from being elucidated.By organizing recent research,in this review,we discuss the local and intersystem neuroimmune interactions and their roles in Alzheimer’s disease,Parkinson’s disease and amyotrophic lateral sclerosis.Unveiling these will help us gain a better understanding of the process of interplay inside the body and how the organism maintains homeostasis.It will also facilitate a view of the diseases from a holistic,pluralistic and interconnected perspective,thus providing a basis of developing novel and effective methods to diagnose,intervene and treat diseases.
基金supported by the National Key Research and Development Program of China(No.2020YFA0804000)the National Natural Science Foundation of China(Nos.81971211,12026606,and 81601131)+5 种基金Key Project of Clinical Medicine Research of National Clinical Research Center for Child Health and Disorders,Children's Hospital of Chongqing Medical University(No.NCRCCHD-2021-KP-02)Beijing Natural Science Foundation(No.7212109)the Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases(No.BZ0317)the Capital Health Research and Development of Special Fund(No.2020-1-4071)National High Level Hospital Clinical Research Funding(Scientific Research Seed Fund of Peking University First Hospital)(No.2022SF29)the Fundamental Research Funds for the Central Universities(Nos.BMU2017JI002,BMU2018XY006,and PKU2017LCX06)。
文摘Background The PACS gene family has been demonstrated to be related to intracellular vesicular trafficking.The phenotypic manifestations caused by the pathogenic variants of PACS include epilepsy,intellectual disability/developmental delay,and malformations,such as facial abnormalities.Methods We identified seven new cases with pathogenic or likely pathogenic PACS variants using next-generation sequencing.Detailed information obtained from these patients was analyzed along with that obtained from previously reported patients.Results With the inclusion of the newly diagnosed cases in this study,103 cases with PACS gene family-related neurological diseases were reported,of which 43 were PACS2-related cases and the remaining were PACSI-related cases.Most patients had seizures,which have been reported to be effectively controlled by several types of anti-seizure medications(ASMs).The most efficacious and frequently prescribed ASMs included sodium valproate(43.3%,13/30),oxcarbazepine/carbamazepine(26.7%,8/30),and levetiracetam(20%,6/30).Almost all patients had intellectual disability/developmental delay.The most common pathogenic missense variants were PACSI p.Arg203Trp and PACS2 p.Glu209Lys.In addition,we report a patient carrying a likely pathogenic copy number variation(CNV)(de novo heterozygous deletion of chr14:105821380-106107443,286 kilobase,destroyed part of the furin-binding region domain and the protein structure after it)with more severe and refractory late-onset epilepsy.Conclusions The clinical phenotypes of the different PACS heterozygous missense variants were similar.The pathogenic variant sites of PACSI and PACS2 were quite limited but located in different regions.A CNV destroying part of the PACS2 gene might also be pathogenic.These findings may provide an important clue for further functional studies on the pathogenic mechanism of neurological disorders related to the PACS gene family.
基金supported by the National Natural Science Foundation of China(82230041,91949205,31730035,81721005)the National Key R&D Program of China(2016YFC1305800)the Guangdong Provincial Key S&T Program(018B030336001)。
文摘Abnormal hyperphosphorylation and accumulation of tau protein play a pivotal role in neurodegeneration in Alzheimer’s disease(AD)and many other tauopathies.Selective elimination of hyperphosphorylated tau is promising for the therapy of these diseases.We have conceptualized a strategy,named dephosphorylation-targeting chimeras(DEPTACs),for specifically hijacking phosphatases to tau to debilitate its hyperphosphorylation.Here,we conducted the step-by-step optimization of each constituent motif to generate DEPTACs with reasonable effectiveness in facilitating the dephosphorylation and subsequent clearance of pathological tau.Specifically,for one of the selected chimeras,D16,we demonstrated its significant efficiency in rescuing the neurodegeneration caused by neurotoxic K18-tau seeds in vitro.Moreover,intravenous administration of D16 also alleviated tau pathologies in the brain and improved memory deficits in AD mice.These results suggested DEPTACs as targeted modulators of tau phosphorylation,which hold therapeutic potential for AD and other tauopathies.
基金supported by grants from the National Key Technology R&D Program(No.2008BAK41B01-5)the National Science and Technology Major Project—Development New Genetically Modified Organism(No.2009ZX08012-006B).
文摘Infectious diseases,mostly caused by bacteria and viruses but also a result of fungal and parasitic infection,have been one of the most important public health concerns throughout human history.The first step in combating these pathogens is to get a timely and accurate diagnosis at an affordable cost.Many kinds of diagnostics have been developed,such as pathogen culture,biochemical tests and serological tests,to help detect and fight against the causative agents of diseases.However,these diagnostic tests are generally unsatisfactory because they are not particularly sensitive and specific and are unable to deliver speedy results.Nucleic acid-based diagnostics,detecting pathogens through the identification of their genomic sequences,have shown promise to overcome the above limitations and become more widely adopted in clinical tests.Here we review some of the most popular nucleic acid-based diagnostics and focus on their adaptability and applicability to routine clinical usage.We also compare and contrast the characteristics of different types of nucleic acid-based diagnostics.
基金supported by grants from the National Natural Science Foundation of China (81171042,81070893 and 81221002)the Beijing Outstanding Ph.D.Program Mentor Grantthe Specialized Research Fund for Doctoral Programs of Higher Education, China(20110001110058)
文摘Objective Formaldehyde at high concentrations is a contributor to air pollution. It is also an endogenous metabolic product in cells, and when beyond physiological concentrations, has pathological effects on neurons. Formaldehyde induces mis-folding and aggregation of neuronal tau protein, hippocampal neuronal apoptosis, cognitive impairment and loss of memory functions, as well as excitation of peripheral nociceptive neurons in cancer pain models. Intracellular calcium ([Ca2+]i) is an important intracellular messenger, and plays a key role in many pathological processes. The present study aimed to investigate the effect of formaldehyde on [Ca2+]i and the possible involvement of N-methyl-D-aspartate receptors (NMDARs) and T-type Ca2+ channels on the cell membrane. Methods Using primary cultured hippocampal neurons as a model, changes of [Ca2+]i in the presence of formaldehyde at a low concentration were detected by confocal laser scanning microscopy. Results Formaldehyde at 1 mmol/L approximately doubled [Ca2+]i. (2R)-amino-5-phosphonopentanoate (AP5, 25 μmol/L, an NMDAR antagonist) and mibefradil (MIB, 1 μmol/L, a T-type Ca2+ channel blocker), given 5 min after formaldehyde perfusion, each partly inhibited the formaldehyde-induced increase of [Ca:+]i, and this inhibitory effect was reinforced by combined application of AP5 and MIB. When applied 3 min before formaldehyde perfusion, AP5 (even at 50μmol/L) did not inhibit the formaldehyde-induced increase of [Ca2+]i, but MIB (1 μmol/L) significantly inhibited this increase by 70%. Conclusion These results suggest that formaldehyde at a low concentration increases [Ca2+]i in cultured hippocampal neurons; NMDARs and T-type Ca2+ channels may be involved in this process.
基金supported by the National Basic Research Program of China(Nos.2007CB512501,2009CB522003).
文摘Drug addiction is a chronic brain disorder characterized by withdrawal symptoms that occur during drug abstinence and a high tendency of relapse.Compared with the currently available pharmacological interventions,acupuncture therapy has the potential to help drug addicts stay away from drugs without major adverse side effects.It has taken decades of research to optimize the parameters of electrical acupoint stimulation for detoxification and for relapse prevention,as well as to establish a safe and easy procedure by which drug addicts can use it on themselves.The discovery that acupuncture can trigger the release of opioid substances from the brain in the 1970s provided the inspiration.Following this,basic research on animals made it possible to understand the mechanisms of action and establish the procedure for treating drug addictions.This article reviews the past,present,and foreseeable future regarding the use of acupuncture-related technique for the treatment of opiate addiction from the perspective of translational medicine.
基金supported by Grants from the National Natural Science Foundation of China(81230023,81571067,and 81521063)National Basic Research Development Program(973 Program)of China(2013CB531905)the‘‘111’’Project of China
文摘The local field potential(LFP) is a signal reflecting the electrical activity of neurons surrounding the electrode tip. Synchronization between LFP signals provides important details about how neural networks are organized. Synchronization between two distant brain regions is hard to detect using linear synchronization algorithms like correlation and coherence. Synchronization likelihood(SL) is a non-linear synchronization-detecting algorithm widely used in studies of neural signals from two distant brain areas. One drawback of non-linear algorithms is the heavy computational burden. In the present study, we proposed a graphic processing unit(GPU)-accelerated implementation of an SL algorithm with optional 2-dimensional time-shifting. We tested the algorithm with both artificial data and raw LFP data. The results showed that this method revealed detailed information from original data with the synchronization values of two temporal axes,delay time and onset time, and thus can be used to reconstruct the temporal structure of a neural network. Our results suggest that this GPU-accelerated method can be extended to other algorithms for processing time-series signals(like EEG and f MRI) using similar recording techniques.
文摘Frontiers of Medicine 2011,5(2):141–150 A mistake appeared in the sentence on lines 4–6 on the right column of page 148.The sentence“Low frequency(represented by 2 Hz)EA is most effective for suppressing the withdrawal syndromes and high frequency(100 Hz)EA is best for alleviating craving.”should be changed to“Low frequency(represented by 2 Hz)EA is most effective for alleviating craving and high frequency(100 Hz)EA is best for suppressing the withdrawal syndromes.”
文摘Background NR2F1 mutations are associated with Bosch-Boonstra-Schaaf optic atrophy syndrome(BBSOAS).Although~46.7%of BBSOAS patients present with epilepsy,which is always drug-resistant and associated with higher rates of behavioral and cognitive problems,the treatment and outcomes of NR2F1-related epilepsy have rarely been described.Here,we present new cases of BBSOAS-related epilepsy and summarize all previously reported cases to explore the effective treatment for this type of epilepsy.Methods We identified six new Chinese cases of BBSOAS with epilepsy.Five different de novo heterozygous NR2F1 mutations were identified in these cases,including two novel mutations c.365G>T,p.Cys122Phe and c.449G>T,p.Gly150Val.By combining the six cases and 14 previously reported cases,we analyzed the characteristics and treatment outcomes of NR2F1-related epilepsy.Results Twelve of the 20 patients(60%)had infantile epileptic spasms,while the other patients had generalized tonic/tonic-clonic,focal,myoclonic,absence,or unclassified seizures.Several anti-seizure medications,steroids,and a ketogenic diet were administered in these cases.However,seizures were controlled in only 50%of previously reported cases,while all of the six new cases became seizure-free after perampanel as an add-on treatment.The average time from the addition of perampanel to seizure control was 7.33±4.59 months(range,1–12 months).The median time to seizure freedom was 14 months(1–32 months,>19 months in 3 cases).The average dosage of perampanel needed for epilepsy control was 0.22±0.17 mg/kg per day.Conclusions In this paper,we comprehensively summarized the clinical characteristics,treatments and outcomes of NR2F1-related epilepsy for the first time.Perampanel exhibits dramatic efficacy for NR2F1-related epilepsy.This will help optimize the treatment of this type of epilepsy and provide clues for its pathogenic mechanisms.The two novel mutations expand the genotype spectrum of this disease.
基金National Natural Science Foundation of China,Grant/Award Numbers:92249305,82120108010,81930028,31921003Academy of Medical Sciences(Newton Advanced Fellowship),Grant/Award Number:NAF/R11/1010National Institutes of Health,Grant/Award Number:R01DA056739。
文摘The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease(AD)and associated socioeconomic burdens.Abnormal metabolism of amyloid-β(Aβ)has been proposed as a significant pathomechanism in AD,supported by results of recent clinical trials using anti-Aβantibodies.Nonetheless,the cognitive benefits of the current treatments are limited.The etiology of AD is multifactorial,encompassing Aβand tau accumulation,neuroinflammation,demyelination,vascular dysfunction,and comorbidities,which collectively lead to widespread neurodegeneration in the brain and cognitive impairment.Hence,solely removing Aβfrom the brain may be insufficient to combat neurodegeneration and preserve cognition.To attain effective treatment for AD,it is necessary to(1)conduct extensive research on various mechanisms that cause neurodegeneration,including advances in neuroimaging techniques for earlier detection and a more precise characterization of molecular events at scales ranging from cellular to the full system level;(2)identify neuroprotective intervention targets against different neurodegeneration mechanisms;and(3)discover novel and optimal combinations of neuroprotective intervention strategies to maintain cognitive function in AD patients.The Alzheimer's Disease Neuroprotection Research Initiative's objective is to facilitate coordinated,multidisciplinary efforts to develop systemic neuroprotective strategies to combat AD.The aim is to achieve mitigation of the full spectrum of pathological processes underlying AD,with the goal of halting or even reversing cognitive decline.