Using the negative eigenvalue theory and the infinite order perturbation theory, a new method was developed to solve the eigenvectors of disordered systems. The result shows that eigenvectors change from the extended ...Using the negative eigenvalue theory and the infinite order perturbation theory, a new method was developed to solve the eigenvectors of disordered systems. The result shows that eigenvectors change from the extended state to the localized state with the increase of the site points and the disordered degree of the system. When electric field is exerted, the electrons transfer from one localized state to another one. The conductivity is induced by the electron transfer. The authors derive the formula of electron conductivity and find the electron hops between localized states whose energies are close to each other, whereas localized positions differ from each other greatly. At low temperature the disordered system has the character of the negative differential dependence of resistivity and temperature.展开更多
A Yb:CaGd_(0.33)Y_(0.625)AlO_(4)(Yb:CGYA)laser crystal of high optical quality has been successfully synthesized via the Czochralski method.The introduction of Gd^(3+)ions preserves the original structure and efficien...A Yb:CaGd_(0.33)Y_(0.625)AlO_(4)(Yb:CGYA)laser crystal of high optical quality has been successfully synthesized via the Czochralski method.The introduction of Gd^(3+)ions preserves the original structure and efficiently generates inhomogeneous broadening of the Yb^(3+)ion emission spectra.The fluorescence emission peak wavelength of the Yb:CGYA crystal is 1053 nm,and the corresponding measured full width at halfmaximum is 93 nm.A tunable laser output ranging from 1017 nm to 1073 nm is achieved by using a birefringent filter,which represents the broadest tuning range reported in a short cavity to date.The compact laser offers significant advantages for its applications around the 1μm wavelength band.展开更多
妊娠期高血压疾病(hypertensive disorders of pregnancy,HDP)是一类妊娠和血压升高并存的产科常见并发症,涵盖了妊娠期高血压(gestational hypertension,GH)、子痫前期(preeclampsia,PE)、妊娠合并慢性高血压(chronic hypertension)和...妊娠期高血压疾病(hypertensive disorders of pregnancy,HDP)是一类妊娠和血压升高并存的产科常见并发症,涵盖了妊娠期高血压(gestational hypertension,GH)、子痫前期(preeclampsia,PE)、妊娠合并慢性高血压(chronic hypertension)和慢性高血压并发子痫前期(chronic hypertension with superimposed pre-eclampsia)。这些疾病是导致孕产妇及围产儿死亡的主要原因之一。展开更多
Objective Autism spectrum disorder(ASD)is a neurodevelopmental condition characterized by difficulties with communication and social interaction,restricted and repetitive behaviors.Previous studies have indicated that...Objective Autism spectrum disorder(ASD)is a neurodevelopmental condition characterized by difficulties with communication and social interaction,restricted and repetitive behaviors.Previous studies have indicated that individuals with ASD exhibit early and lifelong attention deficits,which are closely related to the core symptoms of ASD.Basic visual attention processes may provide a critical foundation for their social communication and interaction abilities.Therefore,this study explores the behavior of children with ASD in capturing attention to changes in topological properties.Methods Our study recruited twenty-seven ASD children diagnosed by professional clinicians according to DSM-5 and twenty-eight typically developing(TD)age-matched controls.In an attention capture task,we recorded the saccadic behaviors of children with ASD and TD in response to topological change(TC)and non-topological change(nTC)stimuli.Saccadic reaction time(SRT),visual search time(VS),and first fixation dwell time(FFDT)were used as indicators of attentional bias.Pearson correlation tests between the clinical assessment scales and attentional bias were conducted.Results This study found that TD children had significantly faster SRT(P<0.05)and VS(P<0.05)for the TC stimuli compared to the nTC stimuli,while the children with ASD did not exhibit significant differences in either measure(P>0.05).Additionally,ASD children demonstrated significantly less attention towards the TC targets(measured by FFDT),in comparison to TD children(P<0.05).Furthermore,ASD children exhibited a significant negative linear correlation between their attentional bias(measured by VS)and their scores on the compulsive subscale(P<0.05).Conclusion The results suggest that children with ASD have difficulty shifting their attention to objects with topological changes during change detection.This atypical attention may affect the child’s cognitive and behavioral development,thereby impacting their social communication and interaction.In sum,our findings indicate that difficulties in attentional capture by TC may be a key feature of ASD.展开更多
Alzheimer's disease(AD)is a prevalent neurodegenerative disease characterized by cognitive decline in the early stage.Mild cognitive impairment(MCI)is considered as an intermediate stage between normal aging and A...Alzheimer's disease(AD)is a prevalent neurodegenerative disease characterized by cognitive decline in the early stage.Mild cognitive impairment(MCI)is considered as an intermediate stage between normal aging and AD.In recent years,studies related to resting-state functional MRI(rs-fMRI)indicated that the occurrence and development process of MCI and AD might be closely linked to spontaneous brain activity and alterations in functional connectivity among brain regions,and rs-fMRI could provide important reference for specific diagnosis and early treatment of MCI and AD.The research progresses of rs-fMRI for MCI and AD were reviewed in this article.展开更多
Objective:Active and passive smoking are common environmental risk factors,but there is no definite conclusion about their effects on relapse and disability progression in multiple sclerosis(MS)and neuromyelitis optic...Objective:Active and passive smoking are common environmental risk factors,but there is no definite conclusion about their effects on relapse and disability progression in multiple sclerosis(MS)and neuromyelitis optica spectrum disorder(NMOSD).Methods:This was a retrospective cohort study.Patients were included from four centers.Demographic and clinical data were extracted from the clinical database,while data involving environmental exposures during daily life,relapse,and disability progression were obtained through telephone follow-up interviews.Determinants of relapse were assessed by Cox proportional models,and disability progression was assessed by linear regression.Kaplan‒Meier survival was used to estimate relapse within five years after the first attack.Results:A total of 130 MS patients and 318 NMOSD patients were included in this study,and females accounted for 60%and 79.6%,respectively.MS patients with an active smoking history had a higher risk of relapse,for which the association became borderline significant after accounting for covariates(aHR=1.52,95%CI=1.00,2.31;p=0.052).The relapse risk between ever-smokers who smoked more than 10 cigarettes per day and smokers who smoked less than 10 cigarettes per day was not significantly different(aHR=0.96,95%CI=0.63,1.47;p=0.859).However,exposure to passive smoking was associated with a reduced risk of MS relapse(aHR=0.75,95%CI=0.56,1.00;p=0.044)compared with never-exposed patients.No associations were observed between active smoking/passive smoking and the risk of NMOSD relapse,but patients with a history of smoking were associated with a lower annual progression rate by Expanded Disability Status Scale(EDSS)(aβ=−0.20,95%CI=−0.38,−0.01;p=0.036)and Multiple Sclerosis Severity Score(MSSS)(aβ=−0.23,95%CI=−0.44,−0.03;p=0.028).Conclusion:Our research shows that active smoking increases the relapse risk of MS and has a negative impact on disability progression;thus,smoking cessation should be encouraged.展开更多
Methylenetetrahydrofolate reductase(MTHFR)deficiency is a rare autosomal recessive genetic disorder caused by mutations in the MTHFR gene,leading to a variety of clinical manifestations.In October 2022,the Second Xian...Methylenetetrahydrofolate reductase(MTHFR)deficiency is a rare autosomal recessive genetic disorder caused by mutations in the MTHFR gene,leading to a variety of clinical manifestations.In October 2022,the Second Xiangya Hospital of Central South University admitted a 21-year-old male patient with neuropsychiatric disorders,presenting primarily with cognitive decline,limb tremors,abnormal mental and behavioral symptoms,seizures,and gait disturbances.These symptoms had gradually developed over 5 years,worsening significantly in the past year.The patient’s plasma homocysteine levels were 10 times higher than normal,and brain MRI revealed brain atrophy and significant abnormal signals in the bilateral paraventricular nuclei and heads of the bilateral caudate nuclei.Further genetic testing identified a paternal mutation c.1604G>A(p.R535Q)and a maternal mutation c.227T>G(p.L76R)of the MTHFR gene.After betaine supplementation,the plasma homocysteine levels decreased within a week,and the symptoms improved.The patient was ultimately diagnosed with severe hyperhomocysteinemia due to MTHFR deficiency.The c.227T>G(p.L76R)mutation represents a novel missense mutation in the MTHFR gene associated with MTHFR deficiency,but further research is needed to confirm its potential pathogenicity.Early treatment with betaine can fully reverse the symptoms.展开更多
There is an ever-growing demand for lightweighting of steel for structural applications,particularly for automobile and transportation applications.It is mainly to improve the fuel efficiency,reduce the CO_(2) emissio...There is an ever-growing demand for lightweighting of steel for structural applications,particularly for automobile and transportation applications.It is mainly to improve the fuel efficiency,reduce the CO_(2) emissions and cater the increased passenger safety.Hence,the main focus is to reduce the density of the steel structure without affecting other properties.This can be achieved by down-gauging of the conventional steel by replacing the steel with higher strength,however,it is limited by dent resistance and stiffness.So,the novel idea is to reduce the density of the steel itself.It is well-known that addition of Al to steel reduces the density of the steel.About 1wt% of Al addition to steel can reduce the density by 1.3%,decreases the elastic modulus by 2% and it improves the strength by about 40 MPa.There is a new class of low-density/lightweight steel with addition of about 6-9 wt% Al to steel.Addition of higher than 9 wt%of Al in steel leads to embrittlement issues due to ordering and environmental effect.These disordered Fe-Al lightweight steels have raised considerable interest due to their low-density,high ductility,costeffectiveness and feasibility for bulk production.The low-density steels are envisaged in the development of an advanced lightweight ground transportation system,huge structures and also for certain defence applications and in thermal power plants.展开更多
OBJECTIVE Major depressive disorder(MDD) is a highly heterogeneous mental illness.Further classification may help characterize its heterogeneity.The purpose of this study was to examine metabolomic and brain connectom...OBJECTIVE Major depressive disorder(MDD) is a highly heterogeneous mental illness.Further classification may help characterize its heterogeneity.The purpose of this study was to examine metabolomic and brain connectomic associations with traditional Chinese medicine(TCM) diagnostic classification of MDD.METHODS Fifty unmedicated depressed patients were classified into Liver Qi Stagnation(LQS,n=30) and Heart and Spleen Deficiency(HSD,n=20) subtypes according to TCM diagnosis.Healthy volunteers(n=28) were included as controls.Gas chromatography-mass spectrometry(GC-MS) and diffusion tensor imaging were used to detect serum and urinary metabolomic profiles and whole-brain white matter connectivity,respectively.RESULTS In metabolomic analysis,28 metabolites were identified for good separations between TCM subtypes and healthy controls in serum and urine samples.While both TCM subtypes had similar profiles in proteinogenic branched-chain amino acids and energy metabolism-related metabolites that were differentiated from healthy controls,the LQS subtype additionally differed from healthy controls in multiple amino acid metabolites that are involved in the biosynthesis of monoamine and amino acid neurotransmitters.Several metabolites are differentially associated with the two subtypes.In connectomic analysis,The LQS subtype showed significant differences in multiple network metrics of the angular gyrus,middle occipital gyrus,calcarine sulcus,and Heschl′ s gyrus when compared to the other two groups.The HSD subtype had markedly greater regional connectivity of the insula,parahippocampal gyrus,and posterior cingulate gyrus than the other two groups,and microstructural abnormalities of the frontal medial orbital gyrus and middle temporal pole.The insular betweenness centrality was strongly inversely correlated with the severity of depression and dichotomized the two subtypes at the optimal cutoff value with acceptable sensitivity and specificity.CONCLUSION The LQS subtype may represent an MDD subpopulation mainly characterized by abnormalities in the biosynthesis of monoamine and amino acid neurotransmitters,closer associations with stress-related pathophysiology,and aberrant connectivity of the audiovisual perception-related temporal-occipital network,whereas the HSD subtype is more closely associated with hyperconnectivity and microstructural abnormalities of the limbicparalimbic network.Certain metabolomic and connectomic variables are potential biomarkers for TCM diagnostic subtypes which is perhaps an alternative classification for depressive disorders.展开更多
Phytomedicines have been used for treating or preventing diseases throughout human history.We have been conducting in exploration of traditional or folk herbal medicines as an attempt to identify novel phytocompounds ...Phytomedicines have been used for treating or preventing diseases throughout human history.We have been conducting in exploration of traditional or folk herbal medicines as an attempt to identify novel phytocompounds candidates for further development into botanical supplements or drugs for inflammation related diseases,including cancer,acute liver hepatitis,and sepsis.Comparative″OMICS″technology platforms in combination with various in vitro and in vivo cell-and gene-based bioassays,murine skin inflammatory and syngeneic and xenograft mammary tumor and melanoma models are employed to validate the pharmacological effects and the underlying mechanistic insights of the identified bioactive phytocompounds.The therapeutic potential of phytoagents,alone or in combination,in sensitizing the chemotherapeutic drug efficacy and/or reduction of its side effects in tumor-bearing mice are investigated.In addition,how phytoagents modulate pro-or anti-inflammatory lipid mediators,such as oxylipins,and related signaling cascades systemically or at organ levels are also addressed for understanding sepsis or cancer pathogenesis and the modes of action of bioactive phytoagents.展开更多
In the past decades,single target drugs showed less therapeutic action and more side effects in treatment of complicated diseases such as tumor,AIDS,inflammation,diabetes,stroke and neurodegenerative disorders.The rea...In the past decades,single target drugs showed less therapeutic action and more side effects in treatment of complicated diseases such as tumor,AIDS,inflammation,diabetes,stroke and neurodegenerative disorders.The reason for this is that complicated diseases have multiple pathogenesis and multiple genes or pathological changes occur in many organs or in different kinds of cells.Therefore,scientists of worldwide hope to develop multi-target drugs recently traditional Chinese medicine(TCM)and their many effective components are characterized by inducing multi-target effects,the following 2 components isolated from TCM were proved in our laboratory to have multi-target effects which benefit complicated diseases.Anti-stroke drug-salvianolic acid B(Sal B):In MCAO rats,Sal B was shown to have many biological activities.Firstly,Sal B could past through blood-brain barrier(BBB)and could repair damage of BBB induced by cerebral ischemia.Secondly,Sal B improved blood flow in ischemic hemisphere with no steal blood and without hypotention,inhibited platelet aggregation a thrombosis but no hemorrhagic risk.More importantly,Sal B could inhibit three risk factors-intracellular Ca2+ overload,excessive regeneration of free radicals,excitotoxicity which aggravate ischemic brain injuries.Thirdly,Sal B activated organism protective mechanism such as increasing neurogenesis,angiogenesis,and many anti-oxidative substances and improving energy supply.Taking all these results we believe that sal B is a good anti-stroke agent.Anti-dementia drug-(-)clausenamide:(-)Clausenamide is a novel compound isolated from clausena lansium(Lour)which is the first chiral compound having anti-dementia effect in recent years.As the content in the plant is very low,after long term of effort this compound now been chemically synthesized by our institute and the production are has reached semi-industry scale that satisfies the demand for clinical trial and hereafter therapeutic use.For pharmacology,(-)clausenamide improved cognition and inhibited Aβpathogenesis including inhibition of Aβtoxicity and tau hyperphosphorylation.According to the new theory″Synaptic loss=AD″,agood anti-dementia drug must be able to improve synaptic plasticity and promote synaptogenesis.Fortunately,(-)clausenamide happened to be such compound.As proved in our study that(-)clausenamide increased synaptic plasticity both in efficacy and structure.For latter,(-)clausenamide increased synaptic density and expression of growth associate protein(GAP-43)in the brain significantly.Now(-)clausenamide has been developed to phaseⅡ of clinical trial.展开更多
In recent years,miR-124 has emerged as a critical modulator of immunity and inflammation.Here,we summarize studies on the function and mechanism of miR-124 in the immune system and immunity-related diseases.They indic...In recent years,miR-124 has emerged as a critical modulator of immunity and inflammation.Here,we summarize studies on the function and mechanism of miR-124 in the immune system and immunity-related diseases.They indicated that miR-124 exerts a crucial role in the development of immune system,regulation of immune responses,and inflammatory disorders.It is evident that miR-124 may serve as an informative diagnostic biomarker and therapeutic target in the future.展开更多
OBJECTIVE Social anxiety disorder,also known as social phobia,is the most common of all anxiety disorders.Despite the seriousness of this disorder,it has rarely been studied and as a consequence,little is known about ...OBJECTIVE Social anxiety disorder,also known as social phobia,is the most common of all anxiety disorders.Despite the seriousness of this disorder,it has rarely been studied and as a consequence,little is known about its underlying neurobiology.Growing evidence suggests that inhibitory neurons dysfunction could affect the balance of neuronal activity in psychotic disorders including anxiety,SAD,etc.Ephrin-B(EB) proteins were previously demonstrated to ensure normal distribution and function of inhibitory interneurons in the brain.We thus proposed that deletion of EB2 in inhibitory neurons might destroy the homeostasis of excitatory neurons and inhibitory neurons,and induce behavioral deficits associated with psychotic diseases.METHODS(1)Mice.We generated conditional EB2 knockout mice as a model of SAD and characterized the behaviors and the biochemical changes in the brains of the knockout mice.We also generated a mouse line with a selective deletion of EB2 from vGAT neurons by breeding a v GAT-Cre line with a loxP-flanked alleles in EB2.For EB2 detection,we crossed vGAT-Cre;EphrinB2 loxp/loxp mice with Rosa26-STOP-tdTomato Cre indicator(Ai9) mice to label the vGAT neurons with tdTomato.Mice were maintained in a mixed CD1/129 genetic background.Al experiments involving mice were carried out in accordance with the Shanghai Jiaotong University.Genotypes were unlocked only after completion of analysis.(2) General procedures for behavioral testing.Open field test:Locomotor activity was measured using an open field test.The size of the open field box was 44 cm×44 cm×44 cm.Each mouse was placed in the corner of the open-field apparatus at the beginning of the test,and allowed to explore it for 15 min.The total distance traveled(in cm) and counts for stereotyped behaviors were recorded and analyzed.The total distance traveled was used as an index of locomotor activity.The percentage of center zone entries was considered as anxiety indexes.EPM test:The elevated plus maze apparatus was made of dark gray plastic and comprised two open arms(30 cm×7 cm×0.25 cm) opposed to two enclosed arms(30 cm × 7 cm × 15 cm) elevated60 cm from the floor.Animals were placed in the central area of the apparatus with their head facing an enclosed arm(test duration,5 min).Digitized video recordings with EthoVision software were used for behavioral analysis.The percentage of time spent in open arms and the percentage of open-arm entries were calculated.Social behaviors:Briefly,a top open acrylic box was divided into three compartments by two clear acrylic glass partitions with an opening in the bottom.Wire mesh cages that are either empty or have social stimulus mouse in it were put in the center of each outer compartment.Unfamiliar naive CD1/129 mice of the same age were used as stimulus mice.Prior to the test,the mouse was introduced into the center chamber for 5 min,with both gates closed.Gates were then open and the test mouse was acclimated to explore the empty three-chambered apparatus freely for another 10 min.After the initial 15 min habituation session,mice were placed in the center compartment and allowed to explore freely all the three compartments.To examine the social contact,the following activities were recorded via a video surveillance for 10 min.The number of entries to each compartment,the time spent in each compartment as well as the time and frequency each mouse spent in sniffing were analyzed with EthoVision XT 8.5(Noldus,Wageningen,Netherlands).RESULTS(1)Social preference assays were performed in WT-vGATCre,EB2-flox,and EB2-vGATCre mice respectively.To evaluate social approach behavior,we used a three-chamber social arena to evaluate animals for their social interaction.The control groups of WTvGATCre,EB2-flox mice showed a significant preference for spending time in the social chamber(P<0.05);whereas the EB2-vGATCre mice did not show this preference and spent roughly equal time in the social and nonsocial chambers.(2)To determine if the decrease in social preference could result from changes in locomotion,we compared locomotor activity in EB2-vG ATCre mice and control mice.We did not observe a significant lower locomotive activity in mice.Hence,EB2 deletion caused a change in social preference but not in locomotion.Taken together,EB2 deletion exerts abnormal psychotogenic activity of social deficits which was often considered as an important feature of SAD.(3) The time spent in the open arms is widely used to measure anxiety in mice,with greater time spent in the open arm being considered as less anxious behavior.To normalize for individual differences in overall activity level,the time spent in the open arms was divided by the total time.The ratio was higher for WT-vGATCre mice and EB2-loxp mice as compared to the EB2-vG ATCre mice(P=0.0112,P=0.0197).Thus,results showed that there was a change in anxiety levels from in EB2-vGATCre mice as compared with control mice.CONCLUSION EB2 may be a candidate risk gene for SAD and that the EB2 conditional knockout model could be a tool for studying the underlying mechanisms in SAD.展开更多
It has been demonstrated that inflammation and dysregulation of immune response are involved in the pathogenesis of Alzheimer disease (AD). Inflammation is an early event in AD development, especially inflammasome and...It has been demonstrated that inflammation and dysregulation of immune response are involved in the pathogenesis of Alzheimer disease (AD). Inflammation is an early event in AD development, especially inflammasome and pro-inflammatory molecules are pathogenic factor in AD. Our data showed that activated immune cells may contribute to the pathogenesis of AD, since the mice with immune cells knock out demonstrated differentsings in the neurodegenerative process and T cells aid clearance of plaques in mice and infiltrating parenchymal T-cell in AD brain mainly in the light of amyloid pathology, and immune treatment is effective, etc. However, the direct evidence on T and B cells infiltrating into the brain of APP transgenic mice have not yet found. Whether aged T cells are pathogenic in AD?How is role of aged B cells? These questions are still unclear. In conclusion, activated immune cells,and inflammatory molecules may play important roles in neurodegenerative disorders, such as AD. The mechanisms of behind this are needed to further study. Inhibiting inflammation in the early phase of AD and restore normal immune regulation are new drug target for the future.展开更多
Major depressive disorder(MDD)is a common neuropsychiatric disorder characterized by diverse symptoms.There are big limitations of clinic medicine which highlighted an urgent and clear need for more efficacious and fa...Major depressive disorder(MDD)is a common neuropsychiatric disorder characterized by diverse symptoms.There are big limitations of clinic medicine which highlighted an urgent and clear need for more efficacious and faster-acting therapeutic agents to treat patients with MDD,especially those who are refractory to the traditional antidepressants.In the present study,we assessed a novel compound,YY-21,from timosaponin B-Ⅲ derived from sarsasapogenin of Anemarrhenae Rhizoma.We found that YY-21 obviously increased presynaptic glutamate release and enhanced long-term synaptic activity within 10 min as determined by excitatory postsynaptic current(EPSC) and field excitatory postsynaptic potential(fEPSP) in medial prefrontal cortex(mPFC) slices.YY-21 demonstrated anxiolytic-like effects following acute administration in animals and reversed the depressivelike and anxiety phenotypes induced by chronic unpredictable mild stress(CMS) with a relatively fast therapeutic onset.Our mechanism research reveals that NMDA receptors and two-pore domain potassium(K2P)(TREK1) channels emerged as new drug targets for faster acting antidepressants.K2 P channels generate leak currents that are responsible the maintenance of resting membrane potential.They are potential targets for the treatment of multiple diseases.Here we identify TKDC,an inhibitor of the TREK subfamily,including TREK1,TREK2 and TRAAK channels.Using TKDC as a chemical probe,a combined study of computations,mutagenesis,and electrophysiology reveal an allosteric ligand-binding site in the extracellular cap of the channels.The molecular dynamics simulations suggest that ligand-induced allosteric conformational transitions cause a blockage of the ion conductive pathway.The identification of the extracellular ligand-binding site is confirmed by the discovery of new inhibitors targeting this site using virtual screening.These results suggest that the extracellular cap of a K2P channel can act as a new allosteric site and may serve as a direct drug target.展开更多
OBJECTIVE To explore the antipost-traumatic-stress-disorder(PTSD) effects and its probable mechanism of YQA14,a dopamine D3 receptor antagonist.METHODS Two PTSD animal models,the rat single prolonged stress(SPS) model...OBJECTIVE To explore the antipost-traumatic-stress-disorder(PTSD) effects and its probable mechanism of YQA14,a dopamine D3 receptor antagonist.METHODS Two PTSD animal models,the rat single prolonged stress(SPS) model and the mouse pre-shock model,were used in this experiment.In the SPS model,adult male Sprague-Dawley(SD) rats were randomly divided into control group,model group,positive group and YQA14 groups with different dosages.In the mouse pre-chock model,dopamine D3 receptor knockout(KO) and wild type(WT) mice were randomly divided into control group,model group,positive group and YQA14 group.After the establishment of animal models,the saline,sertraline(ig) and YQA14(ip)were administered to the animals in the control,model,positive control and test groups respectively.The open field test(OFT) was used to evaluate the locomotor activity while the contextual freezing(CF) measurement and elevated plus maze(EPM) test were used to evaluate the PTSD-like behaviors.RESULTS In the rat SPS model,neither SPS nor drug treatment affected the locomotor activity in rats.However,SPS rats showed significant PTSD-like behaviors with enhanced freezing time in CF(P<0.01) and decreased percentage of entries into open arms and time spent in open arms in EPM(P<0.05,P<0.01).Moreover,compared with the model group,the repeated administration of YQA14(3.125,6.25 and 12.5 mg·kg-1)significantly reduced the freezing time(P<0.01)and increased the percentages of entries into open arms and time spent in open arms(P<0.05).In the mouse pre-shock model,when both model groups showed significant higher freezing time compared with the respective control groups(P<0.05,P<0.01),YQA14 selectively alleviated the freezing time on WT mice(P<0.05) while had no effect on KO mice.In the EPM tests,the WT mice model group showed a significant reduction in the percentage of entries into open arms and time spent in open arms(P<0.05) while D3 R KO mice model group didn′ t show any reduction,compared with respective control groups.Furthermore,daily administration of YQA14 at 12.5 mg·kg-1 both significantly reduced the percentages of entries into and time spent in open arms(P<0.05) but not D3 R KO mice.None of the locomotor activity were significantly affected.CONCLUSION YQA14 could significantly alleviate the PTSD-like behaviors in rodents and the effects were mediated by the blockade of brain D3 receptors.展开更多
Genotype of IgH, TCRγ and TCR δ gene rearrangement in 42 cases of malignant lymphoproliferative disorders were studied by using polymerase chain reaction (PCR) technique. The results suggested that among the 23 case...Genotype of IgH, TCRγ and TCR δ gene rearrangement in 42 cases of malignant lymphoproliferative disorders were studied by using polymerase chain reaction (PCR) technique. The results suggested that among the 23 cases, in which malignant cells expressed B-lineage cell surface markers, 20 showed IgH gene rearrangement and 11 had TCRγ gene rearrangement and / or TCRδ gene deletion. All the 11 cases expressed T-lineage cell differentiation antigens were found to have TCRγand TCRδ gene rearrangement or deletion and only one had IgH gene rearrangement. Double rearrangements of IgH and TCRγ genes were detected in all the 3 cases of T and B double-phenotype ALL. In the cases malignant cells did not express any lineage specific antigens while 4/5 had TCRγ gene rearrangement but all failed in IgH gene rearrangement. The relation of cellular differentiation origin and rearrangement of antigen receptor genes with clinical manifestations was discussed.展开更多
Berberine(BBR)is an alkaloid from plants like Coptis chinensis and is for many years an OTC drug in China for bacterial-caused diarrhea.We have identified BBR to be an effective drug in treating hyperlipidemia as well...Berberine(BBR)is an alkaloid from plants like Coptis chinensis and is for many years an OTC drug in China for bacterial-caused diarrhea.We have identified BBR to be an effective drug in treating hyperlipidemia as well as hyperglycemia.Clinical studies showed that oral administration of BBR caused significant reduction of blood cholesterol,triglyceride as well as glucose in patients with hyperlipidemia and T2D,with no obvious side-effect.Mechanism studies have identified several molecular mechanisms involving in the mode of action of BBR.The cholesterol-lowering effect was associated with the extracellular-signalregulated kinase(ERK)mediated LDLR mRNA up-regulation;the glucose-lowering effect mainly resulted from the protein kinase D mediated InsR expression and the activation of AMPK.The observed reduction of triglyceride by BBR might reflect its synergistic effect on both sugar and lipid metabolism.The interaction between gut microbiota and BBR explained the molecular mechanism of BBR′s intestinal absorption.BBR concentrated in liver after oral administration with a level many times more than that in blood.At least three CYP450 subtypes were responsible for BBR phase-Ⅰ metabolism.Structure-activity relationship of BBR was analyzed,and the clinical advantage of BBR was demonstrated.We consider BBR a new medicine for metabolic disorders.展开更多
Time: March 5-8, 2020Venue: Lasvegas, USWebsite: https://www.cns.org/Spine Summit 2020, the 36th Annual Meeting of the Section on Disorders of the Spine and Peripheral Nerves will take placein Lasvegas, US on March 5-...Time: March 5-8, 2020Venue: Lasvegas, USWebsite: https://www.cns.org/Spine Summit 2020, the 36th Annual Meeting of the Section on Disorders of the Spine and Peripheral Nerves will take placein Lasvegas, US on March 5-8, 2020.展开更多
OBJECTIVE Cisplatin is a formidable chemotherapy agent widely applying in antineoplastic treatments,but its side effects often limit the clinical usage.Metabolic disorders are one of the side effects induced by cispla...OBJECTIVE Cisplatin is a formidable chemotherapy agent widely applying in antineoplastic treatments,but its side effects often limit the clinical usage.Metabolic disorders are one of the side effects induced by cisplatin,which closely relate to the onset of chemotherapy-induced anorexia(CIA)in cancer patients but lacks effective controls.Liujunzi decoction(LJZD)is a traditional Chinese formula that has a promising effect in treating CIA.However,whether LJZD ameliorates CIA through adjusting cisplatin-induced metabolic disorders remain unknow.The present study evaluated the mechanism of cisplatin-induced metabolic disorders,and the effect of LJZD in ameliorating these disturbances.METHODS 42 male Sprague-Dawley(SD)rats(180-220 g)were randomly divided into 3 groups:normal control group(distilled water+saline),model group(distilled water+cisplatin),LJZD group(4.8 g·kg^(-1)Liujunzi decoction ingredients+cisplatin).Intragastrical administered each drug twice a day(7∶00-19∶00)since day 0 for 4 d,animals were intraperitoneal injected with cisplatin 6 mg·kg^(-1)1 h after administration while normal control groups were injected with same volume of saline.On day 3,each group was anesthetized with pentobarbital sodium 45 mg·kg^(-1)(ip),and blood samples were collected from aorta abdominalis.Then the samples were analyzed using an LC-ESI-MS/MS system.Significantly regulated metabolites between groups were determined by VIP≥1 and absolute Log2FC(fold change)≥1.Identified metabolites were mapped to Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway database using Metaboanalyst 5.0(https://www.metaboanalyst.ca/).RESULTS A total of 133,77 and 32 differential metabolites were filtrated in control vs model,control vs LJZD and model vs LJZD groups respectively.Comparing to control,the levels of hexadecanoic acid(Log2FC=6.3153),linoleic acid(Log2FC=5.3478),and 8,11-icosadienoic acid(Log2FC=5.2342)significantly increased,and the levels of N-acetyl-L-tyrosine(Log2FC=-2.6283),cinnamic acid(Log2FC=-2.3381),N-acetylphenylalanine(Log2FC=-2.2501)significantly decreased in model group.The KEGG pathway enrichments of these metabolites indicated that,cisplatin-induced metabolic disorders by disturbing metabolism pathways such as linoleic acid metabolism,biosynthesis of unsaturated fatty acids,and phenylalanine metabolism,which suggested that the onset of CIA was partly associated with the metabolic disorders of linoleic acid,unsaturated fatty acids,and phenylalanine.Compared to control,treatment of LJZD significantly increased the levels of 4-hydroxytryptamine(Log2FC=12.0186),hexadecanoic acid(Log2FC=5.7412),linoleic acid(Log2FC=5.1877)and significantly decreased the levels of N-acetylmethionine(Log2FC=-1.7317),2-aminoethanesulfinic acid(Log2FC=-1.6578),N-acetyl-L-tyrosine(Log2FC=-1.5355).And comparing to the model group,4-hydroxytryptamine(Log2FC=12.0186),7,12-diketocholic acid(Log2FC=2.0998),N-acetylneuraminic acid(Log2FC=2.0560)markedly increased,and 3-hydroxy-3-methylpentane-1(Log2FC=-1.9202),5-dioic acid(Log2FC=-1.7166),N-isovaleroylglycine,hexanoyl glycine(Log2FC=-1.4958)markedly decreased in LJZD group.It was worth noting that,there were 23 differential metabolites filtrated both in control vs model and model vs LJZD groups,which were the key metabolites of LJZD in treating CIA.Among these 23 common metabolites,there were 16 metabolites excluding the control vs LJZD group,that was,LJZD had no effect in normal rats while being able to ameliorated cisplatin-induced metabolic disorders by regulating these 16 metabolites.Cisplatin-induced downregulation of 11 metabolites such as hydrocinnamic acid,(±)12(13)epoxy-9Z-octadecenoic acid,cinnamic acid were upregulated after LJZD treatment,and cisplatin-induced upregulation of imidazoleacetic acid,2′-deoxycytidine-5′-monophosphate and other 5 metabolites were downregulated by LJZD.The KEGG pathway analysis indicated that the linoleic acid metabolism,histidine metabolism,and pyrimidine metabolism were the most enriched metabolic pathway.Thus,cisplatin-induced metabolic disturbances mainly by disturbing linoleic acid metabolism,histidine metabolism,and pyrimidine metabolism,and LJZD interacted with these metabolic pathways to reduce metabolic disorders and thus ameliorated CIA.CONCLUSION Cisplatin-induced anorexia was closely related to the metabolic disorders of linoleic acid metabolism,biosynthesis of unsaturated fatty acids,and phenylalanine metabolism.The mechanism of LJZD in ameliorating CIA was in concerned with the metabolic adjustments,relating to the regulation of linoleic acid metabolism,histidine metabolism,and pyrimidine metabolism.展开更多
文摘Using the negative eigenvalue theory and the infinite order perturbation theory, a new method was developed to solve the eigenvectors of disordered systems. The result shows that eigenvectors change from the extended state to the localized state with the increase of the site points and the disordered degree of the system. When electric field is exerted, the electrons transfer from one localized state to another one. The conductivity is induced by the electron transfer. The authors derive the formula of electron conductivity and find the electron hops between localized states whose energies are close to each other, whereas localized positions differ from each other greatly. At low temperature the disordered system has the character of the negative differential dependence of resistivity and temperature.
文摘A Yb:CaGd_(0.33)Y_(0.625)AlO_(4)(Yb:CGYA)laser crystal of high optical quality has been successfully synthesized via the Czochralski method.The introduction of Gd^(3+)ions preserves the original structure and efficiently generates inhomogeneous broadening of the Yb^(3+)ion emission spectra.The fluorescence emission peak wavelength of the Yb:CGYA crystal is 1053 nm,and the corresponding measured full width at halfmaximum is 93 nm.A tunable laser output ranging from 1017 nm to 1073 nm is achieved by using a birefringent filter,which represents the broadest tuning range reported in a short cavity to date.The compact laser offers significant advantages for its applications around the 1μm wavelength band.
文摘妊娠期高血压疾病(hypertensive disorders of pregnancy,HDP)是一类妊娠和血压升高并存的产科常见并发症,涵盖了妊娠期高血压(gestational hypertension,GH)、子痫前期(preeclampsia,PE)、妊娠合并慢性高血压(chronic hypertension)和慢性高血压并发子痫前期(chronic hypertension with superimposed pre-eclampsia)。这些疾病是导致孕产妇及围产儿死亡的主要原因之一。
文摘Objective Autism spectrum disorder(ASD)is a neurodevelopmental condition characterized by difficulties with communication and social interaction,restricted and repetitive behaviors.Previous studies have indicated that individuals with ASD exhibit early and lifelong attention deficits,which are closely related to the core symptoms of ASD.Basic visual attention processes may provide a critical foundation for their social communication and interaction abilities.Therefore,this study explores the behavior of children with ASD in capturing attention to changes in topological properties.Methods Our study recruited twenty-seven ASD children diagnosed by professional clinicians according to DSM-5 and twenty-eight typically developing(TD)age-matched controls.In an attention capture task,we recorded the saccadic behaviors of children with ASD and TD in response to topological change(TC)and non-topological change(nTC)stimuli.Saccadic reaction time(SRT),visual search time(VS),and first fixation dwell time(FFDT)were used as indicators of attentional bias.Pearson correlation tests between the clinical assessment scales and attentional bias were conducted.Results This study found that TD children had significantly faster SRT(P<0.05)and VS(P<0.05)for the TC stimuli compared to the nTC stimuli,while the children with ASD did not exhibit significant differences in either measure(P>0.05).Additionally,ASD children demonstrated significantly less attention towards the TC targets(measured by FFDT),in comparison to TD children(P<0.05).Furthermore,ASD children exhibited a significant negative linear correlation between their attentional bias(measured by VS)and their scores on the compulsive subscale(P<0.05).Conclusion The results suggest that children with ASD have difficulty shifting their attention to objects with topological changes during change detection.This atypical attention may affect the child’s cognitive and behavioral development,thereby impacting their social communication and interaction.In sum,our findings indicate that difficulties in attentional capture by TC may be a key feature of ASD.
文摘Alzheimer's disease(AD)is a prevalent neurodegenerative disease characterized by cognitive decline in the early stage.Mild cognitive impairment(MCI)is considered as an intermediate stage between normal aging and AD.In recent years,studies related to resting-state functional MRI(rs-fMRI)indicated that the occurrence and development process of MCI and AD might be closely linked to spontaneous brain activity and alterations in functional connectivity among brain regions,and rs-fMRI could provide important reference for specific diagnosis and early treatment of MCI and AD.The research progresses of rs-fMRI for MCI and AD were reviewed in this article.
基金supported by the National Natural Science Foundation of China (U20A20357)Program for Innovative Research Team of the First Affiliated Hospital of USTC。
文摘Objective:Active and passive smoking are common environmental risk factors,but there is no definite conclusion about their effects on relapse and disability progression in multiple sclerosis(MS)and neuromyelitis optica spectrum disorder(NMOSD).Methods:This was a retrospective cohort study.Patients were included from four centers.Demographic and clinical data were extracted from the clinical database,while data involving environmental exposures during daily life,relapse,and disability progression were obtained through telephone follow-up interviews.Determinants of relapse were assessed by Cox proportional models,and disability progression was assessed by linear regression.Kaplan‒Meier survival was used to estimate relapse within five years after the first attack.Results:A total of 130 MS patients and 318 NMOSD patients were included in this study,and females accounted for 60%and 79.6%,respectively.MS patients with an active smoking history had a higher risk of relapse,for which the association became borderline significant after accounting for covariates(aHR=1.52,95%CI=1.00,2.31;p=0.052).The relapse risk between ever-smokers who smoked more than 10 cigarettes per day and smokers who smoked less than 10 cigarettes per day was not significantly different(aHR=0.96,95%CI=0.63,1.47;p=0.859).However,exposure to passive smoking was associated with a reduced risk of MS relapse(aHR=0.75,95%CI=0.56,1.00;p=0.044)compared with never-exposed patients.No associations were observed between active smoking/passive smoking and the risk of NMOSD relapse,but patients with a history of smoking were associated with a lower annual progression rate by Expanded Disability Status Scale(EDSS)(aβ=−0.20,95%CI=−0.38,−0.01;p=0.036)and Multiple Sclerosis Severity Score(MSSS)(aβ=−0.23,95%CI=−0.44,−0.03;p=0.028).Conclusion:Our research shows that active smoking increases the relapse risk of MS and has a negative impact on disability progression;thus,smoking cessation should be encouraged.
基金supported by the National Natural Science Foundation(81971696)the Natural Science Foundation of Hunan Province(2022JJ30861),China.
文摘Methylenetetrahydrofolate reductase(MTHFR)deficiency is a rare autosomal recessive genetic disorder caused by mutations in the MTHFR gene,leading to a variety of clinical manifestations.In October 2022,the Second Xiangya Hospital of Central South University admitted a 21-year-old male patient with neuropsychiatric disorders,presenting primarily with cognitive decline,limb tremors,abnormal mental and behavioral symptoms,seizures,and gait disturbances.These symptoms had gradually developed over 5 years,worsening significantly in the past year.The patient’s plasma homocysteine levels were 10 times higher than normal,and brain MRI revealed brain atrophy and significant abnormal signals in the bilateral paraventricular nuclei and heads of the bilateral caudate nuclei.Further genetic testing identified a paternal mutation c.1604G>A(p.R535Q)and a maternal mutation c.227T>G(p.L76R)of the MTHFR gene.After betaine supplementation,the plasma homocysteine levels decreased within a week,and the symptoms improved.The patient was ultimately diagnosed with severe hyperhomocysteinemia due to MTHFR deficiency.The c.227T>G(p.L76R)mutation represents a novel missense mutation in the MTHFR gene associated with MTHFR deficiency,but further research is needed to confirm its potential pathogenicity.Early treatment with betaine can fully reverse the symptoms.
文摘There is an ever-growing demand for lightweighting of steel for structural applications,particularly for automobile and transportation applications.It is mainly to improve the fuel efficiency,reduce the CO_(2) emissions and cater the increased passenger safety.Hence,the main focus is to reduce the density of the steel structure without affecting other properties.This can be achieved by down-gauging of the conventional steel by replacing the steel with higher strength,however,it is limited by dent resistance and stiffness.So,the novel idea is to reduce the density of the steel itself.It is well-known that addition of Al to steel reduces the density of the steel.About 1wt% of Al addition to steel can reduce the density by 1.3%,decreases the elastic modulus by 2% and it improves the strength by about 40 MPa.There is a new class of low-density/lightweight steel with addition of about 6-9 wt% Al to steel.Addition of higher than 9 wt%of Al in steel leads to embrittlement issues due to ordering and environmental effect.These disordered Fe-Al lightweight steels have raised considerable interest due to their low-density,high ductility,costeffectiveness and feasibility for bulk production.The low-density steels are envisaged in the development of an advanced lightweight ground transportation system,huge structures and also for certain defence applications and in thermal power plants.
基金National Natural Science Foundation of China(81403502)General Research Fund ofResearch Grants Council of Hong Kong (17124418).
文摘OBJECTIVE Major depressive disorder(MDD) is a highly heterogeneous mental illness.Further classification may help characterize its heterogeneity.The purpose of this study was to examine metabolomic and brain connectomic associations with traditional Chinese medicine(TCM) diagnostic classification of MDD.METHODS Fifty unmedicated depressed patients were classified into Liver Qi Stagnation(LQS,n=30) and Heart and Spleen Deficiency(HSD,n=20) subtypes according to TCM diagnosis.Healthy volunteers(n=28) were included as controls.Gas chromatography-mass spectrometry(GC-MS) and diffusion tensor imaging were used to detect serum and urinary metabolomic profiles and whole-brain white matter connectivity,respectively.RESULTS In metabolomic analysis,28 metabolites were identified for good separations between TCM subtypes and healthy controls in serum and urine samples.While both TCM subtypes had similar profiles in proteinogenic branched-chain amino acids and energy metabolism-related metabolites that were differentiated from healthy controls,the LQS subtype additionally differed from healthy controls in multiple amino acid metabolites that are involved in the biosynthesis of monoamine and amino acid neurotransmitters.Several metabolites are differentially associated with the two subtypes.In connectomic analysis,The LQS subtype showed significant differences in multiple network metrics of the angular gyrus,middle occipital gyrus,calcarine sulcus,and Heschl′ s gyrus when compared to the other two groups.The HSD subtype had markedly greater regional connectivity of the insula,parahippocampal gyrus,and posterior cingulate gyrus than the other two groups,and microstructural abnormalities of the frontal medial orbital gyrus and middle temporal pole.The insular betweenness centrality was strongly inversely correlated with the severity of depression and dichotomized the two subtypes at the optimal cutoff value with acceptable sensitivity and specificity.CONCLUSION The LQS subtype may represent an MDD subpopulation mainly characterized by abnormalities in the biosynthesis of monoamine and amino acid neurotransmitters,closer associations with stress-related pathophysiology,and aberrant connectivity of the audiovisual perception-related temporal-occipital network,whereas the HSD subtype is more closely associated with hyperconnectivity and microstructural abnormalities of the limbicparalimbic network.Certain metabolomic and connectomic variables are potential biomarkers for TCM diagnostic subtypes which is perhaps an alternative classification for depressive disorders.
文摘Phytomedicines have been used for treating or preventing diseases throughout human history.We have been conducting in exploration of traditional or folk herbal medicines as an attempt to identify novel phytocompounds candidates for further development into botanical supplements or drugs for inflammation related diseases,including cancer,acute liver hepatitis,and sepsis.Comparative″OMICS″technology platforms in combination with various in vitro and in vivo cell-and gene-based bioassays,murine skin inflammatory and syngeneic and xenograft mammary tumor and melanoma models are employed to validate the pharmacological effects and the underlying mechanistic insights of the identified bioactive phytocompounds.The therapeutic potential of phytoagents,alone or in combination,in sensitizing the chemotherapeutic drug efficacy and/or reduction of its side effects in tumor-bearing mice are investigated.In addition,how phytoagents modulate pro-or anti-inflammatory lipid mediators,such as oxylipins,and related signaling cascades systemically or at organ levels are also addressed for understanding sepsis or cancer pathogenesis and the modes of action of bioactive phytoagents.
文摘In the past decades,single target drugs showed less therapeutic action and more side effects in treatment of complicated diseases such as tumor,AIDS,inflammation,diabetes,stroke and neurodegenerative disorders.The reason for this is that complicated diseases have multiple pathogenesis and multiple genes or pathological changes occur in many organs or in different kinds of cells.Therefore,scientists of worldwide hope to develop multi-target drugs recently traditional Chinese medicine(TCM)and their many effective components are characterized by inducing multi-target effects,the following 2 components isolated from TCM were proved in our laboratory to have multi-target effects which benefit complicated diseases.Anti-stroke drug-salvianolic acid B(Sal B):In MCAO rats,Sal B was shown to have many biological activities.Firstly,Sal B could past through blood-brain barrier(BBB)and could repair damage of BBB induced by cerebral ischemia.Secondly,Sal B improved blood flow in ischemic hemisphere with no steal blood and without hypotention,inhibited platelet aggregation a thrombosis but no hemorrhagic risk.More importantly,Sal B could inhibit three risk factors-intracellular Ca2+ overload,excessive regeneration of free radicals,excitotoxicity which aggravate ischemic brain injuries.Thirdly,Sal B activated organism protective mechanism such as increasing neurogenesis,angiogenesis,and many anti-oxidative substances and improving energy supply.Taking all these results we believe that sal B is a good anti-stroke agent.Anti-dementia drug-(-)clausenamide:(-)Clausenamide is a novel compound isolated from clausena lansium(Lour)which is the first chiral compound having anti-dementia effect in recent years.As the content in the plant is very low,after long term of effort this compound now been chemically synthesized by our institute and the production are has reached semi-industry scale that satisfies the demand for clinical trial and hereafter therapeutic use.For pharmacology,(-)clausenamide improved cognition and inhibited Aβpathogenesis including inhibition of Aβtoxicity and tau hyperphosphorylation.According to the new theory″Synaptic loss=AD″,agood anti-dementia drug must be able to improve synaptic plasticity and promote synaptogenesis.Fortunately,(-)clausenamide happened to be such compound.As proved in our study that(-)clausenamide increased synaptic plasticity both in efficacy and structure.For latter,(-)clausenamide increased synaptic density and expression of growth associate protein(GAP-43)in the brain significantly.Now(-)clausenamide has been developed to phaseⅡ of clinical trial.
基金supported by National Natural Science Foundation of China(grant number 81273606,81473259 to XL,81603116 to YS)National Science and Technology Major Project(grant number 2014ZX09J14103-08C to XL)
文摘In recent years,miR-124 has emerged as a critical modulator of immunity and inflammation.Here,we summarize studies on the function and mechanism of miR-124 in the immune system and immunity-related diseases.They indicated that miR-124 exerts a crucial role in the development of immune system,regulation of immune responses,and inflammatory disorders.It is evident that miR-124 may serve as an informative diagnostic biomarker and therapeutic target in the future.
基金National Natural Science Foundation of China (8150115381571326).
文摘OBJECTIVE Social anxiety disorder,also known as social phobia,is the most common of all anxiety disorders.Despite the seriousness of this disorder,it has rarely been studied and as a consequence,little is known about its underlying neurobiology.Growing evidence suggests that inhibitory neurons dysfunction could affect the balance of neuronal activity in psychotic disorders including anxiety,SAD,etc.Ephrin-B(EB) proteins were previously demonstrated to ensure normal distribution and function of inhibitory interneurons in the brain.We thus proposed that deletion of EB2 in inhibitory neurons might destroy the homeostasis of excitatory neurons and inhibitory neurons,and induce behavioral deficits associated with psychotic diseases.METHODS(1)Mice.We generated conditional EB2 knockout mice as a model of SAD and characterized the behaviors and the biochemical changes in the brains of the knockout mice.We also generated a mouse line with a selective deletion of EB2 from vGAT neurons by breeding a v GAT-Cre line with a loxP-flanked alleles in EB2.For EB2 detection,we crossed vGAT-Cre;EphrinB2 loxp/loxp mice with Rosa26-STOP-tdTomato Cre indicator(Ai9) mice to label the vGAT neurons with tdTomato.Mice were maintained in a mixed CD1/129 genetic background.Al experiments involving mice were carried out in accordance with the Shanghai Jiaotong University.Genotypes were unlocked only after completion of analysis.(2) General procedures for behavioral testing.Open field test:Locomotor activity was measured using an open field test.The size of the open field box was 44 cm×44 cm×44 cm.Each mouse was placed in the corner of the open-field apparatus at the beginning of the test,and allowed to explore it for 15 min.The total distance traveled(in cm) and counts for stereotyped behaviors were recorded and analyzed.The total distance traveled was used as an index of locomotor activity.The percentage of center zone entries was considered as anxiety indexes.EPM test:The elevated plus maze apparatus was made of dark gray plastic and comprised two open arms(30 cm×7 cm×0.25 cm) opposed to two enclosed arms(30 cm × 7 cm × 15 cm) elevated60 cm from the floor.Animals were placed in the central area of the apparatus with their head facing an enclosed arm(test duration,5 min).Digitized video recordings with EthoVision software were used for behavioral analysis.The percentage of time spent in open arms and the percentage of open-arm entries were calculated.Social behaviors:Briefly,a top open acrylic box was divided into three compartments by two clear acrylic glass partitions with an opening in the bottom.Wire mesh cages that are either empty or have social stimulus mouse in it were put in the center of each outer compartment.Unfamiliar naive CD1/129 mice of the same age were used as stimulus mice.Prior to the test,the mouse was introduced into the center chamber for 5 min,with both gates closed.Gates were then open and the test mouse was acclimated to explore the empty three-chambered apparatus freely for another 10 min.After the initial 15 min habituation session,mice were placed in the center compartment and allowed to explore freely all the three compartments.To examine the social contact,the following activities were recorded via a video surveillance for 10 min.The number of entries to each compartment,the time spent in each compartment as well as the time and frequency each mouse spent in sniffing were analyzed with EthoVision XT 8.5(Noldus,Wageningen,Netherlands).RESULTS(1)Social preference assays were performed in WT-vGATCre,EB2-flox,and EB2-vGATCre mice respectively.To evaluate social approach behavior,we used a three-chamber social arena to evaluate animals for their social interaction.The control groups of WTvGATCre,EB2-flox mice showed a significant preference for spending time in the social chamber(P<0.05);whereas the EB2-vGATCre mice did not show this preference and spent roughly equal time in the social and nonsocial chambers.(2)To determine if the decrease in social preference could result from changes in locomotion,we compared locomotor activity in EB2-vG ATCre mice and control mice.We did not observe a significant lower locomotive activity in mice.Hence,EB2 deletion caused a change in social preference but not in locomotion.Taken together,EB2 deletion exerts abnormal psychotogenic activity of social deficits which was often considered as an important feature of SAD.(3) The time spent in the open arms is widely used to measure anxiety in mice,with greater time spent in the open arm being considered as less anxious behavior.To normalize for individual differences in overall activity level,the time spent in the open arms was divided by the total time.The ratio was higher for WT-vGATCre mice and EB2-loxp mice as compared to the EB2-vG ATCre mice(P=0.0112,P=0.0197).Thus,results showed that there was a change in anxiety levels from in EB2-vGATCre mice as compared with control mice.CONCLUSION EB2 may be a candidate risk gene for SAD and that the EB2 conditional knockout model could be a tool for studying the underlying mechanisms in SAD.
文摘It has been demonstrated that inflammation and dysregulation of immune response are involved in the pathogenesis of Alzheimer disease (AD). Inflammation is an early event in AD development, especially inflammasome and pro-inflammatory molecules are pathogenic factor in AD. Our data showed that activated immune cells may contribute to the pathogenesis of AD, since the mice with immune cells knock out demonstrated differentsings in the neurodegenerative process and T cells aid clearance of plaques in mice and infiltrating parenchymal T-cell in AD brain mainly in the light of amyloid pathology, and immune treatment is effective, etc. However, the direct evidence on T and B cells infiltrating into the brain of APP transgenic mice have not yet found. Whether aged T cells are pathogenic in AD?How is role of aged B cells? These questions are still unclear. In conclusion, activated immune cells,and inflammatory molecules may play important roles in neurodegenerative disorders, such as AD. The mechanisms of behind this are needed to further study. Inhibiting inflammation in the early phase of AD and restore normal immune regulation are new drug target for the future.
文摘Major depressive disorder(MDD)is a common neuropsychiatric disorder characterized by diverse symptoms.There are big limitations of clinic medicine which highlighted an urgent and clear need for more efficacious and faster-acting therapeutic agents to treat patients with MDD,especially those who are refractory to the traditional antidepressants.In the present study,we assessed a novel compound,YY-21,from timosaponin B-Ⅲ derived from sarsasapogenin of Anemarrhenae Rhizoma.We found that YY-21 obviously increased presynaptic glutamate release and enhanced long-term synaptic activity within 10 min as determined by excitatory postsynaptic current(EPSC) and field excitatory postsynaptic potential(fEPSP) in medial prefrontal cortex(mPFC) slices.YY-21 demonstrated anxiolytic-like effects following acute administration in animals and reversed the depressivelike and anxiety phenotypes induced by chronic unpredictable mild stress(CMS) with a relatively fast therapeutic onset.Our mechanism research reveals that NMDA receptors and two-pore domain potassium(K2P)(TREK1) channels emerged as new drug targets for faster acting antidepressants.K2 P channels generate leak currents that are responsible the maintenance of resting membrane potential.They are potential targets for the treatment of multiple diseases.Here we identify TKDC,an inhibitor of the TREK subfamily,including TREK1,TREK2 and TRAAK channels.Using TKDC as a chemical probe,a combined study of computations,mutagenesis,and electrophysiology reveal an allosteric ligand-binding site in the extracellular cap of the channels.The molecular dynamics simulations suggest that ligand-induced allosteric conformational transitions cause a blockage of the ion conductive pathway.The identification of the extracellular ligand-binding site is confirmed by the discovery of new inhibitors targeting this site using virtual screening.These results suggest that the extracellular cap of a K2P channel can act as a new allosteric site and may serve as a direct drug target.
基金National Key Research and DevelopmentProgram of China (2016YFC0800907)MedicalInnovation Program (16CXZ033)+2 种基金National KeyBasic Research Program (2015CB553504)National Natural Science Foundation of China(8157340581373385).
文摘OBJECTIVE To explore the antipost-traumatic-stress-disorder(PTSD) effects and its probable mechanism of YQA14,a dopamine D3 receptor antagonist.METHODS Two PTSD animal models,the rat single prolonged stress(SPS) model and the mouse pre-shock model,were used in this experiment.In the SPS model,adult male Sprague-Dawley(SD) rats were randomly divided into control group,model group,positive group and YQA14 groups with different dosages.In the mouse pre-chock model,dopamine D3 receptor knockout(KO) and wild type(WT) mice were randomly divided into control group,model group,positive group and YQA14 group.After the establishment of animal models,the saline,sertraline(ig) and YQA14(ip)were administered to the animals in the control,model,positive control and test groups respectively.The open field test(OFT) was used to evaluate the locomotor activity while the contextual freezing(CF) measurement and elevated plus maze(EPM) test were used to evaluate the PTSD-like behaviors.RESULTS In the rat SPS model,neither SPS nor drug treatment affected the locomotor activity in rats.However,SPS rats showed significant PTSD-like behaviors with enhanced freezing time in CF(P<0.01) and decreased percentage of entries into open arms and time spent in open arms in EPM(P<0.05,P<0.01).Moreover,compared with the model group,the repeated administration of YQA14(3.125,6.25 and 12.5 mg·kg-1)significantly reduced the freezing time(P<0.01)and increased the percentages of entries into open arms and time spent in open arms(P<0.05).In the mouse pre-shock model,when both model groups showed significant higher freezing time compared with the respective control groups(P<0.05,P<0.01),YQA14 selectively alleviated the freezing time on WT mice(P<0.05) while had no effect on KO mice.In the EPM tests,the WT mice model group showed a significant reduction in the percentage of entries into open arms and time spent in open arms(P<0.05) while D3 R KO mice model group didn′ t show any reduction,compared with respective control groups.Furthermore,daily administration of YQA14 at 12.5 mg·kg-1 both significantly reduced the percentages of entries into and time spent in open arms(P<0.05) but not D3 R KO mice.None of the locomotor activity were significantly affected.CONCLUSION YQA14 could significantly alleviate the PTSD-like behaviors in rodents and the effects were mediated by the blockade of brain D3 receptors.
文摘Genotype of IgH, TCRγ and TCR δ gene rearrangement in 42 cases of malignant lymphoproliferative disorders were studied by using polymerase chain reaction (PCR) technique. The results suggested that among the 23 cases, in which malignant cells expressed B-lineage cell surface markers, 20 showed IgH gene rearrangement and 11 had TCRγ gene rearrangement and / or TCRδ gene deletion. All the 11 cases expressed T-lineage cell differentiation antigens were found to have TCRγand TCRδ gene rearrangement or deletion and only one had IgH gene rearrangement. Double rearrangements of IgH and TCRγ genes were detected in all the 3 cases of T and B double-phenotype ALL. In the cases malignant cells did not express any lineage specific antigens while 4/5 had TCRγ gene rearrangement but all failed in IgH gene rearrangement. The relation of cellular differentiation origin and rearrangement of antigen receptor genes with clinical manifestations was discussed.
文摘Berberine(BBR)is an alkaloid from plants like Coptis chinensis and is for many years an OTC drug in China for bacterial-caused diarrhea.We have identified BBR to be an effective drug in treating hyperlipidemia as well as hyperglycemia.Clinical studies showed that oral administration of BBR caused significant reduction of blood cholesterol,triglyceride as well as glucose in patients with hyperlipidemia and T2D,with no obvious side-effect.Mechanism studies have identified several molecular mechanisms involving in the mode of action of BBR.The cholesterol-lowering effect was associated with the extracellular-signalregulated kinase(ERK)mediated LDLR mRNA up-regulation;the glucose-lowering effect mainly resulted from the protein kinase D mediated InsR expression and the activation of AMPK.The observed reduction of triglyceride by BBR might reflect its synergistic effect on both sugar and lipid metabolism.The interaction between gut microbiota and BBR explained the molecular mechanism of BBR′s intestinal absorption.BBR concentrated in liver after oral administration with a level many times more than that in blood.At least three CYP450 subtypes were responsible for BBR phase-Ⅰ metabolism.Structure-activity relationship of BBR was analyzed,and the clinical advantage of BBR was demonstrated.We consider BBR a new medicine for metabolic disorders.
文摘Time: March 5-8, 2020Venue: Lasvegas, USWebsite: https://www.cns.org/Spine Summit 2020, the 36th Annual Meeting of the Section on Disorders of the Spine and Peripheral Nerves will take placein Lasvegas, US on March 5-8, 2020.
基金National Natural Science Foundation of China(82174143)and Scientific Research Foundation of Guangdong Pharmaceutical University(51348136)。
文摘OBJECTIVE Cisplatin is a formidable chemotherapy agent widely applying in antineoplastic treatments,but its side effects often limit the clinical usage.Metabolic disorders are one of the side effects induced by cisplatin,which closely relate to the onset of chemotherapy-induced anorexia(CIA)in cancer patients but lacks effective controls.Liujunzi decoction(LJZD)is a traditional Chinese formula that has a promising effect in treating CIA.However,whether LJZD ameliorates CIA through adjusting cisplatin-induced metabolic disorders remain unknow.The present study evaluated the mechanism of cisplatin-induced metabolic disorders,and the effect of LJZD in ameliorating these disturbances.METHODS 42 male Sprague-Dawley(SD)rats(180-220 g)were randomly divided into 3 groups:normal control group(distilled water+saline),model group(distilled water+cisplatin),LJZD group(4.8 g·kg^(-1)Liujunzi decoction ingredients+cisplatin).Intragastrical administered each drug twice a day(7∶00-19∶00)since day 0 for 4 d,animals were intraperitoneal injected with cisplatin 6 mg·kg^(-1)1 h after administration while normal control groups were injected with same volume of saline.On day 3,each group was anesthetized with pentobarbital sodium 45 mg·kg^(-1)(ip),and blood samples were collected from aorta abdominalis.Then the samples were analyzed using an LC-ESI-MS/MS system.Significantly regulated metabolites between groups were determined by VIP≥1 and absolute Log2FC(fold change)≥1.Identified metabolites were mapped to Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway database using Metaboanalyst 5.0(https://www.metaboanalyst.ca/).RESULTS A total of 133,77 and 32 differential metabolites were filtrated in control vs model,control vs LJZD and model vs LJZD groups respectively.Comparing to control,the levels of hexadecanoic acid(Log2FC=6.3153),linoleic acid(Log2FC=5.3478),and 8,11-icosadienoic acid(Log2FC=5.2342)significantly increased,and the levels of N-acetyl-L-tyrosine(Log2FC=-2.6283),cinnamic acid(Log2FC=-2.3381),N-acetylphenylalanine(Log2FC=-2.2501)significantly decreased in model group.The KEGG pathway enrichments of these metabolites indicated that,cisplatin-induced metabolic disorders by disturbing metabolism pathways such as linoleic acid metabolism,biosynthesis of unsaturated fatty acids,and phenylalanine metabolism,which suggested that the onset of CIA was partly associated with the metabolic disorders of linoleic acid,unsaturated fatty acids,and phenylalanine.Compared to control,treatment of LJZD significantly increased the levels of 4-hydroxytryptamine(Log2FC=12.0186),hexadecanoic acid(Log2FC=5.7412),linoleic acid(Log2FC=5.1877)and significantly decreased the levels of N-acetylmethionine(Log2FC=-1.7317),2-aminoethanesulfinic acid(Log2FC=-1.6578),N-acetyl-L-tyrosine(Log2FC=-1.5355).And comparing to the model group,4-hydroxytryptamine(Log2FC=12.0186),7,12-diketocholic acid(Log2FC=2.0998),N-acetylneuraminic acid(Log2FC=2.0560)markedly increased,and 3-hydroxy-3-methylpentane-1(Log2FC=-1.9202),5-dioic acid(Log2FC=-1.7166),N-isovaleroylglycine,hexanoyl glycine(Log2FC=-1.4958)markedly decreased in LJZD group.It was worth noting that,there were 23 differential metabolites filtrated both in control vs model and model vs LJZD groups,which were the key metabolites of LJZD in treating CIA.Among these 23 common metabolites,there were 16 metabolites excluding the control vs LJZD group,that was,LJZD had no effect in normal rats while being able to ameliorated cisplatin-induced metabolic disorders by regulating these 16 metabolites.Cisplatin-induced downregulation of 11 metabolites such as hydrocinnamic acid,(±)12(13)epoxy-9Z-octadecenoic acid,cinnamic acid were upregulated after LJZD treatment,and cisplatin-induced upregulation of imidazoleacetic acid,2′-deoxycytidine-5′-monophosphate and other 5 metabolites were downregulated by LJZD.The KEGG pathway analysis indicated that the linoleic acid metabolism,histidine metabolism,and pyrimidine metabolism were the most enriched metabolic pathway.Thus,cisplatin-induced metabolic disturbances mainly by disturbing linoleic acid metabolism,histidine metabolism,and pyrimidine metabolism,and LJZD interacted with these metabolic pathways to reduce metabolic disorders and thus ameliorated CIA.CONCLUSION Cisplatin-induced anorexia was closely related to the metabolic disorders of linoleic acid metabolism,biosynthesis of unsaturated fatty acids,and phenylalanine metabolism.The mechanism of LJZD in ameliorating CIA was in concerned with the metabolic adjustments,relating to the regulation of linoleic acid metabolism,histidine metabolism,and pyrimidine metabolism.
