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memory stem T cells generated by Wnt signaling from blood of human renal clear cell carcinoma patients

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Cancer Biology & Medicine 2019年第1期16卷 109-120页

作者： Cihui Yan Jingjing Chang Xinmiao Song Fan Yan Wenwen Yu Yang An Feng Wei Lili Yang Xiubao Ren Department of Immunology Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and TherapyTianjin Tianjin's Clinical Research Center for Cancer Department of Electromyogram 3rd Affiliated Hospital of Hebei Medical University

Objective: memory stem T cells(Tscm) have attracted attention because of their enhanced self-renewal, multipotent capacity, and anti-tumor capacities. However, little is known about Tscm in patients with renal clear cell carcinoma(RCC) and the role of Wnt signaling in these cells. We evaluated Tscm from RCC patients concerning their activation of Wnt signaling in vitro and explored the mechanism of preferential survival.Methods: Flow cytometry identified surface markers and cytokines produced from accumulated Tscm in the presence of the glycogen synthase kinase beta inhibitor TWS119. Apoptosis was evaluated after induction using tumor necrosis factor-alpha.Immunofluorescence and Western blot analyses were used to investigate the activation of the nuclear factor-kappa B(NF-КB)pathway.Results: RCC patients had a similar percentage of CD4^+ and CD8^+ Tscm as healthy donors. Activation of Wnt signaling by TWS119 resulted in the accumulation of Tscm in activated T cells, but reversal of differentiated T cells to Tscm was not achieved.Preferential survival of Tscm was associated with increased anti-apoptotic ability mediated downstream of the NF-КB activation pathway.Conclusions: The finding that Tscm can accumulate by Wnt signaling in vitro in blood from RCC patients will help in devising new cancer therapy strategies of Tscm-based adoptive immunotherapy, such as dendritic cell-stimulated Tscm, and T cell receptor or chimeric antigen receptor-engineered Tscm.

关键词： memory stem T cell TWS119 Wnt signaling apoptosis renal clear cell carcinoma

memory Analysis for Memristors and Memristive Recurrent Neural Networks

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IEEE/CAA Journal of Automatica Sinica 2020年第1期7卷 96-105页

作者： Gang Bao Yide Zhang Zhigang Zeng Key Laboratory of Cascaded Hydropower Stations Operation and Control Electrical Engineering and New EnergyChina Three Gorges UniversityYichang 443002and Hubei Key Laboratory of Applied Mathematics(Hubei University)Wuhan 430074China Department of Medical Engineering California Institute of TechnologyPasadenaCalifornia 91125 USA School of Artificial Intelligence and Automation Huazhong University of Science and Technologyand also with the Key Laboratory of Image Processing and Intelligent Control of Education Ministry of ChinaWuhan 430074China

Traditional recurrent neural networks are composed of capacitors, inductors, resistors, and operational amplifiers.Memristive neural networks are constructed by replacing resistors with memristors. This paper focuses on the memory analysis,i.e. the initial value computation, of memristors. Firstly, we present the memory analysis for a single memristor based on memristors’ mathematical models with linear and nonlinear drift.Secondly, we present the memory analysis for two memristors in series and parallel. Thirdly, we point out the difference between traditional neural networks and those that are memristive. Based on the current and voltage relationship of memristors, we use mathematical analysis and SPICE simulations to demonstrate the validity of our methods.

关键词： Index Terms—Dopant drift memory memristive neural networks,memristor

Dissociation between source and item memory in Parkinson＆#39;s disease

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Chinese Medical Journal 2014年第18期127卷 3224-3228页

作者： Hu Panpan Li Youhai Ma Huijuan Xi Chunhua Chen Xianwen Wang Kai Department of Neurology First Affiliated Hospital of Anhui Medical University Hefei Anhui 230022 China Department of Neurology Second Affiliated Hospital of Anhui Medical University Hefei Anhui 230601 China Department of Neurology Third Affiliated Hospital of Anhui Medical University Hefei Anhui 230061 China

Background Episodic memory includes information about item memory and source memory.Many researches support the hypothesis that these two memory systems are implemented by different brain structures.The aim of this study was to investigate the characteristics of item memory and source memory processing in patients with Parkinson＇s disease （PD）,and to further verify the hypothesis of dual-process model of source and item memory.Methods We established a neuropsychological battery to measure the performance of item memory and source memory.Totally 35 PD individuals and 35 matched healthy controls （HC） were administrated with the battery.Item memory task consists of the learning and recognition of high-frequency national Chinese characters; source memory task consists of the learning and recognition of three modes （character,picture,and image） of objects.Results Compared with the controls,the idiopathic PD patients have been impaired source memory （PD vs.HC：0.65±0.06 vs.0.72±0.09,P=0.001）,but not impaired in item memory （PD vs.HC：0.65±0.07 vs.0.67±0.08,P=0.240）.Conclusions The present experiment provides evidence for dissociation between item and source memory in PD patients,thereby strengthening the claim that the item or source memory rely on different brain structures.PD patients show poor source memory,in which dopamine plays a critical role.

关键词： Parkinson disease memory episodic cognition

High-Throughput Automatic Training System for Spatial Working memory in Free-Moving Mice

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Neuroscience Bulletin 2019年第3期35卷 389-400页

作者： Shimin Zou Chengyu Tony Li Institute of Neuroscience State Key Laboratory of NeuroscienceChinese Academy of SciencesCAS Center for Excellence in Brain Science and Intelligence TechnologyShanghai Center for Brain Science and Brain-Inspired TechnologyShanghai 200031China School of Future Technology University of Chinese Academy of SciencesBeijing 100049China

Effcient behavioral assays are crucial for understanding the neural mechanisms of cognitive functions.Here, we designed a high-throughput automatic training system for spatial cognition(HASS) for free-moving mice.Mice were trained to return to the home arm and remain there during a delay period. Software was designed to enable automatic training in all its phases, including habituation, shaping, and learning. Using this system, we trained mice to successfully perform a spatially delayed nonmatch to sample task, which tested spatial cognition,working memory, and decision making. Performance depended on the delay duration, which is a hallmark of working memory tasks. The HASS enabled a human operator to train more than six mice simultaneously with minimal intervention, therefore greatly enhancing experimental efficiency and minimizing stress to the mice.Combined with the optogenetic method and neurophysiological techniques, the HASS will be useful in deciphering the neural circuitry underlying spatial cognition.

关键词： Cognitive functions Automatic training Free-moving mice Working memory Spatial cognition

Inhibition of Rac1-dependent forgetting alleviates memory deficits in animal models of Alzheimer's disease

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Protein & Cell 2019年第10期10卷 745-759页

作者： Wenjuan Wu Shuwen Du Wei Shi Yunlong Liu Ying Hu Zuolei Xie Xinsheng Yao Zhenyu Liu Weiwei Ma Lin Xu Chao Ma Yi Zhong Tsinghua-Peking Center for Life Science IDG/McGovem Institutes for Brain ResearchMOE Key Laboratory of Protein ScienceSchool of Life SciencesTsinghua UniversityBeijing 100084China Life Science Division Graduate school at ShenzhenTsinghua UniversityShenzhen 518055China JoeKai Biotech.LLC LianQiang International BuildingYongfeng BaseBeijing 100084China Institute of Traditional Chinese Medicine and Natural Products College of PharmacyJinan UniversityGuangzhou 510632China Key Lab of Animal Models and Human Disease Mechanisms Kunming Institute of ZoologyChinese Academy of SciencesKunming 650223China Institute of Basic Medical Sciences Chinese Academy of Medical SciencesDepartment of Human AnatomyHistology and EmbryologyNeuroscienee CenterJoint Laboratory of Anesthesia and PainSchool of Basic MedicinePeking Union Medical CollegeBeijing 100005China

Accelerated forgetting has been identified as a feature of Alzheimer's disease(AD),but the therapeutic efficacy of the manipulation of biological mechanisms of forgetting has not been assessed in AD animal models.Ras-re-lated C3 botulinum toxin substrate 1(Rac1),a small GTPase,has been shown to regulate active forgetting in Drosophila and mice?Here,we showed that Rac1 activity is aberrantly elevated in the hippocampal tissues of AD patients and AD animal models.Moreover,amyloid-beta 42 could induce Rac1 activation in cultured cells.The elevation of Rac1 activity not only accelerated 6-hour spatial memory decay in 3-month-old APP/PS1 mice,but also significantly contributed to severe memory loss in aged APP/PS1 mice.A similar age-dependent Rac1 activity-based memory loss was also observed in an AD fly model.Moreover,inhibition of Rac1 activity could ameliorate cognitive defects and synaptic plasticity in AD animal models.Finally,two novel compounds,identified through behavioral screening of a randomly selected pool of brain permeable small molecules for their positive effect in rescuing memory loss in both fly and mouse models,were found to be capable of inhibiting Rac1 activity.Thus,multiple lines of evidence corroborate in supporting the idea that inhibition of Rac1 activity is effective for treating AD-related memory loss.

关键词： Alzheimer's disease Rac1 forgetting memory loss hippocampus

Inhibition of α5 GABAA receptors has preventive but not therapeutic effects on isoflurane-induced memory impairment in aged rats

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Neural Regeneration Research 2019年第6期14卷 1029-1036页

作者： Zi-Fang Zhao Lei Du Teng Gao Lin Bao Yuan Luo Yi-Qing Yin Yong-An Wang Department of Anesthesiology China-Japan Friendship Hospital Department of Radiology China-Japan Friendship Hospital Department of Anesthesiology Beijing Shijitan Hospital Affiliated to Capital Medical University Institute of Pharmacology and Toxicology Academy of Military Medical Sciences

The α5 subunit-containing gamma-amino butyric acid type A receptors(α5 GABAARs) are a distinct subpopulation that are specifically distributed in the mammalian hippocampus and also mediate tonic inhibitory currents in hippocampal neurons. These tonic currents can be enhanced by low-dose isoflurane, which is associated with learning and memory impairment. Inverse agonists of α5 GABAARs, such as L-655,708, are able to reverse the short-term memory deficit caused by low-dose isoflurane in young animals. However, whether these negative allosteric modulators have the same effects on aged rats remains unclear. In the present study, we mainly investigated the effects of L-655,708 on low-dose(1.3%) isoflurane-induced learning and memory impairment in elderly rats. Young(3-month-old) and aged(24-month-old) Wistar rats were randomly assigned to receive L-655,708 0.5 hour before or 23.5 hours after 1.3% isoflurane anesthesia.The Morris Water Maze tests demonstrated that L-655,708 injected before or after anesthesia could reverse the memory deficit in young rats. But in aged rats, application of L-655,708 only before anesthesia showed similar effects. Reverse transcription-polymerase chain reaction showed that low-dose isoflurane decreased the mRNA expression of α5 GABAARs in aging hippocampal neurons but increased that in young animals. These findings indicate that L-655,708 prevented but could not reverse 1.3% isoflurane-induced spatial learning and memory impairment in aged Wistar rats. All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Academy of Military Medical Science of China(approval No. NBCDSER-IACUC-2015128) in December 2015.

关键词： isoflurane postoperative cognitive dysfunction hippocampus inverse agonist α5 GABAA receptors L-655,708 aged Morris Water Maze memory impairment neural regeneration

Sevoflurane plays a reduced role in cognitive impairment compared with isoflurane: limited effect on fear memory retention

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Neural Regeneration Research 2020年第1期15卷 96-102页

作者： Ying Du Xiang-Dan Gong Xin Fang Fang Xing Tian-Jiao Xia Xiao-Ping Gu Department of Anesthesiology Affiliated Drum Tower Hospital of Medical Department of Nanjing UniversityNanjingJiangsu ProvinceChina Jiangsu Key Laboratory of Molecular Medicine Nanjing UniversityNanjingJiangsu ProvinceChina

Isoflurane and sevoflurane are both inhalation anesthetics,but in clinical application,sevoflurane has been considered to be less suitable for long-term anesthesia because of its catabolic compounds and potential nephrotoxicity.Nevertheless,recent studies have shown that these two inhalation anesthetics are similar in hepatorenal toxicity,cost,and long-term anesthetic effect.Moreover,sevoflurane possibly has less cognitive impact on young mice.In this study,C57BL/6 mice aged 8–10 weeks were exposed to 1.2%isoflurane or 2.4%sevoflurane for 6 hours.Cognitive function and memory were examined in young mice using the novel object recognition,contextual fear conditioning,and cued-fear extinction tests.Western blot assay was performed to detect expression levels of D1 dopamine receptor,catechol-O-methyltransferase,phospho-glycogen synthase kinase-3β,and total glycogen synthase kinase-3βin the hippocampus.Our results show that impaired performance was not detected in mice exposed to sevoflurane during the novel object recognition test.Contextual memory impairment in the fear conditioning test was shorter in the sevoflurane group than the isoflurane group.Long-term sevoflurane exposure did not affect memory consolidation,while isoflurane led to memory consolidation and reduced retention.Downregulation of hippocampal D1 dopamine receptors and phosphorylated glycogen synthase kinase-3β/total glycogen synthase kinase-3βand upregulation of catechol-O-methyltransferase may be associated with differing memory performance after exposure to isoflurane or sevoflurane.These results confirm that sevoflurane has less effect on cognitive impairment than isoflurane,which may be related to expression of D1 dopamine receptors and catechol-O-methyltransferase and phosphorylation of glycogen synthase kinase-3βin the hippocampus.This study was approved by the Institutional Animal Care and Use Committee,Nanjing University,China on November 20,2017(approval No.20171102).

关键词： catechol-O-methyltransferase cognitive impairment D1 dopamine receptors fear memory glycogen synthase kinase-3β isoflurane neurotoxicology sevoflurane

Age-dependent loss of cholinergic neurons in learning and memory-related brain regions and impaired learning in SAMP8 mice with trigeminal nerve damage

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Neural Regeneration Research 2014年第22期9卷 1985-1994页

作者： Yifan He Jihong Zhu Fang Huang Liu Qin Wenguo Fan Hongwen He Guanghua School of Stomatology Sun Yat-sen UniversityGuangdong Provincial Key Laboratory of Stomatology Huaihe Hospital Henan University

The tooth belongs to the trigeminal sensory pathway. Dental damage has been associated with impairments in the central nervous system that may be mediated by injury to the trigeminal nerve. In the present study, we investigated the effects of damage to the inferior alveolar nerve, an important peripheral nerve in the trigeminal sensory pathway, on learning and memory be-haviors and structural changes in related brain regions, in a mouse model of Alzheimer’s disease. Inferior alveolar nerve transection or sham surgery was performed in middle-aged （4-month-old） or elderly （7-month-old） senescence-accelerated mouse prone 8 （SAMP8） mice. When the middle-aged mice reached 8 months （middle-aged group 1） or 11 months （middle-aged group 2）, and the elderly group reached 11 months, step-down passive avoidance and Y-maze tests of learn-ing and memory were performed, and the cholinergic system was examined in the hippocampus （Nissl staining and acetylcholinesterase histochemistry） and basal forebrain （choline acetyltrans-ferase immunohistochemistry）. In the elderly group, animals that underwent nerve transection had fewer pyramidal neurons in the hippocampal CA1 and CA3 regions, fewer cholinergic ifbers in the CA1 and dentate gyrus, and fewer cholinergic neurons in the medial septal nucleus and vertical limb of the diagonal band, compared with sham-operated animals, as well as showing impairments in learning and memory. Conversely, no signiifcant differences in histology or be-havior were observed between middle-aged group 1 or group 2 transected mice and age-matched sham-operated mice. The present ifndings suggest that trigeminal nerve damage in old age, but not middle age, can induce degeneration of the septal-hippocampal cholinergic system and loss of hippocampal pyramidal neurons, and ultimately impair learning ability. Our results highlight the importance of active treatment of trigeminal nerve damage in elderly patients and those with Alzheimer’s disease, and indicate that tooth extraction should be avoided in these p

关键词： nerve regeneration Alzheimer＇ s disease trigeminal nerve learning memory hippocampal CA1 hippocampal CA3 dentate gyrus basal forebrain medial septal nucleus vertical limb of the diagonal band cholinergic neurons cholinergic fibers pyramidal cells NSFC grants neural regeneration

Possible mechanisms of lycopene amelioration of learning and memory impairment in rats with vascular dementia

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Neural Regeneration Research 2020年第2期15卷 332-341页

作者： Ning-Wei Zhu Xiao-Lan Yin Ren Lin Xiao-Lan Fan Shi-Jie Chen Yuan-Ming Zhu Xiao-Zhen Zhao Department of Human Anatomy Histology and EmbryologySchool of Basic Medical SciencesFujian Medical UniversityFuzhouFujian ProvinceChina Department of Pharmacy Zhejiang Pharmaceutical CollegeNingboZhejiang ProvinceChina Key Laboratory of Brain Aging and Neurodegenerative Diseases School of Basic Medical SciencesFujian Medical UniversityFuzhouFujian ProvinceChina

Oxidative stress is involved in the pathogenesis of vascular dementia. Studies have shown that lycopene can significantly inhibit oxidative stress;therefore, we hypothesized that lycopene can reduce the level of oxidative stress in vascular dementia. A vascular dementia model was established by permanent bilateral ligation of common carotid arteries. The dosage groups were treated with lycopene(50, 100 and 200 mg/kg) every other day for 2 months. Rats without bilateral carotid artery ligation were prepared as a sham group. To test the ability of learning and memory, the Morris water maze was used to detect the average escape latency and the change of search strategy. Hematoxylin-eosin staining was used to observe changes of hippocampal neurons. The levels of oxidative stress factors, superoxide dismutase and malondialdehyde, were measured in the hippocampus by biochemical detection. The levels of reactive oxygen species in the hippocampus were observed by dihydroethidium staining. The distribution and expression of oxidative stress related protein, neuron-restrictive silencer factor, in hippocampal neurons were detected by immunofluorescence histochemistry and western blot assays. After 2 months of drug administration,(1) in the model group, the average escape latency was longer than that of the sham group, and the proportion of straight and tend tactics was lower than that of the sham group, and the hippocampal neurons were irregularly arranged and the cytoplasm was hyperchromatic.(2) The levels of reactive oxygen species and malondialdehyde in the hippocampus of the model group rats were increased, and the activity of superoxide dismutase was decreased.(3) Lycopene(50, 100 and 200 mg/kg) intervention improved the above changes, and the lycopene 100 mg/kg group showed the most significant improvement effect.(4) Neuron-restrictive silencer factor expression in the hippocampus was lower in the sham group and the lycopene 100 mg/kg group than in the model group.(5) The above data indicate that lycopene 100 mg/kg co

关键词： bilateral carotid artery ligation lycopene hippocampus learning and memory malondialdehyde neuron neuron-restrictive silencer factor reactive oxygen species superoxide dismutase