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Lack of Evidence for Decreased Protein Stability in the 2397 (Met) Haplotype of the Leucine Rich Repeat Kinase 2 Protein Implicated in Parkinson’s Disease

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Advances in Parkinson's Disease 2017年第4期6卷 113-123页

作者： Ryan S. Anderton Lauren Hill Rhiannon Morris Frank L. Mastaglia Wayne Greene Sherif Boulos School of Health Sciences and Institute for Health Research University of Notre Dame Australia Fremantle WA USA Perron Institute for neurological and Translational Sciences Nedlands WA USA centre for neuromuscular and neurological disorders University of Western Australia Nedlands WA USA Institute for Immunology and Infectious Diseases Murdoch University Perth WA USA School of Veterinary and Life Sciences Murdoch University Perth WA USA

Missense mutations in the leucine rich repeat kinase 2 (LRRK2) gene are the leading genetic cause of autosomal dominant familial Parkinson’s disease. We previously reported that two mutations within the ROC domain, namely R1441C and A1442P, exhibit increased protein degradation leading to lowered steady state LRRK2 protein levels in HEK293 cells. More recently, the common WD40 domain LRRK2 haplotype, Met2397, which is a risk factor for Crohn’s disease, has been shown to lower steady state protein levels in HEK293 cells. In view of recent evidence implicating LRRK2 and inflamemation in PD, we investigated the effects of Met2397 on LRRK2 expression, and compared them to the Thr2397 variant and other LRRK2 mutants. In this study, we transfected HEK293 cells with plasmid constructs encoding the different LRRK2 variants, and analyzed the resulting protein levels by Western blot and flow cytometry. Here we found that both the Met2397 and Thr2397 haplotypes yield similar levels of LRRK2 protein expression and do not appear to impact cell viability in HEK293 cells, compared to other LRRK mutants. Thus, we have concluded that the Met2397 haplotype is unlikely to play a role in LRRK2 mediated or idiopathic PD.

关键词： Parkinson’s Disease LRRK2 Met2397 Thr2397 A1442P R1441C

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Stepping up to meet the challenge of freezing of gait in Parkinson’s disease

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Translational Neurodegeneration 2022年第1期11卷 589-600页

作者： Simon Lewis Stewart Factor Nir Giladi Alice Nieuwboer John Nutt Mark Hallett ForeFront Parkinson’s Disease Research Clinic Brain and Mind CentreSchool of Medical SciencesUniversity of SydneySydneyNSWAustralia Jean and Paul Amos Parkinson’s Disease and Movement disorders Program Emory University School of MedicineAtlantaGAUSA Movement disorders Unit Department of NeurologyTel-Aviv Sourasky Medical CenterSackler School of Medicine and Sagol School of NeuroscienceTel Aviv UniversityTel AvivIsrael Department of Rehabilitation Sciences KU LeuvenLeuvenBelgium Movement Disorder Section Department of NeurologyOregon Health&Science UniversityPortlandORUSA Human Motor Control Section National Institute of Neurological Disorders and StrokeNational Institutes of HealthBethesdaMDUSA.

There has been a growing appreciation for freezing of gait as a disabling symptom that causes a significant burden in Parkinson’s disease. Previous research has highlighted some of the key components that underlie the phenomenon, but these reductionist approaches have yet to lead to a paradigm shift resulting in the development of novel treatment strategies. Addressing this issue will require greater integration of multi-modal data with complex computational modeling, but there are a number of critical aspects that need to be considered before embarking on such an approach. This paper highlights where the field needs to address current gaps and shortcomings including the standardization of definitions and measurement, phenomenology and pathophysiology, as well as considering what available data exist and how future studies should be constructed to achieve the greatest potential to better understand and treat this devastating symptom.

关键词： Freezing of gait Computational modeling Standardized definitions and assessments Novel paradigms Phenomenology Pathophysiology Treatment

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A novel variant of GALC in a familial case of Krabbe disease:Insights from structural bioinformatics and molecular dynamics simulation

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Genes & Diseases 2023年第6期10卷 2263-2266页

作者： Ikram Ullah Muhammad Waqas Muhammad Ilyas Sobia Ahsan Halim Akmal Ahmad Natalia Dominik Wahid Ullah Muhammad Abbas Muhammad Aamir Henry Houlden Stephanie Efthymiou Ajmal Khan Ahmed Al-Harrasi centre for Omic Sciences Islamia College University PeshawarPeshawarKhyber Pakhtunkhwa 25120Pakistan Department of Biotechnology and Genetic Engineering Hazara UniversityMansehraDhodial 21120Pakistan Natural and Medical Sciences Research Center University of NizwaNizwa 616Sultanate of Oman Department of Bioengineering University of Engineering and Applied SciencesSwatKhyber Pakhtunkhwa 19060Pakistan Department of neuromuscular disorders UCL Queen Square Institute of NeurologyLondon WC1N 3BGUnited Kingdom

Krabbe disease or globoid cell leukodystrophy(GLD;MIM#245200)is a rare and fatal lysosomal storage disease with an autosomal recessive mode of inheritance that results from the deficiency of galactocerebrosidase(GALC;E.C.3.***.1.46),a lysosomal enzyme encoded by the GALC gene.1 GALC breaks down galactosylceramide,a cerebroside located mainly in the myelin *** in GALC cause the accumulation of a cytotoxic metabolite,galactosylsphingosine or psychosine,which can be toxic to oligodendrocytes and Schwann cells.2 The failure to digest galactosylceramide triggers the formation of multi-nucleated globoid cells,causing severe demyelination,axonopathy,and neuronal death.3 The reported frequency of Krabbe disease is 1 in 100,000 live births with symptoms including irritability,loss of motor ability,spasticity,ataxia,visual dysfunction,seizures,andcognitive impairment.

关键词： dynamics birth GAL

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Big data based precision oncology for glioma

Big data based precision oncology for glioma

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中国神经科学学会第十二届全国学术会议

作者： Tao Jiang Beijing Neurosurgical Institute Department of Neurosurgery Beijing Tiantan Hospital Capital Medical University centre of Brain Tumour Beijing Institute for Brain Disorders China National Clinical Research centre for neurological Diseases

Malignant gliomas are the most common and lethal intracranial tumor in adults. Because of their highly invasive nature, complete neurosurgical resection is impossible, and the presence of residual tumor results in recurrence and malignant progression. Generally, most of low grade glioma（grade I, II and III） will progress to high grade glioma（grade IV, also called glioblastoma multiforme, GBM）. Although advances in current standard of care, the survival for patients with gliomas has remained unchanged at last few decades, especially for the aggressive gliomas（with a poor median survival time of only 12 to 18 months）. Recent high-throughput technologies enable the capability to extensively characterize genomic status including but not limited to genetic alternation, methylation modification, and gene expression regulation. Large-scale data collection and integrative data analysis（such as The Cancer Genome Atlas intuitive） have revealed the mutational landscape of either low-grade or high-grade gliomas, but the molecular changes during the malignant progression have been rarely addressed. Precision medicine in cancer proposes that genomic characterization of tumors can inform personalized targeted therapies. The Chinese Glioma Genome Atlas（CGGA） project, started in 2012, is a comprehensive and coordinated effort to accelerate our understanding of the molecular basis of glioma, particularly in secondary Glioblastomas through the application of high-throughput biotechnologies and bioinformatics. This project aims to catalogue and discover major genomic alternations that drive glioma progression and depict a detailed genomic characterization of a large cohort of Chinese gliomas. Using the CGGA database, we have developed several methods to stratify patients and clarify diagnostic accuracy. Especially, we studied a cohort of 485 diffuse glioma patients from CGGA, and found the PTPRZ1-MET（ZM, an oncogenic fusion gene） fusion in 26.7% of s GBMs. Furthermore, we also identifi

关键词： gliomas high-throughput technologies precision medicine Chinese Glioma Genome Atlas

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Drugging SUMOylation for neuroprotection and oncotherapy

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Neural Regeneration Research 2018年第3期13卷 415-416页

作者： Joshua D. Bernstock Daniel G. Ye Yang-ja Lee Florian Gessler Gregory K. Friedman Wei Zheng John M. Hallenbeck Stroke Branch National Institute of Neurological Disorders and Stroke National institutes of Health (NINDS/NIH) Bethesda MD USA Department of Clinical Neurosciences - Division of Stem Cell Neurobiology Wellcome Trust-Medical Research Council Stem Cell Institute and NIHR Biomedical Research Centre University of Cambridge UK Department of Pediatrics Division of Pediatric Hematology and Oncology University of Alabama at Birmingham Birmingham AL USA National Center for Advancing Translational Sciences National Institutes of Health (NCATS/NIH) Bethesda MD USA

Recently there have been exciting research advances in neuroprotective therapies for ischemic stroke. In the past, the search for neu- roprotective agents has been fraught with failure at the clinical trials stage due to numerous factors, including subject heterogeneity and improper therapeutic windows （Tymianski, 2017）. Moreover, it is becoming clearer that the complex and evolving pathobiology of stroke requires multimodal therapeutic approaches capable of modulating the numerous axes that contribute to ischemia/reperfusion damage, rather than targeting a single axis （Bernstock et al., 2018a）. With the success of recent endovascular thrombectomy （EVT） trials, it has been suggested that clinical trials of EVT with adjunct neuroprotection can overcome past difficulties and maximize the effect size by using imaging to reduce patient heterogeneity （i. e., selecting those with large vessel occlusions, small ischemic cores, and good collateral circulation）, restoring perfusion using better EVT devices, and enrolling patients in the correct therapeutic window （i.e., when they still have salvageable brain tissue）（Tymianski, 2017）. Considering the opportunity that this represents for new, better clinical trials of neuroprotective agents, the search is on for high-potential compounds that may be investigated in these future studies.

关键词： Drugging SUMOylation for neuroprotection and oncotherapy OGD

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Enriched gestation activates the IGF pathway to evoke embryo-adult benefits to prevent Alzheimer’s disease

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Translational Neurodegeneration 2019年第1期8卷 94-110页

作者： Enjie Liu Qiuzhi Zhou Ao-Ji Xie Mengzhu Li Shujuan Zhang Hezhou Huang Zhenyu Liuyang Yali Wang Bingjin Liu Xiaoguang Li Dongsheng Sun Yuping Wei Xiaochuan Wang Qun Wang Dan Ke Xifei Yang Ying Yang Jian-Zhi Wang Department of Pathophysiology School of Basic Medicine and the Collaborative Innovation Center for Brain ScienceKey Laboratory of Ministry of Education of China for Neurological DisordersTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Co-innovation Center of Neuroregeneration Nantong UniversityNantong 226000China Key Laboratory of Modern Toxicology of Shenzhen Shenzhen Centre for Disease Control and Prevention8 Longyuan RoadShenzhen 518055China Department of Pathology the First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China

Background:Building brain reserves before dementia onset could represent a promising strategy to prevent Alzheimer’s disease(AD),while how to initiate early cognitive stimulation is *** that the immature brain is more sensitive to environmental stimuli and that brain dynamics decrease with ageing,we reasoned that it would be effective to initiate cognitive stimulation against AD as early as the fetal ***:After conception,maternal AD transgenic mice(3×Tg AD)were exposed to gestational environment enrichment(GEE)until the day of *** cognitive capacity of the offspring was assessed by the Morris water maze and contextual fear-conditioning tests when the offspring were raised in a standard environment to 7 months of *** blotting,immunohistochemistry,real-time PCR,immunoprecipitation,chromatin immunoprecipitation(ChIP)assay,electrophysiology,Golgi staining,activity assays and sandwich ELISA were employed to gain insight into the mechanisms underlying the beneficial effects of GEE on embryos and 7–10-month-old adult ***:We found that GEE markedly preserved synaptic plasticity and memory capacity with amelioration of hallmark pathologies in 7–10-m-old AD *** beneficial effects of GEE were accompanied by global histone hyperacetylation,including those at bdnf promoter-binding regions,with robust BDNF mRNA and protein expression in both embryo and progeny *** increased insulin-like growth factor 1(IGF1)and activated its receptor(IGF1R),which phosphorylates Ca^(2+)/calmodulin-dependent kinase IV(CaMKIV)at tyrosine sites and triggers its nuclear translocation,subsequently upregulating histone acetyltransferase(HAT)and BDNF *** upregulation of IGF1 mimicked the effects of GEE,while IGF1R or HAT inhibition during pregnancy abolished the GEE-induced CaMKIV-dependent histone hyperacetylation and BDNF ***:These findings suggest that activation of IGF1R/CaMKIV/HAT/BDNF signal

关键词： Alzheimer’s offspring Brain-derived neurotrophic factor Gestational environment enrichment Histone acetyltransferase Insulin-like growth factor 1 receptor

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Discovery of the first potent proteolysis targeting chimera(PROTAC) degrader of indoleamine 2,3-dioxygenase 1

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Acta Pharmaceutica Sinica B 2020年第10期10卷 1943-1953页

作者： Mingxing Hu Weilin Zhou Yijie Wang Dongping Yao Tinghong Ye Yuqin Yao Bin Chen Gongping Liu Xifei Yang Wei Wang Yongmei Xie State Key Laboratory of Biotherapy and Cancer Center Department of Laboratory MedicineWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengdu 610041China Department of Pathophysiology School of Basic Medicine and the Collaborative Innovation Center for Brain ScienceKey Laboratory of Ministry of Education of China and Hubei Province for Neurological DisordersTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Innovation Center of Neuroregeneration Nantong UniversityNantong 226019China Key Laboratory of Modern Toxicology of Shenzhen Shenzhen Centre for Disease Control and PreventionShenzhen 518055China

Cancer immunotherapy is revolutionizing oncology and has emerged as a promising strategy for the treatment of multiple *** 2,3-dioxygenase 1(IDO1),an immune checkpoint,plays an important role in tumor immune escape through the regulation of multiple immune cells and has been regarded as an attractive target for cancer *** Targeting Chimeras(PROTAC)technology has emerged as a new model for drug research and development for its advantageous ***,we reported the application of PROTAC technology in targeted degradation of IDO 1,leading to the discovery of the first IDO1 PROTAC degrader 2 c,which induced significant and persistent degradation of IDO1 with maximum degradation(Dmax)of 93%in HeLa ***-blot based mechanistic studies indicated that IDO 1 was degraded by 2 c through the ubiquitin proteasome system(UPS).Label-free real-time cell analysis(RTCA)indicated that 2 c moderately improved tumorkilling activity of chimeric antigen receptor-modified T(CAR-T)***,these data provide a new insight for the application of PROTAC technology in tumor immune-related proteins and a promising tool to study the function of IDO1.

关键词： IDO1 PROTAC Protein degradation Ubiquitin proteasome system Tumor immune escape

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Roles for the VCP co-factors Npl4 and Ufd1 in neuronal function in Drosophila melanogaster

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Journal of Genetics and Genomics 2017年第10期44卷 493-501页

作者： Dwayne J.Byrne Mark J.Harmon Jeremy C.Simpson Craig Blackstone Niamh C. O'Sullivan UCD School of Biomolecular and Biomedical Science UCD Conway Institute University College Dublin Dublin 4 Ireland UCD School of Biology and Environmental Science UCD Conway Institute of Biomolecular and Biomedical Research University College Dublin Dublin 4Ireland Cell Biology Section Neurogenetics Branch National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda MD 20892 USA

The VCP-Ufd1-Npl4 complex regulates proteasomal processing within cells by delivering ubiquitinated proteins to the proteasome for *** in VCP are associated with two neurodegenerative diseases,amyotrophic lateral sclerosis（ALS） and inclusion body myopathy with Paget＇s disease of the bone and frontotemporal dementia（IBMPFD）,and extensive study has revealed crucial functions of VCP within *** contrast,little is known about the functions of Npl4 or Ufd1 in *** neuronalspecific knockdown of Npl4 or Ufd1 in Drosophila melanogaster,we infer that Npl4 contributes to microtubule organization within developing motor ***,Npl4 RNAi flies present with neurodegenerative phenotypes including progressive locomotor deficits,reduced lifespan and increased accumulation of TAR DNA-binding protein-43 homolog（TBPH）.Knockdown,but not overexpression,of TBPH also exacerbates Npl4 RNAi-associated adult-onset neurodegenerative *** contrast,we find that neuronal knockdown of Ufd1 has little effect on neuromuscular junction（NMJ） organization,TBPH accumulation or adult *** findings suggest the differing neuronal functions of Npl4 and Ufd1 in vivo.

关键词： Proteasome TDP-43 accumulation Neurodegeneration Drosophila

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Long-term outcomes of brainstem arteriovenous malformations after different management modalities: a single-centre experience

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Stroke & Vascular Neurology 2021年第1期6卷 65-73页

作者： Yu Chen Ruinan Li Li Ma Xiangyu Meng Debin Yan Hao Wang Xun Ye Hengwei Jin Youxiang Li Dezhi Gao Shibin Sun Ali Liu Shuo Wang Xiaolin Chen Yuanli Zhao Department of Neurosurgery Beijing Tiantan HospitalBeijingChina China National Clinical Research Center for neurological Diseases BeijingChina Department of Interventional Neuroradiology Beijing Tiantan HospitalBeijingChina Stroke Center Beijing Institute for Brain DisordersBeijingChina Department of Neurosurgery Peking University International HospitalBeijingChina Department of Gamma-Knife Center Beijing Tiantan HospitalBeijingChina

Objective The aims of this study are to clarify the long-term outcomes of brainstem arteriovenous malformations(AVMs)after different management *** The authors retrospectively reviewed 61 brainstem AVMs in their institution between 2011 and *** rupture risk was represented by annualised haemorrhagic *** were divided into five groups:conservation,microsurgery,embolisation,stereotactic radiosurgery(SRS)and embolisation+*** outcomes were evaluated by the modified Rankin Scale(mRS).Subgroup analysis was conducted between different management modalities to compare the long-term outcomes in rupture or unruptured *** All of 61 brainstem AVMs(12 unruptured and 49 ruptured)were followed up for an average of 4.5 *** natural annualised rupture risk was 7.3%,and the natural annualised reruptured risk in the ruptured cohort was 8.9%.13 cases were conservative managed and 48 cases underwent intervention(including 6 microsurgery,12 embolisation,21 SRS and 9 embolisation+SRS).In the selection of interventional indication,diffuse nidus were often suggested conservative management(p=0.004)and nidus involving the midbrain were more likely to be recommended for intervention(p=0.034).The risk of subsequent haemorrhage was significantly increased in partial occlusion compared with complete occlusion and conservative management(p<0.001,p=0.036,respectively).In the subgroup analysis,the follow-up mRS scores of different management modalities were similar whether in the rupture cohort(p=0.064)or the unruptured cohort(p=0.391),as well as the haemorrhage-free survival(p=0.145).In the adjusted Bonferroni correction analysis of the ruptured cohort,microsurgery and SRS could significantly improve the obliteration rate compared with conservation(p<0.001,p=0.001,respectively)and SRS may have positive effect on avoiding new-onset neurofunctional deficit compared with microsurgery and embolisation(p=0.003,p=0.003,respectively).Conclusio

关键词： brainstem modalities conservative

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An updated systematic review of Zika virus-linked complications

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Asian Pacific Journal of Tropical Medicine 2018年第1期11卷 1-8页

作者： Braira Wahid Amjad Ali Muhammad Waqar Muhammad Idrees centre for Applied Molecular Biology University of the Punjab Genome centre for Molecular Based Diagnostics and Research centre Hazara University

Objective: To determine the breadth of Zika virus(ZIKV)-associated brain anomalies in neonates and adults. Methods: Systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA) statement using electronic databases ScienceDirect, Pubmed, Medline, Scopus, and Global Health *** those research articles, case studies, case-control studies, case-cohort studies, crosssectional studies, and organizational survey reports were included in the study that reported any fetal outcomes for pregnant women who had infected with ZIKV during the gestational period and ZIKV-related neurological complications in adults as well. Results: Out of total 72 retrieved articles, 50 met the inclusion criteria. We estimated a significant increase in incidence of neural abnormalities such as Guillain-Barre syndrome and microcephaly in the regions that are experiencing ZIKV outbreaks. Other neurological malformations found in ZIKV patients include hydrancephaly/hydrops fetalis, myasthenia gravis,meningoencephalitis and myelitis. Conclusion: Our systematic analysis provides the broad spectrum of neurological malformations in ZIKV infected patients and these data further support the causal link of ZIKV with neurological disorders.

关键词： Zika virus Microcephaly Guillain-Barre syndrome Acute myelitis Meningoencephalitis hydrancephaly/hydrops fetalis Myasthenia gravis

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