http://www.sciencenet.cn/htmlnews/2009/9/223364.shtm 《自然免疫学》：研究发现人体存在抗癌基因开关 癌症每年造成全球数百万人死亡，是最主要的致死原因之一。不少人因此谈癌色变。 英国科学家研究发现，人体中存在一个抗癌基因开关。通过控制这个基因，人体血液中可以产生抵御并杀死癌细胞的免疫细胞。这一发现为癌症治疗开辟了一条新路。 天生杀手 人体内有一种叫做天然杀伤细胞（又称NK细胞）的免疫细胞。它是血液白细胞的一种，也是所有免疫细胞中的快速反应部队。当人体遭受病毒或细菌感染，或出现肿瘤时，这种细胞会迅速组织防御，杀死被感染和癌变细胞。 虽然天然杀伤细胞作用很大，但科学家对它的了解却不如对免疫T细胞和B细胞那样深入。 英国《每日邮报》9月14日援引伦敦帝国理工学院研究员休布雷迪博士的话说：天然杀伤细胞就像灰姑娘一样神秘。我们对它了解不多。 每个人体内都存在这种天然杀伤细胞，但它们数量有限，约占全部白细胞数的五分之一。研究人员说，如果能增加人体内天然杀伤细胞数量，它们就能对癌细胞发起反击。 基因开关 研究人员曾尝试抽出志愿者体内天然杀伤细胞，然后注入癌症患者体内，期望借此杀死癌细胞。但由于来自他人的天然杀伤细胞与患者身体常出现不匹配现象，因此无法每次起效。 一个关键基因的发现，使癌症患者自身产生大量天然杀伤细胞成为可能。 布雷迪和他的研究小组发现，一个名为E4bp4的基因可以控制血液干细胞转化为天然杀伤细胞。 在实验中，布雷迪利用基因工程培育出一只体内不含E4bp4基因的小白鼠。与普通小白鼠相比，这只小白鼠血液中只缺少天然杀伤细胞，其他成分完全相同。这说明E4bp4基因对天然杀伤细胞的产生起关键作用。 这一研究成果刊登在13日出版的英国《自然免疫学》杂志上。 治疗新路 研究人员正在研制一种新药，通过增加患者体内天然杀伤细胞数量来抗击癌症。预期这种新药将对乳腺癌、肠癌、肺癌和白血病产生明显疗效。 布雷迪说，天然杀伤细胞是一种重要的免疫细胞，但也可能出现机能失常而引发糖尿病和多发性硬化症等疾病。 随着控制天然杀伤细胞的基因开关的发现以及不含这一基因的小白鼠诞生，我们可以进一步研究天然杀伤细胞与一系列疾病之间的关系，他说。 英国癌症研究会新闻官员约瑟芬克里多说：人体免疫系统是抵御疾病的有力武器。这一新发现揭示了这种武器的工作原理，为未来癌症治疗开辟了新路。 http://www.nature.com/ni/journal/vaop/ncurrent/abs/ni.1787.html Nature Immunology Published online: 13 September 2009 | :10.1038/ni.1787 :10.1038/ni.1787 The basic leucine zipper transcription factor E4BP4 is essential for natural killer cell development Duncan M Gascoyne 1 , Elaine Long 1 , Henrique Veiga-Fernandes 2 , 6 , Jasper de Boer 1 , Owen Williams 1 , Benedict Seddon 3 , Mark Coles 4 , Dimitris Kioussis 2 Hugh J M Brady 1 , 5 Abstract Natural killer (NK) cells are a subset of lymphocytes crucial for innate immunity and modification of adaptive immune responses. In contrast to commitment to the T cell or B cell lineage, little is known about NK cell lineage commitment. Here we show that the basic leucine zipper (bZIP) transcription factor E4BP4 (also called NFIL3) is essential for generation of the NK cell lineage. E4BP4-deficient mice ( Nfil3 -/ ; called ' E4bp4 -/ ' here) had B cells, T cells and NKT cells but specifically lack NK cells and showed severely impaired NK cellmediated cytotoxicity. Overexpression of E4bp4 was sufficient to increase NK cell production from hematopoietic progenitor cells. E4BP4 acted in a cell-intrinsic manner 'downstream' of the interleukin 15 receptor (IL-15R) and through the transcription factor Id2. E4bp4 -/- mice may provide a model for definitive analysis of the contribution of NK cells to immune responses and pathologies. Molecular Haematology and Cancer Biology Unit, University College London Institute of Child Health and Great Ormond Street Hospital for Children, London, UK. Division of Molecular Immunology, Medical Research Council National Institute for Medical Research, Mill Hill, London, UK. Division of Immune Cell Biology, Medical Research Council National Institute for Medical Research, Mill Hill, London, UK. Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, UK. Immunology and Infection Section, Division of Cell and Molecular Biology, Sir Alexander Fleming Building, Imperial College, London, UK. Present address: Immunobiology Unit, Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Lisboa, Portugal. Correspondence to: Hugh J M Brady 1 , 5 e-mail: h.brady@imperial.ac.uk . 信息分析平台： http://www.gopubmed.org/web/gopubmed/1?WEB01dvvul63ftcj4I1aI2I00d000j10040001rl 检索策略：E4bp4 and cancer 相关文献计量分析结果： Top Years Publications 2008 3 2004 2 2006 1 2001 1 1998 1 1995 1 1992 1 Top Countries Publications USA 4 Japan 3 United Kingdom 2 Italy 1 Top Cities Publications London 2 Bari 1 Fukuoka 1 Tsukuba 1 Lawrence 1 Tokyo 1 New York 1 Philadelphia 1 Top Journals Publications Mol Cell Biol 2 Clin Cancer Res 1 Gastroenterology 1 Neurosci Res 1 Biochem Bioph Res Co 1 J Virol 1 Brit J Haematol 1 Oncogene 1 J Biol Chem 1 1 2 3 Top Authors Publications Dammacco F 1 Silvestris F 1 Cafforio P 1 De Matteo M 1 Calvani N 1 Frassanito M 1 Ohdo S 1 Murakami Y 1 Higashi Y 1 Matsunaga N 1 Koyanagi S 1 Ishida N 1 Kotaka M 1 Onishi Y 1 Ohno T 1 Akaike T 1 Medh R 1 Priceman S 1 Kirzner J 1 Nary L 1 1 2 3 1 2 3 ... 16 Top Terms Publications e4bp4 10 Genes 8 Basic-Leucine Zipper Transcription Factors 8 Transcription Factors 7 transcription repressor activity 6 positive regulation of transcription 6 Proteins 6 Humans 6 Trans-Activation (Genetics) 5 Binding Sites 4 Luciferases 4 luciferase 4 Animals 4 Plasmids 4 Base Sequence 4 DNA-Binding Proteins 4 G-Box Binding Factors 4 RNA, Messenger 3 hlf 3 Leucine Zippers 3 1 2 3 ... 16 相关研究报道： Negative regulation of the osteoblast function in multiple myeloma through the repressor gene E4BP4 activated by malignant plasma cells. PMID: 18829486 Related Articles Authors: Silvestris, F , Cafforio, P , De Matteo, M , Calvani, N , Frassanito, M A , Dammacco, F Journal: Clin Cancer Res , Vol. 14 (19): 6081-91 , 2008 Abstract: PURPOSE: To explore the pathogenetic mechanisms that suppress the osteoblast function in multiple myeloma because osteogenesis results in defective new bone formation and repair. EXPERIMENTAL DESIGN: Microarray gene analysis revealed the overexpression of E4BP4 , a transcriptional repressor gene, in normal osteoblasts cocultured with myeloma cells that were releasing the parathyroid hormone-related protein ( PTHrP ). Thus, the effect of E4BP4 was assessed in PTHrP -stimulated osteoblasts by measuring the RNA levels of both Runx2 and Osterix as major osteoblast transcriptional activators. Because E4BP4 is a negative regulator of the cyclooxygenase-2 ( COX-2 ) pathway that drives the expression of both Runx2 and Osterix, these factors were investigated after prostaglandin E(2) treatment to overcome the COX-2 defect as well as in E4BP4 -silenced osteoblasts. Finally, E4BP4 , PTHrP , Osterix, and osteocalcin levels were measured in vivo in patients with bone disease together with the E4BP4 protein in bone biopsies. RESULTS: E4BP4 was specifically induced by PTHrP and inhibited both Runx2 and Osterix, whereas E4BP4 -silenced osteoblasts expressed functional levels of both factors. The prostaglandin E(2) treatment of E4BP4 -up-regulated osteoblasts promptly restored Runx2 and Osterix activities, suggesting that integrity of COX-2 pathway is essential for their transcription. Down-regulation of Osterix by E4BP4 was confirmed in vivo by its inverse levels in osteoblasts from myeloma patients with increased serum PTHrP , whose bone biopsies expressed the E4BP4 protein. CONCLUSIONS: Our data support the role of E4BP4 as osteoblast transcriptional repressor in inhibiting both Runx2 and Osterix in myeloma bone disease and correlate its effect with the increased PTHrP activity. Affiliation: Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Piazza Giulio Cesare 11, Bari , Italy . f.silvestris@dimo.uniba.it Pubmed MeSH: Adult , Basic-Leucine Zipper Transcription Factors , Core Binding Factor Alpha 1 Subunit , Dinoprostone , Gene Expression Regulation, Neoplastic , Gene Silencing , Humans , Oligonucleotide Array Sequence Analysis , Transcription Factors Wikipedia: Biopsies , Biopsy , Blood serum , Bone Disease , Bone diseases , Cistron , Client , Cyclooxygenase 2 , Down-regulation , Downregulation , Gene , Gene Expression , Gene activation , Gene expression regulation , Genetic material , Microarray analysis , Multiple Myeloma , Osteoblast , Osteocalcin , Osteogenesis , PTGS2 , PTHrP , Parathyroid hormone-related peptide , Parathyroid hormone-related protein , Patient , Plasma cell , Prostaglandins , Prostanoids , Proteins , RNA , Receptor down-regulation , RiboNucleic Acid , Serum , Transactivation Title: Circadian clock-controlled intestinal expression of the multidrug-resistance gene mdr1a in mice. PMID: 18773899 Related Articles Authors: Murakami, Y , Higashi, Y , Matsunaga, N , Koyanagi, S , Ohdo, S Journal: Gastroenterology , Vol. 135 (5): 1636-1644.e3 , 2008 Abstract: BACKGROUND AIMS: P-glycoprotein, the product of the multidrug resistance (mdr) gene, functions as a xenobiotic transporter contributing to the intestinal barrier. Although intestinal expression of the mdr1a gene and its efflux pump function has been shown to exhibit 24-hour variation, the mechanism of the variations remains poorly understood. Here, we demonstrated that the molecular components of the circadian clock act as regulators to control 24-hour variation in the expression of the mdr1a gene. METHODS: Luciferase reporter assay and gel mobility shift assay were used to study the mechanism of transcriptional regulation of the mdr1a gene by clock gene products. The messenger RNA levels and protein abundances in colon 26 cells and mouse intestine were measured by quantitative real-time polymerase chain reaction and Western blotting, respectively. RESULTS: Hepatic leukemia factor ( HLF ) and E4 promoter binding protein-4 ( E4BP4 ) regulated transcription of the mdr1a gene by competing with each other for the same DNA binding site. Molecular and biochemical analyses of HLF - and E4BP4 -down-regulated colon 26 cells and the intestinal tract of Clock mutant mice suggested that these 2 proteins consisted of a reciprocating mechanism in which HLF activated the transcription of the mdr1a gene, whereas E4BP4 periodically suppressed transcription at the time of day when E4BP4 was abundant. CONCLUSIONS: The intestinal expression of the mdr1a gene is influenced by the circadian organization of molecular clockwork. Our present findings provide a link between the circadian timekeeping system and xenobiotic detoxification. Affiliation: Pharmaceutics, Division of Clinical Pharmacy, Department of Medico-Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka , Japan . Pubmed MeSH: Adenocarcinoma , Animals , Basic-Leucine Zipper Transcription Factors , Chromatin Immunoprecipitation , Circadian Rhythm , Colonic Neoplasms , Disease Models, Animal , Gene Expression Regulation, Neoplastic , Intestinal Mucosa , Leucine Zippers , Mice, Mutant Strains , RNA, Neoplasm Wikipedia: Active site , B-DNA , Binding site , Blotting, western , Cistron , DNA , Deoxyribonucleic Acid , Electrophoretic mobility shift assay , Gel retardation assay , Gene , Genetic material , Hepatitis , House Mouse , House mice , Intestine , Inverse PCR , Inverse polymerase chain reaction , Laboratory mice , Laboratory mouse , Leukemia , Luciferase , Messenger RNA , Mice , Mouse , Multi-drug resistance , Multidrug resistance , Mus , Mus domesticus , Mus musculus , Mus musculus domesticus , Nested PCR , Nested polymerase chain reaction , P-glycoprotein , PCR , Poly(A) tail , Polymerase Chain Reaction , Proteins , RNA , RiboNucleic Acid , Western Blot , Western blotting , Xenobiotics Title: Identification of negative transcriptional factor E4BP4 -binding site in the mouse circadian-regulated gene Mdr2 . PMID: 18242748 Related Articles Authors: Kotaka, M , Onishi, Y , Ohno, T , Akaike, T , Ishida, N Journal: Neurosci Res , Vol. 60 (3): 307-13 , 2008 Abstract: The hepatic transporter Mdr2 is an ATP-binding cassette transporter which excretes phosphatidylcholine into the bile. We showed that the level of Mdr2 mRNA oscillated in circadian fashion in mouse liver whereas such oscillation was dampened in the liver of Clock mutants. To examine transcriptional regulation of the Mdr2 gene we performed luciferase reporter assays using plasmid constructs containing the 5'-flanking region of the Mdr2 gene. Reporter assays using deletion constructs demonstrated that E4BP4 represses the transcriptional activity of the promoter including the D1 and D2 sites within four putative E4BP4 -binding sites. Chromatin immunoprecipitation and gel shift assays showed that E4BP4 binds to the D2 site, but not to the D1 site. These data suggested that E4BP4 is a negative transcription factor for circadian Mdr2 mRNA expression. Affiliation: Clock Cell Biology Research Group, Institute for Biological Resources and Functions, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba 305-8566, Japan . Pubmed MeSH: Animals , Basic-Leucine Zipper Transcription Factors , Carcinoma, Hepatocellular , Cell Line, Tumor , Circadian Rhythm , Humans , Liver , Liver Neoplasms , Mice, Inbred C57BL , Mice, Inbred ICR , Mice, Mutant Strains , P-Glycoproteins , Trans-Activators Wikipedia: ABC transporter , ATP-Binding Cassette Transporter , ATP binding cassette transporters , Atp-binding cassette transporters , Bile , Chromatin , Chromatin immunoprecipitation , Cistron , Co-immunoprecipitation , Episome , Gene , Genetic material , Hepatitis , House Mouse , House mice , Immunoprecipitation , Laboratory mice , Laboratory mouse , Luciferase , Messenger RNA , Mice , Mouse , Mus , Mus domesticus , Mus musculus , Mus musculus domesticus , Phosphatidylcholine , Plasmid , Poly(A) tail , Transactivation , Transcription factor Title: Calcium-dependent upregulation of E4BP4 expression correlates with glucocorticoid-evoked apoptosis of human leukemic CEM cells. PMID: 16630563 Related Articles Authors: Priceman, S J , Kirzner, J D , Nary, L J , Morris, D , Shankar, D B , Sakamoto, K M , Medh, R D Journal: Biochem Biophys Res Commun , Vol. 344 (2): 491-9 , 2006 Abstract: Glucocorticoid (GC)-evoked apoptosis of T-lymphoid cells is preceded by increases in the intracellular Ca2+ concentration ( i), which may contribute to apoptosis. This report demonstrates that GC-mediated upregulation of the bZIP transcriptional repressor gene, E4BP4 , is dependent on i levels, and correlates with GC-evoked apoptosis of GC-sensitive CEM -C7-14 cells. Calcium chelators EGTA and BAPTA reduced i levels and protected CEM -C7-14 cells from Dex -evoked E4BP4 upregulation as well as apoptosis. In the GC-resistant sister clone, CEM -C1-15, Dex treatment did not induce i levels, E4BP4 expression or apoptosis, however, the calcium ionophore A23187 restored Dex-evoked E4BP4 upregulation and apoptosis. CEM -C7-14 cells were more sensitive to GC-independent increases in i levels by thapsigargin, and a corresponding increase in E4BP4 expression and cell death, compared to CEM-C1-15 cells, suggesting a direct correlation between i levels, E4BP4 expression, and apoptosis. Affiliation: Department of Biology, California State University at Northridge, Northridge, CA 91330-8303, USA . Pubmed MeSH: Basic-Leucine Zipper Transcription Factors , Cell Line, Tumor , Dose-Response Relationship, Drug , Humans , Leukemia, Lymphoid , Statistics as Topic Wikipedia: A23187 , Antibiotic A23187 , Apoptosis , Calcimycin , Calcium , Calcium metabolism , Cell death , Chelating agents , Cistron , EGTA , Gene , Genetic material , Glucocorticoids , Ionophores , Thapsigargin , Up-regulation , Upregulation Title: Identification and characterization of cis-acting elements residing in the walleye dermal sarcoma virus promoter. PMID: 15220434 Related Articles Authors: Hronek, B W , Meagher, A , Rovnak, J , Quackenbush, S L Journal: J Virol , Vol. 78 (14): 7590-601 , 2004 Abstract: Walleye dermal sarcoma virus ( WDSV ) is a complex retrovirus found associated with tumors that appear and regress on a seasonal basis. There are quantitative and qualitative differences in the amount of virus expression between developing and regressing tumors. To understand the role of host cell factors in WDSV expression, DNase I footprint analysis, electrophoretic mobility shift assays (EMSA), and reporter gene assays were employed. DNase I footprint analysis of the U3 region of the WDSV long terminal repeat with nuclear extract prepared from a walleye cell line revealed protection of an Oct1 , AP1 , Whn , and two E4BP4 sites. Additionally, three regions that contained no putative transcription factor binding sites were protected. EMSA confirmed the specific binding of the protected sites and revealed three additional sites, NF1 , AP3 , and LVa, not protected in DNase I footprint analysis. Site-directed mutagenesis of the individual sites, in the context of a luciferase reporter plasmid, revealed that the NF1 , Oct1 , AP1 , E4BP4 #2, AP3 , and LVa sites contributed to transcription activation driven by the WDSV U3 region. Mutation of Novel#2 resulted in an increase in luciferase activity, suggesting the Novel#2 site may function to bind a negative regulator of transcription. Anti- Jun and anti- Fos antiserum specifically inhibited protein-DNA complex formation, indicating the presence of c- Jun and c- Fos in the walleye cell nuclear extracts and their participation in binding to the AP1 site. Interestingly, degenerative 15-bp repeats found in the U3 region are differentially protected in DNase I footprint analysis by the walleye cell line nuclear extract and regressing-tumor nuclear extract. EMSA utilizing the 15-bp repeat probe revealed that there are similarities of binding with W12 cell and developing-tumor nuclear extracts and that the binding differs from that observed with regressing-tumor nuclear extract. Affiliation: Department of Molecular Biosciences, University of Kansas, Lawrence , KS 66045, USA . Pubmed MeSH: Animals , Base Sequence , DNA Footprinting , Electrophoresis , Fish Diseases , Gene Deletion , Gene Expression Regulation, Viral , Mutagenesis, Site-Directed , Perciformes , Retroviridae Infections , Tumor Virus Infections Wikipedia: Active site , Animal virus , Benign neoplasm , Binding site , Cancer , Cell line , Cistron , DNAase , DNAse , DNase I , Deoxyribonuclease I , Deoxyribonucleases , Electrophoretic mobility shift assay , Episome , Epithelioid Sarcoma , Epsilonretrovirus , Gel retardation assay , Gene , Genetic material , Host factor , Long terminal repeat , Luciferase , Mutation , Neoplasm , Oncovirus , Plasmid , Reporter gene , Retroviridae , Retrovirus , Sarcoma , Soft Tissue Sarcoma , Spindle cell sarcoma , Terminal repeat , Transactivation , Transcription factor , Tumor , Virus Title: E4BP4 expression is regulated by the t(17;19)-associated oncoprotein E2A - HLF in pro-B cells. PMID: 15147370 Related Articles Authors: Yeung, J , O'Sullivan, E , Hubank, M , Brady, H J Journal: Br J Haematol , Vol. 125 (5): 560-7 , 2004 Abstract: The E4BP4 basic leucine zipper ( bZIP ) transcription factor is regulated by interleukin-3 ( IL-3 ) in pro-B cells and has been reported to promote survival of the murine IL-3 -dependent pro-B cell lines, FL5.12 and Baf-3. The E2A - HLF oncoprotein arises from a t(17;19) translocation in childhood pro-B cell acute lymphoblastic leukaemia and acts as an anti-apoptotic factor in FL5.12 and Baf -3 cells. To assess the functions of E2A - HLF and E4BP4 in cell survival, a tetracycline-inducible system was established in Baf-3 cells to express E4BP4 or E2A - HLF . Upon IL-3 withdrawal, expression of E2A - HLF conferred resistance to apoptosis whereas overexpression of E4BP4 did not. E4BP4 and E2A - HLF both recognized the same DNA sequence in reporter gene assays, but had opposite effects on transcription. E2A - HLF acts as a transcriptional activator and E4BP4 as a transcriptional repressor. Furthermore, E4BP4 is a downstream transcriptional target of E2A - HLF . Our data suggests that the overexpression of E4BP4 is unable to block apoptosis induced by IL-3 withdrawal and that the expression of E2A - HLF does not replace the function of E4BP4 in mediating survival. Affiliation: Molecular Haematology and Cancer Biology Unit, Institute of Child Health, University College London, London , UK . Pubmed MeSH: Blotting, Northern , Blotting, Western , Cell Line, Tumor , Child , Chromosomes, Human, Pair 17 , Chromosomes, Human, Pair 19 , DNA-Binding Proteins , Doxycycline , G-Box Binding Factors , Gene Expression , Humans , Oncogene Proteins, Fusion , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Translocation, Genetic Wikipedia: Apoptosis , B-DNA , Base sequence , Basic-leucine zipper transcription factors , Cell line , Cistron , DNA , DNA sequence , Deoxyribonucleic Acid , Gene , Genetic material , IL-3 , Interleukin-3 , Interleukin 3 , L-Leucine , Leucine , Leucine Zipper , Leucine zippers , Nucleotide sequence , Oncogene protein , Reporter gene , Transactivation , Transcription factor Title: Growth-suppressive effects of BPOZ and EGR2 , two genes involved in the PTEN signaling pathway. PMID: 11494141 Related Articles Authors: Unoki, M , Nakamura, Y K Journal: Oncogene , Vol. 20 (33): 4457-65 , 2001 Abstract: Defects in PTEN , a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN . Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/ Krox-20 , BPOZ , APS, HCLS1 / HS1 , DUSP1 / MKP1 , NDRG1 / Drg1 / RTP , NFIL3 / E4BP4 , and a novel gene ( PINK1 , PTEN -induced putative kinase). Expression of six of them ( PINK1 , EGR2 , HCLS1 , DUSP1 , BPOZ, and NFIL3) was decreased in ovarian tumors compared with corresponding normal tissues. Colony-formation assays using plasmid clones designed to express each gene indicated that EGR2 and BPOZ were able to suppress growth of cancer cells significantly; in particular, cancer -cell lines stably expressing BPOZ grew more slowly than control cells containing mock vector. Flow cytometry suggested that over-expression of BPOZ inhibited progression of the cell cycle at the G(1)/S transition. Anti-sense oligonucleotides for BPOZ or EGR2 effectively inhibited their expression, and cell growth was accelerated. Therefore both genes appear to be novel candidates as mediators of the PTEN growth-suppressive signaling pathway. Affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo , 4-6-1 Shirokanedai, Minato-ku, Tokyo , 108-8639, Japan . Pubmed MeSH: Adaptor Proteins, Vesicular Transport , Adult , Amino Acid Sequence , Ankyrin Repeat , Basic-Leucine Zipper Transcription Factors , Blood Proteins , Cell Cycle Proteins , Cell Division , DNA-Binding Proteins , Dual Specificity Phosphatase 1 , Early Growth Response Protein 2 , Expressed Sequence Tags , G-Box Binding Factors , Gene Expression Profiling , Genes, Tumor Suppressor , Humans , Immediate-Early Proteins , Intracellular Signaling Peptides and Proteins , Neoplasm Proteins , Nerve Tissue Proteins , Oligodeoxyribonucleotides, Antisense , Ovarian Neoplasms , PTEN Phosphohydrolase , Phosphoprotein Phosphatases , Phosphoric Monoester Hydrolases , Protein Kinases , Protein Phosphatase 1 , Protein Structure, Tertiary , Protein Tyrosine Phosphatases , Proteins , RNA Splicing , Recombinant Fusion Proteins , Repressor Proteins , Sequence Alignment , Signal Transduction , Subcellular Fractions , Transcription Factors , Trans-Activation (Genetics) , Transfection , Tumor Cells, Cultured , Tumor Stem Cell Assay , Tumor Suppressor Proteins Wikipedia: Acceleration , Benign neoplasm , Cancer , Cell Cycle , Cell Division Cycle , Cistron , Episome , Flow cytometry , Gene , Genetic material , Kinase , Neoplasm , Oligonucleotides , Oligonucleotides, antisense , Phosphotransferases , Plasmid , Tissue , Trans-acting factor , Trans-activator , Transactivator , Tumor Title: Keratinocyte growth factor down-regulates expression of the sucrase-isomaltase gene in Caco-2 intestinal epithelial cells. PMID: 9837912 Related Articles Authors: Zhou, J , Wu, K , Fernandes, C L , Cheng, A L , Finch, P W Journal: J Biol Chem , Vol. 273 (50): 33367-73 , 1998 Abstract: The molecular mechanisms that regulate the proliferation and differentiation of intestinal mucosal epithelial cells are not well understood. Keratinocyte growth factor ( KGF ) is an epithelial cell-specific growth factor that may be involved in the maintenance of mucosal epithelial populations and in mediating epithelial repair after injury. The sucrase-isomaltase (SI) gene, which encodes an enterocyte brush border disaccharidase, has served as a model for study of intestinal-specific gene expression and differentiation. KGF down-regulated SI mRNA and protein expression in Caco-2 intestinal epithelial cells but not the expression of other brush border enzymes. The down-regulation was dose- and time-dependent and specifically blocked by anti- KGF antibodies. Transfection experiments using SI promoter constructs demonstrated that KGF decreased SI gene transcription. In contrast, the stability of SI mRNA was not affected by incubation of Caco-2 cells with KGF . Electrophoretic mobility shift analysis demonstrated that binding of nuclear proteins to the SI footprint (SIF) 3 and SIF4 regulatory elements within the SI promoter region was increased in Caco-2 cells that had been incubated with KGF . In transfection experiments using a construct in which tandem copies of the SIF4-binding site were inserted upstream of the SV40 promoter and luciferase gene, incubation with KGF resulted in a significant decrease in luciferase activity. However, transfection with a similar construct containing tandem copies of SIF3 had no significant effect on SV40 promoter activity following KGF treatment. SIF4 may bind E4BP4 , a previously identified transcriptional repressor protein. This factor may in part mediate the decrease in SI transcription by KGF in Caco-2 cells. Affiliation: Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York , New York 10029, USA . Pubmed MeSH: Cell Differentiation , Fibroblast Growth Factor 10 , Fibroblast Growth Factors , Growth Substances , Humans , Intestinal Mucosa , Protein Binding , Receptor, Fibroblast Growth Factor, Type 2 , Receptors, Fibroblast Growth Factor , Receptors, Growth Factor , Sucrase-Isomaltase Complex Wikipedia: Antibodies , Brush border , Cistron , Disaccharidases , Down-regulation , Downregulation , Enterocyte , Enzymes , Epithelial cell , Gene , Gene Expression , Genetic material , Growth factors , Incubator , Injuries , Injury , Intercellular signaling peptides and proteins , Intestine , Keratinocyte , Keratinocyte Growth Factor , Luciferase , Maintenance , Messenger RNA , Microvilli , Microvillus , Mucositis , Nuclear protein , Palifermin , Poly(A) tail , Proteins , Receptor down-regulation , Transfection , Trauma , Wound , Wounds and injuries Title: DNA-binding specificity of the PAR basic leucine zipper protein VBP partially overlaps those of the C/EBP and CREB / ATF families and is influenced by domains that flank the core basic region. PMID: 7891686 Related Articles Authors: Haas, N B , Cantwell, C A , Johnson, P F , Burch, J B Journal: Mol Cell Biol , Vol. 15 (4): 1923-32 , 1995 Abstract: The PAR subfamily of basic leucine zipper (bZIP) factors comprises three proteins ( VBP / TEF , DBP , and HLF ) that have conserved basic regions flanked by proline- and acidic-amino-acid-rich (PAR) domains and functionally compatible leucine zipper dimerization domains. We show that VBP preferentially binds to sequences that consist of abutted GTAAY half-sites (which we refer to as PAR sites) as well as to sequences that contain either a C/ EBP half-site (GCAAT) or a CREB / ATF half-site (GTCAT) in place of one of the PAR half-sites. Since the sequences that we describe as PAR sites and PAR- CREB / ATF chimeric sites, respectively, were both previously described as high-affinity binding sites for the E4BP4 transcriptional repressor, we infer that these sequences may be targets for positive and negative regulation. Similarly, since the sequences that we describe as PAR-C / EBP and PAR- CREB / ATF chimeric sites are known to be high-affinity binding sites for C/EBP and CREB / ATF factors, respectively, we infer that these sites may each be targets for multiple subfamilies of bZIP factors. To gain insights regarding the molecular basis for the binding-site specificity of PAR factors, we also carried out an extensive mutational analysis of VBP . By substituting five amino acid residues that differ between the Drosophila giant bZIP factor and the vertebrate PAR bZIP factors, we show that the fork region, which bridges the basic and leucine zipper domains, contributes to half-site sequence specificity. In addition, we report that at least two domains amino terminal to the core basic region are required for VBP to bind to the full spectrum of PAR target sites. Thus, whereas direct base contacts may be restricted to basic-region residues (as indicated by GCN4 -DNA crystal structures), several other domains also influence the DNA-binding specificity of PAR bZIP proteins. Affiliation: Fox Chase Cancer Center, Philadelphia , Pennsylvania 19111. Pubmed MeSH: Activating Transcription Factor 2 , Avian Proteins , Base Sequence , CCAAT-Enhancer-Binding Proteins , Carrier Proteins , Cyclic AMP Response Element-Binding Protein , DNA Mutational Analysis , DNA-Binding Proteins , G-Box Binding Factors , Models, Molecular , Nuclear Proteins , Protein Binding , Structure-Activity Relationship , Transcription Factors Wikipedia: Active site , Amino Acids , Basic-leucine zipper transcription factors , Binding site , Chimerism , Dimerization , Drosophila , L-Leucine , L-Proline , Leucine , Leucine Zipper , Leucine zippers , Microchimerism , Mutation , ProLine , Proteins , Vertebrate Title: Transcriptional repression by a novel member of the bZIP family of transcription factors. PMID: 1620116 Related Articles Authors: Cowell, I G , Skinner, A , Hurst, H C Journal: Mol Cell Biol , Vol. 12 (7): 3070-7 , 1992 Abstract: We describe here a novel member of the bZIP family of DNA-binding proteins, designated E4BP4 , that displays an unusual DNA-binding specificity which overlaps that of the activating transcription factor family of factors. When expressed in a transient transfection assay with a suitable reporter plasmid, E4BP4 strongly repressed transcription in a DNA-binding-site-dependent manner. Examination of a series of deletion mutants revealed that sequences responsible for the repressing potential of E4BP4 lie within the carboxyl-terminal region of the protein. No similarity was found between this region and the repressing domains of other known eukaryotic transcriptional repressors. Affiliation: Gene Transcription Laboratory, Imperial Cancer Research Fund, Hammersmith Hospital, London , England . Pubmed MeSH: Amino Acid Sequence , Animals , Base Sequence , Basic-Leucine Zipper Transcription Factors , Binding Sites , DNA Mutational Analysis , G-Box Binding Factors , Multigene Family , Placenta , Plant Proteins , Protein Conformation , Repressor Proteins , Sequence Homology, Nucleic Acid , Transcription, Genetic Wikipedia: DNA binding protein , Dna-binding proteins , Episome , Plasmid , Proteins , Transcription factor , Transfection 原始研究论文： E4bp4 and cancer 知识发现平台： http://arrowsmith.psych.uic.edu/cgi-bin/arrowsmith_uic/edit_b.cgi?refresh=TID=24532 检索策略：E4bp4 and cancer Start A-Literature C-Literature B-list Filter Literature A-query: E4bp4 C-query: cancer The B-list contains title words and phrases (terms) that appeared in both the A and the C literature. 10 articles appeared in both literatures and were not included in the process of computing the B-list but can be viewed here . The results of this search are saved under id # 24532 and can be accessed from the start page after you leave this session. There are 359 terms on the current B-list (92 are predicted to be relevant), which is shown ranked according to predicted relevance. The list can be further trimmed down using the filters listed in the left margin. To assess whether there appears to be a biologically significant relationship between the AB and BC literatures for specific B-terms, please select one or more B-terms and then click the button to view the corresponding AB and BC literatures. Use Ctrl to select multiple B-terms. Rank Prob B-term 10.99mapk 20.99bcl xl 30.99yy1 40.99hepatitis b virus 50.99expression analysis 60.99kinase signaling 70.99genome wide 80.99gene promoter 90.98circadian gene 100.98transcriptional repression 110.98bcl 120.98hepg2 cell 130.98topoisomerase 140.98clock gene 150.98nuclear receptor 160.98expression profile 170.97transcription factor 180.97body mass index 190.97topoisomerase i 200.97transcriptional repressor 210.96transcriptional 220.96bzip 230.96calcineurin 240.96regulate transcription 250.96nuclear factor 260.95gata 270.95molecular cloning 280.94cyp3a4 290.93gata-1 300.92genome wide expression 310.92cdna 320.92hepatitis b 330.92controlled tumor protein 340.91translationally controlled tumor 350.91factor expression 360.90protein kinase signaling 370.89igh 380.89pai-1 390.88protein protein interaction 400.87hepg2 410.87nf 420.86body mass 430.86enhancer 440.85repression 450.85zebrafish 460.85repressor 470.85signal pathway 480.85adenovirus 490.84protein kinase 500.84na h exchanger 510.84circadian clock 520.84activated t cell 530.83casein kinase 540.83promoter 550.82xl 560.81gene regulation 570.80activated t 580.79calcineurin nuclear factor 590.77clock 600.77transcription 610.77ras 620.76expression gene 630.75nih3t3 cell 640.75hematopoietic cell 650.74ba f3 660.72analysis reveal 670.72gata factor 680.71gene expression 690.70calmodulin 700.69hematopoietic 710.69t cell 720.68rev 730.68na h 740.67cell survival 750.66endothelin 760.62activation nuclear factor 770.61interleukin 780.61genome 790.60potential transcriptional 800.59novel mechanism 810.56down regulate 820.56prion 830.53domain 840.52expression analysis reveal 850.51molecular cloning characterization 860.50mass index 870.50dependent protein kinase 880.49b virus enhancer 890.49cloning characterization 900.49interleukin-4 910.48receptor rev 920.45growth survival 930.45expression cell 940.42protein protein 950.41family member 960.41b cell 970.41osteoblast 980.40regulator 990.39cell specific 1000.38uterine 1010.38kinase 1020.37b lymphocyte 1030.37parathyroid 1040.36nuclear factor activated 1050.35dependent protein 1060.34activator 1070.34protein interaction 1080.30phosphorylation 1090.30nih3t3 1100.29expression cell survival 1110.27mrna 1120.27protein gene 1130.27expression calcineurin 1140.26reperfusion 1150.24pivotal 1160.23expressed gene 1170.23pivotal role 1180.22melatonin 1190.21pineal gland 1200.21expression adenovirus 1210.20parathyroid hormone 1220.20survival murine 1230.19protein gene expression 1240.19pineal 1250.19mediated phosphorylation 1260.19control circadian clock 1270.18expression topoisomerase 1280.18survival 1290.17pro 1300.17exhibit 1310.16exchanger 1320.16nuclear 1330.15bile acid 1340.15gene 1350.15|--gene a 1360.15cloning 1370.15factor activated t 1380.13age body mass 1390.12translationally 1400.12activation nuclear 1410.11tumor protein 1420.11cell line 1430.11regulatory 1440.10expression 1450.10calcium dependent activation 1460.10controlled 1470.10virus gene 1480.09gene regulation glucocorticoid 1490.09characterization human 1500.09molecular 1510.09mrna encoding 1520.09adipose tissue 1530.08wide 1540.08period2 1550.08cluster 1560.08cell identified 1570.07circadian 1580.07glucocorticoid 1590.07ischemia reperfusion 1600.06embryonic 1610.06hepatitis 1620.06adrenal gland 1630.06gene expression mouse 1640.06adipose 1650.06novel 1660.06na 1670.05bile 1680.05regulatory protein 1690.05b cell specific 1700.05hepatic 1710.05identification 1720.05activation 1730.05expressed 1740.05hormone induced 1750.04growth 1760.04regulation 1770.04hydroxylase 1780.04rat heart 1790.04mass 1800.04potential 1810.04negative transcription 1820.04core 1830.04negative 1840.03von willebrand 1850.03signal 1860.03phosphorylated 1870.03key 1880.03tumor 1890.03index 1900.03mouse liver 1910.03liver 1920.03protein 1930.03molecular mechanism 1940.03phase 1950.03signaling 1960.03f3 1970.02mouse brain 1980.02murine 1990.02line 2000.02specific 2010.02adrenal 2020.02minimal 2030.02receptor 2040.02regulated 2050.02rhythm 2060.02multiple 2070.02messenger 2080.02cholesterol 2090.02lymphocyte 2100.023-mediated 2110.02diet 2120.02key enzyme 2130.01cis 2140.01element 2150.01expression mouse 2160.01autonomous 2170.01member 2180.01regulate 2190.01binding protein 2200.01early 2210.01related 2220.01motif 2230.01embryo 2240.01mammalian 2250.01cell 2260.01|--cell calcium 2270.01drive 2280.01reveal 2290.01dependent 2300.01protein human 2310.01binding site 2320.01ontogeny 2330.01response 2340.01family 2350.01high 2360.01adenosine 2370.01tissue 2380.01intrinsic 2390.00antagonistic 2400.00human 2410.00heart 2420.00dependent activation 2430.00molecular basis 2440.00analysis 2450.00encoding 2460.00promote 2470.00alter gene expression 2480.00chicken 2490.00down 2500.00cyclic 2510.00activated 2520.00role 2530.00viability 2540.00regulating 2550.00identified 2560.00distinct 2570.00par 2580.00induce 2590.00von 2600.00survival gene 2610.00gene mouse 2620.00ovine 2630.00rhythmic 2640.00phase delay 2650.00delta 2660.00gland 2670.00enhance 2680.00regulate survival 2690.007alpha 2700.00mouse 2710.00binding 2720.00essential 2730.00responsiveness 2740.00cyclic adenosine 5'-monophosphate 2750.00ischemia 2760.00hormone 2770.00acid synthesis 2780.00virus 2790.00mice 2800.00gamma 2810.00mammal 2820.00biosynthesis 2830.00induction 2840.00site 2850.00pathway 2860.00control 2870.00calcium 2880.00subcutaneous 2890.00mediated 2900.00acid expression 2910.00light 2920.00development 2930.00factor regulated 2940.00brain 2950.00implantation 2960.00multiple mechanism 2970.00level 2980.00synthesis 2990.00specific regulation 3000.00hormone induce 3010.00basis 3020.00early development 3030.00mechanism regulating 3040.00tissue correlation 3050.00daily 3060.00age 3070.00peripheral 3080.00absence 3090.00period 3100.00interaction 3110.00deficiency 3120.00adjacent 3130.00enzyme 3140.00difference 3150.00mechanism 3160.00treated 3170.00inducibility 3180.00factor 3190.00rat 3200.00light induced 3210.00two distinct 3220.00serum 3230.00attenuation 3240.00controlled gene 3250.00characterization peripheral 3260.00induced 3270.00acid 3280.00associated 3290.00body 3300.00alter 3310.00profile 3320.00representational 3330.00correlation 3340.00underlying 3350.00two 3360.00function 3370.00activator human 3380.005'-monophosphate 3390.00system level 3400.00suggest a 3410.00negative control 3420.00associated induction 3430.00delay 3440.00correlation age 3450.00system 3460.00characterization 3470.00amplitude 3480.00rapid 3490.00controlling 3500.00definition 3510.00retained 3520.00suggest 3530.00shocked 3540.00oscillation 3550.00interval 3560.00circuit 3570.00factor role 3580.00function early 3590.00following Restrict by semantic categories? 发现新的知识单元和研究主题，可以作为科研选题的重要参考。 job id # 24532 started Tue Sep 15 03:36:31 2009 Max_citations: 50000 Stoplist: /var/www/html/arrowsmith_uic/data/stopwords_pubmed Ngram_max: 3 24532 Search ARROWSMITH A A_query_raw: E4bp4 Tue Sep 15 03:36:44 2009 A query = E4bp4 started Tue Sep 15 03:36:45 2009 A query resulted in 54 titles 24532 Search ARROWSMITH C C_query_raw: cancer Tue Sep 15 03:36:59 2009 C: cancer 2301845 A: pubmed_query_A 54 AC: ( E4bp4 ) AND ( cancer ) 10 C query = cancer started Tue Sep 15 03:36:59 2009 C query resulted in 50000 titles A AND C query resulted in 10 titles 359 B-terms ready on Tue Sep 15 03:38:08 2009 Viewed B-terms Tue Sep 15 03:40:37 2009 hepatitis b virus Viewed B-terms Tue Sep 15 03:41:15 2009 mapk B-list on Tue Sep 15 03:41:52 2009 1 mapk 2 bcl xl 3 yy1 4 hepatitis b virus 5 expression analysis 6 kinase signaling 7 genome wide 8 gene promoter 9 circadian gene 10 transcriptional repression 11 bcl 12 hepg2 cell 13 topoisomerase 14 clock gene 15 nuclear receptor 16 expression profile 17 transcription factor 18 body mass index 与（E4bp4、 cancer）的研究报道见后，科研人员可能从中获得科研信息、得到启发，进行选题研究。 19 topoisomerase i 20 transcriptional repressor 21 transcriptional 22 bzip 23 calcineurin 24 regulate transcription 25 nuclear factor 26 gata 27 molecular cloning 28 cyp3a4 29 gata-1 30 genome wide expression 31 cdna 32 hepatitis b 33 controlled tumor protein 34 translationally controlled tumor 35 factor expression 36 protein kinase signaling 37 igh 38 pai-1 39 protein protein interaction 40 hepg2 41 nf 42 body mass 43 enhancer 44 repression 45 zebrafish 46 repressor 47 signal pathway 48 adenovirus 49 protein kinase 50 na h exchanger 51 circadian clock 52 activated t cell 53 casein kinase 54 promoter 55 xl 56 gene regulation 57 activated t 58 calcineurin nuclear factor 59 clock 60 transcription 61 ras 62 expression gene 63 nih3t3 cell 64 hematopoietic cell 65 ba f3 66 analysis reveal 67 gata factor 68 gene expression 69 calmodulin 70 hematopoietic 71 t cell 72 rev 73 na h 74 cell survival 75 endothelin 76 activation nuclear factor 77 interleukin 78 genome 79 potential transcriptional 80 novel mechanism 81 down regulate 82 prion 83 domain 84 expression analysis reveal 85 molecular cloning characterization 86 mass index 87 dependent protein kinase 88 b virus enhancer 89 cloning characterization 90 interleukin-4 91 receptor rev 92 growth survival 93 expression cell 94 protein protein 95 family member 96 b cell 97 osteoblast 98 regulator 99 cell specific 100 uterine 101 kinase 102 b lymphocyte 103 parathyroid 104 nuclear factor activated 105 dependent protein 106 activator 107 protein interaction 108 phosphorylation 109 nih3t3 110 expression cell survival 111 mrna 112 protein gene 113 expression calcineurin 114 reperfusion 115 pivotal 116 expressed gene 117 pivotal role 118 melatonin 119 pineal gland 120 expression adenovirus 121 parathyroid hormone 122 survival murine 123 protein gene expression 124 pineal 125 mediated phosphorylation 126 control circadian clock 127 expression topoisomerase 128 survival 129 pro 130 exhibit 131 exchanger 132 nuclear 133 bile acid 134 gene 135 gene a 136 cloning 137 factor activated t 138 age body mass 139 translationally 140 activation nuclear 141 tumor protein 142 cell line 143 regulatory 144 expression 145 calcium dependent activation 146 controlled 147 virus gene 148 gene regulation glucocorticoid 149 characterization human 150 molecular 151 mrna encoding 152 adipose tissue 153 wide 154 period2 155 cluster 156 cell identified 157 circadian 158 glucocorticoid 159 ischemia reperfusion 160 embryonic 161 hepatitis 162 adrenal gland 163 gene expression mouse 164 adipose 165 novel 166 na 167 bile 168 regulatory protein 169 b cell specific 170 hepatic 171 identification 172 activation 173 expressed 174 hormone induced 175 growth 176 regulation 177 hydroxylase 178 rat heart 179 mass 180 potential 181 negative transcription 182 core 183 negative 184 von willebrand 185 signal 186 phosphorylated 187 key 188 tumor 189 index 190 mouse liver 191 liver 192 protein 193 molecular mechanism 194 phase 195 signaling 196 f3 197 mouse brain 198 murine 199 line 200 specific 201 adrenal 202 minimal 203 receptor 204 regulated 205 rhythm 206 multiple 207 messenger 208 cholesterol 209 lymphocyte 210 3-mediated 211 diet 212 key enzyme 213 cis 214 element 215 expression mouse 216 autonomous 217 member 218 regulate 219 binding protein 220 early 221 related 222 motif 223 embryo 224 mammalian 225 cell 226 cell calcium 227 drive 228 reveal 229 dependent 230 protein human 231 binding site 232 ontogeny 233 response 234 family 235 high 236 adenosine 237 tissue 238 intrinsic 239 antagonistic 240 human 241 heart 242 dependent activation 243 molecular basis 244 analysis 245 encoding 246 promote 247 alter gene expression 248 chicken 249 down 250 cyclic 251 activated 252 role 253 viability 254 regulating 255 identified 256 distinct 257 par 258 induce 259 von 260 survival gene 261 gene mouse 262 ovine 263 rhythmic 264 phase delay 265 delta 266 gland 267 enhance 268 regulate survival 269 7alpha 270 mouse 271 binding 272 essential 273 responsiveness 274 cyclic adenosine 5'-monophosphate 275 ischemia 276 hormone 277 acid synthesis 278 virus 279 mice 280 gamma 281 mammal 282 biosynthesis 283 induction 284 site 285 pathway 286 control 287 calcium 288 subcutaneous 289 mediated 290 acid expression 291 light 292 development 293 factor regulated 294 brain 295 implantation 296 multiple mechanism 297 level 298 synthesis 299 specific regulation 300 hormone induce 301 basis 302 early development 303 mechanism regulating 304 tissue correlation 305 daily 306 age 307 peripheral 308 absence 309 period 310 interaction 311 deficiency 312 adjacent 313 enzyme 314 difference 315 mechanism 316 treated 317 inducibility 318 factor 319 rat 320 light induced 321 two distinct 322 serum 323 attenuation 324 controlled gene 325 characterization peripheral 326 induced 327 acid 328 associated 329 body 330 alter 331 profile 332 representational 333 correlation 334 underlying 335 two 336 function 337 activator human 338 5'-monophosphate 339 system level 340 suggest a 341 negative control 342 associated induction 343 delay 344 correlation age 345 system 346 characterization 347 amplitude 348 rapid 349 controlling 350 definition 351 retained 352 suggest 353 shocked 354 oscillation 355 interval 356 circuit 357 factor role 358 function early 359 following Start A-Literature C-Literature B-list Filter Literature AB literature B-term BC literature E4bp4 body mass index cancer 1: Expression profile of mRNAs encoding core circadian regulatory proteins in human subcutaneous adipose tissue: correlation with age and body mass index .2009 Add to clipboard 1: Impact of body mass index on clinical and cost outcomes after radical cystectomy.2009 Add to clipboard 2: Body mass index as a prognostic marker for biochemical recurrence in Dutch men treated with radical prostatectomy.2009 Add to clipboard 3: The effect of preoperative weight loss and body mass index on postoperative outcome in patients with esophagogastric carcinoma.2009 Add to clipboard 4: Increase in body mass index category since age 20 years and all-cause mortality: a prospective cohort study (the Ohsaki Study).2009 Add to clipboard 5: Impact of body mass index on colorectal cancer treatment and outcomes: need for prospective and comprehensive data.2009 Add to clipboard 6: Effect of body mass index on short-term outcomes after colectomy for cancer .2009 Add to clipboard 7: 2009 Add to clipboard 8: Effect of population trends in body mass index on prostate cancer incidence and mortality in the United States.2009 Add to clipboard 9: Perceived barriers to physical activity according to stage of change and body mass index in the west virginia wisewoman population.2009 Add to clipboard 10: Ovarian stimulation in polycystic ovary syndrome patients: the role of body mass index .2009 Add to clipboard 11: Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies.2009 Add to clipboard 12: Triple-negative breast cancer s are increased in black women regardless of age or body mass index .2009 Add to clipboard 13: Body Mass Index and Barrett's Oesophagus in Women.2009 Add to clipboard 14: Body mass index predicts insulin resistance in survivors of pediatric acute lymphoblastic leukemia.2009 Add to clipboard 15: Diabetes prevalence and body mass index differ by ethnicity: the Multiethnic Cohort.2009 Add to clipboard 16: The impact of a high body mass index on laparoscopy assisted gastrectomy for gastric cancer .2009 Add to clipboard 17: Correlation of body mass index and menopausal status with the intra-tumoral estrogen system in invasive breast cancer .2009 Add to clipboard 18: Self-perception and Body Image Associations with Body Mass Index among 8-10-year-old African American Girls.2009 Add to clipboard 19: Body mass index before and after breast cancer diagnosis: associations with all-cause, breast cancer , and cardiovascular disease mortality.2009 Add to clipboard 20: Association of diabetes and body mass index with levels of prostate-specific antigen: implications for correction of prostate-specific antigen cutoff values?2009 Add to clipboard 21: Effect of body mass index on the outcome of patients with rectal cancer receiving curative anterior resection: disparity between the upper and lower rectum.2009 Add to clipboard 22: The association between body mass index and Barrett's esophagus: a systematic review.2009 Add to clipboard 23: Role of educational level in the relationship between Body Mass Index (BMI) and health-related quality of life (HRQL) among rural Spanish women.2009 Add to clipboard 24: Body mass index in the evaluation of thyroid cancer risk.2009 Add to clipboard 25: Effect of body mass index and waist circumference on prostate specific antigen and prostate volume in a generally healthy Korean population.2009 Add to clipboard 26: Abdominal obesity and physical inactivity are associated with erectile dysfunction independent of body mass index .2009 Add to clipboard 27: Body mass index , height, and risk of lymphatic malignancies: a prospective cohort study.2009 Add to clipboard 28: Body mass index and breast cancer survival in relation to the introduction of mammographic screening.2009 Add to clipboard 29: Polycystic ovary syndrome, body mass index and outcomes of assisted reproductive technologies.2009 Add to clipboard 30: A cohort study of p27 localization in colon cancer , body mass index , and patient survival.2009 Add to clipboard 31: Influence of body mass index on operability, morbidity and disease outcome following radical cystectomy.2009 Add to clipboard 32: Temporal association of changes in fasting blood glucose and body mass index with diagnosis of pancreatic cancer .2009 Add to clipboard 33: A cohort study of STMN1 expression in colorectal cancer : body mass index and prognosis.2009 Add to clipboard 34: Body mass index is not a prognostic marker for prostate-specific antigen failure and survival in Dutch men treated with brachytherapy.2009 Add to clipboard 35: The role of pretreatment percutaneous endoscopic gastrostomy in facilitating therapy of head and neck cancer and optimizing the body mass index of the obese patient.2009 Add to clipboard 36: Body mass index and prostate specific antigen as predictors of adverse pathology and biochemical recurrence after prostatectomy.2009 Add to clipboard 37: A quantitative analysis of body mass index and colorectal cancer : findings from 56 observational studies.2009 Add to clipboard 38: Trends in esophageal cancer and body mass index by race and gender in the state of Michigan.2009 Add to clipboard 39: Body mass index and risk, age of onset, and survival in patients with pancreatic cancer .2009 Add to clipboard 40: Physical activity attenuates the body mass index -increasing influence of genetic variation in the FTO gene.2009 Add to clipboard 41: Body mass index and mortality from lung cancer in smokers and nonsmokers: a nationally representative prospective study of 220,000 men in China.2009 Add to clipboard 42: Liver transplantation at the extremes of the body mass index .2009 Add to clipboard 43: Incident Cancer Burden Attributable to Excess Body Mass Index in 30 European countries.2009 Add to clipboard 44: Body mass index , waist circumference and waist:hip ratio as predictors of cardiovascular risk-a review of the literature.2009 Add to clipboard 45: The dependency of vitamin D status on body mass index , gender, age and season.2009 Add to clipboard 46: Different Markers of Alcohol Consumption, Smoking and Body Mass Index in Relation to Risk of Pancreatic Cancer . A Prospective Cohort Study within the Malmo Preventive Project.2009 Add to clipboard 47: p21 expression in colon cancer and modifying effects of patient age and body mass index on prognosis.2009 Add to clipboard 48: 2009 Add to clipboard 49: The effect of body mass index on overall and disease-free survival in node-positive breast cancer patients treated with docetaxel and doxorubicin-containing adjuvant chemotherapy: the experience of the BIG 02-98 trial.2009 Add to clipboard
http://www.sciencenet.cn/htmlpaper/20099895997607248.shtm 发现老年痴呆症相关三个基因 英国和法国的研究人员发现了与阿尔茨海默症（俗称老年痴呆症）有关的3个基因。 据英国广播公司报道，这是16年来研究人员首次找到阿尔茨海默症与基因有关联的新证据。过去唯一找到的和一般老年痴呆症有关的基因APOE4一直是研究的焦点。 在最新的研究中，英法科学家对两万人的染色体样本进行了分析，发现了CR1、CLU和PICALM三个基因与阿尔茨海默症之间的关系。 报道称，CLU和PICALM基因都有保护大脑的功能。研究人员说，如果基因有变异，不仅可能失去保护大脑的功能，甚至保护者还有可能成为攻击者。 这项研究成果发表在最新出版的《自然遗传学》杂志上。它将促使科学家重新审视现在的有关阿尔茨海默症病因的理论。此外，研究成果还有助于医学界研发新的诊断、治疗手段。 英国阿尔茨海默研究基金会将这项新发现称为向前迈出了一大步。 据估计，全世界共有3000万阿尔茨海默症患者。而这一数字还将继续增长。 http://www.nature.com/ng/journal/vaop/ncurrent/abs/ng.440.html Nature Genetics Published online: 6 September 2009 | :10.1038/ng.440 :10.1038/ng.440 Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease Denise Harold 1 , 45 , Richard Abraham 1 , 45 , Paul Hollingworth 1 , 45 , Rebecca Sims 1 , Amy Gerrish 1 , Marian L Hamshere 1 , Jaspreet Singh Pahwa 1 , Valentina Moskvina 1 , Kimberley Dowzell 1 , Amy Williams 1 , Nicola Jones 1 , Charlene Thomas 1 , Alexandra Stretton 1 , Angharad R Morgan 1 , Simon Lovestone 2 , John Powell 3 , Petroula Proitsi 3 , Michelle K Lupton 3 , Carol Brayne 4 , David C Rubinsztein 5 , Michael Gill 6 , Brian Lawlor 6 , Aoibhinn Lynch 6 , Kevin Morgan 7 , Kristelle S Brown 7 , Peter A Passmore 8 , David Craig 8 , Bernadette McGuinness 8 , Stephen Todd 8 , Clive Holmes 9 , David Mann 10 , A David Smith 11 , Seth Love 12 , Patrick G Kehoe 12 , John Hardy 13 , Simon Mead 14 , Nick Fox 15 , Martin Rossor 15 , John Collinge 14 , Wolfgang Maier 16 , Frank Jessen 16 , Britta Schrmann 16 , Hendrik van den Bussche 17 , Isabella Heuser 18 , Johannes Kornhuber 19 , Jens Wiltfang 20 , Martin Dichgans 21 , 22 , Lutz Frlich 23 , Harald Hampel 24 , 25 , Michael Hll 26 , Dan Rujescu 25 , Alison M Goate 27 , John S K Kauwe 28 , Carlos Cruchaga 27 , Petra Nowotny 27 , John C Morris 27 , Kevin Mayo 27 , Kristel Sleegers 29 , 30 , Karolien Bettens 29 , 30 , Sebastiaan Engelborghs 30 , 31 , Peter P De Deyn 30 , 31 , Christine Van Broeckhoven 29 , 30 , Gill Livingston 32 , Nicholas J Bass 32 , Hugh Gurling 32 , Andrew McQuillin 32 , Rhian Gwilliam 33 , Panagiotis Deloukas 33 , Ammar Al-Chalabi 34 , Christopher E Shaw 34 , Magda Tsolaki 35 , Andrew B Singleton 36 , Rita Guerreiro 36 , Thomas W Mhleisen 37 , 38 , Markus M Nthen 37 , 38 , Susanne Moebus 39 , Karl-Heinz Jckel 39 , Norman Klopp 40 , H-Erich Wichmann 40 , 41 , 42 , Minerva M Carrasquillo 43 , V Shane Pankratz 44 , Steven G Younkin 43 , Peter A Holmans 1 , Michael O'Donovan 1 , Michael J Owen 1 Julie Williams 1 We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E ( APOE ) locus (most significant SNP, rs2075650, P = 1.8 10 -157 ) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ ) gene (rs11136000, P = 1.4 10 -9 ) and 5' to the PICALM gene (rs3851179, P = 1.9 10 -8 ). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 10 -10 , odds ratio = 0.86; rs3851179, P = 1.3 10 -9 , odds ratio = 0.86). Top of page Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK. National Institute for Health Research Biomedical Research Centre for Mental Health at the South London and Maudsley National Health Service Foundation Trust and Institute of Psychiatry, Kings College, London, UK. Department of Neuroscience, Institute of Psychiatry, Kings College, London, UK. Institute of Public Health, St. James Hospital and Trinity College, Dublin, Ireland. Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK. Mercer's Institute for Research on Aging, St. James Hospital and Trinity College, Dublin, Ireland. Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, UK. Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK. Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, UK. Clinical Neuroscience Research Group, Greater Manchester Neurosciences Centre, University of Manchester, Salford, UK. Oxford Project to Investigate Memory and Ageing, University of Oxford, John Radcliffe Hospital, Oxford, UK. Dementia Research Group, University of Bristol Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, UK. Department of Molecular Neuroscience and Reta Lilla Weston Laboratories, Institute of Neurology, London, UK. MRC Prion Unit, UCL Institute of Neurology, London, UK. Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK. Department of Psychiatry, University of Bonn, Bonn, Germany. Institute of Primary Medical Care, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Department of Psychiatry, Charit Berlin, Berlin, Germany. Department of Psychiatry and Psychotherapy, University of Erlangen-Nrnberg, Erlangen, Germany. Landschaftsverband Rheinland-Hospital Essen, Department of Psychiatry and Psychotherapy, University Duisburg-Essen, Essen, Germany. Institute for Stroke and Dementia Research, Klinikum der Universitt Mnchen, Munich, Germany. Department of Neurology, Klinikum der Universitt Mnchen, Munich, Germany. Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. Discipline of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience, Laboratory of Neuroimaging Biomarker Research, Trinity College, University of Dublin, Dublin, Ireland. Alzheimer Memorial Center and Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany. Centre for Geriatric Medicine and Section of Gerontopsychiatry and Neuropsychology, Medical School, University of Freiburg, Freiburg, Germany. Departments of Psychiatry, Neurology and Genetics, Washington University School of Medicine, St. Louis, Missouri, USA. Department of Biology, Brigham Young University, Provo, Utah, USA. Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium. Institute Born-Bunge and University of Antwerp, Antwerpen, Belgium. Memory Clinic and Department of Neurology, Ziekenhuis Netwerk Antwerpen Middelheim, Antwerpen, Belgium. Department of Mental Health Sciences, University College London, London, UK. The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. MRC Centre for Neurodegeneration Research, Department of Clinical Neuroscience, King's College London, Institute of Psychiatry, London, UK. Third Department of Neurology, Aristotle University of Thessaloniki, Thessaloniki, Greece. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. Department of Genomics, Life Brain Center, University of Bonn, Bonn, Germany. Institute of Human Genetics, University of Bonn, Bonn, Germany. Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany. Institute of Epidemiology, Helmholtz Zentrum Mnchen, German Research Center for Environmental Health, Neuherberg, Germany. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universitt, Munich, Germany. Klinikum Grosshadern, Munich, Germany. Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA. Division of Biomedical Statistics and Informatics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA. These authors contributed equally to this work. Correspondence to: Julie Williams 1 e-mail: williamsj@cardiff.ac.uk Correspondence to: Michael J Owen 1 e-mail: owenmj@cardiff.ac.uk 原文请见： Genome-wide association study identifies variants 信息分析平台： http://www.gopubmed.org/web/gopubmed/2?WEB016o3080s6rvr5I2fI1I00d000j10040001rl 相关文献计量分析结果（43 documents analyzed） Top Years Publications 2000 6 2005 5 1996 5 1994 4 1998 3 1995 3 1992 3 2006 2 2004 2 2002 2 1999 2 2009 1 2008 1 2001 1 1993 1 1991 1 1990 1 Top Countries Publications USA 26 Japan 6 Canada 3 Switzerland 2 Sweden 2 Spain 2 Austria 1 1 2 Top Cities Publications Los Angeles 8 New York 4 St. Louis 3 Tokyo 3 Gothenburg 2 Boston 2 Montreal 2 Lausanne 1 Minneapolis 1 Sun City 1 Graz 1 Majadahonda 1 Fukuoka 1 Cleveland 1 New Haven 1 San Francisco 1 Chicago 1 Kyoto 1 Geneva 1 Sapporo 1 1 2 1 2 Top Journals Publications J Biol Chem 3 Brain Res 3 Acta Neuropathol 3 Neurobiol Aging 2 P Natl Acad Sci Usa 2 Microsc Res Techniq 2 Ann Ny Acad Sci 2 Exp Neurol 2 Neurochem Int 1 Alz Dis Assoc Dis 1 Brain Pathol 1 Neurotox Res 1 Eur J Cell Biol 1 Subcell Biochem 1 J Mol Neurosci 1 Neurobiol Dis 1 J Gastrointest Surg 1 Am J Pathol 1 Brit J Ophthalmol 1 Nippon Ronen Igakkai Zasshi 1 1 2 1 2 3 ... 9 Top Authors Publications Finch C 7 Oda T 4 Johnson S 4 Pasinetti G 4 Ghiso J 3 Frangione B 3 Holtzman D 3 Matsubara E 3 Rozovsky I 3 Choi-Miura N 3 Blennow K 2 Davidsson P 2 Calero M 2 Rostagno A 2 Parsadanian M 2 Zlokovic B 2 Wisniewski K 2 Morgan T 2 Osterburg H 2 Poirier J 2 1 2 3 ... 9 1 2 3 ... 34 Top Terms Publications Alzheimer Disease 43 Clusterin 40 Humans 38 Glycoproteins 38 Molecular Chaperones 38 Proteins 28 Apolipoproteins 23 lipid transporter activity 23 Senile Plaques 19 Animals 18 Amyloid beta-Protein 18 Brain 16 Apolipoproteins E 16 Immunohistochemistry 15 Aged 14 Nerve Tissue Proteins 13 apolipoprotein j 13 Neurons 12 Peptides 12 clusterin 12 1 2 3 ... 34 Top Terms Publications apolipoprotein E receptor activity 12 Tissues 11 Mice 11 apoj 11 apolipoprotein E binding 10 Hippocampus 9 RNA, Messenger 9 apoe 9 pathogenesis 8 Patients 8 Aged, 80 and over 8 hippocampus development 7 Gene Expression 7 Genes 7 cerebrospinal fluid secretion 7 Antibodies 7 antigen binding 7 Neurites 7 neuron projection 7 apolipoprotein e 7 1 2 3 4 ... 34 Top Terms Publications Up-Regulation 6 Mice, Transgenic 6 Cerebrospinal Fluid 6 Peptide Fragments 6 Middle Aged 6 Blotting, Western 6 Brain Chemistry 6 Neurofibrillary Tangles 6 Lipoproteins 6 Astrocytes 6 Amyloid 6 Membranes 5 membrane 5 Rats 5 Enzyme-Linked Immunosorbent Assay 5 Neuroglia 5 Complement Membrane Attack Complex 5 catabolic process 5 Adult 5 Metabolism 5 1 2 3 4 5 ... 34 Top Terms Publications metabolic process 5 Antibodies, Monoclonal 5 Oxidative Stress 5 Oxides 5 Lipids 5 Cerebral Cortex 5 Amyloid beta-Protein Precursor 5 sgp-2 5 Serum 5 Sulfates 5 gene expression 4 Population Groups 4 Dementia 4 Complement System Proteins 4 Microscopy 4 Cells, Cultured 4 Alleles 4 Amino Acids 4 Base Sequence 4 Microglia 4 1 2 3 4 5 6 ... 34 知识发现平台： http://arrowsmith.psych.uic.edu/cgi-bin/arrowsmith_uic/edit_b.cgi?refresh=TID=4780 Start A-Literature C-Literature B-list Filter Literature A-query: Alzheimer Disease C-query: PICALM The B-list contains title words and phrases (terms) that appeared in both the A and the C literature. 1 articles appeared in both literatures and were not included in the process of computing the B-list but can be viewed here . The results of this search are saved under id # 4780 and can be accessed from the start page after you leave this session. There are 191 terms on the current B-list ( 20 are predicted to be relevant), which is shown ranked according to predicted relevance. The list can be further trimmed down using the filters listed in the left margin. To assess whether there appears to be a biologically significant relationship between the AB and BC literatures for specific B-terms, please select one or more B-terms and then click the button to view the corresponding AB and BC literatures. Use Ctrl to select multiple B-terms. Rank Prob B-term 10.99caspase 20.99clathrin assembly protein 30.99alternative splicing 40.99clathrin assembly 50.98ap180 60.97clathrin 70.97expression profiling 80.97gene expression profiling 90.94genome wide 100.93calpain 110.93protein ap180 120.85associated alzheimer disease 130.84wide association study 140.81cdna 150.76genome wide association 160.75clathrin mediated 170.74genetic susceptibility 180.73associated alzheimer 190.69upregulation 200.66overexpression 210.64association study 220.55endocytic 230.21mouse model 240.15ethnic difference 250.15protein family 260.10splicing 270.09nucleation 280.06hybridisation 290.06iron metabolism 300.04ethnic 310.04molecular signature 320.03association study identify 330.03alzheimer disease 340.02mutation 350.02alzheimer 360.02gene expression 370.01encoding a 380.01cleavage 390.01trafficking 400.00assembly 410.00endocytosis 420.00inositol 430.00coated pits 440.00encode a 450.00knee 460.00potential role 470.00genomic 480.00protein rat 490.00neuronal 500.00gene 510.0011q23 520.00gst 530.00signature 540.00subcellular localization 550.00chromosomal inversion 560.00expression 570.00genetic 580.00truncated 590.00molecular 600.00stem cell 610.00hematopoietic 620.00auditory 630.00event 640.00encoding 650.00family 660.00novel 670.00profiling 680.00susceptibility 690.00mouse 700.00chromosomal 710.00mice 720.00abnormality 730.00purification 740.00lymphoid 750.00variant 760.00role truncated 770.00potential 780.00cell free 790.00impact 800.00protein 810.00e coli 820.00osteoarthritis 830.00difference 840.00phospholipid 850.00member 860.00regulator 870.00stem 880.00inositol phospholipid 890.00model 900.00monocytic 910.00iron 920.00suggest a 930.00association 940.00structural organization 950.00functional 960.00inversion 970.00genome 980.00structural 990.00coli 1000.00nucleocytoplasmic 1010.00formation 1020.00fusion protein 1030.00regulatory 1040.00wild 1050.00mechanism 1060.00subtype 1070.00protein localization 1080.00cell line 1090.00suggest 1100.00leukemia 1110.00polypeptide 1120.00fusion 1130.00cat 1140.00calm 1150.00reveal 1160.00deletion 1170.00p2 1180.00binding 1190.00aberration 1200.00lattice 1210.00role 1220.00depletion 1230.00lymphoid myeloid 1240.00interactor 1250.00sex 1260.00fish 1270.00alternative 1280.00localization 1290.00expression functional 1300.00protein alter 1310.00disease 1320.00coat 1330.00neuropathy 1340.00line 1350.00interaction 1360.00expressed 1370.00metabolism 1380.00alter subcellular 1390.00subcellular 1400.00minor 1410.00identify 1420.00alter subcellular localization 1430.00alter 1440.00coexpression 1450.00comp 1460.00liver 1470.00organization 1480.00membrane 1490.00rare 1500.00wide 1510.00subtype specific 1520.00study 1530.00specific 1540.00myeloid 1550.00simultaneous 1560.00traffic 1570.00free 1580.00transformation 1590.00property 1600.00acute 1610.00involve 1620.00evidence 1630.00rat 1640.00conserved 1650.00regulatory mechanism 1660.00metabolism abnormality 1670.00reconstitution 1680.00comparative 1690.00lymphoma 1700.00cell 1710.00coated 1720.00responsible 1730.00characteristic a 1740.00multi 1750.00infant 1760.00child 1770.00purified 1780.00rat liver 1790.00effect 1800.00new 1810.00mediated 1820.00associated 1830.00suggest a potential 1840.00result 1850.00produced 1860.00rare event 1870.00characterisation 1880.00unusual 1890.00characteristic 1900.00influence 1910.00directing Restrict by semantic categories? 发现的新知识单元： job id # 4780 started Wed Sep 9 05:21:34 2009 Max_citations: 50000 Stoplist: /var/www/html/arrowsmith_uic/data/stopwords_pubmed Ngram_max: 3 4780 Search ARROWSMITH A A_query_raw: Alzheimer Disease Wed Sep 9 05:22:05 2009 A query = Alzheimer Disease started Wed Sep 9 05:22:05 2009 A query resulted in 50000 titles 4780 Search ARROWSMITH C C_query_raw: PICALM Wed Sep 9 05:22:18 2009 C: PICALM 27 A: pubmed_query_A 50928 AC: ( Alzheimer Disease ) AND ( PICALM ) 1 C query = PICALM started Wed Sep 9 05:22:18 2009 C query resulted in 27 titles A AND C query resulted in 1 titles 191 B-terms ready on Wed Sep 9 05:24:57 2009 B-list on Wed Sep 9 05:27:33 2009 1 caspase 2 clathrin assembly protein 3 alternative splicing 4 clathrin assembly 5 ap180 6 clathrin 7 expression profiling 8 gene expression profiling 9 genome wide 10 calpain 11 protein ap180 12 associated alzheimer disease 13 wide association study 14 cdna 15 genome wide association 16 clathrin mediated 17 genetic susceptibility 18 associated alzheimer 19 upregulation 20 overexpression 21 association study 22 endocytic 23 mouse model 24 ethnic difference 25 protein family 26 splicing 27 nucleation 28 hybridisation 29 iron metabolism 30 ethnic 31 molecular signature 32 association study identify 33 alzheimer disease 34 mutation 35 alzheimer 36 gene expression 37 encoding a 38 cleavage 39 trafficking 40 assembly 41 endocytosis 42 inositol 43 coated pits 44 encode a 45 knee 46 potential role 47 genomic 48 protein rat 49 neuronal 50 gene 51 11q23 52 gst 53 signature 54 subcellular localization 55 chromosomal inversion 56 expression 57 genetic 58 truncated 59 molecular 60 stem cell 61 hematopoietic 62 auditory 63 event 64 encoding 65 family 66 novel 67 profiling 68 susceptibility 69 mouse 70 chromosomal 71 mice 72 abnormality 73 purification 74 lymphoid 75 variant 76 role truncated 77 potential 78 cell free 79 impact 80 protein 81 e coli 82 osteoarthritis 83 difference 84 phospholipid 85 member 86 regulator 87 stem 88 inositol phospholipid 89 model 90 monocytic 91 iron 92 suggest a 93 association 94 structural organization 95 functional 96 inversion 97 genome 98 structural 99 coli 100 nucleocytoplasmic 101 formation 102 fusion protein 103 regulatory 104 wild 105 mechanism 106 subtype 107 protein localization 108 cell line 109 suggest 110 leukemia 111 polypeptide 112 fusion 113 cat 114 calm 115 reveal 116 deletion 117 p2 118 binding 119 aberration 120 lattice 121 role 122 depletion 123 lymphoid myeloid 124 interactor 125 sex 126 fish 127 alternative 128 localization 129 expression functional 130 protein alter 131 disease 132 coat 133 neuropathy 134 line 135 interaction 136 expressed 137 metabolism 138 alter subcellular 139 subcellular 140 minor 141 identify 142 alter subcellular localization 143 alter 144 coexpression 145 comp 146 liver 147 organization 148 membrane 149 rare 150 wide 151 subtype specific 152 study 153 specific 154 myeloid 155 simultaneous 156 traffic 157 free 158 transformation 159 property 160 acute 161 involve 162 evidence 163 rat 164 conserved 165 regulatory mechanism 166 metabolism abnormality 167 reconstitution 168 comparative 169 lymphoma 170 cell 171 coated 172 responsible 173 characteristic a 174 multi 175 infant 176 child 177 purified 178 rat liver 179 effect 180 new 181 mediated 182 associated 183 suggest a potential 184 result 185 produced 186 rare event 187 characterisation 188 unusual 189 characteristic 190 influence 191 directing 通过知识发现选择新的研究课题： 1. 老年痴呆症与白血病的研究 2. 白血病与 PICALM 基因的研究 Alzheimer Disease leukemia PICALM Start A-Literature C-Literature B-list Filter Literature AB literature B-term BC literature Alzheimer Disease leukemia PICALM 1: 2005 Add to clipboard 2: Chronic lymphocytic leukemia presenting with symptomatic central nervous system involvement.2002 Add to clipboard 3: Expression of the cytokine leukemia inhibitory factor and pro-apoptotic insulin-like growth factor binding protein-3 in Alzheimer's disease.2002 Add to clipboard 4: Immunohistochemistry and in situ hybridization of T-cell acute lymphoblastic leukemia -associated antigen 1 in human brain tissues.1999 Add to clipboard 5: Expression of adult T cell leukemia -derived factor in human brain and peripheral nerve tissues.1998 Add to clipboard 6: A monoclonal antibody to common acute lymphoblastic leukemia antigen (neutral endopeptidase) immunostains senile plaques in the brains of patients with Alzheimer's disease.1991 Add to clipboard 1: The CALM-AF10 fusion is a rare event in acute megakaryoblastic leukemia .2007 Add to clipboard 2: Acute monocytic leukemia with coexpression of minor BCR-ABL1 and PICALM -MLLT10 fusion genes along with overexpression of HOXA9.2006 Add to clipboard 3: Acute myeloid leukemia is propagated by a leukemic stem cell with lymphoid characteristics in a mouse model of CALM/AF10-positive leukemia .2006 Add to clipboard 4: Effect of clathrin assembly lymphoid myeloid leukemia protein depletion on clathrin coat formation.2005 Add to clipboard 5: A novel chromosomal inversion at 11q23 in infant acute myeloid leukemia fuses MLL to CALM, a gene that encodes a clathrin assembly protein.2003 Add to clipboard 6: Clathrin assembly lymphoid myeloid leukemia (CALM) protein: localization in endocytic-coated pits, interactions with clathrin, and the impact of overexpression on clathrin-mediated traffic.1999 Add to clipboard
免费期刊信息分析平台： http://www.scimagojr.com/aboutus.php 分析内容和方法可以参考博主的相关分析报告 The SCImago Journal Country Rank is a portal that includes the journals and country scientific indicators developed from the information contained in the Scopus database ( Elsevier B.V. ). These indicators can be used to assess and analyze scientific domains. This platform takes its name from the SCImago Journal Rank (SJR) indicator , developed by SCImago from the widely known algorithm Google PageRank . This indicator shows the visibility of the journals contained in the Scopus database from 1996. SCImago is a research group from the Consejo Superior de Investigaciones Cientficas (CSIC), University of Granada, Extremadura, Carlos III (Madrid) and Alcal de Henares, dedicated to information analysis, representation and retrieval by means of visualisation techniques. As well as SJR Portal, SCImago has developed The Atlas of Science project , which proposes the creation of an information system whose major aim is to achieve a graphic representation of IberoAmerican Science Research. Such representation is conceived as a collection of interactive maps, allowing navigation functions throughout the semantic spaces formed by the maps. Contact e-mail : scimagojr@scimago.es
http://www.sciencenet.cn/htmlnews/2009/9/223053.shtm 熊思东小组揭示抗乙肝病毒感染新机制 经过4年多的不懈努力，复旦大学免疫生物学研究所熊思东教授领衔的科研小组在研究乙型肝炎病毒感染人体固有免疫机制中，发现人体内的TRIM22分子在抗乙型肝炎病毒感染中有重要作用，这一研究成果已发表在最新一期的国际著名刊物《肝脏病学》（ Hepatology ）杂志上。 科研小组经无数次体内外试验证实，TRIM22分子对抑制乙型肝炎病毒复制、防止乙型肝炎发生意义重大。在进一步研究中发现，TRIM22可明显抑制乙型肝炎病毒核心启动子的活性，从而达到抑制病毒复制的目的，这一成果将对深入研究乙型肝炎病毒与机体免疫系统的相互作用，以及进一步阐明临床常用抗病毒药物的作用新机制产生重大和深远的影响，同时也将为新一代抗乙型肝炎病毒药物的设计和研制提供新的靶点和研究思路。 科学家新近研究发现，人体内普遍存在着一种TRIM22分子，但人们对它的作用和功能并不了解。熊思东率领的团队研究表明，这种新分子其实是一种对人体有益的固有免疫分子。有的人感染乙肝病毒后，能迅速激发体内固有免疫和特异免疫机制抑制病毒复制，清除乙肝病毒，从而痊愈，其中TRIM22分子起了重要作用；而另一部分人感染乙肝病毒后，因体内TRIM22分子不能适时有效发挥作用而导致乙肝病毒感染，并会进一步发展为慢性肝炎，甚至肝癌。 此外，目前干扰素是治疗慢性乙肝的有效药物之一，相关研究发现，干扰素可能就是通过激发TRIM22分子，抑制了乙肝病毒复制。研究成果首次揭示了人体抵抗乙肝病毒感染的重要固有免疫机制，对科学界继续研发新一代抗乙肝病毒感染药物有重要意义。 http://www3.interscience.wiley.com/journal/122306762/abstract?CRETRY=1SRETRY=0 Tripartite motif-containing 22 inhibits the activity of hepatitis B virus core promoter, which is dependent on nuclear-located RING domain Bo Gao 1 , Zhijian Duan 1 , Wei Xu 1 , Sidong Xiong 1 2 * 1 Institute for Immunobiology, Department of Immunology, Shanghai Medical College of Fudan University, People's Republic of China 2 Immunology Division, E-Institutes of Shanghai Universities, Shanghai, People's Republic of China email: Sidong Xiong ( sdxiongfd@126.com ) * Correspondence to Sidong Xiong, Institute for Immunobiology, Fudan University, 138 Yi Xue Yuan Road, Shanghai, 200032, China Potential conflict of interest: Nothing to report. These authors contributed equally to this work. fax: (86)21-54237749 setDOI("ADOI=10.1002/hep.23011") Funded by: National Natural Science Foundation of China; Grant Number: 30872355, 30890141 Major State Basic Research Development Program of China; Grant Number: 2007CB512401 Shanghai STCSM; Grant Number: 07QA14005, 08JC1401200 China 863; Grant Number: 2006AA02Z403 Program for Outstanding Medical Academic Leader; Grant Number: LJ06011 Abstract Members of the tripartite motif (TRIM) family are a part of the innate immune system to counter intracellular pathogens. TRIM22 has been reported to possess antiretroviral activity. Here we report that TRIM22 is involved in antiviral immunity against hepatitis B virus (HBV). Our results showed that TRIM22, being a strongly induced gene by interferons in human hepatoma HepG2 cells, could inhibit HBV gene expression and replication in a cell culture system as well as in a mouse model system. Importantly, it was found that TRIM22 could inhibit the activity of HBV core promoter (CP) in a dose-dependent manner. However, TRIM22 lacking the C terminal SPRY domain lost this activity. Further study showed that the SPRY domain deletion mutant was localized exclusively to the cytoplasm of HepG2 cells. In contrast, the wild-type TRIM22 was localized to the nucleus, as expected for a transcriptional suppressor. Interestingly, although RING domain mutants of TRIM22 were localized to the nucleus, they could not inhibit HBV CP activity, indicating that TRIM22-mediated anti-HBV activity was dependent on the nuclear-located RING domain. Conclusion: These findings suggest that TRIM22, which exhibits anti-HBV activity by acting as a transcriptional suppressor, may play an important role in the clearance of HBV. (H EPATOLOGY 2009.) Received: 23 November 2008; Accepted: 26 March 2009 信息分析平台： http://www.gopubmed.org/web/gopubmed/2?WEB01atvlf6qvocb2IeI1I00d000j100500001002000001200401011000606 相关文献计量分析：100 documents analyzed Top Countries Publications USA 30 China 22 Germany 11 South Korea 10 Taiwan 9 Japan 6 France 3 Singapore 3 Israel 2 Canada 1 Spain 1 United Kingdom 1 Switzerland 1 1 2 3 Top Cities Publications Taipei 9 Seoul 6 Shanghai 4 Beijing 4 Guangzhou 4 Wuhan 3 Singapur 3 Hamburg 3 Los Angeles 3 Providence 2 Boston 2 New Haven 2 Suita 2 Indianapolis 2 Daejeon 2 Hanover 2 Edmonton 1 Cologne 1 Montpellier 1 Rostock 1 1 2 3 1 2 3 Top Journals Publications J Virol 23 Virology 8 J Gen Virol 7 Hepatology 6 World J Gastroentero 4 J Biol Chem 3 J Viral Hepatitis 3 Biochem Biophys Res Commun 2 J Hepatol 2 Antivir Res 2 Zhonghua Gan Zang Bing Za Zhi 2 Di Yi Jun Yi Da Xue Xue Bao 2 Plos Pathog 1 Gastroenterology 1 J Biomed Sci 1 J Mol Biol 1 J Immunol 1 Febs Lett 1 Front Biosci 1 Int J Cancer 1 1 2 3 1 2 3 ... 25 Top Authors Publications McLachlan A 6 Raney A 4 Ou J 4 Chisari F 4 Guidotti L 4 Lee Y 3 Shih C 3 Chen S 3 Wands J 3 Will H 3 Rho H 3 Yang D 2 Lei Y 2 Tian Y 2 Wang B 2 Yang Y 2 Hao Y 2 Zhao X 2 Lu M 2 Gong F 2 1 2 3 ... 25 1 2 3 ... 57 Top Terms Publications Viruses 94 Hepatitis B virus 90 Hepatitis Viruses 89 Hepatitis 89 Hepatitis B 88 Herpesvirus 1, Cercopithecine 88 Humans 85 Proteins 65 Virus Replication 64 Genes 63 viral genome replication 57 Transfection 56 Cell Line 48 DNA 47 Gene Expression Regulation, Viral 42 Mutation 41 DNA, Viral 40 Antigens 39 Animals 39 gene expression 39 1 2 3 ... 57 1 2 Top Years Publications 2009 12 2008 9 2003 8 1996 8 2002 8 2006 7 2005 7 1999 6 2007 5 2001 5 2004 5 1992 4 1998 3 1995 2 1997 2 2000 2 1994 2 1993 1 1990 1 1987 1 1 2 原文请见： Hepatitis B Virus
http://www.nature.com/ncb/journal/v11/n9/abs/ncb1927.html Nature Cell Biology 11 , 1128 - 1134 (2009) Published online: 23 August 2009 | Corrected online: 28 August 2009 | :10.1038/ncb1927 :10.1038/ncb1927 Axin determines cell fate by controlling the p53 activation threshold after DNA damage Qinxi Li 1 , 2 , Shuyong Lin 1 , 2 , Xuan Wang 1 , 2 , Guili Lian 1 , Zailian Lu 1 , Huiling Guo 1 , Ka Ruan 1 , Yanhai Wang 1 , Zhiyun Ye 1 , Jiahuai Han 1 Sheng-Cai Lin 1 Top of page Cells can undergo either cell-cycle arrest or apoptosis after genotoxic stress, based on p53 activity 1, 2, 3, 4, 5, 6 . Here we show that cellular fate commitment depends on Axin forming distinct complexes with Pirh2, Tip60, HIPK2 and p53. In cells treated with sublethal doses of ultra-violet (UV) radiation or doxorubicin (Dox), Pirh2 abrogates Axin-induced p53 phosphorylation at Ser 46 catalysed by HIPK2, by competing with HIPK2 for binding to Axin. However, on lethal treatment, Tip60 interacts with Axin and abrogates Pirh2Axin binding, forming an AxinTip60HIPK2p53 complex that allows maximal p53 activation to trigger apoptosis. We also provide evidence that the ATM/ATR pathway mediates the AxinTip60 complex assembly. An axin mutation promotes carcinogenesis in Axin Fu /+ (Axin-Fused) mice, consistent with a dominant-negative role for Axin Fu in p53 activation. Thus, Axin is a critical determinant in p53-dependent tumour suppression in which Pirh2 and Tip60 have different roles in triggering cell-cycle arrest or apoptosis depending on the severity of genotoxic stress. Key Laboratory for Cell Biology and Tumor Cell Engineering of the Ministry of Education, School of Life Sciences, Xiamen University, Fujian 361005, China. These authors contributed equally to this work. Correspondence to: Sheng-Cai Lin 1 e-mail: linsc@xmu.edu.cn http://www.sciencenet.cn/htmlpaper/2009911030497507161.shtm 揭示细胞如何防止癌变内在机理 近日，厦门大学生命科学学院院长林圣彩教授课题组的一项研究成果揭示了细胞如何防止癌变的内在机理，被认为是癌症研究的一个新突破。 医学认为，癌变发生的一个很重要的原因是因为细胞基因组发生了突变，继而出现细胞生长和分裂的异常，并将有缺陷的遗传物质传递下去，直至癌组织的出现。 林圣彩教授课题组的一项研究表明，存在于细胞内的一种名为Axin的蛋白分子可以通过控制一种名为p53的抑癌基因的活性来决定细胞命运，这就意味着含有过度受损基因的细胞命运，可以通过二者特定的相互作用促使细胞进行死亡，从而避免个体发生癌变。这一发现可能为癌症治疗提供新的思路和途径。 这一最新研究成果8月23日刊登在国际著名学术期刊《自然细胞生物学》（ Nature Cell Biology ）上。该杂志系英国《自然》杂志的子刊。 据课题组成员、厦门大学生命科学学院副教授李勤喜介绍，林圣彩教授是细胞生物学与肿瘤细胞工程教育部重点实验室和福建省肿瘤生物学重点实验室主任，他领导的课题组长期致力于肿瘤细胞生物学的研究，并独家发现了Axin和p53之间的关系。 此前，课题组已经在国际著名学术期刊上发表了系列文章。 信息分析平台： http://www.gopubmed.org/web/gopubmed/2?WEB01cu9hfn72kx3jIgI1I00d000j10040001rl Increased Wnt signaling triggers oncogenic conversion of human breast epithelial cells by a Notch -dependent mechanism. PMID: 16501043 Related Articles Authors: Ayyanan, A , Civenni, G , Ciarloni, L , Morel, C , Mller, N , Lefort, K , Mandinova, A , Raffoul, W , Fiche, M , Dotto, G P , Brisken, C Journal: Proc Natl Acad Sci U S A , Vol. 103 (10): 3799-804 , 2006 Abstract: Wnt and Notch signaling have long been established as strongly oncogenic in the mouse mammary gland. Aberrant expression of several Wnts and other components of this pathway in human breast carcinomas has been reported, but evidence for a causative role in the human disease has been missing. Here we report that increased Wnt signaling, as achieved by ectopic expression of Wnt-1 , triggers the DNA damage response (DDR) and an ensuing cascade of events resulting in tumorigenic conversion of primary human mammary epithelial cells. Wnt-1 -transformed cells have high telomerase activity and compromised p53 and Rb function, grow as spheres in suspension, and in mice form tumors that closely resemble medullary carcinomas of the breast. Notch signaling is up-regulated through a mechanism involving increased expression of the Notch ligands Dll1 , Dll3 , and Dll4 and is required for expression of the tumorigenic phenotype. Increased Notch signaling in primary human mammary epithelial cells is sufficient to reproduce some aspects of Wnt -induced transformation. The relevance of these findings for human breast cancer is supported by the fact that expression of Wnt-1 and Wnt-4 and of established Wnt target genes, such as Axin -2 and Lef-1 , as well as the Notch ligands, such as Dll3 and Dll4 , is up-regulated in human breast carcinomas. Affiliation: Swiss Institute for Experimental Cancer Research, National Center of Competence in Research in Molecular Oncology, 155 Chemin des Boveresses, CH-1066 Epalinges/ Lausanne , Switzerland . Pubmed MeSH: Animals , Breast , Cell Transformation, Neoplastic , Cells, Cultured , Humans , Mice, Inbred C57BL , Mice, Knockout , RNA, Messenger , RNA, Neoplasm , Receptors, Notch , Signal Transduction , Wnt1 Protein 信息分析结果： Top Years Publications 2001 4 2006 3 2004 3 2002 3 2008 2 2007 2 2009 1 2000 1 Top Countries Publications China 5 USA 4 France 4 Switzerland 1 Japan 1 Israel 1 Germany 1 Taiwan 1 Sweden 1 Top Cities Publications Paris 4 Xiamen 3 Indianapolis 1 Ann Arbor 1 Lausanne 1 Kyoto 1 Munich 1 Taipei 1 Linkping 1 Salt Lake City 1 Top Journals Publications Oncogene 4 Int J Oncol 1 Prog Biophys Mol Bio 1 J Biol Chem 1 Cell Res 1 Cancer Res 1 Cell Signal 1 P Natl Acad Sci Usa 1 Embo J 1 Digestion 1 Hepatology 1 Gastroen Clin Biol 1 Mol Carcinogen 1 Mol Cell 1 Gastroenterology 1 Semin Cancer Biol 1 1 2 3 ... 6 Top Authors Publications Zucman-Rossi J 3 Laurent-Puig P 3 Lin S 2 Li Q 2 Rui Y 2 Ye Z 2 Bluteau O 2 Li Q 1 Zhang L 1 Ye J 1 Zhang F 1 Li F 1 Li H 1 Gu Y 1 Liu F 1 Chen G 1 Dunker A 1 Cortese M 1 Uversky V 1 Lin S 1 1 2 3 ... 6 1 2 3 ... 21 Top Terms Publications Humans 18 p53 16 Neoplasms 13 Proteins 13 Genes 12 axin 12 wnt 12 Signal Transduction 11 Mutation 11 Cytoskeletal Proteins 11 beta Catenin 11 Repressor Proteins 10 signal transduction 10 Genes, p53 10 Trans-Activators 10 Tumor Suppressor Protein p53 9 Animals 8 Phosphorylation 7 regulation of cell cycle 6 Apoptosis 6 1 2 3 ... 21 中国学者的研究成果： Title: Axin induces cell death and reduces cell proliferation in astrocytoma by activating the p53 pathway. PMID: 19513548 Related Articles Authors: Zhang, L , Ye, J , Zhang, F , Li, F , Li, H , Gu, Y , Liu, F , Chen, G , Li, Q Journal: Int J Oncol , Vol. 35 (1): 25-32 , 2009 Abstract: Astrocytic tumors are the most common brain tumors with various genetic defects. As a tumor suppressor gene, Axin could control cell death and growth. Axin possesses a separate domain that directly interacts with p53 and regulates the activity of p53 pathway. Our aims were to elucidate the effects of Axin on the progression of astrocytoma. We examined the expression of Axin in 96 cases of astrocytoma using immunohistochemistry. The apoptotic index, proliferactive acitivity and the expression levels of p53 and its downstream genes, p21 and Cyclin D1 , were evaluated in the C6 astrocytoma cells with overexpression or silencing of Axin . The results showed the levels of Axin correlated significantly inversely with the grades of astrocytoma (R=-0.286, P0.05) and correlated negatively with Ki-67 labeling index (R=-0.227, P0.05). Overexpression of Axin in C6 cells induces cell death, and reduces the cell proliferation, up-regulates the expression of p53 . Silencing of Axin reduces p53 expression. The p53 inhibitor, pifithrin-alpha, was able to counteract the effect of Axin in C6 cells. Our data demonstrate that the expression of Axin is associated negatively with the progression of astrocytoma. In conclusion, Axin induces cell death and reduces cell proliferation, partially by activating the p53 pathway in astrocytoma cells. This knowledge is helpful in understanding the role of Axin in the progression of astrocytoma. Affiliation: State Key Laboratory of Cancer Biology and Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, P.R. China . Pubmed MeSH: Adolescent , Adult , Aged , Animals , Apoptosis , Benzothiazoles , Cell Line, Tumor , Child , Child, Preschool , Cyclin D1 , Cyclin-Dependent Kinase Inhibitor p21 , Glioblastoma , Humans , Middle Aged , Neoplasm Staging , RNA Interference , Rats , Repressor Proteins , Reverse Transcriptase Polymerase Chain Reaction , Time Factors , Toluene , Transfection , Tumor Suppressor Protein p53 Wikipedia: Antioncogene , Astrocyte , Astrocytoma , Astroglia , Benign neoplasm , Brain Cancer , Brain Neoplasms , Brain Tumor , Cancer , Cell death , Cell proliferation , Cistron , Critique , Cyclin , EpistemOlogy , Evaluation , Evaluation research , Gene , Genes, tumor suppressor , Genetic material , Helper T-cell , Helper T cells , Helper cell , Immunocytochemistry , Immunohistochemistry , Juvenile Pilocytic Astrocytoma , KnowLedge , Metastasis suppressor gene , Neoplasm , Pilocytic astrocytoma , Suppressor gene , T-lymphocytes, helper-inducer , Tumor , Tumor suppressor gene , Up-regulation , Upregulation Title: Protein encoded by the Axin ( Fu ) allele effectively down-regulates Wnt signaling but exerts a dominant negative effect on c-Jun N-terminal kinase signaling. PMID: 18316368 Related Articles Authors: Lu, Z , Liu, W , Huang, H , He, Y , Han, Y , Rui, Y , Wang, Y , Li, Q , Ruan, K , Ye, Z , Low, B C , Meng, A , Lin, S Journal: J Biol Chem , Vol. 283 (19): 13132-9 , 2008 Abstract: Axin plays an architectural role in many important signaling pathways that control various aspects of development and tumorigenesis, including the Wnt , transforming growth factor-beta, MAP kinase pathways, as well as p53 activation cascades. It is encoded by the mouse Fused (Fu) locus; the Axin (Fu) allele is caused by insertion of an IAP transposon. Axin (Fu/Fu) mice display varying phenotypes ranging from embryonic lethality to relatively normal adulthood with kinky tails. However, the protein product(s) has not been identified or characterized. In the present study, we conducted immunoprecipitation using brain extracts from the Axin (Fu) mice with specific antibodies against different regions of Axin and found that a truncated Axin containing amino acids 1-596 (designated as Axin (Fu- NT )) and the full-length complement of Axin ( Axin (WT)) can both be generated from the Axin (Fu) allele. When tested for functionality changes, Axin (Fu-NT) was found to abolish Axin -mediated activation of JNK , which plays a critical role in dorsoventral patterning. Together with a proteomics approach, we found that Axin (Fu- NT ) contains a previously uncharacterized dimerization domain and can form a heterodimeric interaction with Axin (WT). The Axin (Fu-NT)/ Axin (WT) is not conducive to JNK activation, providing a molecular explanation for the dominant negative effect of Axin (Fu- NT ) on JNK activation by wild-type Axin . Importantly, Axin (Fu-NT) exhibits no difference in the inhibition of Wnt signaling compared with Axin (WT) as determined by reporter gene assays, interaction with key Wnt regulators, and expression of Wnt marker genes in zebrafish embryos, suggesting that altered JNK signaling contributes, at least in part, to the developmental defects seen in Axin (Fu) mice. Affiliation: School of Life Sciences, Xiamen University, Xiamen , Fujian 361005, China . Pubmed MeSH: Animals , Cell Line , Enzyme Activation , Humans , Mice, Transgenic , Mutation , Repressor Proteins , Signal Transduction , Wnt Proteins Wikipedia: Allele , Allelomorph , Amino Acids , Antibodies , Brachydanio rerio , C-Jun N-terminal kinase , Cistron , Co-immunoprecipitation , Danio rerio , Dimerization , Down-regulation , Downregulation , Gene , Genetic material , House Mouse , House mice , Immunoprecipitation , Kinase , Laboratory mice , Laboratory mouse , Mice , Mouse , Mus , Mus domesticus , Mus musculus , Mus musculus domesticus , Phenotype , Phosphotransferases , Proteins , Proteome , Proteomics , Receptor down-regulation , Reporter gene , Zebra Danio , Zebra Fish , Zebrafish Title: Axin bridges Daxx to p53 . PMID: 17404597 Related Articles Authors: Lin, S C , Li, Q Journal: Cell Res , Vol. 17 (4): 301-2 , 2007 No abstract given. Affiliation: Key Laboratory of Ministry of Education for Cell Biology and Tumor Cell Engineering, Xiamen University, Xiamen 361005, China . linsc@xmu.edu.cn Pubmed MeSH: Active Transport, Cell Nucleus , Adaptor Proteins, Signal Transducing , Animals , Apoptosis , Carrier Proteins , Cell Nucleus , Humans , Intracellular Signaling Peptides and Proteins , Mice , Mice, Knockout , Nuclear Proteins , Phosphorylation , Protein Binding , Protein-Serine-Threonine Kinases , Repressor Proteins , Signal Transduction , Tumor Suppressor Protein p53 Title: Daxx cooperates with the Axin / HIPK2 / p53 complex to induce cell death. PMID: 17210684 Related Articles Authors: Li, Q , Wang, X , Wu, X , Rui, Y , Liu, W , Wang, J , Wang, Xinghao , Liou, Y C , Ye, Z D , Lin, S C Journal: Cancer Res , Vol. 67 (1): 66-74 , 2007 Abstract: Daxx, a death domain-associated protein, has been implicated in proapoptosis, antiapoptosis, and transcriptional regulation. Many factors known to play critically important roles in controlling apoptosis and gene transcription have been shown to associate with Daxx , including the Ser/Thr protein kinase HIPK2 , promyelocytic leukemia protein, histone deacetylases, and the chromatin remodeling protein ATRX . Although it is clear that Daxx may exert multiple functions, the underlying mechanisms remain far from clear. Here, we show that Axin , originally identified for its scaffolding role to control beta-catenin levels in Wnt signaling, strongly associates with Daxx at endogenous levels. The Daxx / Axin complex formation is enhanced by UV irradiation. Axin tethers Daxx to the tumor suppressor p53 , and cooperates with Daxx , but not DaxxDeltaAxin, which is unable to interact with Axin , to stimulate HIPK2 -mediated Ser(46) phosphorylation and transcriptional activity of p53 . Interestingly, Axin and Daxx seem to selectively activate p53 target genes, with strong activation of PUMA , but not p21 or Bax . Daxx -stimulated p53 transcriptional activity was significantly diminished by small interfering RNA against Axin ; Daxx fails to inhibit colony formation in Axin (-/-) cells. Moreover, UV-induced cell death was attenuated by the knockdown of Axin and Daxx . All these results show that Daxx cooperates with Axin to stimulate p53 , and implicate a direct role for Axin , HIPK2 , and p53 in the proapoptotic function of Daxx . We have hence unraveled a novel aspect of p53 activation and shed new light on the ultimate understanding of the Daxx protein, perhaps most pertinently, in relation to stress-induced cell death. Affiliation: Key Laboratory of Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Fujian 361005, China . Pubmed MeSH: Adaptor Proteins, Signal Transducing , Carrier Proteins , Cell Line, Tumor , Cell Nucleus , Cytochromes c , Hela Cells , Humans , Nuclear Proteins , Protein-Serine-Threonine Kinases , Repressor Proteins , Tumor Suppressor Protein p53 , Ultraviolet Rays Wikipedia: Apoptosis , Benign neoplasm , Cancer , Cell death , Chromatin , Cistron , Gene , Genes, p53 , Genetic material , Granulocyte precursor cells , Helper T-cell , Helper T cells , Helper cell , Histone , Histone H1 , Histone H3 , Histone H4 , Histone H5 , Histone deacetylase , Kinase , Leukemia , Metamyelocyte , Myeloblast , Myelocyte , Neoplasm , Phosphorylation , Phosphotransferases , Piwi-interacting RNA , Promyelocyte , Protein Kinase , Protein kinases , Proteins , RNA , RiboNucleic Acid , Sirna , Small interfering RNA , T-lymphocytes, helper-inducer , TP53 gene , Transactivation , Tumor Title: Axin stimulates p53 functions by activation of HIPK2 kinase through multimeric complex formation. PMID: 15526030 Related Articles Authors: Rui, Y , Xu, Z , Lin, S C , Li, Q , Rui, H L , Luo, W J , Zhou, H M , Cheung, P Y , Wu, Z , Ye, Z D , Li, P , Han, J , Lin, Sheng-Cai Journal: EMBO J , Vol. 23 (23): 4583-94 , 2004 Abstract: Axin and p53 are tumor suppressors, controlling cell growth, apoptosis, and development. We show that Axin interacts with homeodomain-interacting protein kinase-2 ( HIPK2 ), which is linked to UV-induced p53 -dependent apoptosis by interacting with, and phosphorylating Ser 46 of, p53 . In addition to association with p53 via HIPK2 , Axin contains a separate domain that directly interacts with p53 at their physiological concentrations. Axin stimulates p53 -dependent reporter transcription in 293 cells, but not in 293T, H1299, or SaOS-2 cells that are defective in p53 signaling. Axin , but not AxindeltaHIPK2, activates HIPK2 -mediated p53 phosphorylation at Ser 46, facilitating p53 -dependent transcriptional activity and apoptosis. Specific knockdown of Axin by siRNA reduced UV-induced Ser-46 phosphorylation and apoptosis. Kinase-dead HIPK2 reduced Axin -induced p53 -dependent transcriptional activity, indicating that Axin stimulates p53 function through HIPK2 kinase activity. Interestingly, HIPK2deltaAxin that lacks its Axin -binding region acts as a dominant-positive form in p53 activation, suggesting that the Axin -binding region of HIPK2 is a putative autoinhibitory domain. These results show that Axin acts as a tumor suppressor by facilitating p53 function through integration of multiple factors. Affiliation: Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China . Pubmed MeSH: Carrier Proteins , Cell Line, Tumor , Enzyme Activation , Genes, Reporter , Humans , Mutation , Protein Binding , Protein-Serine-Threonine Kinases , Repressor Proteins , Serine , Transcription, Genetic , Tumor Suppressor Protein p53 , Ultraviolet Rays Wikipedia: Apoptosis , Benign neoplasm , Cancer , Kinase , Neoplasm , Phosphorylation , Phosphotransferases , Piwi-interacting RNA , Proteins , Sirna , Small interfering RNA , Transactivation , Tumor
http://www.sciencenet.cn/htmlpaper/20098311584937150.shtm 神经元轴突发育研究取得新成果 2009年8月26日，《美国科学院院刊》（PNAS）在线发表了神经科学研究所周嘉伟研究组的最新研究成果 - MSC p43 Required for Axonal Development in Motor Neurons，这项工作主要是由该研究组的朱孝东、刘洋、尹延青等人共同完成。 人和动物肢体运动的控制离不开脊髓运动神经元的参与，但是目前对于脊髓运动神经元发育的分子机制并未完全了解。研究发现，蛋白翻译合成过程所需的氨基酰tRNA合成酶复合物的一个辅助因子MSC p43在脊髓运动神经元轴突发育过程中发挥了关键作用。MSC p43蛋白与神经中间丝蛋白neurofilament（一类神经元特异的细胞骨架蛋白）的轻链NF-L之间存在直接相互作用: MSC p43基因敲除后，小鼠神经元neurofilament 的组装发生明显障碍，脊髓运动神经元轴突发育显著迟缓，在整体动物行为上表现为运动能力的下降，表明MSC p43蛋白对轴突发育必不可少。进一步观察发现，MSC p43蛋白参与神经元轴突发育过程中所必需的neurofilament蛋白磷酸化正常水平的维持。这些发现揭示了MSC p43在神经系统的新功能，有助于理解轴突发育及其调节过程，同时，p43缺失所致功能异常可帮助进一步研究脊髓运动神经元轴突退行性病变的分子机理。 http://www.pnas.org/content/early/2009/08/25/0901872106.abstract?sid=1a75f30b-5d56-4a62-9052-ad9e8530850f MSC p43 required for axonal development in motor neurons Xiaodong Zhu a , b , Yang Liu b , Yanqing Yin b , Aiyun Shao b , Bo Zhang b , Sunghoon Kim c and Jiawei Zhou b , 1 + Author Affiliations a Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, and b State Key Laboratory of Neuroscience Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; and c Center for Medicinal Protein Network and Systems Biology, College of Pharmacy, Seoul National University, Seoul 151-742, Korea Edited by Paul R. Schimmel, The Scripps Research Institute, La Jolla, CA, and approved July 28, 2009 (received for review March 4, 2009) Abstract Neuron connectivity and correct neural function largely depend on axonal integrity. Neurofilaments (NFs) constitute the main cytoskeletal network maintaining the structural integrity of neurons and exhibit dynamic changes during axonal and dendritic growth. However, the mechanisms underlying axonal development and maintenance remain poorly understood. Here, we identify that multisynthetase complex p43 (MSC p43) is essential for NF assembly and axon maintenance. The MSC p43 protein was predominantly expressed in central neurons and interacted with NF light subunit in vivo. Mice lacking MSC p43 exhibited axon degeneration in motor neurons, defective neuromuscular junctions, muscular atrophy, and motor dysfunction. Furthermore, MSC p43 depletion in mice caused disorganization of the axonal NF network. Mechanistically, MSC p43 is required for maintaining normal phosphorylation levels of NFs. Thus, MSC p43 is indispensable in maintaining axonal integrity. Its dysfunction may underlie the NF disorganization and axon degeneration associated with motor neuron degenerative diseases. assembly axon degeneration multisynthetase complex neurofilament 信息分析平台： http://www.gopubmed.org/web/gopubmed/2?WEB0qd28zkk7waahI11I1I00d000j10040001rl 信息分析结果： 1 2 Top Countries Publications USA 292 United Kingdom 57 Japan 42 Germany 35 France 35 Canada 29 Australia 25 Spain 18 Switzerland 16 Sweden 12 Italy 10 Netherlands 8 Taiwan 5 Norway 4 Belgium 3 China 3 Puerto Rico 3 Argentina 2 Poland 2 Austria 2 1 2 1 2 3 ... 11 Top Cities Publications London 35 New York 20 St. Louis 16 Paris 15 Philadelphia 14 San Diego 14 Bethesda 10 Los Angeles 10 Eugene 9 Pittsburgh 9 Montreal 8 Marseilles 8 Hamburg 7 Milan 7 Boston 7 Cleveland 7 Stanford 7 Cambridge, USA 7 Stockholm 7 Tokyo 6 1 2 3 ... 11 1 2 3 ... 10 Top Journals Publications J Comp Neurol 62 J Neurosci 57 Development 35 Neuron 23 Dev Biol 22 J Neurobiol 22 Brain Res 20 Exp Neurol 18 Neuroscience 18 J Neurosci Res 15 Eur J Neurosci 14 J Neurochem 12 Dev Brain Res 12 P Natl Acad Sci Usa 9 Nature 8 J Cell Biol 8 J Neuropath Exp Neur 8 Exp Brain Res 8 J Neurocytol 8 Acta Neuropathol 8 1 2 3 ... 10 1 2 3 ... 214 Top Terms Publications Axons 652 axon 648 Animals 646 Neurons 533 Motor Neurons 498 Spinal Cord 261 Proteins 235 Rats 211 Muscles 207 Adult 196 Mice 183 Anxiety 153 Genes 149 Humans 135 Axonal Transport 132 axonogenesis 117 Immunohistochemistry 113 Wounds and Injuries 105 Nerve Tissue Proteins 102 central nervous system development 98 1 2 3 ... 214 1 2 3 ... 121 Top Authors Publications Eisen J 8 Oppenheim R 8 Snider W 7 Sendtner M 6 Goldstein L 6 Greensmith L 6 Lichtman J 6 Sanes J 6 Vrbova G 6 Granato M 5 Miranda J 5 Whittemore S 5 Henderson C 5 Cullheim S 5 Schachner M 4 Jessell T 4 Arber S 4 Kiernan M 4 Tetzlaff W 4 Figueroa J 4 1 2 3 ... 121 1 2 Top Years Publications 2008 43 2003 38 2004 37 2000 37 2001 35 2009 34 2006 34 2005 34 2002 33 1990 29 1999 28 1994 27 1998 26 2007 25 1992 24 1997 23 1996 21 1993 21 1995 20 1988 19 1 2
http://www.sciencenet.cn/htmlnews/2009/8/222801.shtm 据《自然》网站报道，线粒体DNA只会由母亲传给后代，因为精子中的线粒体并不向胚胎贡献DNA。线粒体DNA突变与许多疾病存在关联，比如Ⅱ型糖尿病、线粒体肌病以及Leigh综合症（常见于婴儿的神经退化性疾病）等。如今，一种在卵细胞间转移遗传物质的新技术有望被用来预防由线粒体DNA突变导致的遗传性疾病。 美国俄勒冈州国家灵长类动物研究中心的Shoukhrat Mitalipov及其小组以恒河猴为实验对象，将一个卵细胞中的核DNA移入另一个去核卵细胞中，之后进行授精并植入子宫。这样生下的后代将具有一个母体的线粒体DNA和另一个母体的核DNA。 共15个胚胎被植入9个代孕母体，3个成功怀孕，其中1个为双胞胎，共产下4个后代。这与人类中的试管授精成功率相当。相关论文报告8月26日在线发表于《自然》杂志。该论文共报告了其中的3个后代，目前没有发现异常状况。 线粒体疾病研究界对此研究感到鼓舞。澳大利亚墨尔本默多克儿童研究所专攻线粒体疾病的遗传学家David Thorburn表示，该研究屏除了所有携带致病突变的线粒体DNA，而且是在灵长类动物中完成的，这使得该研究具有高度的创新意义，非常有前途，它应该能够比小鼠更近地模拟人类状况，如果能在人体中证明安全，将是一个巨大的进步。美国联合线粒体疾病基金会科学与医学顾问委员会成员、迈阿密大学细胞生物学家Carlos Moraes说：（这类）研究需要成本，也存在风险，但获益大于弊端。 http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature08368.html Nature advance online publication 26 August 2009 | :10.1038/nature08368 :10.1038/nature08368 ; Received 29 June 2009; Accepted 10 August 2009; Published online 26 August 2009 Mitochondrial gene replacement in primate offspring and embryonic stem cells Masahito Tachibana 1 , Michelle Sparman 1 , Hathaitip Sritanaudomchai 1 , Hong Ma 1 , Lisa Clepper 1 , Joy Woodward 1 , Ying Li 1 , Cathy Ramsey 1 , Olena Kolotushkina 1 Shoukhrat Mitalipov 1 , 2 , 3 Oregon National Primate Research Center, Oregon Stem Cell Center and, Departments of Obstetrics and Gynecology and Molecular and Medical Genetics, Oregon Health and Science University, 505 N.W. 185 th Avenue, Beaverton, Oregon 97006, USA Correspondence to: Shoukhrat Mitalipov 1 , 2 , 3 Correspondence and requests for materials should be addressed to S.M. (Email: mitalipo@ohsu.edu ). Top of page Abstract Mitochondria are found in all eukaryotic cells and contain their own genome (mitochondrial DNA or mtDNA). Unlike the nuclear genome, which is derived from both the egg and sperm at fertilization, the mtDNA in the embryo is derived almost exclusively from the egg; that is, it is of maternal origin. Mutations in mtDNA contribute to a diverse range of currently incurable human diseases and disorders. To establish preclinical models for new therapeutic approaches, we demonstrate here that the mitochondrial genome can be efficiently replaced in mature non-human primate oocytes ( Macaca mulatta ) by spindlechromosomal complex transfer from one egg to an enucleated, mitochondrial-replete egg. The reconstructed oocytes with the mitochondrial replacement were capable of supporting normal fertilization, embryo development and produced healthy offspring. Genetic analysis confirmed that nuclear DNA in the three infants born so far originated from the spindle donors whereas mtDNA came from the cytoplast donors. No contribution of spindle donor mtDNA was detected in offspring. Spindle replacement is shown here as an efficient protocol replacing the full complement of mitochondria in newly generated embryonic stem cell lines. This approach may offer a reproductive option to prevent mtDNA disease transmission in affected families. 信息分析平台： http://www.gopubmed.org/web/gopubmed/ 检索策略：lMitochondrial DNA mutation and primate and mtDNA disease transmission 分析结果： 1 2 Top Years Publications 2006 12 2007 10 1998 9 2008 8 1999 8 1995 8 2000 6 2005 5 2001 5 2004 4 1992 4 2003 3 2002 3 1997 3 1994 3 1993 3 1996 2 1990 2 1991 1 1989 1 1 2 1 2 Top Countries Publications USA 20 United Kingdom 14 France 10 Germany 9 Spain 6 Italy 5 Japan 4 Netherlands 4 Brazil 4 Sweden 4 Taiwan 2 Thailand 2 Finland 2 Canada 2 Australia 2 Tunisia 1 Hungary 1 Czech Republic 1 Malaysia 1 Argentina 1 1 2 1 2 3 Top Cities Publications London 8 Paris 8 Munich 4 Maastricht 3 Newcastle upon Tyne 3 Barcelona 3 New York 3 Gttingen 3 Boston 2 So Paulo 2 Braslia 2 Bangkok 2 Gothenburg 2 Pasadena, CA, USA 2 Milan 2 Tsukuba 1 Salt Lake City 1 Tunis 1 Tbingen 1 Stony Brook 1 1 2 3 1 2 3 4 Top Journals Publications Am J Hum Genet 6 Hum Mutat 4 Eur J Hum Genet 3 Neuromuscular Disord 3 Neurology 3 Lancet 3 Neuropediatrics 3 Hum Reprod Update 2 J Med Genet 2 J Neurol Sci 2 Am J Med Genet A 2 Ann Neurol 2 Rinsho Shinkeigaku 1 Braz J Otorhinolaryngol 1 J Virol 1 Exp Neurol 1 Diagn Mol Pathol 1 J Antimicrob Chemother 1 Ophthalmologe 1 Embo J 1 1 2 3 4 1 2 3 ... 27 Top Authors Publications Jardel C 3 Estivill X 3 Munnich A 3 Rtig A 3 Smeets H 3 Morgan-Hughes J 3 Oldfors A 3 Larsson N 3 Hanefeld F 3 Ohlenbusch A 3 Wilichowski E 3 Harding A 3 Spinelli M 2 Chinnery P 2 Sternberg D 2 Mller-Hcker J 2 Pongratz D 2 Bonnefont J 2 Steffann J 2 Gigarel N 2 1 2 3 ... 27 1 2 3 ... 53 Top Terms Publications Humans 101 DNA, Mitochondrial 88 Mutation 87 mitochondrial chromosome 82 DNA 71 Patients 57 Genes 52 Adult 42 Genomics 35 Genome 35 Phenotype 34 Pedigree 32 Mitochondrial Diseases 29 Child 29 Syndrome 29 DNA Mutational Analysis 28 Muscles 28 Point Mutation 27 Middle Aged 27 Tissues 23 1 2 3 ... 53 publications over time world map Network: Top Authors
http://www.sciencenet.cn/htmlnews/2009/8/222736.shtm 利用从罕见神经系统疾病患者身上产生的干细胞，科学家们正在解析该种疾病的发病原理，并以此来测试若干候选药物的疗效。发表在8月20日《自然》杂志上的该项研究致力于实现干细胞研究的主要目标之一，即利用源于成体细胞重组的干细胞诱导多能干细胞（iPS）来研究患者自体细胞疾病的影响，这种细胞是用其他方式所无法获得的。 美国斯隆凯特林研究所的研究人员专注于研究家族性植物神经功能不全症（FD），该种疾病会对控制触觉、血压和流泪等功能的神经元产生影响。症状一般发端于生命早期，有时甚至从一出生就会发病，主要表现为肌肉缺乏张力和反射控制，从而产生疼痛、血压升高和呼吸困难等问题。该疾病是由一种已知的基因变异引起的，但科学家们一直无法建立这种疾病的动物模型。 研究人员从FD患者身上获取皮肤细胞，然后利用病毒将4个基因插入这些细胞中，从而创建出iPS细胞系。这些重组细胞的行为类似于胚胎干细胞，也能转化成所有类型的细胞。接着，研究人员将那些未分化的细胞诱导为特定的细胞类型，如神经嵴细胞（它能产生受FD影响的神经元）。 FD患者有一个基因突变，该基因对一种称为IKAP的蛋白进行编码，基因突变导致基因被转译成蛋白时部分基因序列被跳过。为了了解这种疾病的更多信息，研究人员检视了不同细胞类型中的正常和突变蛋白。研究人员预计这些神经细胞将会拥有更多的异常蛋白。但事实上，他们发现错误的转译在各种不同细胞中发生的几率是同等的。不过，正常IKAP的水平在神经细胞中要低得多，这也许是疾病为何攻击这些细胞的原因。 该研究小组还发现，这些细胞在分化成神经元的能力上是具有缺陷的，其并不像培养皿中的正常细胞一样容易迁移。研究人员利用此种差异来衡量3种药物的疗效，这几种药已被提议作为治疗FD的候选药物，其中一种药物就是激动素（kinetin）。激动素是一种天然植物激素，通常用作抗皱治疗化妆品。研究人员表示，激动素可几乎完全扭转剪接缺陷，进一步的治疗还可扭转分化缺陷，但不能影响细胞的迁移能力。 美国马萨诸塞州总医院的神经学家苏珊斯劳根豪特认为，这些细胞给长期以来令人沮丧的神经系统疾病研究注入了一支强心剂。该技术首次提供了对来自患者的疾病相关细胞类型进行检视的能力。此一研究也首次表明激动素能改善神经细胞疾病病情，为使用激动素进行长期治疗可能有益于FD患者的观点提供了最好的证据。 美国斯克里普斯研究所再生医学中心主任珍妮罗琳认为，此项工作将成为未来使用干细胞来研究及治疗神经系统疾病的一个蓝本。 http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature08320.html Letter Nature advance online publication 19 August 2009 | :10.1038/nature08320 :10.1038/nature08320 ; Received 30 March 2009; Accepted 28 July 2009; Published online 19 August 2009 Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs Gabsang Lee 1 , Eirini P. Papapetrou 2 , Hyesoo Kim 1 , Stuart M. Chambers 1 , Mark J. Tomishima 1 , 2 , 3 , Christopher A. Fasano 1 , Yosif M. Ganat 1 , 6 , Jayanthi Menon 4 , Fumiko Shimizu 4 , Agnes Viale 5 , Viviane Tabar 2 , 4 , Michel Sadelain 2 Lorenz Studer 1 , 2 , 4 Developmental Biology Program, Center for Cell Engineering, SKI Stem Cell Research Facility, Department of Neurosurgery, Genomics Core Facility, Sloan-Kettering Institute, 1275 York Ave, Weill Cornell Graduate School, New York, New York 10065, USA Correspondence to: Lorenz Studer 1 , 2 , 4 Correspondence and requests for materials should be addressed to L.S. (Email: studerl@mskcc.org ). Top of page The isolation of human induced pluripotent stem cells (iPSCs) 1, 2, 3 offers a new strategy for modelling human disease. Recent studies have reported the derivation and differentiation of disease-specific human iPSCs 4, 5, 6, 7 . However, a key challenge in the field is the demonstration of disease-related phenotypes and the ability to model pathogenesis and treatment of disease in iPSCs. Familial dysautonomia (FD) is a rare but fatal peripheral neuropathy, caused by a point mutation in the IKBKAP 8 gene involved in transcriptional elongation 9 . The disease is characterized by the depletion of autonomic and sensory neurons. The specificity to the peripheral nervous system and the mechanism of neuron loss in FD are poorly understood owing to the lack of an appropriate model system. Here we report the derivation of patient-specific FD-iPSCs and the directed differentiation into cells of all three germ layers including peripheral neurons. Gene expression analysis in purified FD-iPSC-derived lineages demonstrates tissue-specific mis-splicing of IKBKAP in vitro . Patient-specific neural crest precursors express particularly low levels of normal IKBKAP transcript, suggesting a mechanism for disease specificity. FD pathogenesis is further characterized by transcriptome analysis and cell-based assays revealing marked defects in neurogenic differentiation and migration behaviour. Furthermore, we use FD-iPSCs for validating the potency of candidate drugs in reversing aberrant splicing and ameliorating neuronal differentiation and migration. Our study illustrates the promise of iPSC technology for gaining new insights into human disease pathogenesis and treatment. 信息分析平台： http://www.gopubmed.org/web/gopubmed/ 相关文献分析结果： Top Years Publications 2003 7 2008 5 2007 5 2002 3 2001 3 2004 3 2009 2 2005 2 2006 1 1999 1 1996 1 Top Countries Publications USA 22 Israel 6 Denmark 2 Belgium 2 Canada 1 Top Cities Publications Boston 8 New York 4 Copenhagen 2 Lige 2 Ramat Gan 2 Bethesda 1 Chicago 1 Toronto 1 1 2 Top Journals Publications Am J Hum Genet 3 Biochem Bioph Res Co 3 Hum Mol Genet 2 Pediatr Res 2 Am J Med Genet A 2 Cell Adh Migr 1 Genomics 1 Brain Res 1 Curr Opin Genet Dev 1 Neuromolecular Med 1 J Mol Med-jmm 1 Hum Mutat 1 Mol Cell Biol 1 J Cell Sci 1 Bull Mem Acad R Med Belg 1 Mol Cell 1 Differentiation 1 Stem Cells 1 Muscle Nerve 1 Reprod Biomed Online 1 1 2 1 2 3 ... 8 Top Authors Publications Slaugenhaupt S 14 Leyne M 10 Mull J 9 Gusella J 9 Gill S 8 Axelrod F 7 Cuajungco M 6 Maayan C 5 Rubin B 5 Hims M 4 Anderson S 4 Blumenfeld A 3 Naumanen T 2 Shetty R 2 Liu L 2 Liebert C 2 Idelson M 2 Gold-von Simson G 2 Goldberg J 2 Creppe C 2 1 2 3 ... 8 1 2 3 ... 22 Top Terms Publications Dysautonomia, Familial 33 Autonomic Nervous System Diseases 33 Humans 31 Genes 30 Mutation 29 ikbkap 27 Carrier Proteins 25 Proteins 23 ikap 18 RNA, Messenger 17 Patients 16 Exons 12 Neurons 11 Introns 10 Anxiety 10 Animals 10 RNA 9 Tissues 8 autosome 8 Cell Line 7 1 2 3 ... 22
http://www.sciencenet.cn/htmlnews/2009/8/222568.shtm 记者日前获悉，中国科学院院士、南开大学校长饶子和领衔的研究小组继去年在国际顶尖科学杂志《自然》上发表重要科研成果，2009年新成果频出。 今年年初，该研究小组在《病毒学杂志》（ JVI ）上公布研究成果：确定了两个关键的ADRP位点晶体结构，首次进行了冠状病毒ADRP位点系统结构分析。 在这篇文章中，研究人员确定了两个关键ADRP位点的结晶结构，包括I型人类冠状病毒2299E和II型鸡传染性支气管炎病毒，以及其各自与ADP核糖形成的复合物的结构，从这些结构分析得到的数据对于冠状病毒的研究十分重要，这也是首次对冠状病毒ADRP位点进行系统的结构分析，为了解这一结构域位点在冠状病毒复制过程中扮演的角色打下了一个基础。 Journal of Virology, January 2009, p. 1083-1092, Vol. 83, No. 2 0022-538X/09/$08.00+0 doi:10.1128/JVI.01862-08 Copyright 2009 , American Society for Microbiology . All Rights Reserved. Crystal Structures of Two Coronavirus ADP-Ribose-1''-Monophosphatases and Their Complexes with ADP-Ribose: a Systematic Structural Analysis of the Viral ADRP Domain Yuanyuan Xu, 1 Le Cong, 1 Cheng Chen, 1 Lei Wei, 1 Qi Zhao, 1 Xiaoling Xu, 1 Yanlin Ma, 2 Mark Bartlam, 3 and Zihe Rao 1 ,2 ,3 * Laboratory of Structural Biology, Tsinghua University, Beijing 100084, China, 1 National Laboratory of Biomacromolecules, Institute of Biophysics (IBP), Chinese Academy of Sciences, Beijing 100101, China, 2 College of Life Sciences and Tianjin State Laboratory of Protein Science, Nankai University, Tianjin 300071, China 3 Received 4 September 2008/ Accepted 22 October 2008 The coronaviruses are a large family of plus-strand RNA viruses that cause a wide variety of diseases both in humans and in other organisms. The coronaviruses are composed of three main lineages and have a complex organization of nonstructural proteins (nsp's). In the coronavirus, nsp3 resides a domain with the macroH2A-like fold and ADP-ribose-1-monophosphatase (ADRP) activity, which is proposed to play a regulatory role in the replication process. However, the significance of this domain for the coronaviruses is still poorly understood due to the lack of structural information from different lineages. We have determined the crystal structures of two viral ADRP domains, from the group I human coronavirus 229E and the group III avian infectious bronchitis virus, as well as their respective complexes with ADP-ribose. The structures were individually solved to elucidate the structural similarities and differences of the ADRP domains among various coronavirus species. The active-site residues responsible for mediating ADRP activity were found to be highly conserved in terms of both sequence alignment and structural superposition, whereas the substrate binding pocket exhibited variations in structure but not in sequence. Together with data from a previous analysis of the ADRP domain from the group II severe acute respiratory syndrome coronavirus and from other related functional studies of ADRP domains, a systematic structural analysis of the coronavirus ADRP domains was realized for the first time to provide a structural basis for the function of this domain in the coronavirus replication process. 相关文献如下： http://www.gopubmed.org/web/gopubmed/2?WEB0115alzrvhlmizIsI1I00d000j10040001rl documents Title: Mouse hepatitis virus liver pathology is dependent on ADP-ribose-1''-phosphatase, a viral function conserved in the alpha-like supergroup. PMID: 18922871 Related Articles Authors: Eriksson, K K , Cervantes-Barragn, L , Ludewig, B , Thiel, V Journal: J Virol , Vol. 82 (24): 12325-34 , 2008 Abstract: Viral infection of the liver can lead to severe tissue damage when high levels of viral replication and spread in the organ are coupled with strong induction of inflammatory responses. Here we report an unexpected correlation between the expression of a functional X domain encoded by the hepatotropic mouse hepatitis virus strain A59 (MHV- A59 ), the high-level production of inflammatory cytokines, and the induction of acute viral hepatitis in mice. X-domain (also called macro domain) proteins possess poly-ADP-ribose binding and/or ADP -ribose-1''-phosphatase ( ADRP ) activity. They are conserved in coronaviruses and in members of the alpha-like supergroup of phylogenetically related positive-strand RNA viruses that includes viruses of medical importance, such as rubella virus and hepatitis E virus . By using reverse genetics, we constructed a recombinant murine coronavirus MHV- A59 mutant encoding a single-amino-acid substitution of a strictly conserved residue that is essential for coronaviral ADRP activity. We found that the mutant virus replicated to slightly reduced titers in livers but, strikingly, did not induce liver disease. In vitro, the mutant virus induced only low levels of the inflammatory cytokines tumor necrosis factor alpha and interleukin-6 ( IL-6 ). In vivo, we found that IL-6 production, in particular, was reduced in the spleens and livers of mutant virus -infected mice. Collectively, our data demonstrate that the MHV X domain exacerbates MHV-induced liver pathology, most likely through the induction of excessive inflammatory cytokine expression. Affiliation: Kantonal Hospital St. Gallen , Research Department and Institute of Pathology, 9007 St . Gallen , Switzerland . 近期，饶子和研究小组又取得了一项重要的研究成果确定了小鼠肝炎病毒A59(Hepatitis Virus A59)中非结构蛋白4的C末端位点晶体结构。这一研究成果公布在《公共科学图书馆综合》（ PLoS One ）杂志上。 冠状病毒的复制发生在内质网双膜泡上，研究发现，冠状病毒复制复合物在膜上定位需要三个穿膜非结构性蛋白：nsp3, nsp4和nsp6，其中nsp4单独表达后会结合在内质网膜上，但是这种蛋白在感染细胞中则会定位在复制复合物上。该成果中，研究人员确定了A59中nsp4的C末端亲水位点晶体结构，这对于进一步了解这种蛋白在感染过程中的作用，以及整个病毒复制过程具有重要的意义。 Crystal Structure of the C-Terminal Cytoplasmic Domain of Non-Structural Protein 4 from Mouse Hepatitis Virus A59 Xiaoling Xu 1 , Zhiyong Lou 1 , Yanlin Ma 1 , Xuehui Chen 1 , 2 , Zhangsheng Yang 2 , Xiaohang Tong 1 , 2 , Qi Zhao 1 , Yuanyuan Xu 1 , Hongyu Deng 2 , Mark Bartlam 3 , Zihe Rao 1 , 2 , 3 * 1 Laboratory of Structural Biology, Tsinghua University, Beijing, China, 2 National Laboratory of Biomacromolecules, Institute of Biophysics (IBP), Chinese Academy of Sciences, Beijing, China, 3 College of Life Sciences and Tianjin Key Laboratory of Protein Science, Nankai University, Tianjin, China Background The replication of coronaviruses takes place on cytoplasmic double membrane vesicles (DMVs) originating in the endoplasmic reticulum (ER). Three trans-membrane non-structural proteins, nsp3, nsp4 and nsp6, are understood to be membrane anchors of the coronavirus replication complex. Nsp4 is localized to the ER membrane when expressed alone but is recruited into the replication complex in infected cells. It is revealed to contain four trans-membrane regions and its N- and C-termini are exposed to the cytosol. Methodology/Principal Findings We have determined the crystal structures of the C-terminal hydrophilic domain of nsp4 (nsp4C) from MHV strain A59 and a C425S site-directed mutant. The highly conserved 89 amino acid region from T408 to Q496 is shown to possess a new fold. The wild-type (WT) structure features two monomers linked by a Cys425-Cys425 disulfide bond in one asymmetric unit. The monomers are arranged with their N- and C-termini in opposite orientations to form an open conformation. Mutation of Cys425 to Ser did not affect the monomer structure, although the mutant dimer adopts strikingly different conformations by crystal packing, with the cross-linked C-termini and parallel N-termini of two monomers forming a closed conformation. The WT nsp4C exists as a dimer in solution and can dissociate easily into monomers in a reducing environment. Conclusions/Significance As nsp4C is exposed in the reducing cytosol, the monomer of nsp4C should be physiological. This structure may serve as a basis for further functional studies of nsp4. 信息分析平台： http://www.gopubmed.org/web/gopubmed/WEB10O00d000j100300.y 检索策略： nsp3 or nsp4 or nsp6 and Hepatitis Virus A59 相关文献459篇计量分析结果如下： 1 2 Top Years Publications 2008 52 2007 44 2006 43 2009 31 2004 28 2000 27 2001 26 2005 25 2003 25 2002 23 1998 18 1999 17 1996 16 1997 13 1994 12 1991 10 1990 9 1993 8 1989 8 1995 7 1 2 1 2 Top Countries Publications USA 189 China 34 Japan 30 France 29 Finland 25 India 18 Netherlands 17 United Kingdom 17 Italy 9 Germany 8 Mexico 8 Sweden 8 Australia 7 New Zealand 7 Venezuela 6 Brazil 6 Hungary 5 Spain 5 Estonia 4 Belgium 3 1 2 1 2 3 ... 7 Top Cities Publications Houston 21 Helsinki 21 Pasadena, CA, USA 15 St. Louis 15 Atlanta 14 Bethesda 14 Leiden 12 Beijing 11 Toledo 11 Laizhou 11 Galveston 11 Tokyo 10 Jouy-le-Moutier 10 Paris 9 College Station 7 Auckland 7 Loma Linda 7 Sapporo 6 Bangalore 6 Cuernavaca 6 1 2 3 ... 7 1 2 3 4 5 Top Journals Publications J Virol 126 Virology 59 J Gen Virol 29 J Med Virol 27 Arch Virol 24 Virus Genes 13 Virus Res 13 J Clin Microbiol 12 J Biol Chem 11 J Virol Methods 7 J Infect Dis 6 Microbiol Immunol 6 Embo J 6 J Clin Virol 5 Arch Virol Suppl 5 J Med Microbiol 4 P Natl Acad Sci Usa 4 Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi 4 J Mol Biol 3 Emerg Infect Dis 3 1 2 3 4 5 1 2 3 ... 122 Top Terms Publications Viruses 335 Proteins 331 Viral Nonstructural Proteins 305 Animals 304 Rotavirus 251 nsp4 224 Genes 187 Humans 182 Amino Acid Sequence 171 RNA 169 Amino Acids 160 RNA, Viral 147 Glycoproteins 141 Rotavirus Infections 138 Genomics 133 Genome 133 Cell Line 132 Base Sequence 119 Viral Proteins 111 Toxins, Biological 110 1 2 3 ... 122 1 2 3 ... 80 Top Authors Publications Estes M 23 Strauss J 21 Rice C 19 Kriinen L 16 Ball J 15 Gorbalenya A 14 Strauss E 14 Snijder E 13 Zeng C 13 Sawicki S 12 Glass R 11 Nakagomi O 11 Sawicki D 11 Kirkwood C 10 Gentsch J 10 Poncet D 10 Ushijima H 9 Hoshino Y 9 Martella V 9 Morris A 9 1 2 3 ... 80 请阅读原文全文： Crystal Structure of the C-Terminal Cytoplasmic Do 对此研究论文的学术反应和引用情况： Related Articles info Related Articles on the Web Google Scholar PubMed Cited in No related citations found Search for citations on Google Scholar . 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Transinsight Press Release 两周前听说GOPUBMED 获奖了，昨天收到了他们的来信，非常高兴，祝贺他们。 2009-08-1221:02:26 Transinsight GmbH Tatzberg 47-51 D-01307 Dresden, Germany http://www.transinsight.com/news09#NewsRedDotDesign Transinsights GoPubMed.com wins the 2009 red dot: best of the best award for excellence in communication design Dresden, Germany August 12th, 2009 Transinsights GoPubMed.com, the semantic search engine for the life sciences, has been recognized with the 2009 red dot: best of the best award in the category communication design graphical user interfaces and interactive tool. A total of 6,112 submissions were received from 42 countries. The jury selected 470 entries for the red dot design award. A group of only 56 submissions were selected as the best of the best and will be participating in the final round for the grand prix award. The Transinsight team is proud to receive this prestigious award. The upcoming challenges in the area of the semantic web are mainly related to user interaction. Fostering communication between humans and large scale data volumes beyond todays key word search is of great importance to make data, information and knowledge manageable. The design philosophy behind GoPubMed.com is strictly aligned with this overall principle: knowledge- and meaning-based computing. The brain-like use of a knowledge network of more than 15 million concepts and half a billion of documents brings up extremely difficult issues when it comes to dealing with these overwhelming amounts of data. For the first time, this was achieved with the technology used in the novel semantic search engine. It is a great satisfaction that this innovation in communication design was recognized by a distinguished international team of reviewers. For us, this award shows recognition of our design competence and quality as well as an outstanding confirmation of our performance when it comes to the development of leading edge technology for information-heavy tasks. In the field of semantic search, acceptance by users is of utmost importance, since people in real life were not made for dealing with billions of data in the critical decision making process, said Dr. Michael R. Alvers, CEO of Transinsight. The entire team technicians and designers enjoy this show of appreciation for their three years of hard work. I thank team members for this outstanding achievement, he continued. GoPubMed.com is free of charge for non-commercial use. 许老师： 今天听您讲很受启发，科学计量学肯定是情报学的发展方向。关于GoPubmed，我想钱助理的理解还是从IT角度，觉得本所做一个这样的系统也不是 很难。确实能做，但是关键人家先想到了，而且产品已经出来了，还获大奖了，人家在做的 过程中肯定还是有很多技巧和技术的。我想您想做汉化主要原因还是引进、介绍一种信息分析的思路和方法，而这种思路还 是很新颖的，需要我们年轻一代借鉴并从中得到启示的。如果我们这一代人还是跟着别人的 模式做数据库、做系统，没有情报学的思路，那就完了。有机会我们还是跟钱助理好好谈谈，汉化的项目早一点提上日程来。 栗文靖 是啊,我们的认识是一致的,我认为美国,德国,西班牙等国家在信息分析技术方面做的很好,我们要建立发展医学信息分析中心,靠你们年轻一代的努力,开发中文信息分析平台非常必要.你与钱主任他们多交流和研究,我一定支持你们. 许老师
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