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  • Articles  (29)
  • Animals  (28)
  • *Phenotype  (3)
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  • 1
    Publication Date: 2015-09-10
    Description: Somaclonal variation arises in plants and animals when differentiated somatic cells are induced into a pluripotent state, but the resulting clones differ from each other and from their parents. In agriculture, somaclonal variation has hindered the micropropagation of elite hybrids and genetically modified crops, but the mechanism responsible remains unknown. The oil palm fruit 'mantled' abnormality is a somaclonal variant arising from tissue culture that drastically reduces yield, and has largely halted efforts to clone elite hybrids for oil production. Widely regarded as an epigenetic phenomenon, 'mantling' has defied explanation, but here we identify the MANTLED locus using epigenome-wide association studies of the African oil palm Elaeis guineensis. DNA hypomethylation of a LINE retrotransposon related to rice Karma, in the intron of the homeotic gene DEFICIENS, is common to all mantled clones and is associated with alternative splicing and premature termination. Dense methylation near the Karma splice site (termed the Good Karma epiallele) predicts normal fruit set, whereas hypomethylation (the Bad Karma epiallele) predicts homeotic transformation, parthenocarpy and marked loss of yield. Loss of Karma methylation and of small RNA in tissue culture contributes to the origin of mantled, while restoration in spontaneous revertants accounts for non-Mendelian inheritance. The ability to predict and cull mantling at the plantlet stage will facilitate the introduction of higher performing clones and optimize environmentally sensitive land resources.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ong-Abdullah, Meilina -- Ordway, Jared M -- Jiang, Nan -- Ooi, Siew-Eng -- Kok, Sau-Yee -- Sarpan, Norashikin -- Azimi, Nuraziyan -- Hashim, Ahmad Tarmizi -- Ishak, Zamzuri -- Rosli, Samsul Kamal -- Malike, Fadila Ahmad -- Bakar, Nor Azwani Abu -- Marjuni, Marhalil -- Abdullah, Norziha -- Yaakub, Zulkifli -- Amiruddin, Mohd Din -- Nookiah, Rajanaidu -- Singh, Rajinder -- Low, Eng-Ti Leslie -- Chan, Kuang-Lim -- Azizi, Norazah -- Smith, Steven W -- Bacher, Blaire -- Budiman, Muhammad A -- Van Brunt, Andrew -- Wischmeyer, Corey -- Beil, Melissa -- Hogan, Michael -- Lakey, Nathan -- Lim, Chin-Ching -- Arulandoo, Xaviar -- Wong, Choo-Kien -- Choo, Chin-Nee -- Wong, Wei-Chee -- Kwan, Yen-Yen -- Alwee, Sharifah Shahrul Rabiah Syed -- Sambanthamurthi, Ravigadevi -- Martienssen, Robert A -- R01 GM067014/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Sep 24;525(7570):533-7. doi: 10.1038/nature15365. Epub 2015 Sep 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Malaysian Palm Oil Board, 6, Persiaran Institusi, Bandar Baru Bangi, 43000 Kajang, Selangor, Malaysia. ; Orion Genomics, 4041 Forest Park Avenue, St Louis, Missouri 63108, USA. ; United Plantations Berhad, Jendarata Estate, 36009 Teluk Intan, Perak, Malaysia. ; Applied Agricultural Resources Sdn Bhd, No. 11, Jalan Teknologi 3/6, Taman Sains Selangor 1, 47810 Kota Damansara, Petaling Jaya, Selangor, Malaysia. ; FELDA Global Ventures R&D Sdn Bhd, c/o FELDA Biotechnology Centre, PT 23417, Lengkuk Teknologi, 71760 Bandar Enstek, Negeri Sembilan, Malaysia. ; Howard Hughes Medical Institute-Gordon and Betty Moore Foundation, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26352475" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Alternative Splicing/genetics ; Arecaceae/*genetics/metabolism ; *DNA Methylation ; Epigenesis, Genetic/*genetics ; *Epigenomics ; Fruit/genetics ; Genes, Homeobox/genetics ; Genetic Association Studies ; Genome, Plant/*genetics ; Introns/genetics ; Molecular Sequence Data ; *Phenotype ; Plant Oils/analysis/metabolism ; RNA Splice Sites/genetics ; RNA, Small Interfering/genetics ; Retroelements/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2013-11-12
    Description: In multicellular organisms, transcription regulation is one of the central mechanisms modelling lineage differentiation and cell-fate determination. Transcription requires dynamic chromatin configurations between promoters and their corresponding distal regulatory elements. It is believed that their communication occurs within large discrete foci of aggregated RNA polymerases termed transcription factories in three-dimensional nuclear space. However, the dynamic nature of chromatin connectivity has not been characterized at the genome-wide level. Here, through a chromatin interaction analysis with paired-end tagging approach using an antibody that primarily recognizes the pre-initiation complexes of RNA polymerase II, we explore the transcriptional interactomes of three mouse cells of progressive lineage commitment, including pluripotent embryonic stem cells, neural stem cells and neurosphere stem/progenitor cells. Our global chromatin connectivity maps reveal approximately 40,000 long-range interactions, suggest precise enhancer-promoter associations and delineate cell-type-specific chromatin structures. Analysis of the complex regulatory repertoire shows that there are extensive colocalizations among promoters and distal-acting enhancers. Most of the enhancers associate with promoters located beyond their nearest active genes, indicating that the linear juxtaposition is not the only guiding principle driving enhancer target selection. Although promoter-enhancer interactions exhibit high cell-type specificity, promoters involved in interactions are found to be generally common and mostly active among different cells. Chromatin connectivity networks reveal that the pivotal genes of reprogramming functions are transcribed within physical proximity to each other in embryonic stem cells, linking chromatin architecture to coordinated gene expression. Our study sets the stage for the full-scale dissection of spatial and temporal genome structures and their roles in orchestrating development.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954713/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954713/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Yubo -- Wong, Chee-Hong -- Birnbaum, Ramon Y -- Li, Guoliang -- Favaro, Rebecca -- Ngan, Chew Yee -- Lim, Joanne -- Tai, Eunice -- Poh, Huay Mei -- Wong, Eleanor -- Mulawadi, Fabianus Hendriyan -- Sung, Wing-Kin -- Nicolis, Silvia -- Ahituv, Nadav -- Ruan, Yijun -- Wei, Chia-Lin -- 1U54HG004557-01/HG/NHGRI NIH HHS/ -- GGP12152/Telethon/Italy -- GM61390/GM/NIGMS NIH HHS/ -- R01 DK090382/DK/NIDDK NIH HHS/ -- R01 HD059862/HD/NICHD NIH HHS/ -- R01 HG004456-01/HG/NHGRI NIH HHS/ -- R01 NS079231/NS/NINDS NIH HHS/ -- R01DK090382/DK/NIDDK NIH HHS/ -- R01HD059862/HD/NICHD NIH HHS/ -- R01HG003521-01/HG/NHGRI NIH HHS/ -- R01HG005058/HG/NHGRI NIH HHS/ -- R01HG006768/HG/NHGRI NIH HHS/ -- R01NS079231/NS/NINDS NIH HHS/ -- U01 GM061390/GM/NIGMS NIH HHS/ -- U19 GM061390/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Dec 12;504(7479):306-10. doi: 10.1038/nature12716. Epub 2013 Nov 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Sequencing Technology Group, Joint Genome Institute, Lawrence Berkeley National Laboratory, Walnut Creek, California 94598, USA [2] [3] Department of Life Sciences, Faculty of Natural Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel (R.Y.B.); National Heart, Lung, and Blood Institute, National Institutes of Health, Systems Biology Center, 9000 Rockville Pike, Bethesda, Maryland 20892, USA (Y.Z.). ; 1] Sequencing Technology Group, Joint Genome Institute, Lawrence Berkeley National Laboratory, Walnut Creek, California 94598, USA [2]. ; 1] Department of Bioengineering and Therapeutic Sciences, Institute for Human Genetics, UCSF, San Francisco, California 94158, USA [2] [3] Department of Life Sciences, Faculty of Natural Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel (R.Y.B.); National Heart, Lung, and Blood Institute, National Institutes of Health, Systems Biology Center, 9000 Rockville Pike, Bethesda, Maryland 20892, USA (Y.Z.). ; 1] The Jackson Laboratory for Genomic Medicine, and Department of Genetic and Development Biology, University of Connecticut, 400 Farmington, Connecticut 06030, USA [2] Genome Institute of Singapore, 60 Biopolis Street, 138672 Singapore. ; Department of Biological Sciences and Biotechnology, University of Milano-Bicocca, 20126 Milano, Italy. ; Sequencing Technology Group, Joint Genome Institute, Lawrence Berkeley National Laboratory, Walnut Creek, California 94598, USA. ; Genome Institute of Singapore, 60 Biopolis Street, 138672 Singapore. ; Department of Bioengineering and Therapeutic Sciences, Institute for Human Genetics, UCSF, San Francisco, California 94158, USA. ; The Jackson Laboratory for Genomic Medicine, and Department of Genetic and Development Biology, University of Connecticut, 400 Farmington, Connecticut 06030, USA. ; 1] Sequencing Technology Group, Joint Genome Institute, Lawrence Berkeley National Laboratory, Walnut Creek, California 94598, USA [2] Genome Institute of Singapore, 60 Biopolis Street, 138672 Singapore.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24213634" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cell Lineage ; Chromatin/*genetics/*metabolism ; Embryonic Stem Cells/metabolism ; Enhancer Elements, Genetic/*genetics ; Gene Expression Regulation/*genetics ; In Situ Hybridization, Fluorescence ; Mice ; Neural Stem Cells/metabolism ; Promoter Regions, Genetic/*genetics ; RNA Polymerase II/metabolism ; Transcription, Genetic/genetics ; Zebrafish/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2012-03-20
    Description: Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385933/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385933/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Zhao -- Cheng, Katherine -- Walton, Zandra -- Wang, Yuchuan -- Ebi, Hiromichi -- Shimamura, Takeshi -- Liu, Yan -- Tupper, Tanya -- Ouyang, Jing -- Li, Jie -- Gao, Peng -- Woo, Michele S -- Xu, Chunxiao -- Yanagita, Masahiko -- Altabef, Abigail -- Wang, Shumei -- Lee, Charles -- Nakada, Yuji -- Pena, Christopher G -- Sun, Yanping -- Franchetti, Yoko -- Yao, Catherine -- Saur, Amy -- Cameron, Michael D -- Nishino, Mizuki -- Hayes, D Neil -- Wilkerson, Matthew D -- Roberts, Patrick J -- Lee, Carrie B -- Bardeesy, Nabeel -- Butaney, Mohit -- Chirieac, Lucian R -- Costa, Daniel B -- Jackman, David -- Sharpless, Norman E -- Castrillon, Diego H -- Demetri, George D -- Janne, Pasi A -- Pandolfi, Pier Paolo -- Cantley, Lewis C -- Kung, Andrew L -- Engelman, Jeffrey A -- Wong, Kwok-Kin -- 1U01CA141576/CA/NCI NIH HHS/ -- CA122794/CA/NCI NIH HHS/ -- CA137008/CA/NCI NIH HHS/ -- CA137008-01/CA/NCI NIH HHS/ -- CA137181/CA/NCI NIH HHS/ -- CA140594/CA/NCI NIH HHS/ -- CA147940/CA/NCI NIH HHS/ -- K23 CA157631/CA/NCI NIH HHS/ -- P01 CA120964/CA/NCI NIH HHS/ -- P30 CA016086/CA/NCI NIH HHS/ -- P50 CA090578/CA/NCI NIH HHS/ -- P50 CA090578-06/CA/NCI NIH HHS/ -- P50CA090578/CA/NCI NIH HHS/ -- R01 CA122794/CA/NCI NIH HHS/ -- R01 CA122794-01/CA/NCI NIH HHS/ -- R01 CA137008/CA/NCI NIH HHS/ -- R01 CA137008-01/CA/NCI NIH HHS/ -- R01 CA137181/CA/NCI NIH HHS/ -- R01 CA137181-01A2/CA/NCI NIH HHS/ -- R01 CA140594/CA/NCI NIH HHS/ -- R01 CA140594-01/CA/NCI NIH HHS/ -- R01 CA163896/CA/NCI NIH HHS/ -- RC2 CA147940/CA/NCI NIH HHS/ -- RC2 CA147940-01/CA/NCI NIH HHS/ -- U01 CA141576/CA/NCI NIH HHS/ -- U01 CA141576-01/CA/NCI NIH HHS/ -- England -- Nature. 2012 Mar 18;483(7391):613-7. doi: 10.1038/nature10937.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22425996" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Combined Chemotherapy Protocols ; Benzimidazoles/*pharmacology/therapeutic use ; Biomarkers, Tumor/genetics/metabolism ; *Clinical Trials, Phase II as Topic ; *Disease Models, Animal ; Drug Evaluation, Preclinical ; Fluorodeoxyglucose F18 ; Genes, p53/genetics ; Humans ; Lung Neoplasms/*drug therapy/enzymology/*genetics/metabolism ; MAP Kinase Signaling System/drug effects ; Mice ; Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors ; Mutation/genetics ; Pharmacogenetics/*methods ; Positron-Emission Tomography ; Protein-Serine-Threonine Kinases/deficiency/genetics ; Proto-Oncogene Proteins/genetics/metabolism ; Proto-Oncogene Proteins p21(ras)/genetics/metabolism ; Randomized Controlled Trials as Topic ; Reproducibility of Results ; Taxoids/*therapeutic use ; Tomography, X-Ray Computed ; Treatment Outcome ; ras Proteins/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2012-12-04
    Description: Although initially viewed as unregulated, increasing evidence suggests that cellular necrosis often proceeds through a specific molecular program. In particular, death ligands such as tumour necrosis factor (TNF)-alpha activate necrosis by stimulating the formation of a complex containing receptor-interacting protein 1 (RIP1) and receptor-interacting protein 3 (RIP3). Relatively little is known regarding how this complex formation is regulated. Here, we show that the NAD-dependent deacetylase SIRT2 binds constitutively to RIP3 and that deletion or knockdown of SIRT2 prevents formation of the RIP1-RIP3 complex in mice. Furthermore, genetic or pharmacological inhibition of SIRT2 blocks cellular necrosis induced by TNF-alpha. We further demonstrate that RIP1 is a critical target of SIRT2-dependent deacetylation. Using gain- and loss-of-function mutants, we demonstrate that acetylation of RIP1 lysine 530 modulates RIP1-RIP3 complex formation and TNF-alpha-stimulated necrosis. In the setting of ischaemia-reperfusion injury, RIP1 is deacetylated in a SIRT2-dependent fashion. Furthermore, the hearts of Sirt2(-/-) mice, or wild-type mice treated with a specific pharmacological inhibitor of SIRT2, show marked protection from ischaemic injury. Taken together, these results implicate SIRT2 as an important regulator of programmed necrosis and indicate that inhibitors of this deacetylase may constitute a novel approach to protect against necrotic injuries, including ischaemic stroke and myocardial infarction.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Narayan, Nisha -- Lee, In Hye -- Borenstein, Ronen -- Sun, Junhui -- Wong, Renee -- Tong, Guang -- Fergusson, Maria M -- Liu, Jie -- Rovira, Ilsa I -- Cheng, Hwei-Ling -- Wang, Guanghui -- Gucek, Marjan -- Lombard, David -- Alt, Fredrick W -- Sack, Michael N -- Murphy, Elizabeth -- Cao, Liu -- Finkel, Toren -- Intramural NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Dec 13;492(7428):199-204. doi: 10.1038/nature11700. Epub 2012 Nov 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23201684" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Animals ; Cell Line ; Female ; HEK293 Cells ; HeLa Cells ; Humans ; Jurkat Cells ; Male ; Mice ; Necrosis/*enzymology ; Nuclear Pore Complex Proteins/metabolism ; Protein Binding ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Sirtuin 2/*genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2015-08-27
    Description: The GGGGCC (G4C2) repeat expansion in a noncoding region of C9orf72 is the most common cause of sporadic and familial forms of amyotrophic lateral sclerosis and frontotemporal dementia. The basis for pathogenesis is unknown. To elucidate the consequences of G4C2 repeat expansion in a tractable genetic system, we generated transgenic fly lines expressing 8, 28 or 58 G4C2-repeat-containing transcripts that do not have a translation start site (AUG) but contain an open-reading frame for green fluorescent protein to detect repeat-associated non-AUG (RAN) translation. We show that these transgenic animals display dosage-dependent, repeat-length-dependent degeneration in neuronal tissues and RAN translation of dipeptide repeat (DPR) proteins, as observed in patients with C9orf72-related disease. This model was used in a large-scale, unbiased genetic screen, ultimately leading to the identification of 18 genetic modifiers that encode components of the nuclear pore complex (NPC), as well as the machinery that coordinates the export of nuclear RNA and the import of nuclear proteins. Consistent with these results, we found morphological abnormalities in the architecture of the nuclear envelope in cells expressing expanded G4C2 repeats in vitro and in vivo. Moreover, we identified a substantial defect in RNA export resulting in retention of RNA in the nuclei of Drosophila cells expressing expanded G4C2 repeats and also in mammalian cells, including aged induced pluripotent stem-cell-derived neurons from patients with C9orf72-related disease. These studies show that a primary consequence of G4C2 repeat expansion is the compromise of nucleocytoplasmic transport through the nuclear pore, revealing a novel mechanism of neurodegeneration.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631399/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631399/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Freibaum, Brian D -- Lu, Yubing -- Lopez-Gonzalez, Rodrigo -- Kim, Nam Chul -- Almeida, Sandra -- Lee, Kyung-Ha -- Badders, Nisha -- Valentine, Marc -- Miller, Bruce L -- Wong, Philip C -- Petrucelli, Leonard -- Kim, Hong Joo -- Gao, Fen-Biao -- Taylor, J Paul -- AG019724/AG/NIA NIH HHS/ -- N079725/PHS HHS/ -- NS079725/NS/NINDS NIH HHS/ -- P01 AG019724/AG/NIA NIH HHS/ -- R01 NS057553/NS/NINDS NIH HHS/ -- R01 NS079725/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Sep 3;525(7567):129-33. doi: 10.1038/nature14974. Epub 2015 Aug 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell and Molecular Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. ; Memory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, California 94158, USA. ; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida 32224, USA. ; Howard Hughes Medical Institute, Department of Cell and Molecular Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26308899" target="_blank"〉PubMed〈/a〉
    Keywords: Active Transport, Cell Nucleus/*genetics ; Amyotrophic Lateral Sclerosis/genetics/pathology ; Animals ; Animals, Genetically Modified ; DNA Repeat Expansion/*genetics ; Drosophila melanogaster/*cytology/genetics/*metabolism ; Eye/metabolism ; Female ; Frontotemporal Dementia/genetics/pathology ; HeLa Cells ; Humans ; Induced Pluripotent Stem Cells/cytology/metabolism ; Male ; Muscles/cytology/metabolism ; Neurons/cytology/metabolism ; Nuclear Pore/genetics/metabolism/pathology ; Open Reading Frames/*genetics ; Phenotype ; Protein Biosynthesis ; Proteins/*genetics ; RNA/genetics/metabolism ; RNA Transport/*genetics ; Salivary Glands/cytology/metabolism/pathology
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2011-02-04
    Description: Effective clinical management of prostate cancer (PCA) has been challenged by significant intratumoural heterogeneity on the genomic and pathological levels and limited understanding of the genetic elements governing disease progression. Here, we exploited the experimental merits of the mouse to test the hypothesis that pathways constraining progression might be activated in indolent Pten-null mouse prostate tumours and that inactivation of such progression barriers in mice would engender a metastasis-prone condition. Comparative transcriptomic and canonical pathway analyses, followed by biochemical confirmation, of normal prostate epithelium versus poorly progressive Pten-null prostate cancers revealed robust activation of the TGFbeta/BMP-SMAD4 signalling axis. The functional relevance of SMAD4 was further supported by emergence of invasive, metastatic and lethal prostate cancers with 100% penetrance upon genetic deletion of Smad4 in the Pten-null mouse prostate. Pathological and molecular analysis as well as transcriptomic knowledge-based pathway profiling of emerging tumours identified cell proliferation and invasion as two cardinal tumour biological features in the metastatic Smad4/Pten-null PCA model. Follow-on pathological and functional assessment confirmed cyclin D1 and SPP1 as key mediators of these biological processes, which together with PTEN and SMAD4, form a four-gene signature that is prognostic of prostate-specific antigen (PSA) biochemical recurrence and lethal metastasis in human PCA. This model-informed progression analysis, together with genetic, functional and translational studies, establishes SMAD4 as a key regulator of PCA progression in mice and humans.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753179/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753179/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ding, Zhihu -- Wu, Chang-Jiun -- Chu, Gerald C -- Xiao, Yonghong -- Ho, Dennis -- Zhang, Jingfang -- Perry, Samuel R -- Labrot, Emma S -- Wu, Xiaoqiu -- Lis, Rosina -- Hoshida, Yujin -- Hiller, David -- Hu, Baoli -- Jiang, Shan -- Zheng, Hongwu -- Stegh, Alexander H -- Scott, Kenneth L -- Signoretti, Sabina -- Bardeesy, Nabeel -- Wang, Y Alan -- Hill, David E -- Golub, Todd R -- Stampfer, Meir J -- Wong, Wing H -- Loda, Massimo -- Mucci, Lorelei -- Chin, Lynda -- DePinho, Ronald A -- P50 CA090381/CA/NCI NIH HHS/ -- P50 CA090381-08/CA/NCI NIH HHS/ -- P50 CA90381/CA/NCI NIH HHS/ -- R01 5R01CA136578/CA/NCI NIH HHS/ -- R01 CA131945/CA/NCI NIH HHS/ -- R01CA131945/CA/NCI NIH HHS/ -- R01CA141298/CA/NCI NIH HHS/ -- U01-CA84313/CA/NCI NIH HHS/ -- England -- Nature. 2011 Feb 10;470(7333):269-73. doi: 10.1038/nature09677. Epub 2011 Feb 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21289624" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bone Morphogenetic Proteins/metabolism ; Cell Proliferation ; Cyclin D1/genetics/metabolism ; *Disease Progression ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Genes, Tumor Suppressor/physiology ; Humans ; Lung Neoplasms/secondary ; Lymphatic Metastasis ; Male ; Mice ; Mice, Transgenic ; Models, Biological ; Neoplasm Invasiveness/genetics/pathology ; Neoplasm Metastasis/genetics/*pathology ; Osteopontin/genetics/metabolism ; PTEN Phosphohydrolase/deficiency/genetics ; Penetrance ; Prognosis ; Prostate/metabolism ; Prostate-Specific Antigen/metabolism ; Prostatic Neoplasms/diagnosis/genetics/*pathology ; Smad4 Protein/deficiency/genetics/*metabolism ; Transforming Growth Factor beta
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2011-11-04
    Description: Measles virus is an aerosol-transmitted virus that affects more than 10 million children each year and accounts for approximately 120,000 deaths. Although it was long believed to replicate in the respiratory epithelium before disseminating, it was recently shown to infect initially macrophages and dendritic cells of the airways using signalling lymphocytic activation molecule family member 1 (SLAMF1; also called CD150) as a receptor. These cells then cross the respiratory epithelium and transport the infection to lymphatic organs where measles virus replicates vigorously. How and where the virus crosses back into the airways has remained unknown. On the basis of functional analyses of surface proteins preferentially expressed on virus-permissive human epithelial cell lines, here we identify nectin-4 (ref. 8; also called poliovirus-receptor-like-4 (PVRL4)) as a candidate host exit receptor. This adherens junction protein of the immunoglobulin superfamily interacts with the viral attachment protein with high affinity through its membrane-distal domain. Nectin-4 sustains measles virus entry and non-cytopathic lateral spread in well-differentiated primary human airway epithelial sheets infected basolaterally. It is downregulated in infected epithelial cells, including those of macaque tracheae. Although other viruses use receptors to enter hosts or transit through their epithelial barriers, we suggest that measles virus targets nectin-4 to emerge in the airways. Nectin-4 is a cellular marker of several types of cancer, which has implications for ongoing measles-virus-based clinical trials of oncolysis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245798/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245798/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Muhlebach, Michael D -- Mateo, Mathieu -- Sinn, Patrick L -- Prufer, Steffen -- Uhlig, Katharina M -- Leonard, Vincent H J -- Navaratnarajah, Chanakha K -- Frenzke, Marie -- Wong, Xiao X -- Sawatsky, Bevan -- Ramachandran, Shyam -- McCray, Paul B Jr -- Cichutek, Klaus -- von Messling, Veronika -- Lopez, Marc -- Cattaneo, Roberto -- MOP-66989/Canadian Institutes of Health Research/Canada -- P30 DK-54759/DK/NIDDK NIH HHS/ -- P30 DK054759/DK/NIDDK NIH HHS/ -- R01 AI063476/AI/NIAID NIH HHS/ -- R01 AI063476-05A2/AI/NIAID NIH HHS/ -- R01 CA090636/CA/NCI NIH HHS/ -- R01 CA090636-09/CA/NCI NIH HHS/ -- England -- Nature. 2011 Nov 2;480(7378):530-3. doi: 10.1038/nature10639.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Medical Biotechnology, Paul-Ehrlich-Institut, 63225 Langen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22048310" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; CHO Cells ; Cell Adhesion Molecules/genetics/*metabolism ; Cell Line ; Cricetinae ; Gene Expression Profiling ; Humans ; Measles/*metabolism ; Measles virus/*metabolism ; Receptors, Virus/genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2014-07-22
    Description: Mutations that deregulate Notch1 and Ras/phosphoinositide 3 kinase (PI3K)/Akt signalling are prevalent in T-cell acute lymphoblastic leukaemia (T-ALL), and often coexist. Here we show that the PI3K inhibitor GDC-0941 is active against primary T-ALLs from wild-type and Kras(G12D) mice, and addition of the MEK inhibitor PD0325901 increases its efficacy. Mice invariably relapsed after treatment with drug-resistant clones, most of which unexpectedly had reduced levels of activated Notch1 protein, downregulated many Notch1 target genes, and exhibited cross-resistance to gamma-secretase inhibitors. Multiple resistant primary T-ALLs that emerged in vivo did not contain somatic Notch1 mutations present in the parental leukaemia. Importantly, resistant clones upregulated PI3K signalling. Consistent with these data, inhibiting Notch1 activated the PI3K pathway, providing a likely mechanism for selection against oncogenic Notch1 signalling. These studies validate PI3K as a therapeutic target in T-ALL and raise the unexpected possibility that dual inhibition of PI3K and Notch1 signalling could promote drug resistance in T-ALL.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4213126/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4213126/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dail, Monique -- Wong, Jason -- Lawrence, Jessica -- O'Connor, Daniel -- Nakitandwe, Joy -- Chen, Shann-Ching -- Xu, Jin -- Lee, Leslie B -- Akagi, Keiko -- Li, Qing -- Aster, Jon C -- Pear, Warren S -- Downing, James R -- Sampath, Deepak -- Shannon, Kevin -- K08 CA134649/CA/NCI NIH HHS/ -- K99 CA157950/CA/NCI NIH HHS/ -- P01 CA119070/CA/NCI NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- R01 CA180037/CA/NCI NIH HHS/ -- R37 CA072614/CA/NCI NIH HHS/ -- R37 CA72614/CA/NCI NIH HHS/ -- U01 CA084221/CA/NCI NIH HHS/ -- England -- Nature. 2014 Sep 25;513(7519):512-6. doi: 10.1038/nature13495. Epub 2014 Jul 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatrics and Benniof Children's Hospital, University of California, San Francisco, California 94143, USA. ; Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Translational Oncology, Genentech Inc., South San Francisco, California 94080, USA. ; Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, Ohio 43210, USA. ; Division of Haematology/Oncology, Department of Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA. ; Department of Pathology, Brigham &Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Abramson Family Cancer Research Institute and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043004" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Benzamides/pharmacology/therapeutic use ; Clone Cells/drug effects/metabolism/pathology ; Diphenylamine/analogs & derivatives/pharmacology/therapeutic use ; Down-Regulation/drug effects ; *Drug Resistance, Neoplasm/drug effects/genetics ; Drug Synergism ; Genes, ras/genetics ; Indazoles/*pharmacology/therapeutic use ; Male ; Mice ; Mice, Inbred C57BL ; Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors ; Phosphatidylinositol 3-Kinases/*antagonists & inhibitors ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/*drug ; therapy/*genetics/metabolism/pathology ; Protein Kinase Inhibitors/*pharmacology/therapeutic use ; Protein Structure, Tertiary ; Proto-Oncogene Proteins c-akt/metabolism ; Receptor, Notch1/chemistry/deficiency/genetics/*metabolism ; Signal Transduction/drug effects ; Sulfonamides/*pharmacology/therapeutic use
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2014-08-30
    Description: Without an approved vaccine or treatments, Ebola outbreak management has been limited to palliative care and barrier methods to prevent transmission. These approaches, however, have yet to end the 2014 outbreak of Ebola after its prolonged presence in West Africa. Here we show that a combination of monoclonal antibodies (ZMapp), optimized from two previous antibody cocktails, is able to rescue 100% of rhesus macaques when treatment is initiated up to 5 days post-challenge. High fever, viraemia and abnormalities in blood count and blood chemistry were evident in many animals before ZMapp intervention. Advanced disease, as indicated by elevated liver enzymes, mucosal haemorrhages and generalized petechia could be reversed, leading to full recovery. ELISA and neutralizing antibody assays indicate that ZMapp is cross-reactive with the Guinean variant of Ebola. ZMapp exceeds the efficacy of any other therapeutics described so far, and results warrant further development of this cocktail for clinical use.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214273/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214273/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Qiu, Xiangguo -- Wong, Gary -- Audet, Jonathan -- Bello, Alexander -- Fernando, Lisa -- Alimonti, Judie B -- Fausther-Bovendo, Hugues -- Wei, Haiyan -- Aviles, Jenna -- Hiatt, Ernie -- Johnson, Ashley -- Morton, Josh -- Swope, Kelsi -- Bohorov, Ognian -- Bohorova, Natasha -- Goodman, Charles -- Kim, Do -- Pauly, Michael H -- Velasco, Jesus -- Pettitt, James -- Olinger, Gene G -- Whaley, Kevin -- Xu, Bianli -- Strong, James E -- Zeitlin, Larry -- Kobinger, Gary P -- U19 AI109762/AI/NIAID NIH HHS/ -- U19AI109762/AI/NIAID NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2014 Oct 2;514(7520):47-53. doi: 10.1038/nature13777. Epub 2014 Aug 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Laboratory for Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada. ; 1] National Laboratory for Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada [2] Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada. ; 1] National Laboratory for Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada [2] Institute of Infectious Disease, Henan Centre for Disease Control and Prevention, Zhengzhou, 450012 Henan, China. ; Kentucky BioProcessing, Owensboro, Kentucky 42301, USA. ; Mapp Biopharmaceutical Inc., San Diego, California 92121, USA. ; 1] United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Frederick, Maryland 21702, USA [2] Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland 21702, USA. ; Institute of Infectious Disease, Henan Centre for Disease Control and Prevention, Zhengzhou, 450012 Henan, China. ; 1] National Laboratory for Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada [2] Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada [3] Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba R3A 1S1, Canada. ; 1] National Laboratory for Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada [2] Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada [3] Department of Immunology, University of Manitoba, Winnipeg, Manitoba R3E 0T5, Canada [4] Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25171469" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Antibodies, Monoclonal/immunology/*therapeutic use ; Antibodies, Neutralizing/immunology/therapeutic use ; Antibodies, Viral/immunology/*therapeutic use ; Cross Reactions/immunology ; Ebolavirus/immunology ; Enzyme-Linked Immunosorbent Assay ; Female ; Guinea ; Guinea Pigs ; Hemorrhagic Fever, Ebola/blood/*drug therapy/immunology/virology ; *Immunization, Passive ; Macaca mulatta/immunology/virology ; Male ; Molecular Sequence Data ; Sequence Alignment ; Viral Envelope Proteins/chemistry/immunology ; Viremia/drug therapy/immunology/virology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2014-05-16
    Description: Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is essential for normal brain growth and cognitive function. Consistent with its importance in the brain, DHA is highly enriched in brain phospholipids. Despite being an abundant fatty acid in brain phospholipids, DHA cannot be de novo synthesized in brain and must be imported across the blood-brain barrier, but mechanisms for DHA uptake in brain have remained enigmatic. Here we identify a member of the major facilitator superfamily--Mfsd2a (previously an orphan transporter)--as the major transporter for DHA uptake into brain. Mfsd2a is found to be expressed exclusively in endothelium of the blood-brain barrier of micro-vessels. Lipidomic analysis indicates that Mfsd2a-deficient (Mfsd2a-knockout) mice show markedly reduced levels of DHA in brain accompanied by neuronal cell loss in hippocampus and cerebellum, as well as cognitive deficits and severe anxiety, and microcephaly. Unexpectedly, cell-based studies indicate that Mfsd2a transports DHA in the form of lysophosphatidylcholine (LPC), but not unesterified fatty acid, in a sodium-dependent manner. Notably, Mfsd2a transports common plasma LPCs carrying long-chain fatty acids such LPC oleate and LPC palmitate, but not LPCs with less than a 14-carbon acyl chain. Moreover, we determine that the phosphor-zwitterionic headgroup of LPC is critical for transport. Importantly, Mfsd2a-knockout mice have markedly reduced uptake of labelled LPC DHA, and other LPCs, from plasma into brain, demonstrating that Mfsd2a is required for brain uptake of DHA. Our findings reveal an unexpected essential physiological role of plasma-derived LPCs in brain growth and function.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nguyen, Long N -- Ma, Dongliang -- Shui, Guanghou -- Wong, Peiyan -- Cazenave-Gassiot, Amaury -- Zhang, Xiaodong -- Wenk, Markus R -- Goh, Eyleen L K -- Silver, David L -- England -- Nature. 2014 May 22;509(7501):503-6. doi: 10.1038/nature13241. Epub 2014 May 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Graduate Medical School Singapore, 8 College Road, 169857 Singapore. ; Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, 8 College Road, 169857 Singapore. ; Department of Biochemistry, National University of Singapore, 8 Medical Drive, Block MD7, 117597 Singapore.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24828044" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anxiety/physiopathology ; Biological Transport ; Blood-Brain Barrier/metabolism ; Brain/*metabolism/pathology/physiopathology ; Cognition Disorders/pathology/physiopathology ; Docosahexaenoic Acids/deficiency/*metabolism ; Endothelium, Vascular/metabolism ; Female ; Lysophosphatidylcholines/chemistry/metabolism ; Male ; Membrane Transport Proteins/deficiency/genetics/*metabolism ; Mice ; Mice, Knockout ; Microcephaly/metabolism/pathology ; Microvessels/metabolism ; Neurons/metabolism/pathology ; Organ Size ; Sodium/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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