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  • 1
    Publication Date: 2011-04-15
    Description: Schizophrenia (SCZD) is a debilitating neurological disorder with a world-wide prevalence of 1%; there is a strong genetic component, with an estimated heritability of 80-85%. Although post-mortem studies have revealed reduced brain volume, cell size, spine density and abnormal neural distribution in the prefrontal cortex and hippocampus of SCZD brain tissue and neuropharmacological studies have implicated dopaminergic, glutamatergic and GABAergic activity in SCZD, the cell types affected in SCZD and the molecular mechanisms underlying the disease state remain unclear. To elucidate the cellular and molecular defects of SCZD, we directly reprogrammed fibroblasts from SCZD patients into human induced pluripotent stem cells (hiPSCs) and subsequently differentiated these disorder-specific hiPSCs into neurons (Supplementary Fig. 1). SCZD hiPSC neurons showed diminished neuronal connectivity in conjunction with decreased neurite number, PSD95-protein levels and glutamate receptor expression. Gene expression profiles of SCZD hiPSC neurons identified altered expression of many components of the cyclic AMP and WNT signalling pathways. Key cellular and molecular elements of the SCZD phenotype were ameliorated following treatment of SCZD hiPSC neurons with the antipsychotic loxapine. To date, hiPSC neuronal pathology has only been demonstrated in diseases characterized by both the loss of function of a single gene product and rapid disease progression in early childhood. We now report hiPSC neuronal phenotypes and gene expression changes associated with SCZD, a complex genetic psychiatric disorder.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392969/" 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/PMC3392969/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brennand, Kristen J -- Simone, Anthony -- Jou, Jessica -- Gelboin-Burkhart, Chelsea -- Tran, Ngoc -- Sangar, Sarah -- Li, Yan -- Mu, Yangling -- Chen, Gong -- Yu, Diana -- McCarthy, Shane -- Sebat, Jonathan -- Gage, Fred H -- P01 NS028121/NS/NINDS NIH HHS/ -- P30 NS072031/NS/NINDS NIH HHS/ -- R01 MH083911/MH/NIMH NIH HHS/ -- England -- Nature. 2011 May 12;473(7346):221-5. doi: 10.1038/nature09915. Epub 2011 Apr 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Salk Institute for Biological Studies, Laboratory of Genetics, 10010 North Torrey Pines Road, La Jolla California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21490598" target="_blank"〉PubMed〈/a〉
    Keywords: Adolescent ; Adult ; Antipsychotic Agents/pharmacology ; Cell Differentiation ; Cells, Cultured ; Cellular Reprogramming/genetics ; Child ; Female ; Fibroblasts/cytology ; Gene Expression Profiling ; *Gene Expression Regulation/drug effects ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Loxapine/pharmacology ; Male ; Membrane Proteins/metabolism ; Models, Biological ; Neurites ; Neurons/*cytology/drug effects/*metabolism ; Phenotype ; Pluripotent Stem Cells/*cytology/*metabolism/pathology ; Receptors, Glutamate/metabolism ; Schizophrenia/*pathology ; Young Adult
    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: 2012-01-27
    Description: Our understanding of Alzheimer's disease pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of the disease. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). Here we reprogrammed primary fibroblasts from two patients with familial Alzheimer's disease, both caused by a duplication of the amyloid-beta precursor protein gene (APP; termed APP(Dp)), two with sporadic Alzheimer's disease (termed sAD1, sAD2) and two non-demented control individuals into iPSC lines. Neurons from differentiated cultures were purified with fluorescence-activated cell sorting and characterized. Purified cultures contained more than 90% neurons, clustered with fetal brain messenger RNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APP(Dp) patients and patient sAD2 exhibited significantly higher levels of the pathological markers amyloid-beta(1-40), phospho-tau(Thr 231) and active glycogen synthase kinase-3beta (aGSK-3beta). Neurons from APP(Dp) and sAD2 patients also accumulated large RAB5-positive early endosomes compared to controls. Treatment of purified neurons with beta-secretase inhibitors, but not gamma-secretase inhibitors, caused significant reductions in phospho-Tau(Thr 231) and aGSK-3beta levels. These results suggest a direct relationship between APP proteolytic processing, but not amyloid-beta, in GSK-3beta activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial Alzheimer's disease samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to Alzheimer's disease, even though it can take decades for overt disease to manifest in patients.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338985/" 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/PMC3338985/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Israel, Mason A -- Yuan, Shauna H -- Bardy, Cedric -- Reyna, Sol M -- Mu, Yangling -- Herrera, Cheryl -- Hefferan, Michael P -- Van Gorp, Sebastiaan -- Nazor, Kristopher L -- Boscolo, Francesca S -- Carson, Christian T -- Laurent, Louise C -- Marsala, Martin -- Gage, Fred H -- Remes, Anne M -- Koo, Edward H -- Goldstein, Lawrence S B -- K12 HD001259/HD/NICHD NIH HHS/ -- P30 NS047101/NS/NINDS NIH HHS/ -- P50 AG005131/AG/NIA NIH HHS/ -- RC1 NS068705/NS/NINDS NIH HHS/ -- RC1 NS068705-01/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jan 25;482(7384):216-20. doi: 10.1038/nature10821.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22278060" target="_blank"〉PubMed〈/a〉
    Keywords: Aged, 80 and over ; Alzheimer Disease/*metabolism/*pathology ; Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism ; Amyloid beta-Peptides/metabolism/secretion ; Amyloid beta-Protein Precursor/genetics/metabolism/secretion ; Astrocytes/cytology ; Biomarkers/metabolism ; Cells, Cultured ; Cellular Reprogramming ; Coculture Techniques ; Endosomes/metabolism ; Enzyme Activation ; Female ; Fibroblasts/cytology/metabolism ; Glycogen Synthase Kinase 3/metabolism ; Humans ; Induced Pluripotent Stem Cells/*metabolism/*pathology ; Male ; Middle Aged ; Models, Biological ; Neurons/drug effects/*metabolism/pathology ; Peptide Fragments/metabolism/secretion ; Phosphoproteins/metabolism ; Phosphorylation/drug effects ; Protease Inhibitors/pharmacology ; Proteolysis ; Synapsins/metabolism ; tau Proteins/metabolism
    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: 2018-09-01
    Description: Dynamic nuclear polarization (DNP) is an important technique that uses polarization transfer from electron to nuclear spins to achieve nuclear hyperpolarization. Combining efficient DNP with optically polarized nitrogen-vacancy (NV) centers offers promising opportunities for novel technological applications, including nanoscale nuclear magnetic resonance spectroscopy of liquids, hyperpolarized nanodiamonds as magnetic resonance imaging contrast agents, and the initialization of nuclear spin–based diamond quantum simulators. However, none of the current realizations of polarization transfer are simultaneously robust and sufficiently efficient, making the realization of the applications extremely challenging. We introduce the concept of systematically designing polarization sequences by Hamiltonian engineering, resulting in polarization sequences that are robust and fast. We theoretically derive sequences and experimentally demonstrate that they are capable of efficient polarization transfer from optically polarized NV centers in diamond to the surrounding 13 C nuclear spin bath even in the presence of control errors, making the abovementioned novel applications possible.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 4
    Publication Date: 2018-05-16
    Description: Purpose: Wnt/β-catenin signaling is required for leukemic stem cell function. FLT3 mutations are frequently observed in acute myeloid leukemia (AML). Anomalous FLT3 signaling increases β-catenin nuclear localization and transcriptional activity. FLT3 tyrosine kinase inhibitors (TKI) are used clinically to treat FLT3 -mutated AML patients, but with limited efficacy. We investigated the antileukemia activity of combined Wnt/β-catenin and FLT3 inhibition in FLT3 -mutant AML. Experimental Design: Wnt/β-catenin signaling was inhibited by the β-catenin/CBP antagonist C-82/PRI-724 or siRNAs, and FLT3 signaling by sorafenib or quizartinib. Treatments on apoptosis, cell growth, and cell signaling were assessed in cell lines, patient samples, and in vivo in immunodeficient mice by flow cytometry, Western blot, RT-PCR, and CyTOF. Results: We found significantly higher β-catenin expression in cytogenetically unfavorable and relapsed AML patient samples and in the bone marrow–resident leukemic cells compared with circulating blasts. Disrupting Wnt/β-catenin signaling suppressed AML cell growth, induced apoptosis, abrogated stromal protection, and synergized with TKIs in FLT3 -mutated AML cells and stem/progenitor cells in vitro . The aforementioned combinatorial treatment improved survival of AML-xenografted mice in two in vivo models and impaired leukemia cell engraftment. Mechanistically, the combined inhibition of Wnt/β-catenin and FLT3 cooperatively decreased nuclear β-catenin and the levels of c-Myc and other Wnt/β-catenin and FLT3 signaling proteins. Importantly, β-catenin inhibition abrogated the microenvironmental protection afforded the leukemic stem/progenitor cells. Conclusions: Disrupting Wnt/β-catenin signaling exerts potent activities against AML stem/progenitor cells and synergizes with FLT3 inhibition in FLT3 -mutant AML. These findings provide a rationale for clinical development of this strategy for treating FLT3 -mutated AML patients. Clin Cancer Res; 24(10); 2417–29. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 5
    Publication Date: 2018-03-06
    Description: Purpose: Barrett's esophagus represents an early stage in carcinogenesis leading to esophageal adenocarcinoma. Considerable evidence supports a major role for chronic inflammation and diverse chemokine pathways in the development of Barrett's esophagus and esophageal adenocarcinoma. Experimental Design: Here we utilized an IL1β transgenic mouse model of Barrett's esophagus and esophageal adenocarcinoma and human patient imaging to analyze the importance of CXCR4-expressing cells during esophageal carcinogenesis. Results: IL1β overexpression induces chronic esophageal inflammation and recapitulates the progression to Barrett's esophagus and esophageal adenocarcinoma. CXCR4 expression is increased in both epithelial and immune cells during disease progression in pL2-IL1β mice and also elevated in esophageal adenocarcinoma patient biopsy samples. Specific recruitment of CXCR4-positive (CXCR4 + ) immune cells correlated with dysplasia progression, suggesting that this immune population may be a key contributor to esophageal carcinogenesis. Similarly, with progression to dysplasia, there were increased numbers of CXCR4 + columnar epithelial cells at the squamocolumnar junction (SCJ). These findings were supported by stronger CXCR4-related signal intensity in ex vivo fluorescence imaging and autoradiography with advanced dysplasia. Pilot CXCR4-directed PET/CT imaging studies in patients with esophageal cancer demonstrate the potential utility of CXCR4 imaging for the diagnosis and staging of esophageal cancer. Conclusion: In conclusion, the recruitment of CXCR4 + immune cells and expansion of CXCR4 + epithelial cells in esophageal dysplasia and cancer highlight the potential of CXCR4 as a biomarker and molecular target for diagnostic imaging of the tumor microenvironment in esophageal adenocarcinoma. Clin Cancer Res; 24(5); 1048–61. ©2017 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 6
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Polyhedron 10 (1991), S. 1239-1245 
    ISSN: 0277-5387
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Optics Communications 110 (1994), S. 334-339 
    ISSN: 0030-4018
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 0022-4073
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Oxford [u.a.] : International Union of Crystallography (IUCr)
    Acta crystallographica 55 (1999), S. 728-730 
    ISSN: 1600-5759
    Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001
    Topics: Chemistry and Pharmacology , Geosciences , Physics
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1572-9559
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract We report a deductive method used in the incomplete far-infrared reflection spectrum analysis. The inherent restriction between the oscillator model and Kramers-Kronig relation is used to deduct the dielectric constant. In this way, one can analysis the incomplete far-infrared reflection spectrum of a crystal by combining both oscillator model and Kramers-Kronig relation.
    Type of Medium: Electronic Resource
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