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  • 1
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    Single cell resolution in vivo imaging of DNA damage following PARP inhibition (2015)
    Springer Nature
    Details
    Publication Date: 2015-05-19
    Description: Targeting DNA repair pathways is a powerful strategy to treat cancers. To gauge efficacy in vivo, typical response markers include late stage effects such as tumor shrinkage, progression free survival, or invasive repeat biopsies. These approaches are often difficult to answer critical questions such as how a given drug affects single cell populations as a function of dose and time, distance from microvessels or how drug concentration (pharmacokinetics) correlates with DNA damage (pharmacodynamics). Here, we established a single-cell in vivo pharmacodynamic imaging read-out based on a truncated 53BP1 double-strand break reporter to determine whether or not poly(ADP-ribose) polymerase (PARP) inhibitor treatment leads to accumulation of DNA damage. Using this reporter, we show that not all PARP inhibitor treated tumors incur an increase in DNA damage. The method provides a framework for single cell analysis of cancer therapeutics in vivo. Scientific Reports 5 doi: 10.1038/srep10129
    Electronic ISSN: 2045-2322
    Topics: Natural Sciences in General
    Published by Springer Nature
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  • 2
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    Prediction of Wave Propagation in Buildings Using Data from a Single Seismometer (2015)
    Seismological Society of America (SSA)
    Details
    Publication Date: 2015-01-30
    Description: Crowd-sourced seismic networks in buildings collect important scientific data, in addition to allowing a diverse audience to visualize the vibrations of buildings. Visualization of a building’s deformation requires spatiotemporal interpolation of motions from seismometers that are located wherever the crowd places them. In many cases, a crowd-sourced building network may actually be just a single seismometer. A method to rapidly estimate the total displacement response of a building based on limited observational data, in some cases from only a single seismometer, is presented. In general, the earliest part of the response is simulated by assuming a vertically propagating shear wave. Later motions are simulated using mode shapes derived from a beam model (a shear beam, or more generally a Timoshenko beam), the parameters of which are determined from the ratios of the modal frequencies and the building’s exterior dimensions. The method is verified by (1) comparing predicted and actual records from a 54-story building in downtown Los Angeles, California, and (2) comparing finite-element simulations of the 17-story University of California, Los Angeles (UCLA) Factor building. The response of each of these buildings can be simulated with a simple shear beam. The importance of including the traveling wave part of the solution depends on the characteristics of the base ground shaking; the traveling wave becomes more apparent as the excitation becomes more impulsive. The method can be straightforwardly applied to multiple instrumented buildings, resulting in a tool to visualize linear elastic motions of those buildings.
    Print ISSN: 0037-1106
    Electronic ISSN: 1943-3573
    Topics: Geosciences , Physics
    Published by Seismological Society of America (SSA)
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  • 3
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    Carbamylation and aging [Chemistry] (2016)
    National Academy of Sciences
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    Publication Date: 2016-02-03
    Description: Aging is a progressive process determined by genetic and acquired factors. Among the latter are the chemical reactions referred to as nonenzymatic posttranslational modifications (NEPTMs), such as glycoxidation, which are responsible for protein molecular aging. Carbamylation is a more recently described NEPTM that is caused by the nonenzymatic binding of...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 4
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    Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug (2015)
    Springer Nature
    Details
    Publication Date: 2015-10-29
    Description: Article Drug-loaded nanoparticles allow controlled release and enhanced delivery, yet understanding in vivo behavior has been difficult. Here, the authors develop a platinum prodrug coupled to a polymer platform, and use intravital imaging to show that the nanoparticle accumulates in macrophages, from the which drug redistributes to neighboring tumour cells. Nature Communications doi: 10.1038/ncomms9692 Authors: Miles A. Miller, Yao-Rong Zheng, Suresh Gadde, Christina Pfirschke, Harshal Zope, Camilla Engblom, Rainer H. Kohler, Yoshiko Iwamoto, Katherine S. Yang, Bjorn Askevold, Nagesh Kolishetti, Mikael Pittet, Stephen J. Lippard, Omid C. Farokhzad, Ralph Weissleder
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 5
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    Single cell imaging of Bruton's Tyrosine Kinase using an irreversible inhibitor (2014)
    Springer Nature
    Details
    Publication Date: 2014-04-25
    Description: A number of Bruton's tyrosine kinase (BTK) inhibitors are currently in development, yet it has been difficult to visualize BTK expression and pharmacological inhibition in vivo in real time. We synthesized a fluorescent, irreversible BTK binder based on the drug Ibrutinib and characterized its behavior in cells and in vivo. We show a 200 nM affinity of the imaging agent, high selectivity, and irreversible binding to its target following initial washout, resulting in surprisingly high target-to-background ratios. In vivo, the imaging agent rapidly distributed to BTK expressing tumor cells, but also to BTK-positive tumor-associated host cells. Scientific Reports 4 doi: 10.1038/srep04782
    Electronic ISSN: 2045-2322
    Topics: Natural Sciences in General
    Published by Springer Nature
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  • 6
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    Parametric correlations versus fidelity decay: The symmetry breaking case (2011)
    American Physical Society (APS)
    Details
    Publication Date: 2011-12-20
    Description: Author(s): H. Kohler, T. Nagao, and H.-J. Stöckmann [Phys. Rev. E 84, 061133] Published Mon Dec 19, 2011
    Keywords: Statistical physics
    Print ISSN: 1539-3755
    Electronic ISSN: 1550-2376
    Topics: Physics
    Published by American Physical Society (APS)
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  • 7
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    Exchange of protein molecules through connections between higher plant plastids (1997)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1997-06-27
    Description: Individual plastids of vascular plants have generally been considered to be discrete autonomous entities that do not directly communicate with each other. However, in transgenic plants in which the plastid stroma was labeled with green fluorescent protein (GFP), thin tubular projections emanated from individual plastids and sometimes connected to other plastids. Flow of GFP between interconnected plastids could be observed when a single plastid or an interconnecting plastid tubule was photobleached and the loss of green fluorescence by both plastids was seen. These tubules allow the exchange of molecules within an interplastid communication system, which may facilitate the coordination of plastid activities.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kohler, R H -- Cao, J -- Zipfel, W R -- Webb, W W -- Hanson, M R -- R07719/PHS HHS/ -- RR04224/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 1997 Jun 27;276(5321):2039-42.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Section of Genetics and Development, Cornell University, Biotechnology Building, Ithaca, NY 14853-2703, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9197266" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Base Sequence ; Chloroplasts/*metabolism/*ultrastructure ; Cytoplasm/metabolism ; Green Fluorescent Proteins ; Luminescent Proteins/*metabolism ; Microscopy/methods ; Microscopy, Fluorescence ; Molecular Sequence Data ; Plant Leaves/*ultrastructure ; Plants, Genetically Modified ; Plants, Toxic ; Recombinant Fusion Proteins/metabolism ; Tobacco
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 8
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    PIK3CA(H1047R) induces multipotency and multi-lineage mammary tumours (2015)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2015-08-13
    Description: The adult mouse mammary epithelium contains self-sustained cell lineages that form the inner luminal and outer basal cell layers, with stem and progenitor cells contributing to its proliferative and regenerative potential. A key issue in breast cancer biology is the effect of genomic lesions in specific mammary cell lineages on tumour heterogeneity and progression. The impact of transforming events on fate conversion in cancer cells of origin and thus their contribution to tumour heterogeneity remains largely elusive. Using in situ genetic lineage tracing and limiting dilution transplantation, we have unravelled the potential of PIK3CA(H1047R), one of the most frequent mutations occurring in human breast cancer, to induce multipotency during tumorigenesis in the mammary gland. Here we show that expression of PIK3CA(H1047R) in lineage-committed basal Lgr5-positive and luminal keratin-8-positive cells of the adult mouse mammary gland evokes cell dedifferentiation into a multipotent stem-like state, suggesting this to be a mechanism involved in the formation of heterogeneous, multi-lineage mammary tumours. Moreover, we show that the tumour cell of origin influences the frequency of malignant mammary tumours. Our results define a key effect of PIK3CA(H1047R) on mammary cell fate in the pre-neoplastic mammary gland and show that the cell of origin of PIK3CA(H1047R) tumours dictates their malignancy, thus revealing a mechanism underlying tumour heterogeneity and aggressiveness.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Koren, Shany -- Reavie, Linsey -- Couto, Joana Pinto -- De Silva, Duvini -- Stadler, Michael B -- Roloff, Tim -- Britschgi, Adrian -- Eichlisberger, Tobias -- Kohler, Hubertus -- Aina, Olulanu -- Cardiff, Robert D -- Bentires-Alj, Mohamed -- U01 CA141582/CA/NCI NIH HHS/ -- England -- Nature. 2015 Sep 3;525(7567):114-8. doi: 10.1038/nature14669. Epub 2015 Aug 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Friedrich Miescher Institute for Biomedical Research (FMI), 4058 Basel, Switzerland. ; Swiss Institute of Bioinformatics, 4058 Basel, Switzerland. ; Department of Pathology, Center for Comparative Medicine, University of California Davis, Davis, California 95616, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26266975" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Breast Neoplasms/*genetics/*pathology ; Cell Dedifferentiation/genetics ; Cell Lineage/*genetics ; Cell Transformation, Neoplastic/genetics ; Female ; Humans ; Mammary Glands, Animal/metabolism/pathology ; Mammary Neoplasms, Animal/*genetics/*pathology ; Mice ; Multipotent Stem Cells/*metabolism/pathology ; Mutation/genetics ; Neoplasm Invasiveness/genetics/pathology ; Phosphatidylinositol 3-Kinases/*genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 9
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    Identification of splenic reservoir monocytes and their deployment to inflammatory sites (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-08-01
    Description: A current paradigm states that monocytes circulate freely and patrol blood vessels but differentiate irreversibly into dendritic cells (DCs) or macrophages upon tissue entry. Here we show that bona fide undifferentiated monocytes reside in the spleen and outnumber their equivalents in circulation. The reservoir monocytes assemble in clusters in the cords of the subcapsular red pulp and are distinct from macrophages and DCs. In response to ischemic myocardial injury, splenic monocytes increase their motility, exit the spleen en masse, accumulate in injured tissue, and participate in wound healing. These observations uncover a role for the spleen as a site for storage and rapid deployment of monocytes and identify splenic monocytes as a resource that the body exploits to regulate inflammation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2803111/" 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/PMC2803111/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Swirski, Filip K -- Nahrendorf, Matthias -- Etzrodt, Martin -- Wildgruber, Moritz -- Cortez-Retamozo, Virna -- Panizzi, Peter -- Figueiredo, Jose-Luiz -- Kohler, Rainer H -- Chudnovskiy, Aleksey -- Waterman, Peter -- Aikawa, Elena -- Mempel, Thorsten R -- Libby, Peter -- Weissleder, Ralph -- Pittet, Mikael J -- 1R01HL095612/HL/NHLBI NIH HHS/ -- P01 A154904/PHS HHS/ -- P01 AI054904/AI/NIAID NIH HHS/ -- P01 AI054904-010001/AI/NIAID NIH HHS/ -- P50 CA086355/CA/NCI NIH HHS/ -- P50 CA086355-07/CA/NCI NIH HHS/ -- P50 CA86355/CA/NCI NIH HHS/ -- R00 HL094533/HL/NHLBI NIH HHS/ -- R01 HL095629/HL/NHLBI NIH HHS/ -- R01 HL096576/HL/NHLBI NIH HHS/ -- R24 CA69246/CA/NCI NIH HHS/ -- U01 HL080731/HL/NHLBI NIH HHS/ -- U01 HL080731-05/HL/NHLBI NIH HHS/ -- U54 CA126515/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2009 Jul 31;325(5940):612-6. doi: 10.1126/science.1175202.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. fswirski@mgh.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19644120" target="_blank"〉PubMed〈/a〉
    Keywords: Angiotensin II/blood/pharmacology ; Animals ; Antigens, Ly/metabolism ; Bone Marrow Cells/physiology ; Cell Differentiation ; Cell Movement ; Cell Size ; Female ; Inflammation/*pathology ; Mice ; Mice, Inbred C57BL ; Monocytes/cytology/*physiology ; Myocardial Infarction/immunology/*pathology/*physiopathology ; Myocardium/*immunology/*pathology ; Rats ; Rats, Wistar ; Receptors, Angiotensin/metabolism ; Spleen/cytology/*immunology ; Splenectomy
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 10
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    Grassland biodiversity bounces back from long-term nitrogen addition (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-12-04
    Description: The negative effect of increasing atmospheric nitrogen (N) pollution on grassland biodiversity is now incontrovertible. However, the recent introduction of cleaner technologies in the UK has led to reductions in the emissions of nitrogen oxides, with concomitant decreases in N deposition. The degree to which grassland biodiversity can be expected to 'bounce back' in response to these improvements in air quality is uncertain, with a suggestion that long-term chronic N addition may lead to an alternative low biodiversity state. Here we present evidence from the 160-year-old Park Grass Experiment at Rothamsted Research, UK, that shows a positive response of biodiversity to reducing N addition from either atmospheric pollution or fertilizers. The proportion of legumes, species richness and diversity increased across the experiment between 1991 and 2012 as both wet and dry N deposition declined. Plots that stopped receiving inorganic N fertilizer in 1989 recovered much of the diversity that had been lost, especially if limed. There was no evidence that chronic N addition has resulted in an alternative low biodiversity state on the Park Grass plots, except where there has been extreme acidification, although it is likely that the recovery of plant communities has been facilitated by the twice-yearly mowing and removal of biomass. This may also explain why a comparable response of plant communities to reduced N inputs has yet to be observed in the wider landscape.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Storkey, J -- Macdonald, A J -- Poulton, P R -- Scott, T -- Kohler, I H -- Schnyder, H -- Goulding, K W T -- Crawley, M J -- Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2015 Dec 17;528(7582):401-4. doi: 10.1038/nature16444. Epub 2015 Dec 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Rothamsted Research, Harpenden, Hertfordshire AL5 2JQ, UK. ; Lehrstuhl fur Grunlandlehre, Technische Universitat Munchen, Alte Akademie 12, 85354 Freising-Weihenstephan, Germany. ; Department of Biological Sciences, Imperial College London, Silwood Park, Ascot, Berkshire SL5 7PY, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26633635" target="_blank"〉PubMed〈/a〉
    Keywords: Air Pollution/*adverse effects/analysis ; Atmosphere/chemistry ; *Biodiversity ; Biomass ; *Environmental Restoration and Remediation ; Fabaceae/drug effects/metabolism ; Fertilizers/adverse effects/analysis ; *Grassland ; Great Britain ; Hydrogen-Ion Concentration ; Nitrogen/*adverse effects/analysis ; Parks, Recreational ; Poaceae/*classification/*drug effects/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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