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  • 1
    Publication Date: 2012-12-14
    Description: At the end of cell division, cytokinesis splits the cytoplasm of nascent daughter cells and partitions segregated sister genomes. To coordinate cell division with chromosome segregation, the mitotic spindle controls cytokinetic events at the cell envelope. The spindle midzone stimulates the actomyosin-driven contraction of the cleavage furrow, which proceeds until the formation of a microtubule-rich intercellular bridge with the midbody at its centre. The midbody directs the final membrane abscission reaction and has been proposed to attach the cleavage furrow to the intercellular bridge. How the mitotic spindle is connected to the plasma membrane during cytokinesis is not understood. Here we identify a plasma membrane tethering activity in the centralspindlin protein complex, a conserved component of the spindle midzone and midbody. We demonstrate that the C1 domain of the centralspindlin subunit MgcRacGAP associates with the plasma membrane by interacting with polyanionic phosphoinositide lipids. Using X-ray crystallography we determine the structure of this atypical C1 domain. Mutations in the hydrophobic cap and in basic residues of the C1 domain of MgcRacGAP prevent association of the protein with the plasma membrane, and abrogate cytokinesis in human and chicken cells. Artificial membrane tethering of centralspindlin restores cell division in the absence of the C1 domain of MgcRacGAP. Although C1 domain function is dispensable for the formation of the midzone and midbody, it promotes contractility and is required for the attachment of the plasma membrane to the midbody, a long-postulated function of this organelle. Our analysis suggests that centralspindlin links the mitotic spindle to the plasma membrane to secure the final cut during cytokinesis in animal cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lekomtsev, Sergey -- Su, Kuan-Chung -- Pye, Valerie E -- Blight, Ken -- Sundaramoorthy, Sriramkumar -- Takaki, Tohru -- Collinson, Lucy M -- Cherepanov, Peter -- Divecha, Nullin -- Petronczki, Mark -- Cancer Research UK/United Kingdom -- England -- Nature. 2012 Dec 13;492(7428):276-9. doi: 10.1038/nature11773.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cell Division and Aneuploidy Laboratory, Cancer Research UK London Research Institute, Clare Hall Laboratories, Blanche Lane, South Mimms, Hertfordshire EN6 3LD, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23235882" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Membrane/*metabolism ; Cytokinesis/genetics/*radiation effects ; GTPase-Activating Proteins/chemistry/genetics/*metabolism ; HEK293 Cells ; HeLa Cells ; Humans ; Microtubule-Associated Proteins/chemistry/genetics/*metabolism ; Microtubules/chemistry/metabolism ; Models, Molecular ; Protein Binding ; Protein Kinase C-alpha/metabolism ; Protein Structure, Tertiary ; Protein Transport/drug effects ; Spindle Apparatus/*metabolism ; Tetradecanoylphorbol Acetate/analogs & derivatives/pharmacology
    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: 2018-08-01
    Description: The transport of proteins across or into membranes is a vital biological process, achieved in every cell by the conserved Sec machinery. In bacteria, SecYEG combines with the SecA motor protein for secretion of preproteins across the plasma membrane, powered by ATP hydrolysis and the transmembrane proton-motive force (PMF). The...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 3
    Publication Date: 2018-08-02
    Description: Dysregulation of nuclear envelope (NE) assembly results in various cancers; for example, renal and some lung carcinomas ensue due to NE malformation. The NE is a dynamic membrane compartment and its completion during mitosis is a highly regulated process, but the detailed mechanism still remains incompletely understood. Previous studies have found that isolated diacylglycerol (DAG)-containing vesicles are essential for completing the fusion of the NE in nonsomatic cells. We investigated the impact of DAG depletion from the cis -Golgi in mammalian cells on NE reassembly. Using advanced electron microscopy, we observed an enriched DAG population of vesicles at the vicinity of the NE gaps of telophase mammalian cells. We applied a mini singlet oxygen generator-C1-domain tag that localized DAG-enriched vesicles at the perinuclear region, which suggested the existence of NE fusogenic vesicles. We quantified the impact of Golgi-DAG depletion by measuring the in situ NE rim curvature of the reforming NE. The rim curvature in these cells was significantly reduced compared with controls, which indicated a localized defect in NE morphology. Our novel results demonstrate the significance of the role of DAG from the cis -Golgi for the regulation of NE assembly.
    Print ISSN: 0022-2275
    Electronic ISSN: 1539-7262
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 4
    Publication Date: 2018-10-16
    Description: Jonathan N. Smith, Heather M. Walker, Hannah Thompson, J. Martin Collinson, Neil Vargesson, and Lynda Erskine Absence of the developing lens results in severe eye defects, including substantial reductions in eye size. How the lens controls eye expansion and the underlying signalling pathways are very poorly defined. We identified RDH10 , a gene crucial for retinoic acid synthesis during embryogenesis, as a key factor downregulated in the peripheral retina (presumptive ciliary body region) of lens-removed embryonic chicken eyes prior to overt reductions in eye size. This is associated with a significant decrease in retinoic acid synthesis by lens-removed eyes. Restoring retinoic acid signalling in lens-removed eyes by implanting beads soaked in retinoic acid or retinal, but not vitamin A, rescued eye size. Conversely, blocking retinoic acid synthesis decreased eye size in lens-containing eyes. Production of collagen II and collagen IX, which are major vitreal proteins, is also regulated by the lens and retinoic acid signalling. These data mechanistically link the known roles of both the lens and retinoic acid in normal eye development, and support a model whereby retinoic acid production by the peripheral retina acts downstream of the lens to support vitreous production and eye expansion.
    Print ISSN: 0950-1991
    Electronic ISSN: 1477-9129
    Topics: Biology
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  • 5
    Publication Date: 2018-01-04
    Description: Immune checkpoint inhibitors, including those targeting programmed cell death protein 1 (PD-1), are reshaping cancer therapeutic strategies. Evidence suggests, however, that tumor response and patient survival are determined by tumor programmed death ligand 1 (PD-L1) expression. We hypothesized that preconditioning of the tumor immune microenvironment using targeted, virus-mediated interferon (IFN) stimulation would up-regulate tumor PD-L1 protein expression and increase cytotoxic T cell infiltration, improving the efficacy of subsequent checkpoint blockade. Oncolytic viruses (OVs) represent a promising form of cancer immunotherapy. For brain tumors, almost all studies to date have used direct intralesional injection of OV, because of the largely untested belief that intravenous administration will not deliver virus to this site. We show, in a window-of-opportunity clinical study, that intravenous infusion of oncolytic human Orthoreovirus (referred to herein as reovirus) leads to infection of tumor cells subsequently resected as part of standard clinical care, both in high-grade glioma and in brain metastases, and increases cytotoxic T cell tumor infiltration relative to patients not treated with virus. We further show that reovirus up-regulates IFN-regulated gene expression, as well as the PD-1/PD-L1 axis in tumors, via an IFN-mediated mechanism. Finally, we show that addition of PD-1 blockade to reovirus enhances systemic therapy in a preclinical glioma model. These results support the development of combined systemic immunovirotherapy strategies for the treatment of both primary and secondary tumors in the brain.
    Print ISSN: 1946-6234
    Electronic ISSN: 1946-6242
    Topics: Medicine
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  • 6
    Publication Date: 2018-02-09
    Description: J. Martin Collinson, Nils O. Lindström, Carlos Neves, Karen Wallace, Caroline Meharg, Rebecca H. Charles, Zoe K. Ross, Amy M. Fraser, Ivan Mbogo, Kadri Oras, Masaru Nakamoto, Simon Barker, Suzanne Duce, Zosia Miedzybrodzka, and Neil Vargesson Genetic factors underlying the human limb abnormality congenital talipes equinovarus (‘clubfoot’) remain incompletely understood. The spontaneous autosomal recessive mouse ‘peroneal muscular atrophy’ mutant (PMA) is a faithful morphological model of human clubfoot. In PMA mice, the dorsal (peroneal) branches of the sciatic nerves are absent. In this study, the primary developmental defect was identified as a reduced growth of sciatic nerve lateral motor column (LMC) neurons leading to failure to project to dorsal (peroneal) lower limb muscle blocks. The pma mutation was mapped and a candidate gene encoding LIM-domain kinase 1 ( Limk1 ) identified, which is upregulated in mutant lateral LMC motor neurons. Genetic and molecular analyses showed that the mutation acts in the EphA4–Limk1–Cfl1/cofilin–actin pathway to modulate growth cone extension/collapse. In the chicken, both experimental upregulation of Limk1 by electroporation and pharmacological inhibition of actin turnover led to defects in hindlimb spinal motor neuron growth and pathfinding, and mimicked the clubfoot phenotype. The data support a neuromuscular aetiology for clubfoot and provide a mechanistic framework to understand clubfoot in humans.
    Keywords: Neural development, Musculoskeletal system
    Print ISSN: 0950-1991
    Electronic ISSN: 1477-9129
    Topics: Biology
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  • 7
    Publication Date: 2015-11-07
    Description: Coupling between the lower and upper atmosphere, combined with loss of gas from the upper atmosphere to space, likely contributed to the thin, cold, dry atmosphere of modern Mars. To help understand ongoing ion loss to space, the Mars Atmosphere and Volatile Evolution (MAVEN) spacecraft made comprehensive measurements of the Mars upper atmosphere, ionosphere, and interactions with the Sun and solar wind during an interplanetary coronal mass ejection impact in March 2015. Responses include changes in the bow shock and magnetosheath, formation of widespread diffuse aurora, and enhancement of pick-up ions. Observations and models both show an enhancement in escape rate of ions to space during the event. Ion loss during solar events early in Mars history may have been a major contributor to the long-term evolution of the Mars atmosphere.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jakosky, B M -- Grebowsky, J M -- Luhmann, J G -- Connerney, J -- Eparvier, F -- Ergun, R -- Halekas, J -- Larson, D -- Mahaffy, P -- McFadden, J -- Mitchell, D F -- Schneider, N -- Zurek, R -- Bougher, S -- Brain, D -- Ma, Y J -- Mazelle, C -- Andersson, L -- Andrews, D -- Baird, D -- Baker, D -- Bell, J M -- Benna, M -- Chaffin, M -- Chamberlin, P -- Chaufray, Y-Y -- Clarke, J -- Collinson, G -- Combi, M -- Crary, F -- Cravens, T -- Crismani, M -- Curry, S -- Curtis, D -- Deighan, J -- Delory, G -- Dewey, R -- DiBraccio, G -- Dong, C -- Dong, Y -- Dunn, P -- Elrod, M -- England, S -- Eriksson, A -- Espley, J -- Evans, S -- Fang, X -- Fillingim, M -- Fortier, K -- Fowler, C M -- Fox, J -- Groller, H -- Guzewich, S -- Hara, T -- Harada, Y -- Holsclaw, G -- Jain, S K -- Jolitz, R -- Leblanc, F -- Lee, C O -- Lee, Y -- Lefevre, F -- Lillis, R -- Livi, R -- Lo, D -- Mayyasi, M -- McClintock, W -- McEnulty, T -- Modolo, R -- Montmessin, F -- Morooka, M -- Nagy, A -- Olsen, K -- Peterson, W -- Rahmati, A -- Ruhunusiri, S -- Russell, C T -- Sakai, S -- Sauvaud, J-A -- Seki, K -- Steckiewicz, M -- Stevens, M -- Stewart, A I F -- Stiepen, A -- Stone, S -- Tenishev, V -- Thiemann, E -- Tolson, R -- Toublanc, D -- Vogt, M -- Weber, T -- Withers, P -- Woods, T -- Yelle, R -- New York, N.Y. -- Science. 2015 Nov 6;350(6261):aad0210. doi: 10.1126/science.aad0210.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of Colorado, Boulder, CO, USA. bruce.jakosky@lasp.colorado.edu. ; NASA/Goddard Space Flight Center, Greenbelt, MD, USA. ; University of California at Berkeley, Berkeley, CA, USA. ; University of Colorado, Boulder, CO, USA. ; University of Iowa, Iowa City, IA, USA. ; Jet Propulsion Laboratory, California Institute of Technology, Pasadena, CA, USA. ; University of Michigan, Ann Arbor, MI, USA. ; University of California at Los Angeles, Los Angeles, CA, USA. ; CNRS-Institut de Recherche en Astrophysique et Planetologie (IRAP), Toulouse, France. University Paul Sabatier, Toulouse, France. ; Swedish Institute of Space Physics, Uppsala, Sweden. ; NASA/Johnson Space Center, Houston, TX, USA. ; National Institute of Aerospace, Hampton, VA, USA. ; Laboratoire atmospheres, milieux et observations spatiales (LATMOS)-CNRS, Paris, France. ; Boston University, Boston, MA, USA. ; University of Kansas, Lawrence, KS, USA. ; Computational Physics, Inc., Boulder, CO, USA. ; Wright State University, Dayton, OH, USA. ; University of Arizona, Tucson, AZ, USA. ; Nagoya University, Nagoya, Japan. ; Naval Research Laboratory, Washington, DC, USA. ; North Carolina State University, Raleigh, NC, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26542576" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2012-01-28
    Description: During the activation of humoral immune responses, B cells acquire antigen for subsequent presentation to cognate T cells. Here we show that after mouse B cells accumulate antigen, it is maintained in a polarized distribution for extended periods in vivo. Using high-throughput imaging flow cytometry, we observed that this polarization is preserved during B cell division, promoting asymmetric antigen segregation among progeny. Antigen inheritance correlates with the ability of progeny to activate T cells: Daughter cells receiving larger antigen stores exhibit a prolonged capacity to present antigen, which renders them more effective in competing for T cell help. The generation of progeny with differential capacities for antigen presentation may have implications for somatic hypermutation and class switching during affinity maturation and as B cells commit to effector cell fates.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Thaunat, Olivier -- Granja, Aitor G -- Barral, Patricia -- Filby, Andrew -- Montaner, Beatriz -- Collinson, Lucy -- Martinez-Martin, Nuria -- Harwood, Naomi E -- Bruckbauer, Andreas -- Batista, Facundo D -- Cancer Research UK/United Kingdom -- New York, N.Y. -- Science. 2012 Jan 27;335(6067):475-9. doi: 10.1126/science.1214100.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Lymphocyte Interaction Laboratory, London Research Institute, Cancer Research UK, 44 Lincoln's Inn Fields, London, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22282815" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Antigen Presentation ; Antigens/*analysis/*immunology ; B-Lymphocytes/cytology/*immunology ; Cell Division ; Cell Proliferation ; Cells, Cultured ; Coculture Techniques ; Computer Simulation ; Flow Cytometry ; *Lymphocyte Activation ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Models, Immunological ; Muramidase/analysis/immunology ; T-Lymphocytes/*immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2015-11-07
    Description: The Mars Atmosphere and Volatile Evolution (MAVEN) mission, during the second of its Deep Dip campaigns, made comprehensive measurements of martian thermosphere and ionosphere composition, structure, and variability at altitudes down to ~130 kilometers in the subsolar region. This altitude range contains the diffusively separated upper atmosphere just above the well-mixed atmosphere, the layer of peak extreme ultraviolet heating and primary reservoir for atmospheric escape. In situ measurements of the upper atmosphere reveal previously unmeasured populations of neutral and charged particles, the homopause altitude at approximately 130 kilometers, and an unexpected level of variability both on an orbit-to-orbit basis and within individual orbits. These observations help constrain volatile escape processes controlled by thermosphere and ionosphere structure and variability.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bougher, S -- Jakosky, B -- Halekas, J -- Grebowsky, J -- Luhmann, J -- Mahaffy, P -- Connerney, J -- Eparvier, F -- Ergun, R -- Larson, D -- McFadden, J -- Mitchell, D -- Schneider, N -- Zurek, R -- Mazelle, C -- Andersson, L -- Andrews, D -- Baird, D -- Baker, D N -- Bell, J M -- Benna, M -- Brain, D -- Chaffin, M -- Chamberlin, P -- Chaufray, J-Y -- Clarke, J -- Collinson, G -- Combi, M -- Crary, F -- Cravens, T -- Crismani, M -- Curry, S -- Curtis, D -- Deighan, J -- Delory, G -- Dewey, R -- DiBraccio, G -- Dong, C -- Dong, Y -- Dunn, P -- Elrod, M -- England, S -- Eriksson, A -- Espley, J -- Evans, S -- Fang, X -- Fillingim, M -- Fortier, K -- Fowler, C M -- Fox, J -- Groller, H -- Guzewich, S -- Hara, T -- Harada, Y -- Holsclaw, G -- Jain, S K -- Jolitz, R -- Leblanc, F -- Lee, C O -- Lee, Y -- Lefevre, F -- Lillis, R -- Livi, R -- Lo, D -- Ma, Y -- Mayyasi, M -- McClintock, W -- McEnulty, T -- Modolo, R -- Montmessin, F -- Morooka, M -- Nagy, A -- Olsen, K -- Peterson, W -- Rahmati, A -- Ruhunusiri, S -- Russell, C T -- Sakai, S -- Sauvaud, J-A -- Seki, K -- Steckiewicz, M -- Stevens, M -- Stewart, A I F -- Stiepen, A -- Stone, S -- Tenishev, V -- Thiemann, E -- Tolson, R -- Toublanc, D -- Vogt, M -- Weber, T -- Withers, P -- Woods, T -- Yelle, R -- New York, N.Y. -- Science. 2015 Nov 6;350(6261):aad0459. doi: 10.1126/science.aad0459.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CLaSP Department, University of Michigan, Ann Arbor, MI, USA. bougher@umich.edu. ; Laboratory for Atmospheric and Space Physics, University. of Colorado, Boulder, CO, USA. ; Department of Physics and Astronomy, University of Iowa, Iowa City, IA, USA. ; NASA/Goddard Space Flight Center, Greenbelt, MD, USA. ; Space Sciences Laboratory, University of California at Berkeley, Berkeley, CA, USA. ; Jet Propulsion Laboratory, California Institute of Technology, Pasadena, CA, USA. ; CNRS/Institut de Recherche en Astrophysique et Planetologie, Toulouse, France. University Paul Sabatier, Toulouse, France. ; Swedish Institute of Space Physics, Kiruna, Sweden. ; NASA/Johnson Space Center, Houston, TX, USA. ; National Institute of Aerospace, Hampton, VA, USA. ; Laboratoire Atmospheres, Milieux, Observations Spatiales /CNRS, Verrieres-le-Buisson, France. ; Department of Astronomy, Boston University, Boston, MA, USA. ; CLaSP Department, University of Michigan, Ann Arbor, MI, USA. ; Department of Physics and Astronomy, University of Kansas, Lawrence, KS, USA. ; Computational Physics, Springfield, VA, USA. ; Department of Physics, Wright State University, Fairborn, OH, USA. ; Lunar and Planetary Laboratory, University of Arizona, Tucson, AZ, USA. ; Institute of Geophysics and Planetary Physics, University of California, Los Angeles, Los Angeles, CA, USA. ; Solar-Terrestrial Environment Laboratory, Nagoya University, Nagoya, Aichi, Japan. ; Naval Research Laboratory, Washington, DC, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26542579" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 10
    ISSN: 1573-2614
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science , Medicine
    Type of Medium: Electronic Resource
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