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  • 1
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    Multiple breast cancer risk variants are associated with differential transcript isoform expression in tumors (2015)
    Oxford University Press
    Details
    Publication Date: 2015-12-01
    Description: Genome-wide association studies have identified over 70 single-nucleotide polymorphisms (SNPs) associated with breast cancer. A subset of these SNPs are associated with quantitative expression of nearby genes, but the functional effects of the majority remain unknown. We hypothesized that some risk SNPs may regulate alternative splicing. Using RNA-sequencing data from breast tumors and germline genotypes from The Cancer Genome Atlas, we tested the association between each risk SNP genotype and exon-, exon–exon junction- or transcript-specific expression of nearby genes. Six SNPs were associated with differential transcript expression of seven nearby genes at FDR 〈 0.05 ( BABAM1 , DCLRE1B/PHTF1 , PEX14 , RAD51L1, SRGAP2D and STXBP4 ). We next developed a Bayesian approach to evaluate, for each SNP, the overlap between the signal of association with breast cancer and the signal of association with alternative splicing. At one locus ( SRGAP2D ), this method eliminated the possibility that the breast cancer risk and the alternate splicing event were due to the same causal SNP. Lastly, at two loci, we identified the likely causal SNP for the alternative splicing event, and at one, functionally validated the effect of that SNP on alternative splicing using a minigene reporter assay. Our results suggest that the regulation of differential transcript isoform expression is the functional mechanism of some breast cancer risk SNPs and that we can use these associations to identify causal SNPs, target genes and the specific transcripts that may mediate breast cancer risk.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 2
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    Measuring mechanical tension across vinculin reveals regulation of focal adhesion dynamics (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-07-09
    Description: Mechanical forces are central to developmental, physiological and pathological processes. However, limited understanding of force transmission within sub-cellular structures is a major obstacle to unravelling molecular mechanisms. Here we describe the development of a calibrated biosensor that measures forces across specific proteins in cells with piconewton (pN) sensitivity, as demonstrated by single molecule fluorescence force spectroscopy. The method is applied to vinculin, a protein that connects integrins to actin filaments and whose recruitment to focal adhesions (FAs) is force-dependent. We show that tension across vinculin in stable FAs is approximately 2.5 pN and that vinculin recruitment to FAs and force transmission across vinculin are regulated separately. Highest tension across vinculin is associated with adhesion assembly and enlargement. Conversely, vinculin is under low force in disassembling or sliding FAs at the trailing edge of migrating cells. Furthermore, vinculin is required for stabilizing adhesions under force. Together, these data reveal that FA stabilization under force requires both vinculin recruitment and force transmission, and that, surprisingly, these processes can be controlled independently.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901888/" 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/PMC2901888/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Grashoff, Carsten -- Hoffman, Brenton D -- Brenner, Michael D -- Zhou, Ruobo -- Parsons, Maddy -- Yang, Michael T -- McLean, Mark A -- Sligar, Stephen G -- Chen, Christopher S -- Ha, Taekjip -- Schwartz, Martin A -- 5T32-HL007284/HL/NHLBI NIH HHS/ -- R01 GM033775/GM/NIGMS NIH HHS/ -- R21 RR025341/RR/NCRR NIH HHS/ -- U54 GM064346/GM/NIGMS NIH HHS/ -- U54 GM064346-099039/GM/NIGMS NIH HHS/ -- U54 GM64346/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Jul 8;466(7303):263-6. doi: 10.1038/nature09198.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia 22908, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20613844" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biosensing Techniques ; Calibration ; Cattle ; Cell Line ; Cell Movement/*physiology ; Fluorescent Dyes ; Focal Adhesions/*metabolism ; Humans ; Mice ; Microscopy, Confocal ; Movement ; Optical Tweezers ; Spectrometry, Fluorescence ; *Stress, Mechanical ; Vinculin/chemistry/deficiency/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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  • 3
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    IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-07-06
    Description: Mutations in the IDH1 and IDH2 genes encoding isocitrate dehydrogenases are frequently found in human glioblastomas and cytogenetically normal acute myeloid leukaemias (AML). These alterations are gain-of-function mutations in that they drive the synthesis of the 'oncometabolite' R-2-hydroxyglutarate (2HG). It remains unclear how IDH1 and IDH2 mutations modify myeloid cell development and promote leukaemogenesis. Here we report the characterization of conditional knock-in (KI) mice in which the most common IDH1 mutation, IDH1(R132H), is inserted into the endogenous murine Idh1 locus and is expressed in all haematopoietic cells (Vav-KI mice) or specifically in cells of the myeloid lineage (LysM-KI mice). These mutants show increased numbers of early haematopoietic progenitors and develop splenomegaly and anaemia with extramedullary haematopoiesis, suggesting a dysfunctional bone marrow niche. Furthermore, LysM-KI cells have hypermethylated histones and changes to DNA methylation similar to those observed in human IDH1- or IDH2-mutant AML. To our knowledge, our study is the first to describe the generation and characterization of conditional IDH1(R132H)-KI mice, and also the first report to demonstrate the induction of a leukaemic DNA methylation signature in a mouse model. Our report thus sheds light on the mechanistic links between IDH1 mutation and human AML.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005896/" 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/PMC4005896/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sasaki, Masato -- Knobbe, Christiane B -- Munger, Joshua C -- Lind, Evan F -- Brenner, Dirk -- Brustle, Anne -- Harris, Isaac S -- Holmes, Roxanne -- Wakeham, Andrew -- Haight, Jillian -- You-Ten, Annick -- Li, Wanda Y -- Schalm, Stefanie -- Su, Shinsan M -- Virtanen, Carl -- Reifenberger, Guido -- Ohashi, Pamela S -- Barber, Dwayne L -- Figueroa, Maria E -- Melnick, Ari -- Zuniga-Pflucker, Juan-Carlos -- Mak, Tak W -- R01 AI081773/AI/NIAID NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2012 Aug 30;488(7413):656-9. doi: 10.1038/nature11323.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22763442" target="_blank"〉PubMed〈/a〉
    Keywords: Aging ; Animals ; Bone Marrow/pathology ; Cell Lineage ; CpG Islands/genetics ; DNA Methylation ; Disease Models, Animal ; Epigenesis, Genetic/*genetics ; Female ; Gene Knock-In Techniques ; Glioma/pathology ; Hematopoiesis ; Hematopoietic Stem Cells/*cytology/metabolism ; Histones/metabolism ; Humans ; Isocitrate Dehydrogenase/*genetics/*metabolism ; Leukemia, Myeloid, Acute/genetics ; Male ; Mice ; Mutant Proteins/genetics/*metabolism ; Mutation/*genetics ; Myeloid Cells/cytology/metabolism ; Spleen/pathology
    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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  • 4
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    Somatically evoked magnetic fields of the human brain (1978)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1978-01-06
    Description: The human brain is found to produce a magnetic field near the scalp which varies in synchrony with periodic electrical stimulation applied to a finger. Use of a highly sensitive superconducting quantum interference device as a magnetic field detector reveals that the brain's field is sharply localized over the primary projection area of the sensory cortex contralateral to the digit being stimulated. The phase of the response at the stimulus frequency varies monotonically with the repetition rate and at intermediate frequencies yields a latency of approximately 70 milliseconds for cortical response.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brenner, D -- Lipton, J -- Kaufman, L -- Williamson, S J -- New York, N.Y. -- Science. 1978 Jan 6;199(4324):81-3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physics, New York University, New York, NY 10003, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17569490" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Brain/*physiology ; Brain Mapping ; Electric Stimulation ; *Electromagnetic Fields ; Fingers ; Humans ; Male ; Reaction Time ; Thumb
    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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  • 5
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    A modern Sr/Ca-δ18O-Sea Surface Temperature calibration for Isopora corals on the Great Barrier Reef (2017)
    Wiley
    Details
    Publication Date: 2017-02-07
    Description: Isopora (Acroporidae) is a genus of often encrusting, branching to sub-massive corals that are common in many shallow habitats on modern and fossil Indo-West Pacific reefs. Although abundant, Isopora is largely absent from paleoceanographic literature. The scarcity of large Porites and the abundance of Isopora retrieved from the Great Barrier Reef (GBR) on Integrated Ocean Drilling Program (IODP) Expedition 325 focused paleoceanographic attention on Isopora. Here we provide the first independent high-resolution calibration of both Sr/Ca and δ 18 O for temperature analyses based on Isopora and demonstrate its consistency with Porites records. We developed modern skeletal Sr/Ca- and δ 18 O-sea surface temperature (SST) calibrations based on five modern Isopora colonies from Heron Island in the southern GBR. Pairing the coral Sr/Ca record with monthly SST data yielded Sr/Ca-SST sensitivities from −0.061 ± 0.004 (centered) to −0.083 ± 0.007 (raw) mmol/mol°C −1 based on Reduced Major Axis (RMA) regressions. These sensitivities are in the middle of the range of published Porites values and overlap most published values for Isopora , −0.075 ± 0.011 to −0.065 ± 0.011 mmol/mol°C −1 . The δ 18 O-SST sensitivities range from −0.184 ± 0.014 (centered) to −0.185 ± 0.014 (raw) ‰°C −1 , assuming all seasonal variation in δ 18 O was due to SST. These δ 18 O-SST sensitivities are smaller than the widely accepted value of −0.23‰°C −1 for biogenic aragonite but are at the upper end of high-resolution Porites -defined sensitivities that are consistently less than the aforementioned established value. Our results validate the use of Isopora as an alternative source of paleoceanographic records in habitats where large massive Porites are scarce or absent.
    Print ISSN: 0883-8305
    Electronic ISSN: 1944-9186
    Topics: Geosciences
    Published by Wiley on behalf of American Geophysical Union (AGU).
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  • 6
    Electronic Resource
    Electronic Resource
    IR multiphoton pumping of optically selected levels of the ~A 1A2 state of thiophosgene (1980)
    s.l. : American Chemical Society
    The @journal of physical chemistry 〈Washington, DC〉 84 (1980), S. 3341-3344 
    Details
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/j100462a004
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  • 7
    Electronic Resource
    Electronic Resource
    Infrared multiphoton dissociation in two-channel systems. Pulse-duration effects (1982)
    s.l. : American Chemical Society
    The @journal of physical chemistry 〈Washington, DC〉 86 (1982), S. 41-49 
    Details
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/j100390a009
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  • 8
    Electronic Resource
    Electronic Resource
    Geometric and electronic structures of C60H60, C60F60, and C60H36 (1991)
    s.l. : American Chemical Society
    The @journal of physical chemistry 〈Washington, DC〉 95 (1991), S. 5763-5768 
    Details
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/j100168a012
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  • 9
    Electronic Resource
    Electronic Resource
    MECHANICAL AND ELECTRICAL PROPERTIES OF NANOTUBES (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Materials Research 32 (2002), S. 347-375 
    Details
    ISSN: 1531-7331
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Abstract We review the recent progress in our understanding of the mechanical and electrical properties of carbon nanotubes, emphasizing the theoretical aspects. Nanotubes are the strongest materials known, but the ultimate limits of their strength have yet to be reached experimentally. Modeling of nanotube-reinforced composites indicates that the addition of small numbers of nanotubes may lead to a dramatic increase in the modulus, with only minimal crosslinking. Deformations in nanotube structures lead to novel structural transformations, some of which have clear electrical signatures that can be utilized in nanoscale sensors and devices. Chemical reactivity of nanotube walls is facilitated by strain, which can be used in processing and functionalization. Scanning tunneling microscopy and spectroscopy have provided a wealth of information about the structure and electronic properties of nanotubes, especially when coupled with appropriate theoretical models. Nanotubes are exceptional ballistic conductors, which can be used in a variety of nanodevices that can operate at room temperature. The quantum transport through nanotube structures is reviewed at some depth, and the critical roles played by band structure, one-dimensional confinement, and coupling to nanoscale contacts are emphasized. Because disorder or point defect-induced scattering is effectively averaged over the circumference of the nanotube, electrons can propagate ballistically over hundreds of nanometers. However, severe deformations or highly resistive contacts isolate nanotube segments and lead to the formation of quantum dots, which exhibit Coulomb blockade effects, even at room temperature. Metal-nanotube and nanotube-nanotube contacts range from highly transmissive to very resistive, depending on the symmetry of two structures, the charge transfer, and the detailed rehybridization of the wave functions. The progress in terms of nanotube applications has been extraordinarily rapid, as evidenced by the development of several nanotube-based prototypical devices, including memory and logic circuits, chemical sensors, electron emitters and electromechanical actuators.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.matsci.32.112601.134925
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  • 10
    Electronic Resource
    Electronic Resource
    On the way to fullerenes: molecular dynamics study of the curling and closure of graphitic ribbons (1992)
    s.l. : American Chemical Society
    The @journal of physical chemistry 〈Washington, DC〉 96 (1992), S. 6133-6135 
    Details
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/j100194a011
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