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  • 1
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    A molecular mechanism for electrical tuning of cochlear hair cells (1999)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1999-01-08
    Description: Cochlear frequency selectivity in lower vertebrates arises in part from electrical tuning intrinsic to the sensory hair cells. The resonant frequency is determined largely by the gating kinetics of calcium-activated potassium (BK) channels encoded by the slo gene. Alternative splicing of slo from chick cochlea generated kinetically distinct BK channels. Combination with accessory beta subunits slowed the gating kinetics of alpha splice variants but preserved relative differences between them. In situ hybridization showed that the beta subunit is preferentially expressed by low-frequency (apical) hair cells in the avian cochlea. Interaction of beta with alpha splice variants could provide the kinetic range needed for electrical tuning of cochlear hair cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ramanathan, K -- Michael, T H -- Jiang, G J -- Hiel, H -- Fuchs, P A -- DC00276/DC/NIDCD NIH HHS/ -- New York, N.Y. -- Science. 1999 Jan 8;283(5399):215-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Hearing Sciences, Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9880252" target="_blank"〉PubMed〈/a〉
    Keywords: Alternative Splicing ; Animals ; Calcium/metabolism ; Cell Line ; Electrophysiology ; Gene Expression ; Hair Cells, Auditory/*physiology ; Humans ; In Situ Hybridization ; *Ion Channel Gating ; Kinetics ; Large-Conductance Calcium-Activated Potassium Channel beta Subunits ; Large-Conductance Calcium-Activated Potassium Channels ; Membrane Potentials ; Patch-Clamp Techniques ; Potassium Channels/genetics/*physiology ; *Potassium Channels, Calcium-Activated ; Quail ; RNA, Messenger/genetics/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Transfection
    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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  • 2
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    Cholinergic synaptic inhibition of inner hair cells in the neonatal mammalian cochlea (2000)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2000-07-06
    Description: Efferent feedback onto sensory organs provides a means to modulate input to the central nervous system. In the developing mammalian cochlea, inner hair cells are transiently innervated by efferent fibers, even before sensory function begins. Here, we show that neonatal inner hair cells are inhibited by cholinergic synaptic input before the onset of hearing. The synaptic currents, as well as the inner hair cell's response to acetylcholine, are mediated by a nicotinic (alpha9-containing) receptor and result in the activation of small-conductance calcium-dependent potassium channels.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Glowatzki, E -- Fuchs, P A -- DC 00276/DC/NIDCD NIH HHS/ -- New York, N.Y. -- Science. 2000 Jun 30;288(5475):2366-8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Center for Hearing Sciences, Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. eglowatz@bme.jhu.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10875922" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylcholine/*pharmacology ; Action Potentials ; Animals ; Animals, Newborn ; Apamin/pharmacology ; Bungarotoxins/pharmacology ; Calcium/metabolism ; Cholinergic Antagonists/pharmacology ; Electric Conductivity ; Hair Cells, Auditory, Inner/drug effects/*physiology ; In Vitro Techniques ; *Neural Inhibition ; Neurons, Efferent/physiology ; Patch-Clamp Techniques ; Potassium/metabolism ; Potassium Channels/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Nicotinic/*metabolism ; Strychnine/pharmacology ; Synapses/*physiology ; Synaptic Transmission/*drug effects
    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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  • 3
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    HRP2 determines the efficiency and specificity of HIV-1 integration in LEDGF/p75 knockout cells but does not contribute to the antiviral activity of a potent LEDGF/p75-binding site integrase inhibitor (2012)
    Oxford University Press
    Details
    Publication Date: 2012-12-14
    Description: The binding of integrase (IN) to lens epithelium-derived growth factor (LEDGF)/p75 in large part determines the efficiency and specificity of HIV-1 integration. However, a significant residual preference for integration into active genes persists in Psip1 (the gene that encodes for LEDGF/p75) knockout (KO) cells. One other cellular protein, HRP2, harbors both the PWWP and IN-binding domains that are important for LEDGF/p75 co-factor function. To assess the role of HRP2 in HIV-1 integration, cells generated from Hdgfrp2 (the gene that encodes for HRP2) and Psip1 / Hdgfrp2 KO mice were infected alongside matched control cells. HRP2 depleted cells supported normal infection, while disruption of Hdgfrp2 in Psip1 KO cells yielded additional defects in the efficiency and specificity of integration. These deficits were largely restored by ectopic expression of either LEDGF/p75 or HRP2. The double-KO cells nevertheless supported residual integration into genes, indicating that IN and/or other host factors contribute to integration specificity in the absence of LEDGF/p75 and HRP2. Psip1 KO significantly increased the potency of an allosteric inhibitor that binds the LEDGF/p75 binding site on IN, a result that was not significantly altered by Hdgfrp2 disruption. These findings help to rule out the host factor-IN interactions as the primary antiviral targets of LEDGF/p75-binding site IN inhibitors.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 4
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    IN inhibitors that block HIV-1 core formation [Microbiology] (2013)
    National Academy of Sciences
    Details
    Publication Date: 2013-05-22
    Description: Integration is essential for HIV-1 replication, and the viral integrase (IN) protein is an important therapeutic target. Allosteric IN inhibitors (ALLINIs) that engage the IN dimer interface at the binding site for the host protein lens epithelium-derived growth factor (LEDGF)/transcriptional coactivator p75 are an emerging class of small molecule antagonists....
    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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  • 5
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    Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics (2018)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2018-01-12
    Description: Chemogenetic characterization through in vitro evolution combined with whole-genome analysis can identify antimalarial drug targets and drug-resistance genes. We performed a genome analysis of 262 Plasmodium falciparum parasites resistant to 37 diverse compounds. We found 159 gene amplifications and 148 nonsynonymous changes in 83 genes associated with drug-resistance acquisition, where gene amplifications contributed to one-third of resistance acquisition events. Beyond confirming previously identified multidrug-resistance mechanisms, we discovered hitherto unrecognized drug target–inhibitor pairs, including thymidylate synthase and a benzoquinazolinone, farnesyltransferase and a pyrimidinedione, and a dipeptidylpeptidase and an arylurea. This exploration of the P. falciparum resistome and druggable genome will likely guide drug discovery and structural biology efforts, while also advancing our understanding of resistance mechanisms available to the malaria parasite.
    Keywords: Genetics, Microbiology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 6
    Electronic Resource
    Electronic Resource
    MECHANISMS OF HAIR CELL TUNING (1999)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 61 (1999), S. 809-834 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract Mechanosensory hair cells of the vertebrate inner ear contribute to acoustic tuning through feedback processes involving voltage-gated channels in the basolateral membrane and mechanotransduction channels in the apical hair bundle. The specific number and kinetics of calcium-activated (BK) potassium channels determine the resonant frequency of electrically tuned hair cells. Kinetic variation among BK channels may arise through alternative splicing of slo gene mRNA and combination with modulatory beta subunits. The number of transduction channels and their rate of adaptation rise with hair cell response frequency along the cochlea's tonotopic axis. Calcium-dependent feedback onto transduction channels may underlie active hair bundle mechanics. The relative contributions of electrical and mechanical feedback to active tuning of hair cells may vary as a function of sound frequency.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.61.1.809
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  • 7
    Electronic Resource
    Electronic Resource
    Voltage oscillations and ionic conductances in hair cells isolated from the alligator cochlea (1988)
    Springer
    Journal of comparative physiology 164 (1988), S. 151-163 
    Details
    ISSN: 1432-1351
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Tall hair cells were isolated by enzymatic and mechanical dissociation from selected regions of the apical half of the alligator (A. mississippiensis) cochlea. Single cells were subjected to voltage-clamp and current-clamp using the tight-seal whole-cell recording technique. Most hair cells isolated from the apex of the cochlea produced slowly regenerative depolarizations or Na action potentials during current injection, whereas hair cells isolated from more basal regions usually produced voltage oscillations (ringing) in response to depolarizing current injection, an indication of electrical resonance. Resonant frequencies ranged from 50 to 157 Hz in different cells. The higher-frequency cells tended to have larger and more rapidly activating outward currents than did the lower-frequency cells. An inward Ca current and an outward Ca-activated K current were present in all hair cells. In addition, an inwardly rectifying current and a small, transient outward current were often seen. Thus, we conclude that an electrical tuning mechanism is present in alligator hair cells. The role of the ionic conductances in shaping hair cell responses to current injection, and the possible contributions of these electrical responses to cochlear function are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00603947
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  • 8
    Electronic Resource
    Electronic Resource
    Ultrasonic Instrumentation for Measuring Applied Stress on Bridges (1998)
    Springer
    Journal of nondestructive evaluation 17 (1998), S. 141-152 
    Details
    ISSN: 1573-4862
    Keywords: Ultrasonic ; EMAT ; applied stress ; strain ; Rayleigh wave ; bridge
    Source: Springer Online Journal Archives 1860-2000
    Topics: Electrical Engineering, Measurement and Control Technology , Mathematics
    Notes: Abstract The measurement of applied stress on bridges can provide valuable information on the condition of the structure. The conventional technique for measuring applied stress is with a strain gage. However, strain gages can be time consuming to install because first the surface must usually be prepared. On a bridge, paint removal will most likely be necessary as part of this surface preparation. When dealing with lead-based paints, which are considered hazardous waste, many time consuming removal procedures are required. Because of these factors, a device that measures applied stress without requiring paint removal could be useful. While a “clamp-on” strain gage can also be used to measure applied stress without requiring paint removal, this type of strain gage can not be used on some bridge details, such as webs of I-beams and tops of box girders. An ultrasonic technique using non-contact electromagnetic transducers provides a possible method for applied stress measurement which is not limited by the same factors as those with conventional strain gages. The transducers operate through nonconductive and conductive (lead-based) paint and work on rusted, pitted surfaces. Our previous research developed a technique for measuring applied stresses on bridges with EMATs and included many laboratory tests. This paper describes field applications of the technique on actual bridge structures, as well as additional system testing and instrument calibration in the laboratory.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1022659014426
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  • 9
    Electronic Resource
    Electronic Resource
    Ultrasonic instrumentation for measuring applied stress on bridges (1998)
    Springer
    Journal of nondestructive evaluation 17 (1998), S. 141-152 
    Details
    ISSN: 1573-4862
    Keywords: Ultrasonic ; EMAT ; applied stress ; strain ; Rayleigh wave ; bridge
    Source: Springer Online Journal Archives 1860-2000
    Topics: Electrical Engineering, Measurement and Control Technology , Mathematics
    Notes: Abstract The measurement of applied stress on bridges can provide valuable information on the condition of the structure. The conventional technique for measuring applied stress is with a strain gage. However, strain gages can be time consuming to install because first the surface must usually be prepared. On a bridge, paint removal will most likely be necessary as part of this surface preparation. When dealing with lead-based paints, which are considered hazardous waste, many time consuming removal procedures are required. Because of these factors, a device that measures applied stress without requiring paint removal could be useful. While a “clamp-on” strain gage can also be used to measure applied stress without requiring paint removal, this type of strain gage can not be used on some bridge details, such as webs of I-beams and tops of box girders. An ultrasonic technique using non-contact electromagnetic transducers provides a possible method for applied stress measurement which is not limited by the same factors as those with conventional strain gages. The transducers operate through nonconductive and conductive (lead-based) paint and work on rusted, pitted surfaces. Our previous research developed a technique for measuring applied stresses on bridges with EMATs and included many laboratory tests. This paper describes field applications of the technique on actual bridge structures, as well as additional system testing and instrument calibration in the laboratory.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02446117
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  • 10
    Electronic Resource
    Electronic Resource
    Ultrasonic Measurement of Stress in Pin and Hanger Connections (1999)
    Springer
    Journal of nondestructive evaluation 18 (1999), S. 103-113 
    Details
    ISSN: 1573-4862
    Keywords: acoustoelasticity ; stress ; EMATs ; bridges
    Source: Springer Online Journal Archives 1860-2000
    Topics: Electrical Engineering, Measurement and Control Technology , Mathematics
    Notes: Abstract Pin and hanger connections are used in bridges to suspend an interior span from the outer spans. The connections can sometimes lock up due to corrosion. If lockup occurs the stresses in the connection are cycled due to thermal expansion and contraction of the bridge; fatigue cracking and failure may occur. We constructed an apparatus to simulate a locked-up pin and hanger connection. We performed proof-of-concept tests of a method to detect stresses in pin and hanger connections. The method uses the stress-induced changes in sound velocity of shear waves polarized parallel and perpendicular to the hanger axis. The birefringence is the normalized difference in these shear wave velocities. We measured the birefringence at opposite sides of the hangers, at midsection. We simulated three scenarios: continuous monitoring of hanger status; intermittent monitoring from a known initial state; measurement with no a priori knowledge of hanger status. Good agreement with strain gauge data was obtained for all three scenarios.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1021860727643
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