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  • 1
    Publication Date: 2011-03-19
    Description: Decreased cardiac contractility is a central feature of systolic heart failure. Existing drugs increase cardiac contractility indirectly through signaling cascades but are limited by their mechanism-related adverse effects. To avoid these limitations, we previously developed omecamtiv mecarbil, a small-molecule, direct activator of cardiac myosin. Here, we show that it binds to the myosin catalytic domain and operates by an allosteric mechanism to increase the transition rate of myosin into the strongly actin-bound force-generating state. Paradoxically, it inhibits adenosine 5'-triphosphate turnover in the absence of actin, which suggests that it stabilizes an actin-bound conformation of myosin. In animal models, omecamtiv mecarbil increases cardiac function by increasing the duration of ejection without changing the rates of contraction. Cardiac myosin activation may provide a new therapeutic approach for systolic heart failure.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4090309/" 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/PMC4090309/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Malik, Fady I -- Hartman, James J -- Elias, Kathleen A -- Morgan, Bradley P -- Rodriguez, Hector -- Brejc, Katjusa -- Anderson, Robert L -- Sueoka, Sandra H -- Lee, Kenneth H -- Finer, Jeffrey T -- Sakowicz, Roman -- Baliga, Ramesh -- Cox, David R -- Garard, Marc -- Godinez, Guillermo -- Kawas, Raja -- Kraynack, Erica -- Lenzi, David -- Lu, Pu Ping -- Muci, Alexander -- Niu, Congrong -- Qian, Xiangping -- Pierce, Daniel W -- Pokrovskii, Maria -- Suehiro, Ion -- Sylvester, Sheila -- Tochimoto, Todd -- Valdez, Corey -- Wang, Wenyue -- Katori, Tatsuo -- Kass, David A -- Shen, You-Tang -- Vatner, Stephen F -- Morgans, David J -- 1-R43-HL-66647-1/HL/NHLBI NIH HHS/ -- R01 HL106511/HL/NHLBI NIH HHS/ -- R43 HL066647/HL/NHLBI NIH HHS/ -- New York, N.Y. -- Science. 2011 Mar 18;331(6023):1439-43. doi: 10.1126/science.1200113.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Preclinical Research and Development, Cytokinetics, Inc., South San Francisco, CA 94080, USA. fmalik@cytokinetics.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21415352" target="_blank"〉PubMed〈/a〉
    Keywords: Actin Cytoskeleton/metabolism ; Actins/metabolism ; Adenosine Triphosphatases/metabolism ; Adenosine Triphosphate/metabolism ; Adrenergic beta-Agonists/pharmacology ; Allosteric Regulation ; Animals ; Binding Sites ; Calcium/metabolism ; Cardiac Myosins/chemistry/*metabolism ; Cardiac Output/drug effects ; Dogs ; Female ; Heart Failure, Systolic/*drug therapy/physiopathology ; Isoproterenol/pharmacology ; Male ; Myocardial Contraction/*drug effects ; Myocytes, Cardiac/*drug effects/physiology ; Phosphates/metabolism ; Protein Binding ; Protein Conformation ; Protein Isoforms/chemistry/metabolism ; Rats ; Rats, Sprague-Dawley ; Urea/*analogs & derivatives/chemistry/metabolism/pharmacology ; Ventricular Function, Left/drug effects
    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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  • 2
    Publication Date: 2007-03-03
    Description: Stimulant addiction is often linked to excessive risk taking, sensation seeking, and impulsivity, but in ways that are poorly understood. We report here that a form of impulsivity in rats predicts high rates of intravenous cocaine self-administration and is associated with changes in dopamine (DA) function before drug exposure. Using positron emission tomography, we demonstrated that D2/3 receptor availability is significantly reduced in the nucleus accumbens of impulsive rats that were never exposed to cocaine and that such effects are independent of DA release. These data demonstrate that trait impulsivity predicts cocaine reinforcement and that D2 receptor dysfunction in abstinent cocaine addicts may, in part, be determined by premorbid influences.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1892797/" 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/PMC1892797/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dalley, Jeffrey W -- Fryer, Tim D -- Brichard, Laurent -- Robinson, Emma S J -- Theobald, David E H -- Laane, Kristjan -- Pena, Yolanda -- Murphy, Emily R -- Shah, Yasmene -- Probst, Katrin -- Abakumova, Irina -- Aigbirhio, Franklin I -- Richards, Hugh K -- Hong, Young -- Baron, Jean-Claude -- Everitt, Barry J -- Robbins, Trevor W -- 076244/Wellcome Trust/United Kingdom -- G0001354/Medical Research Council/United Kingdom -- G0401068/Medical Research Council/United Kingdom -- G0600196/Medical Research Council/United Kingdom -- G0600986/Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2007 Mar 2;315(5816):1267-70.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Behavioral and Clinical Neuroscience Institute, University of Cambridge, Downing Street, Cambridge CB2 3EB, UK. jwd20@cam.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17332411" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Basal Ganglia/metabolism/radionuclide imaging ; Benzamides/metabolism ; Cocaine/*administration & dosage ; *Cocaine-Related Disorders/metabolism/psychology ; Corpus Striatum/metabolism/radionuclide imaging ; Dopamine/metabolism ; Dopamine Antagonists/metabolism/pharmacology ; *Impulsive Behavior ; Male ; Nucleus Accumbens/*metabolism/radionuclide imaging ; Positron-Emission Tomography ; Pyrrolidines/metabolism ; Rats ; Reaction Time ; Receptors, Dopamine D2/*metabolism ; Receptors, Dopamine D3/*metabolism ; *Reinforcement (Psychology) ; Self Administration ; Synaptic Transmission
    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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  • 3
    Publication Date: 2010-01-16
    Description: Quantifying the costs and benefits of migration distance is critical to understanding the evolution of long-distance migration. In migratory birds, life history theory predicts that the potential survival costs of migrating longer distances should be balanced by benefits to lifetime reproductive success, yet quantification of these reproductive benefits in a controlled manner along a large geographical gradient is challenging. We measured a controlled effect of predation risk along a 3350-kilometer south-north gradient in the Arctic and found that nest predation risk declined more than twofold along the latitudinal gradient. These results provide evidence that birds migrating farther north may acquire reproductive benefits in the form of lower nest predation risk.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McKinnon, L -- Smith, P A -- Nol, E -- Martin, J L -- Doyle, F I -- Abraham, K F -- Gilchrist, H G -- Morrison, R I G -- Bety, J -- New York, N.Y. -- Science. 2010 Jan 15;327(5963):326-7. doi: 10.1126/science.1183010.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departement de Biologie, Universite du Quebec a Rimouski and Centre d'Etudes Nordiques, Rimouski, Quebec, G5L3A1, Canada. laura.mckinnon3@gmail.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20075251" target="_blank"〉PubMed〈/a〉
    Keywords: *Animal Migration ; Animals ; Arctic Regions ; Birds/*physiology ; *Ecosystem ; Geography ; *Nesting Behavior ; *Predatory Behavior ; *Reproduction ; Risk
    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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  • 4
    Publication Date: 1978-05-05
    Description: Ellipsosomes are dense spherical bodies containing a very large concentration of a heme pigment spectroscopically resembling pure cytochrome c. They are located at the outer ends of the inner segments of the cones of certain fishes. Although, superficially, they resemble the similarly located oil droplets in the cones of birds and reptiles, their ultrastructure and staining properties resemble those of the neighboring mitochondria. However, like the oil droplets, they may serve as intracellular color filters.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉MacNichol, E F Jr -- Kunz, Y W -- Levine, J S -- Harosi, F I -- Collins, B A -- New York, N.Y. -- Science. 1978 May 5;200(4341):549-52.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/644317" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cytochromes/*analysis ; Fishes/*physiology ; Mitochondria/analysis ; Organoids/analysis/enzymology ; Photoreceptor Cells/*analysis/ultrastructure ; Pigments, Biological/analysis ; Succinate Dehydrogenase/metabolism
    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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  • 5
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 1983-12-02
    Description: Microspectrophotometric measurements of optically isolated photoreceptors in the Japanese dace, a cyprinid fish, revealed four spectroscopically distinguishable cone pigments and one rod pigment. A visual pigment that absorbs in the near ultraviolet was found in small single cones.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Harosi, F I -- Hashimoto, Y -- EY02399/EY/NEI NIH HHS/ -- New York, N.Y. -- Science. 1983 Dec 2;222(4627):1021-3.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/6648514" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cyprinidae/*metabolism ; Photoreceptor Cells/*analysis ; Retinal Pigments/*analysis ; Rod Cell Outer Segment/analysis ; Spectrophotometry, Ultraviolet
    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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  • 6
    Publication Date: 2014-10-31
    Description: There is much interest in developing synthetic analogues of biological membrane channels with high efficiency and exquisite selectivity for transporting ions and molecules. Bottom-up and top-down methods can produce nanopores of a size comparable to that of endogenous protein channels, but replicating their affinity and transport properties remains challenging. In principle, carbon nanotubes (CNTs) should be an ideal membrane channel platform: they exhibit excellent transport properties and their narrow hydrophobic inner pores mimic structural motifs typical of biological channels. Moreover, simulations predict that CNTs with a length comparable to the thickness of a lipid bilayer membrane can self-insert into the membrane. Functionalized CNTs have indeed been found to penetrate lipid membranes and cell walls, and short tubes have been forced into membranes to create sensors, yet membrane transport applications of short CNTs remain underexplored. Here we show that short CNTs spontaneously insert into lipid bilayers and live cell membranes to form channels that exhibit a unitary conductance of 70-100 picosiemens under physiological conditions. Despite their structural simplicity, these 'CNT porins' transport water, protons, small ions and DNA, stochastically switch between metastable conductance substates, and display characteristic macromolecule-induced ionic current blockades. We also show that local channel and membrane charges can control the conductance and ion selectivity of the CNT porins, thereby establishing these nanopores as a promising biomimetic platform for developing cell interfaces, studying transport in biological channels, and creating stochastic sensors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Geng, Jia -- Kim, Kyunghoon -- Zhang, Jianfei -- Escalada, Artur -- Tunuguntla, Ramya -- Comolli, Luis R -- Allen, Frances I -- Shnyrova, Anna V -- Cho, Kang Rae -- Munoz, Dayannara -- Wang, Y Morris -- Grigoropoulos, Costas P -- Ajo-Franklin, Caroline M -- Frolov, Vadim A -- Noy, Aleksandr -- England -- Nature. 2014 Oct 30;514(7524):612-5. doi: 10.1038/nature13817.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Biology and Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, California 94550, USA [2] School of Natural Sciences, University of California, Merced, California 95340, USA [3] The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA. ; 1] Biology and Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, California 94550, USA [2] The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA [3] Mechanical Engineering Department, University of California, Berkeley, California 94720, USA. ; School of Natural Sciences, University of California, Merced, California 95340, USA. ; Biophysics Unit (CSIC, UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country, 48940 Leioa, Spain. ; 1] Biology and Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, California 94550, USA [2] The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA. ; Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA. ; 1] Department of Materials Science and Engineering, University of California, Berkeley, California 94720, USA [2] Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA [3] National Center for Electron Microscopy, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA. ; Biology and Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, California 94550, USA. ; Materials Science Division, Lawrence Livermore National Laboratory, Livermore, California 94550, USA. ; Mechanical Engineering Department, University of California, Berkeley, California 94720, USA. ; 1] The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA [2] Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA [3] Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA. ; 1] Biophysics Unit (CSIC, UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country, 48940 Leioa, Spain [2] Ikerbasque, Basque Foundation for Science, 48011 Bilbao, Spain.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25355362" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biological Transport ; CHO Cells ; Cell Membrane/*chemistry/*metabolism ; Cell Survival ; Cricetulus ; DNA/metabolism ; HEK293 Cells ; Humans ; Ion Channels/metabolism ; Lipid Bilayers/*chemistry/*metabolism ; Liposomes ; *Nanotubes, Carbon/ultrastructure ; Porins/chemistry/*metabolism ; *Stochastic Processes
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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