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  • 1
    Publication Date: 2012-12-14
    Description: The clinical efficacy and safety of a drug is determined by its activity profile across many proteins in the proteome. However, designing drugs with a specific multi-target profile is both complex and difficult. Therefore methods to design drugs rationally a priori against profiles of several proteins would have immense value in drug discovery. Here we describe a new approach for the automated design of ligands against profiles of multiple drug targets. The method is demonstrated by the evolution of an approved acetylcholinesterase inhibitor drug into brain-penetrable ligands with either specific polypharmacology or exquisite selectivity profiles for G-protein-coupled receptors. Overall, 800 ligand-target predictions of prospectively designed ligands were tested experimentally, of which 75% were confirmed to be correct. We also demonstrate target engagement in vivo. The approach can be a useful source of drug leads when multi-target profiles are required to achieve either selectivity over other drug targets or a desired polypharmacology.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653568/" 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/PMC3653568/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Besnard, Jeremy -- Ruda, Gian Filippo -- Setola, Vincent -- Abecassis, Keren -- Rodriguiz, Ramona M -- Huang, Xi-Ping -- Norval, Suzanne -- Sassano, Maria F -- Shin, Antony I -- Webster, Lauren A -- Simeons, Frederick R C -- Stojanovski, Laste -- Prat, Annik -- Seidah, Nabil G -- Constam, Daniel B -- Bickerton, G Richard -- Read, Kevin D -- Wetsel, William C -- Gilbert, Ian H -- Roth, Bryan L -- Hopkins, Andrew L -- 083481/Wellcome Trust/United Kingdom -- BB/FOF/PF/15/09/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/J010510/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- MH082441/MH/NIMH NIH HHS/ -- R01 DA017204/DA/NIDA NIH HHS/ -- R01 MH061887/MH/NIMH NIH HHS/ -- U19 MH082441/MH/NIMH NIH HHS/ -- WT 083481/Wellcome Trust/United Kingdom -- England -- Nature. 2012 Dec 13;492(7428):215-20. doi: 10.1038/nature11691.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23235874" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Automation ; Drug Delivery Systems ; *Drug Design ; Female ; *Ligands ; Male ; Mice ; Mice, Inbred C57BL ; Models, Theoretical ; Pharmacological Phenomena ; Reproducibility of Results
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    ISSN: 1619-7089
    Keywords: Binswanger's dementia ; Subcortical dementia ; Hexamethylpropylene amine oxime ; Singlephoton emission tomography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In 24 patients with vascular dementia of Binswanger's type (VDBT) and 14 age-matched neurologically normal volunteers, we investigated the relationship between clinical features, white matter lesions (leucoaraiosis) and cerebral atrophy on computed tomography (CT) scan, and regional cerebral blood flow. All subjects underwent the Mini-Mental State Examination of Taiwan, version 1 (MMSE-T1), for assessing the severity of cognitive impairment. The patients were subdivided into two groups, one with mild to moderate (group I, MMSE-T1 scores: 11–24,n=ll), and the other with severe dementia (group II, MMSE-T1 scores: below 10,n=13). White matter degeneration was evaluated with densitometric methods. Loss of brain parenchyma was estimated with seven linear measurements (Evan's ratio, third ventricle ratio, width of temporal horn tip, anterior-posterior length of temporal horn, anterior-posterior length of Sylvian fissure and width of frontal interhemispheric fissure) by CT scans. Regional cerebral blood flow was determined with technetium-99m hexamethylpropylene amine oxime (HMPAO) single-photon emission tomography (SPET). In neuroimaging studies, subcortical leuco-araiosis was localized at the frontal region in group I patients and scattered diffusely in group II patients.99mTc-HMPAO SPET analysis revealed reduction of regional cerebral blood flow in the frontal lobe in group I patients and widespread reduction of regional cerebral blood flow in group II patients. A correlation between frontal leuco-araiosis and perfusion defect of the frontal pole was demonstrated in group I patients, showing findings typical of subcortical dementia. There was no difference in frontal atrophic measurements between group I patients and controls. Ratios of volumes of lost brain parenchyma and leuco-araiosis were significantly higher in group II patients than in the age-matched controls, corresponding to a diffuse cerebral perfusion defect. These results suggest that patients with VDBT have early frontal lobe involvement with posterior progression. Patients with mild VDBT are more likely to show reduction of frontal cerebral blood flow and leuco-araiosis, while those with severe VDBT are more likely to have diffuse leuco-araiosis, cerebral hypoperfusion and brain atrophy.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-2072
    Keywords: Key words GABA ; GABAB receptor ; Baclofen ; Growth hormone ; Mania ; Bipolar disorder
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Growth hormone (GH) response to a challenge with a GABAB receptor agonist, baclofen, is considered to provide an in vivo index of hypothalamic GABAB receptor function in humans. Objectives: The purpose of this study was to explore the role of GABAB receptors in the pathophysiology of mania by measuring plasma GH response to baclofen in ten manic patients and ten matched healthy controls. Methods: After obtaining blood samples for baseline GH levels, a single dose of 20 mg baclofen was administered orally to all the subjects, and further blood samples were obtained at 30-min intervals for the following 3 h. Results: We found that baclofen administration led to a significant increase in GH release both in manic patients and healthy controls, but the GH response to baclofen in manic patients was significantly enhanced when compared to healthy controls. Conclusions: Our results suggest that manic patients may have an up-regulated hypothalamic GABAB receptor function. However, in light of the limitations including small sample size and absence of placebo control, our results should be viewed as preliminary. Further studies with a larger number of manic patients and a placebo control design are needed to replicate our finding before any firm conclusion can be drawn.
    Type of Medium: Electronic Resource
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  • 4
    Publication Date: 2018-10-27
    Description: The key component currently missing for the next generation of transparent and flexible displays is a high-performance polymer material that is flexible, while showing optical and thermal properties of glass. It must be transparent to visible light and show a low coefficient of thermal expansion (CTE). While specialty plastics such as aromatic polyimides are promising, reducing their CTE and improving transparency simultaneously proved challenging, with increasing coloration the main problem to be resolved. We report a new poly(amide-imide) material that is flexible and displays glass-like behavior with a CTE value of 4 parts per million/°C. This novel polymer was successfully used as a substrate to fabricate transparent and flexible indium-gallium-zinc oxide thin-film transistors.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 5
    ISSN: 1573-4838
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Technology
    Notes: Methyl methacrylate and six solutions of methyl methacrylate/dibutyl phthalate (nominally 5 to 30% v/v) were polymerized into thin sheets using gamma radiation. Dynamic mechanical spectra of the storage modulus, loss modulus and loss tangent, as well as changes in length, were investigated as a function of temperature. From these measurements, the depression of the storage modulus and glass-transition temperature were obtained. Subsequently, differential scanning calorimetry (DSC) and cross-polarization-magic-angle-spinning NMR were used to obtain additional glass-transition and relaxation-time measurements. Based upon these experiments, a specific form of the rule of mixtures described the depression of the glass-transition temperature. From storage-modulus measurements, antiplasticization was evidenced at very low temperatures and at compositions greater than 25% v/v. Solid-state NMR confirmed that plasticization causes an increase in polymer main-chain motion via the physical loosening of secondary bonds between polymer chains.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1546-1718
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] The genome sequences of Caenorhabditis elegans, Drosophila melanogaster and Arabidopsis thaliana have been predicted to contain 19,000, 13,600 and 25,500 genes, respectively. Before this information can be fully used for evolutionary and functional studies, several issues need to be addressed. ...
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  • 7
    ISSN: 0887-6266
    Keywords: polytetrahydrofuran-urea inclusion compound ; Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: Combination of differential scanning calorimetry, x-ray diffraction, Fourier transform infrared, and C-13 nuclear magnetic resonance observations made on the crystalline inclusion compound (IC) formed between polytetrahydrofuran (PTHF) and urea (U), together with their comparison to identical observations performed on bulk semicrystalline samples of PTHF, have permitted an analysis of the conformations, motions, and environments available to PTHF chains in both solid-state phases. The isolated PTHF chains occupying the narrow channels of the PTHF-U-IC are highly extended, though small rotational deviations averaging 24° from the nearly all trans, planar zig zag conformation of bulk crystalline PTHF chains produce some significant differences in their behaviors. PTHF chains in PTHF-U-IC possess much greater mobility than bulk crystalline PTHF chains as evidenced by C-13 spin lattice relaxation times, T1, 50 times shorter (1.5 s) than observed for bulk crystalline PTHF chains (75 s). FTIR observations are consistent with very little specific interaction between guest PTHF chains and host urea matrix molecules and result in similar spectra for bulk and IC PTHF, except for the presence of the CH2 rocking vibration band at 745 cm-1 observed for bulk PTHF. The absence of this band in the IC PTHF can be understood by considering the symmetry of the all trans, planar zig zag conformation of bulk crystalline PTHF chains, which prevents the CH2 rocking mode from coupling with skeletal stretching and bending modes as occurs in the nonplanar, helical PTHF chains in PTHF-U-IC. © 1995 John Wiley & Sons, Inc.
    Additional Material: 7 Ill.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] The organizer of the vertebrate gastrula is an important signalling centre that induces and patterns dorsal axial structures. Although a topic of long-standing interest, the evolutionary origin of the organizer remains unclear. Here we show that the gastrula of the cephalochordate amphioxus ...
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  • 9
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] Small, compact genomes of ultrasmall unicellular algae provide information on the basic and essential genes that support the lives of photosynthetic eukaryotes, including higher plants. Here we report the 16,520,305-base-pair sequence of the 20 chromosomes of the unicellular red alga ...
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  • 10
    ISSN: 0305-0491
    Keywords: Calcium ; Diacylglycerol ; Fertilization ; Fertilized egg ; Frog ; Inositol 1,4,5-trisphosphate ; Protein kinase ; Protein phosphorylation ; Rana dybowskii
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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