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  • 1
    Publication Date: 2014-10-18
    Description: Small molecules are useful tools for probing the biological function and therapeutic potential of individual proteins, but achieving selectivity is challenging when the target protein shares structural domains with other proteins. The Bromo and Extra-Terminal (BET) proteins have attracted interest because of their roles in transcriptional regulation, epigenetics, and cancer. The BET bromodomains (protein interaction modules that bind acetyl-lysine) have been targeted by potent small-molecule inhibitors, but these inhibitors lack selectivity for individual family members. We developed an ethyl derivative of an existing small-molecule inhibitor, I-BET/JQ1, and showed that it binds leucine/alanine mutant bromodomains with nanomolar affinity and achieves up to 540-fold selectivity relative to wild-type bromodomains. Cell culture studies showed that blockade of the first bromodomain alone is sufficient to displace a specific BET protein, Brd4, from chromatin. Expansion of this approach could help identify the individual roles of single BET proteins in human physiology and disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458378/" 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/PMC4458378/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Baud, Matthias G J -- Lin-Shiao, Enrique -- Cardote, Teresa -- Tallant, Cynthia -- Pschibul, Annica -- Chan, Kwok-Ho -- Zengerle, Michael -- Garcia, Jordi R -- Kwan, Terence T-L -- Ferguson, Fleur M -- Ciulli, Alessio -- 097945/Z/11/Z/Wellcome Trust/United Kingdom -- 100476/Z/12/Z/Wellcome Trust/United Kingdom -- BB/G023123/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/J001201/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- New York, N.Y. -- Science. 2014 Oct 31;346(6209):638-41. doi: 10.1126/science.1249830. Epub 2014 Oct 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee, DD1 5EH, UK. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. ; Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee, DD1 5EH, UK. ; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. ; Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee, DD1 5EH, UK. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. a.ciulli@dundee.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25323695" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Azepines/chemistry/pharmacology ; Cell Line, Tumor ; Chromatin/chemistry ; Crystallography, X-Ray ; Humans ; Leucine/genetics ; Models, Molecular ; Molecular Probes/*chemistry ; Mutation ; Nuclear Proteins/antagonists & inhibitors/*chemistry/genetics ; Protein Engineering/*methods ; Protein Structure, Tertiary ; Transcription Factors/antagonists & inhibitors/*chemistry/genetics ; Triazoles/chemistry/pharmacology
    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: 2017-11-16
    Description: Middle East respiratory syndrome coronavirus (MERS-CoV) has caused human respiratory infections with a high case fatality rate since 2012. However, the mode of virus transmission is not well understood. The findings of epidemiological and virological studies prompted us to hypothesize that the human gastrointestinal tract could serve as an alternative route to acquire MERS-CoV infection. We demonstrated that human primary intestinal epithelial cells, small intestine explants, and intestinal organoids were highly susceptible to MERS-CoV and can sustain robust viral replication. We also identified the evidence of enteric MERS-CoV infection in the stool specimen of a clinical patient. MERS-CoV was considerably resistant to fed-state gastrointestinal fluids but less tolerant to highly acidic fasted-state gastric fluid. In polarized Caco-2 cells cultured in Transwell inserts, apical MERS-CoV inoculation was more effective in establishing infection than basolateral inoculation. Notably, direct intragastric inoculation of MERS-CoV caused a lethal infection in human DPP4 transgenic mice. Histological examination revealed MERS-CoV enteric infection in all inoculated mice, as shown by the presence of virus-positive cells, progressive inflammation, and epithelial degeneration in small intestines, which were exaggerated in the mice pretreated with the proton pump inhibitor pantoprazole. With the progression of the enteric infection, inflammation, virus-positive cells, and live viruses emerged in the lung tissues, indicating the development of sequential respiratory infection. Taken together, these data suggest that the human intestinal tract may serve as an alternative infection route for MERS-CoV.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 3
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Abacus 15 (1979), S. 0 
    ISSN: 1467-6281
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Economics
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Oxford, UK; Malden, USA : Blackwell Science Ltd
    Journal of fish biology 67 (2005), S. 0 
    ISSN: 1095-8649
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Biology
    Notes: Prolonged swimming performances of two as yet unnamed species of three-spined stickleback, Gasterosteus spp., were compared. The two fishes (not yet formally described, referred to here as benthic and limnetic) inhabit different niches within Paxton Lake, Texada Island, British Columbia, Canada, and are recent, morphologically distinct species. Limnetics had longer endurance during prolonged swimming than did benthics. The mean regression of the log10 of fatigue time (Ft, s) on swimming speed (U, standard length, LS s−1) for limnetics (log10Ft = 7·03 − 0·46U) had a similar slope, but a significantly higher intercept than that for benthics (log10Ft = 5·55 − 0·43U). Adult benthics were larger, heavier and deeper-bodied fish than limnetics. Limnetics, however, had a significantly greater pectoral fin edge:base ratio (mean ± s.e.: limnetics, 4·58 ± 0·43; benthics, 3·63 ± 0·27). In addition, limnetics had significantly lower drag coefficients (CD) than benthics (limnetics, log10CD = −0·49log10Re + 0·66; benthics, log10CD = −0·26log10Re − 0·30) where Re is the Reynolds number [(LSU (ν−1), where U and ν are swimming velocity and the kinematic viscosity of the water, respectively]. Compared to their ancestral form, the anadromous three-spined stickleback Gasterosteus aculeatus L., limnetics and benthics had significantly longer and shorter endurance times, respectively. In addition, both these fishes had significantly higher fast-start velocities than their ancestral form. Selection due to differential resource use may have lead to divergence of body form, and, therefore, of steady swimming performance. Therefore predation may be the selective force for the similar high escape performance in these two fishes.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Oxford, UK; Malden, USA : Blackwell Science Ltd
    Journal of fish biology 67 (2005), S. 0 
    ISSN: 1095-8649
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Biology
    Notes: The functional significance of finlets on the steady swimming performance of yellowfin tuna Thunnus albacares was evaluated by measuring the speed and tail-beat frequency of the fish with and without them. It was hypothesized that if finlets do improve swimming performance, fish without finlets would have to work harder to maintain the same swimming speed as fish with them and that this would be reflected in kinematic differences. Two-way ANOVA showed significant effects between individuals on speed (d.f. = 5 and 228, P 〈 0·001) and tail-beat frequency (d.f. = 5 and 48, P 〈 0·001), but no significant effects of treatment on speed (d.f. = 1 and 228, P = 0·25) and tail-beat frequency (d.f. = 1 and 48, P 〉 0·1). No interaction effects on speed (d.f. = 5 and 228, P 〉 0·1) and tail-beat frequency (d.f. = 5 and 48, P 〉 0·25) were found. This suggested that finlets were unlikely to function as significant drag reduction and thrust enhancing devices in routine steady swimming. Though not statistically significant, small percentage differences between the mean swimming speeds and tail-beat frequency of the untreated and treated groups (fish with and without finlets respectively) of the order of 0·5% may be meaningful over the life of a fish. Also, finlets may improve performance at high sustained speeds in rapid accelerations and turns.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    International Journal of Mass Spectrometry and Ion Physics 46 (1983), S. 119-122 
    ISSN: 0020-7381
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
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  • 7
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    Menasha, Wis. : Periodicals Archive Online (PAO)
    The Accounting Review. 54:3 (1979:July) 643 
    ISSN: 0001-4826
    Topics: Economics
    Description / Table of Contents: COMMENTS
    Notes: Departments
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Medical & biological engineering & computing 25 (1987), S. 41-44 
    ISSN: 1741-0444
    Keywords: Doppler microwaves ; Heart rate ; Microprocessor-based ; Respiration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract A portable microprocessor-based noninvasive cardiopulmonary heart rate monitor is described for use in situations in which direct contact with the subject is either impossible or undesirable. Low-power Doppler microwaves are employed to measure the chest movements associated with the expansion and contraction of the heart and the lung. After proper analogue signal conditioning, the signal is digitised and processed by an Intel-85 microprocessor system. Pattern-recognition techniques are applied to extract the heart and respiration rates. The algorithm is tested on anaesthetised rats. The system has also been tested on a limited number of human subjects. Results indicate that the meter can detect the desired physiological signals, with good accuracy, of a standing or supine human subject wearing ordinary clothing.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Hoboken, NJ : Wiley-Blackwell
    Journal of Biomedical Materials Research 23 (1989), S. 819-831 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: This study was conducted to investigate some fundamental fatigue testing variables as they apply to the response characteristics of acrylic bone cement. Cyclic loading under load control was conducted at frequencies of 1, 2, 5, 10, and 20 Hz in air at room temperature. At a tensile stress range of 0.3-20.0 MPa the fatigue life increased linearly with logarithmic frequency. The effect of conditioning and testing in saline at both room temperature and 37°C at similar stress levels and a frequency of 10 Hz were also examined. When compared to dry testing at room temperature, testing in saline at 37°C resulted in a reduction in fatigue life while testing in saline at room temperature produced an increase in fatigue life. Of a number of statistical distributions considered, the Weibull was found to be the most appropriate in documenting the findings of this investigation. A companion fractographic investigation of the failure surfaces demonstrated distinct regions of crack growth and fast fracture.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    New York : Wiley-Blackwell
    Journal of Polymer Science: Polymer Chemistry Edition 20 (1982), S. 575-582 
    ISSN: 0360-6376
    Keywords: Physics ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The hindered amine-induced decomposition of polypropylene hydroperoxide was studied in the solid state and in the presence of a liquid solvent and the polymer was compared with model hydroperoxides. The high reactivity of the macrohydroperoxides appears to be related to the adjacent, hydrogen-bonded hydroperoxide groups that occur in the polymer. The hindered amines are converted to nitroxides in the reaction via hydroxylamine intermediates. Amine-induced decomposition of polypropylene hydroperoxide is faster in the absence of a liquid solvent for the amine than in the presence of the solvent, probably because of the strong amine-hydroperoxide association that occurs in the solid state. The decomposition process in the solid state is sufficiently rapid for the reaction to contribute to the effectiveness of hindered amines in the light stabilization of polymers.
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
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