573 research outputs found
Electrophysiology-based investigations of G protein-coupled receptor pharmacology
No full textG protein-coupled receptors (GPCRs) constitute targets for ~34% of approved drugs. The muscarinic acetylcholine M2 receptor (M2R) activates G protein-coupled receptor inward rectifying potassium (GIRK) channels in the central nervous system and heart. Membrane potential modulates agonist potency at several GPCRs. However, the mechanism underlying the voltage sensitivity remains debated. A highly conserved aspartate residue (D2.5069) has been proposed to mediate the voltage-sensitivity of the M2R, although the low expression of D69 mutants has complicated further functional investigations.Dopamine D2 and D3 receptors (D2R and D3R) are pre- and postsynaptic inhibitory receptors in the central nervous system, involved in locomotion, cognition and endocrine functions. D2R antagonists and weak partial agonists are used clinically as antipsychotics but are associated with several side effects. Various strategies have been suggested to reduce the side-effect profile of novel antipsychotic drugs. One such strategy includes the selective targeting of non-canonical signaling pathways, e.g., the β-arrestin pathway, while leaving the classical, G protein pathway, undisturbed. Additionally, binding affinity and kinetics at the D2R, as well as ligand lipophilicity, have been suggested to be of significance in determining the side-effect liability of antipsychotics.In the thesis, M2R, D2R and D3R were investigated using two-electrode voltage-clamp in Xenopus laevis oocytes co-expressing the respective receptor and GIRK channels. M2R carrying a charge-neutralizing D69N mutation demonstrated a voltage-dependent shift of agonist-potency, similar to the wild type M2R. This finding is in line with a recent alternative hypothesis, which implicates three tyrosine residues in the M2R voltage sensor. The proposed β-arrestin-selective partial D2R agonist, UNC9994, was found to be a weak partial- and almost full agonist at D2R and D3R mediated GIRK activation, respectively. These findings are incongruent with β-arrestin-selectivity and suggest that the promising effects of UNC9994 in animal models of psychosis may be related, at least in part, to involvement of the D3R. Finally, the partial D2R agonist positron emission tomography ligand, SV-III-130, demonstrated an insurmountable, yet competitive, binding mechanism at the D2R. Mutations of residues in a secondary binding pocket, engaging the secondary pharmacophore, abolished the insurmountable binding. Kinetic models incorporating an irreversible, SV-III-130-bound state captured the experimentally observed data. Molecular dynamics simulations suggested that D2R extracellular linkers participate in an induced-fit binding mechanism.In summary, the thesis addresses the mechanism of voltage-dependent agonist-potency at GPCRs and contradicts earlier reports of a β-arrestin-selective action of the experimental antipsychotic, UNC9994, at the D2R. Finally, a two-step induced-fit binding mechanism was demonstrated for the aripiprazole analogue, SV-III-130, at the D2R. The findings may guide further mechanistic investigations and provide insights for the development of novel diagnostic and therapeutic GPCR ligands.List of scientific papersI. Ågren R, Sahlholm K, Nilsson J, Århem P. Point mutation of a conserved aspartate, D69, in the muscarinic M2 receptor does not modify voltage-sensitive agonist potency. Biochem Biophys Res Commun. 2018 Jan 29;496(1):101-104. https://doi.org/10.1016/j.bbrc.2018.01.005 II. Ågren R, Århem P, Nilsson J*, Sahlholm K*. The Beta-Arrestin-Biased Dopamine D2 Receptor Ligand, UNC9994, Is a Partial Agonist at G-Protein-Mediated Potassium Channel Activation. Int J Neuropsychopharmacol. 2018 Dec 1;21(12):1102-1108. *Equal contributions. https://doi.org/10.1093/ijnp/pyy059 III. Ågren R, Zeberg H, Stepnięwski TM, Reilly SW, Luedtke R, Århem P, Mach RH, Selent J, Nilsson J, Sahlholm K. A ligand with two modes of interaction with the dopamine D2 receptor – An induced-fit mechanism of irreversible binding. [Manuscript]</p
Dan Andersson
No full textSpecial feature issue on the Swedish author Dan Andersson, with articles by Anders Hallengren, Nisse Munck, Lars Furuland, Lars Järnemo (2), Gösta Ågren, Inge Mattsson, Arne Säll, and Bure Holmbäck.</p
Suppression of cation intermixing highly boosts the performance of core-shell lanthanide upconversion nanoparticles
No full textThis folder contains all raw data underlying the results presented in a manuscript, submitted to Journal of American Chemistry Society, and entitled:
Suppression of cation intermixing highly boosts the performance of core-shell lanthanide upconversion nanoparticles
Authored by:
Fuhua Huang2,3, Niusha Bagheri1, Li Wang *2,3, Hans Ågren*2,3, Jinglai Zhang*2,3, Jerker Widengren1, Haichun Liu*1
1 Department of Applied Physics, KTH Royal Institute of Technology, S-10691, Stockholm, Sweden
2 College of Chemistry and Chemical Engineering, Henan University, Kaifeng, Henan 475004, P. R. China
3 Henan Center for Outstanding Overseas Scientists, Henan University, Kaifeng 475004, P. R. China
*Corresponding author: E-mail: [email protected]
Data files containing the raw data and the results of the analysis are grouped according to the order of the figures in the manuscript.
ABSTRACT
Lanthanide upconversion nanoparticles (UCNPs) have been extensively explored as biomarkers, energy transducers and information carriers in wide-ranging applications in areas from healthcare and energy to information technology. In boosting the brightness and enriching the functionalities of UCNPs, core-shell structural engineering has been well established as an important approach. Despite its importance, a strong limiting issue has been identified, namely cation intermixing in the interfacial region of the synthesized core-shell nanoparticles. Currently there still exists confusion regarding this destructive phenomenon and there is still a lack of facile means to reach a delicate control of it. By means of a new set of experiments, we provide in this work a clear picture for the physical mechanism of cation intermixing occurring in core-shell UCNPs, i.e. partial or substantial core nanoparticle dissolution followed by epitaxial growth of the outer layer and ripening of the entire particle. Based on this picture, we provide an easy but effective approach to tackle this issue that enables producing UCNPs with highly boosted optical properties.
*Corresponding authors.
E-mail addresses:[email protected] (H. Liu), [email protected] (H. Ågren), [email protected] (L. Wang), [email protected] (J. Zhang
Structured ionospheric outflow during the Cassini T55–T59 Titan flybys
No full textDuring the final three of the five consecutive and similar Cassini Titan flybys T55–T59 we observe a region characterized by high plasma densities (electron densities of 1–8 cm3 ) in the tail/nightside of Titan. This region is observed progressively farther downtail from pass to pass and is interpreted as a plume of ionospheric plasma escaping Titan, which appears steady in both location and time. The ions
in this plasma plume are moving in the direction away from Titan and are a mixture of both light and heavy ions with composition revealing that their origin are in Titan’s ionosphere, while the electrons are more isotropically distributed. Magnetic field measurements indicate the presence of a current sheet at the inner edge of this region. We discuss the mechanisms behind this outflow, and suggest that it could be caused by ambipolar diffusion, magnetic moment pumping or dispersive Alfve´n waves.Fil: Edberg, N. J. T.. Swedish Institute of Space Physics; SueciaFil: Ågren, K.. Swedish Institute of Space Physics; SueciaFil: Wahlund, J. E.. Swedish Institute of Space Physics; SueciaFil: Morooka, M. W.. Swedish Institute of Space Physics; SueciaFil: Andrews, D. J.. University of Leicester; Reino UnidoFil: Cowley, S. W. H.. University of Leicester; Reino UnidoFil: Wellbrock, A.. University College London; Estados UnidosFil: Coates, A. J.. University College London; Estados UnidosFil: Bertucci, Cesar. Consejo Nacional de Investigaciónes Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Astronomía y Física del Espacio. - Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Astronomía y Física del Espacio; ArgentinaFil: Dougherty, M. K.. Imperial College London; Reino Unid
High prevalence and genetic diversity of Treponema paraluisleporidarum isolates in European lagomorphs
No full textABSTRACT The bacterium Treponema paraluisleporidarum causes syphilis in lagomorphs. In a set of 1,095 samples from four species—European brown hare, mountain hare, Corsican hare, and European rabbit—we tested for infection and genotyped the strains that infect wild lagomorphs. Samples originate from Sweden, the Netherlands, the United Kingdom, Germany, the Czech Republic, and Italy. The phylogenetic analyses of two informative gene targets ( tp0488 and tp0548 ) showed high genetic diversity among the lagomorph-infecting treponemes. More specifically, we found a high number of nucleotide variants and various short repeat units in the tp0548 locus that have not been described for human syphilis and primate yaws causing Treponema pallidum . While the functional aspect of these short repeat units remains subject to ongoing investigations, it likely enables the pathogen to better survive in its lagomorph host. Our data did not support any geographic clustering, which is equally reflected in the host population genetics as shown by mitochondrial genome data corresponding to the sampled lagomorph populations. This is unexpected and in contrast with what has been shown for nonhuman primate infection with T. pallidum . In the future, the combination of multi-locus sequence typing and whole genome data from modern and ancient samples from a wide geographic range and multiple lagomorph species will contribute to a better understanding of the epidemiology and evolutionary path of lagomorph-infecting treponemes. In conclusion, our current study demonstrates widespread infection and a high genetic variation of the syphilis-causing pathogen in a higher number of positively PCR-tested European lagomorphs ( n = 302/1,095). IMPORTANCE Syphilis is an ancient disease of humans and lagomorphs caused by two distinct but genetically closely related bacteria (>98% sequence identity based on the whole genome) of the genus Treponema . While human syphilis is well studied, little is known about the disease in the lagomorph host. Yet, comparative studies are needed to understand mechanisms in host–pathogen coevolution in treponematoses. Importantly, Treponema paraluisleporidarum –infected hare populations provide ample opportunity to study the syphilis-causing pathogen in a naturally infected model population without antibiotic treatment, data that cannot be obtained from syphilis infection in humans. We provide data on genetic diversity and are able to highlight various types of repetitions in one of the two hypervariable regions at the tp0548 locus that have not been described in the human syphilis-causing sister bacterium Treponema pallidum subsp. pallidum .Syphilis is an ancient disease of humans and lagomorphs caused by two distinct but genetically closely related bacteria (>98% sequence identity based on the whole genome) of the genus Treponema . While human syphilis is well studied, little is known about the disease in the lagomorph host. Yet, comparative studies are needed to understand mechanisms in host–pathogen coevolution in treponematoses. Importantly, Treponema paraluisleporidarum –infected hare populations provide ample opportunity to study the syphilis-causing pathogen in a naturally infected model population without antibiotic treatment, data that cannot be obtained from syphilis infection in humans. We provide data on genetic diversity and are able to highlight various types of repetitions in one of the two hypervariable regions at the tp0548 locus that have not been described in the human syphilis-causing sister bacterium Treponema pallidum subsp. pallidum .Deutsche Forschungsgemeinschaft 501100001659Czech Science Foundation 501100001824National Institute of Virology and Bacteriolog
Fish oil and vitamin E supplementation in oxidative stress at rest and after physical exercise
No full textSen, Chandan K., Mustafa Atalay, Jyrki Ågren, David E. Laaksonen, Sashwati Roy, and Osmo Hänninen. Fish oil and vitamin E supplementation in oxidative stress at rest and after physical exercise. J. Appl. Physiol.83(1): 189–195, 1997.—Fish oil supplementation and physical exercise may induce oxidative stress. We tested the effects of 8 wk of α-tocopherol (vitamin E) and fish oil (FO) supplementation on resting and exercise-induced oxidative stress. Rats ( n = 80) were divided into groups supplemented with FO, FO and vitamin E (FOVE), soy oil (SO), and SO and vitamin E (SOVE), and for FOVE and SOVE they were divided into corresponding exercise groups (FOVE-Ex and SOVE-Ex). Lipid peroxidation [thiobarbituric acid-reacting substances (TBARS)] was 33% higher in FO compared with SO in the liver, but oxidative protein damage (carbonyl levels) remained similar in both liver and red gastrocnemius muscle (RG). Vitamin E supplementation, compared with FO and SO, markedly decreased liver and RG TBARS, but liver TBARS remained 32% higher in FOVE vs. SOVE. Vitamin E also markedly decreased liver and RG protein carbonyl levels, although levels in FOVE and SOVE were similar. Exercise increased liver and RG TBARS and RG protein carbonyl levels markedly, with similar levels in FOVE-Ex and SOVE-Ex. FO increased lipid peroxidation but not protein oxidation in a tissue-specific manner. Vitamin E markedly decreased lipid peroxidation and protein oxidation in both FOVE and SOVE, although liver lipid peroxidation remained higher in FOVE. Despite higher levels of hepatic lipid peroxidation at rest in FOVE compared with SOVE, liver appeared to be relatively less susceptible to exercise-induced oxidative stress in FOVE.</jats:p
Reply to Comment on ‘Nondipole Resonant X-ray-Raman Spectroscopy: Polarized Inelastic Scattering at the K Edge of Cl2,’
No full textMills et al. Reply: In their Comment on our Letter [1], Gel’mukhanov and Ågren [2] reiterate recent assertions [3] based on their earlier theoretical studies [4]. The primary purpose of their Comment is apparently to refute our stated conclusion that core-excited-state localization/ delocalization mechanisms are irrelevant to interpretations of reported Raman scattering experiments on homonuclear diatomic molecules
Kulturvetarlinjen i Umeå
No full textVid Umeå universitet finns sedan 1981 en specialutbildning för dem som vill ägna sig åt museer och kulturminnesvård. Västerbottens museum har blivit skolbildande i flera avseenden och dess förutvarande chef Per-Uno Ågren har nu Sveriges enda tjänst som universitetslektor i museikunskap. Undervisningen har vuxit fram ur den s k kulturvetarlinjen, som finns vid alla landets universitet och högskolor. Hur det gick till och hur utbildningen nu är organiserad, beskrivs här av Marianne Ek, utbildningsledare vid Umeå universitet
Kulturvetarlinjen i Umeå [Elektronisk resurs]
No full textVid Umeå universitet finns sedan 1981 en specialutbildning för dem som vill ägna sig åt museer och kulturminnesvård. Västerbottens museum har blivit skolbildande i flera avseenden och dess förutvarande chef Per-Uno Ågren har nu Sveriges enda tjänst som universitetslektor i museikunskap. Undervisningen har vuxit fram ur den s k kulturvetarlinjen, som finns vid alla landets universitet och högskolor. Hur det gick till och hur utbildningen nu är organiserad, beskrivs här av Marianne Ek, utbildningsledare vid Umeå universitet.</p
Competition between decay and dissociation of core-excited carbonyl sulfide studied by x-ray scattering
No full textWe show evidence of dissociation during resonant inelastic soft x-ray scattering. Carbon and oxygen K-shell and sulfur L-shell resonant and nonresonant x-ray emission spectra were measured using monochromatic synchrotron radiation for excitation and ionization. After sulfur L2,3→π*, σ* excitation, atomic lines are observed in the emission spectra as a consequence of competition between de-excitation and dissociation. In contrast the carbon and oxygen spectra show weaker line-shape variations and no atomic lines. The spectra are compared to results from ab initio calculations. The discussion of the dissociation paths is based on calculated potential energy surfaces and atomic transition energies.Original Publication: Martin Magnuson, J. Guo, C. Såthe, J.-E. Rubensson, J. Nordgren, P. Glans, L. Yang, P. Sałek and H. Ågren, Competition between decay and dissociation of core-excited carbonyl sulfide studied by x-ray scattering, 1999, Physical Review A. Atomic, Molecular, and Optical Physics, (59), 4281-4287. http://dx.doi.org/10.1103/PhysRevA.59.4281 Copyright: American Physical Society http://www.aps.org/</p
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