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5-HT1A targeting PARCEST agent DO3AM-MPP with potential for receptor imaging : Synthesis, physico-chemical and MR studies
- 2021
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Ingår i: Bioorganic chemistry. - : Elsevier. - 0045-2068. ; 106
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Tidskriftsartikel (refereegranskat)abstract
- Contrast enhancement in MRI using magnetization or saturation transfer techniques promises better sensitivity, and faster acquisition compared to T-1 or T-2 contrast. This work reports the synthesis and evaluation of 5-HT1A targeted PARACEST MRI contrast agent using 1,4,7,10-tetraazacycloDOdecane-4,7,10-triacetAMide (DO3AM) as the bifunctional chelator, and 5-HT1A-antagonist methoxyphenyl piperazine (MPP) as a targeting unit. The multistep synthesis led to the MPP conjugated DO3AM with 60% yield. CEST-related physicochemical parameters were evaluated after loading DO3AM-MPP with paramagnetic MRI active lanthanides: Gadolinium (Gd-DO3AM-MPP) and Europium (Eu-DO3AM-MPP). Luminescence lifetime measurements with Eu-DO3AM-MPP and computational DFT studies using Gd-DO3AM-MPP revealed the coordination of one water molecule (q = 1.43) with metal-water distance (r(M)-H2O) of 2.7 angstrom and water residence time (tau(m)) of 0.23 ms. The dissociation constant of K-d 62 +/- 0.02 pM as evaluated from fluorescence quenching of 5-HT1A (protein) and docking score of -4.81 in theoretical evaluation reflect the binding potential of the complex Gd-DO3AM-MPP with the receptor 5-HT1A. Insights of the docked pose reflect the importance of NH2 (amide) and aromatic ring in Gd-DO3AM-MPP while interacting with Ser 374 and Phe 370 in the antagonist binding pocket of 5-HT1A. Gd-DO3AM-MPP shows longitudinal relaxivity 5.85 mM(-1)s(-1) with a water residence lifetime of 0.93 ms in hippocampal homogenate containing 5-HT1A. The potentiometric titration of DO3AM-MPP showed strong selectivity for Gd3+ over physiological metal ions such as Zn2+ and Cu2+. The in vitro and in vivo studies confirmed the minimal cytotoxicity and presential binding of Gd-DO3AM-MPP with 5-HT1A receptor in the hippocampus region of the mice. Summarizing, the complex Gd-DO3AM-MPP can have a potential for CEST imaging of 5-HT1A receptors.
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| 3. |
- Aabel, Peder, et al.
(författare)
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Transcription and microRNA Profiling of Cultured Human Tympanic Membrane Epidermal Keratinocytes
- 2018
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Ingår i: Journal of the Association for Research in Otolaryngology. - : SPRINGER. - 1525-3961 .- 1438-7573. ; 19:3, s. 243-260
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Tidskriftsartikel (refereegranskat)abstract
- The human tympanic membrane (TM) has a thin outer epidermal layer which plays an important role in TM homeostasis and ear health. The specialised cells of the TM epidermis have a different physiology compared to normal skin epidermal keratinocytes, displaying a dynamic and constitutive migration that maintains a clear TM surface and assists in regeneration. Here, we characterise and compare molecular phenotypes in keratinocyte cultures from TM and normal skin. TM keratinocytes were isolated by enzymatic digestion and cultured in vitro. We compared global mRNA and microRNA expression of the cultured cells with that of human epidermal keratinocyte cultures. Genes with either relatively higher or lower expression were analysed further using the biostatistical tools g:Profiler and Ingenuity Pathway Analysis. Approximately 500 genes were found differentially expressed. Gene ontology enrichment and Ingenuity analyses identified cellular migration and closely related biological processes to be the most significant functions of the genes highly expressed in the TM keratinocytes. The genes of low expression showed a marked difference in homeobox (HOX) genes of clusters A and C, giving the TM keratinocytes a strikingly low HOX gene expression profile. An in vitro scratch wound assay showed a more individualised cell movement in cells from the tympanic membrane than normal epidermal keratinocytes. We identified 10 microRNAs with differential expression, several of which can also be linked to regulation of cell migration and expression of HOX genes. Our data provides clues to understanding the specific physiological properties of TM keratinocytes, including candidate genes for constitutive migration, and may thus help focus further research.
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| 6. |
- Aabloo, A, et al.
(författare)
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Molecular dynamics simulations of a poly(ethylene oxide) surface
- 1997
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Ingår i: POLYMER. - 0032-3861. ; 38:18, s. A47-A51
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Tidskriftsartikel (refereegranskat)abstract
- Potentials developed earlier for crystalline and amorphous bulk PEO systems have been used for the MD simulation of a PEO surface model. The surface comprises the outer region of a 122 Angstrom-thick sheet of PEO in which the PEO, -(CH2-CH2-O)(n)- chains
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| 7. |
- Aaboud, M., et al.
(författare)
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Direct top-quark decay width measurement in the t(t)over-bar lepton plus jets channel at root s=8 TeV with the ATLAS experiment
- 2018
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Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 78
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Tidskriftsartikel (refereegranskat)abstract
- This paper presents a direct measurement of the decay width of the top quark using t (t) over bar events in the lepton+jets final state. The data sample was collected by the ATLAS detector at the LHC in proton-proton collisions at a centre-of-mass energy of 8 TeV and corresponds to an integrated luminosity of 20.2 fb(-1). The decay width of the top quark is measured using a template fit to distributions of kinematic observables associated with the hadronically and semileptonically decaying top quarks. The result, Gamma(t) = 1.76 +/- 0.33 (stat.) (+0.79)(-0.68) (syst.) GeV for a top-quark mass of 172.5 GeV, is consistent with the prediction of the Standard Model.
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| 8. |
- Aaboud, M, et al.
(författare)
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Measurement of fiducial and differential W+W- production cross-sections at √s=13 TeV with the ATLAS detector
- 2019
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Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 79:10
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Tidskriftsartikel (refereegranskat)abstract
- A measurement of fiducial and differential cross-sections for W+W- production in proton–proton collisions at s=13 TeV with the ATLAS experiment at the Large Hadron Collider using data corresponding to an integrated luminosity of 36.1 fb - 1 is presented. Events with one electron and one muon are selected, corresponding to the decay of the diboson system as WW→ e±νμ∓ν. To suppress top-quark background, events containing jets with a transverse momentum exceeding 35 GeV are not included in the measurement phase space. The fiducial cross-section, six differential distributions and the cross-section as a function of the jet-veto transverse momentum threshold are measured and compared with several theoretical predictions. Constraints on anomalous electroweak gauge boson self-interactions are also presented in the framework of a dimension-six effective field theory. © 2019, CERN for the benefit of the ATLAS collaboration.
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| 9. |
- Aaboud, M, et al.
(författare)
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Measurement of jet pT correlations in Pb + Pb and pp collisions at sNN=2.76 TeVwith the ATLAS detector
- 2017
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Ingår i: Physics Letters B. - : Elsevier BV. - 0370-2693 .- 1873-2445. ; 774, s. 379-402
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Tidskriftsartikel (refereegranskat)abstract
- Measurements of dijet pT correlations in Pb+Pb and pp collisions at a nucleon–nucleon centre-of-mass energy of sNN=2.76 TeV are presented. The measurements are performed with the ATLAS detector at the Large Hadron Collider using Pb+Pb and pp data samples corresponding to integrated luminosities of 0.14 nb−1 and 4.0 pb−1, respectively. Jets are reconstructed using the anti-kt algorithm with radius parameter values R=0.3 and R=0.4. A background subtraction procedure is applied to correct the jets for the large underlying event present in Pb+Pb collisions. The leading and sub-leading jet transverse momenta are denoted pT1 and pT2. An unfolding procedure is applied to the two-dimensional (pT1,pT2) distributions to account for experimental effects in the measurement of both jets. Distributions of (1/N)dN/dxJ, where xJ=pT2/pT1, are presented as a function of pT1 and collision centrality. The distributions are found to be similar in peripheral Pb+Pb collisions and pp collisions, but highly modified in central Pb+Pb collisions. Similar features are present in both the R=0.3 and R=0.4 results, indicating that the effects of the underlying event are properly accounted for in the measurement. The results are qualitatively consistent with expectations from partonic energy loss models. © 2017 The Author
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| 10. |
- Aaboud, M, et al.
(författare)
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Measurement of lepton differential distributions and the top quark mass in tt¯ production in pp collisions at √s=8 TeV with the ATLAS detector
- 2017
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Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 77:11
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Tidskriftsartikel (refereegranskat)abstract
- This paper presents single lepton and dilepton kinematic distributions measured in dileptonic tt¯ events produced in 20.2fb - 1 of s=8 TeV pp collisions recorded by the ATLAS experiment at the LHC. Both absolute and normalised differential cross-sections are measured, using events with an opposite-charge eμ pair and one or two b-tagged jets. The cross-sections are measured in a fiducial region corresponding to the detector acceptance for leptons, and are compared to the predictions from a variety of Monte Carlo event generators, as well as fixed-order QCD calculations, exploring the sensitivity of the cross-sections to the gluon parton distribution function. Some of the distributions are also sensitive to the top quark pole mass; a combined fit of NLO fixed-order predictions to all the measured distributions yields a top quark mass value of mtpole=173.2±0.9±0.8±1.2 GeV, where the three uncertainties arise from data statistics, experimental systematics, and theoretical sources. © 2017, CERN for the benefit of the ATLAS collaboration.
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