Browsing by Subject "GAMMA"

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  • Skledar, Darja Gramec; Carino, Adriana; Trontelj, Jurij; Troberg, Johanna; Distrutti, Eleonora; Marchiano, Silvia; Tornasic, Tihomir; Zega, Anamarija; Finel, Moshe; Fiorucci, Stefano; Maisic, Lucija Peterlin (2019)
    Bisphenol AF (BPAF) is a fluorinated analog of bisphenol A (BPA), and it is a more potent estrogen receptor (ER) agonist. BPAF is mainly metabolized to BPAF-glucuronide (BPAF-G), which has been reported to lack ER agonist activity and is believed to be biologically inactive. The main goal of the current study was to examine the influence of the metabolism of BPAF via glucuronidation on its ER activity and adipogenesis. Also, as metabolites can have different biological activities, the effects of BPAF-G on other nuclear receptors were evaluated. First, in-vitro BPAF glucuronidation was investigated using recombinant human enzymes. Specific reporter-gene assays were used to determine BPAF and BPAF-G effects on estrogen, androgen, glucocorticoid, and thyroid receptor pathways, and on PXR, FXR, and PPAR gamma pathways. Their effects on lipid accumulation and differentiation were determined in murine 3T3L1 preadipocytes using Nile Red, with mRNA expression analysis of the adipogenic markers adiponectin, Fabp4, Cebp alpha, and PPAR gamma. BPAF showed strong agonistic activity for hER alpha and moderate antagonistic activities for androgen and thyroid receptors, and for PXR. BPAF-G was antagonistic for PXR and PPAR gamma. BPAF (0.1 mu M) and BPAF-G (1.0 mu M) induced lipid accumulation and increased expression of key adipogenic markers in murine preadipocytes. BPAF-G is therefore not an inactive metabolite of BPAF. Further toxicological and epidemiological investigations of BPAF effects on human health are warranted, to provide better understanding of the metabolic end-elimination of BPAF. (C) 2018 Elsevier Ltd. All rights reserved.
  • Vilen, M.; Kankainen, A.; Baczyk, P.; Canete, L.; Dobaczewski, J.; Eronen, T.; Geldhof, S.; Jokinen, A.; Konieczka, M.; Kostensalo, J.; Moore, I. D.; Nesterenko, D. A.; Penttilä, H.; Pohjalainen, I.; Reponen, M.; Rinta-Antila, S.; de Roubin, A.; Satula, W.; Suhonen, J. (2019)
    An upgraded ion-guide system for the production of neutron-deficient isotopes with heavy-ion beams has been commissioned at the IGISOL facility with an Ar-36 beam on a Ni-nat target. It was used together with the JYFLTRAP double Penning trap to measure the masses of Zr-82, Nb-84, Mo-86, Tc-88, and Ru-89 ground states and the isomeric state Tc-88(m). Of these, Ru-89 and Tc-88(m) weremeasured for the first time. The precision of measurements of Zr-82, Nb-84, and Tc-88 was significantly improved. The literature value for Mo-86 was verified. The measured states in Tc-88 were compared to shell-model calculations and additional constraints on the spins and level scheme were obtained. The masses of Mo-82 and Ru-86 have been predicted using the measured masses of their mirror partners and theoretical mirror displacement energies, resulting in more tightly bound nuclei with smaller atomic mass uncertainties than reported in the literature.
  • Hammaren, Henrik M.; Virtanen, Anniina T.; Abraham, Bobin George; Peussa, Heidi; Hubbard, Stevan R.; Silvennoinen, Olli (2019)
    Background: Janus kinases (JAKs; JAK1 to JAK3 and tyrosine kinase 2) mediate cytokine signals in the regulation of hematopoiesis and immunity. JAK2 clinical mutations cause myeloproliferative neoplasms and leukemia, and the mutations strongly concentrate in the regulatory pseudokinase domain Janus kinase homology (JH) 2. Current clinical JAK inhibitors target the tyrosine kinase domain and lack mutation and pathway selectivity. Objective: We sought to characterize mechanisms and differences for pathogenic and cytokine-induced JAK2 activation to enable design of novel selective JAK inhibitors. Methods: We performed a systematic analysis of JAK2 activation requirements using structure-guided mutagenesis, cell-signaling assays, microscopy, and biochemical analysis. Results: Distinct structural requirements were identified for activation of different pathogenic mutations. Specifically, the predominant JAK2 mutation, V617F, is the most sensitive to structural perturbations in multiple JH2 elements (C helix [aC], Src homology 2-JH2 linker, and ATP binding site). In contrast, activation of K539L is resistant to most perturbations. Normal cytokine signaling shows distinct differences in activation requirements: JH2 ATP binding site mutations have only a minor effect on signaling, whereasJH2aCmutations reduce homomeric (JAK2-JAK2) erythropoietin signaling and almost completely abrogate heteromeric (JAK2-JAK1) IFN-gamma signaling, potentially by disrupting a dimerization interface on JH2. Conclusions: These results suggest that therapeutic approaches targeting the JH2 ATP binding site and aC could be effective in inhibiting most pathogenic mutations. JH2 ATP site targeting has the potential for reduced side effects by retaining erythropoietin and IFN-gamma functions. Simultaneously, however, we identified the JH2 aC interface as a potential target for pathway-selective JAK inhibitors in patients with diseases with unmutated JAK2, thus providing new insights into the development of novel pharmacologic interventions.
  • Brücken, Erik; Bharthuar, Shudhashil; Emzir, M.; Golovleva, Maria; Gädda, Akiko; Hostettler, R.; Härkönen, J.; Kirschenmann, Stefanie; Litichevskyi, Vladyslav; Luukka, Panja; Martikainen, Laura; Naaranoja, Tiina; Nincâ, Ilona Stefana; Ott, Jennifer; Petrow, H.; Purisha, Zenith; Siiskonen, Teemu; Särkkä, Simo; Tikkanen, Joonas Samuli; Tuuva, Tuure; Winkler, Alexander (2020)
    We present the current status of our project of developing a photon counting detector for medical imaging. An example motivation lays in producing a monitoring and dosimetry device for boron neutron capture therapy, currently not commercially available. Our approach combines in-house developed detectors based on cadmium telluride or thick silicon with readout chip technology developed for particle physics experiments at CERN. Here we describe the manufacturing process of our sensors as well as the processing steps for the assembly of first prototypes. The prototypes use currently the PSI46digV2.1-r readout chip. The accompanying readout electronics chain that was used for first measurements will also be discussed. Finally we present an advanced algorithm developed by us for image reconstruction using such photon counting detectors with focus on boron neutron capture therapy. This work is conducted within a consortium of Finnish research groups from Helsinki Institute of Physics, Aalto University, Lappeenranta-Lahti University of Technology LUT and Radiation and Nuclear Safety Authority (STUK) under the RADDESS program of Academy of Finland.
  • Chen, Zuyue; Parkkonen, Lauri; Wei, Jingkuan; Dong, Jin-Run; Ma, Yuanye; Carlson, Synnöve (2018)
    Prepulse inhibition (PPI) refers to a decreased response to a startling stimulus when another weaker stimulus precedes it. Most PPI studies have focused on the physiological startle reflex and fewer have reported the PPI of cortical responses. We recorded local field potentials (LFPs) in four monkeys and investigated whether the PPI of auditory cortical responses (alpha, beta, and gamma oscillations and evoked potentials) can be demonstrated in the caudolateral belt of the superior temporal gyrus (STGcb). We also investigated whether the presence of a conspecific, which draws attention away from the auditory stimuli, affects the PPI of auditory cortical responses. The PPI paradigm consisted of Pulse-only and Prepulse + Pulse trials that were presented randomly while the monkey was alone (ALONE) and while another monkey was present in the same room (ACCOMP). The LFPs to the Pulse were significantly suppressed by the Prepulse thus, demonstrating PPI of cortical responses in the STGcb. The PPI-related inhibition of the N1 amplitude of the evoked responses and cortical oscillations to the Pulse were not affected by the presence of a conspecific. In contrast, gamma oscillations and the amplitude of the N1 response to Pulse-only were suppressed in the ACCOMP condition compared to the ALONE condition. These findings demonstrate PPI in the monkey STGcb and suggest that the PPI of auditory cortical responses in the monkey STGcb is a pre-attentive inhibitory process that is independent of attentional modulation.
  • Łuszczak, Marta; Forthomme, Laurent; Schäfer, Wolfgang; Szczurek, Antoni (2019)
    We discuss the production of t t quark- antiquark pairs in proton- proton collisions via the fusion mechanism. We include topologies in which both protons stay intact or one or even both of them undergo dissociation. The calculations are performed within the k T - factorisation approach, including transverse momenta of intermediate photons. Photon uxes associated with inelastic ( dissociative) processes are calculated based on modern parameterisations of proton structure functions. We fi nd an integrated cross section of about 2.36 fb at p s = 13 TeV for all contributions ( without requirement of rapidity gap). The cross section for the fully elastic process is the smallest. Inelastic contributions are signi fi cantly reduced when a veto on outgoing jets is imposed. We present several di ff erential distributions in rapidity and transverse momenta of single t or t quarks/ antiquarks as well as distributions in invariant mass of both the t t and masses of dissociated systems. A few two- dimensional distributions are presented in addition.