A single evolutionarily divergent mutation determines the different FAD-binding affinities of human and rat NQO1 due to site-specific phosphorylation

The phosphomimetic mutation S82D in the cancer-associated, FAD-dependent human NADP(H):quinone oxidoreductase 1 (hNQO1) causes a decrease in flavin-adenine dinucleotide-binding affinity and intracellular stability. We test in this work whether the evolutionarily recent neutral mutation R80H in the vicinity of S82 may alter the strong functional effects of S82 phosphorylation through electrostatic interactions. We show using biophysical and bioinformatic analyses that the reverse mutation H80R prevents the effects of S82D phosphorylation on hNQO1 by modulating the local stability. Consistently, in rat NQO1 (rNQO1) which contains R80, the effects of phosphorylation were milder, resembling the behaviour found in hNQO1 when this residue was humanized in rNQO1 (by the R80H mutation). Thus, apparently neutral and evolutionarily divergent mutations may determine the functional response of mammalian orthologues towards phosphorylation. © 2021 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societie

Proposal for SPS beam time for the baby MIND and TASD neutrino detector prototypes

The design, construction and testing of neutrino detector prototypes at CERN are ongoing activities. This document reports on the design of solid state baby MIND and TASD detector prototypes and outlines requirements for a test beam at CERN to test these, tentatively planned on the H8 beamline in the North Area, which is equipped with a large aperture magnet. The current proposal is submitted to be considered in light of the recently approved projects related to neutrino activities with the SPS in the North Area in the medium term 2015-2020

Structural basis of the pleiotropic and specific phenotypic consequences of missense mutations in the multifunctional NAD(P)H:quinone oxidoreductase 1 and their pharmacological rescue

The multifunctional nature of human flavoproteins is critically linked to their ability to populate multiple conformational states. Ligand binding, post-translational modifications and disease-associated mutations can reshape this functional landscape, although the structure-function relationships of these effects are not well understood. Herein, we characterized the structural and functional consequences of two mutations (the cancer-associated P187S and the phosphomimetic S82D) on different ligation states which are relevant to flavin binding, intracellular stability and catalysis of the disease-associated NQO1 flavoprotein. We found that these mutations affected the stability locally and their effects propagated differently through the protein structure depending both on the nature of the mutation and the ligand bound, showing directional preference from the mutated site and leading to specific phenotypic manifestations in different functional traits (FAD binding, catalysis and inhibition, intracellular stability and pharmacological response to ligands). Our study thus supports that pleitropic effects of disease-causing mutations and phosphorylation events on human flavoproteins may be caused by long-range structural propagation of stability effects to different functional sites that depend on the ligation-state and site-specific perturbations. Our approach can be of general application to investigate these pleiotropic effects at the flavoproteome scale in the absence of high-resolution structural models. © 202

A Very Intense Neutrino Super Beam Experiment for Leptonic CP Violation Discovery based on the European Spallation Source Linac: A Snowmass 2013 White Paper

Very intense neutrino beams and large neutrino detectors will be needed in order to enable the discovery of CP violation in the leptonic sector. We propose to use the proton linac of the European Spallation Source currently under construction in Lund, Sweden to deliver, in parallel with the spallation neutron production, a very intense, cost effective and high performance neutrino beam. The baseline program for the European Spallation Source linac is that it will be fully operational at 5 MW average power by 2022, producing 2 GeV 2.86 ms long proton pulses at a rate of 14 Hz. Our proposal is to upgrade the linac to 10 MW average power and 28 Hz, producing 14 pulses/s for neutron production and 14 pulses/s for neutrino production. Furthermore, because of the high current required in the pulsed neutrino horn, the length of the pulses used for neutrino production needs to be compressed to a few $\mu$s with the aid of an accumulator ring. A long baseline experiment using this Super Beam and a megaton underground Water Cherenkov detector located in existing mines 300-600 km from Lund will make it possible to discover leptonic CP violation at 5 $\sigma$ significance level in up to 50% of the leptonic Dirac CP-violating phase range. This experiment could also determine the neutrino mass hierarchy at a significance level of more than 3 $\sigma$ if this issue will not already have been settled by other experiments by then. The mass hierarchy performance could be increased by combining the neutrino beam results with those obtained from atmospheric neutrinos detected by the same large volume detector. This detector will also be used to measure the proton lifetime, detect cosmological neutrinos and neutrinos from supernova explosions. Results on the sensitivity to leptonic CP violation and the neutrino mass hierarchy are presented.Comment: 28 page

Baby MIND: A magnetised spectrometer for the WAGASCI experiment

The WAGASCI experiment being built at the J-PARC neutrino beam line will measure the difference in cross sections from neutrinos interacting with a water and scintillator targets, in order to constrain neutrino cross sections, essential for the T2K neutrino oscillation measurements. A prototype Magnetised Iron Neutrino Detector (MIND), called Baby MIND, is being constructed at CERN to act as a magnetic spectrometer behind the main WAGASCI target to be able to measure the charge and momentum of the outgoing muon from neutrino charged current interactions.Comment: Poster presented at NuPhys2016 (London, 12-14 December 2016). Title + 4 pages, LaTeX, 6 figure

Guidance for family about comfort care in dementia: a comparison of an educational booklet adopted in six jurisdictions over a 15 year timespan

BackgroundTo support family caregivers of people with dementia in end-of-life decision making, a family booklet on comfort care has been adapted and adopted by several European jurisdictions since the original publication in Canada in 2005.MethodsWe analyzed and compared the adaptations to the family booklets used in Canada, the Czech Republic, Italy, the Netherlands, the UK and Ireland that were made up to 2021. Qualitative content analysis was used to create a typology of changes to the original booklet. Interviews with the teams that adapted the booklets contributed to methodological triangulation. Further, using an established framework, we assessed whether the contents of the booklets addressed all domains relevant to optimal palliative dementia care.ResultsThe booklets differed in the types of treatment addressed, in particular tube feeding, euthanasia, and spiritual care. There was also variability in the extent to which medical details were provided, an emphasis on previously expressed wishes in medical decision making, addressing of treatment dilemmas at the end of life, the tone of the messages (indirect or explicit) and the discussion of prognosis (as more or less positive), and the involvement of various healthcare professionals and family caregivers in care. All booklets addressed all domains of palliative dementia care.ConclusionsWe identified core elements in providing information on end-of-life care to family caregivers of people with dementia as related to optimal palliative care in dementia. Additionally, local adaptations and updates are required to account for socio-cultural, clinical, and legal differences which may also change over time. These results may inform development of educational and advance care planning materials for different contexts.</div

Baby MIND: A magnetized segmented neutrino detector for the WAGASCI experiment

T2K (Tokai-to-Kamioka) is a long-baseline neutrino experiment in Japan designed to study various parameters of neutrino oscillations. A near detector complex (ND280) is located 280~m downstream of the production target and measures neutrino beam parameters before any oscillations occur. ND280's measurements are used to predict the number and spectra of neutrinos in the Super-Kamiokande detector at the distance of 295~km. The difference in the target material between the far (water) and near (scintillator, hydrocarbon) detectors leads to the main non-cancelling systematic uncertainty for the oscillation analysis. In order to reduce this uncertainty a new WAter-Grid-And-SCintillator detector (WAGASCI) has been developed. A magnetized iron neutrino detector (Baby MIND) will be used to measure momentum and charge identification of the outgoing muons from charged current interactions. The Baby MIND modules are composed of magnetized iron plates and long plastic scintillator bars read out at the both ends with wavelength shifting fibers and silicon photomultipliers. The front-end electronics board has been developed to perform the readout and digitization of the signals from the scintillator bars. Detector elements were tested with cosmic rays and in the PS beam at CERN. The obtained results are presented in this paper.Comment: In new version: modified both plots of Fig.1 and added one sentence in the introduction part explaining Baby MIND role in WAGASCI experiment, added information for the affiliation

Detailed comparison of the pp -> \pi^+pn and pp -> \pi^+d reactions at 951 MeV

The positively charged pions produced in proton-proton collisions at a beam momentum of 1640 MeV/c were measured in the forward direction with a high resolution magnetic spectrograph. The missing mass distribution shows the bound state (deuteron) clearly separated from the $pn$ continuum. Despite the very good resolution, there is no evidence for any significant production of the $pn$ system in the spin-singlet state. However, the $\sigma(pp\to \pi^+pn)/\sigma(pp\to \pi^+d)$ cross section ratio is about twice as large as that predicted from $S$-wave final-state-interaction theory and it is suggested that this is due to $D$-state effects in the $pn$ system.Comment: 8 pages, 3 figure

Clinical value of cytological features of buccal cells in patients with Alzheimer's disease

The article presents the features of the buccal cells in patients with Alzheimer's disease. In the biomaterial of people with this pathology were identified buccal cells with cytogenetic disorders (an increase in the number of cells with micronucleus). The clinical value of the micronucleus test for patients with Alzheimer's disease was estimated.В статье представлены особенности буккальной цитограммы у пациентов с болезнью Альцгеймера. В биоматериале людей с данной патологией выявлены клетки буккального эпителия с цитогенетическими нарушениями (повышение количества клеток с микроядрами). Проведена оценка клинической ценности микроядерного теста буккального эпителия для пациентов с болезнью Альцгеймера

The proposal of a GSSP for the Berriasian Stage (Cretaceous System): Part 1.

Here in the first part of this publication we discuss the possibilities for the selection of a GSSP for the Berriasian Stage of the Cretaceous System, based on the established methods for correlation in the Tithonian/Berriasian interval. This will be followed, in the second part, by an account of the stratigraphic evidence that justifies the locality of Tré Maroua (Hautes-Alpes, SE France) as the proposed GSSP. Here we discuss the possibilities for correlation in the historical J/K boundary interval, and the evolution of thinking on the positioning of the boundary over recent generations, and in relation to research in the last ten years. The Tithonian/Berriasian boundary level is accepted as occurring within magnetosubzone M19n.2n. The detailed distribution of calpionellids has been recorded at numerous sites, tied to magnetostratigraphy, and the base of the calpionellid Alpina Zone is taken to define the base of the Berriasian Stage. This is at a level just below the distinctive reversed magnetic subzone M19n.1r (the so-called Brodno reversal). We discuss a wide range of magnetostratigraphic and biostratigraphic data from key localities globally, in the type Berriasian areas of France and wider regions (Le Chouet, Saint Bertrand, Puerto Escaño, Rio Argos, Bosso, Brodno, Kurovice, Theodosia etc.). The characteristic datums that typify the J/K boundary interval in Tethys and its extensions are detailed, and the correlative viability of various fossil groups is discussed. The boundary level is correlated to well-known J/K sections globally, and a series of secondary markers and proxies are indicated which assist wider correlation. Particularly significant are the primary basal Berriasian marker, the base of the Alpina Subzone (marked by dominance of small Calpionella alpina, Crassicollaria parvula and Tintinopsella carpathica) and secondary markers bracketing the base of the Calpionella Zone, notably the FOs of the calcareous nannofossil species Nannoconus wintereri (just below the boundary) and the FO of Nannoconus steinmannii minor (just above). Notable proxies for the boundary are: 1) the base of the Arctoteuthis tehamaensis Zone in boreal and subboreal regions, 2) the dated base of the Alpina Subzone at 140.22 ± 0.14 Ma, which also gives a precise age estimate for the system boundary; and 3) the base of radiolarian “unitary zone” 14, which is situated just above the base of the Alpina Subzone