The T2K experiment and its time projection chambers

The Tokai to Kamioka (T2K) experiment [1] is a long baseline neutrino oscillation experiment located in Japan and its goal is to gain a more complete understanding of the neutrino oscillation parameters. A highly pure muon neutrino beam is directed from the accelerator center JPARC towards the Super-Kamiokande (SK) detector, which is 295 km away. A key element of the design of the T2K facility is the use of an off-axis technique. The main physics goals of T2K are to measure the mixing angle θ13 in a νe appearance experiment and improve the measurement of the atmospheric parameters ∆m 2 23 and θ23 using the νµ disappearance channel. The near detector (ND280), located 280 m away from the target, will measure the neutrino beam properties and the neutrino interaction cross section and kinematics before the oscillation, in order to predict the relevant neutrino interactions at SK. It consistes of a magnet, a Pi-Zero Detector (optimized for measuring the rate of neutral current π0 production), an electromagnetic calorimeter (whose main purpose is to measure the photons produced in ND280), a Side Muon Range Detector (to measure the range of muons that exit the sides of ND280) and a tracker (optimized for measuring the momenta of charged particles). The tracking device consists of a sandwich of three time projection chambers (TPCs) and two fine grained detectors (FGDs) which provide the target material. An overview of the TPC calibration methods and some results from the tests done at CERN to study the performance of the TPC readout modules are presented

Muon neutrino charged current quasi-elastic interactions in the T2K off-axis near detector

Esta tesis doctoral presenta un método para seleccionar eventos producidos por interacciones quasi-elasticas de corriente cargada (CCQE) de neutrinos muónicos en el sistema de trazado del detector cercano (ND280) del experimento T2K. T2K es un experimento de oscilaciones de neutrinos a larga distancia situado en Japón, y en el panoramana actuál ocupa un papel de primer orden a nivel mundial en la investigación de las propriedades de los neutrinos. T2K ha sido construido para medir el angulo de mezcla θ13 mediante el estudio de la aparición de neutrinos electrónicos en un haz de neutrinos muónicos, y para mejorar la medida de los parámetros atmosféricos utilizando el canal de desaparición del neutrino muónico. T2K consiste en un haz muy puro de neutrinos muónicos producidos por el accelerador del centro de investigación JPARC y dirigidos hacia el detector Super-Kamiokande (SK), situado a 295 km de la fuente, y desplazado 2.5 grados con respecto a la dirección del haz de neutrinos. El detector cercano, ND280, está localizado a 280 m del blanco en la dirección de SK y mide las propiedades del haz de neutrinos, la sección eficaz de interacción y la cinemática de los neutrinos antes de oscilar, para predecir el flujo de neutrinos y las interacciones de neutrinos relevantes en SK. A través del estudio de las propriedades de los eventos simulados por el generador de Monte Carlo (MC) NEUT, en esta tesis doctoral se ha desarrollado un criterio para la selección de eventos CCQE cuando una traza (solo el muón) o dos trazas (el muón y el protón) han sido reconstruidas. La selección está enfocada a interacciones que ocurren en el primer FGD y usa principalmente el sistema de trazado de ND280 para reconstruir la trayectoria de partículas cargadas. Cuatro muestras de eventos, dependiendo de los detectores en los cuales se reconstruyen el muón y el protón, han sido seleccionadas. Los errores sistemáticos asociados al detector y sus efectos sobre la selección han sido estudiados para cada una de las muestras. El estudio separado de topologías con una o dos trazas es importante para entender los detalles de los procesos cuasi-elásticos. La caracterización de las interacciones de neutrinos con núcleos se basa en la identificación del estado final hadrónico, que puede cambiar por efecto de las interacciones del protón primario en el interior del núcleo (FSI). Datos reales correspondientes a un total de 1.58 e20 protones impactando en el blanco y datos simulados por NEUT se han usado en este análisis. Un total de 11026 eventos han sido seleccionados en la muestra de datos reales: 7629 eventos en la muestra de una traza; 1572 eventos con ambos el muón y el proton reconstruidos en la TPC; 1210 eventos con el muón reconstruido en la TPC y el proton en el FGD; 615 eventos con el proton reconstruido en la TPC y el muón en el FGD y en los otros detectores que rodean la TPC. En todos los casos el ruido está altamente dominado por interacciones de corriente cargada con un pión en el estado final, en las que éste no se reconstruye. En general, el acuerdo entre los resultados del análisis con datos reales y simulados es bueno para todas las muestras seleccionadas excepto en la distribución angular del protón, lo cual sugiere que la simulación de FSI en NEUT no es realista. También se ha llevado a cabo un estudio cualitativo del efecto de FSI sobre la selección del protón. El método de selección así como la propagación de errores sistemáticos, desarrollados en este trabajo de investigación, han sido utilizados para calcular la sección eficaz de interacciones cuasi-elásticas de corrientes cargadas en Carbón (el material principal del que está hecho el FGD).T2K (Tokai-to-Kamioka) is a long-baseline neutrino oscillation experiment, currently operating in Japan, built to precisely measure the mixing angle θ13, using the electron neutrino appearance channel, and to refine the measurement of the atmospheric parameters using the muon neutrino disappearance channel. An intense high purity muon neutrino beam, produced at the J-PARC facility, is directed toward the Super-Kamiokande (SK) water Cherenkov detector, located 295 km away. The off-axis near detector, ND280, measures the neutrino beam properties and the neutrino interaction cross-section and kinematics before the oscillation, in order to predict the neutrino flux and the relevant neutrino interactions at SK. This thesis work provides a strategy for selecting muon neutrino-induced charged current quasi-elastic (CCQE) interactions in ND280. The results of the analysis with real data and a comparison with the NEUT Monte Carlo (MC) prediction are provided. A brief qualitative study on the impact of proton final state interactions (FSI) on the selection is also presented. Different CCQE topologies, depending on whether only the muon or both the muon and the proton have been reconstructed and on the detectors crossed by the selected tracks, have been studied. The relevant detector systematic uncertainties have been estimated for each selected sample. A total of 11026 CCQE candidate events have been selected in the real data sample (corresponding to a total of 1.58 e20 protons on target): 7629 events correspond to the one-track sample; 3397 events correspond to the two-track samples. The number of selected events predicted by the MC for the one-track sample is slightly higher than that obtained when the study was performed on real data. On the other hand, the MC prediction is slightly lower than the data result for the two-track samples. These results, together with the study on the impact of proton FSI on the selection, suggest discrepancies between the FSI simulation in NEUT and real data, causing the proton produced in the neutrino-nucleus interaction to escape from the nucleus less frequently in the MC than in data. The results of this thesis work have been used to extract a CCQE cross- section on Carbon

Characterization of the human STAT5A and STAT5B promoters: evidence of a positive and negative mechanism of transcriptional regulation

AbstractWe recently published the genomic characterization of the STAT5A and STAT5B paralogous genes that are located head to head in the 17q21 chromosome and share large regions of sequence identity. We here demonstrate by transient in vitro transfection that STAT5A and STAT5B promoters are able to direct comparable levels of transcription. The expression of basal promoters is enhanced after Sp1 up-regulation in HeLa and SL2 cells while DNA methylation associated to the recruitment of MeCP2 methyl CpG binding protein down-regulates STAT5A and B promoters by interfering with Sp1-induced transcription. In addition, cross-species sequence comparison identified a bi-directional negative cis-acting regulatory element located in the STAT5 intergenic region

Repurposing of tamoxifen ameliorates CLN3 and CLN7 disease phenotype

Batten diseases (BDs) are a group of lysosomal storage disorders characterized by seizure, visual loss, and cognitive and motor deterioration. We discovered increased levels of globotriaosylceramide (Gb3) in cellular and murine models of CLN3 and CLN7 diseases and used fluorescent-conjugated bacterial toxins to label Gb3 to develop a cell-based high content imaging (HCI) screening assay for the repurposing of FDA-approved compounds able to reduce this accumulation within BD cells. We found that tamoxifen reduced the lysosomal accumulation of Gb3 in CLN3 and CLN7 cell models, including neuronal progenitor cells (NPCs) from CLN7 patient-derived induced pluripotent stem cells (iPSC). Here, tamoxifen exerts its action through a mechanism that involves activation of the transcription factor EB (TFEB), a master gene of lysosomal function and autophagy. In vivo administration of tamoxifen to the CLN7Δex2 mouse model reduced the accumulation of Gb3 and SCMAS, decreased neuroinflammation, and improved motor coordination. These data strongly suggest that tamoxifen may be a suitable drug to treat some types of Batten disease

Repurposing of tamoxifen ameliorates CLN3 and CLN7 disease phenotype

Batten diseases (BDs) are a group of lysosomal storage disorders characterized by seizure, visual loss, and cognitive and motor deterioration. We discovered increased levels of globotriaosylceramide (Gb3) in cellular and murine models of CLN3 and CLN7 diseases and used fluorescent-conjugated bacterial toxins to label Gb3 to develop a cell-based high content imaging (HCI) screening assay for the repurposing of FDA-approved compounds able to reduce this accumulation within BD cells. We found that tamoxifen reduced the lysosomal accumulation of Gb3 in CLN3 and CLN7 cell models, including neuronal progenitor cells (NPCs) from CLN7 patient-derived induced pluripotent stem cells (iPSC). Here, tamoxifen exerts its action through a mechanism that involves activation of the transcription factor EB (TFEB), a master gene of lysosomal function and autophagy. In vivo administration of tamoxifen to the CLN7Δex2 mouse model reduced the accumulation of Gb3 and SCMAS, decreased neuroinflammation, and improved motor coordination. These data strongly suggest that tamoxifen may be a suitable drug to treat some types of Batten disease.This work was funded by the European Union’s Horizon 2020 research and innovation programme (BATCure, grant No. 666918 to DLM, JPB, SEM, TB and SS). JPB is funded by the Agencia Estatal de Investigación (PID2019-105699RB-I00/ AEI / 10.13039/501100011033 and RED2018-102576-T), Plan Nacional sobre Drogas (2020I028), Junta de Castilla y León (Escalera de Excelencia CLU-2017-03), Ayudas Equipos Investigación Biomedicina 2017 Fundación BBVA and Fundación Ramón Areces. SS was funded by a grant from the Mila’s Miracle Foundation. TB was supported by German Research Council (DFG) grant FOR2625. SM benefits from MRC funding to the MRC Laboratory for Molecular Cell Biology University Unit at UCL (award code MC_U12266B) towards laboratory and office space. We acknowledge Marcella Cesana for providing the TFEB virus. Graphical abstract was created using BioRender.com

RUOLO DELLA RM-DWI INTEGRATA DAL PARAMETRO ADC NELLO STUDIO DEL COLESTEATOMA

: La Risonanza Magnetica pesata in diffusione (RM-DWI) distingue qualitativamente il colesteatoma dal tessuto di granulazione nei pazienti con otite media cronica. Il calcolo del coefficiente di diffusione apparente (ADC) consente un'analisi quantitativa identificando un cut-off numerico che differenzia le due tipologie tissutali. MATERIALI E METODI: lo studio retrospettivo ha riguardato 100 pazienti sottoposti a Timpanoplastica per colesteatoma primario o residuo/recidivante. Tutti i pazienti sono stati sottoposti a RM-DWI preoperatoria tra Aprile 2015 e Marzo 2019, con calcolo di ADC (R-version 3.2.5). La presenza di colesteatoma è stata accertata intraoperatoriamente e confermata istologicamente. RISULTATI: i reperti chirurgici di 100 pazienti sono stati confrontati con i valori medi ADC ed analizzata la distribuzione di quest’ultimi per colesteatoma/tessuto di granulazione, evidenziando due gruppi. La differenza nel valore medio di ADC tra colesteatoma (0,86 × 10-3mm2/s) e tessuto di granulazione (2.22×10-3mm2/s) ha rilevato una differenza statisticamente significativa di ADC per i pazienti con/senza colesteatoma (p <2.2 × 10-16). Il modello binomiale di regressione logistica prevede la probabilità dello stato patologico, mediante ADC. Il potere predittivo di questo modello è stato misurato mediante curva ROC e applicando la statistica Youden J sulla curva abbiamo stabilito un valore di probabilità di ~ 0,6 per definire un cut-off (specificità = 1.0 sensibilità = 0.9861111) pari a ADC=1,71×10-3mm2/s. CONCLUSIONI: lo studio ha evidenziato che è possibile stabilire un cut-off di ADC per identificare pre-operatoriamente con elevata significatività statistica la presenza di matrice colesteatomatosa. In tal modo la RM-DWI diviene una “tool diagnostico” utile ed affidabile in quei casi in cui il colesteatoma non è certamente evidenziabile in otomicroscopia e/o nel follow-up di pazienti già sottoposti a primo tempo chirurgico

MRX87 family with Aristaless X dup24bp mutation and implication for polyAlanine expansions

<p>Abstract</p> <p>Background</p> <p>Cognitive impairments are heterogeneous conditions, and it is estimated that 10% may be caused by a defect of mental function genes on the X chromosome. One of those genes is <it>Aristaless related homeobox </it>(<it>ARX</it>) encoding a polyA-rich homeobox transcription factor essential for cerebral patterning and its mutations cause different neurologic disorders. We reported on the clinical and genetic analysis of an Italian family with X-linked mental retardation (XLMR) and intra-familial heterogeneity, and provided insight into its molecular defect.</p> <p>Methods</p> <p>We carried out on linkage-candidate gene studies in a new MRX family (MRX87). All coding regions and exon-intron boundaries of ARX gene were analysed by direct sequencing.</p> <p>Results</p> <p>MRX87 patients had moderate to profound cognition impairment and a combination of minor congenital anomalies. The disease locus, MRX87, was mapped between DXS7104 and DXS1214, placing it in Xp22-p21 interval, a hot spot region for mental handicap. An in frame duplication of 24 bp (ARXdup24) in the second polyAlanine tract (polyA_II) in ARX was identified.</p> <p>Conclusion</p> <p>Our study underlines the role of ARXdup24 as a critical mutational site causing mental retardation linked to Xp22. Phenotypic heterogeneity of MRX87 patients represents a new observation relevant to the functional consequences of polyAlanine expansions enriching the puzzling complexity of ARXdup24-linked diseases.</p

Time projection chambers for the T2K near detectors

The T2K experiment is designed to study neutrino oscillation properties by directing a high intensity neutrino beam produced at J-PARC in Tokai, Japan, towards the large Super-Kamiokande detector located 295 km away, in Kamioka, Japan. The experiment includes a sophisticated near detector complex, 280 m downstream of the neutrino production target in order to measure the properties of the neutrino beam and to better understand neutrino interactions at the energy scale below a few GeV. A key element of the near detectors is the ND280 tracker, consisting of two active scintillator-bar target systems surrounded by three large time projection chambers (TPCs) for charged particle tracking. The data collected with the tracker is used to study charged current neutrino interaction rates and kinematics prior to oscillation, in order to reduce uncertainties in the oscillation measurements by the far detector. The tracker is surrounded by the former UA1/Nomad dipole magnet and the TPCs measure the charges, momenta, and particle types of charged particles passing through them. Novel features of the TPC design include its rectangular box layout constructed from composite panels, the use of bulk micromegas detectors for gas amplification, electronics readout based on a new ASIC, and a photoelectron calibration system. This paper describes the design and construction of the TPCs, the micromegas modules, the readout electronics, the gas handling system, and shows the performance of the TPCs as deduced from measurements with particle beams, cosmic rays, and the calibration system

Precise Measurement of the Neutrino Mixing Parameter theta(23) from Muon Neutrino Disappearance in an Off-Axis Beam

New data from the T2K neutrino oscillation experiment produce the most precise measurement of the neutrino mixing parameter theta_{23}. Using an off-axis neutrino beam with a peak energy of 0.6 GeV and a data set corresponding to 6.57 x 10^{20} protons on target, T2K has fit the energy-dependent nu_mu oscillation probability to determine oscillation parameters. Marginalizing over the values of other oscillation parameters yields sin^2 (theta_{23}) = 0.514 +0.055/-0.056 (0.511 +- 0.055), assuming normal (inverted) mass hierarchy. The best-fit mass-squared splitting for normal hierarchy is Delta m^2_{32} = (2.51 +- 0.10) x 10^{-3} eV^2/c^4 (inverted hierarchy: Delta m^2_{13} = (2.48 +- 0.10) x 10^{-3} eV^2/c^4). Adding a model of multinucleon interactions that affect neutrino energy reconstruction is found to produce only small biases in neutrino oscillation parameter extraction at current levels of statistical uncertainty

Measurement of the intrinsic electron neutrino component in the T2K neutrino beam with the ND280 detector

The T2K experiment has reported the first observation of the appearance of electron neutrinos in a muon neutrino beam. The main and irreducible background to the appearance signal comes from the presence in the neutrino beam of a small intrinsic component of electron neutrinos originating from muon and kaon decays. In T2K, this component is expected to represent 1.2% of the total neutrino flux. A measurement of this component using the near detector (ND280), located 280 m from the target, is presented. The charged current interactions of electron neutrinos are selected by combining the particle identification capabilities of both the time projection chambers and electromagnetic calorimeters of ND280. The measured ratio between the observed electron neutrino beam component and the prediction is 1.01 +/- 0.10 providing a direct confirmation of the neutrino fluxes and neutrino cross section modeling used for T2K neutrino oscillation analyses. Electron neutrinos coming from muons and kaons decay are also separately measured, resulting in a ratio with respect to the prediction of 0.68 +/- 0.30 and 1.10 +/- 0.14, respectively