Lithium niobate is a ferro- and piezoelectric material with excellent optical properties and a wide variety of applications. The defect structures of congruent and Mg-doped crystals are still under ...intense discussion. In this work, undoped lithium niobate and magnesium-doped lithium niobate grown from congruent melt with the addition of 0 to 9 mol% MgO were investigated by infrared absorption, establishing the dependence of the absorbance on the Mg-doping level in two bands related to OH- stretching vibrations. The absorption band at 3485 cm-1 peaks at a MgO concentration in melt of 1 mol% and vanishes for MgO concentrations above the threshold level for optical damage suppression (4.8 mol%). A corresponding peak occurs in the minimum yield of the 7Li(p,α)4He reaction during ion channeling measurements, indicating a maximum of disorder in the Li sublattice. A possible explanation for this correlation is the attribution of this absorption band to ilmenite stacking fault sequences instead of isolated NbLi antisites in undoped and low-doped material. On the other hand, the OH- absorption band at 3535 cm-1 stays weak up to the MgO concentration threshold, and then increases, hinting to a defect related to the increase of vacancies due to the lack of charge compensation.
X-ray and neutron diffraction studies succeeded in the 1960s to determine the principal structural properties of congruent lithium niobate. However, the nature of the intrinsic defects related to the ...non-stoichiometry of this material remained an object of controversial discussion. In addition, the incorporation mechanism for dopants in the crystal lattice, showing a solubility range from about 0.1 mol% for rare earths to 9 mol% for some elements (e.g., Ti and Mg), stayed unresolved. Various different models for the formation of these defect structures were developed and required experimental verification. In this paper, we review the outstanding role of nuclear physics based methods in the process of unveiling the kind of intrinsic defects formed in congruent lithium niobate and the rules governing the incorporation of dopants. Complementary results in the isostructural compound lithium tantalate are reviewed for the case of the ferroelectric-paraelectric phase transition. We focus especially on the use of ion beam analysis under channeling conditions for the direct determination of dopant lattice sites and intrinsic defects and on Perturbed Angular Correlation measurements probing the local environment of dopants in the host lattice yielding independent and complementary information.
Calpains are cysteine proteinases that selectively cleave proteins in response to calcium signals. Exacerbated activation of calpain has been implicated as a major component in the signaling cascade ...that leads to β-amyloid (Aβ) production and tau hyperphosphorylation in Alzheimer's disease (AD). In this study, we analyzed the potential therapeutic efficacy of inhibiting the activation of calpain by a novel calpain inhibitor in aged 3xTgAD mice with well-established cognitive impairment, plaques, and tangles. The administration of a novel inhibitor of calpain, A-705253, attenuated cognitive impairment and synaptic dysfunction in a dose-dependent manner in 3xTgAD mice. Inhibition of calpain lowered Aβ40 and Aβ42 levels in both detergent-soluble and detergent-insoluble fractions and also reduced the total number and size of thioflavin S–positive fibrillar Aβ deposits. Mechanistically, these effects were, in part, explained by a down-regulation of β-secretase 1 (BACE1) and an up-regulation of ATP-binding cassette transporter A1 (ABCA1) expression, which, in turn, contributed to reduced production and increased clearance of Aβ, respectively. Moreover, A-705253 decreased the activation of cyclin-dependent kinase 5 (CDK5) and thereby diminished the hyperphosphorylation of tau. Finally, blockage of calpain activation reduced the astrocytic and microglial responses associated with AD-like pathological characteristics in aged 3xTgAD mice. Our data provide relevant functional and molecular insights into the beneficial therapeutic effects of inhibiting calpain activation for the management of AD.
Neutron production yields and energy distributions from (α,n) reactions in light elements were calculated using three different codes (SOURCES, NEDIS and USD) and compared with the existing ...experimental data in the 3.5-10 MeV alpha energy range. SOURCES and NEDIS display an agreement between calculated and measured yields in the decay series of 235U, 238U and 232Th within ±10% for most materials. The discrepancy increases with alpha energy but still an agreement of ±20% applies to all materials with reliable elemental production yields (the few exceptions are identified). The calculated neutron energy distributions describe the experimental data, with NEDIS retrieving very well the detailed features. USD generally underestimates the measured yields, in particular for compounds with heavy elements and/or at high alpha energies. The energy distributions exhibit sharp peaks that do not match the observations. These findings may be caused by a poor accounting of the alpha particle energy loss by the code. A big variability was found among the calculated neutron production yields for alphas from Sm decay; the lack of yield measurements for low (~2 MeV) alphas does not allow to conclude on the codes’ accuracy in this energy region.
Superheated droplet detectors are a promising technique to the measurement of low-intensity neutron fields, as detectors can be rendered insensitive to minimum ionizing radiations. We report on the ...intrinsic neutron-induced signal of C2ClF5 devices fabricated by our group that originate from neutron- and alpha-emitting impurities in the detector constituents. The neutron background was calculated via Monte Carlo simulations using the MCNPX-PoliMi code in order to extract the recoil distributions following neutron interaction with the atoms of the superheated liquid. Various nuclear techniques were employed to characterise the detector materials with respect to source isotopes (238U, 232Th and 147Sm) for the normalisation of the simulations and also light elements (B, Li) having high (α, n) neutron production yields. We derived a background signal of ~10-3 cts/day in a 1 liter detector of 1-3 wt.% C2ClF5, corresponding to a detection limit in the order of 10-8 n cm-2s-1. Direct measurements in a massively shielded underground facility for dark matter search have confirmed this result. With the borosilicate detector containers found to be the dominant background source in current detectors, possibilities for further noise reduction by ~2 orders of magnitude based on selected container materials are discussed.
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Aberrant activation of calpain has been observed in various pathophysiological disorders including neurodegenerative diseases such as Alzheimer’s Disease. Here we describe our efforts ...on ketoamide-based 1-benzyl-5-oxopyrrolidine-2-carboxamides as a novel series of highly selective calpain inhibitors mitigating the metabolic liability of carbonyl reduction. The most advanced compound from this new series, namely A-1212805 (ABT-957, Alicapistat) proceeded to clinical phase I studies.
We propose to apply the superheated droplet detector (SDD) technology to the measurement of alpha-particle emissivity on integrated circuits of ultra-low activity grade (< 1α/khcm2) for high ...reliability applications. This work is based on the SDDs employed within our team to the direct search for dark matter. We describe the modifications in the dark matter SDDs with respect to fabrication, signal analysis and characterization, in order to obtain a device with the adequate detection sensitivity and background noise.
•OTP has processed 20.000 samples to date and contains the data of all German submissions to ICGC and of DKTK.•OTP normally requires no manual intervention for data import, processing and error ...handling enabling 24/7 operation.•OTP can interact with any job execution framework containing bioinformatic pipelines to integrate new pipelines.•OTP integrates a database containing all information about the sequencing data; from the sample preparation to analyses.•OTP provides structured data storage, user management to ensure data security and an intuitive graphical user interface.
The One Touch Pipeline (OTP) is an automation platform managing Next-Generation Sequencing (NGS) data and calling bioinformatic pipelines for processing these data. OTP handles the complete digital process from import of raw sequence data via alignment of sequencing reads to identify genomic events in an automated and scalable way. Three major goals are pursued: firstly, reduction of human resources required for data management by introducing automated processes. Secondly, reduction of time until the sequences can be analyzed by bioinformatic experts, by executing all operations more reliably and quickly. Thirdly, storing all information in one system with secure web access and search capabilities. From software architecture perspective, OTP is both information center and workflow management system. As a workflow management system, OTP call several NGS pipelines that can easily be adapted and extended according to new requirements. As an information center, it comprises a database for metadata information as well as a structured file system. Based on complete and consistent information, data management and bioinformatic pipelines within OTP are executed automatically with all steps book-kept in a database.
Calpain overactivation has been implicated in a variety of pathological disorders including ischemia/reperfusion injury, cataract formation, and neurodegenerative diseases such as Alzheimer’s disease ...(AD). Herein we describe our efforts leading to the identification of ketoamide-based 2-(3-phenyl-1H-pyrazol-1-yl)nicotinamides as potent and reversible inhibitors of calpain with high selectivity versus related cysteine protease cathepsins, other proteases, and receptors. Broad efficacy in a set of preclinical models relevant to AD suggests that inhibition of calpain represents an attractive approach with potential benefit for the treatment of AD.
A novel class of endothelin-A receptor ligands was discovered by high-throughput screening. Lead structure optimization led to highly potent antagonists which can be synthesized in a short sequence. ...The compounds are endothelin-A-selective, are orally available, and show a long duration of action.
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