Low-dose γ-secretase inhibition increases secretion of Aβ peptides and intracellular oligomeric Aβ

γ-Secretase inhibitors have been considered promising drug candidates against Alzheimer's disease (AD) due to their ability to reduce amyloid-β (Aβ) production. However, clinical trials have been halted due to lack of clinical efficacy and/or side effects. Recent in vitro studies suggest that low doses of γ-secretase inhibitors may instead increase Aβ production. Using a stem cell-derived human model of cortical neurons and low doses of the γ-secretase inhibitor DAPT, the effects on a variety of Aβ peptides were studied using mass spectrometry. One major focus was to develop a novel method for specific detection of oligomeric Aβ (oAβ), and this was used to study the effects of low-dose γ-secretase inhibitor treatment on intracellular oAβ accumulation. Low-dose treatment (2 and 20 nM) with DAPT increased the secretion of several Aβ peptides, especially Aβx-42. Furthermore, using the novel method for oAβ detection, we found that 2 nM DAPT treatment of cortical neurons resulted in increased oAβ accumulation. Thus, low dose-treatment with DAPT causes both increased production of long, aggregation-prone Aβ peptides and accumulation of intracellular Aβ oligomers, both believed to contribute to AD pathology

Validation of the LUMIPULSE automated immunoassay for the measurement of core AD biomarkers in cerebrospinal fluid

OBJECTIVES: The core cerebrospinal fluid (CSF) biomarkers; total tau (tTau), phospho-tau (pTau), amyloid β 1-42 (Aβ 1-42), and the Aβ 1-42/Aβ 1-40 ratio have transformed Alzheimer's disease (AD) research and are today increasingly used in clinical routine laboratories as diagnostic tools. Fully automated immunoassay instruments with ready-to-use assay kits and calibrators has simplified their analysis and improved reproducibility of measurements. We evaluated the analytical performance of the fully automated immunoassay instrument LUMIPULSE G (Fujirebio) for measurement of the four core AD CSF biomarkers and determined cutpoints for AD diagnosis. METHODS: Comparison of the LUMIPULSE G assays was performed with the established INNOTEST ELISAs (Fujirebio) for hTau Ag, pTau 181, β-amyloid 1-42, and with V-PLEX Plus Aβ Peptide Panel 1 (6E10) (Meso Scale Discovery) for Aβ 1-42/Aβ 1-40, as well as with a LC-MS reference method for Aβ 1-42. Intra- and inter-laboratory reproducibility was evaluated for all assays. Clinical cutpoints for Aβ 1-42, tTau, and pTau was determined by analysis of three cohorts of clinically diagnosed patients, comprising 651 CSF samples. For the Aβ 1-42/Aβ 1-40 ratio, the cutpoint was determined by mixture model analysis of 2,782 CSF samples. RESULTS: The LUMIPULSE G assays showed strong correlation to all other immunoassays (r>0.93 for all assays). The repeatability (intra-laboratory) CVs ranged between 2.0 and 5.6%, with the highest variation observed for β-amyloid 1-40. The reproducibility (inter-laboratory) CVs ranged between 2.1 and 6.5%, with the highest variation observed for β-amyloid 1-42. The clinical cutpoints for AD were determined to be 409 ng/L for total tau, 50.2 ng/L for pTau 181, 526 ng/L for β-amyloid 1-42, and 0.072 for the Aβ 1-42/Aβ 1-40 ratio. CONCLUSIONS: Our results suggest that the LUMIPULSE G assays for the CSF AD biomarkers are fit for purpose in clinical laboratory practice. Further, they corroborate earlier presented reference limits for the biomarkers

Validation of the LUMIPULSE automated immunoassay for the measurement of core AD biomarkers in cerebrospinal fluid

Altres ajuts: Swedish Research Council (#2017-00915); Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615); Swedish Alzheimer Foundation (#AF-742881); Hjärnfonden, Sweden (#FO2017-0243); Swedish State Under the Agreement Between the Swedish Government and the County Councils, the ALF-Agreement (#ALFGBG-715986); National Program of Sustainability II (MEYS CR); Ministry of Health of the Czech Republic (grant no. 19-04-00560); ZonMW (part of the Dutch national 'Deltaplan for Dementia'; Selfridges Group Foundation; National Institutes of Health, USA (grant number 5R01NS104147-02); Alzheimerfonden (AF-930934); Åhléns-stiftelsen; Stiftelsen för Gamla tjänarinnor; Canadian Institutes of Health Research (CIHR) (MOP-11-51-31; RFN 152985, 159815, 162303); Canadian Consortium of Neurodegeneration and Aging (CCNA; MOP-11-51-31 -team 1); Weston Brain Institute, the Alzheimer's Association (NIRG-12-92090, NIRP-12-259245); Brain Canada Foundation (CFI Project 34874; 33397); Fonds de Recherche du Québec - Santé (FRQS; Chercheur Boursier, 2020-VICO-279314); Wallenberg Scholar supported by grants, Swedish Research Council (#2018-02532); Swedish State Support for Clinical Research (#ALFGBG-720931); Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862); Dementia Research Institute at UCL.Objectives: The core cerebrospinal fluid (CSF) biomarkers; total tau (tTau), phospho-tau (pTau), amyloid β 1-42 (Aβ 1-42), and the Aβ 1-42/Aβ 1-40 ratio have transformed Alzheimer's disease (AD) research and are today increasingly used in clinical routine laboratories as diagnostic tools. Fully automated immunoassay instruments with ready-to-use assay kits and calibrators has simplified their analysis and improved reproducibility of measurements. We evaluated the analytical performance of the fully automated immunoassay instrument LUMIPULSE G (Fujirebio) for measurement of the four core AD CSF biomarkers and determined cutpoints for AD diagnosis. Methods: Comparison of the LUMIPULSE G assays was performed with the established INNOTEST ELISAs (Fujirebio) for hTau Ag, pTau 181, β-amyloid 1-42, and with V-PLEX Plus Aβ Peptide Panel 1 (6E10) (Meso Scale Discovery) for Aβ 1-42/Aβ 1-40, as well as with a LC-MS reference method for Aβ 1-42. Intra- and inter-laboratory reproducibility was evaluated for all assays. Clinical cutpoints for Aβ 1-42, tTau, and pTau was determined by analysis of three cohorts of clinically diagnosed patients, comprising 651 CSF samples. For the Aβ 1-42/Aβ 1-40 ratio, the cutpoint was determined by mixture model analysis of 2,782 CSF samples. Results: The LUMIPULSE G assays showed strong correlation to all other immunoassays (r>0.93 for all assays). The repeatability (intra-laboratory) CVs ranged between 2.0 and 5.6%, with the highest variation observed for β-amyloid 1-40. The reproducibility (inter-laboratory) CVs ranged between 2.1 and 6.5%, with the highest variation observed for β-amyloid 1-42. The clinical cutpoints for AD were determined to be 409 ng/L for total tau, 50.2 ng/L for pTau 181, 526 ng/L for β-amyloid 1-42, and 0.072 for the Aβ 1-42/Aβ 1-40 ratio. Conclusions: Our results suggest that the LUMIPULSE G assays for the CSF AD biomarkers are fit for purpose in clinical laboratory practice. Further, they corroborate earlier presented reference limits for the biomarkers

Design recommendations for stainless steel I-sections under concentrated transverse loading

© 2019 Elsevier Ltd. All rights reserved.Recent investigations have highlighted the need for improved provisions for determining the resistance of stainless steel I-sections under concentrated transverse loading. Such provisions, which reflect the particular characteristics of the material, have been developed and are described herein. A review of the existing European design formulae for members under concentrated transverse loading is firstly presented. Then a series of parametric studies, based on validated finite element models are described covering I-sections with a range of web slenderness values and different stainless steel grades. On the basis of the numerical results, together with existing experimental data, revised design equations are presented and assessed through reliability analysis performed in accordance with Annex D of EN 1990. The new provisions yield enhanced ultimate load predictions and are expected to be included in the next revision of EN 1993-1-4.Peer reviewedFinal Accepted Versio

Dutch Ships and Sailors - Generale Zeemonsterrollen VOC as RDF

Dutch Ships and Sailors is a project that aims to provide an infrastructure for maritime historical datasets, linking correlating data through semantic web technology. It brings together datasets related to recruitment and shipping in the East-India trade (mainly 18th century) and in the shipping of the northern provinces of the Netherlands (mainly 19th century). For the northern provinces, the database contains data on the personnel recruited, the ships, and other variables (muster rolls of the northern provinces of the Netherlands). Dutch Ships and Sailors is a CLARIN IV-project, hosted by Huygens ING in collaboration with VU University Amsterdam, the International Institute of Social History and Scheepvaartmuseum Amsterdam. The data from this project are divided over 5 datasets. See the ‘Thematic collection: Dutch Ships and Sailors’ dataset for a full overview. This dataset contains the conversion to Linked Data of the mustering of ships and crew composition in Asian waters, the general sea muster rolls of the Dutch East India Company (VOC, as an RDF/Turtle version. It is based on a dataset created by Dr. M. van Rossum, Generale Zeemonsterrollen VOC (GZMVOC), containing data collected from archival records. References to the Dutch Asiatic Shipping (DAS) dataset are present through numerical IDs

Dutch Ships and Sailors - VOC Opvarenden as RDF

Dutch Ships and Sailors is a project that aims to provide an infrastructure for maritime historical datasets, linking correlating data through semantic web technology. It brings together datasets related to recruitment and shipping in the East-India trade (mainly 18th century) and in the shipping of the northern provinces of the Netherlands (mainly 19th century). For the northern provinces, the database contains data on the personnel recruited, the ships, and other variables (muster rolls of the northern provinces of the Netherlands). Dutch Ships and Sailors is a Clarin IV-project, hosted by Huygens ING in collaboration with VU University Amsterdam, the International Institute of Social History and Scheepvaartmuseum Amsterdam. The data from this project are divided over 5 datasets. See the ‘Thematic collection: Dutch Ships and Sailors’ dataset for a full overview. This dataset is a RDF/Turtle conversion of EASY dataset: "Velzen, Drs A.J.M. van; Gaastra, Prof.dr. F.S. (2012-01-26), VOC Opvarenden, versie 6 - januari 2012; VOC Sea Voyagers", Persistent Identifier: urn:nbn:nl:ui:13-gupf-pd. This source dataset contains digitized 18th century personnel administration of the VOC (Dutch East India Company) collected from archival data and processed in a relational database. The source dataset was split into three separate parts: ‘opvarenden’, ‘soldijboeken’ and ‘begunstigden’ (voyagers, salary books and benificiaries). This substructuring was left intact in the subsequent conversions

Dutch Ships and Sailors

Dutch Ships and Sailors is a project that aims to provide an infrastructure for maritime historical datasets, linking correlating data through semantic web technology. It brings together datasets related to recruitment and shipping in the East-India trade (mainly 18th century) and in the shipping of the northern provinces of the Netherlands (mainly 19th century). For the northern provinces, the database contains data on the personnel recruited, the ships, and other variables (muster rolls of the northern provinces of the Netherlands). Dutch Ships and Sailors is a CLARIN IV-project, hosted by Huygens ING in collaboration with VU University Amsterdam, the International Institute of Social History and Scheepvaartmuseum Amsterdam. This prioject resulted in the Dutch Ships and Sailors (DSS) data cloud. This Linked Data cloud brings together four Dutch maritime historical datasets, each with its own datamodel. The data is available as five-star linked data making sharing and reuse possible. The data is integrated at a meta-level through common vocabularies and linked to generic external data sources allowing for new types of queries and analysis. The first two datasets ("Generale Zeemonsterrollen VOC" and "Noordelijke Monsterollen Databases") are modeled and converted in close collaboration with the historical researchers responsible for the source datasets and we describe them in more detail. The third ("VOC Opvarenden") and fourth ("Dutch Asiatic Shipping") datasets are conversions of previously published historical datasets and are described less elaborately. They were converted with the help of the historians. These four datasets are mapped to a "DSS interoperability layer", which describes common classes, properties and concepts. Links between datasets have been established through either this interoperability layer or through converting references in the original data into explicit links. The data is made available in RDF/turtle format, but is also live served at http://dutchshipsandsailors.nl/data or http://semanticweb.cs.vu.nl/dss/ The five datasets of this project can be found via the links under 'relations'

Dutch Ships and Sailors - Dutch-Asiatic Shipping as RDF

Dutch Ships and Sailors is a project that aims to provide an infrastructure for maritime historical datasets, linking correlating data through semantic web technology. It brings together datasets related to recruitment and shipping in the East-India trade (mainly 18th century) and in the shipping of the northern provinces of the Netherlands (mainly 19th century). For the northern provinces, the database contains data on the personnel recruited, the ships, and other variables (Monsterrollen Noordelijke Nederlanden). Dutch Ships and Sailors is a CLARIN-IV-project, hosted by Huygens ING in collaboration with VU University Amsterdam, the International Institute of Social History and Scheepvaartmuseum Amsterdam. The data from this project are divided over 5 datasets. See the ‘Thematic collection: Dutch Ships and Sailors’ dataset for a full overview. Between 1595 and 1795 the Dutch East India Company (VOC) and its predecessors before 1602 equipped more than 4,700 ships to sail from the shores of the Netherlands bound for Asia. More than 3,400 ships made the return voyage home. The reference work, ‘Dutch-Asiatic Shipping in the 17th and 18th centuries’ from 1987, by J. R. Bruijn, F. S. Gaastra and I. Schöffer with assistance from A.C.J. Vermeulen, has classified these voyages on which Dutch trade between Europe and Asia was founded in a systematic survey. This dataset is a conversion to Linked Data, to RDF/Turtle, of the digitized version of this publication, the Dutch-Asiatic Shipping (DAS) dataset hosted at Huygens ING, http://resources.huygens.knaw.nl/das/index_html_en

Dutch Ships and Sailors - Noordelijke Monsterrollen Databases as RDF

Dutch Ships and Sailors is a project that aims to provide an infrastructure for maritime historical datasets, linking correlating data through semantic web technology. It brings together datasets related to recruitment and shipping in the East-India trade (mainly 18th century) and in the shipping of the northern provinces of the Netherlands (mainly 19th century). For the northern provinces, the database contains data on the personnel recruited, the ships, and other variables (muster rolls of the northern provinces of the Netherlands). Dutch Ships and Sailors is a CLARIN IV-project, hosted by Huygens ING in collaboration with VU University Amsterdam, the International Institute of Social History and Scheepvaartmuseum Amsterdam. The data from this project are divided over 5 datasets. See the ‘Thematic collection: Dutch Ships and Sailors’ dataset for a full overview. This dataset is a conversion to RDF/Turtle of a previous data collection from Dutch northern muster rolls and mustering registers. These original sources contain information on the ship, the name of the ship, the captain, the crew, the tonnage, the data and place of monstering, and the ships destination. In the original sources this information is broken down in separate categories and is documented according to a standard format. The source data for this dataset were the Noordelijke Monsterollen Databases (MDB) (Northern Muster Rolls Databases) created by historian Jurjen Leinenga. These databases contain mustering information from the period 1803-1837 found in archives, maritime museums and private collections in the four northern Dutch provinces (Groningen, Friesland, Drenthe and Overijssel)