Epigenetic Small Molecules Rescue Nucleocytoplasmic Transport and DNA Damage Phenotypes in C9ORF72 ALS/FTD

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease with available treatments only marginally slowing progression or improving survival. A hexanu-cleotide repeat expansion mutation in the C9ORF72 gene is the most commonly known genetic cause of both sporadic and familial cases of ALS and frontotemporal dementia (FTD). The C9ORF72 expansion mutation produces five dipeptide repeat proteins (DPRs), and while the mechanistic determinants of DPR-mediated neurotoxicity remain incompletely understood, evidence suggests that disruption of nucleocytoplasmic transport and increased DNA damage contributes to pathology. Therefore, characterizing these disturbances and determining the relative contribution of different DPRs is needed to facilitate the development of novel therapeutics for C9ALS/FTD. To this end, we generated a series of nucleocytoplasmic transport “biosensors”, composed of the green fluorescent protein (GFP), fused to different classes of nuclear localization signals (NLSs) and nuclear export signals (NESs). Using these biosensors in conjunction with automated microscopy, we investigated the role of the three most neurotoxic DPRs (PR, GR, and GA) on seven nuclear import and two export pathways. In addition to other DPRs, we found that PR had pronounced inhibitory effects on the classical nuclear export pathway and several nuclear import pathways. To identify compounds capable of counteracting the effects of PR on nucleocytoplasmic transport, we developed a nucleocy-toplasmic transport assay and screened several commercially available compound libraries, totaling 2714 compounds. In addition to restoring nucleocytoplasmic transport efficiencies, hits from the screen also counteract the cytotoxic effects of PR. Selected hits were subsequently tested for their ability to rescue another C9ALS/FTD phenotype—persistent DNA double strand breakage. Overall, we found that DPRs disrupt multiple nucleocytoplasmic transport pathways and we identified small molecules that counteract these effects—resulting in increased viability of PR-expressing cells and decreased DNA damage markers in patient-derived motor neurons. Several HDAC inhibitors were validated as hits, supporting previous studies that show that HDAC inhibitors confer therapeutic effects in neurodegenerative models

A Computing and Detector Simulation Framework for the HIBEAM/NNBAR Experimental Program at the ESS

The HIBEAM/NNBAR program is a proposed two-stage experiment at the European Spallation Source focusing on searches for baryon number violation via processes in which neutrons convert to antineutrons. This paper outlines the computing and detector simulation framework for the HIBEAM/NNBAR program. The simulation is based on predictions of neutron flux and neutronics together with signal and background generation. A range of diverse simulation packages are incorporated, including Monte Carlo transport codes, neutron ray-tracing simulation packages, and detector simulation software. The common simulation package in which these elements are interfaced together is discussed. Data management plans and triggers are also described.Comment: Contribution to CHEP2021. Accepted for publication in the European Physical Journal (EPJ) Web of Conference

Development of a High Intensity Neutron Source at the European Spallation Source: The HighNESS project

The European Spallation Source (ESS), presently under construction in Lund, Sweden, is a multidisciplinary international laboratory that will operate the world's most powerful pulsed neutron source. Supported by a 3M Euro Research and Innovation Action within the EU Horizon 2020 program, a design study (HighNESS) is now underway to develop a second neutron source below the spallation target. Compared to the first source, located above the spallation target and designed for high cold and thermal brightness, the new source will provide higher intensity, and a shift to longer wavelengths in the spectral regions of cold (2 /- 20 {\AA}), very cold (VCN, 10 /- 120 {\AA}), and ultra cold (UCN, > 500 {\AA}) neutrons. The core of the second source will consist of a large liquid deuterium moderator to deliver a high flux of cold neutrons and to serve secondary VCN and UCN sources, for which different options are under study. The features of these new sources will boost several areas of condensed matter research and will provide unique opportunities in fundamental physics. Part of the HighNESS project is also dedicated to the development of future instruments that will make use of the new source and will complement the initial suite of instruments in construction at ESS. The HighNESS project started in October 2020. In this paper, the ongoing developments and the results obtained in the first year are described.Comment: 10 pages, 10 figures, 14th International Topical Meeting on Nuclear Applications of Accelerators, November 30 to December 4, 2021, Washington, D

The Development of the NNBAR Experiment

The NNBAR experiment for the European Spallation Source will search for free neutrons converting to antineutrons with a sensitivity improvement of three orders of magnitude compared to the last such search. This paper describes progress towards a conceptual design report for NNBAR. The design of a moderator, neutron reflector, beamline, shielding and annihilation detector is reported. The simulations used form part of a model which will be used for optimisation of the experiment design and quantification of its sensitivity.Comment: 30 pages, 26 figures, accepted for publication in Journal of Instrumentation (JINST

A tutorial for olfaction-based multisensorial media application design and evaluation

© ACM, 2017. This is the author's version of the work. It is posted here by permission of ACM for your personal use. Not for redistribution. The definitive version was published in PUBLICATION, {VOL50, ISS5, September 2017} https://doi.org/10.1145/310824

New high-sensitivity searches for neutrons converting into antineutrons and/or sterile neutrons at the HIBEAM/NNBAR experiment at the European Spallation Source

The violation of baryon number, B, is an essential ingredient for the preferential creation of matter over antimatter needed to account for the observed baryon asymmetry in the Universe. However, such a process has yet to be experimentally observed. The HIBEAM/NNBAR program is a proposed two-stage experiment at the European Spallation Source to search for baryon number violation. The program will include high-sensitivity searches for processes that violate baryon number by one or two units: free neutron-antineutron oscillation (n -> (n) over bar) via mixing, neutron-antineutron oscillation via regeneration from a sterile neutron state (n -> [n',(n) over bar'] -> (n) over bar), and neutron disappearance (n -> n'); the effective Delta B = 0 process of neutron regeneration (n ->[n',(n) over bar'] -> n) is also possible. The program can be used to discover and characterize mixing in the neutron, antineutron and sterile neutron sectors. The experiment addresses topical open questions such as the origins of baryogenesis and the nature of dark matter, and is sensitive to scales of new physics substantially in excess of those available at colliders. A goal of the program is to open a discovery window to neutron conversion probabilities (sensitivities) by up to three orders of magnitude compared with previous searches. The opportunity to make such a leap in sensitivity tests should not be squandered. The experiment pulls together a diverse international team of physicists from the particle (collider and low energy) and nuclear physics communities, while also including specialists in neutronics and magnetics.Peer reviewe

Pastorale begeleiding aan die persoon met Dissosiatiewe Identiteitsversteuring

A person with Dissociative Identity Disorder (DID) is someone who was exposed to intense trauma impacting that person’s life negatively at various levels. Although dissociative identity disorder is described as a mental disorder in the DSM-IV, there are still unresolved issues regarding the phenomenon. Assistance should take place with care and sensitivity in order to guide the person with dissociative identity disorder taking into consideration integral dimensions of personal humanity. It is submitted that guidance in this respect can therefore not be unilaterally psychological or pastoral by nature. Effective assistance to the person implies an approach where different disciplines are part of a multidisciplinary support team. The question this article explores is how pastoral counselling may contribute to this approach in guidance of the person with dissociative identity disorder. A case study is discussed in which the conclusion is made that pastoral care has an effective role in the healing process of the person with dissociative identity disorder

Web Tool for Creating Educational/Therapeutic Programmes.

Research has shown technology fosters learning environments that stimulate improved academic performance, learners' satisfaction and completion rates. For this reason, an increasing number of researchers focus on the development of tools and applications that support the learning process of children. The tool presented here is a web application for educators, therapists, parents, and children with and without disabilities. The core concept of this tool is aiding professionals in creating relevant educational content and motivating children by presenting learning materials and tasks in a modern, relevant and motivating way. A pilot study was performed with five professionals, daily delivering instruction to children, mostly diagnosed with Autism Spectrum Disorder, at an NGO in Bosnia and Herzegovina. The study findings show a general positive attitude towards the use of the web tool in the classroom and its functionalities for creating teaching material

VIRTUAL MUSEUM APPLICATIONS AND THEIR PUBLIC PERCEPTION IN BOSNIA AND HERZEGOVINA

Bosnia and Herzegovina always has been a place where the East meets the West. Over 1000 years, different cultures, religions and civilizations have left their remains in this small country in Western Balkans. Despite all wars and tragic destructions, today in the heart of Sarajevo one can find mosques, Catholic and Orthodox churches and Jewish synagogues next to each other and people of different nations and religions living together in mutual respect and friendship. Multiethnic spirit of Bosnia and Herzegovina lives through its cultural heritage. Therefore our task is to ensure its presentation and preservation using Information and Communications Technologies (ICT). So far researchers have achieved significant results by creating several virtual museums. In this paper we will present the Museum of Bosnian Traditional Objects, Digital Catalogue of Stecaks and the Virtual Museum of Sarajevo Assassination, giving an overview of the process of creating virtual environments from multiple data sources based on various 3D digitization technologies: some based on traditional 3D modeling, other based on laser scanning or photogrametric techniques