Chemical Imaging of Evolving Amyloid Plaque Pathology and Associated Aβ Peptide Aggregation in a Transgenic Mouse Model of Alzheimer's Disease

One of the major hallmarks of Alzheimer's disease (AD) pathology is the formation of extracellular amyloid β (Aβ) plaques. While Aβ has been suggested to be critical in inducing and, potentially, driving the disease, the molecular basis of AD pathogenesis is still under debate. Extracellular Aβ plaque pathology manifests itself upon aggregation of distinct Aβ peptides, resulting in morphologically different plaque morphotypes, including mainly diffuse and cored senile plaques. As plaque pathology precipitates long before any clinical symptoms occur, targeting the Aβ aggregation processes provides a promising target for early interventions. However, the chain of events of when, where and what Aβ species aggregate and form plaques remains unclear. The aim of the current study was to investigate the potential of MALDI-IMS as a tool to study the evolving pathology in transgenic mouse models for AD. To that end, we used an emerging, chemical imaging modality - MALDI imaging mass spectrometry - that allows for delineating Aβ aggregation with specificity at the single plaque level. We identified that plaque formation occurs first in cortical regions and that these younger plaques contain higher levels of 42 amino acid-long Aβ (Aβ1-42). Plaque maturation was found to be characterized by a relative increase in deposition of Aβ1-40, which was associated with the appearance of a cored morphology of the plaques. Finally, other C-terminally truncated Aβ species (Aβ1-38 and Aβ1-39) exhibited a similar aggregation pattern as Aβ1-40, suggesting that these species have similar aggregation characteristics. These results suggest that initial plaque formation is seeded by Aβ1-42; a process that is followed by plaque maturation upon deposition of Aβ1-40 as well as deposition by other C-terminally modified Aβ species

Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer

Neoadjuvant chemotherapy (NAC) in muscle-invasive bladder cancer was introduced several years ago.&nbsp;Despite the evidence supporting its use in clinical practice, only a minority of patients who undergo&nbsp;radical cystectomy receive preoperative chemotherapy. In addition, recommendations and methods&nbsp;to detect patients who would benefit the most from NAC are still unclear. The European Association of&nbsp;Urology (EAU) guidelines panel on muscle-invasive and metastatic bladder cancer recommends the use&nbsp;of cisplatin-based NAC for T2-T4a, cN0 M0 bladder cancer if the patient has a performance status &ge;2 and if the renal function is not impaired, but the American Urological Association, for example, does not&nbsp;have any guideline recommendations on this topic at all. In this review we describe the current literature&nbsp;supporting NAC in association with radical cystectomy in muscle-invasive urothelial carcinoma of the&nbsp;bladder. Evidence acquisition was made searching the Medline database for original articles published&nbsp;before 1st February 2014, with search terms: &ldquo;neoadjuvant chemotherapy&rdquo;, &ldquo;radical cystectomy&rdquo;, and&nbsp;&ldquo;invasive bladder cancer&rdquo;.</p

Challenges in context-aware mobile language learning: the MASELTOV approach

Smartphones, as highly portable networked computing devices with embedded sensors including GPS receivers, are ideal platforms to support context-aware language learning. They can enable learning when the user is en-gaged in everyday activities while out and about, complementing formal language classes. A significant challenge, however, has been the practical implementation of services that can accurately identify and make use of context, particularly location, to offer meaningful language learning recommendations to users. In this paper we review a range of approaches to identifying context to support mobile language learning. We consider how dynamically changing aspects of context may influence the quality of recommendations presented to a user. We introduce the MASELTOV project’s use of context awareness combined with a rules-based recommendation engine to present suitable learning content to recent immigrants in urban areas; a group that may benefit from contextual support and can use the city as a learning environment

L’utilisation des réseaux sociaux (Snapchat, WhatsApp et Instagram) et le cyberbullying

100% des jeunes possèdent un téléphone portable, 99% ont un ordinateur et 97% ont accès à Internet (Waller et al., 2016). Ces nouveaux moyens technologiques font partie de notre quotidien. Depuis l’apparition de ces réseaux, un nouveau mouvement est né : le cyberbullying. Ce harcèlement par Internet consiste à l’utilisation de technologies modernes de communication afin de nuire aux autres de manière délibérée et agressive. Quand les jeunes arrivent en classe, ils apportent avec eux l’entier de leur vécu quotidien, familial ou encore émotionnel. Les problèmes liés à l’utilisation massive de ces réseaux font partie de notre quotidien d’enseignant. Malheureusement, les études faites jusqu’au jour d’aujourd’hui portent en majeure partie sur les élèves entre 13 ans et plus. Mais qu’en est-il des jeunes âgés entre 9 et 12 ans ? Notre travail de recherche porte donc sur l’utilisation des réseaux sociaux (Snapchat, Instagram et WhatsApp) et le cyberbullying. Deux outils différents ont été utilisés lors de cette recherche : des questionnaires afin d’avoir des résultats quantitatifs et deux entretiens afin d’avoir un point de vue qualitatif. Nos résultats montrent que WhatsApp est le réseau social le plus utilisé, suivi d’Instagram en deuxième position et finalement de Snapchat. Les élèves considèrent le nombre de dangers et de conflits sur les réseaux comme très faibles. Ils avouent tout de même donner plus d’informations personnelles sur WhatsApp que sur les autres réseaux choisis dans l’étude. Concernant leur vision du contrôle des parents, ils l’estiment très faible. Cependant, il s’agit uniquement de leur avis, il serait intéressant de savoir la réalité des faits en interrogeant les parents. Les deux sujets interrogés savent définir le cyberbullying et connaissent les différents acteurs agissant au sein de cette forme de harcèlement. Ils sont également conscients des différents risques, conséquences ou sentiments que peut ressentir une cyber-victime mais n’abordent pas du tout ceux concernant le témoin ou le cyber-harceleur. En conclusion, notre recherche montre que les réseaux sociaux font partie intégrante du quotidien d’un grand nombre d’élèves. Il est donc essentiel que les enseignants s’interrogent sur les moyens de gérer les problèmes que ceux-ci peuvent amener en classe mais également les moyens de les éviter

Interferon regulatory factor 5 (IRF5) gene variants are associated with multiple sclerosis in three distinct populations

Background: IRF5 is a transcription factor involved both in the type I interferon and the toll-like receptor signalling pathways. Previously, IRF5 has been found to be associated with systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel diseases. Here we investigated whether polymorphisms in the IRF5 gene would be associated with yet another disease with features of autoimmunity, multiple sclerosis (MS). Methods: We genotyped nine single nucleotide polymorphisms and one insertion-deletion polymorphism in the IRF5 gene in a collection of 2337 patients with MS and 2813 controls from three populations: two case-control cohorts from Spain and Sweden, and a set of MS trio families from Finland. Results: Two single nucleotide polymorphism (SNPs) (rs4728142, rs3807306), and a 5 bp insertion-deletion polymorphism located in the promoter and first intron of the IRF5 gene, showed association signals with values of p<0.001 when the data from all cohorts were combined. The predisposing alleles were present on the same common haplotype in all populations. Using electrophoretic mobility shift assays we observed allele specific differences in protein binding for the SNP rs4728142 and the 5 bp indel, and by a proximity ligation assay we demonstrated increased binding of the transcription factor SP1 to the risk allele of the 5 bp indel. Conclusion: These findings add IRF5 to the short list of genes shown to be associated with MS in more than one population. Our study adds to the evidence that there might be genes or pathways that are common in multiple autoimmune diseases, and that the type I interferon system is likely to be involved in the development of these diseases.Peer Reviewe

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Alteration in P-glycoprotein Functionality Affects Intrabrain Distribution of Quinidine More Than Brain Entry—A Study in Rats Subjected to Status Epilepticus by Kainate

This study aimed to investigate the use of quinidine microdialysis to study potential changes in brain P-glycoprotein functionality after induction of status epilepticus (SE) by kainate. Rats were infused with 10 or 20 mg/kg quinidine over 30 min or 4 h. Plasma, brain extracellular fluid (brain ECF), and end-of-experiment total brain concentrations of quinidine were determined during 7 h after the start of the infusion. Effect of pretreatment with tariquidar (15 mg/kg, administered 30 min before the start of the quinidine infusion) on the brain distribution of quinidine was assessed. This approach was repeated in kainate-treated rats. Quinidine kinetics were analyzed with population modeling (NONMEM). The quinidine microdialysis assay clearly revealed differences in brain distribution upon changes in P-glycoprotein functionality by pre-administration of tariquidar, which resulted in a 7.2-fold increase in brain ECF and a 40-fold increase in total brain quinidine concentration. After kainate treatment alone, however, no difference in quinidine transport across the blood–brain barrier was found, but kainate-treated rats tended to have a lower total brain concentration but a higher brain ECF concentration of quinidine than saline-treated rats. This study did not provide evidence for the hypothesis that P-glycoprotein function at the blood–brain barrier is altered at 1 week after SE induction, but rather suggests that P-glycoprotein function might be altered at the brain parenchymal level