Spatial heterogeneity in microglial ultrastructural alterations in the APP-PS1 mouse model of Alzheimer's disease amyloid pathology

Les principales caractéristiques de la maladie d'Alzheimer (MA) sont le dépôt de plaques amyloïdes (Aβ) extracellulaires et les enchevêtrements neurofibrillaires intracellulaires composés de protéines tau. À mesure que la maladie progresse, la mort neuronale et une diminution de la densité synaptique sont observées, parallèlement à une augmentation de la neuroinflammation et du dysfonctionnement immunitaire. Le processus de neuroinflammation est étroitement lié à la présence de plaques Aβ et peut affecter les interactions microgliales avec les structures neuronales tout au long de la progression de la maladie. L'activation substantielle et chronique des microglies déclenchée par la présence d'Aβ est supposée affecter l'homéostasie cérébrale en raison d'une altération des actions physiologiques microgliales, notamment au niveau des synapses. Ici, nous visons à générer de nouvelles connaissances sur l'implication microgliale dans la physiopathologie de la MA en combinant la microscopie optique et électronique pour étudier l'ultrastructure microgliale et les interactions neuronales / synaptiques en relation avec le dépôt de plaques Aβ. Des souris APP-PS1 âgées de 14 mois ont été étudiées en même temps que des témoins appariés selon l'âge. En outre, des sections de la MA humaine post-mortem ont également été examinées dans notre étude. Dans nos expériences, les plaques Aβ ont été visualisées en utilisant du méthoxy-XO4 qui se lie sélectivement et irréversiblement aux feuilles d'Aβ et permet leur détection en microscopie optique. De plus, l'immunocoloration post-mortem de la microglie avec le marqueur de la molécule adaptatrice de fixation du calcium ionisée (IBA1) et un traitement supplémentaire pour la microscopie électronique à transmission ont permis d'étudier la microglie à différentes proximités des plaques. Nos analyses ultrastructurelles ont révélé des différences significatives dans les activités phagocytaires et les caractéristiques morphologiques. Les corps cellulaires microgliaux de l'APP-PS1 avaient une surface et un périmètre significativement supérieurs à ceux des témoins de type sauvage et présentaient des signes de stress et une activité phagocytaire diminuée. Ces signes de stress et de phagocytose altérée ont également été observés dans les prolongements microgliaux des échantillons APP-PS1. De plus, les microglies présentaient divers phénotypes morphologiques et réactions cellulaires physiologiques selon leur proximité des plaques. Les corps des cellules microgliales proches des plaques étaient plus larges en surface et en périmètre que les témoins de type sauvage et les autres régions APPPS1 situées plus loin des plaques. Les microglies proches des plaques étaient plus susceptibles de contenir des dépôts Aβ et moins susceptibles de contenir ou d’encercler des éléments neuronaux. En outre, elles présentaient des signes de stress caractérisés par des corps cellulaires assombris et un réticulum endoplasmique dilaté. Tous ces résultats définissent les changements radicaux qui se produisent au niveau ultrastructural dans le cerveau en réponse à la déposition AβThe main hallmarks of Alzheimer’s disease (AD) are the deposition of extracellular amyloid (A)β plaques and intracellular neurofibrillary tangles composed of tau protein. As the disease progresses, neuronal death and decreased synaptic density is observed, concurrent with an increase of neuroinflammation and immune dysfunction. The process of neuroinflammation is tightly linked to the presence of Aβ plaques and may affect microglial interactions with neuronal structures throughout disease progression. Substantial and chronic microglial activation triggered by the presence of Aβ is suspected to affect brain homeostasis due to an alteration of microglial physiological actions, notably at synapses. Here we aim to generate new insights regarding microglial implication in AD pathophysiology by combining light and electron microscopy to study microglial ultrastructure and neuronal/synaptic interactions with relation to Aβ plaque deposition. 14 months old APP-PS1 mice were studied alongside age-matched controls. Also, postmortem human AD sections were examined in our study. In our experiments, Aβ plaques were visualized using Methoxy-XO4 which binds selectively and irreversibly to Aβ sheets and allows their detection under light microscopy. Furthermore, post-mortem immunostaining of microglia with the ionized calcium-binding adapter molecule 1 (IBA1) marker and additional processing for transmission electron microscopy allowed the study of microglia at different proximities to the plaques. Our ultrastructural analyses revealed significant differences in phagocytic activities and morphological features. Microglial cell bodies in APP-PS1 were significantly larger in area and perimeter compared to wild-type controls and displayed signs of stress and decreased phagocytic activity. These signs of stress and impaired phagocytosis were also found in microglial processes in the APP-PS1 samples. Additionally, microglia showed diverse morphological phenotypes and physiological cell reactions dependent on their proximity to plaques. Microglial cell bodies near plaques were larger in area and perimeter compared to wild-type controls and other APP-PS1 regions located farther from plaques. Microglia near plaques were more were more likely to contain Aβ and less likely to contain or encircle neuronal elements. Also, they presented signs of stress characterized by darkened cell bodies and dilated endoplasmic reticulum. All these findings define the drastic changes that are taking place at ultrastructural level in the brain in response to Aβ deposition

Prompt me a Dataset: An investigation of text-image prompting for historical image dataset creation using foundation models

In this paper, we present a pipeline for image extraction from historical documents using foundation models, and evaluate text-image prompts and their effectiveness on humanities datasets of varying levels of complexity. The motivation for this approach stems from the high interest of historians in visual elements printed alongside historical texts on the one hand, and from the relative lack of well-annotated datasets within the humanities when compared to other domains. We propose a sequential approach that relies on GroundDINO and Meta's Segment-Anything-Model (SAM) to retrieve a significant portion of visual data from historical documents that can then be used for downstream development tasks and dataset creation, as well as evaluate the effect of different linguistic prompts on the resulting detections.Comment: 12 pages, 3 figures, Accepted in ICIAP2023, AI4DH worksho

The Conceptual Politics of Democracy Promotion: The Venezuela Case

In 1970 Giovanni Sartori articulated what he saw as the greatest challenge to political science in an increasingly globalized worldconceptual stretching. Sartori was referring to the traveling of western concepts eastward and proposed the use of a conceptual ladder to help inform the decisions political scientists make regarding the concepts they wish to travel. This paper seeks to push the boundaries of Sartori’s critique beyond academia to include policy; a subject where a dynamic and informative relationship between academia and policy should exist, but are instead faced with a one-dimensional arrangement. In that vein, this paper consists of three main parts. The first employs a brief historiography of the conceptual debate between, largely, Schumpeterian and Dahlian definitions of democracy where two main schools of thought will be sketched. The second evokes Venezuela's recent political history to illustrate how the United States Government has, at different times, employed various definitions, and standards, of democracy to describe the Venezuelan regime. The third seeks to establish how American oscillation between standards erodes the value reference point of democracy and draw out the implications of this. In particular, the third part unpacks what this erosion should mean moving forward for academics engaged in the conceptual politics of democracy. In sum, the instrumentalizing of the ambiguity of the concept—democracy—by oscillating between Schumpeterian and Dahlian standards devalues the concept. And unless the academic debate regarding democratic theory begins to account for this devaluation, democracy may well be emptied of its substance.

Homogenization of dislocation dynamics

In this paper we consider the dynamics of dislocations with the same Burgers vector, contained in the same glide plane, and moving in a material with periodic obstacles. We study two cases: i) the particular case of parallel straight dislocations and ii) the general case of curved dislocations. In each case, we perform rigorously the homogenization of the dynamics and predict the corresponding effective macroscopic elasto-visco-plastic flow rule

A Real-Time Video-Streaming System for Monitoring Demining

The most deployed detection technology for landmine clearance is the metal detector (MD).1 Other detection technologies exist, such as ground penetrating radar,2 chemical sensors,3 biological sensors,4 and infrared imaging,5 to name a few. However, despite their widespread use, MDs suffer from high false-alarm (FA) rates since they cannot differentiate between the metal components in a landmine and harmless metal clutter. Deminers using MDs usually rely on their personal experience to differentiate between the sounds emitted by the MD when scanning a landmine or an item of clutter. Usually, they continue to excavate on a large number of occasions and end up finding a harmless piece of metal. For each found single landmine, it is estimated that a hundred to a thousand false positives are encountered.6 The high FA rate substantially slows the demining process and increases costs. This delays the recovery of contaminated land and the resumption of everyday activities around the affected areas

Insightful analysis of historical sources at scales beyond human capabilities using unsupervised Machine Learning and XAI

Historical materials are abundant. Yet, piecing together how human knowledge has evolved and spread both diachronically and synchronically remains a challenge that can so far only be very selectively addressed. The vast volume of materials precludes comprehensive studies, given the restricted number of human specialists. However, as large amounts of historical materials are now available in digital form there is a promising opportunity for AI-assisted historical analysis. In this work, we take a pivotal step towards analyzing vast historical corpora by employing innovative machine learning (ML) techniques, enabling in-depth historical insights on a grand scale. Our study centers on the evolution of knowledge within the `Sacrobosco Collection' -- a digitized collection of 359 early modern printed editions of textbooks on astronomy used at European universities between 1472 and 1650 -- roughly 76,000 pages, many of which contain astronomic, computational tables. An ML based analysis of these tables helps to unveil important facets of the spatio-temporal evolution of knowledge and innovation in the field of mathematical astronomy in the period, as taught at European universities

Analyse gedruckter Initialen aus der Frühen Neuzeit mit neuronalen Netzen

The aim of this project is to find initials of the same style across different books and different printers by extracting the style representations using artificial neural networks. This makes it possible to understand and trace the dissemination, transmission and imitation of woodcuts for printing from the late Middle Ages to the early modern period. In this way, connections between printers and missing information about them can be identified

A Virtual Reality Application for the Training of Deminers

As virtual reality (VR) tools continue to improve, more fields are finding ways of implementing the technology to take advantage of training opportunities that reduce costs, alleviate logistical challenges, and more. Where humanitarian deminers must prepare for dangerous work, VR facilitates training that minimizes the danger while giving trainers a level of control over the different conditions of the training and the ability to easily monitor and instruct the user. For this purpose, the American University of Beirut (AUB) and the Beirut Research and Innovation Center (BRIC) developed a VR application for the basic training of deminers, which is called the VR Demining Trainer (VRDT). The first version of the VRDT, presented herein, teaches trainees how to turn on a metal detector, test the detector, conduct soil compensation, and start searching in a virtual minefield. These activities can be done in a closed room, regardless of time of day or weather conditions. Different training scenario attributes—including soil properties, landmine types, and locations—can be easily selected beforehand via software. The VRDT, which is a lab-ready prototype being developed using the Unreal Engine software and the Oculus Quest VR device, is not meant to replace but supplement field training, cutting down on training time and logistics by performing basic training phases in a VR-controlled environment

The perception of risk in contracting and spreading COVID-19 amongst individuals, households and vulnerable groups in England: a longitudinal qualitative study.

BackgroundSocial distancing restrictions to manage the COVID-19 pandemic were put in place from March 2020 in the United Kingdom (UK), with those classed as "highly clinically vulnerable" advised to shield entirely and remain at home. However, personal risk perception has been shown to comprise of various elements beyond those outlined in the national pandemic guidance. It is unclear whether those deemed COVID-19 vulnerable identified as high-risk to COVID-19 and thus complied with the relevant advice. The aim of this research is to explore the perception of risk in catching and spreading COVID-19, amongst individuals from individual households, and vulnerable groups in a region of the UK.MethodsTwo individual, semi-structured interviews were conducted, four-weeks apart, with adults living in households in the Liverpool City Region. At the follow-up interview, participants were given the option of using photo-elicitation to guide the discussion. Reflexive thematic analysis was employed to conceptualise themes. The qualitative analysis was underpinned with symbolic interactionism.ResultsTwenty-seven participants (13:14 males:females, and 20 with a vulnerable risk factor to COVID-19) completed a baseline interview, and 15 of these completed a follow-up interview four-weeks later. Following thematic analysis, two overarching themes were conceptualised, with subthemes discussed: theme 1) Confusion and trust in the risk prevention guidance; and theme 2) Navigating risk: compliance and non-compliance with public health guidance.ConclusionParticipants developed their own understanding of COVID-19 risk perception through personal experience and comparison with others around them, irrespective of vulnerability status. COVID-19 guidance was not complied with as intended by the government, and at times even rejected due to lack of trust. The format in which future pandemic guidance is conveyed must be carefully considered, and take into account individuals' experiences that may lead to non-compliance. The findings from our study can inform future public health policy and interventions for COVID-19 and future pandemics