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Imaging Mutant Huntingtin Aggregates using [18F]CHDI-650 PET in a preclinical model of Huntington’s disease
Get PDFHuntington’s disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene (HTT) that encodes pathogenic mutant huntingtin (mHTT) protein. Therapeutic strategies aimed at lowering mHTT would benefit from non-invasive PET-based methods to evaluate treatment response. The CHDI foundation developed the first-generation PET ligands labelled with 11C, which advanced to clinical evaluation. Further optimization generated an 18F radioligand with improved metabolic stability, brain exposure and specificity, shown by PET imaging in wild-type mice and autoradiography in HD brain samples1,2. Here, we characterised the PET radioligand [18F]CHDI-650 in the R6/1 mouse model of HD to assess its sensitivity for monitoring treatment response of mHTT lowering therapies.
[18F]CHDI-650 was produced according to an established method3 using a TRACERlab system. Radiochemical purity/molar activity of the final [18F]CHDI-650 product was detected by reverse-phase HPLC analysis. Dynamic PET imaging was conducted using R6/1 mice and wild-type littermates at various disease stages. Image processing and kinetic modelling (2TCM) analysis were performed using PMOD software. Ex vivo brain radioactivity was measured using gamma counting. Brains were cryo-sectioned and processed for immunofluorescence to identify HTT load.
[18F]CHDI-650 was produced (1.3 ± 0.2 GBq) with an average radiochemical purity of 99.9 ± 0.1 % and a molar activity of 32.4 ± 5.2 GBq/µmol (n = 9). The radioligand was able to discriminate R6/1 HET from WT mice at an early presymptomatic age for both dynamic PET imaging (striatal) and ex vivo whole brain gamma. A well-defined age associated increase was also evident using both measures. Dual immunofluorescence spatially defined the level of aggregated HTT in striatal and hippocampal regions across the age groups.
[18F]CHDI-650 PET shows great potential as a non-invasive tool for visualising the development of mHTT pathology and as a biomarker for preclinical efficacy studies.
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Trust: In Search of the Core Features
Get PDFIt has been a long time ago that trusts arrived in different non-common law jurisdictions. Its worldwide adoption, however, has risen some doubts about what are the essential elements that must be present in this legal device. Different scholars have proposed what is called the “essentials” of a trust. This contribution aims to provide another alternative to this doctrine. After some preventions regarding the scope of this work, and using the English, Scottish and Argentinian cases, it is concluded that a trust – for being a proper trust – must fulfilled three requisites: (i) the settlor must not have control over the trust assets; (ii) the trustee must act under an standard of conduct and fiduciary duties; and (iii) the trustee must benefit someone (the beneficiary) or fulfil a purpose. Nevertheless, this is not enough to justify their essentiality when setting up a trust: they are also core features because their absence threats its validity and existence
Adding a Vorticity Source to the Hasegawa-Wakatani Equations
Get PDFInstabilities in fusion reactor plasma are an area of ongoing research as they represent the primary hurdle in producing an ongoing fusion reaction for fusion energy production. To study one possible source of these instabilities, computational simulations to solve the modified Hasegawa-Wakatani Equations and the evolution of edge plasmas through time are required. This work shows that the addition of a source of vortices leads to edge instabilities using the TOKAM2D turbulence code. This is an important step into developing our understanding of how instabilities form in plasmas and maintaining a fusion reaction
Investigating the Inharmonicity of Piano Strings
Get PDFIn classical physics, ideal string vibrations are modelled using the harmonic series, yet real mode frequencies deviate from the integer set of harmonics due to string stiffness, known as inharmonicity. This work investigates this phenomenon in five piano strings on a Yamaha GB1 Grand Piano. Using the audio software Audacity for spectral analysis, the inharmonicity coefficient is determined experimentally and theoretically based on string properties. These values are comparable with previous research, offering insights into tuning techniques to minimise dissonant inharmonicity. Possible innovations from inharmonicity research are explored, with suggestions such as the temperature-dependent self-tuning systems for acoustic pianos
A Topological Investigation of the Cosmic Web Formation
Get PDFN-body simulations of the evolution of the large-scale structure of the universe (the Cosmic Web) were run while altering attractive gravity laws and initial conditions, in order to infer which properties of the universe are revealed by its current large-scale topology. The Cosmic Web was found to develop regardless of the gravitational alteration made. Significantly altering the initial conditions from Gaussian distribution ones was found to eliminate the Cosmic Web. Thus, we require small random perturbations in otherwise uniform initial conditions in the early universe, under an attractive gravitational force, for the Cosmic Web to develop
Re-viewing failure: William McGonagall as Macbeth at the Theatre Royal, Dundee, 1858
Get PDFWilliam McGonagall, Dundee, Macbeth, Theatre Royal, Folklore, Ethnology, Drama, Scottish poetry, Scottish literature, Performance, William Shakespeare, Scottish History, Regional studies, Local studies, Celebrit
Can the Story of Eve (Genesis 2-3) be Interpreted as Feminist
No full textThis essay will argue that Eve in Genesis 2-3 cannot be interpreted as feminist as her story, tied to Adam, is inherently patriarchal. I will argue against three points that form the basis of a feminist re-interpretation of Genesis 2-3: that Adam is ungendered, that Eve is made from Adam’s side rather than his rib, and, that Eve is Adam’s suitable helper rather than his subordinate. I argue that feminist and traditional interpretations of Eve define her existence in relation to Adam’s prior existence. In this way, Eve consistently represents the Other, as she is defined only in reference to the Subject Adam, a man (De Beauvoir, 1949, 26). Eve is incidental while Adam is essential, and for a representation to be truly feminist it must show the woman as the Subject
Las 6W sobre los Buriles: desarrollando un marco analítico para el estudio de los Núcleos-buril
No full textBurins are flexible tools that have been analysed from different perspectives, showing a wide range of technical diversity. The interpretation of this morphotype has oscillated between two dichotomies: form-function and core-tool. In this paper, we analyse the historiographical trajectory of the burin from a typological, technological, and functional perspective to develop a methodological and analytical framework for the study of this morphotype. Likewise, this work aims to propose technical attributes for the study of burins and burin-cores in order to broaden our knowledge about on-edge core reduction strategies. To this end, we have combined historiographical research on burins and burin-cores together with a general overview of the technical attributes of these artefacts in the units 6P and 7P from Cova Gran de Santa Linya.
The analysis of the refits and technical attributes on the lithic assemblage show different degrees of complexity in the configuration and reduction of burin-like artefacts. Simple burins are configured on a fracture, a plane or a previous removal and do not usually record notches or lateral retouch. On the other hand, we recovered more complex artefacts that belong to the technical sphere of cores. Qualitative and quantitative data allowed understanding the technical actions involved in the reduction of the lateral edges of the flakes by 1) identifying core management actions through retouching (shaping); 2) understanding the actions for the opening of the knapping surfaces (burin facets) from the edge, 3) exploring the technical actions involved in the lateral and volumetric reduction of flakes. 4) reconstructing the knapping sequences associated with this knapping method aimed at obtaining homogeneous bladelets through different reduction phases on the edge of flakes.
As a result, we aim to visualise the role of on-edge cores in the technical organisation of the Palaeolithic occupations and extend our knowledge of the technical behaviour of Upper Palaeolithic groups. Likewise, through this case study we address some of the constraints in the study of Upper Palaeolithic lithic assemblages and allow us to visualise how interpretative biases in the analysis of artefacts may remove expressions of human behaviour in past societies. By limiting these preconceptions, we could fill in some gaps in the interpretation of the archaeological record
Blank predetermination in the Iberian Acheulean. Insight from the cleaver on flake assemblage of Casal do Azemel site (Leiria, Portugal) by a Geometric Morphometric approach
Get PDFOver the last decades, the increase of data available for the study of the archaeological topic in the Iberian Peninsula during the Middle Pleistocene has favoured the understanding of the technological trends of the Iberian Acheulean assemblages. These have features of a Large Flake Acheulean (LFA), displaying, among other traits, a significant presence of cleavers on flake, a specific tool type that is of great cultural and technological value. Particularly, these artefacts are privileged to discuss the importance of blank predetermination in the Acheulean techno-complex. Following this reason, in the present work we aimed to explore this topic through the 2D Geometric Morphometric Analysis of the cleaver on flake assemblage from Casal do Azemel (Leiria, Portugal), an example of a paradigmatic Iberian Acheulean site that has one of the largest collections of this type of tools in Western Europe.
The results obtained revealed that no significant morphological differences were found according to the technological solutions applied to the acquisition of the blank and its secondary transformation. Considering that in most of the cases these tools display a low degree of secondary transformation, these data suggest that underlying the production of Casal do Azemel’s cleaver on flake assemblage was not only a technological and cognitive flexibility (given its typological composition), but also a conceptual, structural, and morphological standardisation. These observations allowed us to discuss the significance of blank predetermination in the Acheulean, implying the existence of greatly structured technical and cognitive prerequisites