332 research outputs found
Toxic Protein Spread in Neurodegeneration: Reality versus Fantasy
Over the past decade, the importance of the propagation of amyloidogenic proteins such as α-synuclein and tau in the pathogenesis of neurodegenerative diseases has been supported by numerous neuropathological and experimental studies. While these proteins behave similarly to prions, recent evidence suggests the existence of fundamental differences, as they can propagate in the absence of endogenous template, they do not exhibit a strict 'strain' behavior, and they may not be transmissible between individuals. We therefore propose to name these proteins 'prionoids'. In this review we critically assess the extent of the overlap between these two entities and evaluate how the propagation of prionoids can fit into the wider system dysfunction seen in the brains of patients with Alzheimer's and Parkinson's diseases
Cyclic multiplex fluorescent immunohistochemistry and machine learning reveal distinct states of astrocytes and microglia in normal aging and Alzheimerâs disease
Background
Astrocytes and microglia react to AÎČ plaques, neurofibrillary tangles, and neurodegeneration in the Alzheimerâs disease (AD) brain. Single-nuclei and single-cell RNA-seq have revealed multiple states or subpopulations of these glial cells but lack spatial information. We have developed a methodology of cyclic multiplex fluorescent immunohistochemistry on human postmortem brains and image analysis that enables a comprehensive morphological quantitative characterization of astrocytes and microglia in the context of their spatial relationships with plaques and tangles.
Methods
Single FFPE sections from the temporal association cortex of control and AD subjects were subjected to 8 cycles of multiplex fluorescent immunohistochemistry, including 7 astroglial, 6 microglial, 1 neuronal, AÎČ, and phospho-tau markers. Our analysis pipeline consisted of: (1) image alignment across cycles; (2) background subtraction; (3) manual annotation of 5172 ALDH1L1+âastrocytic and 6226 IBA1+âmicroglial profiles; (4) local thresholding and segmentation of profiles; (5) machine learning on marker intensity data; and (6) deep learning on image features.
Results
Spectral clustering identified three phenotypes of astrocytes and microglia, which we termed âhomeostatic,â âintermediate,â and âreactive.â Reactive and, to a lesser extent, intermediate astrocytes and microglia were closely associated with AD pathology (â€â50 ”m). Compared to homeostatic, reactive astrocytes contained substantially higher GFAP and YKL-40, modestly elevated vimentin and TSPO as well as EAAT1, and reduced GS. Intermediate astrocytes had markedly increased EAAT2, moderately increased GS, and intermediate GFAP and YKL-40 levels. Relative to homeostatic, reactive microglia showed increased expression of all markers (CD68, ferritin, MHC2, TMEM119, TSPO), whereas intermediate microglia exhibited increased ferritin and TMEM119 as well as intermediate CD68 levels. Machine learning models applied on either high-plex signal intensity data (gradient boosting machines) or directly on image features (convolutional neural networks) accurately discriminated control vs. AD diagnoses at the single-cell level.
Conclusions
Cyclic multiplex fluorescent immunohistochemistry combined with machine learning models holds promise to advance our understanding of the complexity and heterogeneity of glial responses as well as inform transcriptomics studies. Three distinct phenotypes emerged with our combination of markers, thus expanding the classic binary âhomeostatic vs. reactiveâ classification to a third state, which could represent âtransitionalâ or âresilientâ glia.España Ministry of Science, Innovation, and Universities FPU fellowship to CM-CMassachusetts Alzheimerâs Disease Research Center grant P30AG062421 to BTH, and 1R56AG061196 to BTHAlzheimerâs Association (AACF17-524184 and AACF-17-524184-RAPID to AS-P
Subnational climate entrepreneurship: innovative climate action in California and SĂŁo Paulo
The distinct role of subnational governments such as states and provinces in addressing climate change has been increasingly acknowledged. But while most studies investigate the causes and consequences of particular governmentsâ actions and networking activities, this article argues that subnational governments can develop climate action as a collective entrepreneurial activity. Addressing many elements explored in this special issue, it focuses on the second question and identifies climate entrepreneurship in two subnational governmentsâthe states of California (USA) and SĂŁo Paulo (Brazil). Examining internal action, as well as interaction with local authorities, national governments and the international regime, entrepreneurial activities are identified in the invention, diffusion and evaluation of subnational climate policy in each case. The article draws from the recent scholarship on policy innovation, entrepreneurship and climate governance. It contributes to the literature by exploring entrepreneurial subnational government activity in addressing climate change and expanding the understanding of the effects of policy innovation at the subnational level
Copper-Mediated Amidation of Heterocyclic and Aromatic CâH Bonds
A copper-mediated aerobic coupling reaction enables direct amidation of heterocycles or aromatics having weakly acidic CâH bonds with a variety of nitrogen nucleophiles. These reactions provide efficient access to many biologically important skeletons, including ones with the potential to serve as inhibitors of HMTs.Chemistry and Chemical Biolog
Management and treatment of children, young people and adults with systemic lupus erythematosus: British Society for Rheumatology guideline scope
\ua9 The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.The objective of this guideline is to provide up-to-date, evidence-based recommendations for the management of SLE that builds upon the existing treatment guideline for adults living with SLE published in 2017. This will incorporate advances in the assessment, diagnosis, monitoring, non-pharmacological and pharmacological management of SLE. General approaches to management as well as organ-specific treatment, including lupus nephritis and cutaneous lupus, will be covered. This will be the first guideline in SLE using a whole life course approach from childhood through adolescence and adulthood. The guideline will be developed with people with SLE as an important target audience in addition to healthcare professionals. It will include guidance related to emerging approved therapies and account for National Institute for Health and Care Excellence Technology Appraisals, National Health Service England clinical commissioning policies and national guidance relevant to SLE. The guideline will be developed using the methods and rigorous processes outlined in âCreating Clinical Guidelines: Our Protocolâ by the British Society for Rheumatology
Interest groups in multiple streams:specifying their involvement in the framework
Although interests inhabit a central place in the multiple streams framework (MSF), interest groups have played only a minor role in theoretical and empirical studies until now. In Kingdonâs original conception, organized interests are a key variable in the politics stream. Revisiting Kingdonâs concept with a particular focus on interest groups and their activitiesâin different streams and at various levelsâin the policy process, we take this argument further. In particular, we argue that specifying groupsâ roles in other streams adds value to the explanatory power of the framework. To do this, we look at how interest groups affect problems, policies, and politics. The influence of interest groups within the streams is explained by linking the MSF with literature on interest intermediation. We show that depending on the number of conditions and their activity level, interest groups can be involved in all three streams. We illustrate this in case studies reviewing labor market policies in Germany and chemicals regulation at the European level
Crime, media and the will-to-representation: Reconsidering relationships in the new media age
This paper considers the ways in which the rise of new media might challenge commonplace criminological assumptions about the crimeâmedia interface. Established debates around crime and media have long been based upon a fairly clear demarcation between production and consumption, between object and audience â the media generates and transmits representations of crime, and audiences engage with them. However, one of the most noticeable changes occurring in the wake of the development of new media is the proliferation of self-organised production by âordinary peopleâ â everything ranging from self-authored web pages and âblogsâ, to self-produced video created using hand-held camcorders, camera-phones and âwebcamsâ. Today we see the spectacle of people them, send them and upload them to the Internet. This kind of âwill to representationâ may be seen in itself as a new kind of causal inducement to law- and rule-breaking behaviour. It may be that, in the new media age, the terms of criminological questioning need to be sometimes reversed: instead of asking whether âmediaâ instigates crime or fear of crime, we must ask how the very possibility of bound up with the genesis of criminal behaviour.performing acts of crime and deviance in order to recordmediating oneself to an audience through self-representation might be bound up with the genesis of criminal behaviour
Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial
Background
Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy
17ÎČ-estradiol induces stearoyl-CoA desaturase-1 expression in estrogen receptor-positive breast cancer cells
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