Contribution of complement activation pathways to neuropathology differs among mouse models of Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>Complement proteins and activation products have been found associated with neuropathology in Alzheimer's disease (AD). Recently, a C5a receptor antagonist was shown to suppress neuropathology in two murine models of AD, Tg2576 and 3xTg. Previously, a genetic deficiency of C1q in the Tg2576 mouse model showed an accumulation of fibrillar plaques similar to the complement sufficient Tg2576, but reactive glia were significantly decreased and neuronal integrity was improved suggesting detrimental consequences for complement activation in AD. The goal of this study was to define the role of the classical complement activation pathway in the progression of pathology in the 3xTg mouse that develops tangles in addition to fibrillar plaques (more closely reflecting human AD pathology) and to assess the influence of complement in a model of AD with a higher level of complement hemolytic activity.</p> <p>Methods</p> <p>3xTg mice deficient in C1q (3xTgQ-/-) were generated, and both 3xTg and 3xTgQ-/- were backcrossed to the BUB mouse strain which has higher in vitro hemolytic complement activity. Mice were aged and perfused, and brain sections stained for pathological markers or analyzed for proinflammatory marker expression.</p> <p>Results</p> <p>3xTgQ-/- mice showed similar amounts of fibrillar amyloid, reactive glia and hyperphosphorylated tau as the C1q-sufficient 3xTg at the ages analyzed. However, 3xTg and 3xTgQ-/- on the BUB background developed pathology earlier than on the original 3xTg background, although the presence of C1q had no effect on neuropathological and pro-inflammatory markers. In contrast to that seen in other transgenic models of AD, C1q, C4 and C3 immunoreactivity was undetectable on the plaques of 3xTg in any background, although C3 was associated with reactive astrocytes surrounding the plaques. Importantly, properdin a component of the alternative complement pathway was associated with plaques in all models.</p> <p>Conclusions</p> <p>In contrast to previously investigated transgenic models of AD, development of neuropathology in 3xTg mice, which progresses much slower than other murine models, may not be influenced by fibrillar amyloid mediated activation of the classical complement pathway, suggesting that the alternative complement pathway activation or a C3-independent cleavage of C5 could account for the detrimental effects in these mice that are prevented by the C5a receptor antagonist. Furthermore, the paucity of complement activation may be a factor in the slower kinetics of progression of pathology in the 3xTg model of this disease.</p

First Dark Matter Limits from a Large-Mass, Low-Background Superheated Droplet Detector

We report on the fabrication aspects and calibration of the first large active mass ($\sim15$ g) modules of SIMPLE, a search for particle dark matter using Superheated Droplet Detectors (SDDs). While still limited by the statistical uncertainty of the small data sample on hand, the first weeks of operation in the new underground laboratory of Rustrel-Pays d'Apt already provide a sensitivity to axially-coupled Weakly Interacting Massive Particles (WIMPs) competitive with leading experiments, confirming SDDs as a convenient, low-cost alternative for WIMP detection.Comment: Final version, Phys. Rev. Lett. (in press

The vulnerability of public spaces: challenges for UK hospitals under the 'new' terrorist threat

This article considers the challenges for hospitals in the United Kingdom that arise from the threats of mass-casualty terrorism. Whilst much has been written about the role of health care as a rescuer in terrorist attacks and other mass-casualty crises, little has been written about health care as a victim within a mass-emergency setting. Yet, health care is a key component of any nation's contingency planning and an erosion of its capabilities would have a significant impact on the generation of a wider crisis following a mass-casualty event. This article seeks to highlight the nature of the challenges facing elements of UK health care, with a focus on hospitals both as essential contingency responders under the United Kingdom's civil contingencies legislation and as potential victims of terrorism. It seeks to explore the potential gaps that exist between the task demands facing hospitals and the vulnerabilities that exist within them

Harnessing inter-disciplinary collaboration to improve emergency care in low- and middle-income countries (LMICs): results of research prioritisation setting exercise

Background More than half of deaths in low- and middle-income countries (LMICs) result from conditions that could be treated with emergency care - an integral component of universal health coverage (UHC) - through timely access to lifesaving interventions. Methods The World Health Organization (WHO) aims to extend UHC to a further 1 billion people by 2023, yet evidence supporting improved emergency care coverage is lacking. In this article, we explore four phases of a research prioritisation setting (RPS) exercise conducted by researchers and stakeholders from South Africa, Egypt, Nepal, Jamaica, Tanzania, Trinidad and Tobago, Tunisia, Colombia, Ethiopia, Iran, Jordan, Malaysia, South Korea and Phillipines, USA and UK as a key step in gathering evidence required by policy makers and practitioners for the strengthening of emergency care systems in limited-resource settings. Results The RPS proposed seven priority research questions addressing: identification of context-relevant emergency care indicators, barriers to effective emergency care; accuracy and impact of triage tools; potential quality improvement via registries; characteristics of people seeking emergency care; best practices for staff training and retention; and cost effectiveness of critical care – all within LMICs. Conclusions Convened by WHO and facilitated by the University of Sheffield, the Global Emergency Care Research Network project (GEM-CARN) brought together a coalition of 16 countries to identify research priorities for strengthening emergency care in LMICs. Our article further assesses the quality of the RPS exercise and reviews the current evidence supporting the identified priorities

Observation of hard scattering in photoproduction events with a large rapidity gap at HERA

Events with a large rapidity gap and total transverse energy greater than 5 GeV have been observed in quasi-real photoproduction at HERA with the ZEUS detector. The distribution of these events as a function of the $\gamma p$ centre of mass energy is consistent with diffractive scattering. For total transverse energies above 12 GeV, the hadronic final states show predominantly a two-jet structure with each jet having a transverse energy greater than 4 GeV. For the two-jet events, little energy flow is found outside the jets. This observation is consistent with the hard scattering of a quasi-real photon with a colourless object in the proton.Comment: 19 pages, latex, 4 figures appended as uuencoded fil

Cell-specific deletion of C1qa identifies microglia as the dominant source of C1q in mouse brain

BACKGROUND: The complement cascade not only provides protection from infection but can also mediate destructive inflammation. Complement is also involved in elimination of neuronal synapses which is essential for proper development, but can be detrimental during aging and disease. C1q, required for several of these complement-mediated activities, is present in the neuropil, microglia, and a subset of interneurons in the brain. METHODS: To identify the source(s) of C1q in the brain, the C1qa gene was selectively inactivated in the microglia or Thy-1(+) neurons in both wild type mice and a mouse model of Alzheimer’s disease (AD), and C1q synthesis assessed by immunohistochemistry, QPCR, and western blot analysis. RESULTS: While C1q expression in the brain was unaffected after inactivation of C1qa in Thy-1(+) neurons, the brains of C1qa (FL/FL) :Cx3cr1 (CreERT2) mice in which C1qa was ablated in microglia were devoid of C1q with the exception of limited C1q in subsets of interneurons. Surprisingly, this loss of C1q occurred even in the absence of tamoxifen by 1 month of age, demonstrating that Cre activity is tamoxifen-independent in microglia in Cx3cr1 (CreERT2/WganJ) mice. C1q expression in C1qa (FL/FL) : Cx3cr1 (CreERT2/WganJ) mice continued to decline and remained almost completely absent through aging and in AD model mice. No difference in C1q was detected in the liver or kidney from C1qa (FL/FL) : Cx3cr1 (CreERT2/WganJ) mice relative to controls, and C1qa (FL/FL) : Cx3cr1 (CreERT2/WganJ) mice had minimal, if any, reduction in plasma C1q. CONCLUSIONS: Thus, microglia, but not neurons or peripheral sources, are the dominant source of C1q in the brain. While demonstrating that the Cx3cr1 (CreERT2/WganJ) deleter cannot be used for adult-induced deletion of genes in microglia, the model described here enables further investigation of physiological roles of C1q in the brain and identification of therapeutic targets for the selective control of complement-mediated activities contributing to neurodegenerative disorders. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12974-017-0814-9) contains supplementary material, which is available to authorized users

Task swapping networks in distributed systems

In this paper we propose task swapping networks for task reassignments by using task swappings in distributed systems. Some classes of task reassignments are achieved by using iterative local task swappings between software agents in distributed systems. We use group-theoretic methods to find a minimum-length sequence of adjacent task swappings needed from a source task assignment to a target task assignment in a task swapping network of several well-known topologies.Comment: This is a preprint of a paper whose final and definite form is published in: Int. J. Comput. Math. 90 (2013), 2221-2243 (DOI: 10.1080/00207160.2013.772985

Nickel and helium evidence for melt above the core–mantle boundary

High ^(3)He/^(4)He ratios in some basalts have generally been interpreted as originating in an incompletely degassed lower-mantle source. This helium source may have been isolated at the core–mantle boundary region since Earth’s accretion. Alternatively, it may have taken part in whole-mantle convection and crust production over the age of the Earth; if so, it is now either a primitive refugium at the core–mantle boundary or is distributed throughout the lower mantle. Here we constrain the problem using lavas from Baffin Island, West Greenland, the Ontong Java Plateau, Isla Gorgona and Fernandina (Galapagos). Olivine phenocryst compositions show that these lavas originated from a peridotite source that was about 20 per cent higher in nickel content than in the modern mid-ocean-ridge basalt source. Where data are available, these lavas also have high ^(3)He/^(4)He. We propose that a less-degassed nickel-rich source formed by core–mantle interaction during the crystallization of a melt-rich layer or basal magma ocean, and that this source continues to be sampled by mantle plumes. The spatial distribution of this source may be constrained by nickel partitioning experiments at the pressures of the core–mantle boundary