Variability in the immune response to Theiler's Murine Encephalomyelitis Virus in different strains of mice

Theiler's Murine Encephalomyelitis Virus (TMEV) has been a favoured model for Multiple Sclerosis (MS) since 1975 when Lipton first reported that infection with TMEV caused a biphasic Central Nervous System (CNS) disease leading to demyelination. TMEV is a picornavirus belonging to the cardiovirus genus and is a natural enteric pathogen of mice which can occasionally initiate a chronic persistent infection of the CNS. This depends on the strain and dose of virus and the strain, age and sex of the mouse. Intracerebral infection of all mouse strains with the avirulent BeAn strain of TMEV results in an acute encephalomyelitis which in susceptible mouse strains, is followed by a persistent CNS infection with lesions of inflammatory demyelination or in resistant mouse strains eradication of the virus. On the other hand i.e. infection with the neurovirulent GDVII strain of Theiler's virus results in a fulminant encephalitis in mice of all genetic backgrounds.The main aim of this study was to determine the cytokine and immunoglobulin profiles elicited in different mouse strains during the acute phase of infection. mRNA transcript levels for numerous cytokines were studied in the brains and spinal cords in Balb/c (resistant), CBA (intermediately susceptibility) and SJL/J (susceptible) mice, during the acute phase of disease, using the technique of RNase protection assay (RPA). The RPA included analysis of transcripts for TNFp, TNFa, TGFp, IFNy, IL-la, ILip, IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-13, IL-12p40 and IL-12p35. There were similarities between the strains in the levels of pro-inflammatory cytokines expressed including TNFa, TNFp and ILla. However, there were several fundamental differences between the strains including the inability of susceptible SJL/J mice to express IL-ip in the brain and the spinal cord when compared to Balb/c and CBA mice. SJL/J mice had an increase in expression of IL-4 and IL-10 and a decrease in expression of IL-2 and IFNy when compared to Balb/c and CBA mice. Expression of pro-inflammatory, anti¬ inflammatory, Thl and Th2 type cytokines correlated with the increase in levels of cellular infiltrates (CD3+, CD4+, CD8+ and F4/80+) in the CNS. Anti¬ viral immunoglobulin isotypes were also different in the three mouse strains studied. All strains produced similar levels of IgM however, Balb/c mice had significantly increased levels of IgGl and IgG2a compared to CBA and SJL/J mice during the acute phase of disease.This study also investigated TMEV persistence in CBA (intermediately susceptible) mice and the cytokine and anti-viral immunoglobulin isotypes associated with persistence. Virus persisted for >60 days in 50% of infected CBA mice, as determined by RT-PCR. Animals in which virus persisted had significantly increased RNA transcripts in the CNS for TNFa, IL-12p35 and IL-12p40. Persistently infected animals also had increased levels of anti-viral IgGl, IgG2a and IgG2b when compared to animals which had cleared the virus.The importance of interferons a/p and y were investigated. Virus spread extensively throughout the white matter regions of the brains in IFNa/pR°/° mice (constructed on a genetically resistant background (FI-2b)), during the acute phase of infection, indicating the importance of IFNa/p in preventing infection of oligodendrocytes. Infection of IFNyR°/° mice (also on a genetically resistant background) resulted in viral persistence and increased levels of anti-viral IgM, IgGl, IgG2a and IgG2b, demonstrating IFNy is essential for viral clearance. Perforin is a functional effector molecule in CTL killing, therefore, its role(s) during the acute and chronic phase of Theiler's virus infection was investigated to ascertain its importance. Studies in perforin knockout mice (also on a resistant genetic background) demonstrated that perforin is essential to control viral infection during the acute phase of infection, and is an absolute requirement for viral clearance.Infection with GDVII resulted in high levels of virus replication in the brains and spinal cords of infected mice. Levels of TNFa, IL-la, IL-2, IFNy and IL- 12p40 increase throughout infection in the brains of infected animals, and TNFa, IL-2 and IL-12p40 increase in the spinal cords. High virus titres, and an increase in the above pro-inflammatory cytokines correlated with an increase in levels of programmed cell death in CNS tissues.Infection of neonatal mice with the BeAn strain results in 100% mortality, with increased virus titres in the CNS. Expression of TNFp, TNFa, IL-4, IL-la and IL-6 increased throughout the course of infection of neonatal mice. TNFa has been implicated in the phenomenon of death by shock. Therefore, TNFa may have important implications in the pathogenesis of Theiler's virus infection in neonates

Using market-based indicators to assess banking system resilience

This report reviews the use of quantitative tools to gauge market participants’ assessment of banking system resilience. These measures complement traditional balance-sheet metrics and suggest that markets consider large Canadian banks to be better placed to weather adverse shocks than banks in other advanced economies. Compared with regulatory capital ratios, however, the measures suggest less improvement in banking system resilience since the pre-crisis period

A self-consistent, absolute isochronal age scale for young moving groups in the solar neighbourhood

This is a pre-copyedited, author-produced PDF of an article accepted for publication in MNRAS following peer review. The version of record is available online at: http://mnras.oxfordjournals.org/content/454/1/593.We present a self-consistent, absolute isochronal age scale for young (< 200 Myr), nearby (< 100 pc) moving groups in the solar neighbourhood based on homogeneous fitting of semi-empirical pre-main-sequence model isochrones using the tau^2 maximum-likelihood fitting statistic of Naylor & Jeffries in the M_V, V-J colour-magnitude diagram. The final adopted ages for the groups are: 149+51-19 Myr for the AB Dor moving group, 24+/-3 Myr for the {\beta} Pic moving group (BPMG), 45+11-7 Myr for the Carina association, 42+6-4 Myr for the Columba association, 11+/-3 Myr for the {\eta} Cha cluster, 45+/-4 Myr for the Tucana-Horologium moving group (Tuc-Hor), 10+/-3 Myr for the TW Hya association, and 22+4-3 Myr for the 32 Ori group. At this stage we are uncomfortable assigning a final, unambiguous age to the Argus association as our membership list for the association appears to suffer from a high level of contamination, and therefore it remains unclear whether these stars represent a single population of coeval stars. Our isochronal ages for both the BPMG and Tuc-Hor are consistent with recent lithium depletion boundary (LDB) ages, which unlike isochronal ages, are relatively insensitive to the choice of low-mass evolutionary models. This consistency between the isochronal and LDB ages instills confidence that our self-consistent, absolute age scale for young, nearby moving groups is robust, and hence we suggest that these ages be adopted for future studies of these groups. Software implementing the methods described in this study is available from http: //www.astro.ex.ac.uk/people/timn/tau-squared/.University of Rochester School of Arts and SciencesNational Science Foundation (NSF

The challenges of joint working: lessons from the Supporting People Health Pilot evaluation

Purpose: This paper reports the findings of the evaluation of the Supporting People Health Pilots programme which was established to demonstrate the policy links between housing support services and health and social care services by encouraging the development of integrated services. The paper highlights the challenges of working across housing, health and social care boundaries. <br><br> Method: The evaluation of the 6 health pilots rested on two main sources of data collection: Quarterly Project Evaluation Reports collected process data as well as reporting progress against aims and objectives. Semi-structured interviews - conducted across all key professional stakeholder groups and agencies and with people who used services - explored their experiences of these new services. <br><br> Results: The ability of pilots to work across organisational boundaries to achieve their aims and objectives was associated not only with agencies sharing an understanding of the purpose of the joint venture, a history of joint working and clear and efficient governance arrangements but on two other characteristics: the extent and nature of statutory sector participation and, whether or not the service is defined by a history of voluntary sector involvement. In particular the pilots demonstrated how voluntary sector agencies appeared to be less constrained by organisational priorities and professional agenda and more able to respond flexibly to meet the complex needs of individuals. <br><br> Conclusion and discussion: The pilots demonstrate that integrating services to support people with complex needs works best when the service is determined by the characteristics of those who use the service rather than pre-existing organisational structures

On Quantizing Implicit Neural Representations

The role of quantization within implicit/coordinate neural networks is still not fully understood. We note that using a canonical fixed quantization scheme during training produces poor performance at low-rates due to the network weight distributions changing over the course of training. In this work, we show that a non-uniform quantization of neural weights can lead to significant improvements. Specifically, we demonstrate that a clustered quantization enables improved reconstruction. Finally, by characterising a trade-off between quantization and network capacity, we demonstrate that it is possible (while memory inefficient) to reconstruct signals using binary neural networks. We demonstrate our findings experimentally on 2D image reconstruction and 3D radiance fields; and show that simple quantization methods and architecture search can achieve compression of NeRF to less than 16kb with minimal loss in performance (323x smaller than the original NeRF).Comment: 10 pages, 10 figure

A Critical Assessment of Ages Derived Using Pre-Main-Sequence Isochrones in Colour-Magnitude Diagrams

In this thesis a critical assessment of the ages derived using theoretical pre-main-sequence (pre-MS) stellar evolutionary models is presented by comparing the predictions to the low-mass pre-MS population of 14 young star-forming regions (SFRs) in colour-magnitude diagrams (CMDs). Deriving pre-MS ages requires precise distances and estimates of the reddening. Therefore, the main-sequence (MS) members of the SFRs have been used to derive a self-consistent set of statistically robust ages, distances and reddenings with associated uncertainties using a maximum-likelihood fitting statistic and MS evolutionary models. A photometric method (known as the Q-method) for de-reddening individual stars in regions where the extinction is spatially variable has been updated and is presented. The effects of both the model dependency and the SFR composition on these derived parameters are also discussed. The problem of calibrating photometric observations of red pre-MS stars is examined and it is shown that using observations of MS stars to transform the data into a standard photometric system can introduce significant errors in the position of the pre-MS locus in CMD space. Hence, it is crucial that precise photometric studies (especially of pre- MS objects) be carried out in the natural photometric system of the observations. This therefore requires a robust model of the system responses for the instrument used, and thus the calculated responses for the Wide-Field Camera on the Isaac Newton Telescope are presented. These system responses have been tested using standard star observations and have been shown to be a good representation of the photometric system. A benchmark test for the pre-MS evolutionary models is performed by comparing them to a set of well-calibrated CMDs of the Pleiades in the wavelength regime 0.4−2.5 μm. The masses predicted by these models are also tested against dynamical masses using a sample of MS binaries by calculating the system magnitude in a given photometric band- pass. This analysis shows that for Teff ≤ 4000 K the models systematically overestimate the flux by a factor of 2 at 0.5 μm, though this decreases with wavelength, becoming negligible at 2.2 μm. Thus before the pre-MS models are used to derive ages, a recalibration of the models is performed by incorporating an empirical colour-Teff relation and bolometric corrections based on the Ks-band luminosity of Pleiades members, with theoretical corrections for the dependence on the surface gravity (log g). The recalibrated pre-MS model isochrones are used to derive ages from the pre-MS populations of the SFRs. These ages are then compared with the MS derivations, thus providing a powerful diagnostic tool with which to discriminate between the different pre- MS age scales that arise from a much stronger model dependency in the pre-MS regime. The revised ages assigned to each of the 14 SFRs are up to a factor two older than previous derivations, a result with wide-ranging implications, including that circumstellar discs survive longer and that the average Class II lifetime is greater than currently believed

Plant yourself where language blooms: Direct experience of nature changes how parents and children talk about nature.

The current study investigated the affordances of direct and indirect experience of nature on parent-child talk. Parents and children produced a wider range of nature words when exploring a park (direct experience) than when exploring a thematically matched indoor visitor center (indirect experience). Parents and children also produced more plant-related nature word types when exploring the park compared to the visitor center. Findings suggest that direct experience of nature increases the diversity and specificity of parent-child talk about nature, and mitigates the phenomenon of “plant blindness” (cf. Wandersee & Schussler, 1999). Direct experience of nature provides an optimal context for children to learn the language of nature and consequently to cultivate children's status as custodians of the natural world

Functional network changes and cognitive control in schizophrenia

Cognitive control is a cognitive and neural mechanism that contributes to managing the complex demands of day-to-day life. Studies have suggested that functional impairments in cognitive control associated brain circuitry contribute to a broad range of higher cognitive deficits in schizophrenia. To examine this issue, we assessed functional connectivity networks in healthy adults and individuals with schizophrenia performing tasks from two distinct cognitive domains that varied in demands for cognitive control, the RiSE episodic memory task and DPX goal maintenance task. We characterized general and cognitive control-specific effects of schizophrenia on functional connectivity within an expanded frontal parietal network (FPN) and quantified network topology properties using graph analysis. Using the network based statistic (NBS), we observed greater network functional connectivity in cognitive control demanding conditions during both tasks in both groups in the FPN, and demonstrated cognitive control FPN specificity against a task independent auditory network. NBS analyses also revealed widespread connectivity deficits in schizophrenia patients across all tasks. Furthermore, quantitative changes in network topology associated with diagnostic status and task demand were observed. The present findings, in an analysis that was limited to correct trials only, ensuring that subjects are on task, provide critical insights into network connections crucial for cognitive control and the manner in which brain networks reorganize to support such control. Impairments in this mechanism are present in schizophrenia and these results highlight how cognitive control deficits contribute to the pathophysiology of this illness