Investigating the Role of PIR1 and CD200R1 in the Innate Immune Response to Viral Pathogens

After initially being infected with a virus, before an adaptive immune response can be mounted, the innate immune system of a cell recognizes and responds to certain patterns present in pathogenic molecules. I studied the role of two genes—PIR1 and CD200R1—on the innate immune responses in two different mouse models of viral infection, infection with the picornavirus EMCV (encephalomyocarditis virus) and infection with HSV-1 (herpes simplex virus) in a mouse model of herpes simplex encephalitis, respectively. PIR1 is a putative RNA phosphatase that has been shown to play an important role in antiviral small RNA processing in C. elegans. It has also been shown to interact with the RIG-I-like receptor LGP2 in preliminary mammalian experiments. I sought to characterize the effect PIR1 has on the innate immune response to the virus EMCV in mice. By developing a PIR1-null mouse, I have found that the role of PIR1 in the progression of EMCV in mice is limited. However, in vitro studies show that PIR1 might play an important role in regulating foreign RNA recognition during the earliest time points post-infection. CD200R1 is an anti-inflammatory signaling molecule that is expressed on myeloidderived cells, and whose ligand is highly expressed within the central nervous system. I investigated the role of this receptor in an intracranial model of herpes simplex encephalitis. CD200R1KO mice show improved survival following direct intracranial infection with HSV. I found this increased survival can be attributed to decreased levels of viral replication in CD200R1KO compared to wild-type mice. Further investigation has shown that CD200R1 affects the signaling and upregulation of the pattern-recognition receptor TLR-2 (toll-like receptor 2), and thus CD200R1 may impact HSV-1 replication by affecting TLR2 signaling

Evidence for changes in historic and future groundwater levels in the UK

We examine the evidence for climate-change impacts on groundwater levels provided by studies of the historical observational record, and future climate-change impact modelling. To date no evidence has been found for systematic changes in groundwater drought frequency or intensity in the UK, but some evidence of multi-annual to decadal coherence of groundwater levels and large-scale climate indices has been found, which should be considered when trying to identify any trends. We analyse trends in long groundwater level time-series monitored in seven observation boreholes in the Chalk aquifer, and identify statistically significant declines at four of these sites, but do not attempt to attribute these to a change in a stimulus. The evidence for the impacts of future climate change on UK groundwater recharge and levels is limited. The number of studies that have been undertaken is small and different approaches have been adopted to quantify impacts. Furthermore, these studies have generally focused on relatively small regions and reported local findings. Consequently, it has been difficult to compare them between locations. We undertake some additional analysis of the probabilistic outputs of the one recent impact study that has produced coherent multi-site projections of changes in groundwater levels. These results suggest reductions in annual and average summer levels, and increases in average winter levels, by the 2050s under a high greenhouse gas emissions scenario, at most of the sites modelled, when expressed by the median of the ensemble of simulations. It is concluded, however, that local hydrogeological conditions can be an important control on the simulated response to a future climate projection

Novel Method for Incorporating Model Uncertainties into Gravitational Wave Parameter Estimates

Posterior distributions on parameters computed from experimental data using Bayesian techniques are only as accurate as the models used to construct them. In many applications these models are incomplete, which both reduces the prospects of detection and leads to a systematic error in the parameter estimates. In the analysis of data from gravitational wave detectors, for example, accurate waveform templates can be computed using numerical methods, but the prohibitive cost of these simulations means this can only be done for a small handful of parameters. In this work a novel method to fold model uncertainties into data analysis is proposed; the waveform uncertainty is analytically marginalised over using with a prior distribution constructed by using Gaussian process regression to interpolate the waveform difference from a small training set of accurate templates. The method is well motivated, easy to implement, and no more computationally expensive than standard techniques. The new method is shown to perform extremely well when applied to a toy problem. While we use the application to gravitational wave data analysis to motivate and illustrate the technique, it can be applied in any context where model uncertainties exist.Comment: 6 pages, 3 figures, accepted for publication in Physical Review Letter

Impact of Scotland’s comprehensive, smoke-free legislation on stroke

<p>Background: Previous studies have reported a reduction in acute coronary events following smoke-free legislation. Evidence is lacking on whether stroke is also reduced. The aim was to determine whether the incidence of stroke, overalland by sub-type, fell following introduction of smoke-free legislation across Scotland on 26 March 2006.</p> <p>Methods and Findings: A negative binomial regression model was used to determine whether the introduction of smokefree legislation resulted in a step and/or slope change in stroke incidence. The model was adjusted for age-group, sex, socioeconomic deprivation quintile, urban/rural residence and month. Interaction tests were also performed. Routine hospital administrative data and death certificates were used to identify all hospital admissions and pre-hospital deaths due to stroke (ICD10 codes I61, I63 and I64) in Scotland between 2000 and 2010 inclusive. Prior to the legislation, rates of all stroke, intracerebral haemorrhage and unspecified stroke were decreasing, whilst cerebral infarction was increasing at 0.97% per annum. Following the legislation, there was a dramatic fall in cerebral infarctions that persisted for around 20 months. No visible effect was observed for other types of stroke. The model confirmed an 8.90% (95% CI 4.85, 12.77, p,0.001) stepwise reduction in cerebral infarction at the time the legislation was implemented, after adjustment for potential cofounders.</p> <p>Conclusions: Following introduction of national, comprehensive smoke-free legislation there was a selective reduction in cerebral infarction that was not apparent in other types of stroke.</p&gt

Hippocampal network abnormalities explain amnesia after VGKCC-Ab related autoimmune limbic encephalitis

Objective Limbic encephalitis associated with antibodies to components of the voltage-gated potassium channel complex (VGKCC-Ab-LE) often leads to hippocampal atrophy and persistent memory impairment. Its long-term impact on regions beyond the hippocampus, and the relationship between brain damage and cognitive outcome, are poorly understood. We investigated the nature of structural and functional brain abnormalities following VGKCC-Ab-LE and its role in residual memory impairment. Method A cross-sectional group study was conducted. Twenty-four VGKCC-Ab-LE patients (20 male, 4 female; mean (SD) age 63.86 (11.31) years) were recruited post-acutely along with age- and sex-matched healthy controls for neuropsychological assessment, structural MRI and resting-state functional MRI (rs-fMRI). Structural abnormalities were determined using volumetry and voxel-based morphometry; rs-fMRI data were analysed to investigate hippocampal functional connectivity (FC). Associations of memory performance with neuroimaging measures were examined. Results Patients showed selective memory impairment. Structural analyses revealed focal hippocampal atrophy within the medial temporal lobes, correlative atrophy in the mediodorsal thalamus, and additional volume reduction in the posteromedial cortex. There was no association between regional volumes and memory performance. Instead, patients demonstrated reduced posteromedial cortico-hippocampal and inter-hippocampal FC, which correlated with memory scores (r = 0.553; r = 0.582, respectively). The latter declined as a function of time since the acute illness (r = -0.531). Conclusion VGKCC-Ab-LE results in persistent isolated memory impairment. Patients have hippocampal atrophy with further reduced mediodorsal thalamic and posteromedial cortical volumes. Crucially, reduced FC of remaining hippocampal tissue correlates more closely with memory function than does regional atrophy

Long-Term Survival after Gamma Knife Radiosurgery in a Case of Recurrent Glioblastoma Multiforme: A Case Report and Review of the Literature

The management of recurrent glioblastoma is highly challenging, and treatment outcomes remain uniformly poor. Glioblastoma is a highly infiltrative tumor, and complete surgical resection of all microscopic extensions cannot be achieved at the time of initial diagnosis, and hence local recurrence is observed in most patients. Gamma Knife radiosurgery has been used to treat these tumor recurrences for select cases and has been successful in prolonging the median survival by 8–12 months on average for select cases. We present the unique case of a 63-year-old male with multiple sequential recurrences of glioblastoma after initial standard treatment with surgery followed by concomitant external beam radiation therapy and chemotherapy (temozolomide). The patient was followed clinically as well as with surveillance MRI scans at every 2-3-month intervals. The patient underwent Gamma Knife radiosurgery three times for 3 separate tumor recurrences, and the patient survived for seven years following the initial diagnosis with this aggressive treatment. The median survival in patients with recurrent glioblastoma is usually 8–12 months after recurrence, and this unique case illustrates that aggressive local therapy can lead to long-term survivors in select situations. We advocate that each patient treatment at the time of recurrence should be tailored to each clinical situation and desire for quality of life and improved longevity

Proglacial groundwater storage dynamics under climate change and glacier retreat

Proglacial aquifers are an important water store in glacierised mountain catchments that supplement meltwater‐fed river flows and support freshwater ecosystems. Climate change and glacier retreat will perturb water storage in these aquifers, yet the climate‐glacier‐groundwater response cascade has rarely been studied and remains poorly understood. This study implements an integrated modelling approach that combines distributed glacio‐hydrological and groundwater models with climate change projections to evaluate the evolution of groundwater storage dynamics and surface‐groundwater exchanges in a temperate, glacierised catchment in Iceland. Focused infiltration along the meltwater‐fed Virkisá River channel is found to be an important source of groundwater recharge and is projected to provide 14%–20% of total groundwater recharge by the 2080s. The simulations highlight a mechanism by which glacier retreat could inhibit river recharge in the future due to the loss of diurnal melt cycling in the runoff hydrograph. However, the evolution of proglacial groundwater level dynamics show considerable resilience to changes in river recharge and, instead, are driven by changes in the magnitude and seasonal timing of diffuse recharge from year‐round rainfall. The majority of scenarios simulate an overall reduction in groundwater levels with a maximum 30‐day average groundwater level reduction of 1 m. The simulations replicate observational studies of baseflow to the river, where up to 15% of the 30‐day average river flow comes from groundwater outside of the melt season. This is forecast to reduce to 3%–8% by the 2080s due to increased contributions from rainfall and meltwater runoff. During the melt season, groundwater will continue to contribute 1%–3% of river flow despite significant reductions in meltwater runoff inputs. Therefore it is concluded that, in the proglacial region, groundwater will continue to provide only limited buffering of river flows as the glacier retreats

Northern Hemisphere atmospheric stilling accelerates lake thermal responses to a warming world

Climate change, in particular the increase in air temperature, has been shown to influence lake thermal dynamics, with climatic warming resulting in higher surface temperatures, stronger stratification, and altered mixing regimes. Less-studied is the influence on lake thermal dynamics of atmospheric stilling, the decrease in near-surface wind speed observed in recent decades. Here we use a lake model to assess the influence of atmospheric stilling, on lake thermal dynamics across the Northern Hemisphere. From 1980-2016, lake thermal responses to warming have accelerated as a result of atmospheric stilling. Lake surface temperatures and thermal stability have changed at respective rates of 0.33 and 0.38°C decade-1, with atmospheric stilling contributing 15 and 27% of the calculated changes, respectively. Atmospheric stilling also resulted in a lengthening of stratification, contributing 23% of the calculated changes. Our results demonstrate that atmospheric stilling has influenced lake thermal responses to warming