Brain disposition of α-Synuclein: roles of brain barrier systems and implications for Parkinson’s disease

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the accumulation of α-Synuclein (a-Syn) into Lewy body inclusions and the loss of dopaminergic neurons in the substantia nigra (SN). Accumulation of a-Syn can induce a progressive, cyclical pathology that results in the transmission of toxic, aggregated a-Syn species to healthy neurons, leading to further neurodegeneration such as occurs in PD. The blood–brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barriers (BCSFB) are responsible for regulating the access of nutrients and other molecules to the brain, but very little is known about their regulatory roles in maintaining the homeostasis of a-Syn in the CSF and brain parenchyma. This review analyzes the current literature reports on the transport of a-Syn by various brain cell types with a particular focus on the potential transport mechanisms of a-Syn at the BBB and BCSFB. The indication of altered a-Syn transport by brain barriers in PD pathoetiology and the perspectives in this research area are also discussed

The effect of heterogeneity on invasion in spatial epidemics: from theory to experimental evidence in a model system

Heterogeneity in host populations is an important factor affecting the ability of a pathogen to invade, yet the quantitative investigation of its effects on epidemic spread is still an open problem. In this paper, we test recent theoretical results, which extend the established “percolation paradigm” to the spread of a pathogen in discrete heterogeneous host populations. In particular, we test the hypothesis that the probability of epidemic invasion decreases when host heterogeneity is increased. We use replicated experimental microcosms, in which the ubiquitous pathogenic fungus Rhizoctonia solani grows through a population of discrete nutrient sites on a lattice, with nutrient sites representing hosts. The degree of host heterogeneity within different populations is adjusted by changing the proportion and the nutrient concentration of nutrient sites. The experimental data are analysed via Bayesian inference methods, estimating pathogen transmission parameters for each individual population. We find a significant, negative correlation between heterogeneity and the probability of pathogen invasion, thereby validating the theory. The value of the correlation is also in remarkably good agreement with the theoretical predictions. We briefly discuss how our results can be exploited in the design and implementation of disease control strategies

Expression and Transport of a-Synuclein at the Blood-Cerebrospinal Fluid Barrier and Effects of Manganese Exposure

The choroid plexus maintains the homeostasis of critical molecules in the brain by regulating their transport between the blood and cerebrospinal fluid (CSF). The current study was designed to investigate the potential role of the blood-CSF barrier (BCSFB) in α-synuclein (a-Syn) transport in the brain as affected by exposure to manganese (Mn), the toxic metal implicated in Parkinsonian disorders. Immunohistochemistry was used to identify intracellular a-Syn expression at the BCSFB. Quantitative real-time PCR was used to quantify the change in a-Syn mRNA expression following Mn treatments at the BCSFB in vitro. ELISA was used to quantify a-Syn levels following in vivo and in vitro treatments of Mn, copper (Cu), and/or external a-Syn. Thioflavin-T assay was used to investigate a-Syn aggregation after incubating with Mn and/or Cu in vitro. A two-chamber Transwell system was used to study a-Syn transport by BCSFB monolayer.Data revealed the expression of endogenous a-Syn in rat choroid plexus tissue and immortalized choroidal epithelial Z310 cells. The cultured primary choroidal epithelia from rats showed the ability to take up a-Syn from extracellular medium and transport a-Syn across the cellular monolayer from the donor to receiver chamber. Exposure of cells with Mn induced intracellular a-Syn accumulation without causing any significant changes in a-Syn mRNA expression. A significant increase in a-Syn aggregation in a cell-free system was observed with the presence of Mn. Moreover, Mn exposure resulted in a significant uptake of a-Syn by primary cells.These data indicate that the BCSFB expresses a-Syn endogenously and is capable of transporting a-Syn across the BCSFB monolayer; Mn exposure apparently increases a-Syn accumulation in the BCSFB by facilitating its uptake and intracellular aggregation

Creating the 2011 area classification for output areas (2011 OAC)

This paper presents the methodology that has been used to create the 2011 Area Classification for Output Areas (2011 OAC). This extends a lineage of widely used public domain census only geodemographic classifications in the UK. It provides an update to the successful 2001 OAC methodology, and summarizes the social and physical structure of neighbourhoods using data from the 2011 UK Census. We also present the results of a user engagement exercise that underpinned the creation of an updated methodology for the 2011 OAC. The 2011 OAC comprises 8 Supergroups, 26 Groups and 76 Subgroups. Finally, we present an example of the results of the classification in Southampton

BradPhys to BradViz or from archaeological science to heritage science

YesArchaeology is a broad church and its role as a “two culture” discipline is frequently cited. This position at the interface of the arts and sciences remains central to archaeological activity but there have been significant changes in the structure of archaeology and its relationship to society overall. The growth of heritage science, in particular, is driving change and development within archaeology at a national and international level. This paper discusses these developments in relation to the author's own research trajectory and discusses the significance of such change

Perspectives on open access high resolution digital elevation models to produce global flood hazard layers

Global flood hazard models have recently become a reality thanks to the release of open access global digital elevation models, the development of simplified and highly efficient flow algorithms, and the steady increase in computational power. In this commentary we argue that although the availability of open access global terrain data has been critical in enabling the development of such models, the relatively poor resolution and precision of these data now limit significantly our ability to estimate flood inundation and risk for the majority of the planet’s surface. The difficulty of deriving an accurate ‘bare-earth’ terrain model due to the interaction of vegetation and urban structures with the satellite-based remote sensors means that global terrain data are often poorest in the areas where people, property (and thus vulnerability) are most concentrated. Furthermore, the current generation of open access global terrain models are over a decade old and many large floodplains, particularly those in developing countries, have undergone significant change in this time. There is therefore a pressing need for a new generation of high resolution and high vertical precision open access global digital elevation models to allow significantly improved global flood hazard models to be developed

Primordial helium recombination III: Thomson scattering, isotope shifts, and cumulative results

Upcoming precision measurements of the temperature anisotropy of the cosmic microwave background (CMB) at high multipoles will need to be complemented by a more complete understanding of recombination, which determines the damping of anisotropies on these scales. This is the third in a series of papers describing an accurate theory of HeI and HeII recombination. Here we describe the effect of Thomson scattering, the $^3$He isotope shift, the contribution of rare decays, collisional processes, and peculiar motion. These effects are found to be negligible: Thomson and $^3$He scattering modify the free electron fraction $x_e$ at the level of several $\times 10^{-4}$. The uncertainty in the $2^3P^o-1^1S$ rate is significant, and for conservative estimates gives uncertainties in $x_e$ of order $10^{-3}$. We describe several convergence tests for the atomic level code and its inputs, derive an overall $C_\ell$ error budget, and relate shifts in $x_e(z)$ to the changes in $C_\ell$, which are at the level of 0.5% at $\ell =3000$. Finally, we summarize the main corrections developed thus far. The remaining uncertainty from known effects is $\sim 0.3$ in $x_e$.Comment: 19 pages, 15 figures, to be submitted to PR

Casein kinase iδ mutations in familial migraine and advanced sleep phase.

Migraine is a common disabling disorder with a significant genetic component, characterized by severe headache and often accompanied by nausea, vomiting, and light sensitivity. We identified two families, each with a distinct missense mutation in the gene encoding casein kinase Iδ (CKIδ), in which the mutation cosegregated with both the presence of migraine and advanced sleep phase. The resulting alterations (T44A and H46R) occurred in the conserved catalytic domain of CKIδ, where they caused reduced enzyme activity. Mice engineered to carry the CKIδ-T44A allele were more sensitive to pain after treatment with the migraine trigger nitroglycerin. CKIδ-T44A mice also exhibited a reduced threshold for cortical spreading depression (believed to be the physiological analog of migraine aura) and greater arterial dilation during cortical spreading depression. Astrocytes from CKIδ-T44A mice showed increased spontaneous and evoked calcium signaling. These genetic, cellular, physiological, and behavioral analyses suggest that decreases in CKIδ activity can contribute to the pathogenesis of migraine

Estimates of present and future flood risk in the conterminous United States

Past attempts to estimate rainfall-driven flood risk across the US either have incomplete coverage, coarse resolution or use overly simplified models of the flooding process. In this paper, we use a new 30m resolution model of the entire conterminous US with a 2D representation of flood physics to produce estimates of flood hazard, which match to within 90% accuracy the skill of local models built with detailed data. These flood depths are combined with exposure datasets of commensurate resolution to calculate current and future flood risk. Our data show that the total US population exposed to serious flooding is 2.6–3.1 times higher than previous estimates, and that nearly 41 million Americans live within the 1% annual exceedance probability floodplain (compared to only 13 million when calculated using FEMA flood maps). We find that population and GDP growth alone are expected to lead to significant future increases in exposure, and this change may be exacerbated in the future by climate change