The genetic basis of multiple sclerosis: a model for MS susceptibility

<p>Abstact</p> <p>Background</p> <p>MS-pathogenesis is known to involve both multiple environmental events, and several independent genetic risk-factors.</p> <p>Methods</p> <p>A model of susceptibility is developed and a mathematical analysis undertaken to elucidate the nature of genetic susceptibility to MS and to understand the constraints that are placed on the genetic basis of MS, both by the known epidemiological facts of this disease and by the known frequency of the HLA DRB1*1501 allele in the general populations of northern Europe and North America.</p> <p>Results</p> <p>For the large majority of cases (possibly all), MS develops, in part, because an individual is genetically susceptible. Nevertheless, 2.2% or less of the general population is genetically susceptible. Moreover, from the model, the number of susceptibility-loci that need to be in a "susceptible allelic state" to produce MS-susceptibility is small (11-18), whereas the total number of such susceptibility-loci is large (50-200), and their "frequency of susceptibility" is low (i.e., ≤ 0.12). The optimal solution to the model equations (which occurs when 80% of the loci are recessive) predicts the epidemiological data quite closely.</p> <p>Conclusions</p> <p>The model suggests that combinations of only a small number of genetic loci in a "susceptible allelic state" produce MS-susceptibility. Nevertheless, genome-wide associations studies with hundreds of thousands of SNPs, are plagued by both false-positive and false-negative identifications and, consequently, emphasis has been rightly placed on the replicability of findings. Nevertheless, because genome-wide screens don't distinguish between true susceptibility-loci and disease-modifying-loci, and because only true susceptibility-loci are constrained by the model, unraveling the two will not be possible using this approach.</p> <p>The model also suggests that HLA DRB1 may not be as uniquely important for MS-susceptibility as currently believed. Thus, this allele is only one among a hundred or more loci involved in MS susceptibility. Even though the "frequency of susceptibility" at the HLA DRB1 locus is four-fold that of other loci, the penetrance of those susceptible genotypes that include this allele is no different from those that don't. Also, almost 50% of genetically-susceptible individuals, lack this allele. Moreover, of those who have it, only a small fraction (≤ 5.2%) are even susceptible to getting MS.</p

Scintillator-based ion beam profiler for diagnosing laser-accelerated ion beams

Next generation intense, short-pulse laser facilities require new high repetition rate diagnostics for the detection of ionizing radiation. We have designed a new scintillator-based ion beam profiler capable of measuring the ion beam transverse profile for a number of discrete energy ranges. The optical response and emission characteristics of four common plastic scintillators has been investigated for a range of proton energies and fluxes. The scintillator light output (for 1 MeV > Ep < 28 MeV) was found to have a non-linear scaling with proton energy but a linear response to incident flux. Initial measurements with a prototype diagnostic have been successful, although further calibration work is required to characterize the total system response and limitations under the high flux, short pulse duration conditions of a typical high intensity laser-plasma interaction

Substrate Induced Strain Field in FeRh Epilayers Grown on Single Crystal MgO (001) Substrates

Equi-atomic FeRh is highly unusual in that it undergoes a first order meta-magnetic phase transition from an antiferromagnet to a ferromagnet above room temperature (Tr ≈ 370 K). This behavior opens new possibilities for creating multifunctional magnetic and spintronic devices which can utilise both thermal and applied field energy to change state and functionalise composites. A key requirement in realising multifunctional devices is the need to understand and control the properties of FeRh in the extreme thin film limit (tFeRh < 10 nm) where interfaces are crucial. Here we determine the properties of FeRh films in the thickness range 2.5–10 nm grown directly on MgO substrates. Our magnetometry and structural measurements show that a perpendicular strain field exists in these thin films which results in an increase in the phase transition temperature as thickness is reduced. Modelling using a spin dynamics approach supports the experimental observations demonstrating the critical role of the atomic layers close to the MgO interface

Climate Change, Foodborne Pathogens, and Illness in Higher Income Countries

Purpose of review: We present a review of the likely consequences of climate change for foodborne pathogens and associated human illness in higher income countries. Recent findings: The relationships between climate and food are complex and hence the impacts of climate change uncertain. This makes it difficult to know which foodborne pathogens will be most affected, what the specific effects will be, and on what timescales changes might occur. Hence, a focus upon current capacity and adaptation potential against foodborne pathogens is essential. We highlight a number of developments that may enhance preparedness for climate change. These include: • Adoption of novel surveillance methods, such as syndromic methods, to speed up detection and increase the fidelity of intervention in foodborne outbreaks • Genotype based approaches to surveillance of food pathogens to enhance spatio-temporal resolution in tracing and tracking of illness • Ever increasing integration of plant, animal and human surveillance systems, one-health, to maximize potential for identifying threats • Increased commitment to cross-border (global) information initiatives (including big data) • Improved clarity regarding the governance of complex societal issues such as the conflict between food safety and food waste • Strong user centric (social) communications strategies to engage diverse stakeholder groups Summary: The impact of climate change upon foodborne pathogens and associated illness is uncertain. This emphasises the need to enhance current capacity and adaptation potential against foodborne illness. A range of developments are explored in this paper to enhance preparedness

Do Gene Variants Influencing Adult Adiposity Affect Birth Weight? A Population-Based Study of 24 Loci in 4,744 Danish Individuals

Several obesity risk alleles affecting adult adiposity have been identified by the recent wave of genome wide association studies. We aimed to examine the potential effect of these variants on fetal body composition by investigating the variants in relation to birth weight and ponderal index of the newborn.Midwife records from the Danish State Archives provided information on mother's age, parity, as well as birth weight, birth length and prematurity of the newborn in 4,744 individuals of the population-based Inter99 study. Twenty-four risk alleles showing genome-wide associations with adult BMI and/or waist circumference were genotyped. None of the 24 risk variants tested showed an association with birth weight or ponderal index after correction for multiple testing. Birth weight was divided into three categories low (≤10(th) percentile), normal (10(th)-90(th) percentile) and high birth weight (≥90th percentile) to allow for non-linear associations. There was no difference in the number of risk alleles between the groups (p = 0.57). No interactions between each risk allele and birth weight in the prediction of adult BMI were observed. An obesity risk score was created by summing up risk alleles. The risk score did not associate with fetal body composition. Moreover there was no interaction between the risk score and birth weight/ponderal index in the prediction of adult BMI.24 common variants associated with adult adiposity did not affect or interact with birth weight among Danes suggesting that the effects of these variants predominantly arise in the post-natal life

Dealing with Food and Eggs in Mouthbrooding Cichlids: Structural and Functional Trade-Offs in Fitness Related Traits

As in any vertebrate, heads of fishes are densely packed with functions. These functions often impose conflicting mechanical demands resulting in trade-offs in the species-specific phenotype. When phenotypical traits are linked to gender-specific parental behavior, we expect sexual differences in these trade-offs. This study aims to use mouthbrooding cichlids as an example to test hypotheses on evolutionary trade-offs between intricately linked traits that affect different aspects of fitness. We focused on the oral apparatus, which is not only equipped with features used to feed and breathe, but is also used for the incubation of eggs. We used this approach to study mouthbrooding as part of an integrated functional system with diverging performance requirements and to explore gender-specific selective environments within a species.Because cichlids are morphologically very diverse, we hypothesize that the implications of the added constraint of mouthbrooding will primarily depend on the dominant mode of feeding of the studied species. To test this, we compared the trade-off for two maternal mouthbrooding cichlid species: a "suction feeder" (Haplochromis piceatus) and a "biter" (H. fischeri). The comparison of morphology and performance of both species revealed clear interspecific and intersex differences. Our observation that females have larger heads was interpreted as a possible consequence of the fact that in both the studied species mouthbrooding is done by females only. As hypothesized, the observed sexual dimorphism in head shape is inferred as being suboptimal for some aspects of the feeding performance in each of the studied species. Our comparison also demonstrated that the suction feeding species had smaller egg clutches and more elongated eggs.Our findings support the hypothesis that there is a trade-off between mouthbrooding and feeding performance in the two studied haplochromine cichlids, stressing the importance of including species-specific information at the gender level when addressing interspecific functional/morphological differences

The Causal Cascade to Multiple Sclerosis: A Model for MS Pathogenesis

BACKGROUND: MS pathogenesis seems to involve both genetic susceptibility and environmental risk factors. Three sequential factors are implicated in the environmental risk. The first acts near birth, the second acts during childhood, and the third acts long thereafter. Two candidate factors (vitamin D deficiency and Epstein-Barr viral infection) seem well suited to the first two environmental events. METHODOLOGY/PRINCIPAL FINDINGS: A mathematical Model for MS pathogenesis is developed, incorporating these environmental and genetic factors into a causal scheme that can explain some of the recent changes in MS-epidemiology (e.g., increasing disease prevalence, a changing sex-ratio, and regional variations in monozygotic twin concordance rates). CONCLUSIONS/SIGNIFICANCE: This Model suggests that genetic susceptibility is overwhelmingly the most important determinant of MS pathogenesis. Indeed, over 99% of individuals seem genetically incapable of developing MS, regardless of what environmental exposures they experience. Nevertheless, the contribution of specific genes to MS-susceptibility seems only modest. Thus, despite HLA DRB1*1501 being the most consistently identified genetic marker of MS-susceptibility (being present in over 50% of northern MS patient populations), only about 1% of individuals with this allele are even genetically susceptible to getting MS. Moreover, because genetic susceptibility seems so similar throughout North America and Europe, environmental differences principally determine the regional variations in disease characteristics. Additionally, despite 75% of MS-patients being women, men are 60% more likely to be genetically-susceptible than women. Also, men develop MS at lower levels of environmental exposure than women. Nevertheless, women are more responsive to the recent changes in environmental-exposure (whatever these have been). This explains both the changing sex-ratio and the increasing disease prevalence (which has increased by a minimum of 32% in Canada over the past 35 years). As noted, environmental risk seems to result from three sequential components of environmental exposure. The potential importance of this Model for MS pathogenesis is that, if correct, a therapeutic strategy, designed to interrupt one or more of these sequential factors, has the potential to markedly reduce or eliminate disease prevalence in the future

Postcolonial manifestations of African spatiality in Europe : the invisible 'public' spaces of Ghent

The focus of this chapter is on everyday spaces of African migration in the mid-sized city of Ghent. One manifestation of African spatiality is discussed in-depth in relation to its (in)visibility and publicity: an African shop located in an ordinary terraced house. With no less than 12 activities taking place in the building, the shop is rather a “public” place than solely a space of commercial transactions, although this is not signaled in very visible ways. By analyzing the modest stylistic appropriations of the façade and the significant re-arrangements of the buildings’ interior spaces that challenge more conventional usages of spaces in Ghent’s ordinary houses, this chapter puts this African shop to the fore as emblematic of how the process of materialization of transnational lifestyles and connections is always a balancing act between the visibility necessary for functioning as a (semi-)pubic place and the invisibility required to circumvent hegemonic regulatory regimes

A Differential Role for Macropinocytosis in Mediating Entry of the Two Forms of Vaccinia Virus into Dendritic Cells

Vaccinia virus (VACV) is being developed as a recombinant viral vaccine vector for several key pathogens. Dendritic cells (DCs) are specialised antigen presenting cells that are crucial for the initiation of primary immune responses; however, the mechanisms of uptake of VACV by these cells are unclear. Therefore we examined the binding and entry of both the intracellular mature virus (MV) and extracellular enveloped virus (EV) forms of VACV into vesicular compartments of monocyte-derived DCs. Using a panel of inhibitors, flow cytometry and confocal microscopy we have shown that neither MV nor EV binds to the highly expressed C-type lectin receptors on DCs that are responsible for capturing many other viruses. We also found that both forms of VACV enter DCs via a clathrin-, caveolin-, flotillin- and dynamin-independent pathway that is dependent on actin, intracellular calcium and host-cell cholesterol. Both MV and EV entry were inhibited by the macropinocytosis inhibitors rottlerin and dimethyl amiloride and depended on phosphotidylinositol-3-kinase (PI(3)K), and both colocalised with dextran but not transferrin. VACV was not delivered to the classical endolysosomal pathway, failing to colocalise with EEA1 or Lamp2. Finally, expression of early viral genes was not affected by bafilomycin A, indicating that the virus does not depend on low pH to deliver cores to the cytoplasm. From these collective results we conclude that VACV enters DCs via macropinocytosis. However, MV was consistently less sensitive to inhibition and is likely to utilise at least one other entry pathway. Definition and future manipulation of these pathways may assist in enhancing the activity of recombinant vaccinia vectors through effects on antigen presentation

A pig model of acute Staphylococcus aureus induced pyemia

<p>Abstract</p> <p>Background</p> <p>Sepsis caused by <it>Staphylococcus aureus </it>constitutes an important cause of morbidity and mortality in humans, and the incidence of this disease-entity is increasing. In this paper we describe the initial microbial dynamics and lesions in pigs experimentally infected with <it>S. aureus</it>, with the aim of mimicking human sepsis and pyemia.</p> <p>Methods</p> <p>The study was conducted in anaesthetized and intravenously inoculated pigs, and was based on bacteriological examination of blood and testing of blood for IL-6 and C-reactive protein. Following killing of the animals and necropsy bacteriological and histological examinations of different organs were performed 4, 5 or 6 h after inoculation.</p> <p>Results</p> <p>Clearance of bacteria from the blood was completed within the first 2 h in some of the pigs and the highest bacterial load was recorded in the lungs as compared to the spleen, liver and bones. This probably was a consequence of both the intravenous route of inoculation and the presence of pulmonary intravascular macrophages. Inoculation of bacteria induced formation of acute microabscesses in the lungs, spleen and liver, but not in the kidneys or bones. No generalized inflammatory response was recorded, i.e. IL-6 was not detected in the blood and C-reactive protein did not increase, probably because of the short time course of the study.</p> <p>Conclusion</p> <p>This study demonstrates the successful induction of acute pyemia (microabscesses), and forms a basis for future experiments that should include inoculation with strains of <it>S. aureus </it>isolated from man and an extension of the timeframe aiming at inducing sepsis, severe sepsis and septic shock.</p