The Genetics Of Vein Of Galen Malformation And Assessment Of Candidate Genes In Xenopus Tropicalis

The Vein of Galen Malformation (VOGM) is a specific subtype of arteriovenous malformation (AVM) that becomes evident in weeks 6-11 of embryonic development. VOGM comprise less than 1% of all vascular malformations, yet represent 30% of all pediatric intracranial vascular malformations. Depending on their specific characteristics, i.e. its feeding vessels, it can present clinically as devastating congestive heart failure in neonates, hydrocephalus in children, or seizures and headaches in young adults. Advances in treatment provide improved survival, primarily through endovascular surgery. The genetic and molecular etiology of VOGM remains relatively unknown, with the only associated genes being in the context of other syndromes, including seven mutations in p120-RasGAP (RASA1) in Cutaneous Malformations-Arteriovenous Malformations (CM-AVM), as well as one mutation each in activin A receptor type II-like 1 (ACVRL1) mutation and Endoglin (ENG) in Hereditary Hemorraghic Teleangiectasia. Our limited knowledge of the molecular genetics of VOGM has hindered the development of novel therapies. We hypothesized that the apparent sporadic occurrence of VOGM may frequently be attributable to damaging de novo mutation events or incomplete penetrance of rare transmitted variants. Unbiased whole-exome sequencing (WES) can overcome these barriers for gene discovery. We recruited 55 patients, including 52 parent-offspring trios. WES revealed statistically significant rare, damaging de novo mutations in chromatin modifier genes involved in brain and vascular development (p=8.9 x 10-4). VOGM probands also had inherited, missense deleterious and loss of function, in ephrin signaling genes, specifically a whole exome significant mutation burden in EPHB4 (p=7.47 x 10−10). Finally, we observed a whole exome significant inherited mutation in Claudin 14 (p= 6.44 x 10−7). Inherited mutations demonstrated incomplete penetrance and variable expressivity with mutation carriers often exhibiting cutaneous vascular abnormalities suggesting a two-hit mechanism. The identified mutations account for 30% of studied VOGM cases. To functionally validate candidate mutations and establish causality, we developed a screening platform using Xenopus tropicalis by using CRISP/Cas9 gene editing and observing the effects of candidate gene knockdown on vasculogenesis and brain vasculature. CRISPR/Cas9 knockdown of EPHB4 and CLDN14 yielded significantly abnormal vasculogenesis (p=0.0028 and p=0.0001 respectively) observed by in situ hybridization. We implemented and modified established clearing techniques to allow visualization of the full thickness of the Xenopus brain vasculature. The evolutionary precursor to the vein of Galen, the posterior vascular plexus (PVP), and the mesencephalic veins (MSV), were imaged. EPHB4 and CLDN14 CRISPR/Cas9 knockdown revealed significant decreases in MSV length (p Together these findings are the first step in better understanding the mechanism and pathogenesis of VOGM and potential novel therapeutic targets. While Xenopus is not a perfect model system, it does show promise as a tool to assess candidate VOGM that merit further study in mammalian systems harboring a true vein of Galen

The effect of plant traits and resource supply characteristics on plant competition : a mechanistic model

An individual-based, spatially explicit model of herbaceous plants is presented in an attempt to investigate some of the predictions made by the CSR model (Grime 1979) and the Resource Ratio and R* hypotheses (Tilman 1982, 1988). The model simulates early growth of herbaceous individuals and competition between these individuals for light and soil nutrients (nitrogen and phosphorus), along a nutrient gradient. Various model plant species are constructed to investigate the effect of plant traits on competition. High allocation to root is predicted to confer a slight advantage in habitats with low nutrient availability, and conversely high allocation to shoots is predicted to confer a competitive advantage in habitats with high nutrient availability. A plastic response to the availability of resources in the allocation of growth between root and shoot is predicted to confer a competitive advantage in all habitats, though the bias of the plasticity {e.g. consistently greater allocation to root than shoot would be a root bia.sed allocation pattern) may affect this. Growth uncoupled from resource acquisition is predicted to be advantageous in nutrient poor habitats, while growth coupled to resource acquisition is predicted to be advantageous in nutrient rich habitats. Above- and below-ground inter-specific competition along nutrient gradients is examined for these .species. Below-ground competition intensity for a .soil re.source in the absence of light competition is predicted to be higher for a highly mobile resource than for a relatively immobile resource, but competition for light is predicted to be greater for the more mobile resource. Competition intensity for soil nutrients is predicted to be maximal at low nutrient availability, and the intensity of light competition is predicted to be greatest in nutrient rich habitats. The implications for current plant competition theories are discussed

Social encounter networks : characterizing Great Britain

A major goal of infectious disease epidemiology is to understand and predict the spread of infections within human populations, with the intention of better informing decisions regarding control and intervention. However, the development of fully mechanistic models of transmission requires a quantitative understanding of social interactions and collective properties of social networks. We performed a cross-sectional study of the social contacts on given days for more than 5000 respondents in England, Scotland and Wales, through postal and online survey methods. The survey was designed to elicit detailed and previously unreported measures of the immediate social network of participants relevant to infection spread. Here, we describe individual-level contact patterns, focusing on the range of heterogeneity observed and discuss the correlations between contact patterns and other socio-demographic factors. We find that the distribution of the number of contacts approximates a power-law distribution, but postulate that total contact time (which has a shorter-tailed distribution) is more epidemiologically relevant. We observe that children, public-sector and healthcare workers have the highest number of total contact hours and are therefore most likely to catch and transmit infectious disease. Our study also quantifies the transitive connections made between an individual's contacts (or clustering); this is a key structural characteristic of social networks with important implications for disease transmission and control efficacy. Respondents' networks exhibit high levels of clustering, which varies across social settings and increases with duration, frequency of contact and distance from home. Finally, we discuss the implications of these findings for the transmission and control of pathogens spread through close contact

Social encounter networks : collective properties and disease transmission

A fundamental challenge of modern infectious disease epidemiology is to quantify the networks of social and physical contacts through which transmission can occur. Understanding the collective properties of these interactions is critical for both accurate prediction of the spread of infection and determining optimal control measures. However, even the basic properties of such networks are poorly quantified, forcing predictions to be made based on strong assumptions concerning network structure. Here, we report on the results of a large-scale survey of social encounters mainly conducted in Great Britain. First, we characterize the distribution of contacts, which possesses a lognormal body and a power-law tail with an exponent of −2.45; we provide a plausible mechanistic model that captures this form. Analysis of the high level of local clustering of contacts reveals additional structure within the network, implying that social contacts are degree assortative. Finally, we describe the epidemiological implications of this local network structure: these contradict the usual predictions from networks with heavy-tailed degree distributions and contain public-health messages about control. Our findings help us to determine the types of realistic network structure that should be assumed in future population level studies of infection transmission, leading to better interpretations of epidemiological data and more appropriate policy decisions

Photoionization of Galactic Halo Gas by Old Supernova Remnants

We present new calculations on the contribution from cooling hot gas to the photoionization of warm ionized gas in the Galaxy. We show that hot gas in cooling supernova remnants (SNRs) is an important source of photoionization, particularly for gas in the halo. We find that in many regions at high latitude this source is adequate to account for the observed ionization so there is no need to find ways to transport stellar photons from the disk. The flux from cooling SNRs sets a floor on the ionization along any line of sight. Our model flux is also shown to be consistent with the diffuse soft X-ray background and with soft X-ray observations of external galaxies. We consider the ionization of the clouds observed towards the halo star HD 93521, for which there are no O stars close to the line of sight. We show that the observed ionization can be explained successfully by our model EUV/soft X-ray flux from cooling hot gas. In particular, we can match the H alpha intensity, the S++/S+ ratio, and the C+* column. From observations of the ratios of columns of C+* and either S+ or H0, we are able to estimate the thermal pressure in the clouds. The slow clouds require high (~10^4 cm^-3 K) thermal pressures to match the N(C+*)/N(S+) ratio. Additional heating sources are required for the slow clouds to maintain their ~7000 K temperatures at these pressures, as found by Reynolds, Hausen & Tufte (1999).Comment: AASTeX 5.01; 34 pages, 2 figures; submitted to Astrophysical Journa

Gravitational lens recovery with glass: measuring the mass profile and shape of a lens

We use a new non-parametric gravitational modelling tool - glass - to determine what quality of data (strong lensing, stellar kinematics, and/or stellar masses) are required to measure the circularly averaged mass profile of a lens and its shape. glass uses an underconstrained adaptive grid of mass pixels to model the lens, searching through thousands of models to marginalize over model uncertainties. Our key findings are as follows: (i) for pure lens data, multiple sources with wide redshift separation give the strongest constraints as this breaks the well-known mass-sheet or steepness degeneracy; (ii) a single quad with time delays also performs well, giving a good recovery of both the mass profile and its shape; (iii) stellar masses - for lenses where the stars dominate the central potential - can also break the steepness degeneracy, giving a recovery for doubles almost as good as having a quad with time-delay data, or multiple source redshifts; (iv) stellar kinematics provide a robust measure of the mass at the half-light radius of the stars r1/2 that can also break the steepness degeneracy if the Einstein radius rE ≠ r1/2; and (v) if rE∼r1/2, then stellar kinematic data can be used to probe the stellar velocity anisotropy β - an interesting quantity in its own right. Where information on the mass distribution from lensing and/or other probes becomes redundant, this opens up the possibility of using strong lensing to constrain cosmological model

Light versus dark in strong-lens galaxies: Dark matter haloes that are rounder than their stars

We measure the projected density profile, shape and alignment of the stellar and dark matter mass distribution in 11 strong-lens galaxies. We find that the projected dark matter density profile - under the assumption of a Chabrier stellar initial mass function - shows significant variation from galaxy to galaxy. Those with an outermost image beyond $\sim 10$ kpc are very well fit by a projected NFW profile; those with images within 10 kpc appear to be more concentrated than NFW, as expected if their dark haloes contract due to baryonic cooling. We find that over several half-light radii, the dark matter haloes of these lenses are rounder than their stellar mass distributions. While the haloes are never more elliptical than $e_{dm} = 0.2$, their stars can extend to $e_* > 0.2$. Galaxies with high dark matter ellipticity and weak external shear show strong alignment between light and dark; those with strong shear ($\gamma \gtrsim 0.1$) can be highly misaligned. This is reassuring since isolated misaligned galaxies are expected to be unstable. Our results provide a new constraint on galaxy formation models. For a given cosmology, these must explain the origin of both very round dark matter haloes and misaligned strong-lens systems.Comment: 16 pages, 7 figures, 4 tables. Accepted for publication by MNRA

Modelling the impact of social mixing and behaviour on infectious disease transmission: application to SARS-CoV-2

In regard to infectious diseases socioeconomic determinants are strongly associated with differential exposure and susceptibility however they are seldom accounted for by standard compartmental infectious disease models. These associations are explored here with a novel compartmental infectious disease model which, stratified by deprivation and age, accounts for population-level behaviour including social mixing patterns. As an exemplar using a fully Bayesian approach our model is fitted, in real-time if required, to the UKHSA COVID-19 community testing case data from England. Metrics including reproduction number and forecasts of daily case incidence are estimated from the posterior samples. From this UKHSA dataset it is observed that during the initial period of the pandemic the most deprived groups reported the most cases however this trend reversed after the summer of 2021. Forward simulation experiments based on the fitted model demonstrate that this reversal can be accounted for by differential changes in population level behaviours including social mixing and testing behaviour, but it is not explained by the depletion of susceptible individuals. In future epidemics, with a focus on socioeconomic factors the approach outlined here provides the possibility of identifying those groups most at risk with a view to helping policy-makers better target their support.Comment: Main article: 25 pages, 6 figures. Appendix 2 pages, 1 figure. Supplementary Material: 15 pages, 14 figures. Version 2 - minor updates: fixed typos, updated mathematical notation and small quantity of descriptive text added. Version 3 - minor update: made colour coding consistent across all time series figure