The relationship between fetal growth and retinal nerve fiber layer thickness in a cohort of young adults

Purpose: To explore relationships between patterns of fetal anthropometric growth, as reflective of fetal wellbeing, and global retinal nerve fiber layer (RNFL) thickness measured in young adulthood. Methods: Participants (n = 481) from within a Western Australian pregnancy cohort study underwent five serial ultrasound scans during gestation, with fetal biometry measured at each scan. Optic disc parameters were measured via spectral-domain optical coherence tomography imaging at a 20-year follow-up eye examination. Generalized estimating equations were used to evaluate differences in global RNFL thickness between groups of participants who had undergone similar growth trajectories based on fetal head circumference (FHC), abdominal circumference (FAC), femur length (FFL), and estimated fetal weight (EFW). Results: Participants with consistently large FHCs throughout gestation had significantly thicker global RNFLs than those with any other pattern of FHC growth (P = 0.023), even after adjustment for potential confounders (P = 0.037). Based on model fit statistics, FHC growth trajectory was a better predictor of global RNFL thickness than birth weight or head circumference at birth. RNFL thickness did not vary significantly between groups of participants with different growth trajectories based on FAC, FFL, or EFW. Conclusions: FHC growth is associated with RNFL thickness in young adulthood and, moreover, is a better predictor than either birth weight or head circumference at birth. Translational Relevance: This research demonstrates an association between intrauterine growth and long-term optic nerve health, providing a basis for further exploring the extent of the influence of fetal wellbeing on clinical conditions linked to RNFL thinning

Construction of repeat-free fluorescence in situ hybridization probes

FISH probes are generally made out of BAC clones with genomic DNA containing a variable amount of repetitive DNA that will need to be removed or blocked for FISH analysis. To generate repeat free (RF) Probes without loss in genomic coverage, a random library is made from BAC clones by whole-genome amplification (WGA). Libraries are denatured in the presence of excess C0t-1 DNA and allowed to re-anneal followed by digestion of all double-stranded elements by duplex-specific nuclease (DSN). Selective amplification of all elements not containing repetitive sequences is realized by a sequential amplification. The final RF products can be re-amplified and used as a stock for future probe production. The RF probes have a lower background, the signal intensity build up is faster and there is no need for blocking DNA. The signal to background ratio of the RF was higher as compared to repeat containing probes

Review article: MHD wave propagation near coronal null points of magnetic fields

We present a comprehensive review of MHD wave behaviour in the neighbourhood of coronal null points: locations where the magnetic field, and hence the local Alfven speed, is zero. The behaviour of all three MHD wave modes, i.e. the Alfven wave and the fast and slow magnetoacoustic waves, has been investigated in the neighbourhood of 2D, 2.5D and (to a certain extent) 3D magnetic null points, for a variety of assumptions, configurations and geometries. In general, it is found that the fast magnetoacoustic wave behaviour is dictated by the Alfven-speed profile. In a $\beta=0$ plasma, the fast wave is focused towards the null point by a refraction effect and all the wave energy, and thus current density, accumulates close to the null point. Thus, null points will be locations for preferential heating by fast waves. Independently, the Alfven wave is found to propagate along magnetic fieldlines and is confined to the fieldlines it is generated on. As the wave approaches the null point, it spreads out due to the diverging fieldlines. Eventually, the Alfven wave accumulates along the separatrices (in 2D) or along the spine or fan-plane (in 3D). Hence, Alfven wave energy will be preferentially dissipated at these locations. It is clear that the magnetic field plays a fundamental role in the propagation and properties of MHD waves in the neighbourhood of coronal null points. This topic is a fundamental plasma process and results so far have also lead to critical insights into reconnection, mode-coupling, quasi-periodic pulsations and phase-mixing.Comment: 34 pages, 5 figures, invited review in Space Science Reviews => Note this is a 2011 paper, not a 2010 pape

Rare variants in optic disc area gene CARD10 enriched in primary open-angle glaucoma

Background: Genome-wide association studies (GWAS) have identified association of common alleles with primary open-angle glaucoma (POAG) and its quantitative endophenotypes near numerous genes. This study aims to determine whether rare pathogenic variants in these disease-associated genes contribute to POAG. Methods: Participants fulfilled strict inclusion criteria of advanced POAG at a young age of diagnosis. Myocilin mutation carriers were excluded using direct sequencing. Whole exome sequencing was performed on 187 glaucoma cases and 103 local screened nonglaucoma controls then joint-called with exomes of 993 previously sequenced Australian controls. GWAS-associated genes were assessed for enrichment of rare predicted pathogenic variants in POAG. Significantly enriched genes were compared against Exome Aggregation Consortium (ExAC) public control. Results: Eighty-six GWAS disease or trait-associated glaucoma genes were captured and sequenced. CARD10 showed enrichment after Bonferroni correction for rare variants in glaucoma cases (OR = 13.2, P = 6.94 × 10−5) with mutations identified in 4.28% of our POAG cohort compared to 0.27% in controls. CARD10 was significantly associated with optic disc parameters in previous GWAS. The whole GWAS gene set showed no enrichment in POAG overall (OR = 1.12, P = 0.51). Conclusion: We report here an enrichment of rare predicted pathogenic coding variants within a GWAS-associated locus in POAG (CARD10). These findings indicate that both common and rare pathogenic coding variants in CARD10 may contribute to POAG pathogenesis.Tiger Zhou, Emmanuelle Souzeau, Shiwani Sharma, Owen M. Siggs, Ivan Goldberg, Paul R. Healey, Stuart Graham, Alex W. Hewitt, David A. Mackey, Robert J. Casson, John Landers, Richard Mills, Jonathan Ellis, Paul Leo, Matthew A. Brown, Stuart MacGregor, Kathryn P. Burdon and Jamie E. Crai

3D MHD Coronal Oscillations About a Magnetic Null Point: Application of WKB Theory

This paper is a demonstration of how the WKB approximation can be used to help solve the linearised 3D MHD equations. Using Charpit's Method and a Runge-Kutta numerical scheme, we have demonstrated this technique for a potential 3D magnetic null point, ${\bf{B}}=(x,\epsilon y -(\epsilon +1)z)$. Under our cold plasma assumption, we have considered two types of wave propagation: fast magnetoacoustic and Alfv\'en waves. We find that the fast magnetoacoustic wave experiences refraction towards the magnetic null point, and that the effect of this refraction depends upon the Alfv\'en speed profile. The wave, and thus the wave energy, accumulates at the null point. We have found that current build up is exponential and the exponent is dependent upon $\epsilon$. Thus, for the fast wave there is preferential heating at the null point. For the Alfv\'en wave, we find that the wave propagates along the fieldlines. For an Alfv\'en wave generated along the fan-plane, the wave accumulates along the spine. For an Alfv\'en wave generated across the spine, the value of $\epsilon$ determines where the wave accumulation will occur: fan-plane ($\epsilon=1$), along the $x-$axis ($0<\epsilon <1$) or along the $y-$axis ($\epsilon>1$). We have shown analytically that currents build up exponentially, leading to preferential heating in these areas. The work described here highlights the importance of understanding the magnetic topology of the coronal magnetic field for the location of wave heating.Comment: 26 pages, 12 figure

A glaucoma polygenic risk score strongly associated with disease prediction and treatment intensity

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.Jamie E Craig; Ayub Qassim; Xikun Han; Mark Hassall; Robert James Casson; Stuart L Graham; David A Mackey; Colin Willoughby; Kathryn P Burdon; John Landers; Emmanuelle Souzeau; Janey L Wiggs; Alex W Hewitt; Stuart MacGrego

ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure

Primary open-angle glaucoma (POAG) is a blinding disease. Two important risk factors for this disease are a positive family history and elevated intraocular pressure (IOP), which is also highly heritable. Genes found to date associated with IOP and POAG are ABCA1, CAV1/CAV2, GAS7 and TMCO1. However, these genes explain only a small part of the heritability of IOP and POAG.We performed a genome-wide association study of IOP in the population-based RotterdamStudy I and Rotterdam Study II using single nucleotide polymorphisms (SNPs) imputed to 1000 Genomes. In this discovery cohort (n = 8105), we identified a newlocus associated with IOP. The most significantly associated SNPwas rs58073046 (ß = 0.44, P-value = 1.87 × 10-8, minor allele frequency = 0.12), within the gene ARHGEF12. Independent replication in five population-based studies (n = 7471) resulted in an effect size in the same direction that was significantly associated (ß = 0.16, P-value = 0.04). The SNP was also significantly associated with POAG in two independent case-control studies [n = 1225 cases and n = 4117 controls; odds ratio (OR) = 1.53, P-value = 1.99 × 10-8], especially with high-tension glaucoma (OR = 1.66, P-value = 2.81 × 10-9; for normal-tension glaucoma OR = 1.29, P-value = 4.23 × 10-2). ARHGEF12 plays an important role in the RhoA/RhoA kinase pathway, which has been implicated in IOP regulation. Furthermore, it binds to ABCA1 and links the ABCA1, CAV1/CAV2 and GAS7 pathway to Mendelian POAG genes (MYOC, OPTN, WDR36). In conclusion, this study identified a novel association between IOP and ARHGEF12

High polygenic risk is associated with earlier treatment initiation and escalation in glaucoma suspects

Abstract #A0360Henry Marshall, Xikun Han, Sean Mullany, Georgie Hollitt, Ella Claire Berry, Lachlan Knight, Richard A Mills, John Landers, Paul Healey, Alex W Hewitt, Stuart L Graham, Robert Casson, Stuart MacGregor, Owen Siggs, Jamie E Crai

A polygenic risk score predicts functional progression in early primary open-angle glaucoma

Abstract #A0353Owen Siggs, Ayub Qassim, Xikun Han, Henry Marshall, Sean Mullany, Emmanuelle Souzeau, Anna Galanopoulos, Ashish Agar, John Landers, Robert Casson, Alex W Hewitt, Paul Healey, Stuart L Graham, Stuart MacGregor, Jamie Crai

Lineage-specific compaction of Tcrb requires a chromatin barrier to protect the function of a long-range tethering element

Gene regulation relies on dynamic changes in three-dimensional chromatin conformation, which are shaped by composite regulatory and architectural elements. However, mechanisms that govern such conformational switches within chromosomal domains remain unknown. We identify a novel mechanism by which cis-elements promote long-range interactions, inducing conformational changes critical for diversification of the TCRβ antigen receptor locus (Tcrb). Association between distal Vβ gene segments and the highly expressed DβJβ clusters, termed the recombination center (RC), is independent of enhancer function and recruitment of V(D)J recombinase. Instead, we find that tissue-specific folding of Tcrb relies on two distinct architectural elements located upstream of the RC. The first, a CTCF-containing element, directly tethers distal portions of the Vβ array to the RC. The second element is a chromatin barrier that protects the tether from hyperactive RC chromatin. When the second element is removed, active RC chromatin spreads upstream, forcing the tether to serve as a new barrier. Acquisition of barrier function by the CTCF element disrupts contacts between distal Vβ gene segments and significantly alters Tcrb repertoires. Our findings reveal a separation of function for RC-flanking regions, in which anchors for long-range recombination must be cordoned off from hyperactive RC landscapes by chromatin barriers