Combined analysis of three whole genome linkage scans for Ankylosing Spondylitis

Objective. Ankylosing spondylitis (AS) is a debilitating chronic inflammatory condition with a high degree of familiality (λs=82) and heritability (>90%) that primarily affects spinal and sacroiliac joints. Whole genome scans for linkage to AS phenotypes have been conducted, although results have been inconsistent between studies and all have had modest sample sizes. One potential solution to these issues is to combine data from multiple studies in a retrospective meta-analysis. Methods: The International Genetics of Ankylosing Spondylitis Consortium combined data from three whole genome linkage scans for AS (n=3744 subjects) to determine chromosomal markers that show evidence of linkage with disease. Linkage markers typed in different centres were integrated into a consensus map to facilitate effective data pooling. We performed a weighted meta-analysis to combine the linkage results, and compared them with the three individual scans and a combined pooled scan. Results: In addition to the expected region surrounding the HLA-B27 gene on chromosome 6, we determined that several marker regions showed significant evidence of linkage with disease status. Regions on chromosome 10q and 16q achieved 'suggestive' evidence of linkage, and regions on chromosomes 1q, 3q, 5q, 6q, 9q, 17q and 19q showed at least nominal linkage in two or more scans and in the weighted meta-analysis. Regions previously associated with AS on chromosome 2q (the IL-1 gene cluster) and 22q (CYP2D6) exhibited nominal linkage in the meta-analysis, providing further statistical support for their involvement in susceptibility to AS. Conclusion: These findings provide a useful guide for future studies aiming to identify the genes involved in this highly heritable condition. . Published by on behalf of the British Society for Rheumatology.

Risk analysis of prostate cancer in PRACTICAL, a multinational consortium, using 25 known prostate cancer susceptibility loci

Background Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer. Methods We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS).We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived agespecific absolute risks of developing prostate cancer by PRS stratum and family history. Results The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4-57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2-5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09). Conclusions Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. Impact:We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs.

Association between biomechanical structural stresses of atherosclerotic carotid plaques and subsequent ischaemic cerebrovascular events - A longitudinal in vivo magnetic resonance imaging-based finite element study

Background: High-resolution magnetic resonance (MR) imaging has been used for MR imaging-based structural stress analysis of atherosclerotic plaques. The biomechanical stress profile of stable plaques has been observed to differ from that of unstable plaques; however, the role that structural stresses play in determining plaque vulnerability remains speculative. Methods: A total of 61 patients with previous history of symptomatic carotid artery disease underwent carotid plaque MR imaging. Plaque components of the index artery such as fibrous tissue, lipid content and plaque haemorrhage (PH) were delineated and used for finite element analysis-based maximum structural stress (M-C Stress) quantification. These patients were followed up for 2 years. The clinical end point was occurrence of an ischaemic cerebrovascular event. The association of the time to the clinical end point with plaque morphology and M-C Stress was analysed. Results: During a median follow-up duration of 514 days, 20% of patients (n=12) experienced an ischaemic event in the territory of the index carotid artery. Cox regression analysis indicated that M-C Stress (hazard ratio (HR): 12.98 (95% confidence interval (CI): 1.32-26.67, pZ0.02), fibrous cap (FC) disruption (HR: 7.39 (95% CI: 1.61e33.82), p Z 0.009) and PH (HR: 5.85 (95% CI: 1.27e26.77), p Z 0.02) are associated with the development of subsequent cerebrovascular events. Plaques associated with future events had higher M-C Stress than those which had remained asymptomatic (median (interquartile range, IQR): 330 kPa (229e494) vs. 254 kPa (166-290), p Z0.04). Conclusions: High biomechanical structural stresses, in addition to FC rupture and PH, are associated with subsequent cerebrovascular events.

Selective herbicide strategies for use in Australian desmanthus seed crops

Grass and broad-leaved weeds can reduce both yields and product marketability of desmanthus (Desmanthus virgatus) seed crops, even when cultural control strategies are used. Selective herbicides might economically control these weeds, but, prior to this study, the few herbicides tolerated by desmanthus did not control key weed contaminants of desmanthus seed crops. In this study, the tolerance of desmanthus cv. Marc to 55 herbicides used for selective weed control in other leguminous crops was assessed in 1 pot trial and 3 Queensland field trials. One field trial assessed the tolerance of desmanthus seedlings to combinations of the most promising pre-emergent and post emergent herbicides. The pre-emergent herbicides, imazaquin, imazethapyr, pendimethalin, oryzalin and trifluralin, gave useful weed control with very little crop damage. The post-emergent herbicides, haloxyfop, clethodim, propyzamide, carbetamide and dalapon, were safe for controlling grass weeds in desmanthus. Selective post-emergence control of broad-leaved weeds was achieved using bentazone, bromoxynil and imazethapyr. One trial investigated salvaging second-year desmanthus crops from mature perennial weeds, and atrazine, terbacil and hexazinone showed some potential in this role. Overall, our results show that desmanthus tolerates herbicides which collectively control a wide range of weeds encountered in Queensland. These, in combination with cultural weed control strategies, should control most weeds in desmanthus seed crops.

Runoff, sediment loss and water quality from forest roads in a southeast Queensland coastal plain Pinus plantation

Runoff and sediment loss from forest roads were monitored for a two-year period in a Pinus plantation in southeast Queensland. Two classes of road were investigated: a gravelled road, which is used as a primary daily haulage route for the logging area, and an ungravelled road, which provides the main access route for individual logging compartments and is intensively used as a haulage route only during the harvest of these areas (approximately every 30 years). Both roads were subjected to routine traffic loads and maintenance during the study. Surface runoff in response to natural rainfall was measured and samples taken for the determination of sediment and nutrient (total nitrogen, total phosphorus, dissolved organic carbon and total iron) loads from each road. Results revealed that the mean runoff coefficient (runoff depth/rainfall depth) was consistently higher from the gravelled road plot with 0.57, as compared to the ungravelled road with 0.38. Total sediment loss over the two-year period was greatest from the gravelled road plot at 5.7 t km−1 compared to the ungravelled road plot with 3.9 t km−1. Suspended solids contributed 86% of the total sediment loss from the gravelled road, and 72% from the ungravelled road over the two years. Nitrogen loads from the two roads were both relatively constant throughout the study, and averaged 5.2 and 2.9 kg km−1 from the gravelled and ungravelled road, respectively. Mean annual phosphorus loads were 0.6 kg km−1 from the gravelled road and 0.2 kg km−1 from the ungravelled road. Organic carbon and total iron loads increased in the second year of the study, which was a much wetter year, and are thought to reflect the breakdown of organic matter in roadside drains and increased sediment generation, respectively. When road and drain maintenance (grading) was performed runoff and sediment loss were increased from both road types. Additionally, the breakdown of the gravel road base due to high traffic intensity during wet conditions resulted in the formation of deep (10 cm) ruts which increased erosion. The Water Erosion Prediction Project (WEPP):Road model was used to compare predicted to observed runoff and sediment loss from the two road classes investigated. For individual rainfall events, WEPP:Road predicted output showed strong agreement with observed values of runoff and sediment loss. WEPP:Road predictions for annual sediment loss from the entire forestry road network in the study area also showed reasonable agreement with the extrapolated observed values.

Sediment and nutrient losses from exotic Pinus plantation management operations under simulated rainfall

Rainfall simulation experiments were carried out to measure runoff and soil water fluxes of suspended solids, total nitrogen, total phosphorus, dissolved organic carbon and total iron from sites in Pinus plantations on the coastal lowlands of south-eastern Queensland subjected to various operations (treatments). The operations investigated were cultivated and nil-cultivated site preparation, fertilised site preparation, clearfall harvesting and prescribed burning; these treatments were compared with an 8-y-old established plantation. Flow-weighted mean concentrations of total nitrogen and total phosphorus in surface runoff from the cultivated and nil-cultivated site-preparation, clearfall harvest, prescribed burning and 8-y-old established plantation treatments were very similar. However, both the soil water and the runoff from the fertilised site preparation treatment contained more nitrogen (N) and phosphorus (P) than the other treatments - with 3.10 mg N L-1 and 4.32 mg P L-1 (4 and 20 times more) in the runoff. Dissolved organic carbon concentrations in runoff from the nil-cultivated site-preparation and prescribed burn treatments were elevated. Iron concentrations were highest in runoff from the nil-cultivated site-preparation and 8-y-old established plantation treatments. Concentrations of suspended solids in runoff were higher from cultivated site preparation and prescribed burn treatments, and reflect the great disturbance of surface soil at these sites. The concentrations of all analytes were highest in initial runoff from plots, and generally decreased with time. Total nitrogen (mean 7.28, range 0.11-13.27 mg L-1) and total phosphorus (mean 11.60, range 0.06-83.99 mg L-1) concentrations in soil water were between 2 and 10 times greater than in surface runoff, which highlights the potential for nutrient fluxes in interflow (i.e. in the soil above the water table) through the general plantation area. Implications in regard to forest management are discussed, along with results of larger catchment-scale studies.

Pasteurella multocida Expresses Two Lipopolysaccharide Glycoforms Simultaneously, but Only a Single Form Is Required for Virulence: Identification of Two Acceptor-Specific Heptosyl I Transferases

Lipopolysaccharide (LPS) is a critical virulence determinant in Pasteurella multocida and a major antigen responsible for host protective immunity. In other mucosal pathogens, variation in LPS or lipooligosaccharide structure typically occurs in the outer core oligosaccharide regions due to phase variation. P. multocida elaborates a conserved oligosaccharide extension attached to two different, simultaneously expressed inner core structures, one containing a single phosphorylated 3-deoxy-D-manno-octulosonic acid (Kdo) residue and the other containing two Kdo residues. We demonstrate that two heptosyltransferases, HptA and HptB, add the first heptose molecule to the Kdo1 residue and that each exclusively recognizes different acceptor molecules. HptA is specific for the glycoform containing a single, phosphorylated Kdo residue (glycoform A), while HptB is specific for the glycoform containing two Kdo residues (glycoform B). In addition, KdkA was identified as a Kdo kinase, required for phosphorylation of the first Kdo molecule. Importantly, virulence data obtained from infected chickens showed that while wild-type P. multocida expresses both LPS glycoforms in vivo, bacterial mutants that produced only glycoform B were fully virulent, demonstrating for the first time that expression of a single LPS form is sufficient for P. multocida survival in vivo. We conclude that the ability of P. multocida to elaborate alternative inner core LPS structures is due to the simultaneous expression of two different heptosyltransferases that add the first heptose residue to the nascent LPS molecule and to the expression of both a bifunctional Kdo transferase and a Kdo kinase, which results in the initial assembly of two inner core structures.

Association of hearing impairment and subsequent driving mobility in older adults

- Purpose of the study Hearing impairment (HI) is associated with driving safety (e.g., increased crashes and poor on-road driving performance). However, little is known about HI and driving mobility. This study examined the longitudinal association of audiometric hearing with older adults’ driving mobility over three years. - Design and Methods Secondary data analyses were conducted of 500 individuals (63-90 years) from the Staying Keen in Later Life (SKILL) study. Hearing (pure tone average of 0.5, 1, and 2 kHz) was assessed in the better hearing ear and categorized into normal hearing <25 dB HL; mild HI 26-40 dB HL; or moderate and greater HI>41 dB HL. The Useful Field of View Test (UFOV) was used to estimate the risk for adverse driving events. MANCOVA compared driving mobility between HI levels across time, adjusting for age, sex, race, hypertension, and stroke. Adjusting for these same covariates, Cox regression analyses examined incidence of driving cessation by HI across three years. - Results Individuals with moderate or greater HI performed poorly on the UFOV, indicating increased risk for adverse driving events (p<.001). No significant differences were found among older adults with varying levels of HI for driving mobility (ps>.05), including driving cessation rates (p=.38), across time. - Implications Although prior research indicates older adults with HI may be at higher risk for crashes, they may not modify driving over time. Further exploration of this issue is required to optimize efforts to improve driving safety and mobility among older adults.

GIS-based tools for management of pine plantations, Queensland, Australia

Two examples of GIS-based multiple-criteria evaluations of plantation forests are presented. These desktop assessments use available topographical, geological and pedological information to establish the risk of occurrence of certain environmentally detrimental processes. The first case study is concerned with the risk that chemical additives (i.e. simazine) applied within the forestry landscape may reach the drainage system. The second case study assesses the vulnerability of forested areas to landslides. The subject of the first multiple-criteria evaluation (MCE) was a 4 km2 logging area, which had been recently site-prepared for a Pinus plantation. The criteria considered relevant to the assessment were proximity to creeks, slope, soil depth to the restrictive layer (i.e. potential depth to a perched water table) and soil erodability (based on clay content). The output of the MCE was in accordance with field observations, showing that this approach has the potential to provide management support by highlighting areas vulnerable to waterlogging, which in turn can trigger overland flow and export of pollutants to the local stream network. The subject of the second evaluation was an Araucaria plantation which is prone to landslips during heavy rain. The parameters included in the assessment were drainage system, the slope of the terrain and geological features such as rocks and structures. A good correlation between the MCE results and field observations was found, suggesting that this GIS approach is useful for the assessment of natural hazards. Multiple-criteria evaluations are highly flexible as they can be designed in either vector or raster format, depending on the type of available data. Although tested on specific areas, the MCEs presented here can be easily used elsewhere and assist both management intervention and the protection of the adjacent environment by assessing the vulnerability of the forest landscape to either introduced chemicals or natural hazards.

Spatial model of site index based on Y-ray spectrometry and a digital elevation model for two Pinus species in Tuan Toolara State Forest, Queensland, Australia

Site index prediction models are an important aid for forest management and planning activities. This paper introduces a multiple regression model for spatially mapping and comparing site indices for two Pinus species (Pinus elliottii Engelm. and Queensland hybrid, a P. elliottii x Pinus caribaea Morelet hybrid) based on independent variables derived from two major sources: g-ray spectrometry (potassium (K), thorium (Th), and uranium (U)) and a digital elevation model (elevation, slope, curvature, hillshade, flow accumulation, and distance to streams). In addition, interpolated rainfall was tested. Species were coded as a dichotomous dummy variable; interaction effects between species and the g-ray spectrometric and geomorphologic variables were considered. The model explained up to 60% of the variance of site index and the standard error of estimate was 1.9 m. Uranium, elevation, distance to streams, thorium, and flow accumulation significantly correlate to the spatial variation of the site index of both species, and hillshade, curvature, elevation and slope accounted for the extra variability of one species over the other. The predicted site indices varied between 20.0 and 27.3 m for P. elliottii, and between 23.1 and 33.1 m for Queensland hybrid; the advantage of Queensland hybrid over P. elliottii ranged from 1.8 to 6.8 m, with the mean at 4.0 m. This compartment-based prediction and comparison study provides not only an overview of forest productivity of the whole plantation area studied but also a management tool at compartment scale.

Detecting quantitative trait loci affecting beef tenderness on bovine chromosome 7 near calpastatin and lysyl oxidase

From a study of 3 large half-sib families of cattle, we describe linkage between DNA polymorphisms on bovine chromosome 7 and meat tenderness. Quantitative trait loci (QTL) for Longissimus lumborum peak force (LLPF) and Semitendonosis adhesion (STADH) were located to this map of DNA markers, which includes the calpastatin ( CAST) and lysyl oxidase (LOX) genes. The LLPF QTL has a maximum lodscore of 4.9 and allele substitution of approximately 0.80 of a phenotypic standard deviation, and the peak is located over the CAST gene. The STADH QTL has a maximum lodscore of 3.5 and an allele substitution of approximately 0.37 of a phenotypic standard deviation, and the peak is located over the LOX gene. This suggests 2 separate likelihood peaks on the chromosome. Further analyses of meat tenderness measures in the Longissimus lumborum, LLPF and LL compression (LLC), in which outlier individuals or kill groups are removed, demonstrate large shifts in the location of LLPF QTL, as well as confirming that there are indeed 2 QTL on bovine chromosome 7. We found that both QTL are reflected in both LLPF and LLC measurements, suggesting that both these components of tenderness, myofibrillar and connective tissue, are detected by both measurements in this muscle.

Decoration of Pasteurella multocida lipopolysaccharide with phosphocholine is important for virulence

Phosphocholine (PCho) is an important substituent of surface structures expressed by a number of bacterial pathogens. Its role in virulence has been investigated in several species, in which it has been shown to play a role in bacterial adhesion to mucosal surfaces, in resistance to antimicrobial peptides, or in sensitivity to complement-mediated killing. The lipopolysaccharide (LPS) structure of Pasteurella multocida strain Pm70, whose genome sequence is known, has recently been determined and does not contain PCho. However, LPS structures from the closely related, virulent P. multocida strains VP161 and X-73 were shown to contain PCho on their terminal galactose sugar residues. To determine if PCho was involved in the virulence of P. multocida, we used subtractive hybridization of the VP161 genome against the Pm70 genome to identify a four-gene locus (designated pcgDABC) which we show is required for the addition of the PCho residues to LPS. The proteins predicted to be encoded by pcgABC showed identity to proteins involved in choline uptake, phosphorylation, and nucleotide sugar activation of PCho. We constructed a P. multocida VP161 pcgC mutant and demonstrated that this strain produces LPS that lacks PCho on the terminal galactose residues. This pcgC mutant displayed reduced in vivo growth in a chicken infection model and was more sensitive to the chicken antimicrobial peptide fowlicidin-1 than the wild-type P. multocida strain

Tools to manage climate risk in cropping (Australia).

Because of the variable and changing environment, advisors and farmers are seeking systems that provide risk management support at a number of time scales. The Agricultural Production Systems Research Unit, Toowoomba, Australia has developed a suite of tools to assist advisors and farmers to better manage risk in cropping. These tools range from simple rainfall analysis tools (Rainman, HowWet, HowOften) through crop simulation tools (WhopperCropper and YieldProphet) to the most complex, APSFarm, a whole-farm analysis tool. Most are derivatives of the APSIM crop model. These tools encompass a range of complexity and potential benefit to both the farming community and for government policy. This paper describes, the development and usage of two specific products; WhopperCropper and APSFarm. WhopperCropper facilitates simulation-aided discussion of growers' exposure to risk when comparing alternative crop input options. The user can readily generate 'what-if' scenarios that separate the major influences whilst holding other factors constant. Interactions of the major inputs can also be tested. A manager can examine the effects of input levels (and Southern Oscillation Index phase) to broadly determine input levels that match their attitude to risk. APSFarm has been used to demonstrate that management changes can have different effects in short and long time periods. It can be used to test local advisors and farmers' knowledge and experience of their desired rotation system. This study has shown that crop type has a larger influence than more conservative minimum soil water triggers in the long term. However, in short term dry periods, minimum soil water triggers and maximum area of the various crops can give significant financial gains.

CYP19A1 fine-mapping and Mendelian randomization: Estradiol is causal for endometrial cancer

Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8x10(-11)). SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4x10(-8)). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11-1.21) is compatible with that predicted by the observed effect on E2 concentrations (1.09, CI=1.03-1.21), consistent with the hypothesis that endometrial cancer risk is driven by E2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (Pinteraction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.