A preliminary study of genetic factors that influence susceptibility to bovine tuberculosis in the British cattle herd

Associations between specific host genes and susceptibility to Mycobacterial infections such as tuberculosis have been reported in several species. Bovine tuberculosis (bTB) impacts greatly the UK cattle industry, yet genetic predispositions have yet to be identified. We therefore used a candidate gene approach to study 384 cattle of which 160 had reacted positively to an antigenic skin test (‘reactors’). Our approach was unusual in that it used microsatellite markers, embraced high breed diversity and focused particularly on detecting genes showing heterozygote advantage, a mode of action often overlooked in SNP-based studies. A panel of neutral markers was used to control for population substructure and using a general linear model-based approach we were also able to control for age. We found that substructure was surprisingly weak and identified two genomic regions that were strongly associated with reactor status, identified by markers INRA111 and BMS2753. In general the strength of association detected tended to vary depending on whether age was included in the model. At INRA111 a single genotype appears strongly protective with an overall odds ratio of 2.2, the effect being consistent across nine diverse breeds. Our results suggest that breeding strategies could be devised that would appreciably increase genetic resistance of cattle to bTB (strictly, reduce the frequency of incidence of reactors) with implications for the current debate concerning badger-culling

Magnetic Moment Collapse-Driven Mott Transition in MnO

The metal-insulator transition in correlated electron systems, where electron states transform from itinerant to localized, has been one of the central themes of condensed matter physics for more than half a century. The persistence of this question has been a consequence both of the intricacy of the fundamental issues and the growing recognition of the complexities that arise in real materials, even when strong repulsive interactions play the primary role. The initial concept of Mott was based on the relative importance of kinetic hopping (measured by the bandwidth) and on-site repulsion of electrons. Real materials, however, have many additional degrees of freedom that, as is recently attracting note, give rise to a rich variety of scenarios for a ``Mott transition.'' Here we report results for the classic correlated insulator MnO which reproduce a simultaneous moment collapse, volume collapse, and metallization transition near the observed pressure, and identify the mechanism as collapse of the magnetic moment due to increase of crystal field splitting, rather than to variation in the bandwidth.Comment: 18 pages, 5 figur

Why Is There a Lack of Consensus on Molecular Subgroups of Glioblastoma? Understanding the Nature of Biological and Statistical Variability in Glioblastoma Expression Data

Gene expression patterns characterizing clinically-relevant molecular subgroups of glioblastoma are difficult to reproduce. We suspect a combination of biological and analytic factors confounds interpretation of glioblastoma expression data. We seek to clarify the nature and relative contributions of these factors, to focus additional investigations, and to improve the accuracy and consistency of translational glioblastoma analyses.We analyzed gene expression and clinical data for 340 glioblastomas in The Cancer Genome Atlas (TCGA). We developed a logic model to analyze potential sources of biological, technical, and analytic variability and used standard linear classifiers and linear dimensional reduction algorithms to investigate the nature and relative contributions of each factor.Commonly-described sources of classification error, including individual sample characteristics, batch effects, and analytic and technical noise make measurable but proportionally minor contributions to inconsistent molecular classification. Our analysis suggests that three, previously underappreciated factors may account for a larger fraction of classification errors: inherent non-linear/non-orthogonal relationships among the genes used in conjunction with classification algorithms that assume linearity; skewed data distributions assumed to be Gaussian; and biologic variability (noise) among tumors, of which we propose three types.Our analysis of the TCGA data demonstrates a contributory role for technical factors in molecular classification inconsistencies in glioblastoma but also suggests that biological variability, abnormal data distribution, and non-linear relationships among genes may be responsible for a proportionally larger component of classification error. These findings may have important implications for both glioblastoma research and for translational application of other large-volume biological databases

Mutations in a Guanylate Cyclase GCY-35/GCY-36 Modify Bardet-Biedl Syndrome–Associated Phenotypes in Caenorhabditis elegans

Ciliopathies are pleiotropic and genetically heterogeneous disorders caused by defective development and function of the primary cilium. Bardet-Biedl syndrome (BBS) proteins localize to the base of cilia and undergo intraflagellar transport, and the loss of their functions leads to a multisystemic ciliopathy. Here we report the identification of mutations in guanylate cyclases (GCYs) as modifiers of Caenorhabditis elegans bbs endophenotypes. The loss of GCY-35 or GCY-36 results in suppression of the small body size, developmental delay, and exploration defects exhibited by multiple bbs mutants. Moreover, an effector of cGMP signalling, a cGMP-dependent protein kinase, EGL-4, also modifies bbs mutant defects. We propose that a misregulation of cGMP signalling, which underlies developmental and some behavioural defects of C. elegans bbs mutants, may also contribute to some BBS features in other organisms

Structural MRI studies of language function in the undamaged brain

In recent years, the demonstration that structural changes can occur in the human brain beyond those associated with development, ageing and neuropathology has revealed a new approach to studying the neural basis of behaviour. In this review paper, we focus on structural imaging studies of language that have utilised behavioural measures in order to investigate the neural correlates of language skills in the undamaged brain. We report studies that have used two different techniques: voxel-based morphometry of whole brain grey or white matter images and diffusion tensor imaging. At present, there are relatively few structural imaging studies of language. We group them into those that investigated (1) the perception of novel speech sounds, (2) the links between speech sounds and their meaning, (3) speech production, and (4) reading. We highlight the validity of the findings by comparing the results to those from functional imaging studies. Finally, we conclude by summarising the novel contribution of these studies to date and potential directions for future research

Recent and historical recombination in the admixed Norwegian Red cattle breed

<p>Abstract</p> <p>Background</p> <p>Comparison of recent patterns of recombination derived from linkage maps to historical patterns of recombination from linkage disequilibrium (LD) could help identify genomic regions affected by strong artificial selection, appearing as reduced recent recombination. Norwegian Red cattle (NRF) make an interesting case study for investigating these patterns as it is an admixed breed with an extensively recorded pedigree. NRF have been under strong artificial selection for traits such as milk and meat production, fertility and health.</p> <p>While measures of LD is also crucial for determining the number of markers required for association mapping studies, estimates of recombination rate can be used to assess quality of genomic assemblies.</p> <p>Results</p> <p>A dataset containing more than 17,000 genome-wide distributed SNPs and 2600 animals was used to assess recombination rates and LD in NRF. Although low LD measured by r²was observed in NRF relative to some of the breeds from which this breed originates, reports from breeds other than those assessed in this study have described more rapid decline in r²at short distances than what was found in NRF. Rate of decline in r²for NRF suggested that to obtain an expected r²between markers and a causal polymorphism of at least 0.5 for genome-wide association studies, approximately one SNP every 15 kb or a total of 200,000 SNPs would be required. For well known quantitative trait loci (QTLs) for milk production traits on <it>Bos Taurus </it>chromosomes 1, 6 and 20, map length based on historic recombination was greater than map length based on recent recombination in NRF.</p> <p>Further, positions for 130 previously unpositioned contigs from assembly of the bovine genome sequence (Btau_4.0) found using comparative sequence analysis were validated by linkage analysis, and 28% of these positions corresponded to extreme values of population recombination rate.</p> <p>Conclusion</p> <p>While LD is reduced in NRF compared to some of the breeds from which this admixed breed originated, it is elevated over short distances compared to some other cattle breeds. Genomic regions in NRF where map length based on historic recombination was greater than map length based on recent recombination coincided with some well known QTL regions for milk production traits.</p> <p>Linkage analysis in combination with comparative sequence analysis and detection of regions with extreme values of population recombination rate proved to be valuable for detecting problematic regions in the Btau_4.0 genome assembly.</p

Whether weather matters: Evidence of association between in utero meteorological exposures and foetal growth among Indigenous and non-Indigenous mothers in rural Uganda

Pregnancy and birth outcomes have been found to be sensitive to meteorological variation, yet few studies explore this relationship in sub-Saharan Africa where infant mortality rates are the highest in the world. We address this research gap by examining the association between meteorological factors and birth weight in a rural population in southwestern Uganda. Our study included hospital birth records (n = 3197) from 2012 to 2015, for which we extracted meteorological exposure data for the three trimesters preceding each birth. We used linear regression, controlling for key covariates, to estimate the timing, strength, and direction of meteorological effects on birth weight. Our results indicated that precipitation during the third trimester had a positive association with birth weight, with more frequent days of precipitation associated with higher birth weight: we observed a 3.1g (95% CI: 1.0–5.3g) increase in birth weight per additional day of exposure to rainfall over 5mm. Increases in average daily temperature during the third trimester were also associated with birth weight, with an increase of 41.8g (95% CI: 0.6–82.9g) per additional degree Celsius. When the sample was stratified by season of birth, only infants born between June and November experienced a significant associated between meteorological exposures and birth weight. The association of meteorological variation with foetal growth seemed to differ by ethnicity; effect sizes of meteorological were greater among an Indigenous subset of the population, in particular for variation in temperature. Effects in all populations in this study are higher than estimates of the African continental average, highlighting the heterogeneity in the vulnerability of infant health to meteorological variation in different contexts. Our results indicate that while there is an association between meteorological variation and birth weight, the magnitude of these associations may vary across ethnic groups with differential socioeconomic resources, with implications for interventions to reduce these gradients and offset the health impacts predicted under climate change

Feasibility and effects of adapted cardiac rehabilitation after stroke: a prospective trial

Abstract Background Despite the cardiovascular etiology of stroke, exercise and risk factor modification programs akin to cardiac rehabilitation (CR) are not available. This study aimed to establish the feasibility of adapting a CR model for individuals with mild to moderate stroke disability. A secondary objective was to determine the program's effects on aerobic and walking capacity, and stroke risk factors. Methods A repeated measures design was used with a 3-month baseline period and 6-month adapted CR intervention (n = 43, mean ± SD age 65 ± 12 years, 30 ± 28 months post stroke). Feasibility was determined by the number of participants who completed the study, occurrence of adverse events and frequency, duration and intensity of exercise performed. To determine effectiveness of the program, outcomes measured included aerobic capacity (VO2peak, ventilatory threshold), 6-Minute Walk Test (6MWT) distance, and risk factors. Descriptive statistics characterized the classes attended and number and intensity of exercise sessions. Paired t-tests, one-factor repeated measures analyses of variance contrasts and chi-square analyses were used to compare changes over time. Results Two participants withdrew during the baseline period. Of the remaining 41 participants who commenced the program, 38 (93%) completed all aspects. No serious adverse effects occurred. Post-intervention, VO2peak improved relative to the stable baseline period (P = 0.046) and the increase in ventilatory threshold approached significance (P = 0.062). Conclusions CR is feasible after stroke and may be adapted to accommodate for those with a range of post-stroke disability. It is effective in increasing aerobic capacity. CR may be an untapped opportunity for stroke survivors to access programs of exercise and risk factor modification to lower future event risk. Trial registration ClinicalTrials.gov registration number: NCT0106749