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

Adaptive Strategy for the Statistical Analysis of Connectomes

We study an adaptive statistical approach to analyze brain networks represented by brain connection matrices of interregional connectivity (connectomes). Our approach is at a middle level between a global analysis and single connections analysis by considering subnetworks of the global brain network. These subnetworks represent either the inter-connectivity between two brain anatomical regions or by the intra-connectivity within the same brain anatomical region. An appropriate summary statistic, that characterizes a meaningful feature of the subnetwork, is evaluated. Based on this summary statistic, a statistical test is performed to derive the corresponding p-value. The reformulation of the problem in this way reduces the number of statistical tests in an orderly fashion based on our understanding of the problem. Considering the global testing problem, the p-values are corrected to control the rate of false discoveries. Finally, the procedure is followed by a local investigation within the significant subnetworks. We contrast this strategy with the one based on the individual measures in terms of power. We show that this strategy has a great potential, in particular in cases where the subnetworks are well defined and the summary statistics are properly chosen. As an application example, we compare structural brain connection matrices of two groups of subjects with a 22q11.2 deletion syndrome, distinguished by their IQ scores

Thermal conductivity of refractory glass fibres

In the present study, the current international standards and corresponding apparatus for measuring the thermal conductivity of refractory glass fibre products have been reviewed. Refractory glass fibres are normally produced in the form of low-density needled mats. A major issue with thermal conductivity measurements of these materials is lack of reproducibility in the test results due to transformation of the test material during the test. Also needled mats are inherently inhomogeneous, and this poses additional problems. To be able to compare the various methods of thermal conductivity measurement, a refractory reference material was designed which is capable of withstanding maximum test temperatures (1673 K) with minimum transformation. The thermal conductivity of this reference material was then measured using various methods according to the different standards surveyed. In order to compare different materials, samples have been acquired from major refractory glass fibre manufacturers and the results have been compared against the newly introduced reference material. Materials manufactured by melt spinning, melt blowing and sol–gel have been studied, and results compared with literature values

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

Crystal Structure of the Minimalist Max-E47 Protein Chimera

Max-E47 is a protein chimera generated from the fusion of the DNA-binding basic region of Max and the dimerization region of E47, both members of the basic region/helix-loop-helix (bHLH) superfamily of transcription factors. Like native Max, Max-E47 binds with high affinity and specificity to the E-box site, 5′-CACGTG, both in vivo and in vitro. We have determined the crystal structure of Max-E47 at 1.7 Å resolution, and found that it associates to form a well-structured dimer even in the absence of its cognate DNA. Analytical ultracentrifugation confirms that Max-E47 is dimeric even at low micromolar concentrations, indicating that the Max-E47 dimer is stable in the absence of DNA. Circular dichroism analysis demonstrates that both non-specific DNA and the E-box site induce similar levels of helical secondary structure in Max-E47. These results suggest that Max-E47 may bind to the E-box following the two-step mechanism proposed for other bHLH proteins. In this mechanism, a rapid step where protein binds to DNA without sequence specificity is followed by a slow step where specific protein:DNA interactions are fine-tuned, leading to sequence-specific recognition. Collectively, these results show that the designed Max-E47 protein chimera behaves both structurally and functionally like its native counterparts

A Genome Wide Association Scan of Bovine Tuberculosis Susceptibility in Holstein-Friesian Dairy Cattle

peer-reviewedBackground: Bovine tuberculosis is a significant veterinary and financial problem in many parts of the world. Although many factors influence infection and progression of the disease, there is a host genetic component and dissection of this may enlighten on the wider biology of host response to tuberculosis. However, a binary phenotype of presence/absence of infection presents a noisy signal for genomewide association study. Methodology/Principal Findings: We calculated a composite phenotype of genetic merit for TB susceptibility based on disease incidence in daughters of elite sires used for artificial insemination in the Irish dairy herd. This robust measure was compared with 44,426 SNP genotypes in the most informative 307 subjects in a genome wide association analysis. Three SNPs in a 65 kb genomic region on BTA 22 were associated (i.e. p,1025, peaking at position 59588069, p = 4.0261026) with tuberculosis susceptibility. Conclusions/Significance: A genomic region on BTA 22 was suggestively associated with tuberculosis susceptibility; it contains the taurine transporter gene SLC6A6, or TauT, which is known to function in the immune system but has not previously been investigated for its role in tuberculosis infection

Network centrality and organizational aspirations: A behavioral interaction in the context of international strategic alliances

Whereas social network analysis has been associated with organizational aspirations, little is known on how firm's structural positioning, and particularly network centrality, affects organizational aspirations to engage in international strategic alliances (ISA). This study examines the impact of network centrality on firm's internationalization behavior within the ISA domain in response to the performance-aspiration gap. We build on social and behavioral perspectives to predict that network centrality and performance-based aspirations will be associated with the number of ISA the firm engages in. Using a sample of 7760 alliance collaborations from the top 81 global pharmaceutical firms for the period of 1991-2012, we find supporting evidence for most of our arguments