Reverse genetics in Candida albicans predicts ARF cycling is essential for drug resistance and virulence

Peer reviewedPublisher PD

Classification of Invariant Star Products up to Equivariant Morita Equivalence on Symplectic Manifolds

In this paper we investigate equivariant Morita theory for algebras with momentum maps and compute the equivariant Picard groupoid in terms of the Picard groupoid explicitly. We consider three types of Morita theory: ring-theoretic equivalence, *-equivalence and strong equivalence. Then we apply these general considerations to star product algebras over symplectic manifolds with a Lie algebra symmetry. We obtain the full classification up to equivariant Morita equivalence.Comment: 28 pages. Minor update, fixed typos

Performance of the EUDET-type beam telescopes

Test beam measurements at the test beam facilities of DESY have been conducted to characterise the performance of the EUDET-type beam telescopes originally developed within the EUDET project. The beam telescopes are equipped with six sensor planes using MIMOSA26 monolithic active pixel devices. A programmable Trigger Logic Unit provides trigger logic and time stamp information on particle passage. Both data acquisition framework and offline reconstruction software packages are available. User devices are easily integrable into the data acquisition framework via predefined interfaces. The biased residual distribution is studied as a function of the beam energy, plane spacing and sensor threshold. Its standard deviation at the two centre pixel planes using all six planes for tracking in a 6\,GeV electron/positron-beam is measured to be (2.88\,\pm\,0.08)\,\upmu\meter.Iterative track fits using the formalism of General Broken Lines are performed to estimate the intrinsic resolution of the individual pixel planes. The mean intrinsic resolution over the six sensors used is found to be (3.24\,\pm\,0.09)\,\upmu\meter.With a 5\,GeV electron/positron beam, the track resolution halfway between the two inner pixel planes using an equidistant plane spacing of 20\,mm is estimated to (1.83\,\pm\,0.03)\,\upmu\meter assuming the measured intrinsic resolution. Towards lower beam energies the track resolution deteriorates due to increasing multiple scattering. Threshold studies show an optimal working point of the MIMOSA26 sensors at a sensor threshold of between five and six times their RMS noise. Measurements at different plane spacings are used to calibrate the amount of multiple scattering in the material traversed and allow for corrections to the predicted angular scattering for electron beams

HLA-DQA1-HLA-DRB1 polymorphism is a major predictor of azathioprine-induced pancreatitis in patients with inflammatory bowel disease

Background: Azathioprine (AZA)-induced pancreatitis is an unpredictable and dose-independent adverse event affecting 2%-7% of patients with inflammatory bowel disease (IBD) patients treated with AZA. There are no tools in clinical practice to identify at-risk individuals; however, a genome wide association study (GWAS) identified a strong association between the Class II HLA gene region polymorphism (rs2647087) and thiopurine-induced pancreatitis. Aim: To independently confirm the findings of the GWAS in an IBD cohort, to evaluate its utility in clinical practice and to offer a novel AZA treatment algorithm for IBD based on pharmacogenomic principles. Methods: A retrospective cohort study evaluated 373 AZA-exposed IBD patients from a tertiary care academic centre in London, Canada. Due to the limited number of patients taking mercaptopurine (MP), such patients were not included this cohort. All subjects underwent screening for the single nucleotide polymorphism (SNP) rs2647087 mapped to the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype and were sub-divided based on the presence (n = 13) or absence (n = 360) of an AZA-induced pancreatitis diagnosis. The risk of AZA-induced pancreatitis was assessed based on rs2647087 genotype. Results: The risk of pancreatitis during AZA-therapy was highly predictable and genotype dependent: 0.53% for wild type (A/A), 4.25% (OR = 4.19, 95% CI 1.02-36.45, P = 0.044) for heterozygous (A/C), and 14.63% (OR = 15.83, 95% CI 3.80-145.26, P = 0.0001) for homozygous variant (C/C) patients. Conclusions: The class II HLA region (at rs2647087) is an important marker of AZA-induced pancreatitis risk. We propose a simple and clinically implementable algorithm based on rs2647087 and TPMT genotypes for AZA selection and dosing for patients with IBD

Chemogenomic profiling predicts antifungal synergies

Chemotherapies, HIV infections, and treatments to block organ transplant rejection are creating a population of immunocompromised individuals at serious risk of systemic fungal infections. Since single-agent therapies are susceptible to failure due to either inherent or acquired resistance, alternative therapeutic approaches such as multi-agent therapies are needed. We have developed a bioinformatics-driven approach that efficiently predicts compound synergy for such combinatorial therapies. The approach uses chemogenomic profiles in order to identify compound profiles that have a statistically significant degree of similarity to a fluconazole profile. The compounds identified were then experimentally verified to be synergistic with fluconazole and with each other, in both Saccharomyces cerevisiae and the fungal pathogen Candida albicans. Our method is therefore capable of accurately predicting compound synergy to aid the development of combinatorial antifungal therapies

Linking heart rate variability to psychological health and brain structure in adolescents with and without conduct disorder

AimsHeart rate variability (HRV) measures have been suggested in healthy individuals as a potential index of self-regulation skills, which include both cognitive and emotion regulation aspects. Studies in patients with a range of psychiatric disorders have however mostly focused on the potential association between abnormally low HRV at rest and specifically emotion regulation difficulties. Emotion regulation deficits have been reported in patients with Conduct Disorder (CD) however, the association between these emotion regulation deficits and HRV measures has yet to be fully understood. This study investigates (i) the specificity of the association between HRV and emotion regulation skills in adolescents with and without CD and (ii) the association between HRV and grey matter brain volumes in key areas of the central autonomic network which are involved in self-regulation processes, such as insula, lateral/medial prefrontal cortices or amygdala.MethodsRespiratory sinus arrhythmia (RSA) measures of HRV were collected from adolescents aged between 9–18 years (693 CD (427F)/753 typically developing youth (TD) (500F)), as part of a European multi-site project (FemNAT-CD). The Inverse Efficiency Score, a speed-accuracy trade-off measure, was calculated to assess emotion and cognitive regulation abilities during an Emotional Go/NoGo task. The association between RSA and task performance was tested using multilevel regression models. T1-weighted structural MRI data were included for a subset of 577 participants (257 CD (125F); 320 TD (186F)). The CerebroMatic toolbox was used to create customised Tissue Probability Maps and DARTEL templates, and CAT12 to segment brain images, followed by a 2 × 2 (sex × group) full factorial ANOVA with RSA as regressor of interest.ResultsThere were no significant associations between RSA and task performance, neither during emotion regulation nor during cognitive regulation trials. RSA was however positively correlated with regional grey matter volume in the left insula (pFWE = 0.011) across all subjects.ConclusionRSA was related to increased grey matter volume in the left insula across all subjects. Our results thus suggest that low RSA at rest might be a contributing or predisposing factor for potential self-regulation difficulties. Given the insula’s role in both emotional and cognitive regulation processes, these brain structural differences might impact either of those

El Niño Southern Oscillation, overseas arrivals and imported chikungunya cases in Australia: A time series analysis.

BACKGROUND: Chikungunya virus (CHIKV) is an emerging mosquito-borne pathogen circulating in tropical and sub-tropical regions. Although autochthonous transmission has not been reported in Australia, there is a potential risk of local CHIKV outbreaks due to the presence of suitable vectors, global trade, frequent international travel and human adaptation to changes in climate. METHODOLOGY/PRINCIPAL FINDINGS: A time series seasonal decomposition method was used to investigate the seasonality and trend of monthly imported CHIKV cases. This pattern was compared with the seasonality and trend of monthly overseas arrivals. A wavelet coherence analysis was applied to examine the transient relationships between monthly imported CHIKV cases and southern oscillation index (SOI) in time-frequency space. We found that the number and geographical distribution of countries of acquisition for CHIKV in travellers to Australia has increased in recent years. The number of monthly imported CHIKV cases displayed an unstable increased trend compared with a stable linear increased trend in monthly overseas arrivals. Both imported CHIKV cases and overseas arrivals showed substantial seasonality, with the strongest seasonal effects in each January, followed by each October and July. The wavelet coherence analysis identified four significant transient relationships between monthly imported CHIKV cases and 6-month lagged moving average SOI, in the years 2009-2010, 2012, 2014 and 2015-2016. CONCLUSION/SIGNIFICANCE: High seasonal peaks of imported CHIKV cases were consistent with the high seasonal peaks of overseas arrivals into Australia. Our analysis also indicates that El Niño Southern Oscillation (ENSO) variation may impact CHIKV epidemics in endemic regions, in turn influencing the pattern of imported cases