Wheat pathogen Zymoseptoria tritici N-myristoyltransferase inhibitors: on-target antifungal activity and an unusual metabolic defense mechanism

Zymoseptoria tritici is the causative agent of Septoria tritici blotch (STB), which costs billions of dollars annually to major wheat-producing countries in terms of both fungicide use and crop loss. Agricultural pathogenic fungi have acquired resistance to most commercially available fungicide classes, and the rate of discovery and development of new fungicides has stalled, demanding new approaches and insights. Here we investigate a potential mechanism of targeting an important wheat pathogen Z. tritici via inhibition of N-myristoyltransferase (NMT). We characterize Z. tritici NMT biochemically for the first time, profile the in vivo Z. tritici myristoylated proteome and identify and validate the first Z. tritici NMT inhibitors. Proteomic investigation of the downstream effects of NMT inhibition identified an unusual and novel mechanism of defense against chemical toxicity in Z. tritici through the application of comparative bioinformatics to deconvolute function from the previously largely unannotated Z. tritici proteome. Research into novel fungicidal modes-of-action is essential to satisfy an urgent unmet need for novel fungicide targets, and we anticipate that this study will serve as a useful proteomics and bioinformatics resource for researchers studying Z. tritici

Fermi Surface as the Driving Mechanism for Helical Antiferromagnetic Ordering in Gd-Y Alloys

The first direct experimental evidence for the Fermi surface (FS) driving the helical antiferromagnetic ordering in a gadolinium-yttrium alloy is reported. The presence of a FS sheet capable of nesting is revealed, and the nesting vector associated with the sheet is found to be in excellent agreement with the periodicity of the helical ordering.Comment: 4 pages, 4 figure

Heavy quasiparticles in the ferromagnetic superconductor ZrZn2

We report a study of the de Haas-van Alphen effect in the normal state of the ferromagnetic superconductor ZrZn2. Our results are generally consistent with an LMTO band structure calculation which predicts four exchange-split Fermi surface sheets. Quasiparticle effective masses are enhanced by a factor of about 4.9 implying a strong coupling to magnetic excitations or phonons. Our measurements provide insight in to the mechanism for superconductivity and unusual thermodynamic properties of ZrZn2.Comment: 5 pages, 2 figures (one color

The association between the type, context, and levels of physical activity amongst adolescents

Background: Little is known about how the type and context of physical activity behaviors varies among adolescents with differing activity levels. The aim of this study was to assess differences in the type and context of physical activity behaviors in adolescents by level of objectively measured physical activity. Methods: Cross-sectional analysis of 2728 adolescents (1299 males, 1429 females) participating in the Avon Longitudinal Study of Parents and Children (ALSPAC). The mean (SD) age was 13.8 (+0.1) years. Physical activity was measured using an Actigraph over 7 days. Adolescents were categorized into tertiles of activity (less, moderately, highly active) using counts/min and min/d of moderate-to-vigorous activity (MVPA). Activity type was reported using the Previous Day Physical Activity Recall (PDPAR). Differences in the type and context of activity by activity level were analyzed using Chi squared. Results: Highly active boys reported more job, outside, and sports activities on school days (P\u3c.05), and more sports activities on nonschool days (P\u3c.05). Highly active girls reported more outside activities on school days (P\u3c.05). Conclusions: Identifying the type and context of physical activity behaviors associated with more active adolescents, can help inform policy and physical activity interventions aimed at increasing activity levels in adolescents

Modelling a response as a function of high frequency count data: the association between physical activity and fat mass

We present a new statistical modelling approach where the response is a function of high frequency count data. Our application is about investigating the relationship between the health outcome fat mass and physical activity (PA) measured by accelerometer. The accelerometer quantifies the intensity of physical activity as counts per epoch over a given period of time. We use data from the Avon longitudinal study of parents and children (ALSPAC) where accelerometer data is available as a time series of accelerometer counts per minute over seven days for a subset of children. In order to compare accelerometer profiles between individuals and to reduce the high dimension a functional summary of the profiles is used. We use the histogram as a functional summary due to its simplicity, suitability and ease of interpretation. Our model is an extension of generalised regression of scalars on functions or signal regression. It allows also multi-dimensional functional predictors and additive non-linear predictors for metric covariates. The additive multidimensional functional predictors allow investigating specific questions about whether the effect of PA varies over its intensity, by gender, by time of day or by day of the week. The key feature of the model is that it utilises the full profile of measured PA without requiring cut-points defining intensity levels for light, moderate and vigorous activity. We show that the (not necessarily causal) effect of PA is not linear and not constant over the activity intensity. Also, there is little evidence to suggest that the effect of PA intensity varies by gender or whether it happens on weekdays or on weekends

Clinical and Epidemiologic Research Time Outdoors and Physical Activity as Predictors of Incident Myopia in Childhood: A Prospective Cohort Study

PURPOSE. Time spent in ''sports/outdoor activity'' has shown a negative association with incident myopia during childhood. We investigated the association of incident myopia with time spent outdoors and physical activity separately. METHODS. Participants in the Avon Longitudinal Study of Parents and Children (ALSPAC) were assessed by noncycloplegic autorefraction at ages 7, 10, 11, 12, and 15 years, and classified as myopic (-1 diopters) or as emmetropic/ hyperopic ( ‡-0.25 diopters) at each visit (N ¼ 4,837-7,747). Physical activity at age 11 years was measured objectively using an accelerometer, worn for 1 week. Time spent outdoors was assessed via a parental questionnaire administered when children were aged 8-9 years. Variables associated with incident myopia were examined using Cox regression. RESULTS. In analyses using all available data, both time spent outdoors and physical activity were associated with incident myopia, with time outdoors having the larger effect. The results were similar for analyses restricted to children classified as either nonmyopic or emmetropic/hyperopic at age 11 years. Thus, for children nonmyopic at age 11, the hazard ratio (95% confidence interval, CI) for incident myopia was 0.66 (0.47-0.93) for a high versus low amount of time spent outdoors, and 0.87 (0.76-0.99) per unit standard deviation above average increase in moderate/vigorous physical activity. CONCLUSION. Time spent outdoors was predictive of incident myopia independently of physical activity level. The greater association observed for time outdoors suggests that the previously reported link between ''sports/outdoor activity'' and incident myopia is due mainly to its capture of information relating to time outdoors rather than physical activity. (Invest Ophthalmol Vis Sci. 2012;53:2856-2865) DOI:10.1167/ iovs.11-9091 M yopia arises from a mismatch between the axial length of the eye and the focal power of its refractive elements, the cornea and crystalline lens. This produces blurred distance vision that requires the use of spectacles, contact lenses or refractive surgery for correction. A high degree of myopia is associated with a number of sight-threatening pathologies. 9,10 Genetic factors also have been shown to be important, because-at least in chickens-they are the major determinant of an individual animal's susceptibility to myopia induced by the visual environment. 12-21 Many studies in humans are consistent with the above findings (but not all, 22,23 perhaps due to the complexity of the visual environment). For example, a shift towards myopia has been observed during childhood in eyes exposed to form deprivation, 24 hyperopic defocus, 37 Jones et al. found that the number of hours per week that children From th

Anti-müllerian hormone is not associated with cardiometabolic risk factors in adolescent females

<p>Objectives: Epidemiological evidence for associations of Anti-Müllerian hormone (AMH) with cardiometabolic risk factors is lacking. Existing evidence comes from small studies in select adult populations, and findings are conflicting. We aimed to assess whether AMH is associated with cardiometabolic risk factors in a general population of adolescent females.</p> <p>Methods: AMH, fasting insulin, glucose, HDLc, LDLc, triglycerides and C-reactive protein (CRP) were measured at a mean age 15.5 years in 1,308 female participants in the Avon Longitudinal Study of Parents and Children (ALSPAC). Multivariable linear regression was used to examine associations of AMH with these cardiometabolic outcomes.</p> <p>Results: AMH values ranged from 0.16–35.84 ng/ml and median AMH was 3.57 ng/ml (IQR: 2.41, 5.49). For females classified as post-pubertal (n = 848) at the time of assessment median (IQR) AMH was 3.81 ng/ml (2.55, 5.82) compared with 3.25 ng/ml (2.23, 5.05) in those classed as early pubertal (n = 460, P≤0.001). After adjusting for birth weight, gestational age, pubertal stage, age, ethnicity, socioeconomic position, adiposity and use of hormonal contraceptives, there were no associations with any of the cardiometabolic outcomes. For example fasting insulin changed by 0% per doubling of AMH (95%CI: −3%,+2%) p = 0.70, with identical results if HOMA-IR was used. Results were similar after additional adjustment for smoking, physical activity and age at menarche, after exclusion of 3% of females with the highest AMH values, after excluding those that had not started menarche and after excluding those using hormonal contraceptives.</p> <p>Conclusion: Our results suggest that in healthy adolescent females, AMH is not associated with cardiometabolic risk factors.</p&gt

A standardized framework for the validation and verification of clinical molecular genetic tests

The validation and verification of laboratory methods and procedures before their use in clinical testing is essential for providing a safe and useful service to clinicians and patients. This paper outlines the principles of validation and verification in the context of clinical human molecular genetic testing. We describe implementation processes, types of tests and their key validation components, and suggest some relevant statistical approaches that can be used by individual laboratories to ensure that tests are conducted to defined standards