The Ataxin-2 (Atx2) protein contributes to the progression of neurodegenerative phenotypes in animal models of amyotrophic lateral sclerosis (ALS), type 2 spinocerebellar ataxia (SCA-2), Parkinson’s disease, and Huntington’s disease (HD). However, because the Atx2 protein contains multiple separable activities, deeper understanding requires experiments to address the exact mechanisms by which Atx2 modulates neurodegeneration (ND) progression. Recent work on two ALS models, C9ORF72 and FUS, in Drosophila has shown that a C-terminal intrinsically disordered region (cIDR) of Atx2 protein, required for assembly of ribonucleoprotein (RNP) granules, is essential for the progression of neurodegenerative phenotypes as well as for accumulation of protein inclusions associated with these ALS models. Here, we show that the Atx2-cIDR also similarly contributes to the progression of degenerative phenotypes and accumulation of Huntingtin protein aggregates in Drosophila models of HD. Because Huntingtin is not an established component of RNP granules, these observations support a recently hypothesized, unexpected protein-handling function for RNP granules, which could contribute to the progression of Huntington’s disease and, potentially, other proteinopathies.We compared how stomatal morphology and physiology control intrinsic leaf water use efficiency (iWUE) in two C3 and six C4 grasses grown at ambient (400 µmol mol -1) or glacial CO2 (180 µmol mol -1) and high (1000 µmol m -2 s -1) or low light intensity (200 µmol m -2 s -1). C4 grasses tended to have higher iWUE and CO2 assimilation rates, and lower stomatal conductance (gs), operational stomatal aperture (aop) and guard cell K + influx rate relative to C3 grasses, while stomatal size (SS) and stomatal density (SD) did not vary according to the photosynthetic type. Overall, iWUE and gs depended most on aop and density of open stomata. In turn, aop correlated with K + influx, stomatal opening speed on transition to high light and SS. Species with higher SD had smaller and faster-opening stomata. Although C4 grasses operated with lower gs and aop at ambient CO2, they showed a greater potential to open stomata relative to maximal stomatal conductance (gmax), indicating heightened stomatal sensitivity and control. We uncovered promising links between aop, gs, iWUE and K + influx among C4 grasses, and differential K + influx responses of C4 guard cells to low light, revealing molecular targets for improving iWUE in C4 crops.

Investigate haemodynamic effects, and their mechanisms, of restoring atrioventricular (AV)-coupling using pacemaker therapy in normal and failing hearts in a combined computational-experimental-clinical study.

Computer simulations were performed in the CircAdapt model of the normal and failing human heart and circulation. Experiments were performed in a porcine model of AV dromotropathy. In a proof-of-principle clinical study, left ventricular (LV) pressure and volume were measured in 22 heart failure (HF) patients (LV ejection fraction <35%) with prolonged PR interval (>230 ms) and narrow or non-left bundle branch block QRS complex. Computer simulations and animal studies in normal hearts showed that restoring of AV-coupling with unchanged ventricular activation sequence significantly increased LV filling, mean arterial pressure, and cardiac output by 10-15%. In computer simulations of failing hearts and in HF patients, reducing PR interval by biventricular (BiV) pacing (patients from 300 ± 61 to 1rove cardiac function in patients with HF and prolonged PR interval.Allele substitution effects at quantitative trait loci (QTL) are part of the basis of quantitative genetics theory and applications such as association analysis and genomic prediction. In the presence of nonadditive functional gene action, substitution effects are not constant across populations. We develop an original approach to model the difference in substitution effects across populations as a first order Taylor series expansion from a “focal” population. This expansion involves the difference in allele frequencies and second-order statistical effects (additive by additive and dominance). The change in allele frequencies is a function of relationships (or genetic distances) across populations. As a result, it is possible to estimate the correlation of substitution effects across two populations using three elements magnitudes of additive, dominance, and additive by additive variances; relationships (Nei’s minimum distances or Fst indexes); and assumed heterozygosities. Similarly, the theory applies as well to distinct generations in a population, in which case the distance across generations is a function of increase of inbreeding. Simulation results confirmed our derivations. Slight biases were observed, depending on the nonadditive mechanism and the reference allele. Our derivations are useful to understand and forecast the possibility of prediction across populations and the similarity of GWAS effects.Essential oils can be a useful alternative to the use of synthetic fungicides because they have biological potential and are relatively safe for food and agricultural products. The objectives of the present study were to evaluate the antifungal and antimycotoxigenic activities of the essential oils from Satureja montana L., Myristica fragrans H. and Cymbopogon flexuosus S. against Aspergillus flavus and Aspergillus ochraceus, as well as their effects on ergosterol synthesis and membrane morphology. The antifungal potential was evaluated by mycelial growth analysis and scanning electron microscopy. Fungicidal effects against Aspergillus flavus, with MFC of 0.98, 15.62 and 0.98 µL mL-1, respectively, were observed for the essential oils from Satureja montana, Myristica fragrans and Cymbopogon flexuosus. Aspergillus ochraceus did not grow in the presence of concentrations of 3.91, 15.62 and 0.98 µL mL-1 of the essential oils from S. montana, M. fragrans and C. flexuosus, respectively. The essential oils significantly inhibited the production of ochratoxin A by the fungus A. ochraceus. The essential oils also inhibited the production of aflatoxin B1 and aflatoxin B2. The biosynthesis of ergosterol was inhibited by the applied treatments. Biological activity in the fungal cell membrane was observed in the presence of essential oils, given that deleterious effects on the morphologies of the fungi were detected. The essential oils under study are promising as food preservatives because they significantly inhibit toxigenic fungi that contaminate food. In addition, the essential oils hindered the biosynthesis of mycotoxins.Spliceosomal introns are non-coding sequences that are spliced from pre-mRNA. TRC051384 in vivo They are ubiquitous in eukaryotic genomes, although the average number of introns per gene varies considerably between different eukaryotic species. Fungi are diverse in terms of intron numbers ranging from 4% to 99% genes with introns. Alternative splicing is one of the most common modes of post transcriptional regulation in eukaryotes, giving rise to multiple transcripts from a single pre-mRNA and is widespread in metazoans and drives extensive proteome diversity. Earlier, alternative splicing was considered to be rare in fungi, but recently, increasing numbers of studies have revealed that alternative splicing is also widespread in fungi and has been implicated in the regulation of fungal growth and development, protein localization, and the improvement of survivability, likely underlying their unique capacity to adapt to changing environmental conditions. However, the role of alternative splicing in pathogenicity and development of drug resistance is only recently gaining attention. In this review, we describe the intronic landscape in fungi. We also present in detail the newly discovered functions of alternative splicing in various cellular processes and outline areas particularly in pathogenesis and clinical drug resistance for future studies that could lead to the development of much needed new therapeutics.

Sudden cardiac death (SCD) is the most common mode of death in childhood hypertrophic cardiomyopathy (HCM). The newly developed HCM Risk-Kids model provides clinicians with individualized estimates of risk. The aim of this study was to externally validate the model in a large independent, multi-centre patient cohort.

A retrospective, longitudinal cohort of 421 patients diagnosed with HCM aged 1-16 years independent of the HCM Risk-Kids development and internal validation cohort was studied. Data on HCM Risk-Kids predictor variables (unexplained syncope, non-sustained ventricular tachycardia, maximal left ventricular wall thickness, left atrial diameter, and left ventricular outflow tract gradient) were collected from the time of baseline clinical evaluation. The performance of the HCM Risk-Kids model in predicting risk at 5 years was assessed. Twenty-three patients (5.4%) met the SCD end-point within 5 years, with an overall incidence rate of 2.03 per 100 patient-years [95% confidence interval (CI) 1.48-2.78]. Model validation showed a Harrell’s C-index of 0.745 (95% CI 0.52-0.97) and Uno’s C-index 0.714 (95% 0.58-0.85) with a calibration slope of 1.15 (95% 0.51-1.80). A 5-year predicted risk threshold of ≥6% identified 17 (73.9%) SCD events with a corresponding C-statistic of 0.702 (95% CI 0.60-0.81).

This study reports the first external validation of the HCM Risk-Kids model in a large and geographically diverse patient population. A 5-year predicted risk of ≥6% identified over 70% of events, confirming that HCM Risk-Kids provides a method for individualized risk predictions and shared decision-making in children with HCM.

This study reports the first external validation of the HCM Risk-Kids model in a large and geographically diverse patient population. A 5-year predicted risk of ≥6% identified over 70% of events, confirming that HCM Risk-Kids provides a method for individualized risk predictions and shared decision-making in children with HCM.Unlike the indispensable function of the steroid hormone brassinosteroid (BR) in regulating growth and development of plants, the metabolism of secondary metabolites regulated by BR is not well known. Here we show that BR reduces carotenoid accumulation in Arabidopsis seedlings. BR-deficient or BR-insensitive mutants accumulated a higher level of carotenoids than the wild-type plant whereas BR treatment reduced carotenoid contents. We demonstrated that BR transcriptionally suppresses 4-hydroxyphenylpyruvate dioxygenase (HPPD) gene involved in carotenogenesis via plastoquinone production. We found that the expression of HPPD displays an oscillation pattern that is expressed more strongly in dark than in the light conditions. Moreover, BR appeared to inhibit more strongly HPPD expression in darkness than in light, leading to suppression of a diurnal oscillation of HPPD expression. BR-responsive transcription factor BZR1 directly bound to HPPD promoter and the HPPD suppression by BR was increased by the bzr1-1D gain-of-function mutation. Interestingly, dark-induced HPPD expression did not cause carotenoid accumulation due to downregulation of other carotenoid biosynthetic genes in the dark. Our results suggest that BR regulates different physiological responses in dark and light through inhibition of HPPD expression.