Towards take-all control:A C-‐21β oxidase required for acylation of triterpene defence compounds in oat

Oats produce avenacins, antifungal triterpenes that are synthesized in the roots and provide protection against take-all and other soilborne diseases. Avenacins are acylated at the carbon-21 position of the triterpene scaffold, a modification critical for antifungal activity. We have previously characterized several steps in the avenacin pathway, including those required for acylation. However, transfer of the acyl group to the scaffold requires the C-21β position to be oxidized first, by an as yet uncharacterized enzyme. We mined oat transcriptome data to identify candidate cytochrome P450 enzymes that may catalyse C-21β oxidation. Candidates were screened for activity by transient expression in Nicotiana benthamiana. We identified a cytochrome P450 enzyme AsCYP72A475 as a triterpene C-21β hydroxylase, and showed that expression of this enzyme together with early pathway steps yields C-21β oxidized avenacin intermediates. We further demonstrate that AsCYP72A475 is synonymous with Sad6, a previously uncharacterized locus required for avenacin biosynthesis. sad6 mutants are compromised in avenacin acylation and have enhanced disease susceptibility. The discovery of AsCYP72A475 represents an important advance in the understanding of triterpene biosynthesis and paves the way for engineering the avenacin pathway into wheat and other cereals for control of take-all and other diseases

Analysis of Two New Arabinosyltransferases Belonging to the Carbohydrate-Active Enzyme (CAZY) Glycosyl Transferase Family1 Provides Insights into Disease Resistance and Sugar Donor Specificity

Glycosylation of small molecules is critical for numerous biological processes in plants, including hormone homeostasis, neutralization of xenobiotics, and synthesis and storage of specialized metabolites. Glycosylation of plant natural products is usually carried out by uridine diphosphate-dependent glycosyltransferases (UGTs). Triterpene glycosides (saponins) are a large family of plant natural products that determine important agronomic traits such as disease resistance and flavor and have numerous pharmaceutical applications. Most characterised plant natural product UGTs are glucosyltransferases, and little is known about enzymes that add other sugars. Here we report the discovery and characterization of AsAAT1 (UGT99D1), which is required for biosynthesis of the antifungal saponin avenacin A-1 in oat. This enzyme adds L-arabinose to the triterpene scaffold at the C-3 position, a modification critical for disease resistance. The only previously reported plant natural product arabinosyltransferase is a flavonoid arabinosyltransferase from Arabidopsis. We show that AsAAT1 has high specificity for UDP-β-L-arabinopyranose, identify two amino acids required for sugar donor specificity, and through targeted mutagenesis convert AsAAT1 into a glucosyltransferase. We further identify a second arabinosyltransferase potentially implicated in the biosynthesis of saponins that determine bitterness in soybean. Our investigations suggest independent evolution of UDP-arabinose sugar donor specificity in arabinosyltransferases in monocots and eudicots

Interventions for mental health problems in children and adults with severe intellectual disabilities: a systematic review

Objective Mental health problems are more prevalent in people with than without intellectual disabilities, yet treatment options have received little attention. The aim of this study was to identify and evaluate the effectiveness of pharmacological and psychological interventions in the treatment of mental health problems in children and adults with severe and profound intellectual disabilities, given their difficulties in accessing standard mental health interventions, particularly talking therapies, and difficulties reporting drug side effects. Design A systematic review using electronic searches of PsycINFO, PsycTESTS, EMBASE, MEDLINE, CINAHL, ERIC, ASSIA, Science Citation Index, Social Science Citation Index and CENTRAL was conducted to identify eligible intervention studies. Study selection, data extraction and quality appraisal were performed by two independent reviewers. Participants Study samples included at least 70% children and/or adults with severe or profound intellectual disabilities or reported the outcomes of this subpopulation separate from participants with other levels of intellectual disabilities. Interventions Eligible intervention studies evaluated a psychological or pharmacological intervention using a control condition or pre-post design. Outcomes Symptom severity, frequency or other quantitative dimension (e.g., impact), as assessed with standardised measures of mental health problems. Results We retrieved 41 232 records, reviewed 573 full-text articles and identified five studies eligible for inclusion: three studies evaluating pharmacological interventions, and two studies evaluating psychological interventions. Study designs ranged from double-blind placebo controlled crossover trials to single-case experimental reversal designs. Quality appraisals of this very limited literature base revealed good experimental control, poor reporting standards and a lack of follow-up data. Conclusions Mental ill health requires vigorous treatment, yet the current evidence base is too limited to identify with precision effective treatments specifically for children or adults with severe and profound intellectual disabilities. Clinicians therefore must work on the basis of general population evidence, while researchers work to generate more precise evidence for people with severe and profound intellectual disabilities

A noncanonical vacuolar sugar transferase required for biosynthesis of antimicrobial defense compounds in oat

Plants produce an array of natural products with important ecological functions. These compounds are often decorated with oligosaccharide groups that influence bioactivity, but the biosynthesis of such sugar chains is not well understood. Triterpene glycosides (saponins) are a large family of plant natural products that determine important agronomic traits, as exemplified by avenacins, antimicrobial defense compounds produced by oats. Avenacins have a branched trisaccharide moiety consisting of L-arabinose linked to 2 D-glucose molecules that is critical for antifungal activity. Plant natural product glycosylation is usually performed by uridine diphosphate-dependent glycosyltransferases (UGTs). We previously characterized the arabinosyltransferase that initiates the avenacin sugar chain; however, the enzymes that add the 2 remaining D-glucose molecules have remained elusive. Here we characterize the enzymes that catalyze these last 2 glucosylation steps. AsUGT91G16 is a classical cytosolic UGT that adds a 1,2-linked D-glucose molecule to L-arabinose. Unexpectedly, the enzyme that adds the final 1,4-linked D-glucose (AsTG1) is not a UGT, but rather a sugar transferase belonging to Glycosyl Hydrolase family 1 (GH1). Unlike classical UGTs, AsTG1 is vacuolar. Analysis of oat mutants reveals that AsTG1 corresponds to Sad3, a previously uncharacterized locus shown by mutation to be required for avenacin biosynthesis. AsTG1 and AsUGT91G16 form part of the avenacin biosynthetic gene cluster. Our demonstration that a vacuolar transglucosidase family member plays a critical role in triterpene biosynthesis highlights the importance of considering other classes of carbohydrate-active enzymes in addition to UGTs as candidates when elucidating pathways for the biosynthesis of glycosylated natural products in plants

Measurement tools for mental health problems and mental well-being in people with severe or profound intellectual disabilities : a systematic review

Mental health problems affect people with intellectual disabilities (ID) at rates similar to or in excess of the non-ID population. People with severe ID are likely to have persistent mental health problems. In this systematic review (PROSPERO 2015:CRD42015024469), we identify and evaluate the methodological quality of available measures of mental health problems or well-being in individuals with severe or profound ID. Electronic searches of ten databases identified relevant publications. Two reviewers independently reviewed titles and abstracts of retrieved records (n = 41,232) and full-text articles (n = 573). Data were extracted and the quality of included papers was appraised. Thirty-two papers reporting on 12 measures were included. Nine measures addressed a broad spectrum of mental health problems, and were largely observational. One physiological measure of well-being was included. The Aberrant Behaviour Checklist, Diagnostic Assessment for the Severely Handicapped Scale-II and Mood, Interest and Pleasure Questionnaire are reliable measures in this population. However, the psychometric properties of six other measures were only considered within a single study – indicating a lack of research replication. Few mental health measures are available for people with severe or profound ID, particularly lacking are tools measuring well-being. Assessment methods that do not rely on proxy reports should be explored further

Subtelomeric assembly of a multi-gene pathway for antimicrobial defense compounds in cereals

Non-random gene organization in eukaryotes plays a significant role in genome evolution. Here, we investigate the origin of a biosynthetic gene cluster for production of defence compounds in oat—the avenacin cluster. We elucidate the structure and organisation of this 12-gene cluster, characterise the last two missing pathway steps, and reconstitute the entire pathway in tobacco by transient expression. We show that the cluster has formed de novo since the divergence of oats in a subtelomeric region of the genome that lacks homology with other grasses, and that gene order is approximately colinear with the biosynthetic pathway. We speculate that the positioning of the late pathway genes furthest away from the telomere may mitigate against a ‘self-poisoning’ scenario in which toxic intermediates accumulate as a result of telomeric gene deletions. Our investigations reveal a striking example of adaptive evolution underpinned by remarkable genome plasticity

Behavioural interventions to treat anxiety in adults with autism and moderate to severe intellectual disabilities: The BEAMS ‐ ID feasibility study

Background: The aim of this feasibility study was to adapt and model a behavioural intervention for anxiety with autistic adults with moderate to severe intellectual disabilities. Method: Twenty‐eight autistic adults with moderate or severe intellectual disabilities, 37 carers, and 40 therapists took part in this single‐group non‐randomised feasibility study designed to test intervention feasibility and acceptability, outcome measures, and research processes. Results: The intervention was judged as feasible and acceptable by autistic adults with intellectual disabilities, carers, and therapists. Minor intervention revisions were suggested. Carers completed 100% of outcome measures and the missing data rate was low. Complying with legislation governing the inclusion of participants who lack capacity to decide whether they wanted to take part in this study led to an average 5‐week enrolment delay. Conclusion: The intervention and associated study processes were judged to be feasible and acceptable and should now be tested within a larger randomised trial

Trials

BACKGROUND: The aim of this open-label, randomized controlled trial conducted in four African countries (Madagascar, Niger, Central African Republic, and Senegal) is to compare three strategies of renutrition for moderate acute malnutrition (MAM) in children based on modulation of the gut microbiota with enriched flours alone, enriched flours with prebiotics or enriched flours coupled with antibiotic treatment. METHODS: To be included, children aged between 6 months and 2 years are preselected based on mid-upper-arm circumference (MUAC) and are included based on a weight-for-height Z-score (WHZ) between - 3 and - 2 standard deviations (SD). As per current protocols, children receive renutrition treatment for 12 weeks and are assessed weekly to determine improvement. The primary endpoint is recovery, defined by a WHZ >/= - 1.5 SD after 12 weeks of treatment. Data collected include clinical and socioeconomic characteristics, side effects, compliance and tolerance to interventions. Metagenomic analysis of gut microbiota is conducted at inclusion, 3 months, and 6 months. The cognitive development of children is evaluated in Senegal using only the Developmental Milestones Checklist II (DMC II) questionnaire at inclusion and at 3, 6, and 9 months. The data will be correlated with renutrition efficacy and metagenomic data. DISCUSSION: This study will provide new insights for the treatment of MAM, as well as original data on the modulation of gut microbiota during the renutrition process to support (or not) the microbiota hypothesis of malnutrition. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03474276 Last update 28 May 2018

Understanding gender differences in schizophrenia : a review of the literature

Schizophrenia is the most severe of the psychotic disorders and has a neurobiological and genetic basis, with environment being a moderating factor but not the primary cause. Numerous studies have demonstrated gender differences in the phenomenology of schizophrenia. This review evaluates three theoretical frameworks that have been developed to explain how gender differences develop in schizophrenia: (1) the neurodevelopmental approach; (2) the structural, neuropathological approach; and (3) the estrogen protection hypothesis. It is concluded that findings are most coherently accounted for by the estrogen protection hypothesis; gender differences in schizophrenia most likely emerge due to the multiple effects of estrogens and their complex interactions with neurotransmitter receptors and in-utero brain development. Women predisposed to schizophrenia appear to be particularly protected from the early-onset form of the illness due to high levels of circulating estrogen, and consequent dopamine suppression. Nonetheless, taken together, the three theoretical frameworks can integrate a wide variety of findings of gender differences in schizophrenia, with compelling evidence existing for all approaches.11 page(s