Updated guidelines for gene nomenclature in wheat.

KEY MESSAGE: Here, we provide an updated set of guidelines for naming genes in wheat that has been endorsed by the wheat research community. The last decade has seen a proliferation in genomic resources for wheat, including reference- and pan-genome assemblies with gene annotations, which provide new opportunities to detect, characterise, and describe genes that influence traits of interest. The expansion of genetic information has supported growth of the wheat research community and catalysed strong interest in the genes that control agronomically important traits, such as yield, pathogen resistance, grain quality, and abiotic stress tolerance. To accommodate these developments, we present an updated set of guidelines for gene nomenclature in wheat. These guidelines can be used to describe loci identified based on morphological or phenotypic features or to name genes based on sequence information, such as similarity to genes characterised in other species or the biochemical properties of the encoded protein. The updated guidelines provide a flexible system that is not overly prescriptive but provides structure and a common framework for naming genes in wheat, which may be extended to related cereal species. We propose these guidelines be used henceforth by the wheat research community to facilitate integration of data from independent studies and allow broader and more efficient use of text and data mining approaches, which will ultimately help further accelerate wheat research and breeding.

Identification, validation and biological characterisation of novel glioblastoma tumour microenvironment subtypes: implications for precision immunotherapy.

BACKGROUND: New precision medicine therapies are urgently required for glioblastoma (GBM). However, to date, efforts to subtype patients based on molecular profiles have failed to direct treatment strategies. We hypothesised that interrogation of the GBM tumour microenvironment (TME) and identification of novel TME-specific subtypes could inform new precision immunotherapy treatment strategies. MATERIALS AND METHODS: A refined and validated microenvironment cell population (MCP) counter method was applied to >800 GBM patient tumours (GBM-MCP-counter). Specifically, partition around medoids (PAM) clustering of GBM-MCP-counter scores in the GLIOTRAIN discovery cohort identified three novel patient clusters, uniquely characterised by TME composition, functional orientation markers and immune checkpoint proteins. Validation was carried out in three independent GBM-RNA-seq datasets. Neoantigen, mutational and gene ontology analysis identified mutations and uniquely altered pathways across subtypes. The longitudinal Glioma Longitudinal AnalySiS (GLASS) cohort and three immunotherapy clinical trial cohorts [treatment with neoadjuvant/adjuvant anti-programmed cell death protein 1 (PD-1) or PSVRIPO] were further interrogated to assess subtype alterations between primary and recurrent tumours and to assess the utility of TME classifiers as immunotherapy biomarkers. RESULTS: TMEHigh tumours (30%) displayed elevated lymphocyte, myeloid cell immune checkpoint, programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 transcripts. TMEHigh/mesenchymal+ patients featured tertiary lymphoid structures. TMEMed (46%) tumours were enriched for endothelial cell gene expression profiles and displayed heterogeneous immune populations. TMELow (24%) tumours were manifest as an 'immune-desert' group. TME subtype transitions upon recurrence were identified in the longitudinal GLASS cohort. Assessment of GBM immunotherapy trial datasets revealed that TMEHigh patients receiving neoadjuvant anti-PD-1 had significantly increased overall survival (P = 0.04). Moreover, TMEHigh patients treated with adjuvant anti-PD-1 or oncolytic virus (PVSRIPO) showed a trend towards improved survival. CONCLUSIONS: We have established a novel TME-based classification system for application in intracranial malignancies. TME subtypes represent canonical 'termini a quo' (starting points) to support an improved precision immunotherapy treatment approach.

Elective and Emergency Deep Brain Stimulation in Refractory Pediatric Monogenetic Movement Disorders Presenting with Dystonia: Current Practice Illustrated by Two Cases.

BACKGROUND: Dystonia is characterized by sustained or intermittent muscle contractions, leading to abnormal posturing and twisting movements. In pediatric patients, dystonia often negatively influences quality of life. Pharmacological treatment for dystonia is often inadequate and causes adverse effects. Deep brain stimulation (DBS) appears to be a valid therapeutic option for pharmacoresistant dystonia in children. METHODS: To illustrate the current clinical practice, we hereby describe two pediatric cases of monogenetic movement disorders presenting with dystonia and treated with DBS. We provide a literature review of similar previously described cases and on different clinical aspects of DBS in pediatric dystonia. RESULTS: The first patient, a 6-year-old girl with severe dystonia, chorea, and myoclonus due to an ADCY5 gene mutation, received DBS in an elective setting. The second patient, an 8-year-old boy with GNAO1-related dystonia and chorea, underwent emergency DBS due to a pharmacoresistant status dystonicus. A significant amelioration of motor symptoms (65% on the Burke-Fahn-Marsden Dystonia Rating Scale) was observed postoperatively in the first patient and her personal therapeutic goals were achieved. DBS was previously reported in five patients with ADCY5-related movement disorders, of which three showed objective improvement. Emergency DBS in our second patient resulted in the successful termination of his GNAO1-related status dystonicus, this being the eighth case reported in the literature. CONCLUSION: DBS can be effective in monogenetic pediatric dystonia and should be considered early in the disease course. To better evaluate the effects of DBS on patients' functioning, patient-centered therapeutic goals should be discussed in a multidisciplinary approach.

The effects of small-scale physical and social environmental interventions on walking behaviour among Dutch older adults living in deprived neighbourhoods: results from the quasi-experimental NEW.ROADS study.

PURPOSE: Improving the physical and social conditions of residential neighbourhoods may increase walking, especially among older people. Evidence on the effects of physical and social environmental interventions, and particularly the combination of both, on walking behaviour is scarce. We evaluated the effects of a small-scale physical environmental intervention (designated walking route), a social environmental intervention (neighbourhood walking group) and the combination of both on walking behaviour of older adults living in deprived neighbourhoods. METHODS: Survey data of 644 older adults residing in four deprived neighbourhoods of Rotterdam, the Netherlands, were used to compare changes in walking behaviour over time (weekly minutes spent recreational walking, utilitarian walking and total walking) of those exposed to 1) a designated walking route (physical condition), 2) walking groups (social condition), 3) walking routes and walking groups (combined condition), and 4) no intervention (control condition). Measurements took place at baseline (T0), and 3 months (T1) and 9 months (T2) after the intervention. Data were analysed on a multiple imputed dataset, using multi-level negative binomial regression models, adjusting for clustering of observations within individuals. All models were adjusted for demographic covariates. RESULTS: Total time spent walking per week increased between T0 and T1 for all conditions. The Incidence Rate Ratio (IRR) for the physical condition was 1.46 (95% CI:1.06;2.05) and for the social intervention 1.52 (95%CI:1.07;2.16). At T2, these differences remained significant for the physical condition, but not for the social condition and the combined condition. These findings were mirrored for utilitarian walking. No evidence was found for an effect on recreational walking. CONCLUSION: Implementing small scale, feasible, interventions in a residential neighbourhood may increase total and utilitarian walking behaviour among older adults.

Effects of urban motorways on physical activity and sedentary behaviour in local residents: a natural experimental study.

BACKGROUND: There is little evidence on how changing the physical environment changes health-related behaviours. We studied the effects of the new M74 motorway (freeway) - opened in 2011 - and the existing M8 motorway in Glasgow, Scotland, on physical activity and sedentary behaviour among local residents. METHODS: This natural experimental study used baseline (T1; 2005) and follow-up data (T2; 2013) from a longitudinal cohort (N = 365) and two cross-sectional samples (T1 N = 980; T2 N = 978). Adult participants were recruited from three study areas: one surrounding the new motorway, one surrounding the existing motorway, and a third, control, area without a motorway. The outcomes were self-reported time spent sitting, walking, and in moderate-to-vigorous physical activity (MVPA). Motorway exposure was defined in terms of (1) study area and (2) distance from home to the nearest motorway junction. Outcomes were regressed on exposures in two-part (walking and MVPA) or linear (sedentary behaviour) cohort and repeat cross-sectional models, adjusted for baseline behaviour and sociodemographic covariates. RESULTS: Cohort participants living in the M8 area were less likely to participate in MVPA at follow-up than those living in the area without a motorway (OR 0.37; 95%CI 0.15, 0.91). Within the M8 area, those living closer to the motorway were also less likely to do so (OR 0.30; 95%CI 0.09, 0.97). No other statistically significant results were found. CONCLUSIONS: We found some evidence of a negative association between exposure to an existing urban motorway and MVPA. However, the behavioural impacts of motorways are likely to be complex and evolve over time.

Physical and social environmental changes to promote walking among Dutch older adults in deprived neighbourhoods: the NEW.ROADS study.

BACKGROUND: Physical activity is important for healthy ageing, and daily walking is seen as a feasible way to be active at older ages. Yet, many older persons, particularly in lower socioeconomic groups and residing in deprived neighbourhoods, are insufficiently active. Creating a physical and social neighbourhood environment that is more supportive for walking has the potential to improve walking behaviour. Current evidence of the impact of changes to the physical and/or social environmental on walking behaviour is scarce. The aim of the NEW.ROADS study is to design, implement and evaluate changes to the physical and social environment for the purpose of increasing walking behaviour among older residents of deprived neighbourhoods. METHODS: Physical and social environmental interventions were developed by matching scientific evidence on environmental determinants of walking, with input from the target population and stakeholders, and ongoing neighbourhood activities. Specifically, a neighbourhood walking route was designed and marked, and neighbourhood walking groups were organised. These environmental interventions were evaluated in a four-armed experimental study. In addition, the design of the study to evaluate the effect of these environmental changes on walking behaviour is described. DISCUSSION: Designing and implementing environmental interventions is a complex endeavour, challenged by limited available theory and evidence. Input from the target population and professional stakeholders is essential, but may also put constraints on the evaluation. TRIAL REGISTRATION: NTR3800 (registered 9/1/2013).

Causal pathways linking environmental change with health behaviour change: Natural experimental study of new transport infrastructure and cycling to work.

BACKGROUND: Mechanisms linking changes to the environment with changes in physical activity are poorly understood. Insights into mechanisms of interventions can help strengthen causal attribution and improve understanding of divergent response patterns. We examined the causal pathways linking exposure to new transport infrastructure with changes in cycling to work. METHODS: We used baseline (2009) and follow-up (2012) data (N=469) from the Commuting and Health in Cambridge natural experimental study (Cambridge, UK). Exposure to new infrastructure in the form of the Cambridgeshire Guided Busway was defined using residential proximity. Mediators studied were changes in perceptions of the route to work, theory of planned behaviour constructs and self-reported use of the new infrastructure. Outcomes were modelled as an increase, decrease or no change in weekly cycle commuting time. We used regression analyses to identify combinations of mediators forming potential pathways between exposure and outcome. We then tested these pathways in a path model and stratified analyses by baseline level of active commuting. RESULTS: We identified changes in perceptions of the route to work, and use of the cycle path, as potential mediators. Of these potential mediators, only use of the path significantly explained (85%) the effect of the infrastructure in increasing cycling. Path use also explained a decrease in cycling among more active commuters. CONCLUSION: The findings strengthen the causal argument that changing the environment led to changes in health-related behaviour via use of the new infrastructure, but also show how some commuters may have spent less time cycling as a result.

Development of a Greenhouse Screening Method for Adult Plant Response in Wheat to Stem Rust.

Screening for adult plant resistance in wheat to stem rust, caused by Puccinia graminis f. sp. tritici, is generally conducted in field plots. Although such evaluations are successful if managed properly, field ratings are time consuming, expensive, weather dependent, and open to inoculum of unwanted races or other confounding diseases. The objective of this study was to develop a dependable system of screening the response of adult plants to stem rust under greenhouse conditions. A comparison of inoculation methods and incubation environments showed that plants inoculated with urediniospores suspended in water, followed by a 24 h dew period in a plastic chamber constructed in a greenhouse, gave the most consistent results. Measurements of response type, stem rust severity, and frequency in follow-up experiments indicated that the most reliable infection was obtained when plants sprayed with 1.25 mg urediniospores per ml water were incubated in the plastic chamber. Using the optimized protocol, a Kariega × Avocet S doubled haploid population was inoculated with two P. graminis f. sp. tritici races. Depending on the race, composite interval mapping showed flag leaf infection type to be significantly influenced by regions on chromosomes 6A, 6D, and 7D. Stem rust severity and reaction type mapped to chromosomes 6D and/or 6A. The Lr34/Yr18/Sr57 gene derived from Kariega on chromosome 7D affected the rust response on flag leaves but not on stems of greenhouse-grown plants. This study showed that phenotyping and genetic analysis of especially major effect stem rust resistance in adult wheat plants is possible and reproducible under controlled conditions in a greenhouse.

Neighbourhood social capital as a moderator between individual cognitions and sports behaviour among Dutch adolescents.

This study aimed to explore whether individual cognitions and neighbourhood social capital strengthen each other in their relation with engaging in sports at least three times per week. Cross-sectional analyses on data from the last wave of the YouRAction trial (2009-2010, Rotterdam, the Netherlands; baseline response: 98%) were conducted. In total 1129 had data on the last wave questionnaire (93%) and 832 of them had complete data on a self-administered questionnaire on frequency of sports participation, perceived neighbourhood social capital, cognitions (attitude, subjective norm, perceived behavioural control and intention toward sport participation) and demographics. Ecometric methods were used to aggregate perceived neighbourhood social capital to the neighbourhood level. Multilevel logistic regression analyses (neighbourhood and individual as levels) were conducted to examine associations of cognitions, neighbourhood social capital and the social capital by individual cognition interaction with fit norm compliance. If the interaction was significant, simple slopes analyses were conducted to decompose interaction effects. It was found that neighbourhood social capital was significantly associated with fit norm compliance (OR: 5.40; 95% CI: 1.13-25.74). Moreover, neighbourhood social capital moderated the association of attitude, perceived behavioural control and intention with fit norm compliance. The simple slope analyses visualized that the associations of cognitions with fit norm compliance were stronger in case of more neighbourhood social capital. Hence, higher levels of neighbourhood social capital strengthen the associations of attitude, perceived behavioural control and intention in their association with fit norm compliance.

How many walking and cycling trips made by elderly are beyond commonly used buffer sizes: results from a GPS study.

In choosing appropriate buffer sizes to study environmental influences on physical activity, studies are hampered by insufficient insight into the distance elderly travel actively. This study aims at getting insight into the number of trips walked and cycled within various buffer sizes using GPS measures. Data were obtained from the Elderly And their Neighborhood study (Spijkenisse, the Netherlands (2011-2012)). Trip length and mode of transport were derived from the GPS data (N=120; total number of trips=337). Distance decay functions were fitted to estimate the percentage of trips to grocery stores within commonly used buffer sizes. Fifty percent of the trips walked had a distance of at least 729m; for trips cycled this was 1665m. Elderly aged under 75 years and those with functional limitations walked and cycled shorter distances than those over 75 years and those without functional limitations. Males cycled shorter distances than females. Distance decay functions may aid the selection of appropriate buffer sizes, which may be tailored to individual characteristics.

Effect of leaded glasses and thyroid shielding on cone beam CT radiation dose in an adult female phantom.

OBJECTIVES: This study aims to demonstrate the effectiveness of leaded glasses in reducing the lens of eye dose and of lead thyroid collars in reducing the dose to the thyroid gland of an adult female from dental cone beam CT (CBCT). The effect of collimation on the radiation dose in head organs is also examined. METHODS: Dose measurements were conducted by placing optically stimulated luminescent dosemeters in an anthropomorphic female phantom. Eye lens dose was measured by placing a dosemeter on the anterior surface of the phantom eye location. All exposures were performed on one commercially available dental CBCT machine, using selected collimation and exposure techniques. Each scan technique was performed without any lead shielding and then repeated with lead shielding in place. To calculate the percent reduction from lead shielding, the dose measured with lead shielding was divided by the dose measured without lead shielding. The percent reduction from collimation was calculated by comparing the dose measured with collimation to the dose measured without collimation. RESULTS: The dose to the internal eye for one of the scans without leaded glasses or thyroid shield was 0.450 cGy and with glasses and thyroid shield was 0.116 cGy (a 74% reduction). The reduction to the lens of the eye was from 0.396 cGy to 0.153 cGy (a 61% reduction). Without glasses or thyroid shield, the thyroid dose was 0.158 cGy; and when both glasses and shield were used, the thyroid dose was reduced to 0.091 cGy (a 42% reduction). CONCLUSIONS: Collimation alone reduced the dose to the brain by up to 91%, with a similar reduction in other organs. Based on these data, leaded glasses, thyroid collars and collimation minimize the dose to organs outside the field of view.

Identification of adult plant resistance to stripe rust in the wheat cultivar Cappelle-Desprez.

Following the appearance of stripe rust in South Africa in 1996, efforts have been made to identify new sources of durable resistance. The French cultivar Cappelle-Desprez has long been considered a source of durable, adult plant resistance (APR) to stripe rust. As Cappelle-Desprez contains the seedling resistance genes Yr3a and Yr4a, wheat lines were developed from which Yr3a and Yr4a had been removed, while selecting for Cappelle-Desprez derived APR effective against South African pathotypes of the stripe rust fungus, Puccinia striiformis f. sp. tritici. Line Yr16DH70, adapted to South African wheat growing conditions, was selected and crossed to the stripe rust susceptible cultivar Palmiet to develop a segregating recombinant inbred line mapping population. A major effect QTL, QYr.ufs-2A was identified on the short arm of chromosome 2A derived from Cappelle-Desprez, along with three QTL of smaller effect, QYr.ufs-2D, QYr.ufs-5B and QYr.ufs-6D. QYr.ufs-2D was located within a region on the short arm of chromosome 2D believed to be the location of the stripe rust resistance gene Yr16. An additional minor effect QTL, QYr.ufs-4B, was identified in the cv. Palmiet. An examination of individual RILs carrying single or combinations of each QTL indicated significant resistance effects when QYr.ufs-2A was combined with the three minor QTL from Cappelle-Desprez, and between QYr.ufs-2D and QYr.ufs-5B.

Significant reduction in dental cone beam computed tomography (CBCT) eye dose through the use of leaded glasses.

OBJECTIVE: In light of the increased recognition of the potential for lens opacification after low-dose radiation exposures, we investigated the effect of leaded eyeglasses worn during dental cone-beam computerized tomography (CBCT) procedures on the radiation absorbed dose to the eye and suggest simple methods to reduce risk of radiation cataract development. STUDY DESIGN: Dose measurements were conducted with the use of 3 anthropomorphic phantoms: male (Alderson radiation therapy phantom), female (CIRS), and juvenile male (CIRS). All exposures were performed on the same dental CBCT machine (Imtec, Ardmore, OK) using 2 different scanning techniques but with identical machine parameters (120 kVp, 3.8 mA, 7.8 s). Scans were performed with and without leaded glasses and repeated 3 times. All measurements were recorded using calibrated thermoluminescent dosimeters and optical luminescent dosimetry. RESULTS: Leaded glasses worn by adult and pediatric patients during CBCT scans may reduce radiation dose to the lens of the eye by as much as 67% (from 0.135 ± 0.004 mGy to 0.044 ± 0.002 mGy in pediatric patients). CONCLUSIONS: Leaded glasses do not appear to have a deleterious effect on the image quality in the area of clinical significance for dental imaging.

On determining the nuclearity of iron sites in Fe-ZSM-5--a critical evaluation.

In order to interpret catalytic data on iron zeolites in terms of structure-activity relationships, reliable characterisation methods are needed. In particular, the nuclearity of the iron species is an important issue, since it is often invoked to explain catalytic activity. In the present contribution, we address the problem of the nuclearity of the iron species in Fe-ZSM-5 by a combination of techniques, that is, UV-Vis, EXAFS, Magnetic Circular Dichroism (MCD) and magnetisation measurements. Based on an in-depth analysis of these data, we show that some of the current interpretations of UV-Vis and EXAFS spectra need to be revised.

A genetic analysis of adult plant resistance to stripe rust in the wheat cultivar Kariega.

The wheat cultivar Kariega expresses complete adult plant resistance to stripe rust in South Africa. The aim of this investigation was to determine the extent and nature of variability in stripe rust resistance in a population of 150 doubled haploid lines generated from a cross between Kariega and the susceptible cultivar Avocet S. Analysis of field data for adult plant stripe rust resistance identified two major QTLs and two minor QTLs in the resistant cultivar Kariega. The two major QTLs were located on chromosomes 7D ( QYr.sgi-7D) and 2B ( QYr.sgi-2B.1), contributing 29% and 30% to the phenotypic variance, respectively. QYr.sgi-2B.1 is primarily associated with a chlorotic and/or necrotic response, unlike QYr.sgi-7D, which is believed to be the adult plant resistance gene Yr18. These two QTLs for adult plant resistance in Kariega appear to represent different forms of resistance, where QYr.sgi-7D may represent potentially more durable resistance than QYr.sgi-2B.1. Mixture model analysis of the field leaf infection scores suggested a genetic model involving two independent genes combining in a classical, epistatic manner. The results of the QTL analysis demonstrate its higher resolution power compared to the mixture model analysis by detecting the presence of minor QTLs.

Cytotoxic T cells infiltrating a glioma express an aberrant phenotype that is associated with decreased function and apoptosis.

In this study, we report on novel alterations found in rat intracranial (i.c.) tumor-infiltrating T lymphocytes (TIL) that are indicative of T cell defects and death. FACS analysis showed that the cytotoxic T cells (CTL) infiltrating rat T9.F gliomas were CD3epsilon+, alphabetaTCR+, CD8alpha+, but CD8beta-. These lymphocytes also stained positive for the B cell-specific marker, CD45RA, as well as Annexin-V, signifying apoptotic changes. Functional and biochemical analyses were performed to assess whether the aberrant phenotype was linked to other defects. When CD8alpha+ TIL were purified and stimulated in vitro, their proliferative capacity was markedly diminished in comparison with CD3+CD8alpha+CD8beta+ T cells isolated from the spleens of naive, non tumor-bearing rats. Furthermore, the mean fluorescence intensity of surface CD3epsilon was dramatically reduced in the CD3+CD8alpha+CD8beta- TIL population as compared with CD3-CD8alpha+CD8beta+ TIL from the same tumor-bearing animal. Biochemical studies revealed that the expression of TCRzeta and LAT were reduced in lysates generated from CD8alpha-purified TIL with respect to CD8alpha-purified T cells from naive spleen. We believe that these degenerative changes are reflective of chronic T cell receptor ligation, because in vitro culture of rat splenocytes or purified T cells with ConA or anti-CD3 mAb induced the same alterations. In vitro, the downregulation of CD8beta could be inhibited by the caspase inhibitor, z-VAD. These results suggest that the aberrant CTL phenotype found in the TIL of glioma-bearing rats may be novel signals for their impending death and degenerating anti-tumor immune function.

QEXAFS study of the sulfidation of NiMo/Al2O3 hydrotreating catalysts.

Quick-scanning extended X-ray absorption fine structure (QEXAFS) spectroscopy was employed to investigate in situ the sulfidation of Mo and Ni in y-AI2O3-supported hydrotreating catalysts modified with chelating ligands. Mo K-edge QEXAFS enabled the detection of an intermediate product in the sulfidation of Mo. The parameters obtained from the fits of the QEXAFS spectra showed that this product consists of compounds similar to Mo2S2-(12) or Mo3S2-(13). QEXAFS also demonstrated that the sulfidation of Ni is strongly influenced by the presence of chelating ligands. Classical EXAFS spectra of the sulfided catalysts showed that Ni forms small sulfided clusters, the size of which is influenced by the presence or absence of the chelating agents.

Vaccination of malignant glioma patients with peptide-pulsed dendritic cells elicits systemic cytotoxicity and intracranial T-cell infiltration.

In this Phase I trial, patients' peripheral blood dendritic cells were pulsed with peptides eluted from the surface of autologous glioma cells. Three biweekly intradermal vaccinations of peptide-pulsed dendritic cells were administered to seven patients with glioblastoma multiforme and two patients with anaplastic astrocytoma. Dendritic cell vaccination elicited systemic cytotoxicity in four of seven tested patients. Robust intratumoral cytotoxic and memory T-cell infiltration was detected in two of four patients who underwent reoperation after vaccination. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous peptide-pulsed dendritic cell vaccine for patients with malignant glioma.