A diverse panel of 755 bread wheat accessions harbors untapped genetic diversity in landraces and reveals novel genetic regions conferring powdery mildew resistance.

KEY MESSAGE: A bread wheat panel reveals rich genetic diversity in Turkish, Pakistani and Iranian landraces and novel resistance loci to diverse powdery mildew isolates via subsetting approaches in association studies. Wheat breeding for disease resistance relies on the availability and use of diverse genetic resources. More than 800,000 wheat accessions are globally conserved in gene banks, but they are mostly uncharacterized for the presence of resistance genes and their potential for agriculture. Based on the selective reduction of previously assembled collections for allele mining for disease resistance, we assembled a trait-customized panel of 755 geographically diverse bread wheat accessions with a focus on landraces, called the LandracePLUS panel. Population structure analysis of this panel based on the TaBW35K SNP array revealed an increased genetic diversity compared to 632 landraces genotyped in an earlier study and 17 high-quality sequenced wheat accessions. The additional genetic diversity found here mostly originated from Turkish, Iranian and Pakistani landraces. We characterized the LandracePLUS panel for resistance to ten diverse isolates of the fungal pathogen powdery mildew. Performing genome-wide association studies and dividing the panel further by a targeted subsetting approach for accessions of distinct geographical origin, we detected several known and already cloned genes, including the Pm2a gene. In addition, we identified 22 putatively novel powdery mildew resistance loci that represent useful sources for resistance breeding and for research on the mildew-wheat pathosystem. Our study shows the value of assembling trait-customized collections and utilizing a diverse range of pathogen races to detect novel loci. It further highlights the importance of integrating landraces of different geographical origins into future diversity studies.

Breeding for durable resistance against biotrophic fungal pathogens using transgenes from wheat.

Breeding for resistant crops is a sustainable way to control disease and relies on the introduction of novel resistance genes. Here, we tested three strategies on how to use transgenes from wheat to achieve durable resistance against fungal pathogens in the field. First, we tested the highly effective, overexpressed single transgene Pm3e in the background of spring wheat cultivar Bobwhite in a long-term field trial over many years. Together with previous results, this revealed that transgenic wheat line Pm3e#2 conferred complete powdery mildew resistance during a total of nine field seasons without a negative impact on yield. Furthermore, overexpressed Pm3e provided resistance to powdery mildew isolates from our worldwide collection when crossed into the elite wheat cultivar Fiorina. Second, we pyramided the four overexpressed transgenes Pm3a, Pm3b, Pm3d, and Pm3f in the background of cultivar Bobwhite and showed that the pyramided line Pm3a,b,d,f was completely resistant to powdery mildew in five field seasons. Third, we performed field trials with three barley lines expressing adult plant resistance gene Lr34 from wheat during three field seasons. Line GLP8 expressed Lr34 under control of the pathogen-inducible Hv-Ger4c promoter and provided partial barley powdery mildew and leaf rust resistance in the field with small, negative effects on yield components which might need compensatory breeding. Overall, our study demonstrates and discusses three successful strategies for achieving fungal disease resistance of wheat and barley in the field using transgenes from wheat. These strategies might confer long-term resistance if applied in a sustainable way. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01451-2.

Pyramiding of transgenic immune receptors from primary and tertiary wheat gene pools improves powdery mildew resistance in the field.

Introgression of resistance genes from wild or related species is a common strategy to improve disease resistance of wheat cultivars. Pm17 is a gene that confers powdery mildew resistance in wheat. It encodes an NLR type of immune receptor and was introgressed from rye to wheat as part of the 1RS chromosome arm translocation several decades ago. So far it has not been possible to separate Pm17 from its co-introgressed rye genes due to suppressed recombination. Here we tested in the field transgenic Bobwhite wheat overexpressing Pm17 without any other rye genes. Four transgenic events showed high levels of PM17 protein accumulation, strong powdery mildew resistance, and no pleiotropic effects during three field seasons. We used a combined approach of transgene insertion and cross-breeding to generate lines co-expressing Pm17 and Pm3, or Pm17 and Pm8. Blumeria graminis f. sp. tritici infection tests confirmed additive, race-specific resistance of the two pyramided transgenes in lines Pm17+Pm3b and Pm17+Pm8. Furthermore, pyramided lines showed strong powdery mildew resistance during three field seasons. We conclude that the combination of overexpressed NLR genes from the extended gene pool broadens and diversifies wheat disease resistance.

Child wasting and concurrent stunting in low- and middle-income countries.

Sustainable Development Goal 2.2-to end malnutrition by 2030-includes the elimination of child wasting, defined as a weight-for-length z-score that is more than two standard deviations below the median of the World Health Organization standards for child growth1. Prevailing methods to measure wasting rely on cross-sectional surveys that cannot measure onset, recovery and persistence-key features that inform preventive interventions and estimates of disease burden. Here we analyse 21 longitudinal cohorts and show that wasting is a highly dynamic process of onset and recovery, with incidence peaking between birth and 3 months. Many more children experience an episode of wasting at some point during their first 24 months than prevalent cases at a single point in time suggest. For example, at the age of 24 months, 5.6% of children were wasted, but by the same age (24 months), 29.2% of children had experienced at least one wasting episode and 10.0% had experienced two or more episodes. Children who were wasted before the age of 6 months had a faster recovery and shorter episodes than did children who were wasted at older ages; however, early wasting increased the risk of later growth faltering, including concurrent wasting and stunting (low length-for-age z-score), and thus increased the risk of mortality. In diverse populations with high seasonal rainfall, the population average weight-for-length z-score varied substantially (more than 0.5 z in some cohorts), with the lowest mean z-scores occurring during the rainiest months; this indicates that seasonally targeted interventions could be considered. Our results show the importance of establishing interventions to prevent wasting from birth to the age of 6 months, probably through improved maternal nutrition, to complement current programmes that focus on children aged 6-59 months.

Early-childhood linear growth faltering in low- and middle-income countries.

Globally, 149 million children under 5 years of age are estimated to be stunted (length more than 2 standard deviations below international growth standards)1,2. Stunting, a form of linear growth faltering, increases the risk of illness, impaired cognitive development and mortality. Global stunting estimates rely on cross-sectional surveys, which cannot provide direct information about the timing of onset or persistence of growth faltering-a key consideration for defining critical windows to deliver preventive interventions. Here we completed a pooled analysis of longitudinal studies in low- and middle-income countries (n = 32 cohorts, 52,640 children, ages 0-24 months), allowing us to identify the typical age of onset of linear growth faltering and to investigate recurrent faltering in early life. The highest incidence of stunting onset occurred from birth to the age of 3 months, with substantially higher stunting at birth in South Asia. From 0 to 15 months, stunting reversal was rare; children who reversed their stunting status frequently relapsed, and relapse rates were substantially higher among children born stunted. Early onset and low reversal rates suggest that improving children's linear growth will require life course interventions for women of childbearing age and a greater emphasis on interventions for children under 6 months of age.

Causes and consequences of child growth faltering in low-resource settings.

Growth faltering in children (low length for age or low weight for length) during the first 1,000 days of life (from conception to 2 years of age) influences short-term and long-term health and survival1,2. Interventions such as nutritional supplementation during pregnancy and the postnatal period could help prevent growth faltering, but programmatic action has been insufficient to eliminate the high burden of stunting and wasting in low- and middle-income countries. Identification of age windows and population subgroups on which to focus will benefit future preventive efforts. Here we use a population intervention effects analysis of 33 longitudinal cohorts (83,671 children, 662,763 measurements) and 30 separate exposures to show that improving maternal anthropometry and child condition at birth accounted for population increases in length-for-age z-scores of up to 0.40 and weight-for-length z-scores of up to 0.15 by 24 months of age. Boys had consistently higher risk of all forms of growth faltering than girls. Early postnatal growth faltering predisposed children to subsequent and persistent growth faltering. Children with multiple growth deficits exhibited higher mortality rates from birth to 2 years of age than children without growth deficits (hazard ratios 1.9 to 8.7). The importance of prenatal causes and severe consequences for children who experienced early growth faltering support a focus on pre-conception and pregnancy as a key opportunity for new preventive interventions.

What every dentist needs to know about the use of artificial intelligence in dentistry.

Artificial intelligence (AI) is a division of computer science that allows machines to emulate human cognitive processes. In dentistry, AI is applied in clinical decision-making and can aid in detecting disease and predicting patterns based on existing data sets. AI can assist clinicians by quickly analyzing massive amounts of data to improve workflow, identify patterns of disease, provide risk assessment, and create individualized patient-centered treatment plans. AI has been shown to increase efficiency in the office by aiding in scheduling, tracking, and updating patient records to better organize patient data. The objective of this article is to outline the various applications of AI in different dental specialties. Applications range from business functions such as marketing, cyber security, and report writing to clinical uses such as lesion detection and surgical guidance. This review will also discuss some of the ethical considerations and drawbacks associated with implementing AI in the dental practice.

Comparative Transcriptome Analysis of Wheat Lines in the Field Reveals Multiple Essential Biochemical Pathways Suppressed by Obligate Pathogens.

Mildew and rust are the most devastating cereal pathogens, and in wheat they can cause up to 50% yield loss every year. Wheat lines containing resistance genes are used to effectively control fungal diseases, but the molecular mechanisms underlying the interaction between wheat and its fungal pathogens are poorly understood. Here, we used RNA sequencing (RNA-Seq) to compare the transcriptomic landscape of susceptible and resistant wheat lines to identify genes and pathways that are targeted by obligate biotrophic fungal pathogens. The five lines differed in the expression of thousands of genes under infection as well as control conditions. Generally, mixed infection with powdery mildew and leaf rust resulted in downregulation of numerous genes in susceptible lines. Interestingly, transcriptomic comparison between the nearly isogenic lines Thatcher and Thatcher-Lr34 identified 753 genes that are uniquely downregulated in the susceptible line upon infection. Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis, revealed the suppression of six major biochemical pathways, namely nuclear transport, alternative splicing, DNA damage response, ubiquitin-mediated proteolysis, phosphoinositol signaling, and photosynthesis. We conclude that powdery mildew and leaf rust evade the wheat defense system by suppression of programmed cell death (PCD) and responses to cellular damage. Considering the broad range of the induced changes, we propose that the pathogen targets "master regulators" at critical steps in the respective pathways. Identification of these wheat genes targeted by the pathogen could inspire new directions for future wheat breeding.

Single residues in the LRR domain of the wheat PM3A immune receptor can control the strength and the spectrum of the immune response.

The development of improved plant nucleotide-binding, leucine-rich repeat (LRR) immune receptors (NLRs) has mostly been based on random mutagenesis or on structural information available for specific receptors complexed with the recognized pathogen effector. Here, we use a targeted mutagenesis approach based on the natural diversity of the Pm3 powdery mildew resistance alleles present in different wheat (Triticum aestivum) genotypes. In order to understand the functional importance of the amino acid polymorphisms between the active immune receptor PM3A and the inactive ancestral variant PM3CS, we exchanged polymorphic regions and residues in the LRR domain of PM3A with the corresponding segments of PM3CS. These novel variants were functionally tested for recognition of the corresponding AVRPM3A2/F2 avirulence protein in Nicotiana benthamiana. We identified polymorphic residues in four regions of PM3A that enhance the immune response, but also residues that reduce it or result in complete loss of function. We found that the identified critical residues in PM3A modify its activation threshold towards different protein variants of AVRPM3A2/F2 . PM3A variants with a lowered threshold gave a stronger overall response and gained an extended recognition spectrum. One of these variant proteins with a single amino acid change was stably transformed into wheat, where it conferred race-specific resistance to mildew. This is a proof of concept that improved PM3A variants with an enlarged recognition spectrum can be engineered based on natural diversity by exchanging single or multiple residues that modulate resistance function.

Cross-Kingdom RNAi of Pathogen Effectors Leads to Quantitative Adult Plant Resistance in Wheat.

Cross-kingdom RNA interference (RNAi) is a biological process allowing plants to transfer small regulatory RNAs to invading pathogens to trigger the silencing of target virulence genes. Transient assays in cereal powdery mildews suggest that silencing of one or two effectors could lead to near loss of virulence, but evidence from stable RNAi lines is lacking. We established transient host-induced gene silencing (HIGS) in wheat, and demonstrate that targeting an essential housekeeping gene in the wheat powdery mildew pathogen (Blumeria graminis f. sp. tritici) results in significant reduction of virulence at an early stage of infection. We generated stable transgenic RNAi wheat lines encoding a HIGS construct simultaneously silencing three B.g. tritici effectors including SvrPm3 a1/f1 , a virulence factor involved in the suppression of the Pm3 powdery mildew resistance gene. We show that all targeted effectors are effectively downregulated by HIGS, resulting in reduced fungal virulence on adult wheat plants. Our findings demonstrate that stable HIGS of effector genes can lead to quantitative gain of resistance without major pleiotropic effects in wheat.

Fostering coping as a mechanism of symptom change in cognitive behavioural therapy for psychosis.

INTRODUCTION: Cognitive behavioural therapy for psychosis (CBTp) has been repeatedly shown to ameliorate psychotic symptoms. However, so far we have little understanding of the mechanisms of change in CBTp. In this study, we tested whether improved cognitive and behavioural efforts to manage taxing external or internal demands (=coping) constitute a mechanism of change in CBTp. METHODS: Using data from a published trial for a secondary analysis, we tested whether the continuous symptomatic improvement of patients (n = 57) who received up to 45 sessions of CBTp and completed weekly self-assessments of symptoms (suspiciousness, individualised positive and negative symptoms, and individualised symptoms of depression) was mediated by preceding improvement in self-assessed coping using multilevel analysis. A reverse model in which symptom improvement predicted improved coping was also tested. RESULTS: Continuous improvement in suspiciousness, negative symptoms, and depression over the course of CBTp was preceded by improvement in coping. Improvement in suspiciousness or positive symptoms did not predict subsequent improvement in coping, whereas improvement in negative symptoms and depression predicted subsequent improvement in coping. CONCLUSION: Coping constitutes a mechanism of change, albeit to a different extent for different symptom clusters. Further research needs to explore how best to utilise this mechanism and optimise its integration with other active ingredients of CBTp to maximise therapeutic gain.

BPG: Seamless, automated and interactive visualization of scientific data.

BACKGROUND: We introduce BPG, a framework for generating publication-quality, highly-customizable plots in the R statistical environment. RESULTS: This open-source package includes multiple methods of displaying high-dimensional datasets and facilitates generation of complex multi-panel figures, making it suitable for complex datasets. A web-based interactive tool allows online figure customization, from which R code can be downloaded for integration with computational pipelines. CONCLUSION: BPG provides a new approach for linking interactive and scripted data visualization and is available at http://labs.oicr.on.ca/boutros-lab/software/bpg or via CRAN at https://cran.r-project.org/web/packages/BoutrosLab.plotting.general.

The impact of negative treatment experiences on persistent refusal of antipsychotics.

AIMS: We investigate reasons for persistent medication refusal in schizophrenia spectrum disorders and test whether factors that speak for a rational decision, such as negative experiences with medication or low symptom distress predict medication refusal, even after taking differences in insight into account. METHOD: We included 45 participants with schizophrenia spectrum disorders, of which 20 had refused antipsychotic medication for at least three months and assessed reasons for taking or not taking medication, labeling condition as mental disorder ("insight"), experiences with the previous treatments, symptoms and symptom distress, positive and negative consequences and experiences of psychosis, causal beliefs, therapeutic relationships with previous clinicians and attitudes towards medication. RESULTS: Groups did not differ in symptom severity but medication refusers reported significantly less insight, less satisfaction with their most-recent psychiatrist and with previous medication, and more negative beliefs about harmful effects of medication. They also felt less informed about medication. After controlling for insight, the perceived helpfulness of the previous treating psychiatrist (OR=0.30, z=5.58, p=0.018) and of previous medication (OR=0.27, z=6.87, p=0.009) and feeling insufficiently informed about medication (OR=0.53, z=3. 85, p=0.050) significantly predicted medication discontinuation. CONCLUSIONS: Building rapport with patients with a different view of the nature of their condition and encouraging informed decisions on medication are likely to improve medication adherence. However, the findings also suggest that refusing medication after a phase of initial adherence is also the consequence of negative experiences with medication and could result from weighing the pros against the cons.

The potential of continuum versus biogenetic beliefs in reducing stigmatization against persons with schizophrenia: An experimental study.

OBJECTIVE: A central aspect of previous anti-stigma campaigns was the promotion of biogenetic causes of schizophrenia. Although biogenetic beliefs have been shown to reduce the blame given to persons with schizophrenia, they tend to increase discrimination and stereotypes such as dangerousness and unpredictability. A novel anti-stigma approach is to incorporate continuum beliefs in order to oppose the perceived separation, which is a main component of the stigma process. The aim of the study was to compare the effects of a continuum, a biogenetic, and a control intervention on stereotypes, fear, and social distance towards persons with schizophrenia. Furthermore, it was intended to replicate earlier findings on the associations between continuum beliefs, biogenetic beliefs, and different facets of stigmatization. METHOD: In an online-experiment, 1189 participants from the general population randomly received either a continuum, a biogenetic, or a control intervention, which consisted of written information texts. RESULTS: The continuum group showed less endorsement of the stereotype incompetence/unpredictability than the biogenetic group. The biogenetic group ascribed less blame to persons with schizophrenia than the other groups. The correlation analyses indicated continuum beliefs to be consistently associated with lower stereotype scores, less fear, and less preferred social distance. LIMITATIONS: The sample was not fully representative and the experimental manipulations in our study consisted of relatively short information texts. CONCLUSION: It is concluded that continuum beliefs have the potential to reduce stigmatization against persons with schizophrenia. However, future studies need to investigate the effects of more powerful interventions to promote them.

Spatial genomic heterogeneity within localized, multifocal prostate cancer.

Herein we provide a detailed molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer to delineate new oncogenes or tumor suppressors. We initially determined the copy number aberration (CNA) profiles of 74 patients with index tumors of Gleason score 7. Of these, 5 patients were subjected to whole-genome sequencing using DNA quantities achievable in diagnostic biopsies, with detailed spatial sampling of 23 distinct tumor regions to assess intraprostatic heterogeneity in focal genomics. Multifocal tumors are highly heterogeneous for single-nucleotide variants (SNVs), CNAs and genomic rearrangements. We identified and validated a new recurrent amplification of MYCL, which is associated with TP53 deletion and unique profiles of DNA damage and transcriptional dysregulation. Moreover, we demonstrate divergent tumor evolution in multifocal cancer and, in some cases, tumors of independent clonal origin. These data represent the first systematic relation of intraprostatic genomic heterogeneity to predicted clinical outcome and inform the development of novel biomarkers that reflect individual prognosis.

Perceived therapist genuineness predicts therapeutic alliance in cognitive behavioural therapy for psychosis.

OBJECTIVES: The quality of therapeutic alliance is a consistent and stable predictor of therapy outcome. Recent studies have shown therapist characteristics to be relevant predictors of the alliance in psychological therapies in general. However, little is known about the specific therapist characteristics that explain differences in therapeutic alliance in cognitive behavioural therapy for psychosis (CBTp). The aim of this study was to identify relevant therapist characteristics that predict early therapeutic alliance in CBTp. DESIGN AND METHODS: Forty-eight patients with a DSM-IV diagnosis of a psychotic disorder participating in a CBTp trial and 11 therapists were included in the analysis. Therapist characteristics as perceived by the patients (empathy, genuineness, positive regard, competence, and convincingness) were assessed at baseline. Alliance was assessed after the fifth therapy session. Data were analyzed using bivariate correlations and multivariate hierarchic regression analysis. RESULTS: All therapist characteristics were positively associated with patient-rated alliance. Patient characteristics were not significantly associated with alliance and did not predict alliance in the multivariate analysis. Regression analysis revealed therapist genuineness and competence to significantly predict higher patient-rated alliance. CONCLUSIONS: Our results suggest that perceived therapist genuineness is the most relevant predictor of patient-rated therapeutic alliance in CBTp. Future trials using control samples with other mental disorders could clarify whether this finding is specific to CBTp. Therapist training concepts for increasing beneficial therapist qualities are needed. PRACTITIONER POINTS: The patients' perception of the therapist as empathic, genuine, accepting, competent and convincing is associated with therapeutic alliance in CBTp. Perceived therapist genuineness and competence are the most relevant predictors of patient-rated therapeutic alliance. Training and supervision should focus on increasing basic therapist qualities. Limitations of this study include homogeneity of therapists, small sample size, and lack of a control group.

Explaining attitudes and adherence to antipsychotic medication: the development of a process model.

Although nonadherence to antipsychotic medication poses a threat to outcome of medical treatment, the processes preceding the intake behavior have not been investigated sufficiently. This study tests a process model of medication adherence derived from the Health Belief Model which is based on cost-benefit considerations. The model includes an extensive set of potential predictors for medication attitudes and uses these attitudes as a predictor for medication adherence. We conducted an online study of 84 participants with a self-reported psychotic disorder and performed a path analysis. More insight into the need for treatment, a higher attribution of the symptoms to a mental disorder, experience of less negative side effects, presence of biological causal beliefs, and less endorsement of psychological causal beliefs were significant predictors of more positive attitudes towards medication. The results largely supported the postulated process model. Mental health professionals should consider attitudes towards medication and the identified predictors when they address adherence problems with the patient in a shared and informed decision process.