The graded multidimensional geometry of phenotypic variation and progression in neurodegenerative syndromes.

Clinical variants of Alzheimer's disease and frontotemporal lobar degeneration display a spectrum of cognitive-behavioural changes varying between individuals and over time. Understanding the landscape of these graded individual-/group-level longitudinal variations is critical for precise phenotyping; however, this remains challenging to model. Addressing this challenge, we leverage the National Alzheimer's Coordinating Center database to derive a unified geometric framework of graded longitudinal phenotypic variation in Alzheimer's disease and frontotemporal lobar degeneration. We included three time-point, cognitive-behavioural and clinical data from 390 typical, atypical and intermediate Alzheimer's disease and frontotemporal lobar degeneration variants (114 typical Alzheimer's disease; 107 behavioural variant frontotemporal dementia; 42 motor variants of frontotemporal lobar degeneration; and 103 primary progressive aphasia patients). On this data, we applied advanced data-science approaches to derive low-dimensional geometric spaces capturing core features underpinning clinical progression of Alzheimer's disease and frontotemporal lobar degeneration syndromes. To do so, we first used principal component analysis to derive six axes of graded longitudinal phenotypic variation capturing patient-specific movement along and across these axes. Then, we distilled these axes into a visualisable 2D manifold of longitudinal phenotypic variation using Uniform Manifold Approximation and Projection. Both geometries together enabled the assimilation and inter-relation of paradigmatic and mixed cases, capturing dynamic individual trajectories, and linking syndromic variability to neuropathology and key clinical end-points such as survival. Through these low-dimensional geometries, we show that (i) specific syndromes (Alzheimer's disease and primary progressive aphasia) converge over time into a de-differentiated pooled phenotype, while others (frontotemporal dementia variants) diverge to look different from this generic phenotype; (ii) phenotypic diversification is predicted by simultaneous progression along multiple axes, varying in a graded manner between individuals and syndromes; and (iii) movement along specific principal axes predicts survival at 36 months in a syndrome-specific manner and in individual pathological groupings. The resultant mapping of dynamics underlying cognitive-behavioural evolution potentially holds paradigm-changing implications to predicting phenotypic diversification and phenotype-neurobiological mapping in Alzheimer's disease and frontotemporal lobar degeneration.

The genetics of Ug99 stem rust resistance in spring wheat variety 'Linkert'.

Wheat stem rust caused by Puccinia graminis f. sp. tritici (Pgt) threatens wheat production worldwide. The objective of this study was to characterize wheat stem rust resistance in 'Linkert', a variety with adult plant resistance effective to emerging wheat stem rust pathogen strain Ug99. Two doubled haploid (DH) populations and one recombinant inbred line (RIL) population were developed with 'Linkert' as a stem rust resistant parent. Hard red spring wheat variety 'Forefront' and genetic stock 'LMPG' were used as stem rust susceptible parents of the DH populations. Breeding line 'MN07098-6' was used as a susceptible parent of the RIL population. Both DH and RIL populations with their parents were evaluated both at the seedling stage and in the field against Pgt races. Genotyping data of the DH populations were generated using the wheat iSelect 90k SNP assay. The RIL population was genotyped by genotyping-by-sequencing. We found QTL consistently associated with wheat stem rust resistance on chromosome 2BS for the Linkert/Forefront DH population and the Linkert/MN07098-6 RIL population both in Ethiopia and Kenya. Additional reliable QTL were detected on chromosomes 5BL (125.91 cM) and 4AL (Sr7a) for the Linkert/LMPG population in Ethiopia and Kenya. Different QTL identified in the populations reflect the importance of examining the genetics of resistance in populations derived from adapted germplasm (Forefront and MN07098-6) in addition to a genetic stock (LMPG). The associated markers in this study could be used to track and select for the identified QTL in wheat breeding programs.

A neuroanatomical and cognitive model of impaired social behaviour in frontotemporal dementia.

Impaired social cognition is a core deficit in frontotemporal dementia (FTD). It is most commonly associated with the behavioural-variant of FTD, with atrophy of the orbitofrontal and ventromedial prefrontal cortex. Social cognitive changes are also common in semantic dementia, with atrophy centred on the anterior temporal lobes. The impairment of social behaviour in FTD has typically been attributed to damage to the orbitofrontal cortex and/or temporal poles and/or the uncinate fasciculus that connects them. However, the relative contributions of each region are unresolved. In this review, we present a unified neurocognitive model of controlled social behaviour that not only explains the observed impairment of social behaviours in FTD, but also assimilates both consistent and potentially contradictory findings from other patient groups, comparative neurology and normative cognitive neuroscience. We propose that impaired social behaviour results from damage to two cognitively- and anatomically-distinct components. The first component is social-semantic knowledge, a part of the general semantic-conceptual system supported by the anterior temporal lobes bilaterally. The second component is social control, supported by the orbitofrontal cortex, medial frontal cortex and ventrolateral frontal cortex, which interacts with social-semantic knowledge to guide and shape social behaviour.

Synaptic density affects clinical severity via network dysfunction in syndromes associated with frontotemporal lobar degeneration.

There is extensive synaptic loss from frontotemporal lobar degeneration, in preclinical models and human in vivo and post mortem studies. Understanding the consequences of synaptic loss for network function is important to support translational models and guide future therapeutic strategies. To examine this relationship, we recruited 55 participants with syndromes associated with frontotemporal lobar degeneration and 24 healthy controls. We measured synaptic density with positron emission tomography using the radioligand [11C]UCB-J, which binds to the presynaptic vesicle glycoprotein SV2A, neurite dispersion with diffusion magnetic resonance imaging, and network function with task-free magnetic resonance imaging functional connectivity. Synaptic density and neurite dispersion in patients was associated with reduced connectivity beyond atrophy. Functional connectivity moderated the relationship between synaptic density and clinical severity. Our findings confirm the importance of synaptic loss in frontotemporal lobar degeneration syndromes, and the resulting effect on behaviour as a function of abnormal connectivity.

Single amino acid change alters specificity of the multi-allelic wheat stem rust resistance locus SR9.

Most rust resistance genes thus far isolated from wheat have a very limited number of functional alleles. Here, we report the isolation of most of the alleles at wheat stem rust resistance gene locus SR9. The seven previously reported resistance alleles (Sr9a, Sr9b, Sr9d, Sr9e, Sr9f, Sr9g, and Sr9h) are characterised using a synergistic strategy. Loss-of-function mutants and/or transgenic complementation are used to confirm Sr9b, two haplotypes of Sr9e (Sr9e_h1 and Sr9e_h2), Sr9g, and Sr9h. Each allele encodes a highly related nucleotide-binding site leucine-rich repeat (NB-LRR) type immune receptor, containing an unusual long LRR domain, that confers resistance to a unique spectrum of isolates of the wheat stem rust pathogen. The only SR9 protein effective against stem rust pathogen race TTKSK (Ug99), SR9H, differs from SR9B by a single amino acid. SR9B and SR9G resistance proteins are also distinguished by only a single amino acid. The SR9 allelic series found in the B subgenome are orthologs of wheat stem rust resistance gene Sr21 located in the A subgenome with around 85% identity in protein sequences. Together, our results show that functional diversification of allelic variants at the SR9 locus involves single and multiple amino acid changes that recognize isolates of wheat stem rust.

Developing adapted wheat lines with broad-spectrum resistance to stem rust: Introgression of Sr59 through backcrossing and selections based on genotyping-by-sequencing data.

Control of stem rust, caused by Puccinia graminis f.sp. tritici, a highly destructive fungal disease of wheat, faces continuous challenges from emergence of new virulent races across wheat-growing continents. Using combinations of broad-spectrum resistance genes could impart durable stem rust resistance. This study attempted transfer of Sr59 resistance gene from line TA5094 (developed through CSph1bM-induced T2DS·2RL Robertsonian translocation conferring broad-spectrum resistance). Poor agronomic performance of line TA5094 necessitates Sr59 transfer to adapted genetic backgrounds and utility evaluations for wheat improvement. Based on combined stem rust seedling and molecular analyses, 2070 BC1F1 and 1230 BC2F1 plants were derived from backcrossing BAJ#1, KACHU#1, and REEDLING#1 with TA5094. Genotyping-by-sequencing (GBS) results revealed the physical positions of 15,116 SNPs on chromosome 2R. The adapted genotypes used for backcrossing were found not to possess broad-spectrum resistance to selected stem rust races, whereas Sr59-containing line TA5094 showed resistance to all races tested. Stem rust seedling assays combined with kompetitive allele-specific PCR (KASP) marker analysis successfully selected and generated the BC2F2 population, which contained the Sr59 gene, as confirmed by GBS. Early-generation data from backcrossing suggested deviations from the 3:1 segregation, suggesting that multiple genes may contribute to Sr59 resistance reactions. Using GBS marker data (40,584 SNPs in wheat chromosomes) to transfer the recurrent parent background to later-generation populations resulted in average genome recovery of 71.2% in BAJ#1*2/TA5094, 69.8% in KACHU#1*2/TA5094, and 70.5% in REEDLING#1*2/TA5094 populations. GBS data verified stable Sr59 introgression in BC2F2 populations, as evidenced by presence of the Ph1 locus and absence of the 50,936,209 bp deletion in CSph1bM. Combining phenotypic selections, stem rust seedling assays, KASP markers, and GBS data substantially accelerated transfer of broad-spectrum resistance into adapted genotypes. Thus, this study demonstrated that the Sr59 resistance gene can be introduced into elite genetic backgrounds to mitigate stem rust-related yield losses.

Mining the Australian Grains Gene Bank for Rust Resistance in Barley.

Global barley production is threatened by plant pathogens, especially the rusts. In this study we used a targeted genotype-by-sequencing (GBS) assisted GWAS approach to identify rust resistance alleles in a collection of 287 genetically distinct diverse barley landraces and historical cultivars available in the Australian Grains Genebank (AGG) and originally sourced from Eastern Europe. The accessions were challenged with seven US-derived cereal rust pathogen races including Puccinia hordei (Ph-leaf rust) race 17VA12C, P. coronata var. hordei (Pch-crown rust) race 91NE9305 and five pathogenically diverse races of P. striiformis f. sp. hordei (Psh-stripe rust) (PSH-33, PSH-48, PSH-54, PSH-72 and PSH-100) and phenotyped quantitatively at the seedling stage. Novel resistance factors were identified on chromosomes 1H, 2H, 4H and 5H in response to Pch, whereas a race-specific QTL on 7HS was identified that was effective only to Psh isolates PSH-72 and PSH-100. A major effect QTL on chromosome 5HL conferred resistance to all Psh races including PSH-72, which is virulent on all 12 stripe rust differential tester lines. The same major effect QTL was also identified in response to leaf rust (17VA12C) suggesting this locus contains several pathogen specific rust resistance genes or the same gene is responsible for both leaf rust and stripe rust resistance. Twelve accessions were highly resistant to both leaf and stripe rust diseases and also carried the 5HL QTL. We subsequently surveyed the physical region at the 5HL locus for across the barley pan genome variation in the presence of known resistance gene candidates and identified a rich source of high confidence protein kinase and antifungal genes in the QTL region.

Virulence Dynamics of the Barley Leaf Rust Pathogen (Puccinia hordei) in the United States from 1989 to 2020.

Barley leaf rust, caused by Puccinia hordei, is an important disease of barley worldwide. The pathogen can develop new races that overcome resistance genes, emphasizing the need for monitoring its virulence. This study characterized 519 P. hordei isolates collected in the United States from the 1989 to 2000 and 2010 to 2020 survey periods on 15 Rph (Reaction to Puccinia hordei) genes. We analyzed linearized infection type data to detect virulence patterns across the United States and in five geographical regions: Pacific/West (PW), Southwest (SW), Midwest (MW), Northeast (NE), and Southeast (SE). Over 32 years, we observed high mean infection scores for Rph1.a, Rph4.d, and Rph8.h; intermediate scores for Rph2.b, Rph9.i, Rph10.o, Rph11.p, and Rph13.x; and low scores for Rph3.c, Rph5.e, Rph5.f, Rph7.g, Rph9.z, Rph14.ab, and Rph15.ad. Virulence for Rph2.b, Rph3.c, Rph5.e, Rph9.z, Rph10.o, Rph11.p, and Rph13.x significantly differed between the two survey periods. From 1989 to 2020, regional patterns of virulence were found for Rph5.e, Rph5.f, Rph7.g, and Rph14.ab, while regionalities of virulence for Rph3.c, Rph9.i, Rph9.z were only observed in the 2010 to 2020 survey period. Virulence associations were also detected in the P. hordei population. Notably, isolates that were virulent to Rph5.e and Rph6.f were more likely to be avirulent to Rph7.g and Rph13.x, and vice versa. In decreasing order of effectiveness, Rph15.ad, Rph5.e, Rph3.c, Rph9.z, Rph7.g, Rph5.f, and Rph14.ab were the most effective Rph genes in the United States from 1989 to 2020. Pyramiding Rph15.ad with other widely effective Rph and adult plant resistance genes may provide long-lasting resistance against P. hordei.

Syndromes associated with frontotemporal lobar degeneration change response patterns on visual analogue scales.

Self-report scales are widely used in cognitive neuroscience and psychology. However, they rest on the central assumption that respondents engage meaningfully. We hypothesise that this assumption does not hold for many patients, especially those with syndromes associated with frontotemporal lobar degeneration. In this study we investigated differences in response patterns on a visual analogue scale between people with frontotemporal degeneration and controls. We found that people with syndromes associated with frontotemporal lobar degeneration respond with more invariance and less internal consistency than controls, with Bayes Factors = 15.2 and 14.5 respectively indicating strong evidence for a group difference. There was also evidence that patient responses feature lower entropy. These results have important implications for the interpretation of self-report data in clinical populations. Meta-response markers related to response patterns, rather than the values reported on individual items, may be an informative addition to future research and clinical practise.

Neurochemistry-enriched dynamic causal models of magnetoencephalography, using magnetic resonance spectroscopy.

We present a hierarchical empirical Bayesian framework for testing hypotheses about neurotransmitters' concertation as empirical prior for synaptic physiology using ultra-high field magnetic resonance spectroscopy (7T-MRS) and magnetoencephalography data (MEG). A first level dynamic causal modelling of cortical microcircuits is used to infer the connectivity parameters of a generative model of individuals' neurophysiological observations. At the second level, individuals' 7T-MRS estimates of regional neurotransmitter concentration supply empirical priors on synaptic connectivity. We compare the group-wise evidence for alternative empirical priors, defined by monotonic functions of spectroscopic estimates, on subsets of synaptic connections. For efficiency and reproducibility, we used Bayesian model reduction (BMR), parametric empirical Bayes and variational Bayesian inversion. In particular, we used Bayesian model reduction to compare alternative model evidence of how spectroscopic neurotransmitter measures inform estimates of synaptic connectivity. This identifies the subset of synaptic connections that are influenced by individual differences in neurotransmitter levels, as measured by 7T-MRS. We demonstrate the method using resting-state MEG (i.e., task-free recording) and 7T-MRS data from healthy adults. Our results confirm the hypotheses that GABA concentration influences local recurrent inhibitory intrinsic connectivity in deep and superficial cortical layers, while glutamate influences the excitatory connections between superficial and deep layers and connections from superficial to inhibitory interneurons. Using within-subject split-sampling of the MEG dataset (i.e., validation by means of a held-out dataset), we show that model comparison for hypothesis testing can be highly reliable. The method is suitable for applications with magnetoencephalography or electroencephalography, and is well-suited to reveal the mechanisms of neurological and psychiatric disorders, including responses to psychopharmacological interventions.

The wheat stem rust resistance gene Sr43 encodes an unusual protein kinase.

To safeguard bread wheat against pests and diseases, breeders have introduced over 200 resistance genes into its genome, thus nearly doubling the number of designated resistance genes in the wheat gene pool1. Isolating these genes facilitates their fast-tracking in breeding programs and incorporation into polygene stacks for more durable resistance. We cloned the stem rust resistance gene Sr43, which was crossed into bread wheat from the wild grass Thinopyrum elongatum2,3. Sr43 encodes an active protein kinase fused to two domains of unknown function. The gene, which is unique to the Triticeae, appears to have arisen through a gene fusion event 6.7 to 11.6 million years ago. Transgenic expression of Sr43 in wheat conferred high levels of resistance to a wide range of isolates of the pathogen causing stem rust, highlighting the potential value of Sr43 in resistance breeding and engineering.

High-resolution mapping of SrTm4, a recessive resistance gene to wheat stem rust.

KEY MESSAGE: The diploid wheat recessive stem rust resistance gene SrTm4 was fine-mapped to a 754-kb region on chromosome arm 2AmL and potential candidate genes were identified. Race Ug99 of Puccinia graminis f. sp. tritici (Pgt), the causal agent of wheat stem (or black) rust is one of the most serious threats to global wheat production. The identification, mapping, and deployment of effective stem rust resistance (Sr) genes are critical to reduce this threat. In this study, we generated SrTm4 monogenic lines and found that this gene confers resistance to North American and Chinese Pgt races. Using a large mapping population (9522 gametes), we mapped SrTm4 within a 0.06 cM interval flanked by marker loci CS4211 and 130K1519, which corresponds to a 1.0-Mb region in the Chinese Spring reference genome v2.1. A physical map of the SrTm4 region was constructed with 11 overlapping BACs from the resistant Triticum monococcum PI 306540. Comparison of the 754-kb physical map with the genomic sequence of Chinese Spring and a discontinuous BAC sequence of DV92 revealed a 593-kb chromosomal inversion in PI 306540. Within the candidate region, we identified an L-type lectin-domain containing receptor kinase (LLK1), which was disrupted by the proximal inversion breakpoint, as a potential candidate gene. Two diagnostic dominant markers were developed to detect the inversion breakpoints. In a survey of T. monococcum accessions, we identified 10 domesticated T. monococcum subsp. monococcum genotypes, mainly from the Balkans, carrying the inversion and showing similar mesothetic resistant infection types against Pgt races. The high-density map and tightly linked molecular markers developed in this study are useful tools to accelerate the deployment of SrTm4-mediated resistance in wheat breeding programs.

Evaluation of Stem Rust Disease in Wheat Fields by Drone Hyperspectral Imaging.

Detecting plant disease severity could help growers and researchers study how the disease impacts cereal crops to make timely decisions. Advanced technology is needed to protect cereals that feed the increasing population using fewer chemicals; this may lead to reduced labor usage and cost in the field. Accurate detection of wheat stem rust, an emerging threat to wheat production, could inform growers to make management decisions and assist plant breeders in making line selections. A hyperspectral camera mounted on an unmanned aerial vehicle (UAV) was utilized in this study to evaluate the severity of wheat stem rust disease in a disease trial containing 960 plots. Quadratic discriminant analysis (QDA) and random forest classifier (RFC), decision tree classification, and support vector machine (SVM) were applied to select the wavelengths and spectral vegetation indices (SVIs). The trial plots were divided into four levels based on ground truth disease severities: class 0 (healthy, severity 0), class 1 (mildly diseased, severity 1-15), class 2 (moderately diseased, severity 16-34), and class 3 (severely diseased, highest severity observed). The RFC method achieved the highest overall classification accuracy (85%). For the spectral vegetation indices (SVIs), the highest classification rate was recorded by RFC, and the accuracy was 76%. The Green NDVI (GNDVI), Photochemical Reflectance Index (PRI), Red-Edge Vegetation Stress Index (RVS1), and Chlorophyll Green (Chl green) were selected from 14 SVIs. In addition, binary classification of mildly diseased vs. non-diseased was also conducted using the classifiers and achieved 88% classification accuracy. This highlighted that hyperspectral imaging was sensitive enough to discriminate between low levels of stem rust disease vs. no disease. The results of this study demonstrated that drone hyperspectral imaging can discriminate stem rust disease levels so that breeders can select disease-resistant varieties more efficiently. The detection of low disease severity capability of drone hyperspectral imaging can help farmers identify early disease outbreaks and enable more timely management of their fields. Based on this study, it is also possible to build a new inexpensive multispectral sensor to diagnose wheat stem rust disease accurately.

Neurophysiological consequences of synapse loss in progressive supranuclear palsy.

Synaptic loss occurs early in many neurodegenerative diseases and contributes to cognitive impairment even in the absence of gross atrophy. Currently, for human disease there are few formal models to explain how cortical networks underlying cognition are affected by synaptic loss. We advocate that biophysical models of neurophysiology offer both a bridge from preclinical to clinical models of pathology and quantitative assays for experimental medicine. Such biophysical models can also disclose hidden neuronal dynamics generating neurophysiological observations such as EEG and magnetoencephalography. Here, we augment a biophysically informed mesoscale model of human cortical function by inclusion of synaptic density estimates as captured by 11C-UCB-J PET, and provide insights into how regional synapse loss affects neurophysiology. We use the primary tauopathy of progressive supranuclear palsy (Richardson's syndrome) as an exemplar condition, with high clinicopathological correlations. Progressive supranuclear palsy causes a marked change in cortical neurophysiology in the presence of mild cortical atrophy and is associated with a decline in cognitive functions associated with the frontal lobe. Using parametric empirical Bayesian inversion of a conductance-based canonical microcircuit model of magnetoencephalography data, we show that the inclusion of regional synaptic density-as a subject-specific prior on laminar-specific neuronal populations-markedly increases model evidence. Specifically, model comparison suggests that a reduction in synaptic density in inferior frontal cortex affects superficial and granular layer glutamatergic excitation. This predicted individual differences in behaviour, demonstrating the link between synaptic loss, neurophysiology and cognitive deficits. The method we demonstrate is not restricted to progressive supranuclear palsy or the effects of synaptic loss: such pathology-enriched dynamic causal models can be used to assess the mechanisms of other neurological disorders, with diverse non-invasive measures of pathology, and is suitable to test the effects of experimental pharmacology.

Synaptic Loss in Frontotemporal Dementia Revealed by [11 C]UCB-J Positron Emission Tomography.

OBJECTIVE: Synaptic loss is an early feature of neurodegenerative disease models, and is severe in post mortem clinical studies, including frontotemporal dementia. Positron emission tomography (PET) with radiotracers that bind to synaptic vesicle glycoprotein 2A enables quantification of synaptic density in vivo. This study used [11 C]UCB-J PET in participants with behavioral variant frontotemporal dementia (bvFTD), testing the hypothesis that synaptic loss is severe and related to clinical severity. METHODS: Eleven participants with clinically probable bvFTD and 25 age- and sex-matched healthy controls were included. Participants underwent dynamic [11 C]UCB-J PET, structural magnetic resonance imaging, and a neuropsychological battery, including the revised Addenbrooke Cognitive Examination, and INECO frontal screening. General linear models compared [11 C]UCB-J binding potential maps and gray matter volume between groups, and assessed associations between synaptic density and clinical severity in patients. Analyses were also performed using partial volume corrected [11 C]UCB-J binding potential from regions of interest (ROIs). RESULTS: Patients with bvFTD showed severe synaptic loss compared to controls. [11 C]UCB-J binding was reduced bilaterally in medial and dorsolateral frontal regions, inferior frontal gyri, anterior and posterior cingulate gyrus, insular cortex, and medial temporal lobe. Synaptic loss in the frontal and cingulate regions correlated significantly with cognitive impairments. Synaptic loss was more severe than atrophy. Results from ROI-based analyses mirrored the voxelwise results. INTERPRETATION: In accordance with preclinical models, and human postmortem evidence, there is widespread frontotemporal loss of synapses in symptomatic bvFTD, in proportion to severity. [11 C]UCB-J PET could support translational studies and experimental medicine strategies for new disease-modifying treatments for neurodegeneration. ANN NEUROL 2023;93:142-154.

A novel locus conferring resistance to Puccinia hordei maps to the genomic region corresponding to Rph14 on barley chromosome 2HS.

Barley leaf rust (BLR), caused by Puccinia hordei, is best controlled through genetic resistance. An efficient resistance breeding program prioritizes the need to identify, characterize, and map new sources of resistance as well as understanding the effectiveness, structure, and function of resistance genes. In this study, three mapping populations were developed by crossing Israelian barley lines "AGG-396," "AGG-397," and "AGG-403" (carrying unknown leaf rust resistance) with a susceptible variety "Gus" to characterize and map resistance. Genetic analysis of phenotypic data from rust testing F3s with a P. hordei pathotype 5457 P+ revealed monogenic inheritance in all three populations. Targeted genotyping-by-sequencing of the three populations detected marker trait associations in the same genomic region on the short arm of chromosome 2H between 39 and 57 Mb (AGG-396/Gus), 44 and 64 Mb (AGG-397/Gus), and 31 and 58 Mb (AGG-403/Gus), suggesting that the resistance in all three lines is likely conferred by the same locus (tentatively designated RphAGG396). Two Kompetitive allele-specific PCR (KASP) markers, HvGBSv2-902 and HvGBSv2-932, defined a genetic distance of 3.8 cM proximal and 7.1 cM distal to RphAGG396, respectively. To increase the marker density at the RphAGG396 locus, 75 CAPS markers were designed between two flanking markers. Integration of marker data resulted in the identification of two critical recombinants and mapping RphAGG396 between markers- Mloc-28 (40.75 Mb) and Mloc-41 (41.92 Mb) narrowing the physical window to 1.17 Mb based on the Morex v2.0 reference genome assembly. To enhance map resolution, 600 F2s were genotyped with markers- Mloc-28 and Mloc-41 and nine recombinants were identified, placing the gene at a genetic distance of 0.5 and 0.2 cM between the two markers, respectively. Two annotated NLR (nucleotide-binding domain leucine-rich repeat) genes (r2.2HG0093020 and r2.2HG0093030) were identified as the best candidates for RphAGG396. A closely linked marker was developed for RphAGG396 that can be used for marker-assisted selection.

Genome-wide association mapping for field and seedling resistance to the emerging Puccinia graminis f. sp. tritici race TTRTF in wheat.

Stem rust of wheat (Triticum spp.), caused by Puccinia graminis f. sp. tritici (Pgt), is one of the most impactful wheat diseases because of its threat to global wheat production. While disease mitigation has primarily been achieved through the deployment of resistant wheat varieties, emerging new virulent races continue to pose risks to the crop. For example, races such as Ug99 (TTKSK), TKTTF, and TTRTF have caused epidemics in different wheat growing regions of the world in recent years. A continual search for new and effective sources of resistance is therefore necessary to safeguard wheat production. This study assessed a breeding panel from the Ethiopian Institute of Agricultural Research (EIAR) wheat breeding program for seedling and field plant resistance to TTRTF and reports genomic regions conferring resistance to TTRTF. Trait correlations (r) were medium to strong (range = .38-.71) and heritabilities were moderate (.32-.56). Association analysis for resistance to TTRTF resulted in detection of 20 markers in 11 chromosomes; the marker S1B_175439851 was associated with resistance at both seedling and adult plant stages. Models with two to four QTL combinations reduced seedling and field disease severity by 12-48 and 9-17%, respectively. Genomic prediction for TTRTF resistance resulted in low to moderately-high predictions (mean correlations of .25-.47). Identification of resistant lines and QTL in the EIAR population is expected to assist in selection toward improved resistance to TTRTF. Specifically, the application of genomic selection (GS) in identifying resistant lines in future related breeding populations will further assist breeding efforts against this new stem rust pathogen race.

A transcriptomic-guided strategy used in identification of a wheat rust pathogen target and modification of the target enhanced host resistance to rust pathogens.

Transcriptional reprogramming is an essential feature of plant immunity and is governed by transcription factors (TFs) and co-regulatory proteins associated with discrete transcriptional complexes. On the other hand, effector proteins from pathogens have been shown to hijack these vast repertoires of plant TFs. Our current knowledge of host genes' role (including TFs) involved in pathogen colonization is based on research employing model plants such as Arabidopsis and rice with minimal efforts in wheat rust interactions. In this study, we begun the research by identifying wheat genes that benefit rust pathogens during infection and editing those genes to provide wheat with passive resistance to rust. We identified the wheat MYC4 transcription factor (TF) located on chromosome 1B (TaMYC4-1B) as a rust pathogen target. The gene was upregulated only in susceptible lines in the presence of the pathogens. Down-regulation of TaMYC4-1B using barley stripe mosaic virus-induced gene silencing (BSMV-VIGS) in the susceptible cultivar Chinese Spring enhanced its resistance to the stem rust pathogen. Knockout of the TaMYC4-1BL in Cadenza rendered new resistance to races of stem, leaf, and stripe rust pathogens. We developed new germplasm in wheat via modifications of the wheat TaMYC4-1BL transcription factor.

The neurophysiological effect of NMDA-R antagonism of frontotemporal lobar degeneration is conditional on individual GABA concentration.

There is a pressing need to accelerate therapeutic strategies against the syndromes caused by frontotemporal lobar degeneration, including symptomatic treatments. One approach is for experimental medicine, coupling neurophysiological studies of the mechanisms of disease with pharmacological interventions aimed at restoring neurochemical deficits. Here we consider the role of glutamatergic deficits and their potential as targets for treatment. We performed a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study in 20 people with symptomatic frontotemporal lobar degeneration (10 behavioural variant frontotemporal dementia, 10 progressive supranuclear palsy) and 19 healthy age- and gender-matched controls. Both magnetoencephalography sessions recorded a roving auditory oddball paradigm: on placebo or following 10 mg memantine, an uncompetitive NMDA-receptor antagonist. Ultra-high-field magnetic resonance spectroscopy confirmed lower concentrations of GABA in the right inferior frontal gyrus of people with frontotemporal lobar degeneration. While memantine showed a subtle effect on early-auditory processing in patients, there was no significant main effect of memantine on the magnitude of the mismatch negativity (MMN) response in the right frontotemporal cortex in patients or controls. However, the change in the right auditory cortex MMN response to memantine (vs. placebo) in patients correlated with individuals' prefrontal GABA concentration. There was no moderating effect of glutamate concentration or cortical atrophy. This proof-of-concept study demonstrates the potential for baseline dependency in the pharmacological restoration of neurotransmitter deficits to influence cognitive neurophysiology in neurodegenerative disease. With changes to multiple neurotransmitters in frontotemporal lobar degeneration, we suggest that individuals' balance of excitation and inhibition may determine drug efficacy, with implications for drug selection and patient stratification in future clinical trials.

Haplotype variants of Sr46 in Aegilops tauschii, the diploid D genome progenitor of wheat.

KEY MESSAGE: Stem rust resistance genes, SrRL5271 and Sr672.1 as well as SrCPI110651, from Aegilops tauschii, the diploid D genome progenitor of wheat, are sequence variants of Sr46 differing by 1-2 nucleotides leading to non-synonymous amino acid substitutions. The Aegilops tauschii (wheat D-genome progenitor) accessions RL 5271 and CPI110672 were identified as resistant to multiple races (including the Ug99) of the wheat stem rust pathogen Puccinia graminis f. sp. tritici (Pgt). This study was conducted to identify the stem rust resistance (Sr) gene(s) in both accessions. Genetic analysis of the resistance in RL 5271 identified a single dominant allele (SrRL5271) controlling resistance, whereas resistance segregated at two loci (SR672.1 and SR672.2) for a cross of CPI110672. Bulked segregant analysis placed SrRL5271 and Sr672.1 in a region on chromosome arm 2DS that encodes Sr46. Molecular marker screening, mapping and genomic sequence analysis demonstrated SrRL5271 and Sr672.1 are alleles of Sr46. The amino acid sequence of SrRL5271 and Sr672.1 is identical but differs from Sr46 (hereafter referred to as Sr46_h1 by following the gene nomenclature in wheat) by a single amino acid (N763K) and is thus designated Sr46_h2. Screening of a panel of Ae. tauschii accessions identified an additional allelic variant that differed from Sr46_h2 by a different amino acid (A648V) and was designated Sr46_h3. By contrast, the protein encoded by the susceptible allele of Ae. tauschii accession AL8/78 differed from these resistance proteins by 54 amino acid substitutions (94% nucleotide sequence gene identity). Cloning and complementation tests of the three resistance haplotypes confirmed their resistance to Pgt race 98-1,2,3,5,6 and partial resistance to Pgt race TTRTF in bread wheat. The three Sr46 haplotypes, with no virulent races detected yet, represent a valuable source for improving stem resistance in wheat.