Discovery of resistance to Pratylenchus neglectus among P. thornei-resistant Iranian landrace wheats and the introgression of both resistances into advanced breeding lines

Root-lesion nematodes (RLNs) Pratylenchus thornei and P. neglectus are globally important pathogens of cereal and pulse crops. These RLNs can occur together in farming systems and must be managed concurrently to minimize substantial yield losses in intolerant crop cultivars. Australian wheat cultivars with resistance to P. neglectus, have either the Rlnn1 resistance gene, which provides a high level of resistance but is linked with yellow flour colour that reduces cultivar marketability for bread production, or QRlnn.lrc-2B, which provides moderate resistance. We evaluated a collection of 91 P. thornei-resistant Iranian landrace wheats (ILWs) for their resistance to P. neglectus in four glasshouse experiments to (a) identify genotypes with resistance to both RLNs, (b) determine if any genotypes carried Rlnn1 and/or QRlnn.lrc-2B and (c) develop ILW-derived advanced breeding lines (ABLs) with resistance to both RLNs. A factor analytic linear mixed model (FA-1) that explained 70% of the genetic variation, where the genetic correlations between the experiments ranged from 0.54 to 0.77, was used for the combined analysis of all experiments. Seven P. neglectus-resistant genotypes were identified, with five that had potentially novel resistance. Subsequently, six breeding lines that were resistant to both RLNs were developed by crossing six ILWs with Australian cultivars and selecting for resistance in each generation. Both the ILWs and ABLs will be valuable genetic resources for wheat breeders to develop cultivars with dual resistance, enabling better management of mixed RLN populations with novel P. neglectus resistance that potentially is not linked with yellow flour colour

Resistance of Wheat Genotypes to Root-Lesion Nematode (Pratylenchus thornei) Can be Used to Predict Final Nematode Population Densities, Crop Greenness, and Grain Yield in the Field

The root-lesion nematode Pratylenchus thornei is a major pathogen of wheat (Triticum aestivum) in many regions globally.. Resistance of wheat genotypes to P. thornei can be determined from final nematode population densities in glasshouse experiments, but combining results across multiple experiments presents challenges. Here we use a factor analytic method for multi-experiment analysis of final population densities of P. thornei for 1096 unique wheat genotypes in 22 glasshouse experiments. The resistance to P. thornei of 18 the genotypes was effectively represented by a two factor model with rotation of the axes to a principal components solution. Principal axes 1 and 2 (PA1 and PA2) respectively accounted for 79% and 11 % of the genetic variance over all experiments. Final population densities of P. thornei as empirical best linear unbiased predictors (PA(1+2)-eBLUPs)) from the 22 combined glasshouse experiments were highly predictive (P<0.001) of final nematode population densities in the soil profile, of crop canopy greenness (NDVI) and of grain yield of wheat genotypes in P. thornei infested fields in the Australian subtropical grain region. Nine categories of resistance ratings for wheat genotypes from resistant to very susceptible6 were based on subdivision of the range of PA(1+2)-eBLUPs for use in growers’ sowing guides. Nine genotypes were nominated as references for future resistance experiments. Most (62%) Australian wheat genotypes were in the most susceptible three categories (S, S–VS and VS). However, resistant germplasm characterized in this study could be used in plant breeding to considerably improve the overall resistance of Australian wheat crops

HMGB1/TLR Receptor Danger Signaling Increases Brain Neuroimmune Activation in Alcohol Dependence

Innate immune gene expression is regulated in part through high mobility group box 1(HMGB1), an endogenous proinflammatory cytokine, that activates multiple members of the interleukin-1/Toll-like receptor (IL-1/TLR) family associated with danger signaling. We investigated expression of HMGB1, TLR2, TLR3 and TLR4 in chronic ethanol treated mouse brain, post-mortem human alcoholic brain, and rat brain slice culture to test the hypothesis that neuroimmune activation in alcoholic brain involves ethanol activation of HMGB1/TLR danger signaling

Azithromycin for sarcoidosis cough: an open label exploratory clinical trial

Background Chronic cough is a distressing symptom for many people with pulmonary sarcoidosis. Continuous treatment with a macrolide antibiotic may improve cough. We aimed to assess the potential efficacy of azithromycin in patients with sarcoidosis and self-reported cough.Methods We did a non-controlled, open label clinical trial of azithromycin 250 mg once daily for 3 months in patients with pulmonary sarcoidosis who reported a chronic cough. The primary outcome was number of coughs in 24 h. Secondary outcomes were cough visual analog scales and quality of life measured using the Leicester Cough Questionnaire and King's Sarcoidosis Questionnaire. Safety outcomes included QTc interval on ECG. Measurements were made at baseline and after one and 3 months of treatment.Results All 21 patients were white, median age 57 years, 9 males/12 females, median 3 years since diagnosis. Five were taking oral corticosteroids and none were taking other immunosuppressants. Twenty patients completed the trial. The median (range) number of coughs in 24 h was 228 (43–1950) at baseline, 122 (20–704) at 1 month, and 81 (16–414) at 3 months (p=0.002, Friedman's test). The median reduction in cough count at 3 months was 49.6%. There were improvements in all patient-reported outcomes. Azithromycin was well tolerated.Conclusion In a non-controlled open-label trial in people with sarcoidosis who reported a chronic cough, 3 months of treatment with azithromycin led to improvements in a range of cough metrics. Azithromycin should be tested as a treatment for sarcoidosis cough in a randomised placebo-controlled trial

Survey for root-lesion and stunt nematodes in the northern Australian grain region

The presence of root-lesion nematodes (Pratylenchus thornei and P. neglectus) and stunt nematode (Merlinius brevidens) in some parts of the northern grain region has been known since the 1960's and yield loss in wheat caused by P. thornei has been demonstrated since the late 1970's. However, the distribution of P. thornei was considered restricted to the Darling Downs in Queensland and to a few localities in northern NSW. Following the diagnosis of P. thornei in a wheat crop in a newer cropping area around Goondiwindi in 1996 a more extensive survey of wheat fields was conducted. Soil samples (0-30cm) collected mainly from under wheat crops were processed manually and nematodes extracted by the Whitehead tray method and enumerated under a compound microscope. Out of 795 fields tested from 1996 to 2002, Pratylenchus thornei occurred in 67%, P. neglectus in 32% (both species occurred together in 26%) and no Pratylenchus spp. were detected in 27%. Merlinius brevidens occurred in 73% of fields. Edaphic factors controlling the incidence of these nematodes were tested on 833 samples collected in 1996-7. All three nematode species had a broad pH range, namely from 6.5 to 9.5 for both Pratylenchus spp. and from 6.0 to 9.5 for Merinlius brevidens. All species were detected in soil samples ranging from <20 to 80% clay and from 80% sand. However, within this range maximum incidence of P. thornei was in finer textured soils than for P. neglectus. Soil organic carbon had no clearcut effect on the incidence of the species. The incidence of P. neglectus appeared to increase with increasing concentration of DTPA-extractable zinc and bicarbonate–extractable phosphorus in the soil. Observations indicate that P. thornei was spreading in the region in run-off water and in soil on farm machinery and increasing under intense cropping to wheat

miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice

Excessive or inappropriate activation of the immune system can be deleterious to the organism, warranting multiple molecular mechanisms to control and properly terminate immune responses. MicroRNAs (miRNAs), ~22-nt-long noncoding RNAs, have recently emerged as key posttranscriptional regulators, controlling diverse biological processes, including responses to non-self. In this study, we examine the biological role of miR-146a using genetically engineered mice and show that targeted deletion of this gene, whose expression is strongly up-regulated after immune cell maturation and/or activation, results in several immune defects. Collectively, our findings suggest that miR-146a plays a key role as a molecular brake on inflammation, myeloid cell proliferation, and oncogenic transformation

Inconsistencies in Guidelines for Visual Health Surveillance of VDT Workers

Objectives: In Europe, 25% of workers use video display terminals (VDTs). Occupational health surveillance has been considered a key element in the protection of these workers. Nevertheless, it is unclear if guidelines available for this purpose, based on EU standards and available evidence, meet currently accepted quality criteria. The aim of this study was to appraise three sets of European VDT guidelines (UK, France, Spain) in which regulatory and evidence-based approaches for visual health have been formulated and recommendations for practice made. Methods: Three independent appraisers used an adapted AGREE instrument with seven domains to appraise the guidelines. A modified nominal group technique approach was used in two consecutive phases: first, individual evaluation of the three guidelines simultaneously, and second, a face-to-face meeting of appraisers to discuss scoring. Analysis of ratings obtained in each domain and variability among appraisers was undertaken (correlation and kappa coefficients). Results: All guidelines had low domain scores. The domain evaluated most highly was Scope and purpose, while Applicability was scored minimally. The UK guidelines had the highest overall score, and the Spanish ones had the lowest. The analysis of reliability and differences between scores in each domain showed a high level of agreement. Conclusions: These results suggest current guidelines used in these countries need an update. The formulation of evidence-base European guidelines on VDT could help to reduce the significant variation of national guidelines, which may have an impact on practical application.This study was supported by the National Institute for Occupational Safety and Health at Work of the Spanish Work and Immigration Ministry (INSHT). Project reference: 606/UAL/PVDVIS

Modest agreement between magnetic resonance and pathological tumor regression after neoadjuvant therapy for rectal cancer in the real world.

Magnetic resonance imaging (MRI) is routinely used for preoperative tumor staging and to assess response to therapy in rectal cancer patients. The aim of our study was to evaluate the accuracy of MRI based restaging after neoadjuvant chemoradiotherapy (CRT) in predicting pathologic response. This multicenter cohort study included adult patients with histologically confirmed locally advanced rectal adenocarcinoma treated with neoadjuvant CRT followed by curative intent elective surgery between January 2014 and December 2019 at four academic high-volume institutions. Magnetic resonance tumor regression grade (mrTRG) and pathologic tumor regression grade (pTRG) were reviewed and compared for all the patients. The agreement between radiologist and pathologist was assessed with the weighted k test. Risk factors for poor agreement were investigated using logistic regression. A total of 309 patients were included. Modest agreement was found between mrTRG and pTRG when regression was classified according to standard five-tier systems (k = 0.386). When only two categories were considered for each regression system, (pTRG 0-3 vs pTRG 4; mrTRG 2-5 vs mrTRG 1) an accuracy of 78% (95% confidence interval [CI] 0.73-0.83) was found between radiologic and pathologic assessment with a k value of 0.185. The logistic regression model revealed that "T3 greater than 5 mm extent" was the only variable significantly impacting on disagreement (OR 0.33, 95% CI 0.15-0.68, P = .0034). Modest agreement exists between mrTRG and pTRG. The chances of appropriate assessment of the regression grade after neoadjuvant CRT appear to be higher in case of a T3 tumor with at least 5 mm extension in the mesorectal fat at the pretreatment MRI

Smc5/6 coordinates formation and resolution of joint molecules with chromosome morphology to ensure meiotic divisions

During meiosis, Structural Maintenance of Chromosome (SMC) complexes underpin two fundamental features of meiosis: homologous recombination and chromosome segregation. While meiotic functions of the cohesin and condensin complexes have been delineated, the role of the third SMC complex, Smc5/6, remains enigmatic. Here we identify specific, essential meiotic functions for the Smc5/6 complex in homologous recombination and the regulation of cohesin. We show that Smc5/6 is enriched at centromeres and cohesin-association sites where it regulates sister-chromatid cohesion and the timely removal of cohesin from chromosomal arms, respectively. Smc5/6 also localizes to recombination hotspots, where it promotes normal formation and resolution of a subset of joint-molecule intermediates. In this regard, Smc5/6 functions independently of the major crossover pathway defined by the MutLγ complex. Furthermore, we show that Smc5/6 is required for stable chromosomal localization of the XPF-family endonuclease, Mus81-Mms4Eme1. Our data suggest that the Smc5/6 complex is required for specific recombination and chromosomal processes throughout meiosis and that in its absence, attempts at cell division with unresolved joint molecules and residual cohesin lead to severe recombination-induced meiotic catastroph