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Introduction: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease with a poor prognosis and increasing incidence. Pirfenidone and nintedanib are the only approved treatments for IPF but have limited efficacy and their mechanisms of action are poorly understood. Here we have examined the effects of pirfenidone and nintedanib in a human model of lung fibrogenesis, and compared these with the putative anti-fibrotic compounds Lipoxin A4 (LXA4), and senicapoc, a KCa3.1 ion channel blocker.Methods: Early fibrosis was induced in cultured human lung parenchyma using TGFβ1 for 7 days, ± pirfenidone, nintedanib, or LXA4. Pro-fibrotic responses were examined by RT-PCR, immunohistochemistry and soluble collagen secretion.Results: Thirty six out of eighty four IPF and fibrosis-associated genes tested were significantly upregulated by TGFβ1 in human lung parenchyma with a ≥0.5 log2FC (n = 32). Nintedanib (n = 13) reduced the mRNA expression of 14 fibrosis-associated genes including MMPs (MMP1,−4,−13,−14), integrin α2, CXCR4 and PDGFB, but upregulated α-smooth muscle actin (αSMA). Pirfenidone only reduced mRNA expression for MMP3 and −13. Senicapoc (n = 11) previously attenuated the expression of 28 fibrosis-associated genes, including αSMA, several growth factors, collagen type III, and αV/β6 integrins. Pirfenidone and nintedanib significantly inhibited TGFβ1-induced fibroblast proliferation within the tissue, but unlike senicapoc, neither pirfenidone nor nintedanib prevented increases in tissue αSMA expression. LXA4 was ineffective.Conclusions: Pirfenidone and nintedanib demonstrate modest anti-fibrotic effects and provide a benchmark for anti-fibrotic activity of new drugs in human lung tissue. Based on these data, we predict that the KCa3.1 blocker senicapoc will show greater benefit than either of these licensed drugs in IPF.

“Synthetic” allopolyploids recreated by interspecific hybridization play an important role in providing novel genomic variation for crop improvement. Such synthetic allopolyploids often undergo rapid genomic structural variation (SV). However, how such SV arises, is inherited and fixed, and how it affects important traits, has rarely been comprehensively and quantitively studied in advanced generation synthetic lines. A better understanding of these processes will aid breeders in knowing how to best utilize synthetic allopolyploids in breeding programs. Here, we analyzed three genetic mapping populations (735 DH lines) derived from crosses between advanced synthetic and conventional Brassica napus (rapeseed) lines, using whole-genome sequencing to determine genome composition. We observed high tolerance of large structural variants, particularly toward the telomeres, and preferential selection for balanced homoeologous exchanges (duplication/deletion events between the A and C genomes resulting in retention of gene/chromosome dosage between homoeologous chromosome pairs), including stable events involving whole chromosomes (“pseudoeuploidy”). Given the experimental design (all three populations shared a common parent), we were able to observe that parental SV was regularly inherited, showed genetic hitchhiking effects on segregation, and was one of the major factors inducing adjacent novel and larger SV. Surprisingly, novel SV occurred at low frequencies with no significant impacts on observed fertility and yield-related traits in the advanced generation synthetic lines. However, incorporating genome-wide SV in linkage mapping explained significantly more genetic variance for traits. Our results provide a framework for detecting and understanding the occurrence and inheritance of genomic SV in breeding programs, and support the use of synthetic parents as an important source of novel trait variation.

Background: A major reform of junior doctor training was undertaken in 2004–5, with the introduction of foundation training (FT) to address perceived problems with work structure, conditions and training opportunities for postgraduate doctors. The well-being and motivation of junior doctors within the context of this change to training (and other changes such as restrictions in working hours of junior doctors and increasing demand for health care) and the consequent impact upon the quality of care provided is not well understood. Objectives: This study aimed to evaluate the well-being of foundation year 2 (F2) doctors in training. Phase 1 describes the aims of delivering foundation training with a focus on the role of training in supporting the well-being of F2 doctors and assesses how FT is implemented on a regional basis, particularly in emergency medicine (EM). Phase 2 identifies how F2 doctor well-being and motivation are influenced over F2 and specifically in relation to EM placements and quality of care provided to patients. Methods: Phase 1 used semistructured interviews and focus groups with postgraduate deanery leads, training leads (TLs) and F2 doctors to explore the strategic aims and implementation of FT, focusing on the specialty of EM. Phase 2 was a 12-month online longitudinal study of F2 doctors measuring levels of and changes in well-being and motivation. In a range of specialties, one of which was EM, data from measures of well-being, motivation, intention to quit, confidence and competence and job-related characteristics (e.g. work demands, task feedback, role clarity) were collected at four time points. In addition, we examined F2 doctor well-being in relation to quality of care by reviewing clinical records (criterion-based and holistic reviews) during the emergency department (ED) placement relating to head injury and chronic obstructive pulmonary disease (COPD). Results: Phase 1 of the study found that variation exists in how successfully FT is implemented locally; F2 lacks a clearly defined end point; there is a minimal focus on the well-being of F2 doctors (only on the few already shown to be ‘in difficulty’); the ED presented a challenging but worthwhile learning environment requiring a significant amount of support from senior ED staff; and disagreement existed about the performance and confidence levels of F2 doctors. A total of 30 EDs in nine postgraduate medical deaneries participated in phase 2 with 217 foundation doctors completing the longitudinal study. F2 doctors reported significantly increased confidence in managing common acute conditions and undertaking practical procedures over their second foundation year, with the biggest increase in confidence and competence associated with their ED placement. F2 doctors had levels of job satisfaction and anxiety/depression that were comparable to or better than those of other NHS workers, and adequate quality and safety of care are being provided for head injury and COPD. Conclusions: There are ongoing challenges in delivering high-quality FT at the local level, especially in time-pressured specialties such as EM. There are also challenges in how FT detects and manages doctors who are struggling with their work. The survey was the first to document the well-being of foundation doctors over the course of their second year, and average scores compared well with those of other doctors and health-care workers. F2 doctors are benefiting from the training provided as we found improvements in perceived confidence and competence over the year, with the ED placement being of most value to F2 doctors in this respect. Although adequate quality of care was demonstrated, we found no significant relationships between well-being of foundation doctors and the quality of care they provided to patients, suggesting the need for further work in this area. Funding: The National Institute for Health Research Health Services and Delivery Research programme.

Relative to the general population, adolescents with psychiatric disorders such as major depression disorder are incarcerated (and reincarcerated) at higher rates. Current research is mixed on whether this association is a cause, consequence, or the product of selection. For example, aggression can lead to more depressive symptoms, yet depression is associated with antisocial behaviors (e.g., delinquency). To better understand the relationship between depression and delinquent behavior, we used the discordant kinship model to examine data from sibling pairs in the National Longitudinal Surveys of Youth 1979, a nationally representative study. By explicitly modeling within- and between-family variance, we reduced the influence of genetic and shared-environmental confounds on our analysis. Our results suggest that the relationship between depression and delinquency is not causal, but rather a product of selection.

Abstract Root architectural traits play pivotal roles in plant adaptation to drought stress, and hence they are considered promising targets in breeding programs. Here, we phenotyped eight root architecture traits in response to well‐watered and drought stress conditions in 200 spring barley (Hordeum vulgare L.) inbred lines over two consecutive field seasons. Root architecture traits were less developed under drought in both seasons when compared with control treatments. Genetic variation in root architectural traits was dissected employing a genome‐wide association study (GWAS) coupled with linkage disequilibrium mapping. GWAS uncovered a total of 186 significant single nucleotide polymorphism‐trait associations for eight root traits under control, drought, and drought‐related indices. Of these, a few loci for root traits were detected on chromosomes 3 and 5, which co‐located with QTL identified in previous studies. Interestingly, 13 loci showed simultaneou associations with multiple root traits under drought and drought‐related indices. These loci harbored candidate genes, which included a wide range of drought‐responsive components such as transcription factors, binding proteins, protein kinases, nutrient and ion transporters, and stress signaling factors. For instance, two candidate genes, HORVU7Hr3G0713160 and HORVU6H r3G0626550, are orthologous to AtACX3 and AtVAMPs, which have reported functions in root length‐mediated drought tolerance and as a key protein in abiotic stress tolerance, respectively. Interestingly, one of these loci underlying a high‐confidence candidate gene NEW ENHANCER OF ROOT DWARFISM1 (NERD1) showed involvement with root development. An allelic variation of this locus in non‐coding region was significantly associated with increased root length under drought. Collectively, these results offer promising multi‐trait affecting loci and candidate genes underlying root phenotypic responses to drought stress, which may provide valuable resources for genetic improvement of drought tolerance in barley.

Objective(s): To evaluate the clinical effectiveness and cost-effectiveness of a range of diagnostic strategies for investigating patients with unilateral hearing loss and/or tinnitus, with a view to confirming or eliminating a diagnosis of acoustic neuroma, and to describe the natural history of acoustic neuroma. Data sources: Major electronic databases were searched from January 1980 to August 2008. Review methods: Selected studies were assessed and subjected to data extraction and quality assessment using standard methods. Results: Studies comparing auditory brainstem response (ABR) with magnetic resonance (MR) imaging were highly heterogeneous. ABR has high sensitivity compared with MR imaging for acoustic neuromas greater than 1 cm in size but not for smaller neuromas. The sensitivities of T2-weighted (T2W) and T2-star-weighted (T2*W) imaging strategies compared with gadolinium-enhanced T1-weighted (GdT1W) MR imaging (gold standard) were high and relatively homogeneous. The specificity of T2W and T2*W studies ranged from 90% to 100% and from 86% to 99% respectively. The review of cost-effectiveness showed that GdT1W MR imaging immediately or in conjunction with ABR appears to be more cost-effective than ‘traditional’ protocols; ABR/GdT1W MR imaging protocols were more cost-effective than going directly to GdT1W MR imaging. Non-contrast-enhanced MR imaging was found to be a more cost-effective test for acoustic neuroma than GdT1W MR imaging. The incidence of acoustic neuroma has increased over the last 30 years, with the median age at diagnosis remaining at 55 years. Most patients present with insidious symptoms of unilateral hearing impairment, tinnitus and/or vertigo. The pattern and rate of growth of acoustic neuroma are highly variable and currently unpredictable. At least 50% of tumours do not grow, at least for some years after diagnosis. Some studies have found large initial size to be a determinant of later growth, with the opposite also being reported. The mean growth rate for all tumours varies between 1 and 2 mm/year, with a rate of 2–4 mm/year for only those that grow; however, there are cases with significant regression (5%) or exceptional growth (which may exceed 18 mm/year). Conclusions: The majority of the evidence reviewed was poorly reported and there is therefore an inherent risk of bias. Given the recent improvement in resolution and reduction in cost of MR imaging, ABR can no longer be considered appropriate as the primary test used to screen for acoustic neuroma. T2W or T2*W sequences enable accurate evaluation of the VIIIth and VIIth cranial nerves within the cerebellopontine angle and internal auditory canal as well as evaluation of the cochlea and labyrinth, and inclusion of GdT1W sequences is unlikely to contribute information that would alter patient management in the screening population. The quality of the imaging chain and experience of the reporting radiologist are key factors determining the efficacy of a non-contrast screening strategy. Based on a cost-effectiveness model developed to reflect UK practice it was concluded that a diagnostic algorithm that deploys non-contrast MR imaging as an initial imaging screen in the investigation of acoustic neuroma is less costly than and likely to be as effective as available contrast MR imaging.

Abstract Within the context of global change, seed dispersal research often focuses on changes in disperser communities (i.e., seed dispersers, such as birds, in an area) resulting from habitat fragmentation. This approach may not be completely illustrative due to certain seed disperser communities being more robust to fragmentation. Additionally, this top‐down approach overlooks how changing food resources on landscapes impacts resource tracking and, subsequently, seed dispersal. We hypothesized resource tracking may promote diffuse plant–animal dispersal mutualisms if resource richness is positively linked to disperser and seed rain richness. We predicted increasing food resource richness attracts more visits and species of avian dispersers, resulting in higher counts and greater species richness of seeds deposited at sites (i.e., seed rain). We tested this mechanism in two replicated field experiments using a model system with bird feeders positioned above seed traps. In the first experiment, we demonstrated resource presence skews seed rain. In the second experiment, we explored how species richness of food resources (0, 4, 8, or 12 species) affected the species richness and visitation of avian seed dispersers at feeders and in subsequent seed rain. Collectively, we observed a positive relationship between available food resources and seed rain, likely mediated by resource tracking behavior of avian dispersers. Our findings underscore a potential key mechanism that may facilitate ecological diversity, whereby accumulating species richness in the plant community attracts a more diverse seed disperser community and indirectly promotes more species in seed rain. Importantly, the resource tracking mechanism driving this potential positive feedback loop may also result in negative ecosystem effects if global change diminishes resource availability through homogenization processes, such as invasive species colonization. Future research should explore the bottom‐up effects of global change on food resources and seed disperser behavior to complement the literature on changing disperser communities.

The problem: Ante-mortem diagnosis of Johne’s disease, caused by Mycobacterium avium subsp. paratuberculosis (MAP), is normally achieved through faecal culture, PCR, or serological tests, but agreement as to which samples are positive for Johne’s disease is often poor and sensitivities are low, particularly in early-stage infections. The potential solution: Mycobacterial cells contain very complex characteristic mixtures of mycolic acid derivatives that elicit antibodies during infection; this has been used to detect infections in humans. Here, we explore its application in providing an assay differentiating infected from vaccinated animals (DIVA assay) for Johne’s disease in cattle. Method: Antibody responses to different classes of mycolic acid derivatives were measured using ELISA for serum from cattle positive for MAP by both faecal PCR and commercial serum ELISA, or just by PCR, and from animals from herds with no history of Johne’s disease, bovine tuberculosis reactors, BCG-vaccinated, BCG-vaccinated and M. bovis-infected, and Gudair-vaccinated animals. Results: The best-performing antigens, ZAM295 and ST123—the latter a molecule present in the cells of MAP but not of Mycobacterium bovis—achieved a sensitivity of 75% and 62.5%, respectively, for serum from animals positive by both faecal PCR and a commercial MAP serum ELISA, at a specificity of 94% compared to 80 no-history negatives. Combining the results of separate assays with two antigens (ST123 and JRRR121) increased the sensitivity/specificity to 75/97.5%. At the same cut-offs, animals vaccinated with Gudair or BCG vaccines and bTB reactors showed a similar specificity. The specificity in BCG-vaccinated but M. bovis-infected animals dropped to 85%. Combining the results of two antigens gave a sensitivity/specificity of 37.5/97.5% for the full set of 80 PCR-positive samples, detecting 30 positives compared 16 for IDEXX. Conclusion: Serum ELISA using synthetic lipids distinguishes effectively between MAP-negative cattle samples and those positive by both PCR and a commercial MAP serodiagnostic, without interference by Gudair or BCG vaccination. It identified almost twice as many PCR positives as the commercial serodiagnostic, offering the possibility of earlier detection of infection.

Relative to the general population, adolescents with psychiatric disorders such as major depression disorder are incarcerated (and reincarcerated) at higher rates. Current research is mixed on whether this association is a cause, consequence, or the product of selection. For example, aggression can lead to more depressive symptoms, yet depression is associated with antisocial behaviors (e.g., delinquency). To better understand the relationship between depression and delinquent behavior, we used the discordant kinship model to examine data from sibling pairs in the National Longitudinal Surveys of Youth 1979, a nationally representative study. By explicitly modeling within- and betweenfamily variance, we reduced the influence of genetic and shared-environmental confounds on our analysis. Our results suggest that the relationship between depression and delinquency is not causal, but rather a product of selection. [ABSTRACT FROM AUTHOR]