Hormetic dietary phytochemicals from Western Canadian plants: Identification, characterization and mechanistic insights

Activation of mammalian stress responsive pathways by plant secondary metabolites may contribute to the protection against certain chronic diseases afforded by fruit and vegetable consumption. This work focuses on the identification of plant compounds that activate the stress-responsive enzyme quinone reductase (QR) by stabilizing the transcription factor NF-E2 related factor-2 (Nrf2). Screening methanolic extracts of plants from Western Canada for QR induction in a mouse hepatoma cell line (Hepa-1c1c7) led to the identification of twenty-one extracts capable of doubling the activity of QR. Bioassay-guided fractionation of six extracts led to the identification of novel classes of compounds with QR-inducing activity including fatty-acid derived polyacetylenes, phthalides, and cannabinoids. Studies using low molecular weight thiols and the recombinantly expressed protein Keap1, the principal negative regulator of Nrf2, supported a mechanism of QR activation involving covalent modification of Keap1 cysteines for the polyacetylenes and phthalides. Analysis of transcriptional changes in response to treatment with a panel of QR-inducing compounds provided strong support for Nrf2 activation by the polyacetylene (3S,8S)-falcarindiol and the isothiocyanate (R)-sulforaphane and weaker support for the compounds (3R,8S)-falcarindiol, 6-isovaleryl-umbelliferone (6-IVU) and (Z)-ligustilide. Additionally, transcript level analyses supported a role for the aryl-hydrocarbon receptor in QR-activation by (3R,8S)-falcarindiol, (Z)-ligustilide, (R)-sulforaphane, 6-IVU and cannabidiol and suggested that treatment with polyacetylenes with a (3R)-configuration, (Z)-ligustilide and 6-IVU causes substantial changes in the expression of genes associated with lipid homeostasis and energy metabolism. As a whole, this work provides evidence that compounds that activate QR (and Nrf2) are widely distributed in the Canadian flora. However, of these QR activators, few are active at concentrations that are expected to be achieved through dietary consumption. Nevertheless, the most exceptional compounds isolated in this work, the compounds (3S,8S)-falcarindiol and epoxyfalcarindiol are highly potent and appear to be or are expected to be specific for activating Nrf2 and thus warrant attention with respect to dietary implications and as drug candidate leads

The impact of interpersonal relationships on rural doctors’ clinical courage

Introduction: Clinical courage occurs when rural doctors push themselves to the limits of their scope of practice to provide the medical care needed by patients in their community. This mental strength to venture, persevere and act out of concern for one’s patient, despite a lack of formally recognised expertise, becomes necessary for doctors who work in relative professional isolation. Previous research by the authors suggested that the clinical courage of rural doctors relies on the relationships around them. This article explores in more depth how relationships with others can impact on clinical courage. Methods: At an international rural medicine conference in 2017, doctors who practised rural/remote medicine were invited to participate in the study. Twenty-seven semistructured interviews were conducted exploring experiences of clinical courage. Initial analysis of the material, using a hermeneutic phenomenological frame, sought to understand the meaning of clinical courage. In the original analysis, an emic question arose: ‘How do interpersonal relationships impact on clinical courage’. The material was re-analysed to explore this question, using Wenger’s community of practice as a theoretical framework. Results: This study found that clinical courage was affected by the relationships rural doctors had with their communities and patients, with each other, with the local members of their healthcare team and with other colleagues and health leaders outside their immediate community of practice. Conclusion: As a collective, rural doctors can learn, use and strengthen clinical courage and support its development in new members of the discipline. Relationships with rural communities, rural patients and urban colleagues can support the clinical courage of rural doctors. When detractors challenge the value of clinical courage, it requires individual rural doctors and their community of practice to champion rural doctors’ way of working

Exploration of rural physicians' lived experience of practising outside their usual scope of practice to provide access to essential medical care (clinical courage): an international phenomenological study

Objectives Rural doctors describe consistent pressure to provide extended care beyond the limits of their formal training in order to meet the needs of the patients and communities they serve. This study explored the lived experience of rural doctors when they practise outside their usual scope of practice to provide medical care for people who would otherwise not have access to essential clinical services. Design A hermeneutic phenomenological study. Setting An international rural medicine conference. Participants All doctors attending the conference who practised medicine in rural/remote areas in a predominantly English-speaking community were eligible to participate; 27 doctors were recruited. Interventions Semi-structured interviews were conducted. The transcripts were initially read and analysed by individual researchers before they were read aloud to the group to explore meanings more fully. Two researchers then reviewed the transcripts to develop the results section which was then rechecked by the broader group. Primary outcome measure An understanding of the lived experiences of clinical courage. Results Participants provided in-depth descriptions of experiences we have termedclinical courage. This phenomenon included the following features: Standing up to serve anybody and everybody in the community; Accepting uncertainty and persistently seeking to prepare; Deliberately understanding and marshalling resources in the context; Humbly seeking to know one's own limits; Clearing the cognitive hurdle when something needs to be done for your patient; Collegial support to stand up again. Conclusion This study elucidated six features of the phenomenon ofclinical couragethrough the narratives of the lived experience of rural generalist doctors

Exploring rural doctors’ early experiences of coping with the emerging COVID-19 pandemic

Purpose: To understand how rural doctors (physicians) responded to the emerging COVID-19 pandemic and their strategies for coping. Methods: Early in the pandemic doctors (physicians) who practise rural and remote medicine were invited to participate through existing rural doctors’ networks. Thirteen semi-structured interviews were conducted with rural doctors from 11 countries. Interviews were transcribed verbatim and coded using NVivo. A thematic analysis was used to identify common ideas and narratives. Findings: Participants’ accounts described highly adaptable and resourceful responses to address the crisis. Rapid changes to organizational and clinical practices were implemented, at a time of uncertainty, anxiety, and fear, and with limited information and resources. Strong relationships and commitment to their colleagues and communities were integral to shaping and sustaining these doctors’ responses. We identified five common themes underpinning rural doctors’ shared experiences: (1) caring for patients in a context of uncertainty, fear, and anxiety; (2) practical solutions through improvising and being resourceful; (3) gaining community trust and cooperation; (4) adapting to unrelenting pressures; and (5) reaffirming commitments. These themes are discussed in relation to the Lazarus and Folkman stress and coping model. Conclusions: With limited resources and support, these rural doctors’ practical responses to the COVID-19 crisis underscore strong problem-focused coping strategies and shared commitments to their communities, patients, and colleagues. They drew support from sharing experiences with peers (emotion-focused coping) and finding positive meanings in their experiences (meaning-based coping). The psychosocial impact on rural doctors working at the limits of their adaptive resources is an ongoing concern

Genetic and transcriptional dissection of resistance to Claviceps purpurea in the durum wheat cultivar Greenshank.

Funder: Canadian Seed Growers' Association; doi: http://dx.doi.org/10.13039/501100000071Funder: National Research Council of Canada: Canadian Wheat Improvement programFour QTL for ergot resistance (causal pathogen Claviceps purpurea) have been identified in the durum wheat cultivar Greenshank. Claviceps purpurea is a pathogen of grasses that infects flowers, replacing the seed with an ergot sclerotium. Ergot presents a significant problem to rye, barley and wheat, in particular hybrid seed production systems. In addition, there is evidence that the highly toxic alkaloids that accumulate within sclerotia can cross-contaminate otherwise healthy grain. Host resistance to C. purpurea is rare, few resistance loci having been identified. In this study, four ergot resistance loci are located on chromosomes 1B, 2A, 5A and 5B in the durum wheat cv. Greenshank. Ergot resistance was assessed through analysis of phenotypes associated with C. purpurea infection, namely the number of inoculated flowers that produced sclerotia, or resulted in ovary death but no sclerotia, the levels of honeydew produced, total sclerotia weight and average sclerotia weight and size per spike. Ergot testing was undertaken in Canada and the UK. A major effect QTL, QCp.aafc.DH-2A, was detected in both the Canadian and UK experiments and had a significant effect on honeydew production levels. QCp.aafc.DH-5B had the biggest influence on total sclerotia weight per spike. QCp.aafc.DH-1B was only detected in the Canadian experiments and QCp.aafc.DH-5A in the UK experiment. An RNASeq analysis, undertaken to identify wheat differentially expressed genes associated with different combinations of the four ergot resistance QTL, revealed a disproportionate number of DEGs locating to the QCp.aafc.DH-1B, QCp.aafc.DH-2A and QCp.aafc.DH-5B QTL intervals

Chromosome-scale genome assembly provides insights into rye biology, evolution and agronomic potential

Rye (Secale cereale L.) is an exceptionally climate-resilient cereal crop, used extensively to produce improved wheat varieties via introgressive hybridization and possessing the entire repertoire of genes necessary to enable hybrid breeding. Rye is allogamous and only recently domesticated, thus giving cultivated ryes access to a diverse and exploitable wild gene pool. To further enhance the agronomic potential of rye, we produced a chromosome-scale annotated assembly of the 7.9-gigabase rye genome and extensively validated its quality by using a suite of molecular genetic resources. We demonstrate applications of this resource with a broad range of investigations. We present findings on cultivated rye's incomplete genetic isolation from wild relatives, mechanisms of genome structural evolution, pathogen resistance, low-temperature tolerance, fertility control systems for hybrid breeding and the yield benefits of rye-wheat introgressions.Peer reviewe

Editorial: Functional Genomics in Plant Breeding 2.0

Scientists agree that the increased human impact on the environment since the 19th century has positioned our planet in a period of rapid and intense change, particularly to our natural ecosystems [...

Developing conceptually sound items for a clinical courage questionnaire

Introduction: Clinical courage can be described as a rural doctor's adaptability and willingness to undertake clinical work at the limits of their training and experience to meet the needs of their patients. This article describes the in-house development of survey items to include in a quantitative measure of clinical courage. Methods: The questionnaire development involved two key concepts: a second-order latent factor model structure and a nominal group technique, used to develop consensus among the research team members. Results: The steps taken to develop a sound clinical courage questionnaire are described in detail. The resulting initial questionnaire is presented, ready for testing with rural clinicians and refinement. Conclusion: This article outlines the psychometric process of questionnaire design and presents the resultant clinical courage questionnaire