F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase

There is an important medical need for new antifungal agents with novel mechanisms of action to treat the increasing number of patients with life-threatening systemic fungal disease and to overcome the growing problem of resistance to current therapies. F901318, the leading representative of a novel class of drug, the orotomides, is an antifungal drug in clinical development that demonstrates excellent potency against a broad range of dimorphic and filamentous fungi. In vitro susceptibility testing of F901318 against more than 100 strains from the four main pathogenic Aspergillus spp. revealed minimal inhibitory concentrations of ≤0.06 µg/mL—greater potency than the leading antifungal classes. An investigation into the mechanism of action of F901318 found that it acts via inhibition of the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH) in a fungal-specific manner. Homology modeling of Aspergillus fumigatus DHODH has identified a predicted binding mode of the inhibitor and important interacting amino acid residues. In a murine pulmonary model of aspergillosis, F901318 displays in vivo efficacy against a strain of A. fumigatus sensitive to the azole class of antifungals and a strain displaying an azole-resistant phenotype. F901318 is currently in late Phase 1 clinical trials, offering hope that the antifungal armamentarium can be expanded to include a class of agent with a mechanism of action distinct from currently marketed antifungals

Valproate, thalidomide and ethyl alcohol alter the migration of HTR-8/SVneo cells

BACKGROUND: Valproate, thalidomide and alcohol (ethanol) exposure during the first trimester of pregnancy is known to cause several developmental disorders. All these teratogens are known to pass the placental barrier and interfere directly with the normal development of the fetus. However, these teratogens also alter the formation and function of the placenta itself which may in turn affect the proper nourishment and development of the fetus. Optimum development of the placenta requires adequate invasion of trophoblast into the maternal uterine tissues. Changes in the migratory behavior of trophoblast by maternal exposure to these teratogens during placentogenesis may therefore alter the structure and function of the placenta. METHODS: In the present study, the effects of sodium valproate, thalidomide and alcohol on the migration of human first trimester trophoblast cell line (HTR-8/SVneo) were examined in vitro. Cells were cultured in the wells of 48-well culture plates as mono or multilayers. Circular patches of cells were removed from the center of the wells by suction, and the migration of cells into the wound was studied using microscopy. Effects of low and high concentrations of valproate, thalidomide and alcohol were examined on the healing of wounds and on the migration rate of cells by determining the wound areas at 0, 3, 6, 12, 24 and 48 h. Effects of drugs and alcohol on the proliferation and the expression levels of integrin subunits beta1 and alpha5 in cells were examined. RESULTS: The migration rates of trophoblast differed between wounds created in mono and multilayers of cells. Exposure to teratogens altered the migration of trophoblast into mono and multilayer wounds. The effects of valproate, thalidomide and alcohol on the proliferation of cells during the rapid migratory phase were mild. Drug exposure caused significant changes in the expression levels of beta1 and alpha5 integrin subunits. CONCLUSION: Results suggest that exposure to valproate, thalidomide or alcohol during the first trimester of pregnancy may change the ultrastructure of the placenta by altering the migration of trophoblast cells and this effect may be mediated by drug- or alcohol-induced changes in the expression levels of beta1 and alpha5 integrin subunits

Search for invisible modes of nucleon decay in water with the SNO+ detector

This paper reports results from a search for nucleon decay through invisible modes, where no visible energy is directly deposited during the decay itself, during the initial water phase of SNO+. However, such decays within the oxygen nucleus would produce an excited daughter that would subsequently deexcite, often emitting detectable gamma rays. A search for such gamma rays yields limits of 2.5×1029  y at 90% Bayesian credibility level (with a prior uniform in rate) for the partial lifetime of the neutron, and 3.6×1029  y for the partial lifetime of the proton, the latter a 70% improvement on the previous limit from SNO. We also present partial lifetime limits for invisible dinucleon modes of 1.3×1028  y for nn, 2.6×1028  y for pn and 4.7×1028  y for pp, an improvement over existing limits by close to 3 orders of magnitude for the latter two

Development, characterisation, and deployment of the SNO+ liquid scintillator

A liquid scintillator consisting of linear alkylbenzene as the solvent and 2,5-diphenyloxazole as the fluor was developed for the SNO+ experiment. This mixture was chosen as it is compatible with acrylic and has a competitive light yield to pre-existing liquid scintillators while conferring other advantages including longer attenuation lengths, superior safety characteristics, chemical simplicity, ease of handling, and logistical availability. Its properties have been extensively characterized and are presented here. This liquid scintillator is now used in several neutrino physics experiments in addition to SNO+

The effect of the novel antifungal drug F901318 (Olorofim) on the growth and viability of Aspergillus fumigatus

We thank our colleagues at F2G Ltd. for their support in this work, as well as the Manchester Fungal Infection Group at the University of Manchester. We also thank Gillian Milne and the Microscopy and Histology Core Facility at the Medical Research Council Centre for Medical Mycology at the University of Aberdeen for their assistance with TEM. We also thank John Rex for critical reading of the manuscript. The Microscopy and Histology Core Facility at the Medical Research Council Centre for Medical Mycology at the University of Aberdeen is supported by grant number MR/N006364/1. S.D.P. and M.C.A. are supported by the European Marie Curie ITN FungiBrain grant PITN-GA-2013-607963. S.D.P. was the primary author and performed the live-cell imaging microscopy, TEM, viability staining, and the analysis of the data. N.B. performed the postexposure effect assays. M.C.A. assisted with TEM. G.E.M.S. designed F901318. N.B., A.C.B., D.L., M.B., N.D.R., and J.D.O. provided guidance and assistance during this project and in the preparation of the manuscript.Peer reviewedPublisher PD

Applying an intersectionality lens to the theoretical domains framework: a tool for thinking about how intersecting social identities and structures of power influence behaviour

Background: A key component of the implementation process is identifying potential barriers and facilitators that need to be addressed. The Theoretical Domains Framework (TDF) is one of the most commonly used frameworks for this purpose. When applying the TDF, it is critical to understand the context in which behaviours occur. Intersectionality, which accounts for the interface between social identity factors (e.g. age, gender) and structures of power (e.g. ageism, sexism), offers a novel approach to understanding how context shapes individual decision-making and behaviour. We aimed to develop a tool to be used alongside applications of the TDF to incorporate an intersectionality lens when identifying implementation barriers and enablers. Methods: An interdisciplinary Framework Committee (n = 17) prioritized the TDF as one of three models, theories, and frameworks (MTFs) to enhance with an intersectional lens through a modified Delphi approach. In collaboration with the wider Framework Committee, a subgroup considered all 14 TDF domains and iteratively developed recommendations for incorporating intersectionality considerations within the TDF and its domains. An iterative approach aimed at building consensus was used to finalize recommendations. Results: Consensus on how to apply an intersectionality lens to the TDF was achieved after 12 rounds of revision. Two overarching considerations for using the intersectionality alongside the TDF were developed by the group as well as two to four prompts for each TDF domain to guide interview topic guides. Considerations and prompts were designed to assist users to reflect on how individual identities and structures of power may play a role in barriers and facilitators to behaviour change and subsequent intervention implementation. Conclusions: Through an expert-consensus approach, we developed a tool for applying an intersectionality lens alongside the TDF. Considering the role of intersecting social factors when identifying barriers and facilitators to implementing research evidence may result in more targeted and effective interventions that better reflect the realities of those involved.Other UBCNon UBCReviewedFacult

Development and usability testing of tools to facilitate incorporating intersectionality in knowledge translation

Background The field of knowledge translation (KT) has been criticized for neglecting contextual and social considerations that influence health equity. Intersectionality, a concept introduced by Black feminist scholars, emphasizes how human experience is shaped by combinations of social factors (e.g., ethnicity, gender) embedded in systemic power structures. Its use has the potential to advance equity considerations in KT. Our objective was to develop and conduct usability testing of tools to support integrating intersectionality in KT through three key phases of KT: identifying the gap; assessing barriers to knowledge use; and selecting, tailoring, and implementing interventions. Methods We used an integrated KT approach and assembled an interdisciplinary development committee who drafted tools. We used a mixed methods approach for usability testing with KT intervention developers that included semi-structured interviews and the System Usability Scale (SUS). We calculated an average SUS score for each tool. We coded interview data using the framework method focusing on actionable feedback. The development committee used the feedback to revise tools, which were formatted by a graphic designer. Results Nine people working in Canada joined the development committee. They drafted an intersectionality primer and one tool that included recommendations, activities, reflection prompts, and resources for each of the three implementation phases. Thirty-one KT intervention developers from three countries participated in usability testing. They suggested the tools to be shorter, contain more visualizations, and use less jargon. Average SUS scores of the draft tools ranged between 60 and 78/100. The development committee revised and shortened all tools, and added two, one-page summary documents. The final toolkit included six documents. Conclusions We developed and evaluated tools to help embed intersectionality considerations in KT. These tools go beyond recommending the use of intersectionality to providing practical guidance on how to do this. Future work should develop guidance for enhancing social justice in intersectionality-enhanced KT.Medicine, Faculty ofNon UBCPhysical Therapy, Department ofReviewedFacultyResearche