Impact of phagostimulants on effectiveness of OMRI‐listed insecticides used for control of spotted‐wing drosophila (Drosophila suzukii Matsumura)

Spotted‐wing drosophila, Drosophila suzukii Matsumura, is an invasive pest in the United States that causes considerable damage to fruit crops. It is responsible for many millions of dollars of revenue loss. The female D. suzukii has a heavily sclerotized ovipositor and can lay eggs in ripening or ripe fruit. The arrival of this invasive species has disrupted existing integrated pest management programmes, and growers rely on repeated insecticide applications to protect fruit. Organic growers have few chemical control options, and their reliance on spinosad increases the risk of developing insecticide resistance. We hypothesized that combining phagostimulants with insecticides would increase insecticide efficacy by prompting flies to spend more time in contact with residues. Therefore, the objective of this study was to evaluate the effectiveness of sucrose and the yeast Saccharomyces cerevisiae as phagostimulants in combination with organic biopesticides against D. suzukii in blueberries. Adding sucrose with or without yeast did not improve insecticide efficacy in terms of adult fly mortality or fruit infestation. Spinosad was very effective in all experiments, and for this product, there is little room for improvement. The phagostimulants had no effect on residual activity of any insecticide. The addition of sucrose with or without yeast did not improve the effectiveness of organic insecticides for D. suzukii. Concentrations of these phagostimulants in our experiments (0.36%) may have been too low to elicit a response. Further research is recommended to test different types and concentrations of phagostimulants.     

First Nations status and emergency department triage scores in Alberta: a retrospective cohort study

Background:Previous studies have found that race is associated with emergency department triage scores, raising concerns about potential health care inequity. As part of a project on quality of care for First Nations people in Alberta, we sought to understand the relation between First Nations status and triage scores.Methods:We conducted a population-based retrospective cohort study of health administrative data from April 2012 to March 2017 to evaluate acuity of triage scores, categorized as a binary outcome of higher or lower acuity score. We developed multivariable multilevel logistic mixed-effects regression models using the levels of emergency department visit, patient (for patients with multiple visits) and facility. We further evaluated the triage of visits related to 5 disease categories and 5 specific diagnoses to better compare triage outcomes of First Nations and non–First Nations patients.Results:First Nations status was associated with lower odds of receiving higher acuity triage scores (odds ratio [OR] 0.93, 95% confidence interval [CI] 0.92–0.94) compared with non–First Nations patients in adjusted models. First Nations patients had lower odds of acute triage for all 5 disease categories and for 3 of 5 diagnoses, including long bone fractures (OR 0.82, 95% CI 0.76–0.88), acute upper respiratory infection (OR 0.90, 95% CI 0.84–0.98) and anxiety disorder (OR 0.67, 95% CI 0.60–0.74).Interpretation:First Nations status was associated with lower odds of higher acuity triage scores across a number of conditions and diagnoses. This may reflect systemic racism, stereotyping and potentially other factors that affected triage assessments.

Health outcomes are markedly worse for First Nations than non–First Nations people. Although this is largely because of inequities in the social determinants of health,^1–4 inequities in the provision of health care also exist.^5,6 Emergency departments serve as a point of accessible health care. Status First Nations patients make up 4.8% of unique patients and 9.4% of emergency visits in Alberta,⁷ and Canadian studies describe First Nations patients’ experiences with racism when seeking emergency care.^8,9Evaluating triage contributes empirically to understanding the health care of First Nations patients insofar as triage is a quantifiable, intermediate process by which systemic racism¹⁰ may influence patient outcomes. The Canadian Triage Acuity Scale¹¹ is a 5-level scale used to classify the severity of patient symptoms. Triage nurses use a brief assessment, medical history, and presenting signs and symptoms to assign each patient a triage score that determines the priority in which the patient should be seen by a provider. Therefore, accurate triage is important for patient health outcomes.¹² In practice, triage is a social interaction where local practice, biases, stereotypes and communication barriers come into play. Studies have found that women receive less acute triage scores than men,^13,14 and that racial minority^13,15–17 and Indigenous^18–20 patients receive less acute triage scores than white or non-Indigenous patients. Indeed, Indigenous patients in Canada have described a perception “of social triaging in the [emergency department], whereby decisions about who is seen first seemed to them [to be] based less on triaged clinical priorities but on the social positioning of the patient.”²¹ Differential triage scores for minority populations raise health equity concerns.As part of a larger mixed-methods project evaluating the quality of emergency care for First Nations people in Alberta, we sought to evaluate quantitative differences in emergency visit characteristics and outcomes of First Nations and non–First Nations people in Alberta. Specifically, we aimed to estimate the relation between First Nations status and acuity of triage, and to evaluate whether predictors of acuity differ by First Nations status.     

T cell receptors employ diverse strategies to target a p53 cancer neoantigen

Adoptive cell therapy with tumor-specific T cells can mediate durable cancer regression. The prime target of tumor-specific T cells are neoantigens arising from mutations in self-proteins during malignant transformation. To understand T cell recognition of cancer neoantigens at the atomic level, we studied oligoclonal T cell receptors (TCRs) that recognize a neoepitope arising from a driver mutation in the p53 oncogene (p53R175H) presented by the major histocompatibility complex class I molecule HLA-A2. We previously reported the structures of three p53R175H-specific TCRs (38-10, 12-6, and 1a2) bound to p53R175H and HLA-A2. The structures showed that these TCRs discriminate between WT and mutant p53 by forming extensive interactions with the R175H mutation. Here, we report the structure of a fourth p53R175H-specific TCR (6-11) in complex with p53R175H and HLA-A2. In contrast to 38-10, 12-6, and 1a2, TCR 6-11 makes no direct contacts with the R175H mutation, yet is still able to distinguish mutant from WT p53. Structure-based in silico mutagenesis revealed that the 60-fold loss in 6-11 binding affinity for WT p53 compared to p53R175H is mainly due to the higher energetic cost of desolvating R175 in the WT p53 peptide during complex formation than H175 in the mutant. This indirect strategy for preferential neoantigen recognition by 6-11 is fundamentally different from the direct strategies employed by other TCRs and highlights the multiplicity of solutions to recognizing p53R175H with sufficient selectivity to mediate T cell killing of tumor but not normal cells.     

Assessing vegetation recovery from energy development using a dynamic reference approach

Ecologically relevant references are useful for evaluating ecosystem recovery, but references that are temporally static may be less useful when environmental conditions and disturbances are spatially and temporally heterogeneous. This challenge is particularly acute for ecosystems dominated by sagebrush (Artemisia spp.), where communities may require decades to recover from disturbance. We demonstrated application of a dynamic reference approach to studying sagebrush recovery using three decades of sagebrush cover estimates from remote sensing (1985–2018). We modelled recovery on former oil and gas well pads (n = 1200) across southwestern Wyoming, USA, relative to paired references identified by the Disturbance Automated Reference Toolset. We also used quantile regression to account for unmodelled heterogeneity in recovery, and projected recovery from similar disturbance across the landscape. Responses to weather and site‐level factors often differed among quantiles, and sagebrush recovery on former well pads increased more when paired reference sites had greater sagebrush cover. Little (<5%) of the landscape was projected to recover within 100 years for low to mid quantiles, and recovery often occurred at higher elevations with cool and moist annual conditions. Conversely, 48%–78% of the landscape recovered quickly (within 25 years) for high quantiles of sagebrush cover. Our study demonstrates advantages of using dynamic reference sites when studying vegetation recovery, as well as how additional inferences obtained from quantile regression can inform management.     

Pharmacological and genetic activation of cAMP synthesis disrupts cholesterol utilization in Mycobacterium tuberculosis

There is a growing appreciation for the idea that bacterial utilization of host-derived lipids, including cholesterol, supports Mycobacterium tuberculosis (Mtb) pathogenesis. This has generated interest in identifying novel antibiotics that can disrupt cholesterol utilization by Mtb in vivo. Here we identify a novel small molecule agonist (V-59) of the Mtb adenylyl cyclase Rv1625c, which stimulates 3’, 5’-cyclic adenosine monophosphate (cAMP) synthesis and inhibits cholesterol utilization by Mtb. Similarly, using a complementary genetic approach that induces bacterial cAMP synthesis independent of Rv1625c, we demonstrate that inducing cAMP synthesis is sufficient to inhibit cholesterol utilization in Mtb. Although the physiological roles of individual adenylyl cyclase enzymes in Mtb are largely unknown, here we demonstrate that the transmembrane region of Rv1625c is required during cholesterol metabolism. Finally, the pharmacokinetic properties of Rv1625c agonists have been optimized, producing an orally-available Rv1625c agonist that impairs Mtb pathogenesis in infected mice. Collectively, this work demonstrates a role for Rv1625c and cAMP signaling in controlling cholesterol metabolism in Mtb and establishes that cAMP signaling can be pharmacologically manipulated for the development of new antibiotic strategies.     

Revisiting the notion of deleterious sweeps

It has previously been shown that, conditional on its fixation, the time to fixation of a semi-dominant deleterious autosomal mutation in a randomly mating population is the same as that of an advantageous mutation. This result implies that deleterious mutations could generate selective sweep-like effects. Although their fixation probabilities greatly differ, the much larger input of deleterious relative to beneficial mutations suggests that this phenomenon could be important. We here examine how the fixation of mildly deleterious mutations affects levels and patterns of polymorphism at linked sites—both in the presence and absence of interference amongst deleterious mutations—and how this class of sites may contribute to divergence between-populations and species. We find that, while deleterious fixations are unlikely to represent a significant proportion of outliers in polymorphism-based genomic scans within populations, minor shifts in the frequencies of deleterious mutations can influence the proportions of private variants and the value of F_ST after a recent population split. As sites subject to deleterious mutations are necessarily found in functional genomic regions, interpretations in terms of recurrent positive selection may require reconsideration.