Homeostatic IL-13 in healthy skin directs dendritic cell differentiation to promote TH2 and inhibit TH17 cell polarization.

The signals driving the adaptation of type 2 dendritic cells (DC2s) to diverse peripheral environments remain mostly undefined. We show that differentiation of CD11blo migratory DC2s-a DC2 population unique to the dermis-required IL-13 signaling dependent on the transcription factors STAT6 and KLF4, whereas DC2s in lung and small intestine were STAT6-independent. Similarly, human DC2s in skin expressed an IL-4 and IL-13 gene signature that was not found in blood, spleen and lung DCs. In mice, IL-13 was secreted homeostatically by dermal innate lymphoid cells and was independent of microbiota, TSLP or IL-33. In the absence of IL-13 signaling, dermal DC2s were stable in number but remained CD11bhi and showed defective activation in response to allergens, with diminished ability to support the development of IL-4+GATA3+ helper T cells (TH), whereas antifungal IL-17+RORγt+ TH cells were increased. Therefore, homeostatic IL-13 fosters a noninflammatory skin environment that supports allergic sensitization.

Real-time genomics for One Health.

The ongoing degradation of natural systems and other environmental changes has put our society at a crossroad with respect to our future relationship with our planet. While the concept of One Health describes how human health is inextricably linked with environmental health, many of these complex interdependencies are still not well-understood. Here, we describe how the advent of real-time genomic analyses can benefit One Health and how it can enable timely, in-depth ecosystem health assessments. We introduce nanopore sequencing as the only disruptive technology that currently allows for real-time genomic analyses and that is already being used worldwide to improve the accessibility and versatility of genomic sequencing. We showcase real-time genomic studies on zoonotic disease, food security, environmental microbiome, emerging pathogens, and their antimicrobial resistances, and on environmental health itself - from genomic resource creation for wildlife conservation to the monitoring of biodiversity, invasive species, and wildlife trafficking. We stress why equitable access to real-time genomics in the context of One Health will be paramount and discuss related practical, legal, and ethical limitations.

Expanding the conservation genomics toolbox: Incorporating structural variants to enhance genomic studies for species of conservation concern.

Structural variants (SVs) are large rearrangements (>50 bp) within the genome that impact gene function and the content and structure of chromosomes. As a result, SVs are a significant source of functional genomic variation, that is, variation at genomic regions underpinning phenotype differences, that can have large effects on individual and population fitness. While there are increasing opportunities to investigate functional genomic variation in threatened species via single nucleotide polymorphism (SNP) data sets, SVs remain understudied despite their potential influence on fitness traits of conservation interest. In this future-focused Opinion, we contend that characterizing SVs offers the conservation genomics community an exciting opportunity to complement SNP-based approaches to enhance species recovery. We also leverage the existing literature-predominantly in human health, agriculture and ecoevolutionary biology-to identify approaches for readily characterizing SVs and consider how integrating these into the conservation genomics toolbox may transform the way we manage some of the world's most threatened species.

De novo assembly of the complex genome of Nippostrongylus brasiliensis using MinION long reads.

BACKGROUND: Eukaryotic genome assembly remains a challenge in part due to the prevalence of complex DNA repeats. This is a particularly acute problem for holocentric nematodes because of the large number of satellite DNA sequences found throughout their genomes. These have been recalcitrant to most genome sequencing methods. At the same time, many nematodes are parasites and some represent a serious threat to human health. There is a pressing need for better molecular characterization of animal and plant parasitic nematodes. The advent of long-read DNA sequencing methods offers the promise of resolving complex genomes. RESULTS: Using Nippostrongylus brasiliensis as a test case, applying improved base-calling algorithms and assembly methods, we demonstrate the feasibility of de novo genome assembly matching current community standards using only MinION long reads. In doing so, we uncovered an unexpected diversity of very long and complex DNA sequences repeated throughout the N. brasiliensis genome, including massive tandem repeats of tRNA genes. CONCLUSION: Base-calling and assembly methods have improved sufficiently that de novo genome assembly of large complex genomes is possible using only long reads. The method has the added advantage of preserving haplotypic variants and so has the potential to be used in population analyses.

Expression QTL analysis of glaucoma endophenotypes in the Norfolk Island isolate provides evidence that immune-related genes are associated with optic disc size.

Primary open-angle glaucoma (POAG) is influenced by both genetic and environmental factors. Despite significant progress in identifying genetic variants associated with POAG, there remains a substantial amount of unexplained heritability. Study design features that may enhance knowledge of the genetic architecture include focusing on multiple quantitative traits related to ocular disorders (i.e. endophenotypes), targeting genetic variants that directly influence gene expression (i.e. cis-eQTLs) and utilising genetically isolated populations to reduce genetic and environmental noise and thus enhance association signals. In this study we performed heritability and blood-based eQTL association analysis of five key POAG endophenotypes in 330 individuals from the Norfolk Island (NI) isolate. Results showed evidence of heritability for all five traits, with H2 estimates ranging from 0.35 for intraocular pressure (IOP) to 0.82 for central corneal thickness (CCT) (P < 0.05). The primary finding was for BTN3A2, whereby both cis-SNP and transcript were significantly associated with disc size within a conditional regression model. Specifically, this model included rs853676 (ß = 0.23,P = 0.008) and transcript (ß = 0.23, P = 0.03). We also observed a cis-SNP association between optic disc size and LPCAT2 independent of transcript (P = 0.0004). These genes have specific functions in immune system pathways and suggest a role for an inherited immune component of POAG risk. This study also demonstrates an alternate approach to understanding the functional genetic basis of POAG and ocular health more generally.

A Phenomic Scan of the Norfolk Island Genetic Isolate Identifies a Major Pleiotropic Effect Locus Associated with Metabolic and Renal Disorder Markers.

Multiphenotype genome-wide association studies (GWAS) may reveal pleiotropic genes, which would remain undetected using single phenotype analyses. Analysis of large pedigrees offers the added advantage of more accurately assessing trait heritability, which can help prioritise genetically influenced phenotypes for GWAS analysis. In this study we performed a principal component analysis (PCA), heritability (h2) estimation and pedigree-based GWAS of 37 cardiovascular disease -related phenotypes in 330 related individuals forming a large pedigree from the Norfolk Island genetic isolate. PCA revealed 13 components explaining >75% of the total variance. Nine components yielded statistically significant h2 values ranging from 0.22 to 0.54 (P<0.05). The most heritable component was loaded with 7 phenotypic measures reflecting metabolic and renal dysfunction. A GWAS of this composite phenotype revealed statistically significant associations for 3 adjacent SNPs on chromosome 1p22.2 (P<1x10-8). These SNPs form a 42kb haplotype block and explain 11% of the genetic variance for this renal function phenotype. Replication analysis of the tagging SNP (rs1396315) in an independent US cohort supports the association (P = 0.000011). Blood transcript analysis showed 35 genes were associated with rs1396315 (P<0.05). Gene set enrichment analysis of these genes revealed the most enriched pathway was purine metabolism (P = 0.0015). Overall, our findings provide convincing evidence for a major pleiotropic effect locus on chromosome 1p22.2 influencing risk of renal dysfunction via purine metabolism pathways in the Norfolk Island population. Further studies are now warranted to interrogate the functional relevance of this locus in terms of renal pathology and cardiovascular disease risk.

Genome-wide linkage and association analysis of primary open-angle glaucoma endophenotypes in the Norfolk Island isolate.

PURPOSE: Primary open-angle glaucoma (POAG) refers to a group of heterogeneous diseases involving optic nerve damage. Two well-established risk factors for POAG are elevated intraocular pressure (IOP) and a thinner central corneal thickness (CCT). These endophenotypes exhibit a high degree of heritability across populations. Large-scale genome-wide association studies (GWASs) of outbred populations have robustly implicated several susceptibility gene variants for both IOP and CCT. Despite this progress, a substantial amount of genetic variance remains unexplained. Population-specific variants that might be rare in outbred populations may also influence POAG endophenotypes. The Norfolk Island population is a founder-effect genetic isolate that has been well characterized for POAG endophenotypes. This population is therefore a suitable candidate for mapping new variants that influence these complex traits. METHODS: Three hundred and thirty participants from the Norfolk Island Eye Study (NIES) core pedigree provided DNA. Ocular measurements of CCT and IOP were also taken for analysis. Heritability analyses and genome-wide linkage analyses of short tandem repeats (STRs) were conducted using SOLAR. Pedigree-based GWASs of single-nucleotide polymorphisms (SNPs) were performed using the GenABEL software. RESULTS: CCT was the most heritable endophenotype in this cohort (h2 = 0.77, p = 6×10-6), while IOP showed a heritability of 0.39 (p = 0.008). A genome-wide linkage analysis of these POAG phenotypes identified a maximum logarithm of the odds (LOD) score of 1.9 for CCT on chromosome 20 (p = 0.0016) and 1.3 for IOP on chromosome 15 (p = 0.0072). The GWAS results revealed a study-wise significant association for IOP at rs790357, which is located within DLG2 on chr11q14.1 (p = 1.02×10-7). DLG2 is involved in neuronal signaling and development, and while it has not previously been associated with IOP, it has been associated with myopia. An analysis of 12 known SNPs for IOP showed that rs12419342 in RAPSN on chromosome 11 was nominally associated in Norfolk Island (NI; p = 0.0021). For CCT, an analysis of 26 known SNPs showed rs9938149 in BANP-ZNF469 on chromosome 16 was nominally associated in NI (p = 0.002). CONCLUSIONS: These study results indicate that CCT and IOP exhibit a substantial degree of heritability in the NI pedigree, indicating a genetic component. A genome-wide linkage analysis of POAG endophenotypes did not reveal any major effect loci, but the GWASs did implicate several known loci, as well as a potential new locus in DLG2, suggesting a role for neuronal signaling in development in IOP and perhaps POAG. These results also highlight the need to target rarer variants via whole genome sequencing in this genetic isolate.

Team deliberate practice in medicine and related domains: a consideration of the issues.

A better understanding of the factors influencing medical team performance and accounting for expert medical team performance should benefit medical practice. Therefore, the aim here is to highlight key issues with using deliberate practice to improve medical team performance, especially given the success of deliberate practice for developing individual expert performance in medicine and other domains. Highlighting these issues will inform the development of training for medical teams. The authors first describe team coordination and its critical role in medical teams. Presented next are the cognitive mechanisms that allow expert performers to accurately interpret the current situation via the creation of an accurate mental "model" of the current situation, known as a situation model. Following this, the authors propose that effective team performance depends at least in part on team members having similar models of the situation, known as a shared situation model. The authors then propose guiding principles for implementing team deliberate practice in medicine and describe how team deliberate practice can be used in an attempt to reduce barriers inherent in medical teams to the development of shared situation models. The paper concludes with considerations of limitations, and future research directions, concerning the implementation of team deliberate practice within medicine.

'Gun! Gun! Gun!': An exploration of law enforcement officers' decision-making and coping under stress during actual events.

Research on decision-making under stress has mainly involved laboratory-based studies with few contextual descriptions of decision-making under stress in the natural ecology. We examined how police officers prepared for, coped with and made decisions under threat-of-death stress during real events. A delayed retrospective report method was used to elicit skilled police officers' thoughts and feelings during attempts to resolve such events. Reports were analysed to identify experiences of stress and coping, and thought processes underpinning decision-making during the event. Officers experienced a wide range of events, coped with stress predominantly via problem-focused strategies, and adapted their decision-making under stress based on the available context. Future officer training should involve a greater variety of training scenarios than is involved in current training, and expose trainees to the possible variants of each situation to foster better situational representation and, thus, a more reliable and adaptive mental model for use in decision-making. Practitioner Summary: This study concerns decision-making and coping strategies used by skilled police officers during real threat-of-death situations. Officers' decision-making strategies differed according to the complexity of the situation and they coped with the stress of these situations via attempts to resolve the situations (e.g. by planning responses) and, to a lesser extent, via attempts to deal with their emotions.

Mapping eQTLs in the Norfolk Island genetic isolate identifies candidate genes for CVD risk traits.

Cardiovascular disease (CVD) affects millions of people worldwide and is influenced by numerous factors, including lifestyle and genetics. Expression quantitative trait loci (eQTLs) influence gene expression and are good candidates for CVD risk. Founder-effect pedigrees can provide additional power to map genes associated with disease risk. Therefore, we identified eQTLs in the genetic isolate of Norfolk Island (NI) and tested for associations between these and CVD risk factors. We measured genome-wide transcript levels of blood lymphocytes in 330 individuals and used pedigree-based heritability analysis to identify heritable transcripts. eQTLs were identified by genome-wide association testing of these transcripts. Testing for association between CVD risk factors (i.e., blood lipids, blood pressure, and body fat indices) and eQTLs revealed 1,712 heritable transcripts (p < 0.05) with heritability values ranging from 0.18 to 0.84. From these, we identified 200 cis-acting and 70 trans-acting eQTLs (p < 1.84 × 10(-7)) An eQTL-centric analysis of CVD risk traits revealed multiple associations, including 12 previously associated with CVD-related traits. Trait versus eQTL regression modeling identified four CVD risk candidates (NAAA, PAPSS1, NME1, and PRDX1), all of which have known biological roles in disease. In addition, we implicated several genes previously associated with CVD risk traits, including MTHFR and FN3KRP. We have successfully identified a panel of eQTLs in the NI pedigree and used this to implicate several genes in CVD risk. Future studies are required for further assessing the functional importance of these eQTLs and whether the findings here also relate to outbred populations.

How do they make it look so easy? The expert orienteer's cognitive advantage.

Expertise in sport can appear so extraordinary that it is difficult to imagine how "normal" individuals may achieve it. However, in this review, we show that experts in the sport of orienteering, which requires on-foot navigation using map and compass through wild terrain, can make the difficult look easy because they have developed a cognitive advantage. Specifically, they have acquired knowledge of cognitive and behavioural strategies that allow them to circumvent natural limitations on attention. Cognitive strategies include avoiding peaks of demand on attention by distributing the processing of map information over time and reducing the need to attend to the map by simplifying the navigation required to complete a race. Behavioural strategies include reducing the visual search required of the map by physically arranging and rearranging the map display during races. It is concluded that expertise in orienteering can be partly attributed to the circumvention of natural limitations on attention achieved via the employment of acquired cognitive and behavioural strategies. Thus, superior performance in sport may not be the possession of only a privileged few; it may be available to all aspiring athletes.

Managing pressure: patterns of appraisals and coping strategies of non-elite and elite athletes during competition.

The purpose of this study was to compare moment-to-moment appraisals and coping strategies of 4 non-elite and 2 elite male trap shooters during competitions and in particular during periods of competition perceived as critical to performance. Appraisals and coping patterns of trap shooters were captured via verbal reports of thinking provided between sets of shots during major competitions. Verbal reports were coded according to an appraisal and coping typology. Coded data as well as shooting performance data were subjected to a sequential analysis of probabilities of pairs of events. Fewer reports of negative appraisals (NEGAs) and more frequent reports of problem-focused coping (PFC) were observed among both elite athletes compared to non-elite athletes. After making a NEGA, non-elite shooters often progressed to the next target without attempting to cope, whereas elite shooters used both PFC and emotion-focused coping (EFC) before proceeding to the next target. After missing a target, the non-elite athletes used more EFC than expected. These results indicate that elite athletes are more likely to cope with NEGAs than non-elite athletes using a wider variety of coping strategies. Athletes might benefit from increased awareness of the potentially detrimental impact of NEGAs on performance and by integrating coping strategies within preparatory routines.

Residual OXPHOS is required to drive primary and metastatic lung tumours in an orthotopic breast cancer model.

Background: Fast adaptation of glycolytic and mitochondrial energy pathways to changes in the tumour microenvironment is a hallmark of cancer. Purely glycolytic ρ0 tumour cells do not form primary tumours unless they acquire healthy mitochondria from their micro-environment. Here we explored the effects of severely compromised respiration on the metastatic capability of 4T1 mouse breast cancer cells. Methods: 4T1 cell lines with different levels of respiratory capacity were generated; the Seahorse extracellular flux analyser was used to evaluate oxygen consumption rates, fluorescent confocal microscopy to assess the number of SYBR gold-stained mitochondrial DNA nucleoids, and the presence of the ATP5B protein in the cytoplasm and fluorescent in situ nuclear hybridization was used to establish ploidy. MinION nanopore RNA sequence analysis was used to compare mitochondrial DNA transcription between cell lines. Orthotopic injection was used to determine the ability of cells to metastasize to the lungs of female Balb/c mice. Results: OXPHOS-deficient ATP5B-KO3.1 cells did not generate primary tumours. Severely OXPHOS compromised ρ0D5 cells generated both primary tumours and lung metastases. Cells generated from lung metastasis of both OXPHOS-competent and OXPHOS-compromised cells formed primary tumours but no metastases when re-injected into mice. OXPHOS-compromised cells significantly increased their mtDNA content, but this did not result in increased OXPHOS capacity, which was not due to decreased mtDNA transcription. Gene set enrichment analysis suggests that certain cells derived from lung metastases downregulate their epithelial-to-mesenchymal related pathways. Conclusion: In summary, OXPHOS is required for tumorigenesis in this orthotopic mouse breast cancer model but even very low levels of OXPHOS are sufficient to generate both primary tumours and lung metastases.

A theoretical framework for simulation in nursing: answering Schiavenato's call.

The aim of this article was to provide a response that supports and extends Schiavenato's call for a theoretically guided approach to simulation use in nursing education.We propose that a theoretical framework for simulation In nursing must first include, as a basis, a theoretical understanding of human performance and how it is enhanced.This understanding will, in turn, allow theorists to provide a framework regarding the utility, application, and design of the training environment, including internal and external validity. The expert performance approach, a technique that recently has been termed Expert-Performance-based Training (ExPerT), is introduced as a guiding frame work for addressing these training needs. We also describe how the theory of deliberate practice within the framework of ExPerT can be useful for developing effective training methods in health care domains and highlight examples of how deliberate practice has been successfully applied to the training of psychomotor and cognitive skills.

HIV case manager preparedness for practice in Ryan White CARE Act funded settings.

While current research on the factors affecting the HIV epidemic within the general population has considered the role of HIV case managers, much remains to be known about case management effectiveness and how it might be enhanced. This article presents the data from a statewide survey of case management professionals in Florida. The study focused on case managers' preparation for practice and barriers to successful practice. The study results reflect a very broad educational preparation in multiple disciplines with highly varied means of case manager training and orientation at entry to practice. Further, the results highlighted the existence of multiple barriers that challenge the ability of case managers to cope with the demands of case management practice in sites serving people living with HIV/AIDS who are socially and economically challenged. The article concludes with recommendations for changes in the system that would enhance the preparation of case management professionals for entry to practice.

Organic self-talk content categories and their relations to sport-specific contextual and personal factors.

While strategic self-talk interventions are well documented, less is known regarding organically occurring self-talk. Previously, eight organic self-talk content categories were identified, however contextual and personal factors relating to these categories is unexplored. The aim of the study was to explore the relationships between stress, coping, athletic identity, demographic and sport-related factors and the eight organic self-talk categories of anxiety control, confidence, disengagement, instruction, psych-up, somatic fatigue, worry, and irrelevant. 216 NCAA student-athletes were recruited. Regression was used to determine the relationships between the contextual and personal variables and organic self-talk. Stress, coping and self-talk categories were compared in and out-of-season. Stress was associated with all self-talk frequencies except confidence. Coping was associated with psych-up, confidence and worry. Athletic identity was associated with psych-up, confidence, instruction and disengagement. Age was associated with anxiety control and instruction. Lastly, sport type and division level were associated with disengagement and instruction self-talk respectively.

"Switching the mind off completely" - Understanding the psychology of rest in coaches.

OBJECTIVES: To better understand the psychology of rest in coaches. Rest appears to be important for coping, recovery, and well-being in coaches, yet there is limited research on and in turn understanding of this concept in this population. DESIGN: A qualitative description study design was employed. METHOD: 22 NCAA Division I coaches were interviewed about what rest means to them, key barriers to rest in coaching, and strategies employed to obtain rest in the face of these barriers. A codebook thematic analysis was undertaken to examine the analytical generalizability (Smith, 2018) to the coaching context of an extant model of the psychology of rest in athletes (Eccles & Kazmier, 2019). RESULTS: The Eccles-Kazmier model appears to offer some analytical generalizability to the coaching context. Consistent with the model, the process of resting in coaches involves both sleep and resting while awake. Resting while awake involves (a) a break from thinking about work, (b) a break from effortful thinking generally, and (c) engaging in life outside coaching. However, departures from the model were also observed; specifically, unlike for athletes, the wakeful resting process for coaches does not appear to involve assuming control or experiencing variety. CONCLUSION: The findings advance the current understanding of the constituents of rest in coaches and can inform coach education about how to obtain the rest needed to perform effectively and stay healthy.

A unique demographic history exists for the MAO-A gene in Polynesians.

Variation in the human monoamine oxidase A (MAO-A) gene can influence neurotransmittor levels and is thought to have a role in many behavioral traits. The genetic architecture of MAO-A is known to vary across different geographic subgroups. Previous studies have reported evidence for positive selection within the MAO-A gene region in seven ethnic groups: Pygmy, Aboriginal Taiwanese, Chinese, Japanese, Mexican and Russian. Polynesian populations have not been tested and repeated founder effects due to the island-hopping voyages of Polynesians across the South Pacific suggest a unique demographic history exists at the MAO-A gene, perhaps including selective effects. To explore this, we genotyped 13 key single-nucleotide polymorphisms (SNPs) spanning MAO-A gene as well as the functional polymorphism (MAO-A-uVNTR) in 47 unrelated Maori individuals. A comparison of genetic variation between Maori and non-Maori groups found a substantial reduction in genetic diversity at the MAO-A gene locus and an increase in the frequency of the most common MAO-A gene variant in the Maori group. Results of this study support previous findings and also point toward a 5-SNP haplotype that may have been influenced by selective effects in the Maori population. Full-sequence data for MAO-A in a large cohort are now required to conclusively determine whether MAO-A has undergone positive selection in Polynesians. Overall, these new data describe a unique demographic history for the MAO-A gene in the Maori population and will be helpful for studies wishing to investigate MAO-A as a candidate gene for influencing behavioral traits in the Polynesians.

What makes an orienteer an expert? A case study of a highly elite orienteer's concerns in the course of competition.

This article reports a highly elite orienteer's cognitive activity over the course of two international competitions. We characterize the orienteer's concerns in relation to the problems raised during the competitions. The participant wore a head-mounted video camera throughout the competitions to enable the capture of an events record from the participant's perspective. During a post-performance self-confrontation interview, the participant was played the video and asked to describe his activity in relation to the events observed. The interview data were then used to identify the orienteer's concerns at each instant during the races. These "local" concerns were then compared and subsequently classified to characterize the typical concerns of the participant. Results showed three typical concerns: (a) find the controls faster than the opponents; (b) optimize running pace throughout the race; and (c) reflect on actions undertaken during performance. Results suggest the performer used a range of knowledge-driven strategies that enhanced the efficiency of task performance, and flexibly switched between strategies and decision-options in the face of presented changes in the task status. He also engaged in various reflective processes concurrent with performance that augmented the use of these strategies. In conclusion, this study provides insight into the cognitive processes underlying expert performance in sports characterized by decision-making under complexity, uncertainty, and time pressure.