Prediction of Listeria monocytogenes Clonal Complexes from Multilocus Variable Number Tandem Repeat Analysis Patterns Using a Machine Learning Approach.

Multilocus variable number tandem repeat analysis (MLVA) is a molecular subtyping technique that remains useful for those without the resources to access whole genome sequencing for the tracking and tracing of bacterial contaminants. Unlike techniques such as multilocus sequence typing (MLST) and pulsed-field gel electrophoresis, MLVA did not emerge as a standardized subtyping method for Listeria monocytogenes, and as a result, there is no reference database of virulent or food-associated MLVA subtypes as there is for MLST-based clonal complexes (CCs). Having previously shown the close congruence of a 5-loci MLVA scheme with MLST, a predictive model was created using the XGBoost machine learning (ML) technique, which enabled the prediction of CCs from MLVA patterns with ∼85% (±4%) accuracy. As well as validating the model on existing data, a straightforward update protocol was simulated for if and when previously unseen subtypes might arise. This article illustrates how ML techniques can be applied with elementary coding skills to add value to previous-generation molecular subtyping data in-built food processing environments.

Correlates of using E-cigarettes with high nicotine concentrations among U.S. adults who exclusively vape E-cigarettes or dual use with cigarettes.

BACKGROUND: Identifying the correlates of using e-cigarettes with high nicotine concentrations in exclusive and dual-using vapers can elucidate which subpopulations might be most impacted by e-cigarette regulatory activities related to nicotine concentration. METHODS: Data are drawn from Wave 5 (December 2018-November 2019) of the Population Assessment of Tobacco and Health (PATH) study. Self-reported nicotine concentration was grouped as high (5.0 %+), moderate (1.8-4.9 %), low (0.1-1.7 %), 0 %, and "I don't know." Multivariable logistic regressions estimated associations of sociodemographic factors, tobacco use status, and e-cigarette use patterns of high nicotine concentration vs. other nicotine levels, stratified by current exclusive e-cigarette use and dual use of e-cigarettes and cigarettes. RESULTS: In the study samples (exclusive e-cigarette use [n = 1,755], dual-use [n = 1,200]), higher proportions of exclusive e-cigarette users reported using high nicotine concentrations than dual users (18.3 % vs. 8.6 %). Among exclusive e-cigarette users, never vs. former smokers and daily (vs. someday) e-cigarette users were more likely to use high vs. low nicotine. In both exclusive and dual users, younger (vs. older) adults were more likely to report using high nicotine concentration e-cigarettes than most other nicotine levels. Current dual users who did vs. did not report using e-cigarettes to quit smoking had higher odds of using high vs. 0 % nicotine concentrations. CONCLUSIONS: High-nicotine e-cigarette use might be elevated in subpopulations that face greater risks for vaping (e.g., never smokers, young adults) than groups who benefit from the potential harm reduction. Regulatory restrictions on high-nicotine products may selectively affect some subgroups adversely impacted by vaping.

Bilateral Buccal Flap Revision Palatoplasty to Correct Velopharyngeal Dysfunction: Perceptual Speech, Acoustic, and Aerodynamic Outcomes.

BACKGROUND: The purpose of this study was to analyze perceptual, acoustic, and aerodynamic changes in speech and velopharyngeal function after bilateral buccal flap revision palatoplasty (BBFRP) in patients with repaired cleft palate. METHODS: Ten consecutive patients ages 4 to 18 years with velopharyngeal dysfunction treated with BBFRP by a single surgeon were evaluated. Using a visual analog scale, nine blinded speech-language pathologists independently rated hypernasality, hyponasality, audible nasal emission, and speech acceptability. Measurements of the acoustic speech signal were used to quantify changes in hypernasality and nasal emission. The pressure flow technique was used to determine changes in velopharyngeal gap size. RESULTS: Complete records were available for eight patients. After surgery, hypernasality decreased ( P < 0.001) and speech acceptability increased ( P < 0.001) significantly. Audible nasal emission was significantly reduced ( P < 0.001). Postoperative acoustic measures showed a reduction of nasal emission and nasalization. Velopharyngeal gap size significantly decreased after BBFRP ( P < 0.001), correlating with lower visual analog scale ratings of hypernasality ( P = 0.015). Hyponasality did not change significantly after surgery ( P = 0.964). No patient developed sleep-disordered breathing. CONCLUSION: BBFRP resulted in a measurable improvement in hypernasal speech, audible nasal emission, and speech acceptability without significant changes in hyponasality or risk of obstructive sleep apnea. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Long-Term Results of Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy: The Randomized Phase II OPRA Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.To assess long-term risk of local tumor regrowth, we report updated organ preservation rate and oncologic outcomes of the OPRA trial (ClinicalTrials.gov identifier: NCT02008656). Patients with stage II/III rectal cancer were randomly assigned to receive induction chemotherapy followed by chemoradiation (INCT-CRT) or chemoradiation followed by consolidation chemotherapy (CRT-CNCT). Patients who achieved a complete or near-complete response after finishing treatment were offered watch-and-wait (WW). Total mesorectal excision (TME) was recommended for those who achieved an incomplete response. The primary end point was disease-free survival (DFS). The secondary end point was TME-free survival. In total, 324 patients were randomly assigned (INCT-CRT, n = 158; CRT-CNCT, n = 166). Median follow-up was 5.1 years. The 5-year DFS rates were 71% (95% CI, 64 to 79) and 69% (95% CI, 62 to 77) for INCT-CRT and CRT-CNCT, respectively (P = .68). TME-free survival was 39% (95% CI, 32 to 48) in the INCT-CRT group and 54% (95% CI, 46 to 62) in the CRT-CNCT group (P = .012). Of 81 patients with regrowth, 94% occurred within 2 years and 99% occurred within 3 years. DFS was similar for patients who underwent TME after restaging (64% [95% CI, 53 to 78]) and patients in WW who underwent TME after regrowth (64% [95% CI, 53 to 78]; P = .94). Updated analysis continues to show long-term organ preservation in half of the patients with rectal cancer treated with total neoadjuvant therapy. In patients who enter WW, most cases of tumor regrowth occur in the first 2 years.

Validating the Utility of Multilocus Variable Number Tandem-repeat Analysis (MLVA) as a Subtyping Strategy to Monitor Listeria monocytogenes In-built Food Processing Environments.

Listeria monocytogenes is a serious human pathogen and an enduring challenge to control for the ready-to-eat food processing industry. Cost-effective tools that can be deployed by commercial or in-house laboratories to rapidly investigate and resolve contamination events in the built food processing environment are of value to the food industry. Multilocus variable number tandem-repeat analysis (MLVA) is a molecular subtyping method, which along with other same-generation methods such as pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) is being superseded in disease tracking and outbreak investigations by whole-genome sequencing (WGS). In this paper, it is demonstrated that MLVA can continue to play a valuable role as a valid, fast, simple, and cost-effective method to identify and track Listeria monocytogenes subtypes in factory environments, with the method being highly congruent with MLST. Although MLVA does not have the discriminatory power of WGS to identify truly persistent clones, with careful interpretation of results alongside isolate metadata, it remains a powerful tool in situations and locations where WGS may not be readily available to food business operators.

Biomarkers of Toxic Exposure and Oxidative Stress Among U.S. Adult Users of Premium Cigar Versus Other Cigar Subtypes: 2013-2019.

INTRODUCTION: Cigars are currently the second-highest-used combustible tobacco product among U.S. adults, but knowledge about health effects of premium cigars versus other cigar subtype use is limited. AIMS AND METHODS: This study analyzed the biospecimen data (n = 31 875) from Waves 1-5 of the Population Assessment of Tobacco and Health Study, collected during 2013-2019. Multivariable generalized estimation equations, accounting for within-person clustering, were conducted to examine differences in urine biomarkers of exposure (BOE) from five classes of harmful and potentially harmful constituents along with a biomarker of oxidative stress (urine 8-isoprostane) among exclusive users of premium cigars versus other exclusive cigar subtypes (ie, non-premium large cigars, cigarillos, and filtered cigars), cigarettes, and non-tobacco users. RESULTS: In comparison to non-tobacco users, exclusive premium cigar users had higher geometric mean concentrations of the nicotine metabolite cotinine (5.8 vs. 0.5ng/mg, p < .0001), tobacco-specific nitrosamine (TSNA) (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL): 7.8 vs. 1.3pg/mg, p < .0001), and volatile organic compound (VOC) (N-Acetyl-S-(2-cyanoethyl)-L-cysteine (CYMA, acrylonitrile): 4.7 vs. 1.6ng/mg, p < .0001). Exclusive premium cigar users were less likely to be daily users than other tobacco user groups and had comparable BOEs with exclusive non-premium large cigar users but generally lower BOEs than exclusive cigarillo, filtered cigar, and cigarette smokers. Daily exclusive premium cigar users had similar nicotine and TSNA exposure but lower exposure to polycyclic aromatic hydrocarbons and volatile organic compounds than exclusive cigarillo and filtered cigar users. CONCLUSIONS: Premium cigar use exhibits different exposure to toxicants from other cigar subtype users. Regulations of premium cigars need to formalize product definition and take the population's health effects into consideration. IMPLICATIONS: This population study provides important information on BOE and potential harm with premium cigar use and its potential health effects. At present, premium cigars appear to pose a relatively low overall population health risk due to low frequency of use. However, future regulation of other tobacco products might change the landscape of premium cigar use and alter the overall health impact.

Improving health outcomes of people with diabetes: target setting for the WHO Global Diabetes Compact.

The Global Diabetes Compact is a WHO-driven initiative uniting stakeholders around goals of reducing diabetes risk and ensuring that people with diabetes have equitable access to comprehensive, affordable care and prevention. In this report we describe the development and scientific basis for key health metrics, coverage, and treatment targets accompanying the Compact. We considered metrics across four domains: factors at a structural, system, or policy level; processes of care; behaviours and biomarkers such as glycated haemoglobin (HbA1c); and health events and outcomes; and three risk tiers (diagnosed diabetes, high risk, or whole population), and reviewed and prioritised them according to their health importance, modifiability, data availability, and global inequality. We reviewed the global distribution of each metric to set targets for future attainment. This process led to five core national metrics and target levels for UN member states: (1) of all people with diabetes, at least 80% have been clinically diagnosed; and, for people with diagnosed diabetes, (2) 80% have HbA1c concentrations below 8·0% (63·9 mmol/mol); (3) 80% have blood pressure lower than 140/90 mm Hg; (4) at least 60% of people 40 years or older are receiving therapy with statins; and (5) each person with type 1 diabetes has continuous access to insulin, blood glucose meters, and test strips. We also propose several complementary metrics that currently have limited global coverage, but warrant scale-up in population-based surveillance systems. These include estimation of cause-specific mortality, and incidence of end-stage kidney disease, lower-extremity amputations, and incidence of diabetes. Primary prevention of diabetes and integrated care to prevent long-term complications remain important areas for the development of new metrics and targets. These metrics and targets are intended to drive multisectoral action applied to individuals, health systems, policies, and national health-care access to achieve the goals of the Global Diabetes Compact. Although ambitious, their achievement can result in broad health benefits for people with diabetes.

Hierarchical Modeling of Psychosocial, Parental, and Environmental Factors for Susceptibility to Tobacco Product Use in 9-10-Year-Old Children.

PURPOSE: Tobacco use during early adolescence can harm brain development and cause adverse health outcomes. Identifying susceptibility in early adolescence before initiation presents an opportunity for tobacco use prevention. METHODS: Data were drawn from the Adolescent Brain and Cognitive Development study that enrolled 9-10-year-old children in 21 US cities between 2016 and 2018 at baseline. Separate nested hierarchical models were performed to incrementally examine the associations of sociodemographic factors, psychosocial influences, parental substance use, immediate social contacts, and perceived neighborhood safety with tobacco use susceptibility among never tobacco users (n = 10,449), overall and stratified by gender. RESULTS: A total of 16.6% of youths who have never used tobacco reported susceptibility to tobacco. Females (vs. males, adjusted odds ratio [AOR] [95% confidence interval {CI}] = 0.80 [0.70-0.91]), positive parental monitoring (AOR [95% CI] = 0.76 [0.66-0.87]) and positive school environment (AOR [95% CI] = 0.95 [0.93-0.98]) were associated with reduced susceptibility to tobacco use. Parental education level (high school, AOR [95% CI] = 1.52 [1.02-2.28]; bachelor's degree, AOR [95% CI] = 1.53 [1.03-2.28]; or postgraduate degree, AOR [95% CI] = 1.54 [1.03-2.3] vs. less than high school), youth substance ever use (AOR [95% CI] = 2.24 [1.95-2.58]), internalizing problems (AOR [95% CI] = 1.03 [1-1.06]), and high scores on negative urgency, lack of premeditation, lack of perseverance, sensation seeking, and positive urgency-impulsive behavior scale were associated with increased susceptibility to tobacco use. Stratified analysis showed that parent-perceived neighborhood safety was associated with reduced susceptibility to tobacco use among males but not among females (AOR [95% CI] = 0.89 [0.81-0.99]) vs. (AOR [95% CI] = 1.01 [0.9-1.13]). A positive school environment was associated with lower susceptibility to tobacco use among females but not among males. DISCUSSION: Parental, environmental, and psychosocial factors influence early childhood tobacco susceptibility. Family and school-based tobacco prevention programs should consider integrating these factors into primary school curricula to reduce youth tobacco susceptibility and later initiation.

Transposable elements maintain genome-wide heterozygosity in inbred populations.

Elevated levels of inbreeding increase the risk of inbreeding depression and extinction, yet many inbred species are widespread, suggesting that inbreeding has little impact on evolutionary potential. Here, we explore the potential for transposable elements (TEs) to maintain genetic variation in functional genomic regions under extreme inbreeding. Capitalizing on the mixed mating system of Arabidopsis lyrata, we assess genome-wide heterozygosity and signatures of selection at single nucleotide polymorphisms near transposable elements across an inbreeding gradient. Under intense inbreeding, we find systematically elevated heterozygosity downstream of several TE superfamilies, associated with signatures of balancing selection. In addition, we demonstrate increased heterozygosity in stress-responsive genes that consistently occur downstream of TEs. We finally reveal that TE superfamilies are associated with specific signatures of selection that are reproducible across independent evolutionary lineages of A. lyrata. Together, our study provides an important hypothesis for the success of self-fertilizing species.

Opioid Prescription Reduction after Dentoalveolar Surgery-A Success Story in the Recruit Training Environment.

Given the public health toll exacted by the Opioid Crisis, it is important for providers in all disciplines to examine their opioid prescribing patterns to see where opioid reduction strategies can be effectively employed. Limiting the impact of the Opioid Crisis on active duty service members is a critical component of maintaining a ready fighting force. One avenue for reducing the potential for opioid diversion and abuse is developing and implementing non-opioid postsurgical pain management strategies that both provide adequate pain relief and also ensure an expedient return to full duty. Dentoalveolar surgeries performed by oral and maxillofacial surgeons to maintain operational dental readiness are a good example of common procedures necessitating post-procedural pain medications and convalescent days impacting availability for full duty. The providers at US Navy Recruit Training Command's oral surgery clinic undertook a process improvement initiative to reduce opioid prescriptions after dentoalveolar surgery. This change was accompanied by a concerted education effort aimed at both providers and patients on the benefits of avoiding opioids as well as the importance of strict adherence to a standardized medication dosing regimen for efficacious non-opioid pain control consisting of maximum doses of ibuprofen and acetaminophen taken every six hours. No increase in convalescent time off and no increase in postoperative visits related to pain control were noted. In our experience, eliminating routine post-procedure opioids for dentoalveolar surgery was a viable strategy for reducing the potential for opioid diversion and abuse among our patients with no negative impact on the operational and training tempo of the associated command.

The Changing Nature of Mortality and Morbidity in Patients with Diabetes.

The number of adults living with diabetes has increased substantially globally over the past 40 years, driven by a combination of increased age-standardized prevalence, population growth, aging, and increases in obesity prevalence. Patients with diabetes in high-income countries are living longer, with large declines in vascular disease mortality rates. This appears to be resulting in a diversification of cause of death, complications, and comorbidities that those with diabetes live with. This has large implications for prevention and management approaches, which should be reviewed to update the breadth of conditions that patients with diabetes are at excess risk of throughout their life. These trends have not yet been seen in low- and middle-income countries, where evidence is also more scarce.

Characterizing Multimorbidity from Type 2 Diabetes: Insights from Clustering Approaches.

Patients with type 2 diabetes mellitus (T2DM) often live with and develop multiple co-occurring conditions, namely multimorbidity, with diffuse impacts on clinical care and patient quality of life. However, literature characterizing T2DM-related multimorbidity patterns is limited. This review summarizes the findings from the emerging literature characterizing and quantifying the association of T2DM with multimorbidity clusters. The authors' findings reveal 3 dominant cluster types appearing in patients with T2DM-related multimorbidity, such as cardiometabolic precursor conditions, vascular conditions, and mental health conditions. The authors recommend that holistic patient care centers around early detection of other comorbidities and consideration of wider risk factors.

Comparative genomic insights into Yersinia hibernica - a commonly misidentified Yersinia enterocolitica-like organism.

Food-associated outbreaks linked to enteropathogenic Yersinia enterocolitica are of concern to public health. Pigs and their meat are recognized risk factors for transmission of Y. enterocolitica. This study aimed to describe the comparative genomics of Y. enterocolitica along with a number of misclassified Yersinia isolates, now constituting the recently described Yersinia hibernica. The latter was originally cultured from an environmental sample taken at a pig slaughterhouse. Unique features were identified in the genome of Y. hibernica, including a novel integrative conjugative element (ICE), denoted as ICEYh-1 contained within a 255 kbp region of plasticity. In addition, a zebrafish embryo infection model was adapted and applied to assess the virulence potential among Yersinia isolates including Y. hibernica.

Plant volatiles induced by herbivore eggs prime defences and mediate shifts in the reproductive strategy of receiving plants.

Plants can detect cues associated with the risk of future herbivory and modify defence phenotypes accordingly; however, our current understanding is limited both with respect to the range of early warning cues to which plants respond and the nature of the responses. Here we report that exposure to volatile emissions from plant tissues infested with herbivore eggs promotes stronger defence responses to subsequent herbivory in two Brassica species. Furthermore, exposure to these volatile cues elicited an apparent shift from growth to reproduction in Brassica nigra, with exposed plants exhibiting increased flower and seed production, but reduced leaf production, relative to unexposed controls. Our results thus document plant defence priming in response to a novel environmental cue, oviposition-induced plant volatiles, while also showing that plant responses to early warning cues can include changes in both defence and life-history traits.

Changing environments and genetic variation: natural variation in inbreeding does not compromise short-term physiological responses.

Selfing plant lineages are surprisingly widespread and successful in a broad range of environments, despite showing reduced genetic diversity, which is predicted to reduce their long-term evolutionary potential. However, appropriate short-term plastic responses to new environmental conditions might not require high levels of standing genetic variation. In this study, we tested whether mating system variation among populations, and associated changes in genetic variability, affected short-term responses to environmental challenges. We compared relative fitness and metabolome profiles of naturally outbreeding (genetically diverse) and inbreeding (genetically depauperate) populations of a perennial plant, Arabidopsis lyrata, under constant growth chamber conditions and an outdoor common garden environment outside its native range. We found no effect of inbreeding on survival, flowering phenology or short-term physiological responses. Specifically, naturally occurring inbreeding had no significant effects on the plasticity of metabolome profiles, using either multivariate approaches or analysis of variation in individual metabolites, with inbreeding populations showing similar physiological responses to outbreeding populations over time in both growing environments. We conclude that low genetic diversity in naturally inbred populations may not always compromise fitness or short-term physiological capacity to respond to environmental change, which could help to explain the global success of selfing mating strategies.

Divergence in Glucosinolate Profiles between High- and Low-Elevation Populations of Arabidopsis halleri Correspond to Variation in Field Herbivory and Herbivore Behavioral Preferences.

Variation in local herbivore pressure along elevation gradients is predicted to drive variation in plant defense traits. Yet, the extent of intraspecific variation in defense investment along elevation gradients, and its effects on both herbivore preference and performance, remain relatively unexplored. Using populations of Arabidopsis halleri (Brassicaceae) occurring at different elevations in the Alps, we tested for associations between elevation, herbivore damage in the field, and constitutive chemical defense traits (glucosinolates) assayed under common-garden conditions. Additionally, we examined the feeding preferences and performance of a specialist herbivore, the butterfly Pieris brassicae, on plants from different elevations in the Alps. Although we found no effect of elevation on the overall levels of constitutive glucosinolates in leaves, relative amounts of indole glucosinolates increased significantly with elevation and were negatively correlated with herbivore damage in the field. In oviposition preference assays, P. brassicae females laid fewer eggs on plants from high-elevation populations, although larval performance was similar on populations from different elevations. Taken together, these results support the prediction that species distributed along elevation gradients exhibit genetic variation in chemical defenses, which can have consequences for interactions with herbivores in the field.

Inception of early-life allergen-induced airway hyperresponsiveness is reliant on IL-13+CD4+ T cells.

Airway hyperresponsiveness (AHR) is a critical feature of wheezing and asthma in children, but the initiating immune mechanisms remain unconfirmed. We demonstrate that both recombinant interleukin-33 (rIL-33) and allergen [house dust mite (HDM) or Alternaria alternata] exposure from day 3 of life resulted in significantly increased pulmonary IL-13+CD4+ T cells, which were indispensable for the development of AHR. In contrast, adult mice had a predominance of pulmonary LinnegCD45+CD90+IL-13+ type 2 innate lymphoid cells (ILC2s) after administration of rIL-33. HDM exposure of neonatal IL-33 knockout (KO) mice still resulted in AHR. However, neonatal CD4creIL-13 KO mice (lacking IL-13+CD4+ T cells) exposed to allergen from day 3 of life were protected from AHR despite persistent pulmonary eosinophilia, elevated IL-33 levels, and IL-13+ ILCs. Moreover, neonatal mice were protected from AHR when inhaled Acinetobacter lwoffii (an environmental bacterial isolate found in cattle farms, which is known to protect from childhood asthma) was administered concurrent with HDM. A. lwoffii blocked the expansion of pulmonary IL-13+CD4+ T cells, whereas IL-13+ ILCs and IL-33 remained elevated. Administration of A. lwoffii mirrored the findings from the CD4creIL-13 KO mice, providing a translational approach for disease protection in early life. These data demonstrate that IL-13+CD4+ T cells, rather than IL-13+ ILCs or IL-33, are critical for inception of allergic AHR in early life.

Restriction associated DNA-genotyping at multiple spatial scales in Arabidopsis lyrata reveals signatures of pathogen-mediated selection.

BACKGROUND: Genome scans based on outlier analyses have revolutionized detection of genes involved in adaptive processes, but reports of some forms of selection, such as balancing selection, are still limited. It is unclear whether high throughput genotyping approaches for identification of single nucleotide polymorphisms have sufficient power to detect modes of selection expected to result in reduced genetic differentiation among populations. In this study, we used Arabidopsis lyrata to investigate whether signatures of balancing selection can be detected based on genomic smoothing of Restriction Associated DNA sequencing (RAD-seq) data. We compared how different sampling approaches (both within and between subspecies) and different background levels of polymorphism (inbreeding or outcrossing populations) affected the ability to detect genomic regions showing key signatures of balancing selection, specifically elevated polymorphism, reduced differentiation and shifts towards intermediate allele frequencies. We then tested whether candidate genes associated with disease resistance (R-gene analogs) were detected more frequently in these regions compared to other regions of the genome. RESULTS: We found that genomic regions showing elevated polymorphism contained a significantly higher density of R-gene analogs predicted to be under pathogen-mediated selection than regions of non-elevated polymorphism, and that many of these also showed evidence for an intermediate site-frequency spectrum based on Tajima's D. However, we found few genomic regions that showed both elevated polymorphism and reduced FST among populations, despite strong background levels of genetic differentiation among populations. This suggests either insufficient power to detect the reduced population structure predicted for genes under balancing selection using sparsely distributed RAD markers, or that other forms of diversifying selection are more common for the R-gene analogs tested. CONCLUSIONS: Genome scans based on a small number of individuals sampled from a wide range of populations were sufficient to confirm the relative scarcity of signatures of balancing selection across the genome, but also identified new potential disease resistance candidates within genomic regions showing signatures of balancing selection that would be strong candidates for further sequencing efforts.

The genomic basis of eco-evolutionary dynamics.

Recent recognition that ecological and evolutionary processes can operate on similar timescales has led to a rapid increase in theoretical and empirical studies on eco-evolutionary dynamics. Progress in the fields of evolutionary biology, genomics and ecology is greatly enhancing our understanding of rapid adaptive processes, the predictability of adaptation and the genetics of ecologically important traits. However, progress in these fields has proceeded largely independently of one another. In an attempt to better integrate these fields, the centre for 'Adaptation to a Changing Environment' organized a conference entitled 'The genomic basis of eco-evolutionary change' and brought together experts in ecological genomics and eco-evolutionary dynamics. In this review, we use the work of the invited speakers to summarize eco-evolutionary dynamics and discuss how they are relevant for understanding and predicting responses to contemporary environmental change. Then, we show how recent advances in genomics are contributing to our understanding of eco-evolutionary dynamics. Finally, we highlight the gaps in our understanding of eco-evolutionary dynamics and recommend future avenues of research in eco-evolutionary dynamics.

Pulmonary ORMDL3 is critical for induction of Alternaria-induced allergic airways disease.

BACKGROUND: Genome-wide association studies have identified the ORM (yeast)-like protein isoform 3 (ORMDL3) gene locus on human chromosome 17q to be a highly significant risk factor for childhood-onset asthma. OBJECTIVE: We sought to investigate in vivo the functional role of ORMDL3 in disease inception. METHODS: An Ormdl3-deficient mouse was generated and the role of ORMDL3 in the generation of allergic airways disease to the fungal aeroallergen Alternaria alternata was determined. An adeno-associated viral vector was also used to reconstitute ORMDL3 expression in airway epithelial cells of Ormdl3 knockout mice. RESULTS: Ormdl3 knockout mice were found to be protected from developing allergic airways disease and showed a marked decrease in pathophysiology, including lung function and airway eosinophilia induced by Alternaria. Alternaria is a potent inducer of cellular stress and the unfolded protein response, and ORMDL3 was found to play a critical role in driving the activating transcription factor 6-mediated arm of this response through Xbp1 and downstream activation of the endoplasmic reticulum-associated degradation pathway. In addition, ORMDL3 mediated uric acid release, another marker of cellular stress. In the knockout mice, reconstitution of Ormdl3 transcript levels specifically in the bronchial epithelium resulted in reinstatement of susceptibility to fungal allergen-induced allergic airways disease. CONCLUSIONS: This study demonstrates that ORMDL3, an asthma susceptibility gene identified by genome-wide association studies, contributes to key pathways that promote changes in airway physiology during allergic immune responses.