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To assess if radiomic feature analysis could help to differentiate between the lipid-poor adenomas and metastases to the adrenal glands.Eighty-six patients (women:men 42:44; mean age 66 years) with biopsy-proven adrenal metastases and 55 patients (women:men 39:16; mean age 67 years) with lipid-poor adenomas who underwent contrast-enhanced, portal-venous phase CT of the abdomen. Radiomic features were extracted using the PyRadiomics extension for 3D Slicer. Following elastic net regularisation, seven of 1,132 extracted radiomic features were selected to build a radiomic signature. This was combined with patient demographics to create a predictive nomogram. The calibration curves in both the training and validation cohorts were assessed using a Hosmer-Lemeshow test.The radiomic signature alone yielded an area under the curve of 91.7% in the training cohort (n=93) and 87.1% in the validation cohort (n=48). The predictive nomogram, which combined age, a previous history of malignancy, and the radiomic signature, had an AUC of 97.2% in the training cohort and 90.4% in the validation cohort.The present nomogram has the potential to differentiate between a lipid-poor adrenal adenoma and adrenal metastasis on portal-venous CT.

Limited research has identified prospective risk factors for young-adult sex work or examined overlapping predictors concurrently. We investigated childhood sexual abuse (CSA), along with other theory-driven predictors of sex work, among a well-characterized sample of girls with and without childhood diagnoses of attention/deficit-hyperactivity disorder (ADHD).Participants were a racially and socioeconomically diverse sample of 140 girls with rigorously diagnosed ADHD (47 Inattentive [ADHD-I], 93 Combined [ADHD-C]), and 88 age- and ethnicity-matched comparison girls, all followed longitudinally into adulthood. Self-report data on young-adult occupations revealed a subsample of 7 participants reporting engagement in "sex work" or "prostitution." Logistic regressions tested whether CSA, measured both dichotomously and by discrete age ranges, predicted later sex work, accounting for other risk factors.A lifetime history of CSA was positively associated with sex work in initial analyses (β = 1.51,Findings from this exploratory study underscore the need for longitudinal research that (a) considers the developmental timing of CSA and (b) accounts for impulsivity and inattention as risk factors for sex work among young-adult women. Implications for clinical practice are briefly discussed.

Background Risk factors for nosocomial COVID-19 outbreaks continue to evolve. The aim of this study was to investigate a multi-ward nosocomial outbreak of COVID-19 between 1st September and 15th November 2020, occurring in a setting without vaccination for any healthcare workers or patients. Methods Outbreak report and retrospective, matched case–control study using incidence density sampling in three cardiac wards in an 1100-bed tertiary teaching hospital in Calgary, Alberta, Canada. Patients were confirmed/probable COVID-19 cases and contemporaneous control patients without COVID-19. COVID-19 outbreak definitions were based on Public Health guidelines. Clinical and environmental specimens were tested by RT-PCR and as applicable quantitative viral cultures and whole genome sequencing were conducted. Controls were inpatients on the cardiac wards during the study period confirmed to be without COVID-19, matched to outbreak cases by time of symptom onset dates, age within ± 15 years and were admitted in hospital for at least 2 days. Demographics, Braden Score, baseline medications, laboratory measures, co-morbidities, and hospitalization characteristics were collected on cases and controls. Univariate and multivariate conditional logistical regression was used to identify independent risk factors for nosocomial COVID-19. Results The outbreak involved 42 healthcare workers and 39 patients. The strongest independent risk factor for nosocomial COVID-19 (IRR 3.21, 95% CI 1.47–7.02) was exposure in a multi-bedded room. Of 45 strains successfully sequenced, 44 (97.8%) were B.1.128 and differed from the most common circulating community lineages. SARS-CoV-2 positive cultures were detected in 56.7% (34/60) of clinical and environmental specimens. The multidisciplinary outbreak team observed eleven contributing events to transmission during the outbreak. Conclusions Transmission routes of SARS-CoV-2 in hospital outbreaks are complex; however multi-bedded rooms play a significant role in the transmission of SARS-CoV-2.

IntroductionB cell activation and differentiation is central to the adaptive immune response. Changes in exon usage can have major impacts on cellular signaling and differentiation but have not been systematically explored in differentiating B cells.MethodsWe analyzed exon usage and intron retention in RNA-Seq data from subsets of human B cells at various stages of differentiation, and in an in vitro laboratory model of B cell activation and differentiation (Epstein Barr virus infection).ResultsBlood naïve B cells were found to have an unusual splicing profile, with unannotated splicing events in over 30% of expressed genes. Splicing changed substantially upon naïve B cell entry into secondary lymphoid tissue and before activation, involving significant increases in exon commitment and reductions in intron retention. These changes preferentially involved short introns with weak splice sites and were likely mediated by an overall increase in splicing efficiency induced by the lymphoid environment. The majority of transcripts affected by splicing changes showed restoration of encoded conserved protein domains and/or reduced targeting to the nonsense-mediated decay pathway. Affected genes were enriched in functionally important immune cell activation pathways such as antigen-mediated signaling, cell cycle control and mRNA processing and splicing.DiscussionFunctional observations from donor B cell subsets in progressive states of differentiation and from timecourse experiments using the in vitro model suggest that these widespread changes in mRNA splicing play a role in preparing naïve B cells for the decisive step of antigen-mediated activation and differentiation.

Enzymatic pockets such as those of histone deacetylases (HDACs) are among the most favored targets for drug development. However, enzymatic inhibitors often exhibit low selectivity and high toxicity due to targeting multiple enzyme paralogs, which are often involved in distinct multisubunit complexes. Here, we report the discovery and characterization of a non-enzymatic small molecule inhibitor of HDAC transcriptional repression functions with comparable anti-tumor activity to the enzymatic HDAC inhibitor Vorinostat, and anti-psychedelic activity of anHDAC2knockoutin vivo. We highlight that these phenotypes are achieved while modulating the expression of 20- and 80-fold fewer genes than enzymatic and genetic inhibition in the respective models. Thus, by achieving the same biological outcomes as established therapeutics while impacting a dramatically smaller number of genes, inhibitors of protein-protein interactions can offer important advantages in improving the selectivity of epigenetic modulators.GRAPHICAL ABSTRACT

OBJECTIVE To investigate whether risk factor-based screening in pregnancy is failing to identify women with hepatitis C virus (HCV) infection and to assess the cost-effectiveness of universal screening. DESIGN Retrospective study and model-based economic evaluation. SETTING Two urban tertiary referral maternity units, currently using risk factor-based screening for HCV infection. POPULATION Pregnant women who had been tested for hepatitis B, HIV but not HCV. METHODS Anonymised sera were tested for HCV antibody. Positive sera were tested for HCV antigen. A cost-effectiveness analysis of a change to universal screening was performed using a Markov model to simulate disease progression and Monte Carlo simulations for probabilistic sensitivity analysis. MAIN OUTCOME MEASURES Presence of HCV antigen and cost per quality-adjusted life year (QALY). RESULTS In all, 4655 samples were analysed. Twenty had HCV antibodies and five HCV antigen. This gives an active infection rate of 5/4655, or 0.11%, compared with a rate of 0.15% in the risk-factor group. This prevalence is 65% lower than a previous study in the same hospitals from 2001 to 2005. The calculated incremental cost-effectiveness ratio (ICER) for universal screening was €3,315 per QALY gained. CONCLUSION This study showed that the prevalence of HCV infection in pregnant women in the Dublin region has declined by 65% over the past two decades. Risk factor-based screening misses a significant proportion of infections. A change to universal maternal screening for hepatitis C would be cost-effective in our population. TWEETABLE ABSTRACT Universal maternal screening for hepatitis C is cost-effective in this urban Irish population.

The genus Scaptomyza is one of the two Drosophilidae genera with Hawaiian endemic species. This genus is an excellent model for biogeographic studies since it is distributed throughout the majority of continents, including continental islands, the Hawaiian Islands, and many other remote oceanic islands. This genus currently comprises 273 described species, 148 of which are endemic to the Hawaiian Islands. However, most descriptions were published before efforts to standardizing the morphological terminology across the Diptera were made in the 1980’s. Since research groups developed their own set of terminologies independently, without considering homologies, multiple terms have been used to refer to the same characters. This is especially true for the male terminalia, which have remarkable modifications within the family Drosophilidae. We reviewed the Scaptomyza literature, in addition to other studies across the Drosophilidae and Diptera, compiled the English synonyms, and provided a visual atlas of each body part, indicating how to recognize the morphological characters. The goal of the present study is to facilitate species identification and propose preferred terms to be adopted for future Scaptomyza descriptions.

This mini configurative review links theory of mind (ToM) research with school-based social skills interventions to reframe theoretical understanding of ToM ability based on a conceptual mapping exercise. The review’s aim was to bridge areas of psychology and education concerned with social cognition. Research questions included: how do dependent variables (DVs) in interventions designed to enhance child social-cognitive skills map onto ToM constructs empirically validated within psychology? In which ways do these mappings reframe conceptualization of ToM ability? Thirty-one studies (conducted from 2012 to 2019) on social-cognitive skill with typically-developing children ages 3–11 were included as opposed to explicit ToM trainings in light of an identified performance plateau on ToM tasks in children. Intervention DVs mapped onto the following ToM constructs in at least 87% of studies: “Representation of Others and/or Self,” “Knowledge/Awareness of Mental States,” “Attributions/Explanations of Mental States,” “Social Competence,” “Predicting Behavior,” and “Understanding Complex Social Situations.” The absence of false-belief understanding as an intervention DV indicated a lack of direct training in ToM ability. A hierarchy to further organize the review’s ToM framework constructs as either skills or competences within the construct of ‘Representation of Others and/or Self’ is proposed. Implications for the conceptualization of ToM and social-cognitive research as well as educational practice are discussed, namely how school social skill interventions conceptualize skill along a continuum in contrast to the common artificial dichotomous assessment of ToM skill (i.e., presence or lack), yet the development of ToM can nevertheless be supported by the school environment.

BackgroundA need arose to divert patients with psychiatric complaints from the emergency department to alternative settings for psychiatric consultations to reduce footfall during COVID-19. We assessed the effectiveness of alternative referral pathway in reducing COVID-19 infection in our service and its effect on service quality: response time and number of patients leaving before the review. We evaluated the satisfaction of patients, general practitioners (GPs) and mental health service staff with the pathway.MethodsAll patients referred to the mental health service over a 2-month period following the introduction of the pathway were included. Findings were compared against the cohort referred for emergency assessment during the same period in 2019. Feedback surveys were distributed to patients, staff and GPs. χ2 and independent sample t-test were used to compare the variables.ResultsOver 2 months, 255 patients received an emergency assessment via the pathway, representing a 22.3% decrease in the volume of presentations from the same period in 2019. There were no COVID-19 cases among our patients or staff on the roster for assessing patients. In comparison to 2019, response times were improved (pConclusionThe pathway was successful in reducing the spread of infection, improving response times and reducing the numbers of patients who left without an assessment. Given the improved outcomes and acceptability, this is a preferable pathway for emergency referrals into the future.

Attention-deficit/hyperactivity disorder (ADHD) - and its underlying behavioral dimensions of inattention and hyperactivity-impulsivity - have been understudied in females. We first cover the conceptual issues of prevalence, diagnostic practices, diversity, comorbidity, and causal factors, plus forces limiting awareness of ADHD in females. After a narrative review of cross-sectional and longitudinal findings, we conclude the following. (a) Girls meet diagnostic criteria for ADHD at just under half the rates of boys, a ratio that becomes much closer to equal by adulthood. (b) Girls and women with ADHD show a predominance of inattention and associated internalizing problems; boys and men display greater levels of hyperactive-impulsive symptoms and associated externalizing problems. (c) Sex differences in ADHD symptoms and related outcomes depend heavily on the clinical versus nonreferred nature of the samples under investigation. (d) Females with ADHD experience, on average, serious impairments, with a particularly heightened risk for problems in close relationships and engagement in self-harm. (e) Clinicians may overlook symptoms and impairments in females because of less overt (but still impairing) symptom manifestations in girls and women and their frequent adoption of compensatory strategies. Our review of predictors and mediators of adult outcomes highlights (a) the potential for heterotypically continuous pathways in females with childhood ADHD and (b) developmental progressions to self-harm, intimate partner violence, unplanned pregnancy, and comorbid psychopathology. Focusing on ADHD in females is necessary to characterize causal and maintaining mechanisms with accuracy and to foster responsive interventions, as highlighted in our closing list of clinical implications and research priorities.

Asymptomatic coronavirus disease 2019 (COVID-19) has been reported as a significant driver of COVID-19 outbreaks. Our hospital ward outbreak analysis suggests that comprehensive symptoms and signs assessment, in combination with adequate follow-up, allows a more precise determination of COVID-19 symptoms. Asymptomatic infection was quite uncommon among adults in this setting.

Objectives:To examine the psychological and social impact of the COVID-19 pandemic on patients with established mood disorders during a period of stringent mandated social restrictions.Methods:Semi-structured interviews were conducted with 36 individuals attending the Galway–Roscommon Mental Health Services with an International Statistical Classification of Diseases and Related Health Problems, tenth revision (ICD-10) diagnosis of either Bipolar Affective Disorder (BPAD) (n = 20) or Emotionally Unstable Personality Disorder (EUPD) (n = 16) in this cross-sectional study. We determined the impact of the COVID-19 restrictions on anxiety and depressive symptoms, impulsivity, thoughts of self-harm, social and occupational functioning and quality of life.Results:The COVID-19 pandemic deleteriously impacted mental health (56.3% v. 15.0%, χ2 = 7.42, p = 0.02), and mood (75.0% v. 20.0%, χ2 = 11.17, p = 0.002) to a greater extent in the EUPD compared to the bipolar disorder cohort, with 43.8% of individuals with EUPD reporting an increase in suicidal ideation. Psychometric rating scales [Beck Anxiety Inventory (BAI), Beck Depression Scale (BDS), Beck Hopelessness Scale (BHS), Barratt Impulsivity Scale (BIS)] and Likert scales for anxiety, mood and quality of life noted significantly higher levels of psychopathology in the EUPD cohort (p < 0.01). Qualitative analysis reflected quantitative data with themes of the employment of maladaptive coping mechanisms and reduced mental health supports notable.Conclusions:Individuals with EUPD are experiencing significant mental health difficulties related to the COVID-19 pandemic. The provision and recommencement of therapeutic interventions to this cohort, in particular, are warranted given the significant distress and symptoms being experienced.

As a fundamental aspect of normal cell signaling and disease states, there is great interest in determining alternative splicing (AS) changes in physiologic, pathologic, and pharmacologic settings. High throughput RNA sequencing and specialized software to detect AS has greatly enhanced our ability to determine transcriptome-wide splicing changes. Despite the richness of this data, deriving meaning from sometimes thousands of AS events is a substantial bottleneck for most investigators. We present SpliceTools, a suite of data processing modules that arms investigators with the ability to quickly produce summary statistics, mechanistic insights, and functional significance of AS changes through command line or through an online user interface. Utilizing RNA-seq datasets for 186 RNA binding protein knockdowns, nonsense mediated RNA decay inhibition, and pharmacologic splicing inhibition, we illustrate the utility of SpliceTools to distinguish splicing disruption from regulated transcript isoform changes, we show the broad transcriptome footprint of the pharmacologic splicing inhibitor, indisulam, we illustrate the utility in uncovering mechanistic underpinnings of splicing inhibition, we identify predicted neo-epitopes in pharmacologic splicing inhibition, and we show the impact of splicing alterations induced by indisulam on cell cycle progression. Together, SpliceTools puts rapid and easy downstream analysis at the fingertips of any investigator studying AS.

Adapting mental health-care interventions to the race, ethnicity, or culture of the target group can enhance the acceptance and effectiveness of the treatment. Dialectical behavior therapy (DBT) is an evidence-based treatment that is principle-driven, rendering it well-suited for adaptations across cultural contexts. This article conducts a systematic review of the literature to determine the nature and extent of cultural adaptations of DBT to date.We searched databases for original articles describing cultural adaptations of DBT, as applied to both (a) people of color within Western countries and (b) populations within non-Western countries. Consistent with the focus on descriptively characterizing extant DBT cultural adaptations, we included both published and nonpublished studies, as well as both observational and experimental studies.Our search yielded 18 articles that met inclusion criteria. Of these articles, half described adaptations made with people and communities of color within the U.S. Most adaptations involved modifications to language, metaphors, methods, and context.Culturally adapted DBT has been implemented and accepted among several racial, ethnic, and cultural groups, although there is insufficient evidence to determine whether culturally adapted DBT is more efficacious than nonadapted DBT. We conclude with recommendations for best practices for DBT researchers and clinicians, and situate our findings among larger efforts to render existing evidence-based psychotherapies more optimal for people of color and people from non-Western countries. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Airway and alveolar epithelial cells express a variety of K+ channels that are specifically localized to either the apical or basolateral membrane depending upon their physiological function. These channels play important roles in maintenance of membrane potential, control of cell volume, regulation of cell proliferation, and support of transepithelial electrolyte and nutrient transport. K+ channels present in the apical membrane of alveolar epithelial cells, for example, facilitate K+ secretion, thus contributing to the elevated K+ concentration observed in alveolar fluid. K+ channels localized to the basolateral membrane of airway epithelial cells contribute to transepithelial electrolyte and fluid transport by sustaining the electrical driving force necessary for anion efflux or cation influx and limit fluctuations in intracellular K+ concentration associated with changes in Na+–K+ ATPase activity. Signaling molecules that control the absorptive and secretory functions of lung epithelia have been shown to regulate specific K+ channel subtypes through the mobilization of intracellular second messengers such as Ca2+ and cAMP. In this review, the diversity of K+ channel expression and the functional role of these channels in transepithelial electrolyte and fluid transport in lung epithelia are addressed.

Alternaria alternata and house dust mite exposure evokes IL-33 secretion from the airway epithelium, which functions as an alarmin to stimulate type 2 immunity. Extracellular DNA (eDNA) is also an alarmin that intensifies inflammation in cystic fibrosis, chronic obstructive pulmonary disease, and asthma.We investigated the mechanisms underlying allergen-evoked DNA mobilization and release from the airway epithelium and determined the role of eDNA in type 2 immunity.Human bronchial epithelial (hBE) cells were used to characterize allergen-induced DNA mobilization and extracellular release using comet assays to measure DNA fragmentation, Qubit double-stranded DNA assays to measure DNA release, and DNA sequencing to determine eDNA composition. Mice were used to investigate the role of eDNA in type 2 immunity.Alternaria extract rapidly induces mitochondrial and nuclear DNA release from human bronchial epithelial cells, whereas house dust mite extract induces mitochondrial DNA release. Caspase-3 is responsible for nuclear DNA fragmentation and becomes activated after cleavage by furin. Analysis of secreted nuclear DNA showed disproportionally higher amounts of promotor and exon sequences and lower intron and intergenic regions compared to predictions of random DNA fragmentation. In mice, Alternaria-induced type 2 immune responses were blocked by pretreatment with a DNA scavenger. In caspase-3-deficient mice, Alternaria-induced DNA release was suppressed. Furthermore, intranasal administration of mouse genomic DNA with Alternaria amplified secretion of IL-5 and IL-13 into bronchoalveolar lavage fluid while DNA alone had no effect.These findings highlight a novel, allergen-induced mechanism of rapid DNA release that amplifies type 2 immunity in airways.

Behaviors associated with reproduction are major contributors to the evolutionary success of organisms and are subject to many evolutionary forces, including natural and sexual selection, and sexual conflict. Successful reproduction involves a range of behaviors, from finding an appropriate mate, courting, and copulation, to the successful production and (in oviparous animals) deposition of eggs following mating. As a consequence, behaviors and genes associated with reproduction are often under strong selection and evolve rapidly. Courtship rituals in flies follow a multimodal pattern, mediated through visual, chemical, tactile, and auditory signals. Premating behaviors allow males and females to assess the species identity, reproductive state, and condition of their partners. Conflicts between the “interests” of individual males, and/or between the reproductive strategies of males and females, often drive the evolution of reproductive behaviors. For example, seminal proteins transmitted by males often show evidence of rapid evolution, mediated by positive selection. Postmating behaviors, including the selection of oviposition sites, are highly variable and Drosophila species span the spectrum from generalists to obligate specialists. Chemical recognition features prominently in adaptation to host plants for feeding and oviposition. Selection acting on variation in pre-, peri-, and postmating behaviors can lead to reproductive isolation and incipient speciation. Response to selection at the genetic level can include the expansion of gene families, such as those for detecting pheromonal cues for mating, or changes in the expression of genes leading to visual cues such as wing spots that are assessed during mating. Here, we consider the evolution of reproductive behavior in Drosophila at two distinct, yet complementary, scales. Some studies take a microevolutionary approach, identifying genes and networks involved in reproduction, and then dissecting the genetics underlying complex behaviors in D. melanogaster. Other studies take a macroevolutionary approach, comparing reproductive behaviors across the genus Drosophila and how these might correlate with environmental cues. A full synthesis of this field will require unification across these levels.

Postcopulatory sexual selection is credited as a principal force behind the rapid evolution of reproductive characters, often generating a pattern of correlated evolution between interacting, sex-specific traits. Because the female reproductive tract is the selective environment for sperm, one taxonomically widespread example of this pattern is the co-diversification of sperm length and female sperm-storage organ dimension. In Drosophila, having testes that are longer than the sperm they manufacture was believed to be a universal physiological constraint. Further, the energetic and time costs of developing long testes have been credited with underlying the steep evolutionary allometry of sperm length and constraining sperm length evolution in Drosophila. Here, we report on the discovery of a novel spermatogenic mechanism—sperm cyst looping—that enables males to produce relatively long sperm in short testis. This phenomenon (restricted to members of the saltans and willistoni species groups) begins early during spermatogenesis and is potentially attributable to heterochronic evolution, resulting in growth asynchrony between spermatid tails and the surrounding spermatid and somatic cyst cell membranes. By removing the allometric constraint on sperm length, this evolutionary innovation appears to have enabled males to evolve extremely long sperm for their body mass while evading delays in reproductive maturation time. On the other hand, sperm cyst looping was found to exact a cost by requiring greater total energetic investment in testes and a pronounced reduction in male lifespan. We speculate on the ecological selection pressures underlying the evolutionary origin and maintenance of this unique adaptation.

Most children in the world grow up bilingual, and bilingualism has been linked to a range of linguistic and other cognitive skills. One such skill is creativity, which is thought could be increased in bilinguals due to enhanced executive functions or more diverse cultural experiences. However, extant literature with children has produced mixed results, perhaps due to methodological limitations. In this study, bilingual and monolingual children (N = 111, 60% bilingual) sampled from the same British schools completed three measures of divergent thinking, alongside measures of nonverbal intelligence, vocabulary, and exposure to English. No differences were found between monolingual and bilingual children across any of the divergent thinking tasks or measures, either before or after controlling for possible confounds, and effect sizes were negligible to small. This well-powered, pre-registered study provides no evidence for a bilingual advantage in the divergent thinking component of creativity amongst children, suggesting that previous mixed results may have been due to a high prevalence of false positives. Thus, while bilingualism has many benefits for children, divergent thinking is not one of them.

Polyethyleneimine (PEI) induced immune responses were investigated in human bronchial epithelial (hBE) cells and mice. PEI rapidly induced ATP release from hBE cells and pretreatment with glutathione (GSH) blocked the response. PEI activated two conductive pathways, VDAC-1 and pannexin 1, which completely accounted for ATP efflux across the plasma membrane. Moreover, PEI increased intracellular Ca2+ concentration ([Ca2+]i), which was reduced by the pannexin 1 inhibitor, 10Panx (50 μM), the VDAC-1 inhibitor, DIDS (100 μM), and was nearly abolished by pretreatment with GSH (5 mM). The increase in [Ca2+]i involved Ca2+ uptake through two pathways, one blocked by oxidized ATP (oATP, 300 μM) and another that was blocked by the TRPV-1 antagonist A784168 (100 nM). PEI stimulation also increased IL-33 mRNA expression and protein secretion. In vivo experiments showed that acute (4.5 h) PEI exposure stimulated secretion of Th2 cytokines (IL-5 and IL-13) into bronchoalveolar lavage (BAL) fluid. Conjugation of PEI with ovalbumin also induced eosinophil recruitment and secretion of IL-5 and IL-13 into BAL fluid, which was inhibited in IL-33 receptor (ST2) deficient mice. In conclusion, PEI-induced oxidative stress stimulated type 2 immune responses by activating ATP-dependent Ca2+ uptake leading to IL-33 secretion, similar to allergens derived from Alternaria.

SummaryAlthough long-term outcomes of girls with attention-deficit hyperactivity disorder are understudied, high risk for adolescent and young-adult self-harm is salient. We present data on predictors and mediators of such risk, highlighting a recent dual-process model involving trait impulsivity plus family- and peer-related contributors. We conclude with recommendations for assessment and preventive intervention.

Maternal prenatal stress influences offspring neurodevelopment and birth outcomes including the ratio of males to females born; however, there is limited understanding of what types of stress matter, and for whom. Using a data-driven approach with 27 variables from questionnaires, ambulatory diaries, and physical assessments collected early in the singleton pregnancies of 187 women, 3 latent profiles of maternal prenatal stress emerged that were differentially associated with sex at birth, birth outcomes, and fetal neurodevelopment. Most women (66.8%) were in the healthy group (HG); 17.1% were in the psychologically stressed group (PSYG), evidencing clinically meaningful elevations in perceived stress, depression, and anxiety; and 16% were in the physically stressed group (PHSG) with relatively higher ambulatory blood pressure and increased caloric intake. The population normative male:female secondary sex ratio (105:100) was lower in the PSYG (2:3) and PHSG (4:9), and higher in the HG (23:18), consistent with research showing diminished male births in maternal stress contexts. PHSG versus HG infants were born 1.5 wk earlier (P

Mucociliary clearance is critically important in protecting the airways from infection and from the harmful effects of smoke and various inspired substances known to induce oxidative stress and persistent inflammation. An essential feature of the clearance mechanism involves regulation of the periciliary liquid layer on the surface of the airway epithelium, which is necessary for normal ciliary beating and maintenance of mucus hydration. The underlying ion transport processes associated with airway surface hydration include epithelial Na+ channel-dependent Na+ absorption occurring in parallel with CFTR and Ca2+-activated Cl− channel-dependent anion secretion, which are coordinately regulated to control the depth of the periciliary liquid layer. Oxidative stress is known to cause both acute and chronic effects on airway ion transport function, and an increasing number of studies in the past few years have identified an important role for autophagy as part of the physiological response to the damaging effects of oxidation. In this review, recent studies addressing the influence of oxidative stress and autophagy on airway ion transport pathways, along with results showing the potential of autophagy modulators in restoring the function of ion channels involved in transepithelial electrolyte transport necessary for effective mucociliary clearance, are presented.

SUMMARYStrict and facultative anaerobic bacteria are widely associated with both acute and chronic airway disease. However, their potential role(s) in disease pathophysiology remain poorly understood due to inherent limitations of existing models and conflicting oxygen demands between anaerobes and host cells. To overcome these limitations, we optimized a dual oxic-anoxic culture (DOAC) platform that maintains an oxygen-limited microenvironment at the epithelial interface while host cells are oxygenated basolaterally. This approach enables host-bacterial co-culture for ∼24h, and here we demonstrate its utility via two applications. First, we show that anaerobe challenge results in epithelial mucus degradation, inflammatory marker gene expression, and enhanced pathogen colonization. Second, we combine DOAC with single cell RNA sequencing (scRNAseq) to reveal a cell type-specific transcriptional response of the airway epithelium to anaerobe infection. Together, these data illustrate the versatility of DOAC while revealing new insights into anaerobe-host interactions and their mechanistic contributions to airway disease pathophysiology.

Introduction Co-morbid insomnia and sleep apnoea (COMISA) is a prevalent and debilitating condition that is difficult to treat. COMISA patients have lower average adherence to continuous positive airway pressure (CPAP) therapy compared to patients with sleep apnoea alone. However, a sub-sample of COMISA patients may show adequate CPAP use that improves both the insomnia and sleep apnoea. It is important to identify this group of CPAP-responsive COMISA patients to guide personalised-medicine approaches. Methods Seventy-three COMISA patients (AHI≥15; ICSD-3 insomnia; 55% male, Age M=57y) completed questionnaires, home-based polysomnography, and one-week sleep diaries before and 6-months after commencing CPAP therapy. No patients accessed CBTi. We investigated baseline predictors of CPAP adherence (min/night) and overall change in Insomnia Severity Index (ISI) scores during treatment. Results Average CPAP adherence was 205 minutes/night (SD=153). 56% of patients used CPAP at least 4h/night. Average CPAP adherence was predicted by higher baseline AHI (r=0.39), arousal index (r=0.28), N1 sleep (r=0.32) and age (r=0.26), and lower N3 sleep (r=-0.28). The ISI decreased from baseline (17.9, CI=1.2) to 6-month follow-up (11.6, CI=1.3; p Conclusion Approximately half of COMISA patients show CPAP adherence of ≥4h/night and one quarter experience insomnia remission with CPAP. CPAP use is positively associated with AHI, light sleep, and age at baseline, and reduction of insomnia severity during treatment. Future randomized controlled trials are required to confirm the results of this small un-controlled study.

Adenosine and uric acid (UA) play a pivotal role in lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). In the present experiments, we measured adenosine synthesis from nicotinamide adenine dinucleotide (NAD+) in membranes prepared from wild type (WT) and CD38 knockout (CD38KO) mouse lungs, from cultured airway smooth muscle and epithelial cells, and in bronchoalveolar lavage fluid after airway challenge with epidemiologically relevant allergens. Adenosine was determined using an enzymatically coupled assay that produces ATP and is detected by luminescence. Uric acid was determined by ELISA. Exposure of cultured airway epithelial cells to Alternaria alternata extract caused significant nucleotide (NAD+ and ATP) release in the culture media. The addition of NAD+ to membranes prepared from WT mice resulted in faster generation of adenosine compared to membranes from CD38KO mice. Formation of adenosine from NAD+ affected UA and ATP concentrations, its main downstream molecules. Furthermore, NAD+ and adenosine concentrations in the bronchoalveolar lavage fluid decreased significantly following airway challenge with house-dust mite extract in WT but not in CD38KO mice. Thus, NAD+ is a significant source of adenosine and UA in the airways in mouse models of allergic airway disease, and the capacity for their generation from NAD+ is augmented by CD38, a major NADase with high affinity for NAD+. This novel non-canonical NAD+-adenosine-UA pathway that is triggered by allergens has not been previously described in the airways.

Background Aedes aegypti is a globally distributed vector of human diseases including dengue, yellow fever, chikungunya, and Zika. Pyrethroid insecticides are the primary means of controlling adult A. aegypti populations to suppress arbovirus outbreaks, but resistance to pyrethroid insecticides has become a global problem. Mutations in the voltage-sensitive sodium channel (Vssc) gene are a major mechanism of pyrethroid resistance in A. aegypti. Vssc resistance alleles in A. aegypti commonly have more than one mutation. However, our understanding of the evolutionary dynamics of how alleles with multiple mutations arose is poorly understood. Methodology/Principal findings We examined the geographic distribution and association between the common Vssc mutations (V410L, S989P, V1016G/I and F1534C) in A. aegypti by analyzing the relevant Vssc fragments in 25 collections, mainly from Asia and the Americas. Our results showed all 11 Asian populations had two types of resistance alleles: 1534C and 989P+1016G. The 1534C allele was more common with frequencies ranging from 0.31 to 0.88, while the 989P+1016G frequency ranged from 0.13 to 0.50. Four distinct alleles (410L, 1534C, 410L+1534C and 410L+1016I+1534C) were detected in populations from the Americas. The most common was 410L+1016I+1534C with frequencies ranging from 0.50 to 1.00, followed by 1534C with frequencies ranging from 0.13 to 0.50. Our phylogenetic analysis of Vssc supported multiple independent origins of the F1534C mutation. Our results indicated the 410L+1534C allele may have arisen by addition of the V410L mutation to the 1534C allele, or by a crossover event. The 410L+1016I+1534C allele was the result of one or two mutational steps from a 1534C background. Conclusions/Significance Our data corroborated previous geographic distributions of resistance mutations and provided evidence for both recombination and sequential accumulation of mutations contributing to the molecular evolution of resistance alleles in A. aegypti., Author summary Mutations in the voltage-sensitive sodium channel (Vssc) gene in Aedes aegypti can confer resistance to insecticides and threaten vector control programs. To date, twelve Vssc mutations have been identified in pyrethroid resistant A. aegypti populations, and F1534C, V1016G/I, S989P and V410L commonly are found alone or in combination. However, the evolutionary dynamics of how alleles came to have multiple mutations is less known. In this study, we found 1534C and 989P+1016G alleles were widely distributed in Asian populations. In contrast, the distinct 410L, 410L+1534C, 410L+1016I+1534C and 1534C alleles were distributed in populations from the Americas. The 410L+1534C allele appears to have arisen by accumulation of the 410L mutation in an individual already having the 1534C allele or by a crossover event. The 410L+1016I+1534C arose by additional mutations from 1534C background. Our data corroborates previous geographic distributions of resistance mutations and provides evidence for both recombination and sequential accumulation of mutations contributing to the molecular evolution of resistance mutations in A. aegypti.

Key points Alternaria aeroallergens induce the release of ATP from human bronchial epithelial (HBE) cells by activating a conductive pathway involving voltage-dependent anion channel-1 (VDAC-1) and by exocytosis of ATP localized within membrane vesicles. Inhibition of VDAC-1 blocked Alternaria-evoked Ca2+ uptake across the plasma membrane of HBE cells and interleukin (IL)-33 release into the extracellular media. Reducing cholesterol content with a cholesterol scavenger (β-methylcyclodextrin) or statin compound (simvastatin) blocked ATP and IL-33 release by lowering the expression of VDAC-1 in the plasma membrane. Pretreatment with simvastatin for 24 h also inhibited the increase in tight junction macromolecule permeability that occurs following Alternaria exposure. These results establish a novel role for VDAC-1 as a mechanism underlying ATP release induced by fungal allergens and suggests a possible therapeutic use for cholesterol lowering compounds in reducing Alternaria-stimulated allergic inflammation. Abstract Human bronchial epithelial (HBE) cells exposed to allergens derived from the common saprophytic fungus, Alternaria alternata release ATP, which in turn stimulates P2X7 receptor-mediated Ca2+ uptake across the plasma membrane. The subsequent increase in intracellular calcium concentration induces proteolytic processing and secretion of interleukin (IL)-33, a critical cytokine involved in the initiation of allergic airway inflammation. A major objective of the present study was to identify the mechanism responsible for conductive ATP release. The results show that pretreatment of HBE cells with inhibitors of the voltage-dependent anion channel-1 (VDAC-1) or treatment with a VDAC-1 selective blocking antibody or silencing mRNA expression of the channel by RNA interference, inhibit Alternaria-evoked ATP release. Moreover, inhibition of VDAC-1 channel activity or reducing protein expression blocked the secretion of IL-33. Similarly, reducing the cholesterol content of HBE cells with simvastatin or the cholesterol scavenger β-methylcyclodextrin also blocked ATP release and IL-33 secretion by decreasing the level of VDAC-1 expression in the plasma membrane. In addition, simvastatin inhibited the increase in tight junction macromolecule permeability that was previously observed after Alternaria exposure. These results demonstrate a novel function for VDAC-1 as the conductive mechanism responsible for Alternaria-induced ATP release, an essential early step in the processing, mobilization and secretion of IL-33 by the airway epithelium. Furthermore, the simvastatin-evoked reduction of VDAC-1 expression in the plasma membrane, suggests the possibility that cholesterol lowering compounds may be beneficial in alleviating allergic airway inflammation induced by fungal allergens.

Understanding phylogenetic relationships among taxa is key to designing and implementing comparative analyses. The genus Drosophila, which contains over 1600 species, is one of the most important model systems in the biological sciences. For over a century, one species in this group, Drosophila melanogaster, has been key to studies of animal development and genetics, genome organization and evolution, and human disease. As whole-genome sequencing becomes more cost-effective, there is increasing interest in other members of this morphologically, ecologically, and behaviorally diverse genus. Phylogenetic relationships within Drosophila are complicated, and the goal of this paper is to provide a review of the recent taxonomic changes and phylogenetic relationships in this genus to aid in further comparative studies.

Glacial legacy, barriers to migration, and dispersal abilities are important determinants of intraspecific genetic diversity. Genetic comparisons can elucidate the distribution of genetic variants among populations, but for many groups of organisms the concordance of population genetic structure and historical refugia among co-occurring species remains unclear. We compared phylogeographic histories of 4 stoneflies (Calineuria californica, Hesperoperla pacifica, Pteronarcys californica, and Pteronarcys princeps) and 1 caddisfly (Dicosmoecus gilvipes) across their species ranges. Study species had large body and wing sizes that suggest strong flying ability and dispersal potential. Nevertheless, riverine habitat restrictions and mating behaviors can inhibit dispersal. We used mitochondrial and nuclear gene sequences to examine population genetic structure relative to potential past and present barriers to dispersal in the western USA. North–south population genetic structure was present for each spe...

In the present study we investigated the role of hydrocortisone (HC) on UTP-stimulated ion transport in differentiated, pseudostratified epithelia derived from normal human bronchial basal cells. The presence of a UTP stimulated, paxilline-sensitive large conductance Ca2+-activated K+ (BK) current was demonstrated in control epithelia but was not stimulated in epithelia differentiated in the absence of HC (HC0). Addition of the BK opener NS11021 directly activated channels in control epithelia however under HC0 conditions, activation only occurred when UTP was added after NS11021. The PKC inhibitors GF109203x and Go6983 blocked BK activation by UTP in control epithelia, suggesting that PKC-mediated phosphorylation plays a permissive role in purinoceptor-stimulated BK activation. Moreover HC0 epithelia expressed significantly more KCNMA1 containing the stress-regulated exon (STREX), a splice-variant of the α-subunit that displays altered channel regulation by phosphorylation, compared to control epithelia. Furthermore, BK channels as well as purinergic receptors were shown to localize in unique and overlapping domains at the apical membrane of ciliated surface cells. These results establish a previously unrecognized role for glucocorticoids in regulation of BK channels in airway epithelial cells. This article is protected by copyright. All rights reserved

The mayfly Baetis tricaudatus is an abundant, widespread, and ecologically important multivoltine benthic macroinvertebrate that is found throughout most of North America. Baetis tricaudatus belongs to the Baetis rhodani species group, which is known to have cryptic species. Some investigators have found that B. tricaudatus morphospecies have cytochrome oxidase I (COI) diversity >20%. However, no investigators have examined whether this diversity is structured temporally, with some haplotypes being more common in certain years or seasons than others. We sequenced COI from 371 B. rhodani specimens. The 371 rhodani species group sequences generated fell into 2 well-supported clades, one with 38 Baetis adonis specimens and another with 333 B. tricaudatus specimens, which were the focus of our study. We examined the temporal and spatial dynamics of genetic diversity in B. tricaudatus populations from northern California using COI haplotype networks. The maximum genetic diversity among B. tricaudatus s...

Background Interleukin (IL)-33 is implicated in the pathophysiology of asthma and allergic diseases. However, our knowledge is limited regarding how IL-33 release is controlled. The transcription factor nuclear factor-erythroid-2-related factor 2 (Nrf2) plays a key role in antioxidant response regulation. Objective The goal of this project was to investigate the role of cellular oxidative stress in controlling IL-33 release in airway epithelium. Methods Complementary approaches were used that included human bronchial epithelial cells and mouse models of airway type-2 immunity that were exposed to fungus Alternaria extract. The clinically available Nrf2 activator 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid methyl ester (CDDO-Me) was used to evaluate the role of Nrf2-induced antioxidant molecules. Results Human bronchial epithelial cells produced reactive oxygen species (ROS) when they were exposed to Alternaria extract. ROS scavengers, such as glutathione (GSH) and N-acetyl cysteine, prevented extracellular secretion of ATP and increases in intracellular calcium concentrations that precede IL-33 release. Administration of CDDO-Me to mice enhanced expression of a number of antioxidant molecules in the lungs and elevated lung levels of endogenous GSH. Importantly, CDDO-Me treatment reduced allergen-induced ATP secretion and IL-33 release by airway epithelial cells in vitro and protected mice from IL-33 release and asthma-like pathological changes in the lungs. Conclusions The balance between oxidative stress and antioxidant responses plays a key role in controlling IL-33 release in airway epithelium. The therapeutic potential of Nrf2 activators needs to be considered for asthma and allergic airway diseases.

International audience; Animal terminalia represent some of the most diverse and rapidly evolving structures in the animal kingdom, and for this reason have been a mainstay in the taxonomic description of species. The terminalia of Drosophila melanogaster, with its wide range of experimental tools, have recently become the focus of increased interest in the fields of development, evolution, and behavior. However, studies from different disciplines have often used discrepant terminologies for the same anatomical structures. Consequently, the terminology of genital parts has become a barrier to integrating results from different fields, rendering it difficult to determine what parts are being referenced. We formed a consortium of researchers studying the genitalia of D. melanogaster to help establish a set of naming conventions. Here, we present a detailed visual anatomy of male genital parts, including a list of synonymous terms, and suggest practices to avoid confusion when referring to anatomical parts in future studies. The goal of this effort is to facilitate interdisciplinary communication and help newcomers orient themselves within the exciting field of Drosophila genitalia. ARTICLE HISTORY