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Environmental exposures interplay with human host factors to promote the development and progression of allergic diseases. The worldwide prevalence of allergic disease is rising as a result of complex gene-environment interactions that shape the immune system and host response. Research shows an association between the rise of allergic diseases and increasingly modern Westernized lifestyles, which are characterized by increased urbanization, time spent indoors, and antibiotic usage. These environmental changes result in increased exposure to air and traffic pollution, fungi, infectious agents, tobacco smoke, and other early-life and lifelong risk factors for the development and exacerbation of asthma and allergic diseases. It is increasingly recognized that the timing, load, and route of allergen exposure affect allergic disease phenotypes and development. Still, our ability to prevent allergic diseases is hindered by gaps in understanding of the underlying mechanisms and interaction of environmental, viral, and allergen exposures with immune pathways that impact disease development. This Review highlights epidemiologic and mechanistic evidence linking environmental exposures to the development and exacerbation of allergic airway responses.

The U.S. Food and Drug Administration requires food processors to implement and validate processes that will result in significantly minimizing or preventing the occurrence of hazards that are reasonably foreseeable in food production. During production of fresh-cut leafy vegetables, microbial contamination that may be present on the product can spread throughout the production batch when the product is washed, thus increasing the risk of illnesses. The use of antimicrobials in the wash water is a critical step in preventing such water-mediated cross-contamination; however, many factors can affect antimicrobial efficacy in the production of fresh-cut leafy vegetables, and the procedures for validating this key preventive control have not been articulated. Producers may consider three options for validating antimicrobial washing as a preventive control for cross-contamination. Option 1 involves the use of a surrogate for the microbial hazard and the demonstration that cross-contamination is prevented by the antimicrobial wash. Option 2 involves the use of antimicrobial sensors and the demonstration that a critical antimicrobial level is maintained during worst-case operating conditions. Option 3 validates the placement of the sensors in the processing equipment with the demonstration that a critical antimicrobial level is maintained at all locations, regardless of operating conditions. These validation options developed for fresh-cut leafy vegetables may serve as examples for validating processes that prevent cross-contamination during washing of other fresh produce commodities.

Atopic dermatitis (AD) is a complex multifactorial inflammatory skin disease that affects ~280 million people worldwide. About 85% of AD cases begin in childhood, a significant portion of which can persist into adulthood. Moreover, a typical progression of children with AD to food allergy, asthma or allergic rhinitis has been reported (\"allergic march\" or \"atopic march\"). AD comprises highly heterogeneous sub-phenotypes/endotypes resulting from complex interplay between intrinsic and extrinsic factors, such as environmental stimuli, and genetic factors regulating cutaneous functions (impaired barrier function, epidermal lipid, and protease abnormalities), immune functions and the microbiome. Though the roles of high-throughput \"omics\" integrations in defining endotypes are recognized, current analyses are primarily based on individual omics data and using binary clinical outcomes. Although individual omics analysis, such as genome-wide association studies (GWAS), can effectively map variants correlated with AD, the majority of the heritability and the functional relevance of discovered variants are not explained or known by the identified variants. The limited success of singular approaches underscores the need for holistic and integrated approaches to investigate complex phenotypes using trans-omics data integration strategies. Integrating omics layers (e.g., genome, epigenome, transcriptome, proteome, metabolome, lipidome, exposome, microbiome), which often have complementary and synergistic effects, might provide the opportunity to capture the flow of information underlying AD disease manifestation. Overlapping genes/candidates derived from multiple omics types include , and in AD pathogenesis. Overlapping pathways include macrophage, endothelial cell and fibroblast activation pathways, in addition to well-known Th1/Th2 and NFkB activation pathways. Interestingly, there was more multi-omics overlap at the pathway level than gene level. Further analysis of multi-omics overlap at the tissue level showed that among 30 tissue types from the GTEx database, skin and esophagus were significantly enriched, indicating the biological interconnection between AD and food allergy. The present work explores multi-omics integration and provides new biological insights to better define the biological basis of AD etiology and confirm previously reported AD genes/pathways. In this context, we also discuss opportunities and challenges introduced by \"big omics data\" and their integration.

Respiratory infections are common precursors to asthma exacerbations in children, but molecular immune responses that determine whether and how an infection causes an exacerbation are poorly understood. By using systems-scale network analysis, we identify repertoires of cellular transcriptional pathways that lead to and underlie distinct patterns of asthma exacerbation. Specifically, in both virus-associated and nonviral exacerbations, we demonstrate a set of core exacerbation modules, among which epithelial-associated SMAD3 signaling is upregulated and lymphocyte response pathways are downregulated early in exacerbation, followed by later upregulation of effector pathways including epidermal growth factor receptor signaling, extracellular matrix production, mucus hypersecretion, and eosinophil activation. We show an additional set of multiple inflammatory cell pathways involved in virus-associated exacerbations, in contrast to squamous cell pathways associated with nonviral exacerbations. Our work introduces an in vivo molecular platform to investigate, in a clinical setting, both the mechanisms of disease pathogenesis and therapeutic targets to modify exacerbations. Respiratory infections are the principal cause of asthma exacerbations in children. Altman and colleagues use a systems approach to describe the pathways associated with asthma exacerbations in a cohort of inner-city children.

This article examines the association between the market for corporate control and firm dividend policies. Specifically, we examine changes in firms' dividend payouts following a plausibly exogenous shock to the threat of takeover with the staggered initiation of country-level merger and acquisition (M&A) laws. Using a global sample of firms across 34 countries, we find that both the likelihood and the amount of dividends decrease significantly after the initiation of an M&A law in a country. Our cross-sectional analyses indicate that the negative effect of M&A laws on dividend payouts is amplified in countries where the institutional environment enables M&A laws to improve the takeover market and for firms that could readily use internal capital to finance growth opportunities. Moreover, this negative effect is attenuated for firms with already sufficient monitoring of managers. These findings suggest that the enactment of M&A laws, by strengthening the market for corporate control, lowered the need for firms to convey their commitment to shareholders' interests through costly dividend payments, especially when the threat of takeover prompted by M&A laws is likely to serve as an effective disciplinary mechanism.

On 3 January 2000, the Galileo spacecraft passed close to Europa when it was located far south of Jupiter's magnetic equator in a region where the radial component of the magnetospheric magnetic field points inward toward Jupiter. This pass with a previously unexamined orientation of the external forcing field distinguished between an induced and a permanent magnetic dipole moment model of Europa's internal field. The Galileo magnetometer measured changes in the magnetic field predicted if a current-carrying outer shell, such as a planet-scale liquid ocean, is present beneath the icy surface. The evidence that Europa's field varies temporally strengthens the argument that a liquid ocean exists beneath the present-day surface.

The timing and duration of traffic-related air pollution (TRAP) exposure may be important for childhood wheezing and asthma development. We examined the relationship between TRAP exposure and longitudinal wheezing phenotypes and asthma at age 7 years. Children completed clinical examinations annually from age 1 year through age 4 years and age 7 years. Parental-reported wheezing was assessed at each age, and longitudinal wheezing phenotypes (early-transient, late-onset, persistent) and asthma were defined at age 7 years. Participants' time-weighted exposure to TRAP, from birth through age 7 years, was estimated using a land-use regression model. The relationship between TRAP exposure and wheezing phenotypes and asthma was examined. High TRAP exposure at birth was significantly associated with both transient and persistent wheezing phenotypes (adjusted odds ratio [aOR] = 1.64; 95% confidence interval [CI], 1.04-2.57 and aOR = 2.31; 95% CI, 1.28-4.15, respectively); exposure from birth to age 1 year and age 1 to 2 years was also associated with persistent wheeze. Only children with high average TRAP exposure from birth through age 7 years were at significantly increased risk for asthma (aOR = 1.71; 95% CI, 1.01-2.88). Early-life exposure to TRAP is associated with increased risk for persistent wheezing, but only long-term exposure to high levels of TRAP throughout childhood was associated with asthma development.

Previous studies have suggested a role for Tet1 in the pathogenesis of childhood asthma. However, how Tet1 contributes to asthma remains unknown. Here we used mice deficient for Tet1 in a well-established model of allergic airway inflammation and demonstrated that loss of Tet1 increased disease severity including airway hyperresponsiveness and lung eosinophilia. Increased expression of Muc5ac , Il1 3 , Il33 , Il 1 7a , Egfr , and Tff 2 were observed in HDM-challenged Tet1-deficient mice compared to Tet1 +/+ littermates. Further, transcriptomic analysis of lung RNA followed by pathway and protein network analysis showed that the IFN signaling pathway was significantly upregulated and the aryl hydrocarbon receptor (AhR) pathway was significantly downregulated in HDM-challenged Tet1 −/− mice. This transcriptional regulation of the IFN and AhR pathways by Tet1 was also present in human bronchial epithelial cells at base line and following HDM challenges. Genes in these pathways were further associated with changes in DNA methylation, predicted binding of transcriptional factors with relevant functions in their promoters, and the presence of histone marks generated by histone enzymes that are known to interact with Tet1. Collectively, our data suggest that Tet1 inhibits HDM-induced allergic airway inflammation by direct regulation of the IFN and AhR pathways.

Single nucleotide polymorphisms (SNPs) in the gene encoding kinesin family member 3A, KIF3A , have been associated with atopic dermatitis (AD), a chronic inflammatory skin disorder. We find that KIF3A SNP rs11740584 and rs2299007 risk alleles create cytosine-phosphate-guanine sites, which are highly methylated and result in lower KIF3A expression, and this methylation is associated with increased transepidermal water loss (TEWL) in risk allele carriers. Kif3a K14 ∆ / ∆ mice have increased TEWL, disrupted junctional proteins, and increased susceptibility to develop AD. Thus, KIF3A is required for skin barrier homeostasis whereby decreased KIF3A skin expression causes disrupted skin barrier function and promotes development of AD. Genetic variants in KIF3A are associated with atopic dermatitis (AD). Here, the authors identify two AD-risk alleles that show high methylation resulting in lower KIF3A expression. Mice with epidermis-specific loss of Kif3a show disrupted skin barrier homeostasis and increased AD susceptibility.

The icy surface of Jupiter’s moon, Europa, is thought to lie on top of a global ocean 1 – 4 . Signatures in some Hubble Space Telescope images have been associated with putative water plumes rising above Europa’s surface 5 , 6 , providing support for the ocean theory. However, all telescopic detections reported were made at the limit of sensitivity of the data 5 – 7 , thereby calling for a search for plume signatures in in-situ measurements. Here, we report in-situ evidence of a plume on Europa from the magnetic field and plasma wave observations acquired on Galileo’s closest encounter with the moon. During this flyby, which dropped below 400 km altitude, the magnetometer 8 recorded an approximately 1,000-kilometre-scale field rotation and a decrease of over 200 nT in field magnitude, and the Plasma Wave Spectrometer 9 registered intense localized wave emissions indicative of a brief but substantial increase in plasma density. We show that the location, duration and variations of the magnetic field and plasma wave measurements are consistent with the interaction of Jupiter’s corotating plasma with Europa if a plume with characteristics inferred from Hubble images were erupting from the region of Europa’s thermal anomalies. These results provide strong independent evidence of the presence of plumes at Europa. The hypothesis of an ocean under the icy surface of Jupiter’s moon Europa is strengthened by in-situ evidence of a plume, inferred by Galileo’s magnetic field and plasma density measurements obtained during the spacecraft’s closest flyby to the moon.