Airline Consolidation and Consumer Welfare

In our model of the deregulated airline industry, consumers care not only about price but also about service convenience, measured by system coverage and connection. We find that the service-enhancing effects of employing large-scale hub-and-spoke networks have outweighed the price-increasing effects of having a smaller number of competing national airlines. Thus, a welfare gain has accrued to consumers as a result of the more consolidated market structure. We conclude that public policymakers should exercise antitrust and bankruptcy authority in a manner which does not impede welfare-enhancing consolidations in the airline industry.Airline

The emerging role of zinc transporters in cellular homeostasis and cancer

Zinc is an essential micronutrient that plays a role in the structural or enzymatic functions of many cellular proteins. Cellular zinc homeostasis involves the opposing action of two families of metal transporters: the ZnT (SLC30) family that functions to reduce cytoplasmic zinc concentrations and the ZIP (SLC39) family that functions to increase cytoplasmic zinc concentrations. Fluctuations in intracellular zinc levels mediated by these transporter families affect signaling pathways involved in normal cell development, growth, differentiation and death. Consequently, changes in zinc transporter localization and function resulting in zinc dyshomeostasis have pathophysiological effects. Zinc dyshomeostasis has been implicated in the progression of cancer. Here we review recent progress toward understanding the structural basis for zinc transport by ZnT and ZIP family proteins, as well as highlight the roles of zinc as a signaling molecule in physiological conditions and in various cancers. As zinc is emerging as an important signaling molecule in the development and progression of cancer, the ZnT and ZIP transporters that regulate cellular zinc homeostasis are promising candidates for targeted cancer therapy

FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes.

Mutations in the transcription factor FOXA1 define a unique subset of prostate cancers but the functional consequences of these mutations and whether they confer gain or loss of function is unknown1-9. Here, by annotating the landscape of FOXA1 mutations from 3,086 human prostate cancers, we define two hotspots in the forkhead domain: Wing2 (around 50% of all mutations) and the highly conserved DNA-contact residue R219 (around 5% of all mutations). Wing2 mutations are detected in adenocarcinomas at all stages, whereas R219 mutations are enriched in metastatic tumours with neuroendocrine histology. Interrogation of the biological properties of wild-type FOXA1 and fourteen FOXA1 mutants reveals gain of function in mouse prostate organoid proliferation assays. Twelve of these mutants, as well as wild-type FOXA1, promoted an exaggerated pro-luminal differentiation program, whereas two different R219 mutants blocked luminal differentiation and activated a mesenchymal and neuroendocrine transcriptional program. Assay for transposase-accessible chromatin using sequencing (ATAC-seq) of wild-type FOXA1 and representative Wing2 and R219 mutants revealed marked, mutant-specific changes in open chromatin at thousands of genomic loci and exposed sites of FOXA1 binding and associated increases in gene expression. Of note, ATAC-seq peaks in cells expressing R219 mutants lacked the canonical core FOXA1-binding motifs (GTAAAC/T) but were enriched for a related, non-canonical motif (GTAAAG/A), which was preferentially activated by R219-mutant FOXA1 in reporter assays. Thus, FOXA1 mutations alter its pioneering function and perturb normal luminal epithelial differentiation programs, providing further support for the role of lineage plasticity in cancer progression

Microfluidic stochastic confinement enhances analysis of rare cells by isolating cells and creating high density environments for control of diffusible signals

Rare cells can be difficult to analyze because they either occur in low numbers or coexist with a more abundant cell type, yet their detection is crucial for diagnosing disease and maintaining human health. In this tutorial review, we introduce the concept of microfluidic stochastic confinement for use in detection and analysis of rare cells. Stochastic confinement provides two advantages: (1) it separates rare single cells from the bulk mixture and (2) it allows signals to locally accumulate to a higher concentration around a single cell than in the bulk mixture. Microfluidics is an attractive method for implementing stochastic confinement because it provides simple handling of small volumes. We present technologies for microfluidic stochastic confinement that utilize both wells and droplets for the detection and analysis of single cells. We address how these microfluidic technologies have been used to observe new behavior, increase speed of detection, and enhance cultivation of rare cells. We discuss potential applications of microfluidic stochastic confinement to fields such as human diagnostics and environmental testing

Data visualization for truth maintenance in clinical decision support systems

Background and objectives The goal is to inform proactive initiatives to expand the knowledge base of clinical decision support systems. Design and setting We describe an initiative in which research informationists and health services researchers employ visualization tools to map logic models for clinical decision support within an electronic health record. Materials and methods We mapped relationships using software for social network analysis: NodeXL and CMAP. We defined relationships by shared observations, such as two Arden rules within medical logic modules that consider the same clinical observation, or by the presence of common keywords that were used to label rules according to standardized vocabularies. Results We studied the Child Health Improvement through Computer Automation (CHICA) system, an electronic medical record that contains 170 unique variables representing discrete clinical observations. These variables were used in 300 medical logic modules (MLM's) that prompted health care providers to deliver preventive counseling or otherwise served as clinical decision support. Using data visualization tools, we generated maps that illustrate connections, or lack thereof, between clinical topics within CHICA's MLMs. Conclusions The development of such maps may allow multiple disciplines commonly interacting over EMR platforms, and various perspectives (clinicians, programmers, informationists) to work more effectively as teams to refine the EMR by programming logic routines to address co-morbidities or other instances where domains of medical knowledge should be connected

Characterizing and Predicting Canadian Adolescents’ Internalizing Symptoms In The First Year Of The COVID-19 Pandemic

To date, most longitudinal studies of adolescents’ internalizing symptoms during the COVID-19 pandemic include few time points, limiting knowledge about the long-term course of adolescents’ mental health during the pandemic. Moreover, examining intraindividual variability in symptoms, which may have important implications for adolescents’ adjustment beyond mean or “typical” symptoms, requires multiple time points. We examined the course of internalizing symptoms in 271 Ontario adolescents (mean n = 193 across time points) during the first year of the pandemic (March 2020–April 2021) via mixed-effect location scale models, drawing upon established internalizing symptom risk factors as predictors of mean trends and intraindividual variability. Adolescents’ internalizing symptoms were relatively stable and generally low over the first year of the pandemic, with severity peaking in February and April 2021. Girls showed more symptoms on average and greater intraindividual variability in symptoms. Parents’ depressive symptoms predicted intraindividual variability in adolescents’ anxious and depressive symptoms. Adolescents’ symptoms were stable and generally below clinical cutoffs. However, female adolescents and those whose parents experienced more depressive symptoms were most vulnerable to the stress of the pandemic. Implications for intervention and prevention efforts are discussed

BMP4 Activation and Secretion Are Negatively Regulated by an Intracellular Gremlin-BMP4 Interaction

Bone morphogenetic protein 4 (BMP4) is a potent growth factor that is involved in many important biological processes. Regulation of the level of secreted mature BMP4 determines the biological effects of BMP4 on cells in the local microenvironment. Previous studies suggested that Gremlin, a member of DAN family proteins, antagonizes BMP4 activity by sequestering extracellular BMP4. Herein, we report a novel intracellular regulatory mechanism by which Gremlin interacts with BMP4 precursor, prevents secretion of mature BMP4, and therefore inhibits BMP4 activity more efficiently. Furthermore, we also defined a 30-amino acid peptide sequence within the Gremlin DAN domain that is essential for BMP4 interaction. This novel Gremlin-mediated BMP4 posttranslational regulatory mechanism implies that the level of BMP4 mRNA expression does not truly reflect BMP4 activity when Gremlin and BMP4 are coexpressed within the same cell. Similar regulatory mechanisms may be utilized by other DAN family proteins

Exploring sensory phenotypes in autism spectrum disorder

Background: Atypical reactions to the sensory environment are often reported in autistic individuals, with a high degree of variability across the sensory modalities. These sensory differences have been shown to promote challenging behaviours and distress in autistic individuals and are predictive of other functions including motor, social, and cognitive abilities. Preliminary research suggests that specific sensory differences may cluster together within individuals creating discrete sensory phenotypes. However, the manner in which these sensory differences cluster, and whether the resulting phenotypes are associated with specific cognitive and social challenges is unclear. Methods: Short sensory profile data from 599 autistic children and adults between the ages of 1 and 21 years were subjected to a K-means cluster analysis. Analysis of variances compared age, adaptive behaviour, and traits associated with autism, attention-deficit and hyperactivity disorder, and obsessive and compulsive disorder across the resultant clusters. Results: A five-cluster model was found to minimize error variance and produce five sensory phenotypes: (1) sensory adaptive, (2) generalized sensory differences, (3) taste and smell sensitivity, (4) under-responsive and sensation seeking, and (5) movement difficulties with low energy. Age, adaptive behaviour, and traits associated with autism, attention-deficit and hyperactivity disorder, and obsessive and compulsive disorder were found to differ significantly across the five phenotypes. Limitations: The results were based on parent-report measures of sensory processing, adaptive behaviour, traits associated with autism, attention-deficit and hyperactivity disorder, and obsessive and compulsive disorder, which may limit the generalizability of the findings. Further, not all measures are standardized, or psychometrically validated with an autism population. Autistic individuals with an intellectual disability were underrepresented in this sample. Further, as these data were obtained from established records from a large provincial database, not all measures were completed for all individuals. Conclusions: These findings suggest that sensory difficulties in autistic individuals can be clustered into sensory phenotypes, and that these phenotypes are associated with behavioural differences. Given the large degree of heterogeneity in sensory difficulties seen in the autistic population, these sensory phenotypes represent an effective way to parse that heterogeneity and create phenotypes that may aid in the development of effective treatments and interventions for sensory difficulties

Migratory zooplankton excreta and its influence on prokaryotic communities

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Maas, A. E., Liu, S., Bolanos, L. M., Widner, B., Parsons, R., Kujawinski, E. B., Blanco-Bercial, L., & Carlson, C. A. Migratory zooplankton excreta and its influence on prokaryotic communities. Frontiers in Marine Science, 7, (2020): 573268, doi:10.3389/fmars.2020.573268.Particulate organic matter (POM) (fecal pellets) from zooplankton has been demonstrated to be an important nutrient source for the pelagic prokaryotic community. Significantly less is known about the chemical composition of the dissolved organic matter (DOM) produced by these eukaryotes and its influence on pelagic ecosystem structure. Zooplankton migrators, which daily transport surface-derived compounds to depth, may act as important vectors of limiting nutrients for mesopelagic microbial communities. In this role, zooplankton may increase the DOM remineralization rate by heterotrophic prokaryotes through the creation of nutrient rich “hot spots” that could potentially increase niche diversity. To explore these interactions, we collected the migratory copepod Pleuromamma xiphias from the northwestern Sargasso Sea and sampled its excreta after 12–16 h of incubation. We measured bulk dissolved organic carbon (DOC), dissolved free amino acids (DFAA) via high performance liquid chromatography and dissolved targeted metabolites via quantitative mass spectrometry (UPLC-ESI-MSMS) to quantify organic zooplankton excreta production and characterize its composition. We observed production of labile DOM, including amino acids, vitamins, and nucleosides. Additionally, we harvested a portion of the excreta and subsequently used it as the growth medium for mesopelagic (200 m) bacterioplankton dilution cultures. In zooplankton excreta treatments we observed a four-fold increase in bacterioplankton cell densities that reached stationary growth phase after five days of dark incubation. Analyses of 16S rRNA gene amplicons suggested a shift from oligotrophs typical of open ocean and mesopelagic prokaryotic communities to more copiotrophic bacterial lineages in the presence of zooplankton excreta. These results support the hypothesis that zooplankton and prokaryotes are engaged in complex and indirect ecological interactions, broadening our understanding of the microbial loop.Funding for this research was provided by Simons Foundation International as part of the BIOS-SCOPE project to AM, LB-B, CC, and EK