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Allergic asthma has traditionally been treated with inhaled and systemic glucocorticosteroids. A continuum of allergic fungal airways disease associated with Aspergillus fumigatus colonization and/or atopic immune responses that encompasses fungal asthma, severe asthma with fungal sensitization and allergic bronchopulmonary aspergillosis is now recognized along a phenotypic severity spectrum of T2-high immune deviation lung disease. Oral triazoles have shown clinical, anti-inflammatory and microbiologic efficacy in this setting; in the future inhaled antifungals may improve the therapeutic index. Humanized monoclonal antibody biologic agents targeting T2-high disease also show efficacy and promise of improved control in difficult cases. Developments in these areas are highlighted in this overview.

Cardiac myosin binding protein C (cMyBP-C) has a key regulatory role in cardiac contraction, but the mechanism by which changes in phosphorylation of cMyBP-C accelerate cross-bridge kinetics remains unknown. In this study, we isolated thick filaments from the hearts of mice in which the three serine residues (Ser273, Ser282, and Ser302) that are phosphorylated by protein kinase A in the m-domain of cMyBP-C were replaced by either alanine or aspartic acid, mimicking the fully nonphosphorylated and the fully phosphorylated state of cMyBP-C, respectively. We found that thick filaments from the cMyBP-C phospho-deficient hearts had highly ordered cross-bridge arrays, whereas the filaments from the cMyBP-C phospho-mimetic hearts showed a strong tendency toward disorder. Our results support the hypothesis that dephosphorylation of cMyBP-C promotes or stabilizes the relaxed/superrelaxed quasi-helical ordering of the myosin heads on the filament surface, whereas phosphorylation weakens this stabilization and binding of the heads to the backbone. Such structural changes would modulate the probability of myosin binding to actin and could help explain the acceleration of crossbridge interactions with actin when cMyBP-C is phosphorylated because of, for example, activation of β₁-adrenergic receptors in myocardium.

This article focuses on the implications for the US National Climate Assessment (NCA) of diversifying information needs to support climate change risk management. It describes how the Third US National Climate Assessment (NCA3) evolved to begin to narrow the gap between information from climate and impact scientists and “intermediaries” (individuals who have expertise in climate science, communication, and decision-support processes)—who are sometimes collectively described as “producers” in this article—and the decision-making needs of a wide range of “users” (individuals involved in advising or making a wide range of policy and management decisions). One step in the evolution of the NCA3 included adding a chapter to assess decision-support tools and systems being used in climate-related decisions. Another involved efforts to improve characterization of the level of confidence of NCA3 authors in their findings to help decision-makers and their advisors differentiate well-established and more preliminary conclusions. This paper lays out an argument for increasing the role of the NCA in assessing decision-support systems in the Fourth Assessment (NCA4) and the Sustained Assessment. It also briefly reviews approaches and potential next steps related to characterizing uncertainty and communicating confidence intended to improve application of assessment findings by decision-makers.

Aspergillus fumigatus (Af) and Pseudomonas aeruginosa (Pa) are leading fungal and bacterial pathogens, respectively, in many clinical situations. Relevant to this, their interface and co-existence has been studied. In some experiments in vitro, Pa products have been defined that are inhibitory to Af. In some clinical situations, both can be biofilm producers, and biofilm could alter their physiology and affect their interaction. That may be most relevant to airways in cystic fibrosis (CF), where both are often prominent residents. We have studied clinical Pa isolates from several sources for their effects on Af, including testing involving their biofilms. We show that the described inhibition of Af is related to the source and phenotype of the Pa isolate. Pa cells inhibited the growth and formation of Af biofilm from conidia, with CF isolates more inhibitory than non-CF isolates, and non-mucoid CF isolates most inhibitory. Inhibition did not require live Pa contact, as culture filtrates were also inhibitory, and again non-mucoid>mucoid CF>non-CF. Preformed Af biofilm was more resistant to Pa, and inhibition that occurred could be reproduced with filtrates. Inhibition of Af biofilm appears also dependent on bacterial growth conditions; filtrates from Pa grown as biofilm were more inhibitory than from Pa grown planktonically. The differences in Pa shown from these different sources are consistent with the extensive evolutionary Pa changes that have been described in association with chronic residence in CF airways, and may reflect adaptive changes to life in a polymicrobial environment.

Changes in the frequencies of cell subsets that (co)express characteristic biomarkers, or levels of the biomarkers on the subsets, are widely used as indices of drug response, disease prognosis, stem cell reconstitution, etc. However, although the currently available computational \"gating\" tools accurately reveal subset frequencies and marker expression levels, they fail to enable statistically reliable judgements as to whether these frequencies and expression levels differ significantly between/among subject groups. Here we introduce flow cytometry data analysis pipeline which includes the Earth Mover's Distance (EMD) metric as solution to this problem. Well known as an informative quantitative measure of differences between distributions, we present three exemplary studies showing that EMD 1) reveals clinically-relevant shifts in two markers on blood basophils responding to an offending allergen; 2) shows that ablative tumor radiation induces significant changes in the murine colon cancer tumor microenvironment; and, 3) ranks immunological differences in mouse peritoneal cavity cells harvested from three genetically distinct mouse strains.

Projections of future climate change play a fundamental role in improving understanding of the climate system as well as characterizing societal risks and response options. The Scenario Model Intercomparison Project (ScenarioMIP) is the primary activity within Phase 6 of the Coupled Model Intercomparison Project (CMIP6) that will provide multi-model climate projections based on alternative scenarios of future emissions and land use changes produced with integrated assessment models. In this paper, we describe ScenarioMIP's objectives, experimental design, and its relation to other activities within CMIP6. The ScenarioMIP design is one component of a larger scenario process that aims to facilitate a wide range of integrated studies across the climate science, integrated assessment modeling, and impacts, adaptation, and vulnerability communities, and will form an important part of the evidence base in the forthcoming Intergovernmental Panel on Climate Change (IPCC) assessments. At the same time, it will provide the basis for investigating a number of targeted science and policy questions that are especially relevant to scenario-based analysis, including the role of specific forcings such as land use and aerosols, the effect of a peak and decline in forcing, the consequences of scenarios that limit warming to below 2°C, the relative contributions to uncertainty from scenarios, climate models, and internal variability, and long-term climate system outcomes beyond the 21st century. To serve this wide range of scientific communities and address these questions, a design has been identified consisting of eight alternative 21st century scenarios plus one large initial condition ensemble and a set of long-term extensions, divided into two tiers defined by relative priority. Some of these scenarios will also provide a basis for variants planned to be run in other CMIP6-Endorsed MIPs to investigate questions related to specific forcings. Harmonized, spatially explicit emissions and land use scenarios generated with integrated assessment models will be provided to participating climate modeling groups by late 2016, with the climate model simulations run within the 2017-2018 time frame, and output from the climate model projections made available and analyses performed over the 2018-2020 period.

Setting the scenes Climatologists use model-based 'scenarios' to provide plausible descriptions of how the future might unfold when evaluating uncertainty about the effects of human actions on climate. The traditional method of establishing these scenarios was a time-consuming sequential process, each discipline taking turns to add data and complexity. As Richard Moss and colleagues explain in a Perspectives review, climate change researchers have now established a new coordinated parallel process that integrates the tasks of developing scenarios, making projections and evaluating their impact. These 'next generation' scenarios should make for faster, more rigorous assessment of proposals for climate mitigation and adaptation. Advances in the science and observation of climate change are providing a clearer understanding of the inherent variability of Earth’s climate system and its likely response to human and natural influences. The implications of climate change for the environment and society will depend not only on the response of the Earth system to changes in radiative forcings, but also on how humankind responds through changes in technology, economies, lifestyle and policy. Extensive uncertainties exist in future forcings of and responses to climate change, necessitating the use of scenarios of the future to explore the potential consequences of different response options. To date, such scenarios have not adequately examined crucial possibilities, such as climate change mitigation and adaptation, and have relied on research processes that slowed the exchange of information among physical, biological and social scientists. Here we describe a new process for creating plausible scenarios to investigate some of the most challenging and important questions about climate change confronting the global community.

Because of the difficulties of recognizing allergic bronchopulmonary aspergillosis (ABPA) in the context of cystic fibrosis (because of overlapping clinical, radiographic, microbiologic, and immunologic features), advances in our understanding of the pathogenesis of allergic aspergillosis, new possibilities in therapy, and the need for agreed-upon definitions, an international consensus conference was convened. Areas addressed included fungal biology, immunopathogenesis, insights from animal models, diagnostic criteria, epidemiology, the use of new immunologic and genetic techniques in diagnosis, imaging modalities, pharmacology, and treatment approaches. Evidence from the existing literature was graded, and the consensus views were synthesized into this document and recirculated for affirmation. Virulence factors in Aspergillus that could aggravate these diseases, and particularly immunogenetic factors that could predispose persons to ABPA, were identified. New information has come from transgenic animals and recombinant fungal and host molecules. Diagnostic criteria that could provide a framework for monitoring were adopted, and helpful imaging features were identified. New possibilities in therapy produced plans for managing diverse clinical presentations.