Process Drivers, Inter-Model Spread, and the Path Forward: A Review of Amplified Arctic Warming

This is the final version. Available on open access from Frontiers Media via the DOI in this recordArctic amplification (AA) is a coupled atmosphere-sea ice-ocean process. This understanding has evolved from the early concept of AA, as a consequence of snow-ice line progressions, through more than a century of research that has clarified the relevant processes and driving mechanisms of AA. The predictions made by early modeling studies, namely the fall/winter maximum, bottom-heavy structure, the prominence of surface albedo feedback, and the importance of stable stratification have withstood the scrutiny of multi-decadal observations and more complex models. Yet, the uncertainty in Arctic climate projections is larger than in any other region of the planet, making the assessment of high-impact, near-term regional changes difficult or impossible. Reducing this large spread in Arctic climate projections requires a quantitative process understanding. This manuscript aims to build such an understanding by synthesizing current knowledge of AA and to produce a set of recommendations to guide future research. It briefly reviews the history of AA science, summarizes observed Arctic changes, discusses modeling approaches and feedback diagnostics, and assesses the current understanding of the most relevant feedbacks to AA. These sections culminate in a conceptual model of the fundamental physical mechanisms causing AA and a collection of recommendations to accelerate progress towards reduced uncertainty in Arctic climate projections. Our conceptual model highlights the need to account for local feedback and remote process interactions within the context of the annual cycle to constrain projected AA. We recommend raising the priority of Arctic climate sensitivity research, improving the accuracy of Arctic surface energy budget observations, rethinking climate feedback definitions, coordinating new model experiments and intercomparisons, and further investigating the role of episodic variability in AA.NASANatural Sciences and Engineering Research Council of Canada (NSERC)US National Science foundationAlfred P. Sloan FoundationNatural Environment Research Council (NERC

Segregation of myoblast fusion and muscle-specific gene expression by distinct ligand-dependent inactivation of GSK-3β

Myogenic differentiation involves myoblast fusion and induction of muscle-specific gene expression, which are both stimulated by pharmacological (LiCl), genetic, or IGF-I-mediated GSK-3β inactivation. To assess whether stimulation of myogenic differentiation is common to ligand-mediated GSK-3β inactivation, myoblast fusion and muscle-specific gene expression were investigated in response to Wnt-3a. Moreover, crosstalk between IGF-I/GSK-3β/NFATc3 and Wnt/GSK-3β/β-catenin signaling was assessed. While both Wnt-3a and LiCl promoted myoblast fusion, muscle-specific gene expression was increased by LiCl, but not by Wnt-3a or β-catenin over-expression. Furthermore, LiCl and IGF-I, but not Wnt-3a, increased NFATc3 transcriptional activity. In contrast, β-catenin-dependent transcriptional activity was increased by Wnt-3a and LiCl, but not IGF-I. These results for the first time reveal a segregated regulation of myoblast fusion and muscle-specific gene expression following stimulation of myogenic differentiation in response to distinct ligand-specific signaling routes of GSK-3β inactivation

Immune sensitization of equine bronchus: glutathione, IL-1β expression and tissue responsiveness

BACKGROUND: Increasing clinical epidemiological and experimental evidence indicates that excess of production of reactive oxygen free radicals (ROS) induced by an oxidative stress is involved in the pathogenesis of a number of human airway disorders, as well as equine recurrent airway obstruction. Free-radicals modulate the activation of transcription factors, such as nuclear factor-(NF)-κB and activator protein (AP)-1, in several different cells. This activation leads to expression of many pro-inflammatory cytokines, including interleukin (IL)-1β. We have hypothesized that equine airway sensitization might induce an oxidative stress and increase the ROS production, which in turn might enhance a production of IL-1β and airway hyperresponsiveness. METHODS: We have examined the effect of passive sensitization on IL-1β mRNA expression and electrical field stimulation (EFS)-induced contraction in equine isolated bronchi, and the potential interference of reduced-glutathione (GSH), an antioxidant, with these responses. Bronchi passively sensitized with serum from animals suffering from heaves and having high total level of IgE, and control tissues, either pretreated or not with GSH (100 μM), were used to quantify IL-1β mRNA. Other tissues were used to study the effect of EFS (3–10–25 Hz). RESULTS: Mean IL-1β mRNA expression was higher in passively sensitized than in control rings. GSH significantly (p < 0.05) reduced the IL-1β mRNA expression only in passively sensitized bronchi. ELF induced a frequency-dependent contraction in both non-sensitized and passively sensitized tissues, with a significantly greater response always observed in sensitized tissues. GSH did not modify the EFS-induced contraction in non-sensitized bronchi, but significantly (p < 0.05) decreased it in passively sensitized tissues. CONCLUSION: Our data indicate that the passive sensitization of equine bronchi induces inflammation and hyperresponsiveness. These effects might be due to an oxidative stress because a pretreatment with GSH decreased the increased IL-1β mRNA expression and responsiveness to EFS of passively sensitized bronchi

Modulation of glutaredoxin in the lung and sputum of cigarette smokers and chronic obstructive pulmonary disease

BACKGROUND: One typical feature in chronic obstructive pulmonary disease (COPD) is the disturbance of the oxidant/antioxidant balance. Glutaredoxins (Grx) are thiol disulfide oxido-reductases with antioxidant capacity and catalytic functions closely associated with glutathione, the major small molecular weight antioxidant of human lung. However, the role of Grxs in smoking related diseases is unclear. METHODS: Immunohistochemical and Western blot analyses were conducted with lung specimens (n = 45 and n = 32, respectively) and induced sputum (n = 50) of healthy non-smokers and smokers without COPD and at different stages of COPD. RESULTS: Grx1 was expressed mainly in alveolar macrophages. The percentage of Grx1 positive macrophages was significantly lower in GOLD stage IV COPD than in healthy smokers (p = 0.021) and the level of Grx1 in total lung homogenate decreased both in stage I–II (p = 0.045) and stage IV COPD (p = 0.022). The percentage of Grx1 positive macrophages correlated with the lung function parameters (FEV1, r = 0.45, p = 0.008; FEV1%, r = 0.46, p = 0.007, FEV/FVC%, r = 0.55, p = 0.001). Grx1 could also be detected in sputum supernatants, the levels being increased in the supernatants from acute exacerbations of COPD compared to non-smokers (p = 0.013) and smokers (p = 0.051). CONCLUSION: The present cross-sectional study showed that Grx1 was expressed mainly in alveolar macrophages, the levels being decreased in COPD patients. In addition, the results also demonstrated the presence of Grx1 in extracellular fluids including sputum supernatants. Overall, the present study suggests that Grx1 is a potential redox modulatory protein regulating the intracellular as well as extracellular homeostasis of glutathionylated proteins and GSH in human lung

Dlk1 Is Necessary for Proper Skeletal Muscle Development and Regeneration

Delta-like 1homolog (Dlk1) is an imprinted gene encoding a transmembrane protein whose increased expression has been associated with muscle hypertrophy in animal models. However, the mechanisms by which Dlk1 regulates skeletal muscle plasticity remain unknown. Here we combine conditional gene knockout and over-expression analyses to investigate the role of Dlk1 in mouse muscle development, regeneration and myogenic stem cells (satellite cells). Genetic ablation of Dlk1 in the myogenic lineage resulted in reduced body weight and skeletal muscle mass due to reductions in myofiber numbers and myosin heavy chain IIB gene expression. In addition, muscle-specific Dlk1 ablation led to postnatal growth retardation and impaired muscle regeneration, associated with augmented myogenic inhibitory signaling mediated by NF-κB and inflammatory cytokines. To examine the role of Dlk1 in satellite cells, we analyzed the proliferation, self-renewal and differentiation of satellite cells cultured on their native host myofibers. We showed that ablation of Dlk1 inhibits the expression of the myogenic regulatory transcription factor MyoD, and facilitated the self-renewal of activated satellite cells. Conversely, Dlk1 over-expression inhibited the proliferation and enhanced differentiation of cultured myoblasts. As Dlk1 is expressed at low levels in satellite cells but its expression rapidly increases upon myogenic differentiation in vitro and in regenerating muscles in vivo, our results suggest a model in which Dlk1 expressed by nascent or regenerating myofibers non-cell autonomously promotes the differentiation of their neighbor satellite cells and therefore leads to muscle hypertrophy

Inhibition of Atrogin-1/MAFbx Mediated MyoD Proteolysis Prevents Skeletal Muscle Atrophy In Vivo

Ubiquitin ligase Atrogin1/Muscle Atrophy F-box (MAFbx) up-regulation is required for skeletal muscle atrophy but substrates and function during the atrophic process are poorly known. The transcription factor MyoD controls myogenic stem cell function and differentiation, and seems necessary to maintain the differentiated phenotype of adult fast skeletal muscle fibres. We previously showed that MAFbx mediates MyoD proteolysis in vitro. Here we present evidence that MAFbx targets MyoD for degradation in several models of skeletal muscle atrophy. In cultured myotubes undergoing atrophy, MAFbx expression increases, leading to a cytoplasmic-nuclear shuttling of MAFbx and a selective suppression of MyoD. Conversely, transfection of myotubes with sh-RNA-mediated MAFbx gene silencing (shRNAi) inhibited MyoD proteolysis linked to atrophy. Furthermore, overexpression of a mutant MyoDK133R lacking MAFbx-mediated ubiquitination prevents atrophy of mouse primary myotubes and skeletal muscle fibres in vivo. Regarding the complex role of MyoD in adult skeletal muscle plasticity and homeostasis, its rapid suppression by MAFbx seems to be a major event leading to skeletal muscle wasting. Our results point out MyoD as the second MAFbx skeletal muscle target by which powerful therapies could be developed

A Systems Biology Approach Identifies Molecular Networks Defining Skeletal Muscle Abnormalities in Chronic Obstructive Pulmonary Disease

Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory process of the lung inducing persistent airflow limitation. Extensive systemic effects, such as skeletal muscle dysfunction, often characterize these patients and severely limit life expectancy. Despite considerable research efforts, the molecular basis of muscle degeneration in COPD is still a matter of intense debate. In this study, we have applied a network biology approach to model the relationship between muscle molecular and physiological response to training and systemic inflammatory mediators. Our model shows that failure to co-ordinately activate expression of several tissue remodelling and bioenergetics pathways is a specific landmark of COPD diseased muscles. Our findings also suggest that this phenomenon may be linked to an abnormal expression of a number of histone modifiers, which we discovered correlate with oxygen utilization. These observations raised the interesting possibility that cell hypoxia may be a key factor driving skeletal muscle degeneration in COPD patients

Greenland ice sheet surface mass loss: recent developments in observation and modeling

Surface processes currently dominate Greenland ice sheet (GrIS) mass loss. We review recent developments in the observation and modelling of GrIS surface mass balance (SMB), published after the July 2012 deadline for the Fifth Assessment Report of the Intergovernmental Panel on Climate Change (IPCC AR5). Since IPCC AR5 our understanding of GrIS SMB has further improved, but new observational and model studies have also revealed that temporal and spatial variability of many processes are still poorly quantified and understood, e.g. bio-albedo, the formation of ice lenses and their impact on lateral meltwater transport, heterogeneous vertical meltwater transport (‘piping’), the impact of atmospheric circulation changes and mixed-phase clouds on the surface energy balance and the magnitude of turbulent heat exchange over rough ice surfaces. As a result, these processes are only schematically or not at all included in models that are currently used to assess and predict future GrIS surface mass loss

Microsatellite Support for Active Inbreeding in a Cichlid Fish

In wild animal populations, the degree of inbreeding differs between species and within species between populations. Because mating with kin often results in inbreeding depression, observed inbreeding is usually regarded to be caused by limited outbreeding opportunities due to demographic factors like small population size or population substructuring. However, theory predicts inclusive benefits from mating with kin, and thus part of the observed variation in inbreeding might be due to active inbreeding preferences. Although some recent studies indeed report kin mating preferences, the evidence is still highly ambiguous. Here, we investigate inbreeding in a natural population of the West African cichlid fish Pelvicachromis taeniatus which showed clear kin mating preferences in standardized laboratory experiments but no inbreeding depression. The presented microsatellite analysis reveals that the natural population has, in comparison to two reference populations, a reduced allelic diversity (A = 3) resulting in a low heterozygosity (Ho = 0.167) pointing to a highly inbred population. Furthermore, we found a significant heterozygote deficit not only at population (Fis = 0.116) but also at subpopulation level (Fis = 0.081) suggesting that inbreeding is not only a by-product of population substructuring but possibly a consequence of behavioral kin preferences

Interaction of Pattern Recognition Receptors with Mycobacterium Tuberculosis.

Tuberculosis (TB) is considered a major worldwide health problem with 10 million new cases diagnosed each year. Our understanding of TB immunology has become greater and more refined since the identification of Mycobacterium tuberculosis (MTB) as an etiologic agent and the recognition of new signaling pathways modulating infection. Understanding the mechanisms through which the cells of the immune system recognize MTB can be an important step in designing novel therapeutic approaches, as well as improving the limited success of current vaccination strategies. A great challenge in chronic disease is to understand the complexities, mechanisms, and consequences of host interactions with pathogens. Innate immune responses along with the involvement of distinct inflammatory mediators and cells play an important role in the host defense against the MTB. Several classes of pattern recognition receptors (PRRs) are involved in the recognition of MTB including Toll-Like Receptors (TLRs), C-type lectin receptors (CLRs) and Nod-like receptors (NLRs) linked to inflammasome activation. Among the TLR family, TLR1, TLR2, TLR4, and TLR9 and their down-stream signaling proteins play critical roles in the initiation of the immune response in the pathogenesis of TB. The inflammasome pathway is associated with the coordinated release of cytokines such as IL-1β and IL-18 which also play a role in the pathogenesis of TB. Understanding the cross-talk between these signaling pathways will impact on the design of novel therapeutic strategies and in the development of vaccines and immunotherapy regimes. Abnormalities in PRR signaling pathways regulated by TB will affect disease pathogenesis and need to be elucidated. In this review we provide an update on PRR signaling during M. tuberculosis infection and indicate how greater knowledge of these pathways may lead to new therapeutic opportunities