Search

Background The effects of air pollutants, particularly polycyclic aromatic hydrocarbons (PAHs), on the skin microbiome remain poorly understood. Thus, to better understand the interplay between air pollutants, microbiomes, and skin conditions, we applied metagenomics and metabolomics to analyze the effects of PAHs in air pollution on the skin microbiomes of over 120 subjects residing in two cities in China with different levels of air pollution. Results The skin microbiomes differentiated into two cutotypes (termed 1 and 2) with distinct taxonomic, functional, resistome, and metabolite compositions as well as skin phenotypes that transcended geography and host factors. High PAH exposure was linked to dry skin and cutotype 2, which was enriched with species with potential biodegradation functions and had reduced correlation network structure integrity. The positive correlations identified between dominant taxa, key functional genes, and metabolites in the arginine biosynthesis pathway in cutotype 1 suggest that arginine from bacteria contributes to the synthesis of filaggrin-derived natural moisturizing factors (NMFs), which provide hydration for the skin, and could explain the normal skin phenotype observed. In contrast, no correlation with the arginine biosynthesis pathway was observed in cutotype 2, which indicates the limited hydration functions of NMFs and explains the observed dry skin phenotype. In addition to dryness, skin associated with cutotype 2 appeared prone to other adverse conditions such as inflammation. Conclusions This study revealed the roles of PAHs in driving skin microbiome differentiation into cutotypes that vary extensively in taxonomy and metabolic functions and may subsequently lead to variations in skin–microbe interactions that affect host skin health. An improved understanding of the roles of microbiomes on skin exposed to air pollutants can aid the development of strategies that harness microbes to prevent undesirable skin conditions.

For the first time in the latest Assessment Report of the Intergovernmental Panel on Climate Change (IPCC), water has been the focus of dedicated chapters in both Working Group 1 (Chapter 8) and 2 (Chapter 4). Nevertheless, we argue here that water has not yet received the full attention it deserves from both scientists and policymakers for several reasons. Firstly, the historical focus on temperature change has been further increased with the use of global warming levels motivated by an aim to be consistent with current policy framings. Secondly, an increasing attention paid to extreme weather has sometimes overshadowed longer time-scale changes such as the aridification of an increasing fraction of arable land and the increasing variability of the water cycle from month to month, season to season, and year to year that also yield cascading impacts on all water use sectors. Thirdly, a stronger focus is needed on understanding the effectiveness of current and future adaptation strategies in reducing water-related climate risks. Finally, the role of water has not been adequately recognized in the assessment of mitigation strategies although the compliance with the Paris Agreement and the current pledges all require a massive deployment of land-based strategies whose feasibility and efficiency heavily depend on water resources. It is thus essential to develop a more integrated approach to water and climate change, that would allow scientists and policymakers to “close the loop” between mitigation options, water cycle changes, hydrological impacts and adaptation.

The significance of the concept of grand strategy as distinct from foreign policy has been exaggerated. Grand strategy is promoted more by analysts than practitioners and rationalized in hindsight more than it has functioned as a plan. Divergence of practice from theory has been explained away by redefinitions that are wrong. Grand strategy is constrained by the complexity of great powers’ interests and the logic of democracy. It has been implemented in reality, but seldom, and lack of it is sometimes preferable anyway given the risks of consistency and coherence.

Grand strategy is in vogue. Its importance as a guidepost for success in foreign affairs is celebrated, and practitioners’ mistakes in the practice of it have been criticized in a bunch of books an...

Ultraviolet exposure has profound effect on the dermal connective tissue of human skin.We aimed to develop and validate an evaluation method/methodology using a full-thickness reconstructed skin model, to assess the anti-photoaging efficacy of cosmetic ingredients and sunscreen formulas by blending multi relevant biological endpoints including the newly developed dermal collagen quantification method with Multi-photon microscopy.The response of ex vivo human skin to UVA exposure was first characterized with multiphoton microscopy. Reconstructed full-thickness skin models was then used to reproduce the data and to create a proof-of-concept study by treating the models with sunscreen prototypes A or B, which differ on their UVA absorption properties, and systemic Vitamin C (Vit C). After exposure to UVA, the collagen density was quantified via multiphoton microscopy with automatic imaging processing. Histology, fibroblasts number, metalloprotease 1 (MMP1) secretion were also assessed.UVA exposure induced pronounced reduction in collagen density and increased MMP1 secretion within both ex vivo human skin and reconstructed skin. Histological damage and fibroblast disappearance was observed with reconstructed skin. Within the proof-of-concept study prototype B, possessing higher UVA filtration, gave better protection than prototype A on the UV associated biological markers, and association with Vit C boosted sunscreen formula efficacy.The photoaging evaluation method, consists of multi biological markers as well as dermal collagen quantification, is a relevant mean to assess the pre-clinical efficacy of anti-photoaging ingredients and sunscreen products. This approach is also beneficial for evaluating the efficacy of sunscreens and photoprotective ingredients.

Background Urban pollution is correlated with an increased prevalence of skin pigmentation disorders, however the physiological processes underlying this association are unclear. Objectives To delineate the relationship between polycyclic aromatic hydrocarbons (PAHs), a key constituent of atmospheric pollution, and immunity/skin pigmentation pathways. Methods We exposed peripheral blood mononuclear cells (PBMC) to PAHs and performed cytokines/chemokine profiling. We then examined the effect of immune activation on pigmentation by co-culturing PBMC and Benzo(a)pyrene (BaP) with reconstructed human pigmented epidermis (RHPE). To study the mechanism, we treated keratinocytes with conditioned medium from BaP-exposed PBMC and studied DNA damage responses, aryl hydrocarbon receptor (AhR) activation and pro-pigmentation factor, proopiomelanocortin (POMC) secretion. Results PAHs induced up-regulation of inflammatory cytokines/chemokine in PBMC. Co-culturing of RHPE with PBMC+BaP resulted in increased melanin content and localization. BaP conditioned medium significantly increased DNA damage, p53 stabilization, AhR activation and POMC secretion in keratinocytes. We found that IFNγ induced DNA damage while TNFα and IL-8 potentiated POMC secretion in keratinocytes. Importantly, BaP conditioned medium-induced DNA damage and POMC secretion is prevented by antioxidants vitamin E, vitamin C and sulforaphane, as well as the prototypical corticosteroid dexamethasone. Finally, vitamin C and sulforaphane enhanced the genome protective and depigmentation effects of dexamethasone, providing proof-of-concept for a combinatorial approach for the prevention and/or correction of PAH-induced pigment spots formation. Conclusion Our study reveals the importance of systemic immunity in regulating PAH-induced skin pigmentation, and provide a new keratinocytes DNA damage response mechanistic target for the prevention or reversal of pollution-associated skin pigmentation.

Allergic contact dermatitis is a primarily T-cell-mediated inflammatory skin disease induced by exposure to small molecular-weight haptens, which covalently bind to proteins. The abundance of cutaneous T cells that recognize CD1a antigen-presenting molecules raises the possibility that MHC-independent antigen presentation may be relevant in some hapten-driven immune responses. Here we examine the ability of contact sensitizers to influence CD1-restricted immunity. Exposure of human antigen-presenting cells such as monocyte-derived dendritic cells and THP-1 cells to the prototypical contact sensitizer dinitrochlorobenzene potentiated the response of CD1a- and CD1d-autoreactive T cells, which released a vast array of cytokines in a CD1- and TCR-dependent manner. The potentiating effects of dinitrochlorobenzene depended upon newly synthesized CD1 molecules and the presence of endogenous stimulatory lipids. Further examination of a broad panel of contact sensitizers revealed 1,4-benzoquinone, resorcinol, isoeugenol, and cinnamaldehyde to activate the same type of CD1-restricted responses. These findings provide a basis for the antigen-specific activation of skin-associated CD1-restricted T cells by small molecules and may have implications for contact sensitizer-induced inflammatory skin diseases.

This chapter places the surge decision in the context of the broader history of the Iraq War and offers a modestly positive appraisal. Indeed, the surge is only important in how it affected the overall project of the American war in Iraq. The significant question is whether the history of the surge offers lessons beyond itself, or at least whether the surge was decisive for achieving US objectives. The chapter then examines various dilemmas and challenges that the war occasioned—of relating strategy to both operations and politics; of promoting democratization in Iraq while also seeking some control over Iraqi decision making; and of seeking to exert presidential command over a complex decision-making process. It argues that the surge decision reflected a “delicate and skillful exercise in leadership” given civil-military tensions, but questions how well the surge answered the broader strategic questions surrounding American involvement.

In given conditions, action and reaction can be ridiculously out of proportion.... One can obtain results monstrously in excess of the effort.... Let's consider this auto smash-up.... The driver lost control at high speed while swiping at a wasp which had flown in through a window and was buzzing around his face.... The weight of a wasp is under half an ounce. Compared with a human being, the wasp's size is minute, its strength negligible. Its sole armament is a tiny syringe holding a drop of irritant, formic acid. ... Nevertheless, that wasp killed four big men and converted a large, powerful car into a heap of scrap. -Eric Frank Russell1

This study aimed to establish a predictive in vitro method for assessing the photoprotective properties of sunscreens using a reconstructed full-thickness skin model.A full-thickness skin model reconstructed with human fibroblasts and keratinocytes isolated from Chinese skin was exposed to daily UV radiation (DUVR). We examined the transcriptomic response, identifying genes for which expression was modulated by DUVR in a dose-dependent manner. We then validated the methodology for efficacy evaluation of different sunscreens formulas.The reconstructed skin model was histologically consistent with human skin, and upon DUVR exposure, the constituent fibroblasts and keratinocytes exhibited transcriptomic alterations in pathways associated with oxidative stress, inflammation and extracellular matrix remodelling. When used to evaluate sunscreen protection on the model, the observed level of protection from UV-induced gene expression was consistent with the corresponding protection factors determined clinically and allowed for statistical ranking of sunscreen efficacy.Within this study we show that quantification of gene modulation within the reconstructed skin model is a biologically relevant approach with sensitivity and predictability to evaluate photoprotection products.Cette étude visait à établir une méthode prédictive in vitro permettant d’évaluer les propriétés photoprotectrices des écrans solaires à l'aide d'un modèle de peau reconstruite sur toute son épaisseur. MATÉRIELS ET MÉTHODES: Un modèle de peau reconstruite sur toute son épaisseur avec des fibroblastes et des kératinocytes humains isolés à partir de peaux chinoises a été exposé au rayonnement UV quotidien (DUVR). Nous avons examiné la réponse transcriptomique en identifiant les gènes dont l'expression était modulée par le DUVR de façon dépendante à la dose. Nous avons ensuite validé la méthodologie d’évaluation de l'efficacité des formules des différents écrans solaires. RÉSULTATS: Le modèle de peau reconstruite correspondait histologiquement à de la peau humaine, et lors de l'exposition à des DUVR, les fibroblastes et les kératinocytes qui la composaient présentaient des altérations transcriptomiques des voies associées au stress oxydatif, à l'inflammation et au remodelage de la matrice extracellulaire. Lorsque ce modèle a été utilisé pour évaluer la protection solaire, le niveau de protection observé de l'expression génique induite par les UV correspondait aux facteurs de protection cliniques déterminés correspondants et permettait un classement statistique de l'efficacité de la protection solaire.Dans cette étude, nous montrons que la quantification de la modulation génique dans le modèle de peau reconstruite est une approche biologiquement pertinente offrant une sensibilité et une prédictibilité pour évaluer les produits de photoprotection.

Population growth and climate change are likely to impact upon food and water availability over the coming decades. In this study we use an ensemble of climate simulations to project the implications of both these drivers on regional changes in food and water. This study highlights the dominant effect of population growth on per capita resource allocation over climate induced changes in our model projections. We find a strong signal for crop yield reductions due to climate change by the 2050s in the absence of CO 2 fertilisation effects. However, when these additional processes are included this trend is reversed. The impacts of climate on water resources are more uncertain. Overall, we find reductions in the global population living in water stressed conditions due to the combined effects of climate and CO 2 . Africa is a key region where projected decreases in runoff and crop productivity from climate change alone are potentially reversed when CO 2 fertilisation effects are included, but this is highly uncertain. Plant physiological response to increasing atmospheric CO 2 is a major driver of the changes in crop productivity and water availability in this study; it is poorly constrained by observations and is thus a critical uncertainty.

Objective To examine the ability of an extract from traditional Chinese medicine, Polygonum multiflorum Radix, to protect melanocyte viability from oxidative stress, a key mechanism in the initiation and progression of hair greying. Methods To assess the antioxidant capacity of Polygonum multiflorum Radix extract, primary human foreskin melanocytes were treated with a commercially available Polygonum multiflorum Radix extract added to culture medium and exposed to hydrogen peroxide (H2O2), using intracellular reactive oxygen species concentrations and glutathione/protein ratios as endpoints. To improve solubility for cosmetic uses, a new Polygonum multiflorum Radix extract was derived. As hair graying is the consequence of melanocyte disappearance in an oxidative stress environment, we checked if the anti-oxidant capacity of the new Polygonum multiflorum Radix extract could preserve melanocyte viability in response to H2O2-induced oxidative stress, and preserve pigmentation within ex vivo human hair follicles. Results In vitro treatment of primary human foreskin melanocytes with traditional available Polygonum multiflorum Radix extract resulted in decreased intracellular ROS accumulation in response to H2O2 exposure with a concomitant preservation of glutathione to protein ratio, consistent with a protective response against H2O2 exposure and demonstrating the promise of this extract for protecting melanocytes against oxidative stress. Melanocytes treated with the improved Polygonum multiflorum Radix extract exhibited attenuated H2O2-induced cell death, demonstrating a clear cytoprotective effect. Treatment of ex vivo human hair follicles with the improved Polygonum multiflorum Radix extract resulted in a higher level of melanin compared to vehicle-treated controls, demonstrating an ex vivo protective effect on hair pigmentation. Conclusion Polygonum multiflorum Radix extract protects in vitro primary human foreskin melanocytes from the deleterious effects of H2O2-exposure and improves pigmentation within ex vivo human hair follicles, demonstrating the utility of Polygonum multiflorum Radix extract as a potential active ingredient for the protection of melanocytes against premature death. This data provides in vitro mechanistic evidence consistent with existing in vivo studies for the use of Polygonum multiflorum Radix extract as a strategy for the prevention of oxidative-stress induced hair greying, in line with traditional Polygonum multiflorum Radix uses. This article is protected by copyright. All rights reserved.

Foxp3 + CD4 + regulatory T cells (Tregs) represent a highly suppressive T cell subset with well-characterized immunosuppressive effects during immune homeostasis and chronic infections, although the role of these cells in acute viral infections is poorly understood. The present study sought to examine the induction of Foxp3 + CD4 + Tregs in a nonlethal murine model of pulmonary viral infection by the use of the prototypical respiratory virus influenza A. We establish that influenza A virus infection results in a robust Foxp3 + CD4 + T cell response and that regulatory T cell induction at the site of inflammation precedes the effector T cell response. Induced Foxp3 + CD4 + T cells are highly suppressive ex vivo , demonstrating that influenza virus-induced Foxp3 + CD4 + T cells are phenotypically regulatory. Influenza A virus-induced regulatory T cells proliferate vigorously in response to influenza virus antigen, are disseminated throughout the site of infection and primary and secondary lymphoid organs, and retain Foxp3 expression in vitro , suggesting that acute viral infection is capable of inducing a foreign-antigen-specific Treg response. The ability of influenza virus-induced regulatory T cells to suppress antigen-specific CD4 + and CD8 + T cell proliferation and cytokine production correlates closely to their ability to respond to influenza virus antigens, suggesting that virus-induced Tregs are capable of attenuating effector responses in an antigen-dependent manner. Collectively, these data demonstrate that primary acute viral infection is capable of inducing a robust, antigen-responsive, and suppressive regulatory T cell response.

Airway epithelium functions not only as a physical barrier, but also a regulator of lung inflammation. IFN-γ plays a critical role in airway inflammation associated with respiratory viral infection. We investigated differential protein profiling in IFN-γ-stimulated normal human bronchial epithelial cells (HBEC) using a 2-dimensional gel electrophoresis followed by MALDI-TOF-MS/MS. IFN-γ markedly stimulated apolipoprotein L2 (ApoL2) protein expression in normal HBEC. ApoL2 mRNA expression was also elevated in normal human lung fibroblasts and smooth muscle cells stimulated with IFN-γ, in lung tissues from an IFN-γ-predominant influenza A virus-infected mouse lung injury model, and in cancer lung tissues from human patients. Normal HBEC showed strong resistance to IFN-γ-induced cytotoxicity. ApoL2 knockdown by siRNA promoted IFN-γ-induced cytotoxicity as revealed by a significant drop in cell viability using MTT and CyQUANT NF cell proliferation assays, and a marked increase in hypodiploid sub-G1 cell population in cell cycle analysis. Furthermore, depletion of ApoL2 facilitated IFN-γ-induced membrane damage and chromatin condensation as observed in Hoechst and propidium iodide-double staining and in transmission electron microscopy, and DNA fragmentation using a DNA laddering assay, in a caspase-dependent manner. Our results reveal a novel function for ApoL2 in conferring anti-apoptotic ability of human bronchial epithelium to the cytotoxic effects of IFN-γ, in maintaining airway epithelial layer integrity. J. Cell. Physiol. 226: 397–406, 2011. © 2010 Wiley-Liss, Inc.

While it is well established that CD4 + T lymphocytes play a crucial role in the initiation, progression and persistence of asthma, the role of CD8 + T cells is less understood. CD8 + T cells form functionally similar subsets which exhibit similar cytokine profiles as Th1 and Th2 cells, known as Tc1 and Tc2. Evidence from animal studies suggest that CD8 + T cells are capable of regulating IgE production through the induction of IL-12 and IL-18 production in dendritic cells, and that CD8 + T cells may act to moderate Th2 polarisation within the localised lymph nodes during allergic sensitisation. Such findings have led to the suggestion that Th1 polarising, CD8 + T cell-inducing vaccines would inhibit the development of airway hyperresponsiveness (AHR) and Th2 cell infiltration. Despite these positive findings, the role of CD8 + T cells within the lung remains poorly understood. While CD8 + T cells, particularly those expressing the Tc1 phenotype, are capable of moderating inflammation and suppressing AHR, it has been postulated that Tc2 CD8 + T cells predominate within established asthma and may act to amplify the inappropriate immune response which defines the condition. Within the clinic, the association between CD8 + T cells and asthma is almost universally defined as injurious, further suggesting a prejudicial role for these cells within the established disease. CD8 + T cells may be a valuable potential target for therapeutic intervention, either by potentiating their regulatory effects prior to the development of sensitisation, or through suppressing their pro-inflammatory properties within established atopy.

Al Qaeda's surprise attacks on the World Trade Center and the Pentagon were the U.S.'s second Pearl Harbor. The shocks jolted Americans out of the complacency about national security that they had enjoyed during the dozen years after the Cold War and launched them into a worldwide war against terrorists. When this shock was followed by the failure to find weapons of mass destruction (WMD) after the invasion of Iraq, recriminations over intelligence failure provoked the most radical reorganization of the intelli gence system since the post-Pearl Harbor National Security Act. In one case, the intelligence community failed to provide enough warning; in the other, it failed by providing too much. The discussions that follow are not complete case studies of the two failures; lengthy examinations are available in definitive official investigations, as well as in the memoirs of the Director of Central Intelligence (DCI), George Tenet.1

There he goes again! John Mueller has made a career of debunking conventional wisdom on a variety of topics with arguments that strike most people at first as ridiculous. For example, he has expoun...

What are the likely trends in the use of force in world politics in the coming 15 years, and how will they relate to U.S. national security policy? Most places in which the United States enters combat will be ones that planners do not now anticipate, because when and where force is used will depend on local crises that the United States cannot control in advance, accumulated lessons from experience, and the particular administration in power in Washington at the time. Limited humanitarian interventions will be frequent, but more often undertaken by other countries than by American forces. Unconventional American counterterror operations will be frequent, since Al Qaeda is unlikely to be neutralized soon. Inter-state conventional wars will be rare, especially since the United States is much more constrained from attacking remaining “rogue” states because of the bad results of the invasion of Iraq and the more complicated political and diplomatic obstacles in regard to Iran and North Korea. Use of ...

The United States persists in aggressively exploiting primacy because the policy has been popular across the domestic political spectrum and is tolerated abroad despite unhappiness with it. Objections prove to be much more about style than substance. Although Democrats in the US criticize Bush for unilateralism, they seldom make the alternative of multilateralism a precondition for American action. When Washington genuflects to principles of multilateral consultation, allied governments allow themselves to be pulled along on US initiatives. Differences between the Bush and Kerry views of the American role in the world have been less than meets the eye. Only a significant disaster-such as the total unravelling of the project in Iraq-is likely to turn either party away from the urge to control the development of world order.

Strategy is the essential ingredient for making war either politically effective or morally tenable. It is the link between military means and political ends, the scheme for how to make one produce the other. Without strategy, there is no rationale for how force will achieve purposes worth the price in blood and treasure. Without strategy, power is a loose cannon and war is mindless. Mindless killing can only be criminal. Politicians and soldiers may debate which strategic choice is best, but only paciasts can doubt that strategy is necessary. Because strategy is necessary, however, does not mean that it is possible. Those who experience or study many wars and strong reasons to doubt that strategists can know enough about causes, effects, and intervening variables to make the operations planned produce the outcomes desired. To skeptics, effective strategy is often an illusion because what happens in the gap between policy objectives and war outcomes is too complex and unpredictable to be manipulated to a speciaed end. When this is true, war cannot be a legitimate instrument of policy. This article surveys ten critiques that throw the practicability of strategy into question. It pulls together many arguments that emerge in bits and pieces from a variety of sources. Some are my own formulation of skepticism implicit but unformed in others’ observations; few analysts have yet attacked the general viability of strategy head-on. The notion that effective strategy must be an illusion emerges cumulatively from arguments that: strategies cannot be evaluated because there are no agreed criteria for which are good or bad; there is little demonstrable relationship between strategies and outcomes in war; good strategies can seldom be formulated because of policymakers’ biases; if good strategies are formulated, they cannot be executed because of organizations’ limitations; and other points explored below. Unifying themes include the bar

Political science attends to causes and consequences of war but only fitfully welcomes study of its conduct, because few grasp how much the dynamics of combat shape politics. Bernard Brodie called for development of strategic studies on the model of the discipline of economics, because neither the military nor academia treated the subject rigorously. His call was answered in the early cold war, with mixed results. Theories about nuclear deterrence burgeoned while empirical studies of war lagged. The late—cold war impasse in nuclear strategy, rooted in NATO doctrine, shifted attention to conventional military operations and empirically grounded theory. Since the cold war, research on general theoretical questions about war and peace has been prospering, but education in military matters has been eroding. Interdisciplinary strategic studies integrate political and military elements of international conflict, but there is no recognized discipline of military science; military analysis is smuggled into political science and history departments, where it is resisted by calls to conceptualize security broadly or focus on purely theoretical work. If serious military studies are squeezed out of universities, there will be no qualified civilian analysts to provide independent expertise in policy and budget debates, and decisions on war and peace will be made irresponsibly by uninformed civilians or by the professional military alone.

Most major wars since 1939 have begun with surprise attacks. Hindsight reveals that the element of surprise in most of these attacks was unwarranted; substantial evidence of an impending strike was available to the victims before the fact. The high incidence of surprise is itself surprising. The voluminous literature on strategic surprise, however, suffers from three fixations. One is a focus on the problem of warning, and how to improve intelligence collection, rather than on the more difficult problem of how to improve political response to ample warning indicators. Another is a common view of surprise as an absolute or dichotomous problem rather than as a matter of degree. Third is the prevalent derivation of theories from single cases rather than from comparative studies. This article puts these fixations in perspective.1

List of Contributors Foreword Bill McGuire and Mark Maslin Chapter 1: Hazardous responses of the solid Earth to a changing climate Bill McGuire Chapter 2: Future climate changes in the context of geological and geomorphological hazards Felicity Liggins, Richard Betts and Bill McGuire Chapter 3: Climate change and collapsing volcanoes: evidence from Mount Etna, Sicily Kim Deeming, Bill McGuire and Paul Harrop Chapter 4: Melting ice and volcanic hazards in the twenty-first century Hugh Tuffen Chapter 5: Multiple effects of ice load changes and associated stress change on magmatic systems Freysteinn Sigmundsson and others Chapter 6: Response of faults to climate-driven changes in ice and water volumes at the surface of the Earth Andrea Hampel, Ralf Hetzel and Georgios Maniatis Chapter 7: Does the El-Nino Southern Oscillation and influence earthquake activity in the eastern tropical Pacific? Serge Guillas, Simon Day and Bill McGuire Chapter 8: Submarine landslides and tsunamis in a changing climate Dave Tappin Chapter 9: Heat waves and slope stability in high mountain terrain Christian Huggel and others Chapter 10: Impacts of recent and future climate change on natural hazards in the European Alps Jasper Knight, Margreth Keiler and Stephan Harrison Chapter 11: Assessing the past and future stability of global gas hydrate reservoirs Mark Maslin, Matthew Owen, Richard Betts, Simon Day, Tom Dunkley Jones and Andrew Ridgwell Chapter 12: Methane hydrate instability: a view from the Palaeogene Tom Dunkley Jones, Andrew Ridgwell, D. J. Lunt, Mark Maslin, D. N. Schmidt and Paul Valdez Index

Proteinase-activated receptor 2 (PAR 2 ) is widely expressed in the respiratory tract and is an integral component of the host antimicrobial defense system. The principal aim of this study was to investigate the influence of a PAR 2 -activating peptide, SLIGRL, on influenza A virus (IAV)-induced pathogenesis in mice. Intranasal inoculation of BALB/c mice with influenza A/PR/8/34 virus caused time-dependent increases in the number of pulmonary leukocytes (recovered from bronchoalveolar lavage fluid), marked airway histopathology characterized by extensive epithelial cell damage, airway hyper-responsiveness to the bronchoconstrictor methacholine, and elevated levels of inflammatory chemokines (keratinocyte-derived chemokine and macrophage inflammatory protein 2) and cytokines (interferon-γ). It is noteworthy that these IAV-induced effects were dose-dependently attenuated in mice treated with a PAR 2 -activating peptide, SLIGRL, at the time of IAV inoculation. However, SLIGRL also inhibited IAV-induced increases in pulmonary leukocytes in PAR 2 -deficient mice, indicating these antiviral actions were not mediated by PAR 2 . The potency order obtained for a series of structural analogs of SLIGRL for anti-IAV activity (IGRL > SLIGRL > LSIGRL >2-furoyl-LIGRL) was also inconsistent with a PAR 2 -mediated effect. In further mechanistic studies, SLIGRL inhibited IAV-induced propagation in ex vivo perfused segments of trachea from wild-type or PAR 2 (−/−) mice, but did not inhibit viral attachment or replication in Madin-Darby canine kidney cells and chorioallantoic membrane cells, which are established hosts for IAV. In summary, SLIGRL protected mice from IAV infection independently of PAR 2 and independently of direct inhibition of IAV attachment or replication, potentially through the activation of endogenous antiviral pathways within the mouse respiratory tract.