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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.

Glycosaminoglycans (GAGs) are long, linear polysaccharides comprised of repeating disaccharide units with pleiotropic biological functions, with the non-sulfated GAG hyaluronic acid (HA), and sulfated GAGs dermatan sulfate, chondroitin sulfate, heparan sulfate, keratan sulfate, and to a lesser extent heparin all being expressed in skin. Their ability to regulate keratinocyte proliferation and differentiation, inflammatory processes and extracellular matrix composition and quality demonstrates their critical role in regulating skin physiology. Similarly, the water-binding properties of GAGs and structural qualities, particularly for HA, are crucial for maintaining proper skin form and hydration. The biological importance of GAGs, as well as extensive evidence that their properties and functions are altered in both chronological and extrinsic skin aging, makes them highly promising targets to improve cosmetic skin quality. Within the present review, we examine the cutaneous biological activity of GAGs alongside the protein complexes they form called proteoglycans and summarize the age-related changes of these molecules in skin. We also examine current topical interventional approaches to modulate GAGs for improved skin quality such as direct exogenous administration of GAGs, with a particular interest in strategies targeted at potentiating GAG levels in skin through either attenuating GAG degradation or increasing GAG production.

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.

Background Polycyclic aromatic hydrocarbons (PAHs) are of environmental and public health concerns and contribute to adverse skin attributes such as premature skin aging and pigmentary disorder. However, little information is available on the potential roles of chronic urban PAH pollutant exposure on the cutaneous microbiota. Given the roles of the skin microbiota have on healthy and undesirable skin phenotypes and the relationships between PAHs and skin properties, we hypothesize that exposure of PAHs may be associated with changes in the cutaneous microbiota. In this study, the skin microbiota of over two hundred Chinese individuals from two cities in China with varying exposure levels of PAHs were characterized by bacterial and fungal amplicon and shotgun metagenomics sequencing. Results Skin site and city were strong parameters in changing microbial communities and their assembly processes. Reductions of bacterial-fungal microbial network structural integrity and stability were associated with skin conditions (acne and dandruff). Multivariate analysis revealed associations between abundances of Propionibacterium and Malassezia with host properties and pollutant exposure levels. Shannon diversity increase was correlated to exposure levels of PAHs in a dose-dependent manner. Shotgun metagenomics analysis of samples (n = 32) from individuals of the lowest and highest exposure levels of PAHs further highlighted associations between the PAHs quantified and decrease in abundances of skin commensals and increase in oral bacteria. Functional analysis identified associations between levels of PAHs and abundance of microbial genes of metabolic and other pathways with potential importance in host-microbe interactions as well as degradation of aromatic compounds. Conclusions The results in this study demonstrated the changes in composition and functional capacities of the cutaneous microbiota associated with chronic exposure levels of PAHs. Findings from this study will aid the development of strategies to harness the microbiota in protecting the skin against pollutants.

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...