Inflammatory cytokines and biofilm production sustain Staphylococcus aureus outgrowth and persistence: A pivotal interplay in the pathogenesis of Atopic Dermatitis

Individuals with Atopic dermatitis (AD) are highly susceptible to Staphylococcus aureus colonization. However, the mechanisms driving this process as well as the impact of S. aureus in AD pathogenesis are still incompletely understood. In this study, we analysed the role of biofilm in sustaining S. aureus chronic persistence and its impact on AD severity. Further we explored whether key inflammatory cytokines overexpressed in AD might provide a selective advantage to S. aureus. Results show that the strength of biofilm production by S. aureus correlated with the severity of the skin lesion, being significantly higher (P < 0.01) in patients with a more severe form of the disease as compared to those individuals with mild AD. Additionally, interleukin (IL)-β and interferon γ (IFN-γ), but not interleukin (IL)-6, induced a concentration-dependent increase of S. aureus growth. This effect was not observed with coagulase-negative staphylococci isolated from the skin of AD patients. These findings indicate that inflammatory cytokines such as IL1-β and IFN-γ, can selectively promote S. aureus outgrowth, thus subverting the composition of the healthy skin microbiome. Moreover, biofilm production by S. aureus plays a relevant role in further supporting chronic colonization and disease severity, while providing an increased tolerance to antimicrobials

The contradictory effect of the methoxy-substituent in palladium-catalyzed ethylene/methyl acrylate cooligomerization

Two new nonsymmetric bis(aryl-imino)acenaphthene ligands (Ar,Ar'-BIAN) and one symmetric Ar2-BIAN were studied. The three ligands share the presence of at least one methoxy group on one of the two aryl rings. These ligands were used for the synthesis of neutral and monocationic palladium(II) complexes of general formula [Pd(CH3)Cl(N-N)] and [Pd(CH3)(L)(N-N)][PF6] (N-N = Ar,Ar'-BIAN, Ar2-BIAN; L = CH3CN, dmso). Due to the nonsymmetric nature of the ligands and their coordination to palladium in a nonsymmetric chemical environment, cis and trans isomers are possible for the three series of complexes with Ar,Ar'-BIANs. Both a detailed NMR investigation in solution and the X-ray characterization in solid state point out that the trans isomer is the preferred species for the neutral derivatives, whereas for the cationic compounds a decrease in the stereoselectivity of the coordination is observed. One of the new Ar,Ar'-BIANs differs from an already reported nonsymmetric \uf061-diimine for the replacement, on one aryl ring, of a methyl group with a methoxy susbtituent, thus allowing a comparison of the structural features of the relevant complexes. The monocationic complexes were tested as precatalysts for the ethylene/methyl acrylate copolymerization under mild reaction conditions. Despite the structural similarities observed in solution with the already known precatalysts, the present compounds demonstrated a remarkable decrease in the productivity values associated to a higher affinity for the polar monomer

Integration of an Innovative Atmospheric Forecasting Simulator and Remote Sensing Data into a Geographical Information System in the Frame of Agriculture 4.0 Concept

In a world in continuous evolution and in which human needs grow exponentially according to the increasing world population, the advent of new technologies plays a fundamental role in all fields of industry, especially in agriculture. Optimizing times, automating machines, and guaranteeing product quality are key objectives in the field of Agriculture 4.0, which integrates various innovative technologies to meet the needs of producers and consumers while guaranteeing respect for the environment and the planet's resources. In this context, our research aims to propose an integrated system using data coming from an innovative experimental atmospheric and forecasting simulator (capable of predicting some characteristic climate variables subsequently validated with local sensors), combined with indices deriving from Remote Sensing and UAV images (treated with the data fusion method), that can give fundamental information related to Agriculture 4.0 with particular reference to the subsequent phases of system automation. These data, in fact, can be collected in an open-source GIS capable of displaying areas that need irrigation and fertilization and, moreover, establishing the path of an automated drone for the monitoring of the crops and the route of a self-driving tractor for the irrigation of the areas of interest

Adaptive plasticity of killifish (Fundulus heteroclitus) embryos: dehydration-stimulated development and differential aquaporin-3 expression

13 pages, 7 figures, 3 tablesEmbryos of the marine killifish Fundulus heteroclitus are adapted to survive aerially. However, it is unknown if they are able to control development under dehydration conditions. Here, we show that air-exposed blastula embryos under saturated relative humidity were able to stimulate development, and hence the time of hatching was advanced with respect to embryos continuously immersed in seawater. Embryos exposed to air at later developmental stages did not hatch until water was added, while development was not arrested. Air-exposed embryos avoided dehydration probably because of their thickened egg envelope, although it suffered significant evaporative water loss. The potential role of aquaporins as part of the embryo response to dehydration was investigated by cloning the aquaporin-0 (FhAqp0), -1a (FhAqp1a), and -3 (FhAqp3) cDNAs. Functional expression in Xenopus laevis oocytes showed that FhaAqp1a was a water-selective channel, whereas FhAqp3 was permeable to water, glycerol, and urea. Expression of fhaqp0 and fhaqp1a was prominent during organogenesis, and their mRNA levels were similar between water- and air-incubated embryos. However, fhaqp3 transcripts were highly and transiently accumulated during gastrulation, and the protein product was localized in the basolateral membrane of the enveloping epithelial cell layer and in the membrane of ingressing and migrating blastomers. Interestingly, both fhaqp3 transcripts and FhAqp3 polypeptides were downregulated in air-exposed embryos. These data demonstrate that killifish embryos respond adaptively to environmental desiccation by accelerating development and that embryos are able to transduce dehydration conditions into molecular responses. The reduced synthesis of FhAqp3 may be one of these mechanisms to regulate water and/or solute transport in the embryo.This study was supported by the European Commission New and Emerging Science and Technologies (NEST) program (contract no. 012674-2 Sleeping Beauty) and by a grant from the Spanish Ministry of Education and Science (MEC; AGL2004-00316/ACU) to J. Cerda`. Participation of C. Zapater and F. Chauvigne´ was financed by a predoctoral fellowship from MEC (Spain) and by the European Commission [Marie Curie Research Training Network Aqua (glycero)porins, MRTN-CT-2006-035995], respectively.Peer reviewe

A Novel murine model identifies cooperating mutations and therapeutic targets critical for chronic myeloid leukemia progression

The introduction of highly selective ABL-tyrosine kinase inhibitors (TKIs) has revolutionized therapy for chronic myeloid leukemia (CML). However, TKIs are only efficacious in the chronic phase of the disease and effective therapies for TKI-refractory CML, or after progression to blast crisis (BC), are lacking. Whereas the chronic phase of CML is dependent on BCR-ABL, additional mutations are required for progression to BC. However, the identity of these mutations and the pathways they affect are poorly understood, hampering our ability to identify therapeutic targets and improve outcomes. Here, we describe a novel mouse model that allows identification of mechanisms of BC progression in an unbiased and tractable manner, using transposon-based insertional mutagenesis on the background of chronic phase CML. Our BC model is the first to faithfully recapitulate the phenotype, cellular and molecular biology of human CML progression. We report a heterogeneous and unique pattern of insertions identifying known and novel candidate genes and demonstrate that these pathways drive disease progression and provide potential targets for novel therapeutic strategies. Our model greatly informs the biology of CML progression and provides a potent resource for the development of candidate therapies to improve the dismal outcomes in this highly aggressive disease.Work in the Huntly laboratory is funded by CRUK, The European Research Council (ERC), Leukaemia Lymphoma Research, the Kay Kendall Leukaemia Fund, Wellcome Trust, the Medical Research Council (UK), the Leukemia Lymphoma Society America and the Cambridge NIHR Biomedical Research centre. David Adams is funded by Cancer Research UK and Wellcome Trust. Steffen Koschmieder has received funding from Deutsche José Carreras Leukämie-Stiftung (DJCLS; grant 10/23).This is the final published version. It first appeared at http://dx.doi.org/10.1084/jem.2014166

Covariant Giant Gaussian Process Models With Improved Reproduction of Palaeosecular Variation

A commonly used family of statistical magnetic field models is based on a giant Gaussian process (GGP), which assumes each Gauss coefficient can be realized from an independent normal distribution. GGP models are capable of generating suites of plausible Gauss coefficients, allowing for palaeomagnetic data to be tested against the expected distribution arising from a time‐averaged geomagnetic field. However, existing GGP models do not simultaneously reproduce the distribution of field strength and palaeosecular variation estimates reported for the past 10 million years and tend to underpredict virtual geomagnetic pole (VGP) dispersion at high latitudes unless trade‐offs are made to the fit at lower latitudes. Here we introduce a new family of GGP models, BB18 and BB18.Z3 (the latter includes non‐zero‐mean zonal terms for spherical harmonic degrees 2 and 3). Our models are distinct from prior GGP models by simultaneously treating the axial dipole variance separately from higher degree terms, applying an odd‐even variance structure, and incorporating a covariance between certain Gauss coefficients. Covariance between Gauss coefficients, a property both expected from dynamo theory and observed in numerical dynamo simulations, has not previously been included in GGP models. Introducing covariance between certain Gauss coefficients inferred from an ensemble of “Earth‐like” dynamo simulations and predicted by theory yields a reduced misfit to VGP dispersion, allowing for GGP models which generate improved reproductions of the distribution of field strengths and palaeosecular variation observed for the last 10 million years

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Critical Illness-Related Corticosteroid Insufficiency (CIRCI): A Narrative Review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM)

Objective: To provide a narrative review of the latest concepts and understanding of the pathophysiology of critical illness-related corticosteroid insufficiency (CIRCI). Participants: A multi-specialty task force of international experts in critical care medicine and endocrinology and members of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Data Sources: Medline, Database of Abstracts of Reviews of Effects (DARE), Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Database of Systematic Reviews. Results: Three major pathophysiologic events were considered to constitute CIRCI: dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, altered cortisol metabolism, and tissue resistance to glucocorticoids. The dysregulation of the HPA axis is complex, involving multidirectional crosstalk between the CRH/ACTH pathways, autonomic nervous system, vasopressinergic system, and immune system. Recent studies have demonstrated that plasma clearance of cortisol is markedly reduced during critical illness, explained by suppressed expression and activity of the primary cortisol-metabolizing enzymes in the liver and kidney. Despite the elevated cortisol levels during critical illness, tissue resistance to glucocorticoids is believed to occur due to insufficient glucocorticoid alpha-mediated anti-inflammatory activity. Conclusions: Novel insights into the pathophysiology of CIRCI add to the limitations of the current diagnostic tools to identify at-risk patients and may also impact how corticosteroids are used in patients with CIRCI