Assessment of the status, development and diversification of fisheries-dependent communities: Urk Case Study Report

This case study about Urk shows which social and economic challenges this traditional fishing community faces due to its specialization on just a few stocks, the increasing independence of a processing sector no longer reliant on it to supply locally caught fish, and culturally preferences in the way of life and ways of doing things, and the additional hardship of limited TACs, forced decommissioning, low stock prices, and high fixed costs (fuel costs)

1,25(OH)2VitD3 supplementation enhances suppression of grass pollen-induced allergic asthma by subcutaneous and sublingual immunotherapy in a mouse model

Allergen specific immunotherapy (AIT) can provide long-term alleviation of symptoms for allergic disease but is hampered by suboptimal efficiency. We and others have previously shown that 1,25(OH)2-VitaminD3 (VitD3) can improve therapeutic efficacy of AIT. However, it is unknown whether VitD3 supplementation has similar effects in sublingual and subcutaneous immunotherapy. Therefore, we aimed to test VitD3 supplementation in both grass pollen (GP) subcutaneous-IT (SCIT) and sublingual-IT (SLIT) in a mouse model for allergic airway inflammation. To this end, GP-sensitized BALB/c mice received GP-SCIT or GP-SLIT with or without 10 ng VitD3, followed by intranasal GP challenges and measurement of airway hyperresponsiveness (AHR) and inflammation. VitD3 supplementation of GP-SCIT resulted in enhanced induction of GP-specific (sp)-IgG2a and suppression of spIgE after challenge. In addition, eosinophil numbers were reduced and levels of IL10 and Amphiregulin were increased in lung tissue. In GP-SLIT, VitD3 supplementation resulted in enhanced sp-IgG2a levels in serum, enhanced suppression of eosinophils and increased IL10 levels in lung tissue, as well as suppression of AHR to methacholine. These data show that VitD3 increases efficacy of both SCIT and SLIT, by enhancing induction of blocking antibodies and suppression of airway inflammation, underscoring the relevance of proficient VitD3 levels for successful AIT

High dose vitamin D3 empowers effects of subcutaneous immunotherapy in a grass pollen-driven mouse model of asthma

Allergen-specific immunotherapy (AIT) has the potential to provide long-term protection against allergic diseases. However, efficacy of AIT is suboptimal, while application of high doses allergen has safety concerns. The use of adjuvants, like 1,25(OH)2VitD3 (VitD3), can improve efficacy of AIT. We have previously shown that low dose VitD3 can enhance suppression of airway inflammation, but not airway hyperresponsiveness in a grass pollen (GP)-subcutaneous immunotherapy (SCIT) mouse model of allergic asthma. We here aim to determine the optimal dose and formulation of VitD3 for the GP SCIT. GP-sensitized BALBc/ByJ mice received three SCIT injections of VitD3-GP (30, 100, and 300 ng or placebo). Separately, synthetic lipids, SAINT, was added to the VitD3-GP-SCIT formulation (300 nmol) and control groups. Subsequently, mice were challenged with intranasal GP, and airway hyperresponsiveness, GP-specific IgE, -IgG1, and -IgG2a, ear-swelling responses (ESR), eosinophils in broncho-alveolar lavage fluid and lung were measured. VitD3 supplementation of GP-SCIT dose-dependently induced significantly enhanced suppression of spIgE, inflammation and hyperresponsiveness, while neutralizing capacity was improved and ESR were reduced. Addition of VitD3 further decreased Th2 cytokine responses and innate cytokines to allergens in lung tissue by GP-SCIT. However, addition of synthetic lipids to the allergen/VitD3 mixes had no additional effect on VitD3-GP-SCIT. We find a clear, dose dependent effect of VitD3 on GP-SCIT-mediated suppression of allergic inflammation and airway hyperresponsiveness. In contrast, addition of synthetic lipids to the allergen/VitD3 mix had no therapeutic effect. These studies underscore the relevance of VitD3 as an adjuvant to improve clinical efficacy of SCIT treatment regimens

Climate model boundary conditions for four Cretaceous time slices

International audienceGeneral circulation models (GCMs) are useful tools for investigating the characteristics and dynamics of past climates. Understanding of past climates contributes significantly to our overall understanding of Earth's climate system. One of the most time consuming, and often daunting, tasks facing the paleoclimate modeler, particularly those without a geological background, is the production of surface boundary conditions for past time periods. These boundary conditions consist of, at a minimum, continental configurations derived from plate tectonic modeling, topography, bathymetry, and a vegetation distribution. Typically, each researcher develops a unique set of boundary conditions for use in their simulations. Thus, unlike simulations of modern climate, basic assumptions in paleo surface boundary conditions can vary from researcher to researcher. This makes comparisons between results from multiple researchers difficult and, thus, hinders the integration of studies across the broader community. Unless special changes to surface conditions are warranted, researcher dependent boundary conditions are not the most efficient way to proceed in paleoclimate investigations. Here we present surface boundary conditions (land-sea distribution, paleotopography, paleobathymetry, and paleovegetation distribution) for four Cretaceous time slices (120 Ma, 110 Ma, 90 Ma, and 70 Ma). These boundary conditions are modified from base datasets to be appropriate for incorporation into numerical studies of Earth's climate and are available in NetCDF format upon request from the lead author. The land-sea distribution, bathymetry, and topography are based on the 1°×1° (latitude × longitude) paleo Digital Elevation Models (paleoDEMs) of Christopher Scotese. Those paleoDEMs were adjusted using the paleogeographical reconstructions of Ronald Blakey (Northern Arizona University) and published literature and were then modified for use in GCMs. The paleovegetation distribution is based on published data and reconstructions and consultation with members of the paleobotanical community and is represented as generalized biomes that should be easily translatable to many vegetation-modeling schemes

Haptic Shared Control in Tele-Manipulation: Effects of Inaccuracies in Guidance on Task Execution

Haptic shared control is a promising approach to improve tele-manipulated task execution, by making safe and effective control actions tangible through guidance forces. In current research, these guidance forces are most often generated based on pre-generated, errorless models of the remote environment. Hence such guidance forces are exempt from the inaccuracies that can be expected in practical implementations. The goal of this research is to quantify the extent to which task execution is degraded by inaccuracies in the model on which haptic guidance forces are based. In a human-in-the-loop experiment, subjects (n = 14) performed a realistic tele-manipulated assembly task in a virtual environment. Operators were provided with various levels of haptic guidance, namely no haptic guidance (conventional tele-manipulation), haptic guidance without inaccuracies, and haptic guidance with translational inaccuracies (one large inaccuracy, in the order of magnitude of the task, and a second smaller inaccuracy). The quality of natural haptic feedback (i.e., haptic transparency) was varied between high and low to identify the operator\u27s ability to detect and cope with inaccuracies in haptic guidance. The results indicate that haptic guidance is beneficial for task execution when no inaccuracies are present in the guidance. When inaccuracies are present, this may degrade task execution, depending on the magnitude and the direction of the inaccuracy. The effect of inaccuracies on overall task performance is dominated by effects found for the Constrained Translational Movement, due to its potential for jamming. No evidence was found that a higher quality of haptic transparency helps operators to detect and cope with inaccuracies in the haptic guidance.</p

A trifunctional linker for palmitoylation and peptide and protein localization in biological membranes

Attachment of lipophilic groups is an important post-translational modification of proteins, which involves the coupling of one or more anchors such as fatty acids, isoprenoids, phospholipids, or glycosylphosphatidyl inositols. To study its impact on the membrane partitioning of hydrophobic peptides or proteins, we designed a tyrosine-based trifunctional linker. The linker allows the facile incorporation of two different functionalities at a cysteine residue in a single step. We determined the effect of the lipid modification on the membrane partitioning of the synthetic α-helical model peptide WALP with or without here and in all cases below; palmitoyl groups in giant unilamellar vesicles that contain a liquid-ordered (Lo) and liquid-disordered (Ld) phase. Introduction of two palmitoyl groups did not alter the localization of the membrane peptides, nor did the membrane thickness or lipid composition. In all cases, the peptide was retained in the Ld phase. These data demonstrate that the Lo domain in model membranes is highly unfavorable for a single membrane-spanning peptide

Mitochondrial dysfunction increases pro-inflammatory cytokine production and impairs repair and corticosteroid responsiveness in lung epithelium

COPD is characterized by chronic lung inflammation and irreversible lung tissue damage. Inhaled noxious gases, including cigarette smoke, are the major risk factor for COPD. Inhaled smoke first encounters the epithelial lining of the lungs, causing oxidative stress and mitochondrial dysfunction. We investigated whether a mitochondrial defect may contribute to increased lung epithelial pro-inflammatory responses, impaired epithelial repair and reduced corticosteroid sensitivity as observed in COPD. We used wild-type alveolar epithelial cells A549 and mitochondrial DNA-depleted A549 cells (A549 Rho-0) and studied pro-inflammatory responses using (multiplex) ELISA as well as epithelial barrier function and repair (real-time impedance measurements), in the presence and absence of the inhaled corticosteroid budesonide. We observed that A549 Rho-0 cells secrete higher levels of pro-inflammatory cytokines than wild-type A549 cells and display impaired repair upon wounding. Budesonide strongly suppressed the production of neutrophil attractant CXCL8, and promoted epithelial integrity in A549 wild-type cells, while A549 Rho-0 cells displayed reduced corticosteroid sensitivity compared to wild-type cells. The reduced corticosteroid responsiveness may be mediated by glycolytic reprogramming, specifically glycolysis-associated PI3K signaling, as PI3K inhibitor LY294002 restored the sensitivity of CXCL8 secretion to corticosteroids in A549 Rho-0 cells. In conclusion, mitochondrial defects may lead to increased lung epithelial pro-inflammatory responses, reduced epithelial repair and reduced corticosteroid responsiveness in lung epithelium, thus potentially contributing to the pathogenesis of COPD

Preeclampsia is Associated with lower Percentages of Regulatory T Cells in Maternal Blood

Objective: Immunological mechanisms are involved in the pathophysiology of preeclampsia. During pregnancy there is an increase in regulatory T (Treg) cells, which has an important role in regulating tolerance to the immunologically distinct fetus. We hypothesised that percentages of Treg cells are decreased in preeclamptic patients. Methods: Peripheral blood was obtained from 26 healthy pregnant controls and 18 preeclamptic patients. Treg cells were measured using flow-cytometry. Results: Women with pregnancies complicated by preeclampsia had significantly lower percentages of CD4(+)FOXP3(+) Treg cells. Conclusion: We conclude that a deficiency of regulatory T cells may play a role in the pathophysiology of preeclampsia

Neutrophilic Asthma Is Associated With Smoking, High Numbers of IRF5+, and Low Numbers of IL10+ Macrophages

Asthma is a heterogenous disease with different inflammatory subgroups that differ in disease severity. This disease variation is hampering treatment and development of new treatment strategies. Macrophages may contribute to asthma phenotypes by their ability to activate in different ways, i.e., T helper cell 1 (Th1)-associated, Th2-associated, or anti-inflammatory activation. It is currently unknown if these different types of activation correspond with specific inflammatory subgroups of asthma. We hypothesized that eosinophilic asthma would be characterized by having Th2-associated macrophages, whereas neutrophilic asthma would have Th1-associated macrophages and both having few anti-inflammatory macrophages. We quantified macrophage subsets in bronchial biopsies of asthma patients using interferon regulatory factor 5 (IRF5)/CD68 for Th1-associated macrophages, CD206/CD68 for Th2-associated macrophages and interleukin 10 (IL10)/CD68 for anti-inflammatory macrophages. Macrophage subset percentages were investigated in subgroups of asthma as defined by unsupervised clustering using neutrophil/eosinophil counts in sputum and tissue and forced expiratory volume in 1 s (FEV1). Asthma patients clustered into four subgroups: mixed-eosinophilic/neutrophilic, paucigranulocytic, neutrophilic with normal FEV1, and neutrophilic with low FEV1, the latter group consisting mainly of smokers. No differences were found for CD206+ macrophages within asthma subgroups. In contrast, IRF5+ macrophages were significantly higher and IL10+ macrophages lower in neutrophilic asthmatics with low FEV1 as compared to those with neutrophilic asthma and normal FEV1 or mixed-eosinophilic asthma. This study shows that neutrophilic asthma with low FEV1 is associated with high numbers of IRF5+, and low numbers of IL10+ macrophages, which may be the result of combined effects of smoking and having asthma.</p

Incomplete Recovery of Pneumococcal CD4 T Cell Immunity after Initiation of Antiretroviral Therapy in HIV-Infected Malawian Adults

HIV-infected African adults are at a considerably increased risk of life-threatening invasive pneumococcal disease (IPD) which persists despite antiretroviral therapy (ART). Defects in naturally acquired pneumococcal-specific T-cell immunity have been identified in HIV-infected adults. We have therefore determined the extent and nature of pneumococcal antigen-specific immune recovery following ART. HIV-infected adults were followed up at 3, 6 and 12 months after initiating ART. Nasopharyngeal swabs were cultured to determine carriage rates. Pneumococcal-specific CD4 T-cell immunity was assessed by IFN-γ ELISpot, proliferation assay, CD154 expression and intracellular cytokine assay. S. pneumoniae colonization was detected in 27% (13/48) of HIV-infected patients prior to ART. The rates remained elevated after 12 months ART, 41% (16/39) (p = 0.17) and significantly higher than in HIV-uninfected individuals (HIVneg 14%(4/29); p = 0.0147). CD4+ T-cell proliferative responses to pneumococcal antigens increased significantly to levels comparable with HIV-negative individuals at 12 months ART (p = 0.0799). However, recovery of the pneumococcal-specific CD154 expression was incomplete (p = 0.0015) as were IFN-γ ELISpot responses (p = 0.0040) and polyfunctional CD4+ T-cell responses (TNF-α, IL-2 and IFN-γ expression) (p = 0.0040) to a pneumolysin-deficient mutant strain. Impaired control of pneumococcal colonisation and incomplete restoration of pneumococcal-specific immunity may explain the persistently higher risk of IPD amongst HIV-infected adults on ART. Whether vaccination and prolonged ART can overcome this immunological defect and reduce the high levels of pneumococcal colonisation requires further evaluation