FAIRMODE: A FORUM FOR AIR QUALITY MODELLING IN EUROPE

FAIRMODE (Forum for AIR quality MODelling in Europe) is an air quality modelling network that was established as a joint initiative of the European Environment Agency (EEA) and European Commission’s Joint Research Centre (JRC). In a common effort EEA and JRC aim at responding to the requirements of the new Air Quality Directive, with particular focus on the introduction of modelling as a necessary tool for air quality assessment and air quality management. The main aim of the modelling network is to bring together air quality modellers and model users in order to promote and support harmonised use of modelling for the assessment of air quality by EU and EEA member countries. The network will thus encourage synergy – at a local, national and European level - through the development and implementation of a common infrastructure based on best practices for reporting and storing information relevant to air quality modelling. A major objective of the FAIRMODE initiative is to provide guidance to present and future air quality model users in EEA’s EIONET partnership network. FAIRMODE also aims to enhance awareness of model usefulness, reliability and accuracy through model validation and intercomparison exercises at a national or European level. The JRC has taken on a leading role in the co-ordination of the latter activities gaining from its experience in leading the “Eurodelta” and “CityDelta” intercomparison exercises. A centralised web portal has been created in support of FAIRMODE, which is currently being used for internal communication purposes of the network participants, but will also provide the means for exchange of relevant material and experiences between all interested modellers and model users. The initial activities of the network will be organised by two main Work Groups, focusing on the preparation of a Guidance Document for model use and on model QA/QC procedures (input data, other uncertainties) respectively. The progress of the preparation of these documents as well as of the rest of the regular activities of the network will be reviewed and discussed within the frame of annual Plenary meetings and Steering Committee meetings

A multimodal real-time MRI articulatory corpus of French for speech research

In this work we describe the creation of ArtSpeechMRIfr: a real-time as well as static magnetic resonance imaging (rtMRI, 3D MRI) database of the vocal tract. The database contains also processed data: denoised audio, its phonetically aligned annotation, articulatory contours, and vocal tract volume information , which provides a rich resource for speech research. The database is built on data from two male speakers of French. It covers a number of phonetic contexts in the controlled part, as well as spontaneous speech, 3D MRI scans of sustained vocalic articulations, and of the dental casts of the subjects. The corpus for rtMRI consists of 79 synthetic sentences constructed from a phonetized dictionary that makes possible to shorten the duration of acquisitions while keeping a very good coverage of the phonetic contexts which exist in French. The 3D MRI includes acquisitions for 12 French vowels and 10 consonants, each of which was pronounced in several vocalic contexts. Ar-ticulatory contours (tongue, jaw, epiglottis, larynx, velum, lips) as well as 3D volumes were manually drawn for a part of the images

A Framework for Integrated Assessment Modelling

“Air quality plans” according to Air Quality Directive 2008/50/EC Art. 23 are the strategic element to be developed, with the aim to reliably meet ambient air quality standards in a cost-effective way. This chapter provides a general framework to develop and assess such plans along the lines of the European Commission’s basic ideas to implement effective emission reduction measures at local, region, and national level. This methodological point of view also allows to analyse the existing integrated approaches

Modelling the dispersion of particle numbers in five European cities

We present an overview of the modelling of particle number concentrations (PNCs) in five major European cities, namely Helsinki, Oslo, London, Rotterdam, and Athens, in 2008. Novel emission inventories of particle numbers have been compiled both on urban and European scales. We used atmospheric dispersion modelling for PNCs in the five target cities and on a European scale, and evaluated the predicted results against available measured concentrations. In all the target cities, the concentrations of particle numbers (PNs) were mostly influenced by the emissions originating from local vehicular traffic. The influence of shipping and harbours was also significant for Helsinki, Oslo, Rotterdam, and Athens, but not for London. The influence of the aviation emissions in Athens was also notable. The regional background concentrations were clearly lower than the contributions originating from urban sources in Helsinki, Oslo, and Athens. The regional background was also lower than urban contributions in traffic environments in London, but higher or approximately equal to urban contributions in Rotterdam. It was numerically evaluated that the influence of coagulation and dry deposition on the predicted PNCs was substantial for the urban background in Oslo. The predicted and measured annual average PNCs in four cities agreed within approximatelyPeer reviewe

Leptin Stimulates Cellular Glycolysis Through a STAT3 Dependent Mechanism in Tilapia

We assessed if leptin, a cytokine hormone known to enhance energy expenditure by promoting lipid and carbohydrate catabolism in response to physiologic stress, might directly regulate cellular glycolysis. A transcriptomic analysis of prolactin cells in the tilapia (Oreochromis mossambicus) pituitary rostral pars distalis (RPD) revealed that recombinant leptin (rtLep) differentially regulates 1,995 genes, in vitro. Machine learning algorithms and clustering analyses show leptin influences numerous cellular gene networks including metabolism; protein processing, transport, and metabolism; cell cycle and the hypoxia response. Leptin stimulates transcript abundance of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (gapdh) in a covariate manner to the hypoxic stress gene network. Orthogonal tests confirm that rtLepA dose-dependently increases gapdh gene expression in the RPD along with transcript abundance of 6-phosphofructo-1-kinase (pfk1), the rate limiting glycolytic enzyme. Functional testing demonstrated that leptin stimulates PFK activity and glycolytic output, while Stattic (a STAT3 blocker) was sufficient to suppress these responses, indicating leptin stimulates glycolysis through a STAT3-dependent mechanism. Leptin also stimulated pfk1 gene expression and lactate production in primary hepatocyte incubations in a similar manner to those shown for the pituitary RPD. This work characterizes a critical metabolic action of leptin to directly stimulate glycolysis across tissue types in a teleost model system, and suggest that leptin may promote energy expenditure, in part, by stimulating glycolysis. These data in a teleost fish, suggest that one of leptin's ancient, highly-conserved functions among vertebrates may be stimulation of glycolysis to facilitate the energetic needs associated with various stressors

Quality standards for managing children and adolescents with bronchiectasis: an international consensus

The global burden of bronchiectasis in children and adolescents is being recognised increasingly. However, marked inequity exists between, and within, settings and countries for resources and standards of care afforded to children and adolescents with bronchiectasis compared with those with other chronic lung diseases. The European Respiratory Society (ERS) clinical practice guideline for the management of bronchiectasis in children and adolescents was published recently. Here we present an international consensus of quality standards of care for children and adolescents with bronchiectasis based upon this guideline. The panel used a standardised approach that included a Delphi process with 201 respondents from the parents and patients’ survey, and 299 physicians (across 54 countries) who care for children and adolescents with bronchiectasis. The seven quality standards of care statements developed by the panel address the current absence of quality standards for clinical care related to paediatric bronchiectasis. These internationally derived, clinician-, parent-and patient-informed, consensus-based quality standards statements can be used by parents and patients to access and advocate for quality care for their children and themselves, respectively. They can also be used by healthcare professionals to advocate for their patients, and by health services as a monitoring tool, to help optimise health outcomes.</p

GLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice

Dual agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPARɑ/ɣ) have beneficial effects on glucose and lipid metabolism in patients with type 2 diabetes, but their development was discontinued due to potential adverse effects. Here we report the design and preclinical evaluation of a molecule that covalently links the PPARɑ/ɣ dual-agonist tesaglitazar to a GLP-1 receptor agonist (GLP-1RA) to allow for GLP-1R-dependent cellular delivery of tesaglitazar. GLP-1RA/tesaglitazar does not differ from the pharmacokinetically matched GLP-1RA in GLP-1R signalling, but shows GLP-1R-dependent PPARɣ-retinoic acid receptor heterodimerization and enhanced improvements of body weight, food intake and glucose metabolism relative to the GLP-1RA or tesaglitazar alone in obese male mice. The conjugate fails to affect body weight and glucose metabolism in GLP-1R knockout mice and shows preserved effects in obese mice at subthreshold doses for the GLP-1RA and tesaglitazar. Liquid chromatography–mass spectrometry-based proteomics identified PPAR regulated proteins in the hypothalamus that are acutely upregulated by GLP-1RA/tesaglitazar. Our data show that GLP-1RA/tesaglitazar improves glucose control with superior efficacy to the GLP-1RA or tesaglitazar alone and suggest that this conjugate might hold therapeutic value to acutely treat hyperglycaemia and insulin resistance

A signalome screening approach in the autoinflammatory disease TNF Receptor Associated Periodic Syndrome (TRAPS) highlights the anti-inflammatory properties of drugs for repurposing

TNF Receptor Associated Periodic Syndrome (TRAPS) is an autoinflammatory disease caused by mutations in TNF Receptor 1 (TNFR1). Current therapies for TRAPS are limited and do not target the pro-inflammatory signalling pathways that are central to the disease mechanism. Our aim was to identify drugs for repurposing as anti-inflammatories based on their ability to down-regulate molecules associated with inflammatory signalling pathways that are activated in TRAPS. This was achieved using rigorously optimised, high through- put cell culture and reverse phase protein microarray systems to screen compounds for their effects on the TRAPS-associated inflammatory signalome. 1360 approved, publically available, pharmacologically active substances were investigated for their effects on 40 signalling molecules associated with pro-inflammatory signalling pathways that are constitutively upregulated in TRAPS. The drugs were screened at four ten-fold concentrations on cell lines expressing both wild-type (WT) TNFR1 and TRAPS-associated C33Y mutant TNFR1, or WT TNFR1 alone; signalling molecule levels were then determined in cell lysates by the reverse phase protein microarray. A novel mathematical methodology was developed to rank the compounds for their ability to reduce the expression of signalling molecules in the C33Y-TNFR1 transfectants towards the level seen in the WT-TNFR1 transfectants. Seven high-ranking drugs were selected and tested by RPPA for effects on the same 40 signalling molecules in lysates of peripheral blood mononuclear cells (PBMCs) from C33Y-TRAPS patients compared to PBMCs from normal controls. The fluoroquinolone antibiotic lomefloxacin, as well as others from this class of compounds, showed the most significant effects on multiple pro-inflammatory signalling pathways that are constitutively activated in TRAPS; lomefloxacin dose-dependently significantly reduced expression of 7/40 signalling molecules across the Jak/Stat, MAPK, NF-kB and PI3K/AKT pathways. This study demonstrates the power of signalome screening for identifying candidates for drug repurposing

Cystic Fibrosis, Atopy, Asthma and ABPA

The role of atopy on cystic fibrosis (CF) progression remains unclear but evidence suggests that it may influence the appearance of co-morbid conditions such as CF asthma or allergic bronchopulmonary aspergillosis (ABPA). Recognising asthma in patients with CF is not always easy but the identification of atopic markers favours the diagnosis. Physicians should be aware of this fact in order to achieve a better control of respiratory symptoms in patients with CF. Bronchial mucosa inflammation and abnormal mucus predispose to mould colonisation. These patients are at higher risk of allergic sensitisation, especially when atopic susceptibility is present. In the particular case of A. fumigatus, allergic sensitisation precedes ABPA development, which occurs in up to 10% of CF patients. Progression of lung function deterioration is most strikingly pronounced in patients with ABPA. Therefore, sensitisation with A. fumigatus should be regularly tested in patients with CF, especially those at higher risk. Recombinant allergens constitute an important advance in differentiating Aspergillus sensitisation from ABPA itself

Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy

The mammalian target of rapamycin (mTOR) is an intracellular serine/threonine protein kinase positioned at a central point in a variety of cellular signaling cascades. The established involvement of mTOR activity in the cellular processes that contribute to the development and progression of cancer has identified mTOR as a major link in tumorigenesis. Consequently, inhibitors of mTOR, including temsirolimus, everolimus, and ridaforolimus (formerly deforolimus) have been developed and assessed for their safety and efficacy in patients with cancer. Temsirolimus is an intravenously administered agent approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for the treatment of advanced renal cell carcinoma (RCC). Everolimus is an oral agent that has recently obtained US FDA and EMEA approval for the treatment of advanced RCC after failure of treatment with sunitinib or sorafenib. Ridaforolimus is not yet approved for any indication. The use of mTOR inhibitors, either alone or in combination with other anticancer agents, has the potential to provide anticancer activity in numerous tumor types. Cancer types in which these agents are under evaluation include neuroendocrine tumors, breast cancer, leukemia, lymphoma, hepatocellular carcinoma, gastric cancer, pancreatic cancer, sarcoma, endometrial cancer, and non-small-cell lung cancer. The results of ongoing clinical trials with mTOR inhibitors, as single agents and in combination regimens, will better define their activity in cancer