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1. Models and methods for in vitro testing of hepatic gap junctional communication

Author: Michaël Maes, Mathieu Vinken, IVTD VUB, Joost Willebrords, Sara Crespo Yanguas, Pharmaceutical and Pharmacological Sciences, Connexin Signalling Research Group, Liver Connexin and Pannexin Research Group, and Experimental in vitro toxicology and dermato-cosmetology
Subjects: connexin, Cell signaling, Tumor Promoters, Connexin, Cell Communication, Biology, liver, Toxicology, Article, gap junction, Humans, Gap junction activity, Dimethyl Sulfoxide, Epigenetics, Cells, Cultured, nongenotoxic carcinogen, Liver cell, Gap junction, Gap Junctions, Hep G2 Cells, General Medicine, Coculture Techniques, In vitro, Cell biology, Intercellular communication, in vitro model, Hepatocytes
Abstract: Inherent to their pivotal roles in controlling all aspects of the liver cell life cycle, hepatocellular gap junctions are frequently disrupted upon impairment of the homeostatic balance, as occurs during liver toxicity. Hepatic gap junctions, which are mainly built up by connexin32, are specifically targeted by tumor promoters and epigenetic carcinogens. This renders inhibition of gap junction functionality a suitable indicator for the in vitro detection of nongenotoxic hepatocarcinogenicity. The establishment of a reliable liver gap junction inhibition assay for routine in vitro testing purposes requires a cellular system in which gap junctions are expressed at an in vivo-like level as well as an appropriate technique to probe gap junction activity. Both these models and methods are discussed in the current paper, thereby focusing on connexin32-based gap junctions.
Published: 2015
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2. Connexin and pannexin signaling in gastrointestinal and liver disease

Author: Michaël Maes, Mathieu Vinken, IVTD VUB, Joost Willebrords, Sara Crespo Yanguas, Bruno Cogliati, Toxicology, Dermato-cosmetology and Pharmacognosy, Pharmaceutical and Pharmacological Sciences, and Experimental in vitro toxicology and dermato-cosmetology
Subjects: Pathology, medicine.medical_specialty, Cirrhosis, Gastrointestinal Diseases, cellular communication, Connexin, Nerve Tissue Proteins, Biology, liver, Connexins, Article, DISEASE, Liver disease, Physiology (medical), Internal medicine, medicine, Animals, Humans, intestine, Hepatitis, Liver Diseases, Biochemistry (medical), Public Health, Environmental and Occupational Health, General Medicine, Hepatology, Pannexin, medicine.disease, JUNÇÕES INTERCELULARES, Gastritis, medicine.symptom, Liver cancer, stomach, Signal Transduction
Abstract: Gap junctions, which mediate intercellular communication, are key players in digestive homeostasis. They are also frequently involved in gastrointestinal and liver pathology. This equally holds true for connexin hemichannels, the structural precursors of gap junctions, and pannexin channels, connexin-like proteins assembled in a hemichannel configuration. Both connexin hemichannels and pannexin channels facilitate extracellular communication and drive a number of deteriorative processes, such as cell death and inflammation. Connexins, pannexins and their channels underlie a wide spectrum of gastrointestinal and liver diseases, including gastritis and peptic ulcer disease, inflammatory intestinal conditions, acute liver failure, cholestasis, hepatitis and steatosis, liver fibrosis and cirrhosis, infectious gastrointestinal pathologies, and gastrointestinal and liver cancer. This could open promising perspectives for the characterization of new targets and biomarkers for therapeutic and diagnostic clinical purposes in the area of gastroenterology and hepatology.
Published: 2015
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3. Roles of connexins and pannexins in digestive homeostasis

Author: Michaël Maes, Mathieu Vinken, IVTD VUB, Joost Willebrords, Sara Crespo Yanguas, Bruno Cogliati, Pharmaceutical and Pharmacological Sciences, Connexin Signalling Research Group, Liver Connexin and Pannexin Research Group, and Experimental in vitro toxicology and dermato-cosmetology
Subjects: connexin, Connexin, Cell Communication, Biology, Pannexin, Connexins, Article, Cellular and Molecular Neuroscience, Digestive System Physiological Phenomena, Extracellular, Animals, Homeostasis, Humans, Secretion, intestine, Molecular Biology, Pharmacology, Innate immune system, SISTEMA GASTROINTESTINAL, Gap junction, Gap Junctions, Cell Biology, Cell biology, physiology, Molecular Medicine, Gastric acid, Digestive System, stomach
Abstract: Connexin proteins are abundantly present in the digestive system. They primarily form gap junctions, which control the intercellular exchange of critical homeostasis regulators. By doing so, gap junctions drive a plethora of gastrointestinal and hepatic functional features, including gastric and gut motility, gastric acid secretion, intestinal innate immune defense, xenobiotic biotransformation, glycogenolysis, bile secretion, ammonia detoxification and plasma protein synthesis. In the last decade, it has become clear that connexin hemichannels, which are the structural precursors of gap junctions, also provide a pathway for cellular communication, namely between the cytosol and the extracellular environment. Although merely pathological functions have been described, some physiological roles have been attributed to connexin hemichannels, in particular in the modulation of colonic motility. This equally holds true for cellular channels composed of pannexins, connexin-like proteins recently identified in the intestine and the liver, which have become acknowledged key players in inflammatory processes and that have been proposed to control colonic motility, secretion and blood flow.
Published: 2015
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4. Inhibitors of connexin and pannexin channels as potential therapeutics

Author: Michaël Maes, Mathieu Vinken, IVTD VUB, Joost Willebrords, Sara Crespo Yanguas, Pharmaceutical and Pharmacological Sciences, Faculty of Medicine and Pharmacy, Experimental in vitro toxicology and dermato-cosmetology, Connexin Signalling Research Group, and Liver Connexin and Pannexin Research Group
Subjects: 0301 basic medicine, connexin, Inhibitor, hemichannel, Connexin, Biology, Pannexin, Antibodies, Connexins, Article, gap junction, 03 medical and health sciences, Protein structure, RNA interference, Animals, Humans, Pharmacology (medical), chemistry.chemical_classification, Peptides/pharmacology, Connexins/antagonists & inhibitors, HEK 293 cells, Gap junction, Cell biology, Amino acid, Cytosol, 030104 developmental biology, chemistry, Biochemistry, Antibodies/pharmacology, pharmacology, Peptides
Abstract: While gap junctions support the exchange of a number of molecules between neighboring cells, connexin hemichannels provide communication between the cytosol and the extracellular environment of an individual cell. The latter equally holds true for channels composed of pannexin proteins, which display an architecture reminiscent of connexin hemichannels. In physiological conditions, gap junctions are usually open, while connexin hemichannels and, to a lesser extent, pannexin channels are typically closed, yet they can be activated by a number of pathological triggers. Several agents are available to inhibit channels built up by connexin and pannexin proteins, including alcoholic substances, glycyrrhetinic acid, anesthetics and fatty acids. These compounds not always strictly distinguish between gap junctions, connexin hemichannels and pannexin channels, and may have effects on other targets as well. An exception lies with mimetic peptides, which reproduce specific amino acid sequences in connexin or pannexin primary protein structure. In this paper, a state-of-the-art overview is provided on inhibitors of cellular channels consisting of connexins and pannexins with specific focus on their mode-of-action and therapeutic potential.
Published: 2017

5. Safeguarding human health using in silico tools?

Author: Birgit Mertens, Melissa Van Bossuyt, Els Van Hoeck, IVTD VUB, Tamara Vanhaecke, Vera Rogiers, Faculty of Medicine and Pharmacy, Pharmaceutical and Pharmacological Sciences, and Experimental in vitro toxicology and dermato-cosmetology
Subjects: Pharmacology. Therapy, In silico, Health, Toxicology and Mutagenesis, Pharmacology toxicology, 04 agricultural and veterinary sciences, General Medicine, Computational biology, 010501 environmental sciences, Safeguarding, Bioinformatics, Toxicology, 040401 food science, 01 natural sciences, Human health, 0404 agricultural biotechnology, Toxicity Tests, Humans, Computer Simulation, Business, 0105 earth and related environmental sciences
Published: 2017

6. Printed paper and board food contact materials as a potential source of food contamination

Author: Birgit Mertens, Melissa Van Bossuyt, Els Van Hoeck, IVTD VUB, Tamara Vanhaecke, Vera Rogiers, Faculty of Medicine and Pharmacy, Pharmaceutical and Pharmacological Sciences, and Experimental in vitro toxicology and dermato-cosmetology
Subjects: Paper, Consumer Product Safety, Food contact materials, Food Contamination, Toxicology, 01 natural sciences, Risk Assessment, Hazardous Substances, 0404 agricultural biotechnology, Toxicity Tests, Humans, Potential source, Operations management, Waste management, business.industry, Pharmacology. Therapy, 010401 analytical chemistry, Food Packaging, cardboard, 04 agricultural and veterinary sciences, General Medicine, Contamination, Food safety, 040401 food science, 0104 chemical sciences, Checklist, Food packaging, visual_art, visual_art.visual_art_medium, Environmental science, Printing, Ink, Human medicine, business, Food contaminant
Abstract: Food contact materials (FCM) are estimated to be the largest source of food contamination. Apart from plastics, the most commonly used FCM are made of printed paper and board. Unlike their plastic counterparts, these are not covered by a specific European regulation. Several contamination issues have raised concerns towards potential adverse health effects caused by exposure to substances migrating from printed paper and board FCM. In the current study, an inventory combining the substances which may be used in printed paper and board FCM, was created. More than 6000 unique compounds were identified, the majority (77%) considered non-evaluated in terms of potential toxicity. Based on a preliminary study of their physicochemical properties, it is estimated that most of the non-evaluated single substances have the potential to migrate into the food and become bioavailable after oral intake. Almost all are included in the FACET tool, indicating that their use in primary food packaging has been confirmed by industry. Importantly, 19 substances are also present in one of the lists with substances of concern compiled by the European Chemicals Agency (ECHA). To ensure consumer safety, the actual use of these substances in printed paper and board FCM should be investigated urgently. (C) 2016 Elsevier Inc. All rights reserved.
Published: 2016

7. Gap junctions and non-neoplastic liver disease

Author: IVTD VUB, Mathieu Vinken, Toxicology, Dermato-cosmetology and Pharmacognosy, and Experimental in vitro toxicology and dermato-cosmetology
Subjects: Liver Cirrhosis, Pathology, medicine.medical_specialty, connexin, Cirrhosis, Connexin, Cell Communication, Biology, liver, Connexins, Hepatitis, gap junction, Liver disease, Cholestasis, medicine, Humans, Hepatology, Liver Diseases, Gap junction, Gap Junctions, Pannexin, medicine.disease, Reperfusion Injury, Immunology, Reperfusion injury
Abstract: SummaryBecause of their critical role as goalkeepers of hepatic homeostasis, gap junctions are frequent targets in liver disease. This concept has been demonstrated on many occasions in the light of hepatocarcinogenesis. Relatively little focus has been put on the fate of gap junctions in other liver pathologies, including hepatitis, liver fibrosis and cirrhosis, cholestasis and hepatic ischemia and reperfusion injury. The present paper provides an in-depth description of the multiple changes in expression, localization and function of connexins, the molecular constituents of gap junctions. The use of connexins as biomarkers and therapeutic targets in liver disease is also illustrated.
Published: 2012
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8. Connexin hemichannels: novel mediators of toxicity

Author: IVTD VUB, Mathieu Vinken, Toxicology, Dermato-cosmetology and Pharmacognosy, and Experimental in vitro toxicology and dermato-cosmetology
Subjects: connexin, Cell signaling, hemichannel, Health, Toxicology and Mutagenesis, Carbenoxolone, Metal Nanoparticles, Connexin, Cell Communication, Biology, Toxicology, Article, Connexins, Connexon, chemistry.chemical_compound, Soot, medicine, Humans, Cyclic adenosine monophosphate, Tissue homeostasis, Gap junction, toxicity, Gap Junctions, General Medicine, Cell biology, chemistry, Biochemistry, Neurotoxicity Syndromes, Intracellular, medicine.drug
Abstract: Tissue homeostasis is driven by a myriad of extracellular, intracellular and intercellular signaling networks. Direct communication between neighboring cells is typically controlled by gap junctions (Decrock et al. 2009; Nielsen et al. 2012; Vinken et al. 2011). Gap junctions mediate the intercellular diffusion of small and hydrophilic substances, including cyclic adenosine monophosphate, adenosine triphosphate, inositol triphosphate, glutathione, glutamate, glucose and several ions (Alexander and Goldberg 2003) (Fig. 1a). This flux is denoted as gap junctional intercellular communication (GJIC) and is considered as a key mechanism in the maintenance of tissue functioning (Decrock et al. 2009; Nielsen et al. 2012; Vinken et al. 2011). Over the last decades, GJIC has been shown indispensable for the establishment of metabolic or electrical intercellular coupling in all vital organs, such as the brain (Eugenin et al. 2012), the heart (Kurtenbach et al. 2014) and the liver (Vinken et al. 2008). Gap junctions are formed by the docking of two hemichannels of adjacent cells, which in turn are composed of six connexin proteins. At present, 21 different connexins have been identified in humans, all which are expressed in a cell-specific way (Kar et al. 2012; Nielsen et al. 2012). They are named based upon their molecular weight. Thus, the most widespread connexin species has a molecular mass of 43 kDa and hence is called Cx43. Connexin proteins share a common molecular structure consisting of four transmembrane domains, two extracellular loops, one cytosolic loop, one cytosolic aminotail and one cytosolic carboxytail (Fig. 1b) (Decrock et al. 2009; Nielsen et al. 2012). Fig. 1 a Gap junctions consist of two connexin hemichannels of adjacent cells and mediate intercellular communication. Connexin hemichannels also provide a pathway for communication, namely between the cytosol and the extracellular environment. Similar messengers ... Although considered as merely structural precursors of gap junctions for a long time, an abundance of reports published in the last few years shows that connexin hemichannels as such can provide a pathway for cellular communication, albeit between the cytosol of individual cells and their extracellular environment and not between adjacent cells as is the case for GJIC. Nonetheless, the messengers that are conveyed through connexin hemichannels are very similar to those involved in GJIC, including adenosine triphosphate, nicotinamide dinucleotide, glutamate, glutathione, prostaglandin, sodium and calcium ions (Fig. 1a) (Chandrasekhar and Bera 2012; Decrock et al. 2009; Kar et al. 2012). Furthermore, connexin hemichannels are regulated by mechanisms that equally affect gap junctions, yet an identical factor can have opposing effects on the two channel types, such as shown for certain inflammatory triggers (De Vuyst et al. 2007; Retamal et al. 2007). In line with this notion, connexin hemichannels, unlike their full channel counterparts, display a low open probability. In fact, connexin hemichannels seem to be preferably activated by pathological stimuli, including ischemia–reperfusion insults and oxidative stress, and thereby drive processes like cell death and inflammation (Chandrasekhar and Bera 2012; Decrock et al. 2009; Kar et al. 2012). For this very reason, connexin hemichannels are sometimes considered as “pathological pores” (Decrock et al. 2009). This concept is clearly relevant to toxicologists, as several toxic substances open up connexin hemichannels. For example, ultrafine carbon black particles activate Cx43-based hemichannels in astrocytes, which may represent a novel mechanism of neurotoxicity (Wei et al. 2014). Similarly, cobalt–chromium nanoparticles can damage human fibroblasts by a mechanism involving transmission of adenosine triphosphate and signaling through connexin hemichannels (Bhabra et al. 2009). The connexin research field has been surrounded by a lot of controversy in the last few years. Specifically, the concept of (dys) functional connexin hemichannels has been debated heavily on several occasions (Saez and Leybaert 2014; Spray et al. 2006). A major reason for this impediment is the ubiquitous lack of tools and technologies to distinguish between the different channel types, in casu between gap junctions and connexin hemichannels (Bodendiek and Raman 2010; Iyyathurai et al. 2013). Classical strategies, such as the use of RNA interference-based technologies, genetically modified animals or even antibodies, are indeed not applicable, as they target connexins, which are the shared building stones of gap junctions and connexin hemichannels. Furthermore, most, if not all, of the routinely used gap junction inhibitors, including long-chain alcohol substances, anaesthetic substances, the glycyrrhetinic acid derivative carbenoxolone and the fenamate family of blockers, equally suppress connexin hemichannel activity (Bodendiek and Raman 2010). Great expectations now lie with peptides that reproduce sequences in the cytosolic loop regions of connexins, as they suppress connexin hemichannel activity without influencing GJIC (Iyyathurai et al. 2013). Among those, a very prominent one is Gap19, a peptide that inhibits Cx43-based hemichannels while leaving the corresponding gap junctions unaffected (Abudara et al. 2014; Wang et al. 2013). In fact, Gap19 was found to reduce experimentally induced cell death in a mouse model of cardiac ischemia–reperfusion (Wang et al. 2013). This area is still in its infancy, but upon further exploration, it can be expected that this will also open new perspectives for the field of toxicology. Indeed, such specific connexin hemichannel inhibitors are not only interesting experimental tools to shed light onto yet unraveled toxicological mechanisms of action, but they may also form the basis for the development of antidotes pertinent for clinical use.
Published: 2014
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9. Adverse outcome pathways as tools to assess drug-induced toxicity

Author: IVTD VUB, Mathieu Vinken, Pharmaceutical and Pharmacological Sciences, Connexin Signalling Research Group, Liver Connexin and Pannexin Research Group, and Experimental in vitro toxicology and dermato-cosmetology
Subjects: 0301 basic medicine, Prioritization, Screening test, Drug-Related Side Effects and Adverse Reactions, Adverse outcomes, Databases, Pharmaceutical, Quantitative Structure-Activity Relationship, Bioinformatics, Animal Testing Alternatives, Models, Biological, Risk Assessment, Article, Economic cooperation, 03 medical and health sciences, 0302 clinical medicine, Adverse Outcome Pathway, Medicine, Humans, Adverse Outcome Pathways, business.industry, Drug induced toxicity, 030104 developmental biology, Liver, 030211 gastroenterology & hepatology, Risk assessment, business
Abstract: Adverse outcome pathways (AOPs) are novel tools in toxicology and human risk assessment with broad potential. AOPs are designed to provide a clear-cut mechanistic representation of toxicological effects that span over different layers of biological organization. AOPs share a common structure consisting of a molecular initiating event, a series of key events connected by key event relationships, and an adverse outcome. Development and evaluation of AOPs ideally complies with guidelines issued by the Organization for Economic Cooperation and Development. AOP frameworks have yet been proposed for major types of drug-induced injury, especially in the liver, including steatosis, fibrosis, and cholestasis. These newly postulated AOPs can serve a number of purposes pertinent to safety assessment of drugs, in particular the establishment of quantitative structure-activity relationships, the development of novel in vitro toxicity screening tests, and the elaboration of prioritization strategies.
Published: 2016

10. Introduction: connexins, pannexins and their channels as gatekeepers of organ physiology

Author: IVTD VUB, Mathieu Vinken, Toxicology, Dermato-cosmetology and Pharmacognosy, and Experimental in vitro toxicology and dermato-cosmetology
Subjects: connexin, hemichannel, Connexin, Biology, Pannexin, Article, Connexins, Ion Channels, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Extracellular, Animals, Humans, Cyclic adenosine monophosphate, Molecular Biology, Pharmacology, Gap junction, Gap Junctions, Cell Biology, Cell biology, chemistry, Molecular Medicine, Signal transduction, Adenosine triphosphate, Intracellular, Signal Transduction
Abstract: Homeostasis relies on the intimate interplay between extracellular, intracellular and intercellular signaling networks. Direct communication between adjacent cells is mediated by gap junctions [1-3]. They allow the intercellular diffusion of small (i.e. less than 1 kDa) and hydrophilic substances, including adenosine triphosphate (ATP), cyclic adenosine monophosphate, inositol triphosphate, glucose, glutathione, glutamate and several ions, like sodium, calcium and potassium (Fig. 1) [4]. This flux is called gap junctional intercellular communication (GJIC) and is considered as a basic mechanism in the maintenance of tissue functioning [1-3]. Over the last decades, GJIC has been shown indispensable for the establishment of metabolic or electrical intercellular coupling in all vital organs, such as the brain [5], the heart [6] and the liver [7], to name a few.
Published: 2015

11. Adverse outcome pathways and drug-induced liver injury testing

Author: IVTD VUB, Mathieu Vinken, Pharmaceutical and Pharmacological Sciences, Connexin Signalling Research Group, Liver Connexin and Pannexin Research Group, and Experimental in vitro toxicology and dermato-cosmetology
Subjects: Drug, Liver Cirrhosis, media_common.quotation_subject, Quantitative Structure-Activity Relationship, Pharmacology, Toxicology, Bioinformatics, Article, Drug withdrawal, Cholestasis, Fibrosis, Adverse Outcome Pathway, medicine, Humans, AOP, media_common, Liver injury, Sulfonamides, business.industry, Valproic Acid, Fatty liver, Bosentan, General Medicine, medicine.disease, 3. Good health, Fatty Liver, Methotrexate, Steatosis, Chemical and Drug Induced Liver Injury, business
Abstract: Drug-induced liver injury is a prominent reason for premarketing and postmarketing drug withdrawal and can be manifested in a number of ways, such as cholestasis, steatosis, and fibrosis. The mechanisms driving these toxicological processes have been well characterized and have been emdedded in adverse outcome pathway frameworks in recent years. This review evaluates these constructs and simultaneously illustrates their use in the preclinical testing of drug-induced liver injury.
Published: 2015

12. The adverse outcome pathway concept: a pragmatic tool in toxicology

Author: IVTD VUB, Mathieu Vinken, Toxicology, Dermato-cosmetology and Pharmacognosy, and Experimental in vitro toxicology and dermato-cosmetology
Subjects: Prioritization, Cholestasis, Screening test, Computer science, Adverse outcomes, Skin sensitization, Toxicology, adverse outcome pathway, Fatty Liver, Structure-Activity Relationship, Liver steatosis, Adverse Outcome Pathway, Hepatic Stellate Cells, Animals, Humans, Bradford Hill criteria, Risk assessment, Skin
Abstract: Adverse outcome pathways (AOPs) are novel tools in toxicology and human risk assessment with broad potential. AOPs are designed to provide a clear-cut mechanistic representation of critical toxicological effects that span over different layers of biological organization. AOPs share a common structure consisting of a molecular initiating event, a series of intermediate steps and key events, and an adverse outcome. Development of AOPs ideally complies with OECD guidelines. This also holds true for AOP evaluation, which includes consideration of the Bradford Hill criteria for weight-of-evidence assessment and meeting a set of key questions defined by the OECD. Elaborate AOP frameworks have yet been proposed for chemical-induced skin sensitization, cholestasis, liver fibrosis and liver steatosis. These newly postulated AOPs can serve a number of ubiquitous purposes, including the establishment of (quantitative) structure-activity relationships, the development of novel in vitro toxicity screening tests and the elaboration of prioritization strategies.
Published: 2013

13. Is the replacement strategy, as it exists today in the EU for cosmetics, the way forward ?

Author: IVTD VUB, Vera Rogiers, Connexin Signalling Research Group, Experimental in vitro toxicology and dermato-cosmetology, and Toxicology, Dermato-cosmetology and Pharmacognosy
Subjects: Cosmetics/standards, Toxicity Tests/methods, Health, Toxicology and Mutagenesis, media_common.quotation_subject, Animal Testing Alternatives/methods, Legislation, Cosmetics, Animal Testing Alternatives, Toxicology, Risk Assessment, animal welfare, local lymph node assay, Pharmacology, Toxicology and Pharmaceutics(all), Animal welfare, Toxicity Tests, media_common.cataloged_instance, Animals, Humans, European Union, Marketing, European union, media_common, Consumer Product Safety/legislation & jurisprudence, Legislature, General Medicine, Risk Assessment/legislation & jurisprudence, Variety (cybernetics), Consumer Product Safety, Business, Reproductive toxicity, Risk assessment
Abstract: During our daily life, we are exposed to a variety of chemical substances and products including cosmetics and their ingredients. When they are brought on the EU market, they must be safe for human health. This safety is traditionally guaranteed through quantitative risk assessment which is not only based on human exposure data, but in particular on testing results derived from experimental animals, assessing both local and whole organism systemic toxicity. For local and short-term toxicity, the development of 3R (Refinement, Reduction and Replacement)—alternative methods had some important success. A number of toxicological endpoints, including skin corrosion, skin irritation, eye irritation, skin sensitization, phototoxicity, dermal absorption, acute toxicity, and in vitro genotoxicity/mutagenicity testing could be covered, although not all with replacement and stand-alone alternatives (EU 2010). Refinement and reduction are, for example at the basis of the local lymph node assay (LLNA), used for skin sensitization testing; for eye irritation only some screening tests for strong irritants are available. For long-term and systemic toxicity testing, consuming in fact the largest number of experimental animals, nearly no alternatives are available and the time required for their scientific development is a huge question mark. Exactly here lies the problem! In the EU, the cosmetic legislation was made the most stringent one of the world by bringing in a rigid time frame through testing and marketing bans (EU 1976 amended by EU 2003). This political decision has positive and negative sides. Positive is the fact that over the last years the number of efforts, made by all stakeholders involved (academic world, industry, animal welfare, and legislative bodies) substantially improved. Also collaboration towards a common goal gained importance and financial resources in the field became more available. A negative outcome, however, is that this politically driven initiative does not take into account the scientific feasibility of the timely and complex development of alternatives to guarantee human safety. Personally spoken, I see as one of the most limiting factors for further progress in the cosmetic field, the way Europe sticks to replacement methods only. This deliberate choice ‘‘kills’’ reduction and refinement efforts. As such, progress made in the practical application of tiered approaches combining in vitro and in vivo methodology, and of read across and weight of evidence strategies, is ignored to a major extend. This is difficult to accept as these strategies became internationally accepted to come to a more balanced risk assessment and at the same time save animal lives. Also very recently, a panel of European experts reported on the current status and future prospects of non-animal methods for cosmetic testing (Adler et al. 2011, this issue). They concluded that specific timelines were impossible to give for these areas in which most animals are consumed, namely for reproductive toxicity, repeated dose toxicity, carcinogenicity, and toxicokinetics. Interesting to note is that they also concluded that significant advances were made in reducing the number of animals in tests by refinement strategies and by the use of nonanimal methods alongside animal tests. From March 2013, however, this is no longer possible. V. Rogiers (&) Department of Toxicology, Center for Pharmaceutical Research, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium e-mail: vrogiers@vub.ac.be
Published: 2011
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14. Genome-wide association analyses identify novel Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Author: Barc, Julien, Tadros, Rafik, Glinge, Charlotte, Chiang, David Y., Jouni, Mariam, Simonet, Floriane, Jurgens, Sean J., Baudic, Manon, Nicastro, Michele, Potet, Franck, Offerhaus, Joost A., Walsh, Roddy, Choi, Seung Hoan, Verkerk, Arie O., Mizusawa, Yuka, Anys, Soraya, Minois, Damien, Arnaud, Marine, Duchateau, Josselin, Wijeyeratne, Yanushi D., Muir, Alison, Papadakis, Michael, Castelletti, Silvia, Torchio, Margherita, Ortuño, Cristina Gil, Lacunza, Javier, Giachino, Daniela F., Cerrato, Natascia, Martins, Raphaël P., Campuzano, Oscar, Van Dooren, Sonia, Thollet, Aurélie, Kyndt, Florence, Mazzanti, Andrea, Clémenty, Nicolas, Bisson, Arnaud, Corveleyn, Anniek, Stallmeyer, Birgit, Dittmann, Sven, Saenen, Johan, Noël, Antoine, Honarbakhsh, Shohreh, Rudic, Boris, Marzak, Halim, Rowe, Matthew K., Federspiel, Claire, Le Page, Sophie, Placide, Leslie, Milhem, Antoine, Barajas-Martinez, Hector, Beckmann, Britt-Maria, Krapels, Ingrid P., Steinfurt, Johannes, Winkel, Bo Gregers, Jabbari, Reza, Shoemaker, Moore B., Boukens, Bas J., Škorić-Milosavljević, Doris, Bikker, Hennie, Manevy, Federico, Lichtner, Peter, Ribasés, Marta, Meitinger, Thomas, Müller-Nurasyid, Martina, Strauch, Konstantin, Peters, Annette, Schulz, Holger, Schwettmann, Lars, Leidl, Reiner, Heier, Margit, Veldink, Jan H., van den Berg, Leonard H., Van Damme, Philip, Cusi, Daniele, Lanzani, Chiara, Rigade, Sidwell, Charpentier, Eric, Baron, Estelle, Bonnaud, Stéphanie, Lecointe, Simon, Donnart, Audrey, Le Marec, Hervé, Chatel, Stéphanie, Karakachoff, Matilde, Bézieau, Stéphane, London, Barry, Tfelt-Hansen, Jacob, Roden, Dan, Odening, Katja E., Cerrone, Marina, Chinitz, Larry A., Volders, Paul G., van de Berg, Maarten P., Laurent, Gabriel, Faivre, Laurence, Antzelevitch, Charles, Kääb, Stefan, Arnaout, Alain Al, Dupuis, Jean-Marc, Pasquie, Jean-Luc, Billon, Olivier, Roberts, Jason D., Jesel, Laurence, Borggrefe, Martin, Lambiase, Pier D., Mansourati, Jacques, Loeys, Bart, Leenhardt, Antoine, Guicheney, Pascale, Maury, Philippe, Schulze-Bahr, Eric, Robyns, Tomas, Breckpot, Jeroen, Babuty, Dominique, Priori, Silvia G., Napolitano, Carlo, Defaye, Pascal, Anselme, Frédéric, Darmon, Jean Philippe, Wiart, François, de Asmundis, Carlo, Brugada, Pedro, Brugada, Ramon, Arbelo, Elena, Brugada, Josep, Mabo, Philippe, Behar, Nathalie, Giustetto, Carla, Molina, Maria Sabater, Gimeno, Juan R., Hasdemir, Can, Schwartz, Peter J., Crotti, Lia, McKeown, Pascal P., Sharma, Sanjay, Behr, Elijah R., Haissaguerre, Michel, Sacher, Frédéric, Rooryck, Caroline, Tan, Hanno L., Remme, Carol A., Postema, Pieter G., Delmar, Mario, Ellinor, Patrick T., Lubitz, Steven A., Gourraud, Jean-Baptiste, Tanck, Michael W., George, Alfred L., MacRae, Calum A., Burridge, Paul W., Dina, Christian, Probst, Vincent, Wilde, Arthur A., Schott, Jean-Jacques, Redon, Richard, Bezzina, Connie R., KORA-Study Group, Nantes Referral Ctr Inherited Card, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Santé - François Bonamy, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Amsterdam UMC - Amsterdam University Medical Center, The MINE study (J.H.V.) has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 772376—EScORIAL). The collaboration project is cofunded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public–private partnerships. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113, 085475 and 090355. The KORA research platform (KORA, Cooperative Research in the Region of Augsburg) was initiated and financed by the Helmholtz Zentrum München—German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. J. Barc is supported by the research program Etoiles montantes des Pays de la Loire REGIOCARD RPH081-U1087-REG-PDL, ANR JCJC LEARN (R21006NN, RPV21014NNA) and by the H2020-MSCA-IF-2014 Program of the European Commission (RISTRAD-661617). R.T. is supported by the Canadian Heart Rhythm Society’s George Mines Award, the European Society of Cardiology research award, and the Philippa and Marvin Carsley Cardiology Chair. D.Y.C. is supported by Fondation Leducq and National Institutes of Health (NIH) NHGRI T32 (no. 1T32HG010464-01). M. Baudic was supported by IRP—VERACITIES—New Mechanisms for VEntricular ARrhythmia And CardIomeTabolic DIseasES, an I-SITE NExT health and engineering initiative (Ecole Centrale and Nantes University) and by the IRP—GAINES—Genetic Architecture IN cardiovascular disEaSes funded by INSERM and CNRS. R.W. is supported by an Amsterdam Cardiovascular Sciences fellowship. S.C. is supported by the NHLBI BioData Catalyst Fellows Program. C.A.R. is supported by Fondation Leducq, the Dutch Heart Foundation (CVON PREDICT2) and the Innovational Research Incentives Scheme Vidi grant from the Netherlands Organisation for Health Research and Development (ZonMw, 91714371). Y.D.W. is supported by the Robert Lancaster Memorial Fund. M.P. is supported by Cardiac Risk in the Young. S.V.D. is supported by Wetenschappelijk Fonds Willy Gepts VUB-UZ Brussel, project ‘Unravelling the molecular genetic pathways of Brugada Syndrome by cardiomics research’, VUB IRP project ‘IMAGica: an Integrative personalized Medical Approach for Genetic diseases, Inherited Cardia Arrhythmias as a model’ and Innoviris BRIDGE 2017, project ‘IGenCare: Integrated Personalised Medical Genomics Care Solution for Patients with Rare Genetic Diseases’. S.H. is supported by the Barts BRC. B.R. is supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research). B.G.W. is supported by the Danish Heart Foundation. M.B.S. is supported by K23HL127704. Project MinE Belgium was supported by a grant from IWT (no. 140935), the ALS Liga België, the National Lottery of Belgium and the KU Leuven Opening the Future Fund. D.C. and C.L. are supported by HYPERGENES (HEALTH-F4-2007). D.R. is supported by R01 HL149826, P50 GM115305. P.J.S. acknowledges the support of Leducq Foundation for Cardiovascular Research grant 18CVD05. P.V.D. is supported by the Netherlands CardioVascular Research Initiative (CVON PREDICT2). C.A. is supported by NIH HL47678 and HL138103, W.W. Smith Charitable Trust and Wistar Morris Fund. M.B. is Supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research). P.D.L. is supported by UCL/UCLH Biomedicine NIHR and Barts BRC. B.L. is supported by GOA—Antigone 33933. J.B. is supported by a Senior Clinical Fellowship of the Flemish Science Foundation (FWO). E.B. is supported by the British Heart Foundation including BHF Clinical Research Training Fellowship (FS/11/71/28918: Future diagnostic role and new genetic loci in SADS), Cardiac Risk in the Young and Robert Lancaster Memorial fund sponsored by McColl’s Ltd. Retail Group. H.L.T. is supported by the European Union’s Horizon 2020 research and innovation program under acronym ESCAPE-NET, registered under grant agreement no. 733381, and the Dutch Heart Foundation (CVON RESCUED and PREDICT2 projects). M.D. is supported by NIH-RO1 HL134328. P.T.E. was supported by the Fondation Leducq (14CVD01), the NIH (1RO1HL092577, R01HL128914, K24HL105780), the American Heart Association (18SFRN34110082) and by a research grant from Bayer AG to the Broad Institute. S.A.L. is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. J.-B.G. received a grant from the Fédération Française de Cardiologie (PREVENT project). A.L.G. is supported by the Fondation Leducq. C.A.M.R. is supported by the Leducq Foundation and Burroughs Wellecome Fund. A.A.W. is supported by the Dutch Heart Foundation (CVON PREDICT2 project). J.-J.S. is supported by the Fondation pour la Recherche Médicale (DEQ20140329545). R.R. and P.G. are supported by the National Agency for Research (ANR-GENSUD-14-CE10-0001). C.R.B. is supported by the Dutch Heart Foundation (CVON PREDICT2 project), the Netherlands Organization for Scientific Research (VICI fellowship, 016.150.610) and Fondation Leducq (17CVD02)., Barc, J, Tadros, R, Glinge, C, Chiang, D, Jouni, M, Simonet, F, Jurgens, S, Baudic, M, Nicastro, M, Potet, F, Offerhaus, J, Walsh, R, Hoan Choi, S, Verkerk, A, Mizusawa, Y, Anys, S, Minois, D, Arnaud, M, Duchateau, J, Wijeyeratne, Y, Muir, A, Papadakis, M, Castelletti, S, Torchio, M, Gil Ortuño, C, Lacunza, J, Giachino, D, Cerrato, N, Martins, R, Campuzano, O, Van Dooren, S, Thollet, A, Kyndt, F, Mazzanti, A, Clémenty, N, Bisson, A, Corveleyn, A, Stallmeyer, B, Dittmann, S, Saenen, J, Noël, A, Honarbakhsh, S, Rudic, B, Marzak, H, Rowe, M, Federspiel, C, Le Page, S, Placide, L, Milhem, A, Barajas-Martinez, H, Beckmann, B, Krapels, I, Steinfurt, J, Gregers Winkel, B, Jabbari, R, Shoemaker, M, Boukens, B, Škorić-Milosavljević, D, Bikker, H, Manevy, F, Lichtner, P, Ribasés, M, Meitinger, T, Müller-Nurasyid, M, Group, K, Veldink, J, van den Berg, L, Van Damme, P, Cusi, D, Lanzani, C, Rigade, S, Charpentier, E, Baron, E, Bonnaud, S, Lecointe, S, Donnart, A, Le Marec, H, Chatel, S, Karakachoff, M, Bézieau, S, London, B, Tfelt-Hansen, J, Roden, D, Odening, K, Cerrone, M, Chinitz, L, Volders, P, van de Berg, M, Laurent, G, Faivre, L, Antzelevitch, C, Kääb, S, Al Arnaout, A, Dupuis, J, Pasquie, J, Billon, O, Roberts, J, Jesel, L, Borggrefe, M, Lambiase, P, Mansourati, J, Loeys, B, Leenhardt, A, Guicheney, P, Maury, P, Schulze-Bahr, E, Robyns, T, Breckpot, J, Babuty, D, Priori, S, Napolitano, C, Referral Center for inherited cardiac arrhythmia, N, de Asmundis, C, Brugada, P, Brugada, R, Arbelo, E, Brugada, J, Mabo, P, Behar, N, Giustetto, C, Sabater Molina, M, Gimeno, J, Hasdemir, C, Schwartz, P, Crotti, L, Mckeown, P, Sharma, S, Behr, E, Haissaguerre, M, Sacher, F, Rooryck, C, Tan, H, Remme, C, Postema, P, Delmar, M, Ellinor, P, Lubitz, S, Gourraud, J, Tanck, M, L. George Jr., A, Macrae, C, Burridge, P, Dina, C, Probst, V, Wilde, A, Schott, J, Redon &amp, R, Bezzina, C, Cardiology, Graduate School, Medical Biology, ACS - Amsterdam Cardiovascular Sciences, ACS - Heart failure & arrhythmias, Human Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, APH - Methodology, Epidemiology and Data Science, MUMC+: DA KG Polikliniek (9), RS: Carim - H02 Cardiomyopathy, Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H04 Arrhythmogenesis and cardiogenetics, and Cardiovascular Centre (CVC)
Subjects: EXPRESSION, [SDV]Life Sciences [q-bio], DIAGNOSIS, GUIDELINES, ANNOTATION, Article, NAV1.5 Voltage-Gated Sodium Channel, Young Adult, MANAGEMENT, Genetics, GWAS, Humans, Genetic Predisposition to Disease, 610 Medicine & health, SCN5A, Alleles, Brugada Syndrome, Allele, [SDV.GEN]Life Sciences [q-bio]/Genetics, HERITABILITY, Microtubule-Associated Protein, Brugada Syndrome, GWAS, SNPs, COMMON VARIANTS, Mutation, Disease Susceptibility, Human medicine, ENRICHMENT, Microtubule-Associated Proteins, SNPs, Human, GENERATION, Genome-Wide Association Study
Abstract: Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na(V)1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na(V)1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings. Genome-wide association analyses identify new susceptibility loci for Brugada syndrome. Functional studies implicate microtubule-related trafficking effects on sodium channel expression as an underlying molecular mechanism., European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program [772376-EScORIAL]; Health~Holland; Top Sector Life Sciences Health; Wellcome Trust [076113, 085475, 090355]; Helmholtz Zentrum Munchen-German Research Center for Environmental Health - German Federal Ministry of Education and Research; State of Bavaria; Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ; research program Etoiles montantes des Pays de la Loire [REGIOCARD RPH081-U1087-REG-PDL]; ANR JCJC LEARN [R21006NN, RPV21014NNA]; H2020-MSCA-IF-2014 Program of the European Commission [RISTRAD-661617]; Canadian Heart Rhythm Society's George Mines Award; European Society of Cardiology research award; Philippa and Marvin Carsley Cardiology Chair; Fondation Leducq; National Institutes of Health (NIH) NHGRI T32 [1T32HG010464-01]; IRP-VERACITIES-New Mechanisms for VEntricular ARrhythmia And CardIomeTabolic DIseasES an I-SITE NExT health and engineering initiative (Ecole Centrale); IRP-VERACITIES-New Mechanisms for VEntricular ARrhythmia And CardIomeTabolic DIseasES an I-SITE NExT health and engineering initiative (Nantes University); IRP-GAINES-Genetic Architecture IN cardiovascular disEaSes - INSERM; CNRS; Amsterdam Cardiovascular Sciences fellowship; NHLBI BioData Catalyst Fellows Program; Dutch Heart Foundation [CVON PREDICT2]; Innovational Research Incentives Scheme Vidi grant from the Netherlands Organisation for Health Research and Development (ZonMw) [91714371]; Robert Lancaster Memorial Fund; Cardiac Risk in the Young; Wetenschappelijk Fonds Willy Gepts VUB-UZ Brussel; VUB IRP project `IMAGica: an Integrative personalized Medical Approach for Genetic diseases, Inherited Cardia Arrhythmias as a model' and Innoviris BRIDGE 2017; project `IGenCare: Integrated Personalised Medical Genomics Care Solution for Patients with Rare Genetic Diseases'; Barts BRC; DZHK (German Centre for Cardiovascular Research); BMBF (German Ministry of Education and Research); Danish Heart Foundation; IWT [140935]; ALS Liga Belgie; National Lottery of Belgium; KU Leuven Opening the Future Fund; HYPERGENES [HEALTH-F4-2007]; Leducq Foundation for Cardiovascular Research grant [18CVD05]; Netherlands CardioVascular Research Initiative [CVON PREDICT2]; NIH [HL47678, HL138103, 1RO1HL092577, R01HL128914, K24HL105780]; W.W. Smith Charitable Trust; Wistar Morris Fund; GOA-Antigone [33933]; Senior Clinical Fellowship of the Flemish Science Foundation (FWO); British Heart Foundation; BHF Clinical Research Training Fellowship [FS/11/71/28918]; Cardiac Risk in the Young and Robert Lancaster Memorial fund - McColl's Ltd. Retail Group; European Union's Horizon 2020 research and innovation program under acronym ESCAPE-NET [733381]; Dutch Heart Foundation; Fondation Leducq [14CVD01, 17CVD02]; American Heart Association [18SFRN34110082, 18SFRN34250007]; Bayer AG; NIH grant [1R01HL139731]; Federation Francaise de Cardiologie (PREVENT project); Leducq Foundation; Burroughs Wellecome Fund; Fondation pour la Recherche Medicale [DEQ20140329545]; National Agency for Research [ANR-GENSUD-14-CE10-0001]; Netherlands Organization for Scientific Research (VICI fellowship) [016.150.610]; [K23HL127704]; [R01 HL149826]; [P50 GM115305]; [NIH-RO1 HL134328], We are greatly indebted to the patients included in the study. We thank V. Cotard, C. Goutsmedt, M.-F. Le Cunff and N. Bourgeais for assistance in patient recruitment and L. Beekman for his technical support. We thank the biological resource centre for biobanking (CHU Nantes, Nantes Universite, Centre de ressources biologiques (BB0033-00040), F-44000 Nantes, France) for applying the following guidelines68. We are most grateful to the Genomics and Bioinformatics Core Facility of Nantes (GenoBiRD, Biogenouest, IFB) for its technical support. This research has been conducted using the UK Biobank resource; we are grateful to UK Biobank participants. The MINE study (J.H.V.) has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement no. 772376-EScORIAL). The collaboration project is cofunded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk.Funding for the project was provided by the Wellcome Trust under award 076113, 085475 and 090355. The KORA research platform (KORA, Cooperative Research in the Region of Augsburg) was initiated and financed by the Helmholtz Zentrum Munchen-German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ. J. Barc is supported by the research program Etoiles montantes des Pays de la Loire REGIOCARD RPH081-U1087-REG-PDL, ANR JCJC LEARN (R21006NN, RPV21014NNA) and by the H2020-MSCA-IF-2014 Program of the European Commission (RISTRAD-661617). R.T. is supported by the Canadian Heart Rhythm Society's George Mines Award, the European Society of Cardiology research award, and the Philippa and Marvin Carsley Cardiology Chair. D.Y.C. is supported by Fondation Leducq and National Institutes of Health (NIH) NHGRI T32 (no. 1T32HG010464-01). M. Baudic was supported by IRP-VERACITIES-New Mechanisms for VEntricular ARrhythmia And CardIomeTabolic DIseasES, an I-SITE NExT health and engineering initiative (Ecole Centrale and Nantes University) and by the IRP-GAINES-Genetic Architecture IN cardiovascular disEaSes funded by INSERM and CNRS. R.W. is supported by an Amsterdam Cardiovascular Sciences fellowship. S.C. is supported by the NHLBI BioData Catalyst Fellows Program. C.A.R. is supported by Fondation Leducq, the Dutch Heart Foundation (CVON PREDICT2) and the Innovational Research Incentives Scheme Vidi grant from the Netherlands Organisation for Health Research and Development (ZonMw; 91714371). Y.D.W. is supported by the Robert Lancaster Memorial Fund. M.P. is supported by Cardiac Risk in the Young. S.V.D. is supported by Wetenschappelijk Fonds Willy Gepts VUB-UZ Brussel, project `Unravelling the molecular genetic pathways of Brugada Syndrome by cardiomics research', VUB IRP project `IMAGica: an Integrative personalized Medical Approach for Genetic diseases, Inherited Cardia Arrhythmias as a model' and Innoviris BRIDGE 2017, project `IGenCare: Integrated Personalised Medical Genomics Care Solution for Patients with Rare Genetic Diseases'. S.H. is supported by the Barts BRC. B.R.; is supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research). B.G.W. is supported by the Danish Heart Foundation. M.B.S. is supported by K23HL127704. Project MinE Belgium was supported by a grant from IWT (no. 140935), the ALS Liga Belgie, the National Lottery of Belgium and the KU Leuven Opening the Future Fund. D.C. and C.L. are supported by HYPERGENES (HEALTH-F4-2007). D.R. is supported by R01 HL149826, P50 GM115305. P.J.S. acknowledges the support of Leducq Foundation for Cardiovascular Research grant 18CVD05. P.V.D. is supported by the Netherlands CardioVascular Research Initiative (CVON PREDICT2). C.A. is supported by NIH HL47678 and HL138103, W.W. Smith Charitable Trust and Wistar Morris Fund. M.B. is Supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research). P.D.L. is supported by UCL/UCLH Biomedicine NIHR and Barts BRC. B.L. is supported by GOA-Antigone 33933. J.B. is supported by a Senior Clinical Fellowship of the Flemish Science Foundation (FWO). E.B. is supported by the British Heart Foundation including BHF Clinical Research Training Fellowship (FS/11/71/28918: Future diagnostic role and new genetic loci in SADS), Cardiac Risk in the Young and Robert Lancaster Memorial fund sponsored by McColl's Ltd. Retail Group. H.L.T. is supported by the European Union's Horizon 2020 research and innovation program under acronym ESCAPE-NET, registered under grant agreement no. 733381, and the Dutch Heart Foundation (CVON RESCUED and PREDICT2 projects). M.D. is supported by NIH-RO1 HL134328. P.T.E. was supported by the Fondation Leducq (14CVD01), the NIH (1RO1HL092577, R01HL128914, K24HL105780), the American Heart Association (18SFRN34110082) and by a research grant from Bayer AG to the Broad Institute. S.A.L. is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. J.-B.G. received a grant from the Federation Francaise de Cardiologie (PREVENT project). A.L.G. is supported by the Fondation Leducq. C.A.M.R. is supported by the Leducq Foundation and Burroughs Wellecome Fund. A.A.W. is supported by the Dutch Heart Foundation (CVON PREDICT2 project). J.-J.S. is supported by the Fondation pour la Recherche Medicale (DEQ20140329545). R.R. and P.G. are supported by the National Agency for Research (ANR-GENSUD-14-CE10-0001). C.R.B. is supported by the Dutch Heart Foundation (CVON PREDICT2 project), the Netherlands Organization for Scientific Research (VICI fellowship, 016.150.610) and Fondation Leducq (17CVD02).
Published: 2022
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15. The SCCS scientific advice on the safety of nanomaterials in cosmetics

Author: Christophe Rousselle, Wim H. de Jong, Susan Wijnhoven, Ulrike Bernauer, Eric Gaffet, Laurent Bodin, Pieter Jan Coenraads, Other experts, Eirini Panteri, Qasim Chaudhry, Natalie von Goetz, Tamara Vanhaecke, Maciej Stępnik, Vera Rogiers, Maria Dusinska, Pharmaceutical and Pharmacological Sciences, Vriendenkring VUB, Experimental in vitro toxicology and dermato-cosmetology, Bundesinstitut für Risikobewertung - Federal Institute for Risk Assessment (BfR), Scientific Committee for Consumer Safety (SCCS) (SCCS), CEA- Saclay (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), University of Chester, University Medical Center Groningen [Groningen] (UMCG), Norwegian Institute for Air Research (NILU), Institut Jean Lamour (IJL), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), National and Kapodistrian University of Athens (NKUA), Vrije Universiteit Brussel (VUB), Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), National Institute for Public Health and the Environment [Bilthoven] (RIVM), Swiss Federal Office of Public Health, and Université de Lorraine (UL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Surface Properties, media_common.quotation_subject, Commission, 010501 environmental sciences, Toxicology, Risk Assessment, 030226 pharmacology & pharmacy, 01 natural sciences, Cosmetics, Consumer safety, 03 medical and health sciences, Pharmacology, Toxicology and Pharmaceutics(all), 0302 clinical medicine, Safety concerns, Humans, European commission, Particle Size, ComputingMilieux_MISCELLANEOUS, 0105 earth and related environmental sciences, media_common, NANOMATERIALS, Dose-Response Relationship, Drug, cosmetics, Consumer health, General Medicine, Nanostructures, 3. Good health, Europe, SCCS, Solubility, Consumer Product Safety, Scientific advice, [PHYS.COND.CM-MS]Physics [physics]/Condensed Matter [cond-mat]/Materials Science [cond-mat.mtrl-sci], Engineering ethics, Business
Abstract: The Cosmetic Regulation (EC) No 1223/2009 specifically covers the risk of nanomaterials used in cosmetic products. If there are concerns regarding the safety of a nanomaterial, the European Commission refers it to the SCCS for a scientific opinion. The Commission mandated the SCCS to identify the scientific basis for safety concerns that could be used as a basis for identifying and prioritising nanomaterials for safety assessment, and to revisit previous inconclusive SCCS opinions on nanomaterials to identify any concerns for potential risks to the consumer health. The SCCS Scientific Advice identified the key general aspects of nanomaterials that should raise a safety concern for a safety assessor/manager, so that the nanomaterial(s) in question could be subjected to safety assessment to establish safety to the consumer. The Advice also developed a list of the nanomaterials notified to the Commission for use in cosmetics in an order of priority for safety assessment, and revisited three previous inconclusive opinions on nanomaterials to highlight concerns over consumer safety that merited further safety assessment.
Published: 2021
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16. Harnessing the Anti-Nociceptive Potential of NK2 and NK3 Ligands in the Design of New Multifunctional mu/delta-Opioid Agonist-Neurokinin Antagonist Peptidomimetics

Author: Charlène Gadais, Justyna Piekielna-Ciesielska, Jolien De Neve, Charlotte Martin, Anna Janecka, Steven Ballet, Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Vrije Universiteit Brussel [Bruxelles] (VUB), Medical University of Łódź (MUL), Research Council of VUB [SRP50], Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Chemistry, Faculty of Sciences and Bioengineering Sciences, Organic Chemistry, and WE Academic Unit
Subjects: Protein Conformation, Receptors, Opioid, mu, Organic chemistry, NK2, NK3, Substance P, Ligands, Article, Structure-Activity Relationship, QD241-441, Neurokinin-1 Receptor Antagonists, designed multiple ligand, opioid agonist, Humans, [CHIM]Chemical Sciences, Amino Acid Sequence, antinociception, δ-opioid receptor, Receptors, Neurokinin-1, peptide, Analgesics, Opioid, peptidomimetics, μ-opioid receptor, mu-opioid receptor, delta-opioid receptor, neurokinin, Oligopeptides, Protein Binding
Abstract: Opioid agonists are well-established analgesics, widely prescribed for acute but also chronic pain. However, their efficiency comes with the price of drastically impacting side effects that are inherently linked to their prolonged use. To answer these liabilities, designed multiple ligands (DMLs) offer a promising strategy by co-targeting opioid and non-opioid signaling pathways involved in nociception. Despite being intimately linked to the Substance P (SP)/neurokinin 1 (NK1) system, which is broadly examined for pain treatment, the neurokinin receptors NK2 and NK3 have so far been neglected in such DMLs. Herein, a series of newly designed opioid agonist-NK2 or -NK3 antagonists is reported. A selection of reported peptidic, pseudo-peptidic, and non-peptide neurokinin NK2 and NK3 ligands were covalently linked to the peptidic μ-opioid selective pharmacophore Dmt-DALDA (H-Dmt-d-Arg-Phe-Lys-NH2) and the dual μ/δ opioid agonist H-Dmt-d-Arg-Aba-βAla-NH2 (KGOP01). Opioid binding assays unequivocally demonstrated that only hybrids SBL-OPNK-5, SBL-OPNK-7 and SBL-OPNK-9, bearing the KGOP01 scaffold, conserved nanomolar range μ-opioid receptor (MOR) affinity, and slightly reduced affinity for the δ-opioid receptor (DOR). Moreover, NK binding experiments proved that compounds SBL-OPNK-5, SBL-OPNK-7, and SBL-OPNK-9 exhibited (sub)nanomolar binding affinity for NK2 and NK3, opening promising opportunities for the design of next-generation opioid hybrids.
Published: 2021
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17. Women’s excess unhealthy life years: disentangling the unhealthy life years gap

Author: Wilma J. Nusselder, Carrol Jagger, Dagmar Wapperom, Renata Tiene de Carvalho Yokota, Caspar W. N. Looman, Herman Van Oyen, Jean-Marie Robine, Emmanuelle Cambois, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Institut national d'études démographiques (INED), Vrije Universiteit [Brussels] (VUB), Ghent University [Belgium] (UGENT), Institute of Health & Society, Newcastle University [Newcastle], CERMES3 - Centre de recherche Médecine, sciences, santé, santé mentale, société (CERMES3 - UM 7 (UMR 8211 / U988)), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-École des hautes études en sciences sociales (EHESS), Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Université Montpellier 2 - Sciences et Techniques (UM2)-École pratique des hautes études (EPHE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Public Health, Vrije Universiteit Brussel (VUB), Universiteit Gent = Ghent University [Belgium] (UGENT), CERMES3 - Centre de recherche Médecine, sciences, santé, santé mentale, société (CERMES3 - UMR 8211 / U988 / UM 7), École des hautes études en sciences sociales (EHESS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)
Subjects: Male, Health Status, SULLIVANS METHOD, SEX_DIFFERENTIALS, cause of death, 0302 clinical medicine, ACTIVITY LIMITATION, Prevalence, Medicine and Health Sciences, 030212 general & internal medicine, Migration, Cause of death, Aged, 80 and over, heart diseases, Age Factors, HEALTH EXPECTANCY, Middle Aged, 3. Good health, musculoskeletal diseases, CAUSES_OF_DEATH, gender differences, DISEASES, Female, Public Health, France, Disability prevalence, BURDEN, 0305 other medical science, Lower mortality, LIFE_EXPECTANCY, medicine.medical_specialty, SEX-DIFFERENCES, accidents, Mixed anxiety-depressive disorder, 03 medical and health sciences, Sex Factors, 030502 gerontology, medicine, Humans, Disabled Persons, Women, INDICATOR, DIFFERENTIAL_MORTALITY, Aged, GENDER-DIFFERENCES, business.industry, DISABILITY, MORTALITY, Public health, Environmental and Occupational Health, CARDIOVASCULAR_DISEASES, Public Health, Environmental and Occupational Health, MENTAL_HEALTH, medicine.disease, Health Surveys, mortality, HEALTH_EXPECTANCY, MENTAL_DISEASES, disability, Mortality data, DIFFERENTIAL_MORBIDITY, life expectancy, Life expectancy, Health survey, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, mixed anxiety-depressive disorder, business, Demography
Abstract: Background Compared to men, women live longer but have more years with disability. We assessed the contribution of gender differences in mortality and disability, total and by cause, to women’s excess unhealthy life years (ULYs). Methods We used mortality data for France 2008 from Eurostat, causes of death from the CépiDc-INSERM-database; and disability and chronic conditions data from the French Disability Health Survey 2008–09. ULYs were calculated by the Sullivan method. The contributions of mortality and disability differences to gender differences in ULY were based on decomposition analyses. Results Life expectancy of French women aged 50 was 36.3 years of which 19.0 were ULYs; life expectancy of men was 30.4 years of which 14.2 were ULYs. Of the 4.8 excess ULYs in women, 4.0 years were due to lower mortality. Of these 4.0 ULYs, 1.8 ULY originated from women’s lower mortality from cancer, 0.8 ULY from heart disease and 0.3 ULY from accidents. The remaining 0.8 excess ULY in women were from higher disability prevalence, including higher disability from musculoskeletal diseases (+1.8 ULY) and anxiety-depression (+0.6 ULY) partly offset by lower disability from heart diseases (−0.8 ULY) and accidents (−0.3 ULY). Conclusion Lower mortality and higher disability prevalence contributed to women’s longer life expectancy with disability. Women’s higher disability prevalence due to non-fatal disabling conditions was partly offset by lower disability from heart disease and accidents. Conditions differentially impact gender differences in ULY, depending on whether they are mainly life-threatening or disabling. The conclusions confirm the health-survival paradox.
Published: 2019
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18. Combination of Aerobic Training and Cocoa Flavanols as Effective Therapies to Reduce Metabolic and Inflammatory Disruptions in Insulin-Resistant Rats: The Exercise, Cocoa, and Diabetes Study

Author: Gleide F. Avelar, Bruno Pereira Melo, Danusa Dias Soares, Samuel Penna Wanner, Elsa Heyman, Letícia Maria de Souza Cordeiro, Mara Lívia dos Santos, Romain Meeusen, Joyce Camilla C. Oliveira, Aline Cruz Zacarias, Federal University of Minas Gerais (UFMG), Vrije Universiteit Brussel [Bruxelles] (VUB), Unité de Recherche Pluridisciplinaire Sport, Santé, Société (URePSSS) - ULR 7369 - ULR 4488 (URePSSS), Université d'Artois (UA)-Université de Lille-Université du Littoral Côte d'Opale (ULCO), Universidade Federal de Minas Gerais = Federal University of Minas Gerais [Belo Horizonte, Brazil] (UFMG), Université d'Artois (UA)-Université du Littoral Côte d'Opale (ULCO)-Université de Lille, Université de Lille, Univ. Artois, Univ. Littoral Côte d’Opale, Vrije Universiteit Brussel [Bruxelles] [VUB], Unité de Recherche Pluridisciplinaire Sport, Santé, Société (URePSSS) - ULR 7369, International Relations and Mobility, Physiotherapy, Human Physiology and Anatomy, and Human Physiology and Sports Physiotherapy Research Group
Subjects: Male, medicine.medical_treatment, Medicine (miscellaneous), Adipose tissue, Type 2 diabetes, GLUT4, cytokines, physical exercise, polyphenols, type 2 diabetes, 0302 clinical medicine, Insulin, Orthopedics and Sports Medicine, 2. Zero hunger, 0303 health sciences, Nutrition and Dietetics, medicine.diagnostic_test, biology, food and beverages, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Lipids, Cytokines, Female, Inflammation Mediators, medicine.medical_specialty, 030209 endocrinology & metabolism, 03 medical and health sciences, Insulin resistance, Diabetes mellitus, Internal medicine, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Aerobic exercise, Animals, Humans, Obesity, Rats, Wistar, 030304 developmental biology, Cacao, business.industry, Polyphenols, medicine.disease, Rats, Endocrinology, Diabetes Mellitus, Type 2, biology.protein, Insulin Resistance, business, Lipid profile, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: We aimed to investigate the combined effects of aerobic exercise (EXE) and cocoa flavanol (COCOA) supplementation on performance, metabolic parameters, and inflammatory and lipid profiles in obese insulin-resistant rats. Therefore, 32 male Wistar rats (230–250 g) were fed a high-fat diet and a fructose-rich beverage for 30 days to induce insulin resistance. Next, the rats were randomized into four groups, orally administered placebo solution or COCOA supplementation (45 mg·kg−1), and either remained sedentary or were subjected to EXE on a treadmill at 60% peak velocity for 30 min, for 8 weeks. Blood samples and peripheral tissues were collected and processed to analyze metabolic and inflammatory parameters, lipid profiles, and morphological parameters. Supplementation with COCOA and EXE improved physical performance and attenuated body mass gain, adipose index, and adipocyte area. When analyzed as individual interventions, supplementation with COCOA and EXE improved glucose intolerance and the lipid profile reduced the concentrations of leptin, glucose, and insulin, and reduced homeostasis assessment index (all effects were p p p p
Published: 2021
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19. Optimized Opioid-Neurotensin Multitarget Peptides: From Design to Structure-Activity Relationship Studies

Author: Simon Gonzalez, Dirk Tourwé, Philippe Sarret, Mariana Spetea, Florine Cavelier, Santo Previti, Charlotte Martin, Linda Kunze, Mélanie Vivancos, Stevany Louis, Louis Gendron, Elke Dewolf, Maria Dumitrascuta, Steven Ballet, Emilie Eiselt, Annalisa Blasiol, Chemistry, Faculty of Economic and Social Sciences and Solvay Business School, WE Academic Unit, Vriendenkring VUB, High Resolution NMR Centre, Organic Chemistry, Vrije Universiteit Brussel [Bruxelles] (VUB), University of Innsbruck, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Université de Sherbrooke (UdeS)
Subjects: Agonist, Male, medicine.drug_class, Stereochemistry, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Receptors, Opioid, mu, Pain, Peptide, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 01 natural sciences, Article, 03 medical and health sciences, chemistry.chemical_compound, Mice, Structure-Activity Relationship, Receptors, Opioid, delta, Drug Discovery, medicine, Structure–activity relationship, Animals, Humans, Receptors, Neurotensin, Amino Acid Sequence, Receptor, Peptide sequence, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Tetrapeptide, Chemistry, 0104 chemical sciences, Amino acid, 010404 medicinal & biomolecular chemistry, Disease Models, Animal, Drug Design, Molecular Medicine, Peptides, Oligopeptides, Neurotensin, Protein Binding
Abstract: International audience; Fusion of nonopioid pharmacophores, such as neurotensin, with opioid ligands represents an attractive approach for pain treatment. Herein, the μ-/δ-opioid agonist tetrapeptide H-Dmt-D-Arg-Aba-β-Ala-NH 2 (KGOP01) was fused to NT(8-13) analogues. Since the NTS1 receptor has been linked to adverse effects, selective MOR-NTS2 ligands are preferred. Modifications were introduced within the native NT sequence, particularly a β 3-homo amino acid in position 8 and Tyr 11 substitutions. Combination of β 3 hArg and Dmt led to peptide 7, a MOR agonist, showing the highest NTS2 affinity described to date (K i = 3 pM) and good NTS1 affinity (K i = 4 nM), providing a >1300-fold NTS2 selectivity. The (6-OH)Tic-containing analogue 9 also exhibited high NTS2 affinity (K i = 1.7 nM), with low NTS1 affinity (K i = 4.7 μM), resulting in an excellent NTS2 selectivity (>2700). In mice, hybrid 7 produced significant and prolonged antinociception (up to 8 h), as compared to the KGOP01 opioid parent compound.
Published: 2020
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20. Chloride ions stabilize the glutamate-induced active state of the metabotropic glutamate receptor 3

Author: Jean-Philippe Pin, Ann Van Eeckhaut, Pauline Scholler, Ilse Julia Smolders, Emmanuel Margeat, Linnea Olofsson, Alexandre Cabayé, Philippe Rondard, Fanny Malhaire, Amélie S. Tora, Xavier Rovira, Cyril Goudet, Anne-Marinette Cao, Francine Acher, Hayeon Baik, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Universitat de Vic, Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Vrije Universiteit [Brussels] (VUB), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Vrije Universiteit Brussel (VUB), Pharmaceutical and Pharmacological Sciences, Experimental Pharmacology, and Alliance for Modulation in Epilepsy
Subjects: 0301 basic medicine, Agonist, medicine.drug_class, Allosteric regulation, Glutamic Acid, Chloride, Radioligand Assay, 03 medical and health sciences, Cellular and Molecular Neuroscience, GPCR, Allosteric Regulation, Chlorides, Constitutive activity, Inosine Monophosphate, medicine, Humans, Receptors, AMPA, Allostery, Receptor, Cells, Cultured, G protein-coupled receptor, Pharmacology, Binding Sites, Chemistry, Glutamate receptor, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, 030104 developmental biology, Metabotropic glutamate receptor, Luminescent Measurements, Mutation, Excitatory postsynaptic potential, Biophysics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Metabotropic glutamate receptor 3, Glutamate
Abstract: International audience; Due to the essential roles of glutamate, detection and response to a large range of extracellular concentrations of this excitatory amino acid are necessary for the fine-tuning of brain functions. Metabotropic glutamate receptors (mGluRs) are implicated in shaping the activity of many synapses in the central nervous system. Among the eight mGluR subtypes, there is increasing interest in studying the mGlu3 receptor which has recently been linked to various diseases, including psychiatric disorders. This receptor displays striking functional properties, with a high and, often, full basal activity, making its study elusive in heterologous systems. Here, we demonstrate that Cl− ions exert strong positive allosteric modulation of glutamate on the mGlu3 receptor. We have also identified the molecular and structural determinants lying behind this allostery: a unique interactive “chloride-lock” network. Indeed, Cl− ions dramatically stabilize the glutamate-induced active state of the extracellular domain of the mGlu3 receptor. Thus, the mGlu3 receptors’ large basal activity does not correspond to a constitutive activity in absence of agonist. Instead, it results mostly from a Cl−mediated amplified response to low ambient glutamate concentrations, such as those measured in cell media. This strong interaction between glutamate and Cl− ions allows the mGlu3 receptor to sense and efficiently react to sub-micromolar concentrations of glutamate, making it the most sensitive member of mGluR family.
Published: 2018
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21. Adverse outcome pathways: opportunities, limitations and open questions

Author: Alberto Mantovani, Tanja Waldmann, Bob van de Water, Cristina Cadenas, Hennicke Kamp, Thomas Braunbeck, Annemarie H. Meijer, Mathieu Vinken, Sylvia Escher, Domenico Gadaleta, Patricio Godoy, Anna Forsby, Stefan Schildknecht, Chris T. Evelo, Stefan Höhme, Rosemarie Marchan, Gerhard F. Ecker, Harry Vrieling, Susanne Hougaard Bennekou, Ciarán Fisher, Alice Limonciel, Enrico Mombelli, Rabea Graepel, Marcel Leist, Ahmed Ghallab, Michael Schwarz, Joost B. Beltman, Jens M. Kelm, Albert Braeuning, Olivier Taboureau, Bart van der Burg, Andrea Terron, Ferran Sanz, Frédéric Y. Bois, Steven Dooley, Dinant Kroese, Jan G. Hengstler, Paul Jennings, Egon Willighagen, Barbara Zdrazil, Barry Hardy, Erik H.J. Danen, Bjørn E. V. Koch, David A. Fluri, Christoph van Thriel, Dirk Drasdo, Ben van Ravenzwaay, Iain Gardner, Franz Oesch, Reham Hassan, Raymond Reif, Marvin Martens, Thomas Hartung, University of Konstanz, Department of Forensic Medicine and Veterinary Toxicology [Qena], Faculty of Veterinary Medicine [Qena], South Valley University [Qena]-South Valley University [Qena], Universiteit Leiden, Leibniz Research Centre for Working Environment and Human Factors [Dortmund] (IFADO), Technische Universität Dortmund [Dortmund] (TU), The Danish Epidemiology Science Centre, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Vrije Universiteit Brussel (VUB), BASF [Ludwigshafen], SimCYP Ltd, Institut National de l'Environnement Industriel et des Risques (INERIS), Bundesinstitut für Risikobewertung - Federal Institute for Risk Assessment (BfR), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Modelling and Analysis for Medical and Biological Applications (MAMBA), Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jacques-Louis Lions (LJLL (UMR_7598)), Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Universität Leipzig, Medical University Graz, Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU), University of Heidelberg, Medical Faculty, Universitat Pompeu Fabra [Barcelona] (UPF), Karolinska Institutet [Stockholm], Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), InSphero [Schlieren], University of Vienna [Vienna], Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), BioDetection Systems, Universität Mannheim, Maastricht University [Maastricht], Institut National de la Santé et de la Recherche Médicale (INSERM), IT University of Copenhagen (ITU), Istituto Superiore di Sanità (ISS), Douglas Connect GmbH, Fraunhofer Institute for Toxicology and Experimental Medicine (Fraunhofer ITEM), Fraunhofer (Fraunhofer-Gesellschaft), Carl Zeiss SMT AG, Carl Zeiss, Oberkochen, Faculty of Biology, Division of Physiology, Department of Physiology and Medical Physics, Innsbruck Medical University [Austria] (IMU), BASF, DRC/VIVA/METO, Institut National de l'Environnement Industriel et des Risques, Department of Experimental and Clinical Pharmacology andToxicology [Tübingen], Eberhard Karls Universität Tübingen, Interdisciplinary Centre for Bioinformatics [Leipzig] (IZBI), Universität Leipzig [Leipzig], Institute for Health and Consumer Protection, European Commission - Joint Research Centre, Université Grenoble Alpes - UFR Médecine [ ?-2019] (UGA UFRM [ ?-2019]), Molecular Hepatology - Alcohol Associated Diseases, Department of Medicine II, University of Heidelberg, Medical Faculty of Mannheim-University of Heidelberg, Medical Faculty of Mannheim, BigCat - Bioinformatics and Systems Biology Research Group, UMR-S973, MTi, Université Paris Diderot - Paris 7 (UPD7), Department of Immunology and Cell Biology, Mario Negri Institute, Leiden University, Vrije Universiteit [Brussels] (VUB), Universiteit Leiden [Leiden], BASF SE, 67056 Ludwigshafen, Johannes Gutenberg - University of Mainz (JGU), Centre for Alternatives to Animal Testing (CAAT EU), Universitat Pompeu Fabra [Barcelona], European Food Safety Authority = Autorité européenne de sécurité des aliments, Université Grenoble Alpes (UGA), Universität Mannheim [Mannheim], Istituto Superiore di Sanita [Rome], Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Johannes Gutenberg - Universität Mainz (JGU), IT University of Copenhagen, Molecular and Computational Toxicology, AIMMS, Bioinformatica, RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health, RS: NUTRIM - R4 - Gene-environment interaction, Promovendi NTM, RS: FHML MaCSBio, Publica, Pharmaceutical and Pharmacological Sciences, Connexin Signalling Research Group, Liver Connexin and Pannexin Research Group, and Experimental in vitro toxicology and dermato-cosmetology
Subjects: CCl4, 0301 basic medicine, Proof of non-toxicity, Health, Toxicology and Mutagenesis, CCl, RAPID - Risk Analysis for Products in Development, Biomedical Innovation, Signal transduction, Ecotoxicology, Toxicology, NATURAL-KILLER-CELLS, Prioritization of compounds, Life, Adverse Outcome Pathway, ACTIVATED STELLATE CELLS, ComputingMilieux_MISCELLANEOUS, Risk assessment, TUMOR-NECROSIS-FACTOR, Event (computing), EVIDENCE-BASED TOXICOLOGY, ENVIRONMENTAL CHEMICALS, General Medicine, Toxicokinetics, Multiple hit events Proof of non-toxicity, Evidence-based toxicology, Identification (information), Paracetamol, Risk analysis (engineering), Vinyl acetate, RISK-ASSESSMENT, Systems biology, Construct (philosophy), Healthy Living, Human, Quality Control, READ-ACROSS, Vinyl Compounds, Plasticity, Liver fibrosis, Nanotechnology, Harmonization, Multiple hit events, Biology, History, 21st Century, Risk Assessment, Binning of events, Adverse outcome, 03 medical and health sciences, Adverse outcome pathway, SDG 3 - Good Health and Well-being, ddc:570, Tumor promotion, Journal Article, Animals, Humans, Vinyl acetate Tumor promotion, Regulatory toxicology, Set (psychology), Epidemiological data, Adverse Outcome Pathways, Interspecies extrapolation, 030111 toxicology, SYSTEMS TOXICOLOGY, Nonhuman, Toxicity assay, [INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation, Mice, Inbred C57BL, Multi-scale integration, Metabolism, 030104 developmental biology, DEVELOPMENTAL NEUROTOXICITY, Computational toxicology, ELSS - Earth, Life and Social Sciences, Pathway unidirectionality
Abstract: Adverse outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory purposes. AOP links a molecular initiating event (MIE) to the adverse outcome (AO) via key events (KE), in a way specified by key event relationships (KER). Although this approach to formalize mechanistic toxicological information only started in 2010, over 200 AOPs have already been established. At this stage, new requirements arise, such as the need for harmonization and re-assessment, for continuous updating, as well as for alerting about pitfalls, misuses and limits of applicability. In this review, the history of the AOP concept and its most prominent strengths are discussed, including the advantages of a formalized approach, the systematic collection of weight of evidence, the linkage of mechanisms to apical end points, the examination of the plausibility of epidemiological data, the identification of critical knowledge gaps and the design of mechanistic test methods. To prepare the ground for a broadened and appropriate use of AOPs, some widespread misconceptions are explained. Moreover, potential weaknesses and shortcomings of the current AOP rule set are addressed (1) to facilitate the discussion on its further evolution and (2) to better define appropriate vs. less suitable application areas. Exemplary toxicological studies are presented to discuss the linearity assumptions of AOP, the management of event modifiers and compensatory mechanisms, and whether a separation of toxicodynamics from toxicokinetics including metabolism is possible in the framework of pathway plasticity. Suggestions on how to compromise between different needs of AOP stakeholders have been added. A clear definition of open questions and limitations is provided to encourage further progress in the field. © 2017, Springer-Verlag GmbH Germany.
Published: 2017
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22. Progress against inequalities in mortality : register-based study of 15 European countries between 1990 and 2015

Author: Maica Rodríguez-Sanz, José Rubio Valverde, Katalin Kovács, Mall Leinsalu, Gwenn Menvielle, Johan P. Mackenbach, Henrik Brønnum-Hansen, Ramune Kalediene, Giuseppe Costa, Pekka Martikainen, Matthias Bopp, Wilma J. Nusselder, Patrick Deboosere, Helsinki Inequality Initiative (INEQ), Doctoral Programme in Social Sciences, Demography, Population Research Unit (PRU), Center for Population, Health and Society, Sociology, Public Health, Brussels Interdisciplinary Research centre on Migration and Minorities, Vriendenkring VUB, Interface Demography, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Universität Zürich [Zürich] = University of Zurich (UZH), IT University of Copenhagen (ITU), Università degli studi di Torino = University of Turin (UNITO), Vrije Universiteit Brussel (VUB), Lithuanian University of Health Sciences [Kaunas, Lithuania], Hungarian Demographic Research Institute [Budapest, Hungary], Södertörn University College, National institute for health development Talinn, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Agència de Salut Pública de Barcelona (ASPB), CIBER de Epidemiología y Salud Pública (CIBERESP), and Gestionnaire, Hal Sorbonne Université
Subjects: Male, Epidemiology, [SDV]Life Sciences [q-bio], 0302 clinical medicine, SOCIOECONOMIC INEQUALITIES, MAGNITUDE, Economic inequality, Cause of Death, Health care, Medicine, LIFE EXPECTANCY, Registries, 030212 general & internal medicine, 10. No inequality, media_common, INCOME, 1. No poverty, Public Health, Global Health, Social Medicine and Epidemiology, 3142 Public health care science, environmental and occupational health, [SDV] Life Sciences [q-bio], Europe, Educational Status, Female, 0305 other medical science, medicine.medical_specialty, Inequality, media_common.quotation_subject, Social inequality, 03 medical and health sciences, Sex Factors, Humans, Healthcare Disparities, Sex Distribution, Mortality, Socioeconomic status, 030505 public health, business.industry, Public health, PERSISTENCE, Health Status Disparities, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Social Class, Socioeconomic Factors, HEALTH-CARE, Life expectancy, Demographic economics, Health Expenditures, Trends, business
Abstract: Socioeconomic inequalities in mortality are a challenge for public health around the world, but appear to be resistant to policy-making. We aimed to identify European countries which have been more successful than others in narrowing inequalities in mortality, and the factors associated with narrowing inequalities. We collected and harmonised mortality data by educational level in 15 European countries over the last 25 years, and quantified changes in inequalities in mortality using a range of measures capturing different perspectives on inequality (e.g., ‘relative’ and ‘absolute’ inequalities, inequalities in ‘attainment’ and ‘shortfall’). We determined which causes of death contributed to narrowing of inequalities, and conducted country- and period-fixed effects analyses to assess which country-level factors were associated with narrowing of inequalities in mortality. Mortality among the low educated has declined rapidly in all European countries, and a narrowing of absolute, but not relative inequalities was seen in many countries. Best performers were Austria, Italy (Turin) and Switzerland among men, and Spain (Barcelona), England and Wales, and Austria among women. Ischemic heart disease, smoking-related causes (men) and amenable causes often contributed to narrowing inequalities. Trends in income inequality, level of democracy and smoking were associated with widening inequalities, but rising health care expenditure was associated with narrowing inequalities. Trends in inequalities in mortality have not been as unfavourable as often claimed. Our results suggest that health care expansion has counteracted the inequalities widening effect of other influences. Electronic supplementary material The online version of this article (10.1007/s10654-019-00580-9) contains supplementary material, which is available to authorized users.
Published: 2019
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23. Hepatitis C virus sequence divergence preserves p7 viroporin structural and dynamic features

Author: Latifah Almanea, Juan H. Bolivar, Nicole Zitzmann, François Dehez, Nicole Holzmann, Chris Chipot, Jolyon K. Claridge, Jason R. Schnell, Benjamin P. Oestringer, Oxford Glycobiology Institute, University of Oxford [Oxford], Department of Biochemistry [Oxford], Immunocore Limited, Structural Biology Brussels (SBB), Vrije Universiteit Brussel (VUB), Structural Biology Research Center, VIB, 1050 Brussels, Belgium, VIB-VUB Center for Structural Biology [Bruxelles], VIB [Belgium]-VIB [Belgium], Laboratoire International Associé (LIA), University of Illinois at Urbana-Champaign [Urbana], University of Illinois System-University of Illinois System-Centre National de la Recherche Scientifique (CNRS), Department of Physics [Illinois at Urbana-Champaign, USA], University of Illinois System-University of Illinois System, Laboratoire de Physique et Chimie Théoriques (LPCT), and Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Genotype, Hepatitis C virus, lcsh:Medicine, Hepacivirus, Viral Nonstructural Proteins, medicine.disease_cause, Endoplasmic Reticulum, Ion Channels, Protein Structure, Secondary, Article, Viroporin Proteins, Viroporin, 03 medical and health sciences, Viral Proteins, medicine, Humans, Secretion, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, lcsh:Science, Protein secondary structure, Ion channel, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Genetics, 0303 health sciences, Multidisciplinary, Chemistry, Endoplasmic reticulum, lcsh:R, 030302 biochemistry & molecular biology, Hepatitis C, 3. Good health, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Transmembrane domain, lcsh:Q, Molecular modelling, Solution-state NMR
Abstract: The hepatitis C virus (HCV) viroporin p7 oligomerizes to form ion channels, which are required for the assembly and secretion of infectious viruses. The 63-amino acid p7 monomer has two putative transmembrane domains connected by a cytosolic loop, and has both N- and C- termini exposed to the endoplasmic reticulum (ER) lumen. NMR studies have indicated differences between p7 structures of distantly related HCV genotypes. A critical question is whether these differences arise from the high sequence variation between the different isolates and if so, how the divergent structures can support similar biological functions. Here, we present a side-by-side characterization of p7 derived from genotype 1b (isolate J4) in the detergent 6-cyclohexyl-1-hexylphosphocholine (Cyclofos-6) and p7 derived from genotype 5a (isolate EUH1480) in n-dodecylphosphocholine (DPC). The 5a isolate p7 in conditions previously associated with a disputed oligomeric form exhibits secondary structure, dynamics, and solvent accessibility broadly like those of the monomeric 1b isolate p7. The largest differences occur at the start of the second transmembrane domain, which is destabilized in the 5a isolate. The results show a broad consensus among the p7 variants that have been studied under a range of different conditions and indicate that distantly related HCVs preserve key features of structure and dynamics.
Published: 2019
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24. Neurotensin Analogues Containing Cyclic Surrogates of Tyrosine at Position 11 Improve NTS2 Selectivity Leading to Analgesia without Hypotension and Hypothermia

Author: Louis Gendron, Cecilia Betti, Magali Chartier, Simon Gonzalez, Steven Ballet, Jean-Michel Longpré, Florine Cavelier, Charlotte Martin, Dirk Tourwé, Emilie Eiselt, Philippe Sarret, Université de Cergy Pontoise (UCP), Université Paris-Seine, CHU Toulouse [Toulouse], Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Department of Organic Chemistry, Vrije Universiteit Brussel (VUB), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Department of Physiology and Biophysics, Université de Sherbrooke (UdeS), Chemistry, WE Academic Unit, Vriendenkring VUB, High Resolution NMR Centre, and Organic Chemistry
Subjects: Male, Physiology, Cognitive Neuroscience, Analgesic, GPCR ligands, CHO Cells, Hypothermia, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Pharmacology, Biochemistry, Rats, Sprague-Dawley, 03 medical and health sciences, chemistry.chemical_compound, Cricetulus, 0302 clinical medicine, Cricetinae, medicine, Animals, Humans, Receptors, Neurotensin, Tyrosine, Receptor, Neurotensin, Receptor selectivity, ED50, ComputingMilieux_MISCELLANEOUS, Pain Measurement, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Dose-Response Relationship, Drug, Neurotensin peptides, analgesia, Biological activity, Cell Biology, General Medicine, Rats, 3. Good health, Amino acid, chemistry, NTS2, Hypotension, medicine.symptom, unnatural amino acids, 030217 neurology & neurosurgery, Protein Binding
Abstract: Neurotensin (NT) exerts its analgesic effects through activation of the G protein-coupled receptors NTS1 and NTS2. This opioid-independent antinociception represents a potential alternative for pain management. While activation of NTS1 also induces a drop in blood pressure and body temperature, NTS2 appears to be an analgesic target free of these adverse effects. Here, we report modifications of NT at Tyr11 to increase selectivity toward NTS2, complemented by modifications at the N-terminus to impair proteolytic degradation of the biologically active NT(8-13) sequence. Replacement of Tyr11 by either 6-OH-Tic or 7-OH-Tic resulted in a significant loss of binding affinity to NTS1 and subsequent NTS2 selectivity. Incorporation of the unnatural amino acid β3hLys at position 8 increased the half-life to over 24 h in plasma. Simultaneous integration of both β3hLys8 and 6-OH-Tic11 into NT(8-13) produced a potent and NTS2-selective analogue with strong analgesic action after intrathecal delivery in the rat formalin-induced pain model with an ED50 of 1.4 nmol. Additionally, intravenous administration of this NT analogue did not produce persistent hypotension or hypothermia. These results demonstrate that NT analogues harboring unnatural amino acids at positions 8 and 11 can enhance crucial pharmacokinetic and pharmacodynamic features for NT(8-13) analogues, i.e., proteolytic stability, NTS2 selectivity, and improved analgesic/adverse effect ratio.
Published: 2019
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25. Specialist health care services use in a European cohort of infants born very preterm

Author: Jennifer Zeitlin, Marina Cuttini, Pernille Pedersen, Eva Cloet, Elaine M. Boyle, Janusz Gadzinowski, Anna-Veera Seppänen, Corine Koopman-Esseboom, Henrique Barros, Florence Bodeau-Livinec, Liis Toome, Anna-Karin Edstedt-Bonamy, Rolf F. Maier, Public Health Sciences, Faculty of Medicine and Pharmacy, Pediatrics, Sorbonne Université (SU), Equipe 1 : EPOPé - Épidémiologie Obstétricale, Périnatale et Pédiatrique (CRESS - U1153), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC), École des Hautes Études en Santé Publique [EHESP] (EHESP), DHU Risques Et Grossesse, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Department of Health Sciences [Leicester, UK], University of Leicester, Department of Medicine [Stockholm, Sweden] (Clinical Epidemiology Unit ), Karolinska Institutet [Stockholm], Women's and Children's Health [Stockholm, Sweden], Clinical Care and Management Innovation Research Area [Rome, Italy], Children's Hospital Bambino Gesù IRCCS [Rome], Tallinn Children's Hospital [Tallinn, Estonia], University of Tartu, Children's Hospital [Marburg, Germany] (University Hospital), Philipps University Marburg [Germany], Public Health [Brussels, Belgium], Vrije Universiteit [Brussels] (VUB), Paediatric Neurology [Brussels, Belgium], Universitair Ziekenhuis [Brussels, Belgium], Department of Neonatology [Utrecht, the Netherlands] (Wilhelmina Children's Hospital), University Medical Center [Utrecht], Department of Neonatology [Hvidovre, Denmark], Hvidovre Hospital, Department of Neonatology [Poznań, Poland], Poznan University of Medical Sciences [Poznan, Poland], ISPUP-EPIUnit, University of Porto Medical School and Institute of Public Health, ISPUP-EPIUnit [Porto, Portugal], Universidade do Porto [Porto], The research received funding from the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement No 259882 and received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 633724. Additional funding is acknowledged from the following regions: France (French Institute of Public Health Research/Institute of Public Health and its partners the French Health Ministry, the National Institute of Health and Medical Research, the National Institute of Cancer, and the National Solidarity Fund for Autonomy, grant ANR-11-EQPX-0038 from the National Research Agency through the French Equipex Program of Investments in the Future, and the PremUp Foundation), Poland (2012- 2015 allocation of funds for international projects from the Polish Ministry of Science and Higher Education), Sweden (Stockholm County Council [ALF-project and Clinical Research Appointment] and by the Department of Neonatal Medicine, Karolinska University Hospital), UK (funding for The Neonatal Survey from Neonatal Networks for East Midlands and Yorkshire and the Humber regions). Anna-Veera Seppänen has a doctoral contract funded by Sorbonne Université, Collège Doctoral, Paris, France., Effective Perinatal Intensive Care in Europe (EPICE) research group : BELGIUM: Flanders (E Martens, G Martens, P Van Reempts), DENMARK: Eastern Region (K Boerch, A Hasselager, L Huusom, O Pryds, T Weber), ESTONIA (L Toome, H Varendi), FRANCE: Burgundy, Ile-de France and Northern Region (PY Ancel, B Blondel, A Burguet, PH Jarreau, P Truffert), GERMANY: Hesse (RF Maier, B Misselwitz, S Schmidt), Saarland (L Gortner), ITALY: Emilia Romagna (D Baronciani, G Gargano), Lazio (R Agostino, D DiLallo, F Franco), Marche (V Carnielli), M Cuttini, NETHERLANDS: Eastern & Central (C Koopman-Esseboom, A Van Heijst, J Nijman), POLAND: Wielkopolska (J Gadzinowski, J Mazela), PORTUGAL: Lisbon and Tagus Valley (LM Graça, MC Machado), Northern region (C Rodrigues, T Rodrigues), H Barros, SWEDEN: Stockholm (AK Bonamy, M Norman, E Wilson), UK: East Midlands and Yorkshire and Humber (E Boyle, ES Draper, BN Manktelow), Northern Region (AC Fenton, DWA Milligan), INSERM, Paris (J Zeitlin, M Bonet, A Piedvache)., ANR-11-EQPX-0038/11-EQPX-0038,RE-CO-NAI,Plateforme de REcherche sur les COhortes d'enfants suivis depuis la NAIssance(2011), European Project: 259882,EC:FP7:HEALTH,FP7-HEALTH-2010-two-stage,EPICE(2011), European Project: 633724,H2020,H2020-PHC-2014-two-stage,SHIPS(2015), Université Paris Descartes - Paris 5 (UPD5)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vrije Universiteit Brussel (VUB), Universidade do Porto, ANR-11-EQPX-0038,RE-CO-NAI,Plateforme de REcherche sur les COhortes d'enfants suivis depuis la NAIssance(2011), Seppanen, Anna-Veera, Equipements d'excellence - Plateforme de REcherche sur les COhortes d'enfants suivis depuis la NAIssance - - RE-CO-NAI2011 - ANR-11-EQPX-0038 - EQPX - VALID, Effective Perinatal Intensive Care in Europe: translating knowledge into evidence based practice - EPICE - - EC:FP7:HEALTH2011-01-01 - 2015-12-31 - 259882 - VALID, Screening to improve Health In very Preterm infantS in Europe - SHIPS - - H20202015-09-01 - 2018-08-31 - 633724 - VALID, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Philipps Universität Marburg = Philipps University of Marburg, Universidade do Porto = University of Porto, and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 030506 rehabilitation, medicine.medical_specialty, Population, Clinical Neurology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Developmental Neuroscience, Risk Factors, Intensive care, Health care, medicine, Humans, Pediatrics, Perinatology, and Child Health, Geography, Medical, education, education.field_of_study, business.industry, Medical record, Infant, Newborn, Infant, Low Birth Weight, Patient Acceptance of Health Care, medicine.disease, 3. Good health, Europe, Low birth weight, Socioeconomic Factors, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Child, Preschool, Infant, Extremely Premature, Family medicine, Infant, Small for Gestational Age, Pediatrics, Perinatology and Child Health, Cohort, Small for gestational age, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), medicine.symptom, 0305 other medical science, business, 030217 neurology & neurosurgery, Specialization, Cohort study
Abstract: Children born very preterm require additional specialist care because of the health and developmental risks associated with preterm birth, but information on their health service use is sparse. We sought to describe the use of specialist services by children born very preterm in Europe.We analysed data from the multi-regional, population-based Effective Perinatal Intensive Care in Europe (EPICE) cohort of births before 32 weeks' gestation in 11 European countries. Perinatal data were abstracted from medical records and parents completed a questionnaire at 2 years corrected age (4322 children; 2026 females, 2296 males; median gestational age 29wks, interquartile range [IQR] 27-31wks; median birthweight 1230g, IQR 970-1511g). We compared parent-reported use of specialist services by country, perinatal risk (based on gestational age, small for gestational age, and neonatal morbidities), maternal education, and birthplace.Seventy-six per cent of the children had consulted at least one specialist, ranging across countries from 53.7% to 100%. Ophthalmologists (53.4%) and physiotherapists (48.0%) were most frequently consulted, but individual specialists varied greatly by country. Perinatal risk was associated with specialist use, but the gradient differed across countries. Children with more educated mothers had higher proportions of specialist use in three countries.Large variations in the use of specialist services across Europe were not explained by perinatal risk and raise questions about the strengths and limits of existing models of care.Use of specialist services by children born very preterm varied across Europe. This variation was observed for types and number of specialists consulted. Perinatal risk was associated with specialist care, but did not explain country-level differences. In some countries, mothers' educational level affected use of specialist services.UTILIZACIÓN DE SERVICIOS DE SALUD ESPECIALIZADOS EN UN ESTUDIO DE COHORTE EUROPEO DE NIÑOS NACIDOS MUY PREMATUROS: OBJETIVO: Niños nacidos muy prematuramente requieren cuidados especializados adicionales debido a su salud y a los riesgos asociados con la prematuros, sin embargo la información sobre el uso de servicios de salud es escasa. Buscamos describir la utilización de servicios especializados por niños nacidos muy prematuramente, en Europa. MÉTODO: Analizamos datos de una cohorte de nacimientos ocurridos antes de las 32 semanas de gestación tomados del Effective Perinatal Intensive Care in Europe (EPICE), basado en la población y multirregional, en 11 países europeos. Los datos perinatales fueron extraídos de las historias clínicas y los padres completaron un cuestionario a los 2 años de edad corregida (4.322 niños; 2026 sexo femenino, 2.296 masculino; edad gestacional mediana 29 semanas, rango intercuartílico (IQR) 27-31 semanas; mediana de peso de nacimiento 1.230 gr, IQR 970-1.511 gr). Comparamos el uso de servicios especializados (según informe de los padres) por país, riesgo perinatal (basado en edad gestacional, bajo peso para edad gestacional y morbilidades neonatales), educación materna y lugar de nacimiento. RESULTADOS: En total 65% de los niños habían consultado por lo menos a un especialista, con un rango entre países de 53,7% a 100%. Los especialistas más frecuentemente consultados fueron Oftalmólogos (53,4%) y Fisioterapeutas (48%) pero los especialistas consultados por cada individuo variaron mucho según el país. El riesgo perinatal se asoció al uso de especialista, pero el gradiente varió entre los países. Niños de madres con mayor nivel educativo tuvieron mayor proporción de uso de especialistas en tres países. INTERPRETACIÓN: Las grandes variaciones en el uso de servicios especializados en Europa no fueron explicadas por el riesgo perinatal y arrojan cuestionamientos sobre las fortalezas y limitaciones de los modelos de cuidados existentes.USO DE SERVIÇOS DE SAÚDE ESPECIALIZADOS EM UMA COORTE EUROPÉIA DE LACTENTES NASCIDOS MUITO PREMATUROS: OBJETIVO: Crianças nascidas muito prematuras requerem cuidado especializado adicional por causa dos riscos à saúde e ao desenvolvimento associados ao nascimento premature, mas informações sobreo uso de serviços de saúde são escassas. Procuramos descrever o uso de serviços especializados por crianças nascidas muito prematuras na Europa. MÉTODO: Analisamos dados de uma coorte populacional multi-regional, do Cuidado Intensivo Neonatal Efetivo na Europa (EPICE), com lactentes nascidos antes de 32 semanas de gestação em 11 países europeus. Dados perinatais foram extraídos dos registros médicos, e os pais completaram um questionário com 2 anos de idade corrigida (4.322 crianças; 2.026 do sexo feminino, 2.296 do sexo masculino; idade gestacional mediana 29semanas, intervalo interquartile [IIQ] 27-31sem; peso ao nascimento mediano 1,230g, IIQ 970-1511g). Comparamos o uso de serviços especializados reportados pelos pais por país, risco perinatal (com base na idade gestacional, pequeno para a idade gestacional e morbidades neonatais), educação materna e local de nascimento. RESULTADOS: Setenta e seis por cento das crianças consultou pelo menos um especialista, variando entre países de 53,7 a 100%. Oftalmologistas (53,4%) e fisioterapeutas (48,0%) foram os mais frequentemente consultados, mas os especialistas individuais variaram bastante por país. O risco perinatal se associou com uso de serviços especializados, mas o gradient diferiu entre países. Crianças com mães mais educadas tinham maior proporção de uso de especialistas em três países. INTERPRETAÇÃO: Grandes variações no uso de serviços especializados na Europa não foram explicadas pelo risco perinatal, e levantam questões sobre as forças e limitações dos modelos de cuidado existentes.
Published: 2019
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26. Neuraxial analgesia is not associated with an increased risk of post-partum relapses in MS

Author: Caroline Lavie, Fabien Rollot, Françoise Durand-Dubief, Romain Marignier, Iuliana Ionescu, Romain Casey, Thibault Moreau, Patricia Tourniaire, Michael Hutchinson, Marie Béatrice D’Hooghe, David-Axel Laplaud, Pierre Clavelou, Jérôme De Sèze, Marc Debouverie, David Brassat, Jean Pelletier, Christine Lebrun-Frenay, Emmanuelle Le Page, Giovanni Castelnovo, Eric Berger, Patrick Hautecoeur, Olivier Heinzlef, Luca Durelli, Marinella Clerico, Maria Trojano, Francesco Patti, Sandra Vukusic, A. Alpérovitch, H. Carton, M.B. d’Hooghe, O. Hommes, M. Hutchinson, P. Adeleine, A. Biron, P. Cortinovis-Tourniaire, J. Grimaud, M. Hours, T. Moreau, S. Vukusic, C. Confavreux, G. Chauplannaz, D. Latombe, M. Clanet, G. Lau, L. Rumbach, J.Y. Goas, F. Rouhart, A. Mazingue, E. Roullet, M. Madigand, P. Hautecoeur, P. Brunet, G. Edan, C. Allaire, G. Riffault, J. Leche, T. Benoit, C. Simonin, F. Ziegler, J.C. Baron, Y. Rivrain, R. Dumas, D. Loche, J.C. Bourrin, B. Huttin, B. Delisse, I. Gibert, C. Boulay, M. Verceletto, G. Durand, G. Bonneviot, R. Gil, M.A. Hedreville, C. Belair, R.J. Poitevin, J.L. Devoize, P. Wyremblewski, F. Delestre, A. Setiey, G. Comi, M. Filippi, A. Ghezzi, V. Martinelli, P. Rossi, M. Zaffaroni, M.R. Tola, M.P. Amato, C. Fioretti, G. Meucci, M. Inglese, G.L. Mancardi, D. Gambi, A. Thomas, M. Cavazzuti, A. Citterio, A. Heltberg, H.J. Hansen, O. Fernandez, F. Romero, T. Arbizu, J.J. Hernandez, C. De Andres de Frutos, D. Geffner Sclarky, Y. Aladro Benito, P. Reyes Yanes, M Aguilar, J.A. Burguera, R. Yaya, W. Bonakim Dib, D. Arzua-Mouronte, C.J.M. Sindic, R. Medaer, H. Roose, K.M.J. Geens, D. Guillaume, M. Van Zandycke, J. Janssens, M. Cornette, L. Mol, F. Weilbach, P. Flachenecker, H.P. Hartung, J. Haas, I. Tendolkar, E. Sindrn, H.W. Kölmel, D. Reichel, M. Rauch, S. Preuss, S. Poser, E. Mauch, S. Strausser-Fuchs, H. Kolleger, S. Hawkins, S.J.L. Howell, J.E. Rees, A. Thompson, M. Johnson, M. Boggild, R.P. Gregory, D. Bates, I. Bone, C. Polman, S. Frequin, P. Jongen, J. Correia de Sa, M.E. Rio, S. Huber, J. Lechner-Scott, L. Kappos, I. Ionescu, C. Cornu, M. El-Etr, E.E. Baulieu, M Schumacher, D.H. Miller, M. Pugeat, C. d’Archangues, J. Conard, J. Ménard, R. Sitruk-Ware, C. Pelissier, S. Dat, J. Belaïsch-Allard, N. Athéa, D. Büschsenschutz, O. Lyon-Caen, R. Gonsette, J.P. Boissel, P. Ffrench, F. Durand-Dubief, F. Cotton, C. Pachai, L. Bracoud, G. Androdias, R. Marignier, D.A. Laplaud, S. Wiertlewski, C. Lanctin-Garcia, G. Couvreur, G. Madinier, P. Clavelou, F. Taithe, D. Aufauvre, N. Guy, A. Ferrier, J. De Sèze, N. Collongues, M. Debouverie, F. Viala, D. Brassat, A. Gerdelat-Mas, P. Henry, J. Pelletier, A. Rico-Lamy, C. Lebrun-Frenay, E. Lepage, V. Deburghraeve, G. Castelnovo, E. Berger, M. Blondiau, O. Heinzlef, M. Coustans, C. Clerc, L. Rieu, M. Lauxerois, G. Hinzelin, J.C. Ouallet, D. Minier, P. Vion, N. Gromaire-Fayolle, N. Derache, E. Thouvenot, M. Sallansonnet-Froment, P. Tourniaire, L. Toureille, F. Borgel, B. Stankoff, C. Moroianu, A.M. Guennoc, C.L. Tournier-Gervason, S. Peysson, M. Trojano, F. Patti, E. D’Amico, L. Motti, L. Durelli, A. Tavella, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Observatoire Français de la Sclérose En Plaques [Lyon] (OFSEP), Service de neurologie fonctionnelle et d'épileptologie [Hôpital Pierre Wertheimer-HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Henri Duffaut (Avignon), National MS Center Melsbroek, Vrije Universiteit Brussel [Bruxelles] (VUB), Vrije Universiteit Brussel (VUB), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service de Neurologie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Laboratoire de Neuroimagerie in Vivo (LNV), CHU Strasbourg-Centre National de la Recherche Scientifique (CNRS), Les Hôpitaux Universitaires de Strasbourg (HUS), Service de neurologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Maladies chroniques, santé perçue, et processus d'adaptation (APEMAC), Université de Lorraine (UL), Neurologie vasculaire, pathologie neuro-dégénérative et explorations fonctionnelles du système nerveux [Toulouse], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse], Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Universitaire de Nice (CHU Nice), Université Côte d'Azur (UCA), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service de Neurologie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Groupe Hospitalier de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL), centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], Università degli studi di Torino = University of Turin (UNITO), University of Catania [Italy], Hospices Civils de Lyon, Departement de Neurologie (HCL), Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), CHU Toulouse [Toulouse], Protéines membranaires transductrices d'énergie (PMTE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut des Géosciences de l’Environnement (IGE), Institut de Recherche pour le Développement (IRD)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre de Recherches sur les Macromolécules Végétales (CERMAV ), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Environnement Ville Société (EVS), École normale supérieure - Lyon (ENS Lyon)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet [Saint-Étienne] (UJM)-École Nationale des Travaux Publics de l'État (ENTPE)-École nationale supérieure d'architecture de Lyon (ENSAL)-Centre National de la Recherche Scientifique (CNRS), Solvay (France), Laboratoire des Mécanismes et Transfert en Géologie (LMTG), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Institute of Evolutionary Biology, University of Edinburgh, Université de Lille, Sciences et Technologies, Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Différenciation, interaction, activation et migration des sous-populations lymphocitaires humaines, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Motricité, interactions, performance EA 4334 / Movement - Interactions - Performance (MIP), Le Mans Université (UM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR des Sciences et Techniques des Activités Physiques et Sportives (UFR STAPS), Laboratoire Ecologie Fonctionnelle et Environnement (ECOLAB), Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Laboratoire de Chimie Physique D'Orsay (LCPO), Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), RMN et optique : De la mesure au biomarqueur, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Department of Neurology, CHU Lyon, Institut de Recherche de Chimie Paris (IRCP), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ministère de la Culture (MC), Hôpital de Hautepierre [Strasbourg], Laboratoire de Réactivité des Surfaces et des Interfaces (LRSI), Département de Physico-Chimie (DPC), CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Empenn, Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SIGNAUX ET IMAGES NUMÉRIQUES, ROBOTIQUE (IRISA-D5), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes 1 (UR1), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Service de Neurologie [Rennes] = Neurology [Rennes], CHU Pontchaillou [Rennes], Biologie des Interactions Neurones / Glie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation pour l'Aide à la Recherche sur la Sclérose en Plaques, European Leukodystrophies Association, PHRC National, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pierre Wertheimer, Département de Neurologie, Laboratoire de Mathématiques (LAMA), Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Nottingham Scientific Limited, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Turin, Università degli studi di Torino (UNITO), University of Bari Aldo Moro (UNIBA), Department of Neurosciences, Università degli studi di Catania [Catania], Centre de recherche en neurosciences de Lyon (CRNL), Neuroépidémiologie, Institut de Physique du Globe de Paris (IPGP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Centre National de la Recherche Scientifique (CNRS), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut de Recherche pour le Développement (IRD)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-École nationale supérieure d'architecture de Lyon (ENSAL)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-École Nationale des Travaux Publics de l'État (ENTPE)-Université Jean Monnet [Saint-Étienne] (UJM)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université Lumière - Lyon 2 (UL2)-École normale supérieure - Lyon (ENS Lyon), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ministère de la Culture (MC), Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lavie, Caroline, Rollot, Fabien, Durand-Dubief, Françoise, Marignier, Romain, Ionescu, Iuliana, Casey, Romain, Moreau, Thibault, Tourniaire, Patricia, Hutchinson, Michael, D’Hooghe, Marie Béatrice, Laplaud, David-Axel, Clavelou, Pierre, De Sèze, Jérôme, Debouverie, Marc, Brassat, David, Pelletier, Jean, Lebrun-Frenay, Christine, Le Page, Emmanuelle, Castelnovo, Giovanni, Berger, Eric, Hautecoeur, Patrick, Heinzlef, Olivier, Durelli, Luca, Clerico, Marinella, Trojano, Maria, Patti, Francesco, Vukusic, Sandra, on behalf of PRIMS and POPARTMUS, Investigator, Filippi, Massimo, Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], Environnement, Ville, Société (EVS), École normale supérieure de Lyon (ENS de Lyon)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-École Nationale des Travaux Publics de l'État (ENTPE)-École nationale supérieure d'architecture de Lyon (ENSAL)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Neuroimagerie: méthodes et applications (Empenn), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Laboratoire de glaciologie et géophysique de l'environnement (LGGE), Observatoire des Sciences de l'Univers de Grenoble (OSUG), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches sur les Macromolécules Végétales (CERMAV), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Laboratoire Motricité, Interactions, Performance, Université de Nantes (UN), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS), Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Ministère de la Culture (MC), Centre Hospitalier Universitaire de Strasbourg (CHU de Strasbourg ), CEA-Direction de l'Energie Nucléaire (CEA-DEN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-CEA-Direction de l'Energie Nucléaire (CEA-DEN), Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Service de neurologie [Besançon], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Service de Neurologie [CHU Besançon], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Service de Neurologie [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Clinical sciences, Neuroprotection & Neuromodulation, and Neurology
Subjects: relapses, Neurology, [SDV]Life Sciences [q-bio], MESH: Pregnancy Complications / physiopathology, 0302 clinical medicine, MESH: Pregnancy, Anesthesia, Conduction, Recurrence, MESH: Anesthesia, Conduction / adverse effects, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, reproductive and urinary physiology, relapse, Postpartum Period, post-partum, MESH: Follow-Up Studies, MESH: Multiple Sclerosis / physiopathology, Obstetrical Analgesia, MESH: Multiple Sclerosis / chemically induced, Anesthesia, Female, pregnancy, Adult, medicine.medical_specialty, Clinical Neurology, Multiple sclerosis, MESH: Postpartum Period, 03 medical and health sciences, medicine, Humans, Multiple sclerosi, Post partum, Retrospective Studies, Pregnancy, MESH: Humans, MESH: Pregnancy Complications / chemically induced, business.industry, Neurotoxicity, MESH: Adult, MESH: Retrospective Studies, neuraxial analgesia, medicine.disease, MESH: Recurrence, Multiple sclerosis, neuraxial analgesia, post-partum, pregnancy, Pregnancy Complications, Increased risk, Neurology (clinical), [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Female, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract: Background: Obstetrical analgesia remains a matter of controversy because of the fear of neurotoxicity of local anesthetics on demyelinated fibers or their potential relationship with subsequent relapses. Objective: To assess the impact of neuraxial analgesia on the risk of relapse during the first 3 months post-partum, with a focus on women who experienced relapses during pregnancy. Methods: We analyzed data of women followed-up prospectively during their pregnancies and at least 3 months post-partum, collected in the Pregnancy in Multiple Sclerosis (PRIMS) and Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPARTMUS) studies between 1992–1995 and 2005–2012, respectively. The association of neuraxial analgesia with the occurrence of a post-partum relapse was estimated by logistic regression analysis. Results: A total of 389 women were included, 215 from PRIMS and 174 from POPARTMUS. In total, 156 women (40%) had neuraxial analgesia. Overall, 24% experienced a relapse during pregnancy and 25% in the 3 months post-partum. Women with a pregnancy relapse were more likely to have a post-partum relapse (odds ratio (OR) = 1.83, p = 0.02), independently of the use of neuraxial analgesia. There was no association between neuraxial analgesia and post-partum relapse (OR = 1.08, p = 0.78). Conclusion: Neuraxial analgesia was not associated with an increased risk of post-partum relapses, whatever multiple sclerosis (MS) activity during pregnancy.
Published: 2019
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27. Contribution of chronic conditions to gender disparities in health expectancies in Belgium, 2001, 2004 and 2008

Author: Renata Tiene de Carvalho Yokota, Patrick Deboosere, Françoise Renard, WJ Nusselder, Jean Tafforeau, Herman Van Oyen, Jean-Marie Robine, Sciensano [Bruxelles], Réseau International des Instituts Pasteur (RIIP), Erasmus University Medical Center [Rotterdam] (Erasmus MC), CERMES3 - Centre de recherche Médecine, sciences, santé, santé mentale, société (CERMES3 - UMR 8211 / U988 / UM 7), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-École des hautes études en sciences sociales (EHESS), Vrije Universiteit Brussel (VUB), École des hautes études en sciences sociales (EHESS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ORANGE, Colette, Faculty of Economic and Social Sciences and Solvay Business School, Interface Demography, Sociology, and Vriendenkring VUB
Subjects: Adult, Male, Adolescent, Cross-sectional study, Trachea Cancer, [SHS]Humanities and Social Sciences, Young Adult, 03 medical and health sciences, Life Expectancy, Sex Factors, 0302 clinical medicine, Belgium, Journal Article, Humans, Medicine, Disabled Persons, 030212 general & internal medicine, Gender disparities in health, Young adult, 10. No inequality, Aged, Aged, 80 and over, business.industry, 030503 health policy & services, Public Health, Environmental and Occupational Health, Health Status Disparities, Middle Aged, 3. Good health, Cross-Sectional Studies, Chronic Disease, Life expectancy, Female, Healthy ageing, Gender gap, [SHS] Humanities and Social Sciences, 0305 other medical science, business, Lower mortality, Forecasting, Demography
Abstract: International audience; Background : We Aim :ed to investigate the contribution of chronic conditions to gender differences in disability-free life expectancy (DFLE) and life expectancy with disability (LED) in Belgium in 2001, 2004 and 2008. Methods: Data on disability and chronic conditions from participants of the 2001, 2004 and 2008 Health Interview Surveys in Belgium were used to estimate disability prevalence by cause using the attribution method. Disability prevalence was applied to life tables to estimate DFLE and LED using the Sullivan method. Decomposition techniques were used to assess the contribution of mortality and disability and further of causes of death and disability to gender disparities in DFLE and LED. Results: Higher LE, DFLE and LED were observed for women compared with men in all years studied. A decrease in the gender gap in LE (2001: 5.9; 2004: 5.6; 2008: 5.3) was observed in our cross-sectional approach followed by a decrease in gender differences in DFLE (2001: 1.9; 2004: 1.3; 2008: 0.5) and increase in LED (2001: 4.0; 2004: 4.4; 2008: 4.8). The higher LED in women was attributed to their lower mortality due to lung/larynx/trachea cancer, ischaemic heart diseases, and external causes (2001 and 2004) and higher disability prevalence due to musculoskeletal conditions (2008). Higher DFLE was observed in women owing to their lower mortality from lung/larynx/trachea cancer, ischaemic heart diseases, digestive cancer and chronic respiratory diseases. Conclusion: To promote healthy ageing of populations, priority should be given to reduce the LED disadvantage in women by targeting non-fatal diseases, such as musculoskeletal conditions.
Published: 2019
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28. Determinants of inequalities in life expectancy : an international comparative study of eight risk factors

Author: José Rubio Valverde, Gwenn Menvielle, Pekka Martikainen, Johan P. Mackenbach, Katalin Kovács, Henrik Brønnum-Hansen, Ramune Kalediene, Mall Leinsalu, Wilma J. Nusselder, Matthias Bopp, Enrique Regidor, Patrick Deboosere, Gestionnaire, Hal Sorbonne Université, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Universität Zürich [Zürich] = University of Zurich (UZH), IT University of Copenhagen (ITU), Vrije Universiteit Brussel (VUB), Lithuanian University of Health Sciences [Kaunas, Lithuania], Hungarian Demographic Research Institute [Budapest, Hungary], Stockholm Centre for Health and Social Change [Stockholm, Sweden], Södertörn University College, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), CIBER de Epidemiología y Salud Pública (CIBERESP), University of Zurich, Mackenbach, Johan P, Brussels Interdisciplinary Research centre on Migration and Minorities, Vriendenkring VUB, Sociology, Interface Demography, IT University of Copenhagen, University of Helsinki, Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Helsinki Inequality Initiative (INEQ), Population Research Unit (PRU), Center for Population, Health and Society, and Public Health
Subjects: Male, Health Behavior, 01 natural sciences, 0302 clinical medicine, Risk Factors, Medicine, SOCIOECONOMIC-STATUS, 030212 general & internal medicine, media_common, Aged, 80 and over, education.field_of_study, lcsh:Public aspects of medicine, Smoking, 1. No poverty, Longevity, Public Health, Global Health, Social Medicine and Epidemiology, Middle Aged, 3142 Public health care science, environmental and occupational health, 3. Good health, Europe, 614.2 [udc], 8. Economic growth, Female, HEALTH, Adult, Inequality, Alcohol Drinking, media_common.quotation_subject, Population, 610 Medicine & health, 03 medical and health sciences, Life Expectancy, SDG 3 - Good Health and Well-being, MILLION MEN, Humans, Social determinants of health, 0101 mathematics, Risk factor, Life expectancy, Health Status, Health services accessibility, Socioeconomic factors, education, Socioeconomic status, EDUCATIONAL INEQUALITIES, Exercise, Aged, Consumption (economics), business.industry, MORTALITY, 010102 general mathematics, Body Weight, Public Health, Environmental and Occupational Health, lcsh:RA1-1270, CONSUMPTION, Health Status Disparities, 10060 Epidemiology, Biostatistics and Prevention Institute (EBPI), 2739 Public Health, Environmental and Occupational Health, Diet, SOCIAL DETERMINANTS, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, 2014 SPECIAL MODULE, Socioeconomic Factors, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, EUROPEAN COUNTRIES, Demography
Abstract: BACKGROUND: Socioeconomic inequalities in longevity have been found in all European countries. We aimed to assess which determinants make the largest contribution to these inequalities.METHODS: We did an international comparative study of inequalities in risk factors for shorter life expectancy in Europe. We collected register-based mortality data and survey-based risk factor data from 15 European countries. We calculated partial life expectancies between the ages of 35 years and 80 years by education and gender and determined the effect on mortality of changing the prevalence of eight risk factors-father with a manual occupation, low income, few social contacts, smoking, high alcohol consumption, high bodyweight, low physical exercise, and low fruit and vegetable consumption-among people with a low level of education to that among people with a high level of education (upward levelling scenario), using population attributable fractions.FINDINGS: In all countries, a substantial gap existed in partial life expectancy between people with low and high levels of education, of 2·3-8·2 years among men and 0·6-4·5 years among women. The risk factors contributing most to the gap in life expectancy were smoking (19·8% among men and 18·9% among women), low income (9·7% and 13·4%), and high bodyweight (7·7% and 11·7%), but large differences existed between countries in the contribution of risk factors. Sensitivity analyses using the prevalence of risk factors in the most favourable country (best practice scenario) showed that the potential for reducing the gap might be considerably smaller. The results were also sensitive to varying assumptions about the mortality risks associated with each risk factor.INTERPRETATION: Smoking, low income, and high bodyweight are quantitatively important entry points for policies to reduce educational inequalities in life expectancy in most European countries, but priorities differ between countries. A substantial reduction of inequalities in life expectancy requires policy actions on a broad range of health determinants.FUNDING: European Commission and Network for Studies on Pensions, Aging, and Retirement.
Published: 2019
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29. Crystal structure of human Mediator subunit MED23

Author: Didier Monté, Bernard Clantin, Frédérique Dewitte, Zoé Lens, Prakash Rucktooa, Els Pardon, Jan Steyaert, Alexis Verger, Vincent Villeret, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Structural Biology Brussels (SBB), Vrije Universiteit [Brussels] (VUB), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Vrije Universiteit Brussel (VUB), Université de Lille-Centre National de la Recherche Scientifique (CNRS), ANR-16-CE12-0021,MEDNET,Le complexe Médiateur: d'un réseau d'interactions protéine-protéine à la régulation génique in vivo(2016), Department of Bio-engineering Sciences, and Structural Biology Brussels
Subjects: Mediator Complex, Chemistry(all), [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Biochemistry, Genetics and Molecular Biology(all), Science, Amino Acid Motifs, Physics and Astronomy(all), Single-Domain Antibodies, Crystallography, X-Ray, Recombinant Proteins, Article, Protein Subunits, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Protein Domains, Humans, lcsh:Q, lcsh:Science, Crystallization, ComputingMilieux_MISCELLANEOUS
Abstract: The Mediator complex transduces regulatory information from enhancers to promoters and performs essential roles in the initiation of transcription in eukaryotes. Human Mediator comprises 26 subunits forming three modules termed Head, Middle and Tail. Here we present the 2.8 Å crystal structure of MED23, the largest subunit from the human Tail module. The structure identifies 25 HEAT repeats-like motifs organized into 5 α-solenoids. MED23 adopts an arch-shaped conformation, with an N-terminal domain (Nter) protruding from a large core region. In the core four solenoids, motifs wrap on themselves, creating triangular-shaped structural motifs on both faces of the arch, with extended grooves propagating through the interfaces between the solenoid motifs. MED23 is known to interact with several specific transcription activators and is involved in splicing, elongation, and post-transcriptional events. The structure rationalizes previous biochemical observations and paves the way for improved understanding of the cross-talk between Mediator and transcriptional activators., Mediator is a large multi-subunits complex essential to the regulation of transcription by RNA pol II. Here the authors report the crystal structure of MED23—one of the largest subunits of the complex together with MED1 and MED14—revealing a complex architecture and filling an important gap in the structural characterization of Mediator.
Published: 2018
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30. Work-Related Outcomes in Self-Employed Cancer Survivors: A European Multi-country Study

Author: Caroline Alleaume, Angela G. E. M. de Boer, Alain Paraponaris, Sietske J. Tamminga, Nick Van Campenhout, Elke Van Hoof, Steffen Torp, Marja-Liisa Lindbohm, Linda Sharp, Department of Health, Social & Welfare Studies [Tønsberg, Norway], University of South-Eastern Norway (USN), Aix-Marseille Sciences Economiques (AMSE), École des hautes études en sciences sociales (EHESS)-Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), Observatoire régional de la santé Provence-Alpes-Côte d'Azur [Marseille] (ORS PACA), Faculty of Psychology and Education Sciences [Brussels, Belgium], Vrije Universiteit [Brussels] (VUB), Finnish Institute of Occupational Health [Helsinki, Finland], University of Tampere [Finland], Coronel Institute of Occupational Health [Amsterdam, The Netherlands] (Academic Medical Center), Amsterdam Public Health Research Institute [The Netherlands], Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Health & Society [Newcastle upon Tyne, UK], Newcastle University [Newcastle], Brussels Heritage Lab, Psychology, Brain, Body and Cognition, Clinical and Lifespan Psychology, Faculty of Law and Criminology, University College of Southeast Norway (USN), ORS PACA, École des hautes études en sciences sociales (EHESS)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Vrije Universiteit Brussel (VUB), National Cancer Registry Ireland (NCRIE), KOm op tegen Kanker, Flemish Cancer League (Belgium) Nordic Cancer Union (Finland) Finnish Work Environment Fund (Finland) Finnish Cancer Organisations (Finland) National Cancer Institute (Institut National du Cancer, France) Health Research Board (Ireland) Irish Cancer Society (Ireland) Prostate Cancer UK (Ireland) Health Research Board (UK) Irish Cancer Society (UK) Prostate Cancer UK (UK) Dutch Cancer Society (Netherlands) Norwegian Cancer Society (Norway), Lhuillier, Elisabeth, Coronel Institute of Occupational Health, APH - Societal Participation & Health, APH - Quality of Care, and CCA - Cancer Treatment and Quality of Life
Subjects: Employment, Quality of life, Social security, 030506 rehabilitation, Employment/classification, Return to work, Social Welfare, Work related, 03 medical and health sciences, 0302 clinical medicine, Occupational Therapy, Cancer Survivors, Social Security/standards, Surveys and Questionnaires, Medicine, Humans, Self-employment, Financial compensation, [SHS.ECO] Humanities and Social Sciences/Economics and Finance, Cancer survivor, business.industry, Rehabilitation, 1. No poverty, [SHS.ECO]Humanities and Social Sciences/Economics and Finance, 030210 environmental & occupational health, humanities, 3. Good health, Europe, Health psychology, Cross-Sectional Studies, Survey data collection, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 0305 other medical science, business, Demography, Cancer Survivors/statistics & numerical data
Abstract: International audience; Purpose To describe: (i) patterns of self-employment and social welfare provisions for self-employed and salaried workers in several European countries; (ii) work-related outcomes after cancer in self-employed people and to compare these with the work-related outcomes of salaried survivors within each sample; and (iii) work-related outcomes for self-employed cancer survivors across countries. Methods Data from 11 samples from seven European countries were included. All samples had cross-sectional survey data on work outcomes in self-employed and salaried cancer survivors who were working at time of diagnosis (n = 22–261 self-employed/101–1871 salaried). The samples included different cancers and assessed different outcomes at different times post-diagnosis. Results Fewer self-employed cancer survivors took time off work due to cancer compared to salaried survivors. More self-employed than salaried survivors worked post-diagnosis in almost all countries. Among those working at the time of survey, self-employed survivors had made a larger reduction in working hours compared to pre-diagnosis, but they still worked more hours per week post-diagnosis than salaried survivors. The self-employed had received less financial compensation when absent from work post-cancer, and more self-employed, than salaried, survivors reported a negative financial change due to the cancer. There were differences between self-employed and salaried survivors in physical job demands, work ability and quality-of-life but the direction and magnitude of the differences differed across countries. Conclusion Despite sample differences, self-employed survivors more often continued working during treatment and had, in general, worse financial outcomes than salaried cancer survivors. Other work-related outcomes differed in different directions across countries.
Published: 2018
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31. Signatures of ecological processes in microbial community time series

Author: Faust, Karoline, Bauchinger, Franziska, Laroche, Béatrice, de Buyl, Sophie, Lahti, Leo, Washburne, Alex D., Gonze, Didier, Widder, Stefanie, Department of Structural Biology, Vrije Universiteit Brussel (VUB), Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE), Institut National de la Recherche Agronomique (INRA), Physique Théorique et Mathématique, Université libre de Bruxelles (ULB), Wageningen University and Research [Wageningen] (WUR), Bioinformatique, Génomes & Réseaux, CUBE, Department of Microbiology and Ecosystem Science, Medizinische Universität Wien = Medical University of Vienna, Academy of Finland [295741, 307127], Konrad Lorenz Institute for Evolution and Cognition Research, Klosterneuburg, Austria, Austrian Science Fund (FWF) [V585-B31], Vrije Universiteit [Brussels] (VUB), Université Libre de Bruxelles [Bruxelles] (ULB), Wageningen University and Research Centre [Wageningen] (WUR), Applied Physics, and Physics
Subjects: Microbiology (medical), DYNAMICS, Pink noise, COMPLEX ECOSYSTEMS, Time series analysis, Microbiology, Models, Biological, lcsh:Microbial ecology, Humans, Computer Simulation, Neutrality test, Community models, ComputingMilieux_MISCELLANEOUS, Community dynamics, Ecosystem, [SDV.EE]Life Sciences [q-bio]/Ecology, environment, Ecotype, Science & Technology, STABILITY, Ecology, Brown noise, Research, NICHE, Généralités, Biodiversity, Noise types, Bacterial Load, NETWORKS, Gastrointestinal Microbiome, Time and Motion Studies, lcsh:QR100-130, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Life Sciences & Biomedicine
Abstract: Background: Growth rates, interactions between community members, stochasticity, and immigration are important drivers of microbial community dynamics. In sequencing data analysis, such as network construction and community model parameterization, we make implicit assumptions about the nature of these drivers and thereby restrict model outcome. Despite apparent risk of methodological bias, the validity of the assumptions is rarely tested, as comprehensive procedures are lacking. Here, we propose a classification scheme to determine the processes that gave rise to the observed time series and to enable better model selection. Results: We implemented a three-step classification scheme in R that first determines whether dependence between successive time steps (temporal structure) is present in the time series and then assesses with a recently developed neutrality test whether interactions between species are required for the dynamics. If the first and second tests confirm the presence of temporal structure and interactions, then parameters for interaction models are estimated. To quantify the importance of temporal structure, we compute the noise-type profile of the community, which ranges from black in case of strong dependency to white in the absence of any dependency. We applied this scheme to simulated time series generated with the Dirichlet-multinomial (DM) distribution, Hubbell's neutral model, the generalized Lotka-Volterra model and its discrete variant (the Ricker model), and a self-organized instability model, as well as to human stool microbiota time series. The noise-type profiles for all but DM data clearly indicated distinctive structures. The neutrality test correctly classified all but DM and neutral time series as non-neutral. The procedure reliably identified time series for which interaction inference was suitable. Both tests were required, as we demonstrated that all structured time series, including those generated with the neutral model, achieved a moderate to high goodness of fit to the Ricker model. Conclusions: We present a fast and robust scheme to classify community structure and to assess the prevalence of interactions directly from microbial time series data. The procedure not only serves to determine ecological drivers of microbial dynamics, but also to guide selection of appropriate community models for prediction and follow-up analysis., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2018
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32. Nucleotide Sequence Database Comparison for Routine Dermatophyte Identification by Internal Transcribed Spacer 2 Genetic Region DNA Barcoding

Author: Renaud Piarroux, Anne-Cécile Normand, Christophe Cassagne, Marijke Hendrickx, Stéphane Ranque, Ann Packeu, Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussel (VUB), Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA), Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS), Vrije Universiteit [Brussel] ( VUB ), Vecteurs - Infections tropicales et méditerranéennes ( VITROME ), Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -Institut de Recherche Biomédicale des Armées ( IRBA ), Laboratoire Chrono-environnement ( LCE ), Université Bourgogne Franche-Comté ( UBFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Laboratoire Chrono-environnement (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)
Subjects: 0301 basic medicine, Microbiology (medical), 030106 microbiology, Mycology, Biology, computer.software_genre, medicine.disease_cause, DNA barcoding, DNA sequencing, 03 medical and health sciences, chemistry.chemical_compound, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, DNA, Ribosomal Spacer, medicine, Cluster Analysis, DNA Barcoding, Taxonomic, Dermatomycoses, Humans, Prospective Studies, Internal transcribed spacer, DNA, Fungal, Phylogeny, 2. Zero hunger, Phylogenetic tree, Database, Arthrodermataceae, Nucleic acid sequence, Sequence Analysis, DNA, Ribosomal RNA, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, chemistry, Dermatophyte, computer, DNA
Abstract: Conventional dermatophyte identification is based on morphological features. However, recent studies have proposed to use the nucleotide sequences of the rRNA internal transcribed spacer (ITS) region as an identification barcode of all fungi, including dermatophytes. Several nucleotide databases are available to compare sequences and thus identify isolates; however, these databases often contain mislabeled sequences that impair sequence-based identification. We evaluated five of these databases on a clinical isolate panel. We selected 292 clinical dermatophyte strains that were prospectively subjected to an ITS2 nucleotide sequence analysis. Sequences were analyzed against the databases, and the results were compared to clusters obtained via DNA alignment of sequence segments. The DNA tree served as the identification standard throughout the study. According to the ITS2 sequence identification, the majority of strains (255/292) belonged to the genus Trichophyton , mainly T. rubrum complex ( n = 184), T. interdigitale ( n = 40), T. tonsurans ( n = 26), and T. benhamiae ( n = 5). Other genera included Microsporum (e.g., M. canis [ n = 21], M. audouinii [ n = 10], Nannizzia gypsea [ n = 3], and Epidermophyton [ n = 3]). Species-level identification of T. rubrum complex isolates was an issue. Overall, ITS DNA sequencing is a reliable tool to identify dermatophyte species given that a comprehensive and correctly labeled database is consulted. Since many inaccurate identification results exist in the DNA databases used for this study, reference databases must be verified frequently and amended in line with the current revisions of fungal taxonomy. Before describing a new species or adding a new DNA reference to the available databases, its position in the phylogenetic tree must be verified.
Published: 2018
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33. Loss of RASSF4 Expression in Multiple Myeloma Promotes RAS-Driven Malignant Progression

Author: Carlo Heirman, Leo A. van Grunsven, Nicolas Robert, Karin Vanderkerken, Eline Menu, Alboukadel Kassambara, Ken Maes, Hui Lui, Anke Maes, Andrew Cakana, Eva De Smedt, Elke De Bruyne, Dirk Hose, Jérôme Moreaux, Kim De Veirman, Karine Breckpot, Stefaan Verhulst, Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium, Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium, Liver Cell Biology Laboratory, Vrije Universiteit Brussel (VUB), Brussels, Belgium., Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China, Cellules souches normales et cancéreuses, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Brussels, Belgium, Janssen Research and Development, High Wycombe, United Kingdom, Medizinische Klinik und Poliklinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany., Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Brussels, Belgium., Laboratory of hematology and immunology, Vrije Universiteit Brussel (VUB), Faculty of Medicine and Pharmacy, Basic (bio-) Medical Sciences, Hematology, Liver Cell Biology, Laboratory of Molecullar and Cellular Therapy, and Translational Liver Cell Biology
Subjects: Male, 0301 basic medicine, MAPK/ERK pathway, Cancer Research, [SDV]Life Sciences [q-bio], Apoptosis, Mice, SCID, Bortezomib, Mice, Mice, Inbred NOD, Tumor Cells, Cultured, Kinome, Promoter Regions, Genetic, Trametinib, Chemistry, Prognosis, 3. Good health, Gene Expression Regulation, Neoplastic, Survival Rate, Oncology, DNA methylation, Disease Progression, Female, RAS mutations, Multiple Myeloma, medicine.drug, MAP Kinase Signaling System, Pyridones, p38 mitogen-activated protein kinases, Pyrimidinones, 03 medical and health sciences, Biomarkers, Tumor, medicine, Animals, Humans, Protein kinase B, PI3K/AKT/mTOR pathway, Cell Proliferation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Tumor Suppressor Proteins, DNA Methylation, Xenograft Model Antitumor Assays, Histone Deacetylase Inhibitors, Mice, Inbred C57BL, 030104 developmental biology, Drug Resistance, Neoplasm, ras Proteins, Cancer research, RASSF4, Proto-Oncogene Proteins c-akt, Follow-Up Studies
Abstract: RAS mutations occur frequently in multiple myeloma (MM), but apart from driving progression, they can also stimulate antitumor effects by activating tumor-suppressive RASSF proteins. Although this family of death effector molecules are often silenced in cancers, functional data about RASSF proteins in MM are lacking. Here, we report that RASSF4 is downregulated during MM progression and correlates with a poor prognosis. Promoter methylation analysis in human cell lines revealed an inverse correlation between RASSF4 mRNA levels and methylation status. Epigenetic modulating agents restored RASSF4 expression. Enforced expression of RASSF4 induced G2-phase cell-cycle arrest and apoptosis in human cell lines, reduced primary MM cell viability, and blocked MM growth in vivo. Mechanistic investigations showed that RASSF4 linked RAS to several pro-death pathways, including those regulated by the kinases MST1, JNK, and p38. By activating MST1 and the JNK/c-Jun pathway, RASSF4 sensitized MM cells to bortezomib. Genetic or pharmacological elevation of RASSF4 levels increased the anti-MM effects of the clinical relevant MEK1/2 inhibitor trametinib. Kinome analysis revealed that this effect was mediated by concomitant activation of the JNK/c-Jun pathway along with inactivation of the MEK/ERK and PI3K/mTOR/Akt pathways. Overall, our findings establish RASSF4 as a tumor-suppressive hub in MM and provide a mechanistic rationale for combining trametinib with HDAC inhibitors or bortezomib to treat patients with tumors exhibiting low RASSF4 expression. Significance: These findings provide a mechanistic rationale for combining trametinib with HDAC inhibitors or bortezomib in patients with multiple myeloma whose tumors exhibit low RASSF4 expression. Cancer Res; 78(5); 1155–68. ©2017 AACR.
Published: 2018
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34. Sufficient levels of 25-hydroxyvitamin D and protein intake required to increase muscle mass in sarcopenic older adults - The PROVIDE study

Author: Tony Mets, Ivan Bautmans, Lorenzo M. Donini, Juergen M. Bauer, Andrea B. Maier, Yves Boirie, Sjors Verlaan, Chris J. Seal, Marcello Maggio, Cornel C. Sieber, Tommy Cederholm, Kirsten Brandt, Marion E. T. McMurdo, S. Wijers, Advanced Medical Nutrition, Nutricia Research, Section of Gerontology and Geriatrics, Department of Internal Medicine, University Amsterdam Medical Center, Vrije Universiteit Amsterdam [Amsterdam] (VU), Move Research Institute Amsterdam, Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), Department of Health and Aged Care, Royal Melbourne Hospital, University of Melbourne, Department of geriatric medicine, Osaka University [Osaka]-Osaka Graduate School of medicine, Frailty in Ageing (FRIA) research department, Vrije Universiteit Brussel (VUB), Human Nutrition Research Centre, Newcastle University, Department Experimental Medicine, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Department of Clinical and Experimental Medicine, Frederico II University, Ninewells Hospital, University of Dundee, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), service Nutrition Clinique, CHU Clermont-Ferrand, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University Hospital, Nutricia Research, Nutricia Advanced Medical Nutrition, Verlaan, Sjors, AMS - Ageing and Morbidity, Neuromechanics, Internal medicine, VU University Amsterdam, Vrije University Brussel, Università degli Studi di Roma 'La Sapienza' [Rome], Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), Centre Hospitalier Universitaire de Clermont-Ferrand, Research in Geriatrics and Gerontology, Gerontology, Rehabilitation Research, Physical Medicine and Rehabilitation, Frailty in Ageing, Vriendenkring VUB, Geriatrics, and Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA)
Subjects: 0301 basic medicine, Male, Sarcopenia, Anabolism, Critical Care and Intensive Care Medicine, Basal (phylogenetics), 0302 clinical medicine, 030212 general & internal medicine, Increase muscle mass, Vitamin D, senior citizens, 2. Zero hunger, Nutrition and Dietetics, medicine.diagnostic_test, Vitamins, Protein intake, Näringslära, medicine.anatomical_structure, Treatment Outcome, Alimentation et Nutrition, Female, Dietary Proteins, medicine.medical_specialty, masse musculaire, Nutritional Status, 25-Hydroxyvitamin D, Oral nutritional supplement, personne âgée, 03 medical and health sciences, Double-Blind Method, sarcopenie, Leucine, Internal medicine, medicine, Vitamin D and neurology, Food and Nutrition, Humans, protéine alimentaire, Muscle Strength, SDG 2 - Zero Hunger, Muscle, Skeletal, Geriatric Assessment, Aged, 030109 nutrition & dietetics, Mini–Mental State Examination, business.industry, Skeletal muscle, Muscle mass, medicine.disease, Endocrinology, Whey Proteins, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: Background: Inadequate nutritional intake and altered response of aging muscles to anabolic stimuli from nutrients contribute to the development of sarcopenia. Nutritional interventions show inconsistent results in sarcopenic older adults, which might be influenced by their basal nutritional status. Objective: To test if baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations and dietary protein intake influenced changes in muscle mass and function in older adults who received nutritional intervention. Methods and design: Post-hoc analysis was performed in the PROVIDE study that was a randomized controlled, double blind trial among 380 sarcopenic older adults. This study showed that those who received a vitamin D and leucine-enriched whey protein medical nutrition drink for 13 weeks gained more appendicular muscle mass (aMM), and improved lower-extremity function as assessed by the chair stand test compared with controls. To define low and high groups, a baseline serum concentration of 50 nmol/L 25(OH)D and baseline dietary protein intake of 1.0 g/kg/d were used as cut offs. Results: At baseline, participants with lower 25(OH)D concentrations showed lower muscle mass, strength and function compared with participants with a high 25(OH)D, while the group with lower protein intake (g/kg/day) had more muscle mass at baseline compared with the participants with higher protein intake. Participants with higher baseline 25(OH)D concentrations and dietary protein intake had, independent of other determinants, greater gain in appendicular muscle mass, skeletal muscle index (aMM/h(2)), and relative appendicular muscle mass (aMM/body weight x 100%) in response to the nutritional intervention. There was no effect modification of baseline 25(OH)D status or protein intake on change in chair-stand test. Conclusions: Sufficient baseline levels of 25(OH)D and protein intake may be required to increase muscle mass as a result of intervention with a vitamin D and protein supplement in sarcopenic older adults. This suggests that current cut-offs in the recommendations for vitamin D and protein intake could be considered the "minimum" for adults with sarcopenia to respond adequately to nutrition strategies aimed at attenuating muscle loss. (C) 2017 The Author(s). Published by Elsevier Ltd.
Published: 2018
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35. Fostering Responsible Research with Genome Editing Technologies: a European Perspective

Author: Mylene Botbol-Baum, Marion Abecassis, Johannes Rath, Ewa Bartnik, François Hirsch, Agnes Saint-Raymond, Albrecht M. Müller, Jennifer Merchant, Hervé Chneiweiss, Mihalis Kritikos, Bernard Baertschi, Ana Sofia Carvalho, Christiane Druml, James A. Houghton, Solveig Fenet, Lluis Montoliu, Bärbel Friedrich, Dirk Lanzerath, Janet Mifsud, Plasticité gliale et neuro-oncologie = Glial Plasticity (NPS-04), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), INSERM Ethics Committee [Paris], Department of Microbiologie [Berlin, Germany], Humboldt-Universität zu Berlin, Pôle Langues [Panthéon-Assas, Paris], Université Panthéon-Assas (UP2), Institute for Biomedical Ethics [Geneva, Switzerland], University of Geneva Medical School, Institut de recherche santé et société [Louvain, Belgium] (IRSS), Université Catholique de Louvain = Catholic University of Louvain (UCL), Cytogenetics Unit [Galway, Ireland], National University of Ireland [Galway] (NUI Galway), Research Group on Law, Science, Technology and Society [Ixelles, Belgique] (LSTS), Vrije Universiteit Brussel (VUB), Department of Biology [Msida, Malta] (Faculty of Science), University of Malta [Malta], Institute of Genetics and Biotechnology [Warsaw, Poland] (Faculty of Biology), University of Warsaw (UW), Department of Integrative Zoology [Vienna, Austria], University of Vienna [Vienna], UNESCO Chair on Bioethics [Vienna, Austria], Medizinische Universität Wien = Medical University of Vienna, German National Academy of Sciences Leopoldina [Halle, Germany], Instituto de Bioética, and Portuguese National Council for Ethics in Life Sciences [Porto, Portugal], Universidade Católica Portuguesa, European Research Ethics Committee Network [Ixelles, Belgium] (EUREC), Human Medicines Development and Evaluation [London, UK], European Medicines Agency [London] (EMA), Veritati - Repositório Institucional da Universidade Católica Portuguesa, UCL - SSS/IRSS - Institut de recherche santé et société, Chneiweiss, Hervé, Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Humboldt University Of Berlin, Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Humboldt Universität zu Berlin, Université Catholique de Louvain (UCL), and Vrije Universiteit [Brussels] (VUB)
Subjects: 0301 basic medicine, Steering committee, [SDV]Life Sciences [q-bio], Research -- Moral and ethical aspects, responsible research and innovation, Legislation, [SDV.GEN] Life Sciences [q-bio]/Genetics, Gene editing, Biology, Bioinformatics, Responsible research and innovation, 03 medical and health sciences, 0302 clinical medicine, Genome editing, Genetics, Humans, 030212 general & internal medicine, CRISPR-Cas, Letter to the Editor, ComputingMilieux_MISCELLANEOUS, Science and society, [SDV.IB] Life Sciences [q-bio]/Bioengineering, [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Responsible Research and Innovation, business.industry, gene editing, Perspective (graphical), Genetic engineering -- Law and legislation, Public relations, science and society, [SDV.ETH] Life Sciences [q-bio]/Ethics, Expert group, [SDV.ETH]Life Sciences [q-bio]/Ethics, Europe, [SDV] Life Sciences [q-bio], 030104 developmental biology, Science -- Social aspects, Animal Science and Zoology, [SDV.IB]Life Sciences [q-bio]/Bioengineering, CRISPR-Cas Systems, business, Agronomy and Crop Science, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Biotechnology
Abstract: In this consensus paper resulting from a meeting that involved representatives from more than 20 European partners, we recommend the foundation of an expert group (European Steering Committee) to assess the potential benefits and draw-backs of genome editing (off-targets, mosaicisms, etc.), and to design risk matrices and scenarios for a responsible use of this promising technology. In addition, this European steering committee will contribute in promoting an open debate on societal aspects prior to a translation into national and international legislation., peer-reviewed
Published: 2017
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36. Antibodies targeting G protein-coupled receptors: Recent advances and therapeutic challenges

Author: Trevor Wilkinson, Jean-Philippe Pin, Hervé Watier, Jan Steyaert, Markus Koglin, Eric Reiter, Marc Parmentier, Anne Poupon, Pascale Crépieux, Mohammed Akli Ayoub, Martine J. Smit, Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Le Studium - Loire Valley Institute for Advanced Studies, Biology Department, College of Science, United Arab Emirates University (UAEU), Heptares Therapeutics Ltd., Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université libre de Bruxelles (ULB), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Dynamiques de populations multi-échelles pour des systèmes physiologiques (MUSCA), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Amsterdam Institute for Molecules Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Vrije Universiteit Amsterdam [Amsterdam] (VU), Structural Biology Brussels (SBB), Vrije Universiteit Brussel (VUB), Génétique, immunothérapie, chimie et cancer (GICC), UMR 7292 CNRS [2012-2017] (GICC UMR 7292 CNRS), Université de Tours-Centre National de la Recherche Scientifique (CNRS), Université Francois Rabelais [Tours], Laboratoire d'Immunologie, Hospices Civils de Lyon (HCL)-Hôpital E. Herriot, Antibody Discovery and Protein Engineering, MedImmune, LE STUDIUM Loire Valley Institute for Advanced Studies, French National Research Agency under the program 'Investissements d'avenir' Grant Agreement LabEx MabImprove: ANR-10-LABX-53, ANR (Contract # ANR-2011-1619 01), ARTE2 (Contract # 32000408), MODUPHAC (Contract # 32000514) , GPCRAb (ARD2020 BIOMÉDICAMENTS, contract # 32000593) grants from Région Centre, European Project: 609398,EC:FP7:PEOPLE,FP7-PEOPLE-2013-COFUND,AGREENSKILLSPLUS(2014), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), Université Libre de Bruxelles [Bruxelles] (ULB), Université de Montpellier (UM), U 1091, Institut National de la Santé et de la Recherche Médicale (INSERM), Vrije Universiteit [Brussels] (VUB), Medicinal chemistry, AIMMS, Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE), Structural Biology Brussels, and Department of Bio-engineering Sciences
Subjects: 0301 basic medicine, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], biologie computationnelle, In silico, Immunology, physiopathologie, G protein coupled receptor, Computational biology, Meeting Report, Pharmacologie, Bioinformatics, Monoclonal IgG, Receptors, G-Protein-Coupled, 03 medical and health sciences, GPCR, SDG 3 - Good Health and Well-being, antibody, Medicine, Immunology and Allergy, Animals, Humans, Antibody, G protein, biopharmaceuticals, nanobody, phage display, β-arrestin, G protein-coupled receptor, Pharmacology, business.industry, récepteur couplé aux protéines G, Molecular Pharmacology, Congresses as Topic, Single-Domain Antibodies, 3. Good health, Structure and function, 030104 developmental biology, anticorps, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, business, hormones, hormone substitutes, and hormone antagonists, rapport de congres, Signal Transduction, Autre (Sciences du Vivant), thérapie
Abstract: International audience; Le STUDIUM conference was held November 24-25, 2016 in Tours, France as a satellite workshop of the 5(th) meeting of the French GDR 3545 on "G Protein-Coupled Receptors (GPCRs) - From Physiology to Drugs", which was held in Tours during November 22-24, 2016. The conference gathered speakers from academia and industry considered to be world leaders in the molecular pharmacology and signaling of GPCRs, with a particular interest in the development of therapeutic GPCR antibodies (Abs). The main topics were new advances and challenges in the development of antibodies targeting GPCRs and their potential applications to the study of the structure and function of GPCRs, as well as their implication in physiology and pathophysiology. The conference included two sessions, with the first dedicated to the recent advances in methodological strategies used for GPCR immunization using thermo-stabilized and purified GPCRs, and the development of various formats of Abs such as monoclonal IgG, single-chain variable fragments and nanobodies (Nbs) by in vitro and in silico approaches. The second session focused on GPCR Nbs as a "hot" field of research on GPCRs. This session started with discussion of the pioneering Nbs developed against GPCRs and their application to structural studies, then transitioned to talks on original ex vivo and in vivo studies on GPCR-selective Nbs showing promising therapeutic applications of Nbs in important physiological systems, such as the central nervous and the immune systems, as well as in cancer. The conference ended with the consensus that Abs and especially Nbs are opening a new era of research on GPCR structure, pharmacology and pathophysiology.
Published: 2017
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37. Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma

Author: Dries Van Rompaey, Ann Dansercoer, Frank Peelman, Guy Lippens, Rudi Beyaert, Juan José Marín López, Isabel Vandenberghe, Kenneth Verstraete, Jan Tavernier, Harald Braun, Hans De Winter, Savvas N. Savvides, Bart N. Lambrecht, Kris Pauwels, Hamida Hammad, VIB-UGent Center for Inflammation Research [Gand, Belgique] (IRC), VIB [Belgium], Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry and Microbiology, Universiteit Gent = Ghent University [Belgium] (UGENT), VIB-UGent Center for Medical Biotechnology, Department of Biomedical Molecular Biology, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Pontifical Catholic University of Peru, Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp (UA), VIB-VUB Center for Structural Biology, Structural Biology Brussels, Bio-Engineering Sciences Department, Vrije Universiteit Brussel (VUB), Department of Respiratory Medicine, Imperial College London, Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés (LISBP), Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Recherche Agronomique (INRA), FWO [G0C2214N], Hercules Foundation [AUGE-11-029], Belspo 'Interuniversity Attraction Poles' [P7/32], Ghent University 'Concerted Research Actions' [BOF13-GOA-005], Ghent University 'Group-ID Multidisciplinary research partnership', FWO, Flemish Government-department EWI, Ghent University [Belgium] (UGENT), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Vrije Universiteit [Brussels] (VUB), Universiteit Gent = Ghent University (UGENT), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Pontificia Universidad Católica del Perú = Pontifical Catholic University of Peru (PUCP), Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Department of Bio-engineering Sciences, and Biology
Subjects: 0301 basic medicine, Models, Molecular, Receptor complex, AIRWAY INFLAMMATION, Chemistry(all), medicine.medical_treatment, General Physics and Astronomy, allergie, VARIANTS, Crystallography, X-Ray, Protein Structure, Secondary, MAMMALIAN-CELLS, Medicine and Health Sciences, Receptor, EOSINOPHILIC, Multidisciplinary, Pharmacology. Therapy, Antibodies, Monoclonal, pathophysiologie, 3. Good health, Cytokine, medicine.anatomical_structure, CYTOKINE RECEPTORS, Cytokines, Signal transduction, dermatite, Chemokines, Engineering sciences. Technology, Hydrophobic and Hydrophilic Interactions, Signal Transduction, Thymic stromal lymphopoietin, cytokine anti inflammatoire, T cell, Science, FLT3 LIGAND, Recombinant Fusion Proteins, STROMAL LYMPHOPOIETIN TSLP, BIOLOGY, Médecine humaine et pathologie, Biology, Physics and Astronomy(all), Antibodies, Monoclonal, Humanized, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Thymic Stromal Lymphopoietin, medicine, Hypersensitivity, Humans, Receptors, Cytokine, Interleukin-7 receptor, ACUTE LYMPHOBLASTIC-LEUKEMIA, skin disease, Receptors, Interleukin-7, Biochemistry, Genetics and Molecular Biology(all), Biology and Life Sciences, General Chemistry, Dendritic Cells, allergy, Fusion protein, Asthma, asthme, 030104 developmental biology, HEK293 Cells, Multiprotein Complexes, Immunology, ESOPHAGITIS, Human health and pathology, bronchial asthma, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, RESPONSES
Abstract: The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) is pivotal to the pathophysiology of widespread allergic diseases mediated by type 2 helper T cell (Th2) responses, including asthma and atopic dermatitis. The emergence of human TSLP as a clinical target against asthma calls for maximally harnessing its therapeutic potential via structural and mechanistic considerations. Here we employ an integrative experimental approach focusing on productive and antagonized TSLP complexes and free cytokine. We reveal how cognate receptor TSLPR allosterically activates TSLP to potentiate the recruitment of the shared interleukin 7 receptor α-chain (IL-7Rα) by leveraging the flexibility, conformational heterogeneity and electrostatics of the cytokine. We further show that the monoclonal antibody Tezepelumab partly exploits these principles to neutralize TSLP activity. Finally, we introduce a fusion protein comprising a tandem of the TSLPR and IL-7Rα extracellular domains, which harnesses the mechanistic intricacies of the TSLP-driven receptor complex to manifest high antagonistic potency., The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) is a promising therapeutic target. Here the authors characterize the assembly mechanism of the receptor complex driven by human TSLP, and its antagonism by the monoclonal antibody Tezepelumab and a fusion protein comprising the TSLP receptors.
Published: 2016
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38. The unexpected structure of the designed protein Octarellin V.1 forms a challenge for protein structure prediction tools

Author: Dominique Maes, Philippe Minard, Jens Meiler, Julie Vandenameele, Mike Sleutel, Els Pardon, Christian Damblon, Marie Valerio-Lepiniec, André Matagne, Marylène Vandevenne, Agathe Urvoas, Maximiliano Figueroa, Dominique Durand, Gregory Parvizi, Sophie Attout, Erik Goormaghtigh, Jan Steyaert, Joseph Martial, Axel Fischer, Olivier Jacquin, Cécile Van de Weerdt, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Research), Université de Liège, Structural Biology Brussels (SBB), Vrije Universiteit Brussel (VUB), Laboratoire d’Enzymologie et Repliement des Protéines, Department of Chemistry, Center for Structural Biology, Vanderbilt University [Nashville], Department of Chemistry, University of Lie'ge, Lie'ge, Belgium, Department of Chemistry, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Groupe Interdisciplinaire de Génoprotéomique Appliquée ( GIGA-Research ), Université de Liège-Faculté de médecine vétérinaire, Structural Biology Brussels ( SBB ), Vrije Universiteit [Brussel] ( VUB ), University of Liege, Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ), Department of Bio-engineering Sciences, Faculty of Sciences and Bioengineering Sciences, and Structural Biology Brussels
Subjects: 0301 basic medicine, Protein Folding, In silico, [SDV]Life Sciences [q-bio], Protein design, Molecular modeling, Computational biology, Biology, Crystallography, X-Ray, 03 medical and health sciences, Structural Biology, Humans, Computer Simulation, 030102 biochemistry & molecular biology, [ SDV ] Life Sciences [q-bio], Artificial proteins, Proteins, Evolutionary pressure, Protein structure prediction, Directed evolution, Protein tertiary structure, Recombinant Proteins, Protein Structure, Tertiary, Crystallography, 030104 developmental biology, De novo design, Protein folding, Threading (protein sequence), Directed Molecular Evolution
Abstract: International audience; Despite impressive successes in protein design, designing a well-folded protein of more 100 amino acids de novo remains a formidable challenge. Exploiting the promising biophysical features of the artificial protein Octarellin V, we improved this protein by directed evolution, thus creating a more stable and soluble protein: Octarellin V.1. Next, we obtained crystals of Octarellin V.1 in complex with crystallization chaperons and determined the tertiary structure. The experimental structure of Octarellin V.1 differs from its in silico design: the (αβα) sandwich architecture bears some resemblance to a Rossman-like fold instead of the intended TIM-barrel fold. This surprising result gave us a unique and attractive opportunity to test the state of the art in protein structure prediction, using this artificial protein free of any natural selection. We tested 13 automated webservers for protein structure prediction and found none of them to predict the actual structure. More than 50% of them predicted a TIM-barrel fold, i.e. the structure we set out to design more than 10years ago. In addition, local software runs that are human operated can sample a structure similar to the experimental one but fail in selecting it, suggesting that the scoring and ranking functions should be improved. We propose that artificial proteins could be used as tools to test the accuracy of protein structure prediction algorithms, because their lack of evolutionary pressure and unique sequences features.
Published: 2016
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39. Nocardia polymerase chain reaction (PCR)-based assay performed on bronchoalveolar lavage fluid after lung transplantation: A prospective pilot study

Author: Julien Coussement, Deborah Steensels, Isabelle Etienne, Vincent Claes, Michel Kohnen, Najla El Bizri, David Lebeaux, Emmanuelle Bergeron, Veronica Rodriguez-Nava, Hélène Salord, Department of Infectious Diseases, CUB-Hôpital Erasme, Vrije Universiteit Brussel [Bruxelles] (VUB)-Vrije Universiteit Brussel [Bruxelles] (VUB), Department of Microbiology, Service de Microbiologie, Unité Mobile de Microbiologie Clinique, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Lung Transplantation Unit, Laboratoire de Bactériologie, Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Laboratoire d'Ecologie Microbienne - UMR 5557 (LEM), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Ecole Nationale Vétérinaire de Lyon (ENVL), and 'Fonds Erasme pour la Recherche Medicale' (Belgium)
Subjects: Bacterial Diseases, RNA viruses, 0301 basic medicine, Influenza Viruses, Pulmonology, Medical Doctors, Opportunistic infection, Health Care Providers, medicine.medical_treatment, Psychologie appliquée, Artificial Gene Amplification and Extension, Pilot Projects, Pathology and Laboratory Medicine, Polymerase Chain Reaction, Gastroenterology, Nocardia, [SPI]Engineering Sciences [physics], 0302 clinical medicine, Belgium, Bronchoscopy, RNA, Ribosomal, 16S, Medicine and Health Sciences, Medicine, Medical Personnel, Prospective Studies, 030212 general & internal medicine, Respiratory System Procedures, Multidisciplinary, medicine.diagnostic_test, biology, Nocardiosis, Middle Aged, Sciences bio-médicales et agricoles, Bacterial Pathogens, 3. Good health, Professions, Infectious Diseases, Medical Microbiology, Viral Pathogens, Viruses, RNA, Viral, Female, Pathogens, Bronchoalveolar Lavage Fluid, Biologie, Research Article, Lung Transplantation, Adult, medicine.medical_specialty, Science, Immunology, 030106 microbiology, Nocardia Infections, Surgical and Invasive Medical Procedures, Opportunistic Infections, Research and Analysis Methods, Microbiology, Sensitivity and Specificity, Bronchoscopies, 03 medical and health sciences, Transplantation Immunology, Physicians, Internal medicine, Humans, Lung transplantation, Molecular Biology Techniques, Microbial Pathogens, Molecular Biology, Aged, Transplantation, Bacteria, business.industry, Transplant Rejection, Organisms, Biology and Life Sciences, Organ Transplantation, medicine.disease, biology.organism_classification, Health Care, Bronchoalveolar lavage, Respiratory Infections, People and Places, Clinical Immunology, Population Groupings, Clinical Medicine, business, Orthomyxoviruses
Abstract: Background Transplant recipients are at risk of pulmonary nocardiosis, a life-threatening opportunistic infection caused by Nocardia species. Given the limitations of conventional diagnostic techniques (i.e. microscopy and culture), a polymerase chain reaction (PCR)-based assay was developed to detect Nocardia spp. on clinical samples. While this test is increasingly being used by transplant physicians, its performance characteristics are not well documented. We evaluated the performance characteristics of this test on bronchoalveolar lavage (BAL) fluid samples from lung transplant recipients (LTRs). Methods We prospectively included all BAL samples from LTRs undergoing bronchoscopy at our institution between December 2016 and June 2017 (either surveillance or clinically-indicated bronchoscopies). Presence of microbial pathogens was assessed using techniques available locally (including microscopy and 10-day culture for Nocardia). BAL samples were also sent to the French Nocardiosis Observatory (Lyon, France) for the Nocardia PCR-based assay. Transplant physicians and patients were blinded to the Nocardia PCR results. Results We included 29 BAL samples from 21 patients (18 surveillance and 11 clinically-indicated bronchoscopies). Nocardiosis was not diagnosed in any of these patients by conventional techniques. However, Nocardia PCR was positive in five BAL samples from five of the patients (24%, 95% confidence interval: 11–45%); four were asymptomatic and undergoing surveillance bronchoscopy, and one was symptomatic and was later diagnosed with influenza virus infection. None of the five PCR-positive patients died or were diagnosed with nocardiosis during the median follow-up of 21 months after the index bronchoscopy (range: 20–23 months). Conclusions In this prospective study, Nocardia PCR was positive on BAL fluid from one fourth of the LTRs. Nocardia PCR-based assays should be used with caution on respiratory samples from LTRs because of the possible detection of airway colonization using this technique. Larger studies are required to determine the usefulness of the Nocardia PCR-based assay in transplant recipients., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2019
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40. A human gut microbial gene catalogue established by metagenomic sequencing

Author: Qin, J., Li, R., Raes, J., Arumugam, M., Burgdorf, K. S., Manichanh, C., Nielsen, T., Pons, N., Levenez, F., Yamada, Takuji, Mende, D. R., Li, J., Xu, J., Li, S., Li, D., Cao, J., Wang, B., Liang, H., Zheng, H., Xie, Y., Tap, J., Lepage, P., Bertalan, M., Batto, J. M., Hansen, T., Le Paslier, D., Linneberg, A., Nielsen, H. B., Pelletier, E., Renault, P., Sicheritz-Ponten, T., Turner, K., Zhu, H., Yu, C., Jian, M., Zhou, Y., Li, Y., Zhang, X., Qin, N., Yang, H., Wang, J., Brunak, S., Dor�, J., Guarner, F., Kristiansen, K., Pedersen, O., Parkhill, J., Weissenbach, J., Bork, P., Ehrlich, S. D., Consortium, MetaHIT, European Molecular Biology Laboratory [Heidelberg] (EMBL), Beijing Genomics Institute [Shenzhen] (BGI), Hagedorn Research Institute, Vrije Universiteit Brussel (VUB), Vall d'Hebron University Hospital [Barcelona], Institut National de la Recherche Agronomique (INRA), School of Software Engineering, Southern University of Science and Technology [Shenzhen] (SUSTech), Genome Research Institute, Shenzhen University Medical School, Center for Biological Sequence Analysis [Lyngby], Technical University of Denmark [Lyngby] (DTU), Center for Biological Sequence Analysis, Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Research Center for Prevention and Health, Glostrup Hospital, The Wellcome Trust Sanger Institute [Cambridge], Department of Biology [Copenhagen], Faculty of Science [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Faculty of Health Sciences, Department of Biomedical Sciences [Copenhagen], Faculty of Health and Medical Sciences, MetaHIT Consortium, European Project: 201052,EC:FP7:HEALTH,FP7-HEALTH-2007-A,METAHIT(2008), Vrije Universiteit [Brussels] (VUB), Hospital Universitari Val d'Hebron, CIBERehd, Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, MetaGenoPolis, Southern University of Science and Technology (SUSTech), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Danmarks Tekniske Universitet = Technical University of Denmark (DTU), and University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)
Subjects: intestinal microbiota, Adult, Denmark, Genomics, Bacterial genome size, Biology, Genome, Microbiology, diversity, Cohort Studies, 03 medical and health sciences, Contig Mapping, Feces, Open Reading Frames, Microbiologie, Humans, Obesity, fermentation, 030304 developmental biology, Inner mucus layer, VLAG, Genetics, 0303 health sciences, Multidisciplinary, Genes, Essential, Bacteria, 030306 microbiology, 16s ribosomal-rna, Human microbiome, alignment, Sequence Analysis, DNA, Overweight, Inflammatory Bowel Diseases, communities, Gastrointestinal Tract, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, host, Metagenomics, Genes, Bacterial, Health, Spain, networks, Metagenome, Enterotype, environment, Genome, Bacterial, Human Microbiome Project
Abstract: Udgivelsesdato: 2010-Mar-4 To understand the impact of gut microbes on human health and well-being it is crucial to assess their genetic potential. Here we describe the Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million non-redundant microbial genes, derived from 576.7 gigabases of sequence, from faecal samples of 124 European individuals. The gene set, approximately 150 times larger than the human gene complement, contains an overwhelming majority of the prevalent (more frequent) microbial genes of the cohort and probably includes a large proportion of the prevalent human intestinal microbial genes. The genes are largely shared among individuals of the cohort. Over 99% of the genes are bacterial, indicating that the entire cohort harbours between 1,000 and 1,150 prevalent bacterial species and each individual at least 160 such species, which are also largely shared. We define and describe the minimal gut metagenome and the minimal gut bacterial genome in terms of functions present in all individuals and most bacteria, respectively.
Published: 2010
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41. Second generation of thiazolylmannosides, FimH antagonists for E. coli-induced Crohn's disease

Author: Julie Bouckaert, D. Alvarez Dorta, Rostyslav Bilyy, Tetiana Dumych, Thibaut Chalopin, Nicolas Barnich, David Deniaud, Sébastien G. Gouin, M. Caudan, Adeline Sivignon, Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation (CEISAM), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA), Laboratoire de Synthèse Organique (Hétérochimie organique, organoéléments et matériaux) (LSOHOOM), Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), Structural Biology Brussels (SBB), Vrije Universiteit Brussel (VUB), Conseil Regional des Pays de La Loire (ERABAC project), Centre National de la Recherche Scientifique (CNRS), Ministere de l'Enseignement Superieur et de la Recherche in France,Ministry of Healthcare (Ukraine) 0116U000759, French National Agency for Research, Equipex ArronaxPlus ANR-11-EQPX-0004, 'Region Pays de la Loire' (NUCSAN project), Université de Nantes - Faculté des Sciences et des Techniques, Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte - Clermont Auvergne (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Vrije Universiteit [Brussels] (VUB), and Université de Nantes (UN)-Université de Nantes (UN)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Magnetic Resonance Spectroscopy, medicine.drug_class, Antibiotics, Enzyme-Linked Immunosorbent Assay, Microbial Sensitivity Tests, 010402 general chemistry, medicine.disease_cause, 01 natural sciences, Biochemistry, Microbiology, Fimbriae Proteins, Crohn Disease, In vivo, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], medicine, Escherichia coli, Humans, Physical and Theoretical Chemistry, ComputingMilieux_MISCELLANEOUS, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, Crohn's disease, Adhesins, Escherichia coli, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, biology, 010405 organic chemistry, Chemistry, Organic Chemistry, In vitro toxicology, medicine.disease, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 0104 chemical sciences, 3. Good health, Bacterial adhesin, Thiazoles, Mannosides, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Bacteria, [SDV.EE.IEO]Life Sciences [q-bio]/Ecology, environment/Symbiosis
Abstract: International audience; The anti-adhesive strategy, consisting of disrupting bacterial attachment to the host cells, is widely explored as an alternative to antibiotic therapies. Recently, thiazolylmannosides (TazMans) have been identified as strong anti-adhesives of E. coli strains implied in the gut inflammation of patients with Crohn's disease. In this work, we developed a second generation of TazMans with improved chemical stability. The anomeric nitrogen was substituted by short linkers and the compounds were assessed against the bacterial adhesin FimH and the clinically isolated LF82 E. coli strain in four in vitro assays. The results obtained on the FimH adhesin alone and the whole bacteria enabled the identification of a candidate for further in vivo evaluations.
Published: 2016
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42. DisProt 7.0 : a major update of the database of disordered proteins

Author: Edoardo Salladini, Eva Schad, Antoine Schramm, Fiorella Tonello, Francesco Tabaro, A. Keith Dunker, Mauricio Macossay-Castillo, Sandra Macedo-Ribeiro, Per Warholm, Norman E. Davey, Maria Cristina Aspromonte, Jordi Pujols, Emanuela Leonardi, Beáta Szabó, Marco Necci, Konstantinos D. Tsirigos, Ivan Mičetić, Salvador Ventura, Wim F. Vranken, Giovanni Minervini, Radoslav Davidovic, Federica Quaglia, Attila Meszaros, Vladimir N. Uversky, Agnes Tantos, Lajos Kalmar, Nikoletta Murvai, Nevena Veljkovic, Peter Tompa, Tamas Lazar, Sonia Longhi, Arne Elofsson, Alessandra Gasparini, Damiano Piovesan, Silvio C. E. Tosatto, Daniel B. Roche, Zsuzsanna Dosztányi, Andrey V. Kajava, András Hatos, Christopher J. Oldfield, Università degli Studi di Padova = University of Padua (Unipd), Institute of Medical Technology and Tampere University Hospital, University of Tampere [Finland], Indiana University School of Medicine, Indiana University System, Conway Institute of Biomolecular & Biomedical Research, University College Dublin [Dublin] (UCD), Vinča Institute of Nuclear Sciences, University of Belgrade [Belgrade], Biophysics Research Group [Budapest] (ELTE-MTA 'Lendület'), Hungarian Academy of Sciences (MTA), Stockholm University, Centre de recherche en Biologie cellulaire de Montpellier (CRBM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Computationnelle (IBC), Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), ITMO University [Russia], University of Cambridge [UK] (CAM), Structural Biology Brussels (SBB), Vrije Universiteit Brussel (VUB), Structural Biology Research Center, VIB, 1050 Brussels, Belgium, VIB-VUB Center for Structural Biology [Bruxelles], VIB [Belgium]-VIB [Belgium], Instituto de Biologia Molecular e Celular (IBMC), Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona (UAB), Architecture et fonction des macromolécules biologiques (AFMB), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Interuniversity Institute of Bioinformatics in Brussels (IB2), Université libre de Bruxelles (ULB)-Vrije Universiteit Brussel (VUB), Institute of Cytology of the Russian Academy of Science (St. Petersburg), Morsani College of Medicine, Department of Pediatrics, University of South Florida [Tampa] (USF), COST Action BM1405 NGP-net, ELIXIR-IIB (elixir-italy.org), ‘Lend ̈ulet’ Grant from the Hungarian Academyof Sciences [LP2014-16 to Z.D.], Hungarian Scientific Re-search Fund [OTKA K 108798 to Z.D.], AIRC ResearchFellowship (to D.P.), Spanish Ministerio de Educaci ́on Cul-tura i Deporte PhD Fellowship (to J.P.), Mexican Na-tional Council for Science and Technology (CONACYT)PhD Fellowship [215503 to M.M.-C.], Grant PortoNeu-roDRIve@i3S funded by Norte Portugal Regional Opera-tional Programme (NORTE 2020), under the PORTUGAL2020 Partnership Agreement, through the European Re-gional Development Fund (ERDF) (to S.M.-R.), DirectionG ́en ́erale des Arm ́ees and Aix-Marseille University PhDFellowship (to E.Sa.), OTKA Grant [PD-OTKA 108772 toE.Sc.], French Ministry of National Education, Researchand Technology PhD Fellowship (to A.S.), Ministry of Ed-ucation, Science and Technological Development of the Re-public of Serbia [173001, 173049 to N.V., R.D.], ICREA-Academia Award (to S.V.), Odysseus Grant from ResearchFoundation Flanders (FWO) [G.0029.12 to P.T.], AIRC IGGrant [17753 to S.T., in part], Italian Ministry of Health[GR-2011-02347754 to E.L., S.T., GR-2011-02346845 toS.T.], Swedish Research Council Grant [VR-NT 2012-5046to A.E.]. Computational resources were provided by theSwedish National Infrastructure for Computing (SNIC)at NSC. Funding for open access charge: COST ActionBM1405 NGP-net, Universita degli Studi di Padova, University of Padova and INFN Padova, Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Department of Veterinary Medicine, University of Cambridge, Cambridge, UK, Vrije Universiteit [Brussels] (VUB), Universitat Autònoma de Barcelona [Barcelona] (UAB), CNR Institute of Neuroscience, University of Padova, Interuniversity Institute of Bioinformatics in Brussels [ULB], Université Libre de Bruxelles [Bruxelles] (ULB), University of South Florida (USF), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)
Subjects: 0301 basic medicine, Protein Conformation, Classification scheme, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Computational biology, Biology, Intrinsically disordered proteins, computer.software_genre, Crystallography, X-Ray, 03 medical and health sciences, Text mining, Protein structure, Research community, Fluorescence Resonance Energy Transfer, Genetics, Database Issue, Animals, Humans, Databases, Protein, Biological sciences, Nuclear Magnetic Resonance, Biomolecular, ComputingMilieux_MISCELLANEOUS, 030102 biochemistry & molecular biology, Database, business.industry, Généralités, Intrinsically Disordered Proteins, 030104 developmental biology, Förster resonance energy transfer, Forms and Records Control, Erratum, business, computer, Forecasting
Abstract: The Database of Protein Disorder (DisProt, URL: www.disprot.org) has been significantly updated and upgraded since its last major renewal in 2007. The current release holds information on more than 800 entries of IDPs/IDRs, i.e. intrinsically disordered proteins or regions that exist and function without a well-defined three-dimensional structure. We have re-curated previous entries to purge DisProt from conflicting cases, and also upgraded the functional classification scheme to reflect continuous advance in the field in the past 10 years or so. We define IDPs as proteins that are disordered along their entire sequence, i.e. entirely lack structural elements, and IDRs as regions that are at least five consecutive residues without well-defined structure. We base our assessment of disorder strictly on experimental evidence, such as X-ray crystallography and nuclear magnetic resonance (primary techniques) and a broad range of other experimental approaches (secondary techniques). Confident and ambiguous annotations are highlighted separately. DisProt 7.0 presents classified knowledge regarding the experimental characterization and functional annotations of IDPs/IDRs, and is intended to provide an invaluable resource for the research community for a better understanding structural disorder and for developing better computational tools for studying disordered proteins., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2016
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43. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota

Author: Forslund, Kristoffer, Hildebrand, Falk, Nielsen, Trine, Falony, Gwen, Le Chatelier, Emmanuelle, Sunagawa, Shinichi, Prifti, Edi, Vieira-Silva, Sara, Gudmundsdottir, Valborg, Pedersen, Helle Krogh, Arumugam, Manimozhiyan, Kristiansen, Karsten, Voigt, Anita Yvonne, Vestergaard, Henrik, Hercog, Rajna, Costea, Paul Igor, Kultima, Jens Roat, Li, Junhua, Jorgensen, Torben, Levenez, Florence, Dore, Joel, Consortium, MetaHit, Nielsen, H. Bjorn, Brunak, Soren, Raes, Jeroen, Hansen, Torben, Wang, Jun, Ehrlich, Dusko S, Bork, Peer, Pedersen, Oluf, Almeida, Mathieu, Batto, Jean-Michel, Blottiere, Hervé H, Cultrone, Antonietta, Delorme, Christine, derwyn, rozenn, Guédon, Eric, Haimet, Florence, Jamet, Alexandre, Juste, Catherine, Kennedy, Sean P., Kaci, Ghalia, Layec, Séverine, Leclerc, Marion, Léonard, Pierre, Maguin, Emmanuelle, Pons, Nicolas, Renault, Pierre, Sanchez, Nicolas, Van De Guchte, Maarten, Van Hylckama Vlieg, Johan, Vandemeulebrouck, Gaetana, Winogradsky, Yohanan, Structural and Computational Biology Unit, European Molecular Biology Laboratory [Hamburg] (EMBL), VIB Center for the Biology of Disease, Université Catholique de Louvain = Catholic University of Louvain (UCL), Department of Bioscience Engineering, Vrije Universiteit Brussel (VUB), Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Bacteriology, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, MetaGenoPolis, Institut National de la Recherche Agronomique (INRA), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark [Lyngby] (DTU), Department of Biology [Copenhagen], Faculty of Science [Copenhagen], Molecular Medicine Partnership Unit, Heidelberg University, Department of Applied Tumor Biology, Institute of Pathology, Beijing Genomics Institute [Shenzhen] (BGI), Faculty of Medicine, Aalborg University [Denmark] (AAU), Research Centre for Prevention and Health, Capital Region of Denmark, Department of Public Health [Copenhagen], Disease Systems Biology [Copenhagen], Novo Nordisk Foundation Center for Protein Research (CPR), University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Faculty of Health and Medical Sciences, Faculty of Health Sciences, University of Southern Denmark (SDU), Macau University of Science and Technology (MUST), Department of Medicine and State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong (HKU), Princess Al Jawhara Albrahim Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Centre for Host-Microbiome Interactions, Dental Institute Central Office, Guy’s Hospital, King‘s College London, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Department of Bioinformatics, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Génie et Microbiologie des Procédés Alimentaires (GMPA), AgroParisTech-Institut National de la Recherche Agronomique (INRA), Département Microbiologie et Chaîne Alimentaire (MICA), Metagenopolis grant ANR-11-DPBS-0001, European Research Council 268985, European Union 600375, Lundbeck Foundation Centre for Applied Medical Genomics in Personalized Disease Prediction, Prevention and Care (LuCamp), Novo Nordisk Foundation NNF14CC0001, European Molecular Biology Laboratory (EMBL), Novo Nordisk Foundation, Innovation Fund Denmark through the MicrobDiab project, European Project: 201052, Faculty of Sciences and Bioengineering Sciences, Department of Bio-engineering Sciences, Microbiology, Université Catholique de Louvain, Vrije Universiteit [Brussels] (VUB), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], University of Heidelberg, Beijing Genomics Institute, Max Delbrück Center for Molecular Medicine, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Danmarks Tekniske Universitet = Technical University of Denmark (DTU), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)-Faculty of Health and Medical Sciences, and Julius-Maximilians-Universität Würzburg (JMU)
Subjects: Male, Diabetes Mellitus, Type 2/drug therapy, endocrine system diseases, GENOMES, CLOSTRIDIUM, Biology, Microbiology, DISEASE, Article, GLUCOSE, Hypoglycemic Agents/pharmacology, Metformin/pharmacology, RNA, Ribosomal, 16S, Nondestructive testing, Forensic engineering, Hypoglycemic Agents, risk factors, Humans, Gastrointestinal Microbiome/drug effects, Metagenome/drug effects, RNA, Ribosomal, 16S/genetics, Multidisciplinary, IDENTIFICATION, SEQUENCES, business.industry, Biodiversity, CANCER, Metformin, Computational biology and bioinformatics, 3. Good health, Gastrointestinal Microbiome, METAGENOME, Diabetes Mellitus, Type 2, SP-NOV, Female, HEALTH, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: In recent years, several associations between common chronic human disorders and altered gut microbiome composition and function have been reported. In most of these reports, treatment regimens were not controlled for and conclusions could thus be confounded by the effects of various drugs on the microbiota, which may obscure microbial causes, protective factors or diagnostically relevant signals. Our study addresses disease and drug signatures in the human gut microbiome of type 2 diabetes mellitus (T2D). Two previous quantitative gut metagenomics studies of T2D patients that were unstratified for treatment yielded divergent conclusions regarding its associated gut microbial dysbiosis. Here we show, using 784 available human gut metagenomes, how antidiabetic medication confounds these results, and analyse in detail the effects of the most widely used antidiabetic drug metformin. We provide support for microbial mediation of the therapeutic effects of metformin through short-chain fatty acid production, as well as for potential microbiota-mediated mechanisms behind known intestinal adverse effects in the form of a relative increase in abundance of Escherichia species. Controlling for metformin treatment, we report a unified signature of gut microbiome shifts in T2D with a depletion of butyrate-producing taxa. These in turn cause functional microbiome shifts, in part alleviated by metformin-induced changes. Overall, the present study emphasizes the need to disentangle gut microbiota signatures of specific human diseases from those of medication. ispartof: Nature vol:528 issue:7581 pages:262-6 ispartof: location:England status: published
Published: 2015
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44. Inhibition profiles of mono- and polyvalent FimH antagonists against 10 different Escherichia coli strains

Author: David Deniaud, Sébastien G. Gouin, Adeline Sivignon, Nicolas Barnich, Yoan Brissonnet, Julie Bouckaert, L. Cremet, Thibaut Chalopin, Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation (CEISAM), Université de Nantes - Faculté des Sciences et des Techniques, Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte - Clermont Auvergne (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Thérapeutiques cliniques et expérimentales des infections (EA 3826) (EA 3826), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Structural Biology Brussels (SBB), Vrije Universiteit [Brussels] (VUB), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA), Vrije Universiteit Brussel (VUB), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), French Agence Nationale de la Recherche [ANR-12-BSV5-0016-01], Conseil Regional des Pays de La Loire (ERABAC project), Centre National de la Recherche Scientifique (CNRS), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), and Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cell, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, medicine.disease_cause, Ligands, 01 natural sciences, Biochemistry, Bacterial Adhesion, Microbiology, Fimbriae Proteins, 03 medical and health sciences, Coli strain, medicine, Escherichia coli, Humans, Physical and Theoretical Chemistry, Gene, ComputingMilieux_MISCELLANEOUS, Escherichia coli Infections, 030304 developmental biology, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, 0303 health sciences, Adhesins, Escherichia coli, 010405 organic chemistry, Chemistry, Organic Chemistry, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 0104 chemical sciences, 3. Good health, Anti-Bacterial Agents, Bacterial adhesin, Inhibitory potency, medicine.anatomical_structure, [SDV.EE.IEO]Life Sciences [q-bio]/Ecology, environment/Symbiosis
Abstract: International audience; Mono- and polyvalent ligands with strong affinities for the mannose-binding adhesin FimH were synthesised, and their anti-adhesive properties against ten E. coli strains were compared in two cell-based assays. The compounds were assessed against the non-pathogenic E. coli K12 and nine strains isolated by coproculture or from patients with osteoarticular infections (OIs), Crohn's disease (CD) and urinary tract infections (UTIs). The results showed that the compounds could inhibit the whole set of bacterial strains but with marked differences in terms of effective concentrations. The relative inhibitory potency of the monovalent compounds was also conserved for the ten strains and in the two assays. These results clearly suggest that a potent monovalent anti-adhesive assessed on a single E. coli strain will probably be effective on a broad range of strains and may treat diverse E. coli infections (OIs, CD and UTIs). In contrast, the polyvalent compounds showed a significant strain-dependancy in preventing E. coli attachment to intestinal cells. The multivalent antiadhesive effect may therefore vary depending on the E. coli strain tested.
Published: 2015
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45. Neurotrophins and cognitive functions in T1D compared with healthy controls

Author: Elsa Heyman, Serge Berthoin, Stephen J. Bailey, Maria Francesca Piacentini, Cajsa Tonoli, Bart Roelands, Nathalie Pattyn, Luk Buyse, Romain Meeusen, Human Physiology and Special Physiology of Physical Education, Experimental and Applied Psychology, Faculty of Medicine and Pharmacy, Spine Research Group, Advanced Rehabilitation Technology & Science, Human Physiology and Sports Physiotherapy Research Group, Univ. Littoral Côte d’Opale, Univ. Artois, Université de Lille, Unité de Recherche Pluridisciplinaire Sport, Santé, Société (URePSSS) - EA 7369, Activité Physique, Muscle, Santé [EA4488], Unité de Recherche Pluridisciplinaire Sport, Santé, Société (URePSSS) - ULR 7369 - ULR 4488 [URePSSS], Vrije Universiteit Brussel [Bruxelles] [VUB], Elon University [NC, USA], Activité Physique, Muscle, Santé (EA4488), Université de Lille, Droit et Santé, Unité de Recherche Pluridisciplinaire Sport, Santé, Société (URePSSS) - ULR 7369 - ULR 4488 (URePSSS), Université d'Artois (UA)-Université de Lille-Université du Littoral Côte d'Opale (ULCO), Vrije Universiteit Brussel [Bruxelles] (VUB), and Université d'Artois (UA)-Université du Littoral Côte d'Opale (ULCO)-Université de Lille
Subjects: Male, cognition, endocrine system diseases, Physiology, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], 0302 clinical medicine, Diabetic Neuropathies, Neurotrophic factors, Heart Rate, Medicine, Insulin, Cognitive decline, Insulin-Like Growth Factor I, Nutrition and Dietetics, diabetes, brain-derived neurotrophic factor, Cognition, General Medicine, Cognitive test, Up-Regulation, insulin-like growth factor-1, Female, Adult, free insulin, medicine.medical_specialty, Neurogenesis, Physical Exertion, 030209 endocrinology & metabolism, Motor Activity, Diabetes Complications, 03 medical and health sciences, Oxygen Consumption, Physiology (medical), Internal medicine, Diabetes mellitus, Humans, Effects of sleep deprivation on cognitive performance, Brain-derived neurotrophic factor, Type 1 diabetes, business.industry, medicine.disease, Bicycling, Endocrinology, Diabetes Mellitus, Type 1, business, Cognition Disorders, 030217 neurology & neurosurgery, Biomarkers
Abstract: Exercise is known to have beneficial effects on cognitive function. This effect is greatly favored by an exercise-induced increase in neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1), especially with high-intensity exercises (HIE). As a complication of type 1 diabetes (T1D), a cognitive decline may occur, mostly ascribed to hypoglycaemia and chronic hyperglycaemia. Therefore, the purpose of this study was to examine the effects of acute HIE on cognitive function and neurotrophins in T1D and matched controls. Ten trained T1D (8 males, 2 females) participants and their matched (by age, sex, fitness level) controls were evaluated on 2 occasions after familiarization: a maximal test to exhaustion and an HIE bout (10 intervals of 60 s at 90% of their maximal wattage followed by 60 s at 50 W). Cognitive tests and analyses of serum BDNF, IGF-1, and free insulin were performed before and after HIE and following 30 min of recovery. At baseline, cognitive performance was better in the controls compared with the T1D participants (p < 0.05). After exercise, no significant differences in cognitive performance were detected. BDNF levels were significantly higher and IGF-1 levels were significantly lower in T1D compared with the control group (p < 0.05) at all time points. Exercise increased BDNF and IGF-1 levels in a comparable percentage in both groups (p < 0.05). In conclusion, although resting levels of serum BDNF and IGF-1 were altered by T1D, comparable increasing effects on BDNF and IGF-1 in T1D and healthy participants were found. Therefore, regularly repeating acute HIE could be a promising strategy for brain health in T1D.
Published: 2015
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46. Comprehensive transcriptome-wide analysis of spliceopathy correction of myotonic dystrophy using CRISPR-Cas9 in iPSCs-derived cardiomyocytes

Author: Kshitiz Singh, Denis Furling, Sumitava Dastidar, Marinee Chuah, Thierry VandenDriessche, Debanjana Majumdar, Jaitip Tipanee, Arnaud F. Klein, Vrije Universiteit Brussel (VUB), Centre de Recherche en Myologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Basic (bio-) Medical Sciences, Division of Gene Therapy & Regenerative Medicine, Faculty of Medicine and Pharmacy, Centre de recherche en Myologie – U974 SU-INSERM, and Furling, Denis
Subjects: Candidate gene, TNNT2, Research & Experimental Medicine, Transcriptome, chemistry.chemical_compound, 0302 clinical medicine, FUNCTIONAL-CHARACTERIZATION, cardiomyogenic differentiation, Drug Discovery, Myotonic Dystrophy, MBNL1, ribonuclear foci, Myocytes, Cardiac, Gene Editing, Genetics & Heredity, 0303 health sciences, CHLORIDE CHANNEL, RNA-Binding Proteins, MUSCLE, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Cell biology, DIFFERENTIATION, Medicine, Research & Experimental, RNA splicing, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Molecular Medicine, MESSENGER-RNA, Life Sciences & Biomedicine, EXPRESSION, musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, PROTEINS, CRISPR ribonucleoprotein, Induced Pluripotent Stem Cells, Biology, spliceopathy, Myotonic dystrophy, Myotonin-Protein Kinase, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, medicine, CACNA1H, Humans, Molecular Biology, 030304 developmental biology, Pharmacology, Science & Technology, Biochemistry, Genetics and Molecular Biology(all), Alternative splicing, alternate splicing, medicine.disease, GENE, Alternative Splicing, Biotechnology & Applied Microbiology, chemistry, biology.protein, SOMATIC-CELLS, Calmodulin-Binding Proteins, CRISPR-Cas Systems, EMBRYONIC STEM-CELLS, Trinucleotide Repeat Expansion, 030217 neurology & neurosurgery
Abstract: CTGrepeat expansion (CTGexp) is associated with aberrant alternate splicing that contributes to cardiac dysfunction in myotonic dystrophy type 1 (DM1). Excision of thisCTGexprepeat using CRISPR-Cas resulted in the disappearance of punctate ribonuclear foci in cardiomyocyte-like cells derived from DM1-induced pluripotent stem cells (iPSCs). This was associated with correction of the underlying spliceopathy as determined byRNA sequencingand alternate splicing analysis. Certain genes were of particular interest due to their role in cardiac development, maturation, and function (TPM4,CYP2J2,DMD,MBNL3,CACNA1H,ROCK2,ACTB) or their association with splicing (SMN2,GCFC2,MBNL3). Moreover, while comparing isogenic CRISPR-Cas9-corrected versus non-corrected DM1 cardiomyocytes, a prominent difference in the splicing pattern for a number of candidate genes was apparent pertaining to genes that are associated with cardiac function (TNNT,TNNT2,TTN,TPM1,SYNE1,CACNA1A,MTMR1,NEBL,TPM1),cellular signaling(NCOR2,CLIP1,LRRFIP2,CLASP1,CAMK2G), and other DM1-related genes (i.e.,NUMA1,MBNL2,LDB3) in addition to the disease-causingDMPKgene itself. Subsequent validation using a selected gene subset, includingMBNL1,MBNL2,INSR,ADD3, andCRTC2, further confirmed correction of the spliceopathy followingCTGexprepeat excision. To our knowledge, the present study provides the first comprehensive unbiased transcriptome-wide analysis of the differential splicing landscape in DM1 patient-derived cardiac cells after excision of theCTGexprepeat using CRISPR-Cas9, showing reversal of the abnormal cardiac spliceopathy in DM1.
Published: 2022
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47. Age-period-cohort modelling of type 1 diabetes incidence rates among children included in the EURODIAB 25-year follow-up study

Author: J. Svensson, E. H. Ibfelt, B. Carstensen, A. Neu, O. Cinek, T. Skrivarhaug, B. Rami-Merhar, R. G. Feltbower, C. Castell, D. Konrad, K. Gillespie, P. Jarosz-Chobot, D. Marčiulionytė, J. Rosenbauer, N. Bratina, C. Ionescu-Tirgoviste, F. Gorus, M. Kocova, C. de Beaufort, C. C. Patterson, Diabetes Clinic, Pathology/molecular and cellular medicine, Vriendenkring VUB, Diabetes Pathology & Therapy, and Clinical sciences
Subjects: Male, Child, preschool, Adolescent, Endocrinology, Diabetes and Metabolism, Infant, Newborn, Infant, General Medicine, Endocrinology, Seizures, Diabetes Mellitus, Type 1/epidemiology, Internal Medicine, incidence, Humans, Female, Registries, Child, Follow-Up Studies
Abstract: AIMS: Specific patterns in incidence may reveal environmental explanations for type 1 diabetes incidence. We aimed to study type 1 diabetes incidence in European childhood populations to assess whether an increase could be attributed to either period or cohort effects. METHODS: Nineteen EURODIAB centres provided single year incidence data for ages 0-14 in the 25-year period 1989-2013. Case counts and person years were classified by age, period and cohort (APC) in 1-year classes. APC Poisson regression models of rates were fitted using restricted cubic splines for age, period and cohort per centre and sex. Joint models were fitted for all centres and sexes, to find a parsimonious model. RESULTS: A total of 57,487 cases were included. In ten and seven of the 19 centres the APC models showed evidence of nonlinear cohort effects or period effects, respectively, in one or both sexes and indications of sex-specific age effects. Models showed a positive linear increase ranging from approximately 0.6 to 6.6%/year. Centres with low incidence rates showed the highest overall increase. A final joint model showed incidence peak at age 11.6 and 12.6 for girls and boys, respectively, and the rate-ratio was according to sex below 1 in ages 5-12. CONCLUSION: There was reasonable evidence for similar age-specific type 1 diabetes incidence rates across the EURODIAB population and peaks at a younger age for girls than boys. Cohort effects showed nonlinearity but varied between centres and the model did not contribute convincingly to identification of environmental causes of the increase.
Published: 2023

48. Gut microbiome composition is associated with long-term disability worsening in multiple sclerosis

Author: Lindsay Devolder, Ayla Pauwels, Ann Van Remoortel, Gwen Falony, Sara Vieira-Silva, Guy Nagels, Jacques De Keyser, Jeroen Raes, Marie B. D’Hooghe, Department of Clinical Microbiology, Clinical sciences, Neurology, Faculty of Medicine and Pharmacy, Artificial Intelligence supported Modelling in clinical Sciences, Neuroprotection & Neuromodulation, and Vriendenkring VUB
Subjects: Microbiology (medical), Bacteroides 2, long-term disability worsening, Multiple Sclerosis, EDSS-Plus, Neuroscience(all), Gastroenterology, gut microbiome, multiple sclerosis, Microbiology, Gastrointestinal Microbiome, Infectious Diseases, neurofilament light chain, Immunology and Microbiology(all), Humans
Abstract: Predicting the long-term outcome of multiple sclerosis (MS) remains an important challenge to this day. As the gut microbiota is emerging as a potential player in MS, we investigated in this study whether gut microbial composition at baseline is related to long-term disability worsening in a longitudinal cohort of 111 MS patients. Fecal samples and extensive host metadata were collected at baseline and 3 months post-baseline, with additional repeated neurological measurements performed over (median) 4.4 y. Worsening (with EDSS-Plus) occurred in 39/95 patients (outcome undetermined for 16 individuals). The inflammation-associated, dysbiotic Bacteroides 2 enterotype (Bact2) was detected at baseline in 43.6% of worsened patients, while only 16.1% of non-worsened patients harbored Bact2. This association was independent of identified confounders, and Bact2 was more strongly associated with EDSS-Plus than neurofilament light chain (NfL) plasma levels. Furthermore, using fecal sampling performed 3 months post-baseline, we observed Bact2 to be relatively stable, suggesting its potential use as a prognostic biomarker in MS clinical practice. ispartof: GUT MICROBES vol:15 issue:1 ispartof: location:United States status: Published online
Published: 2023

49. DFT exchange: sharing perspectives on the workhorse of quantum chemistry and materials science

Author: Andrew M. Teale, Trygve Helgaker, Andreas Savin, Carlo Adamo, Bálint Aradi, Alexei V. Arbuznikov, Paul W. Ayers, Evert Jan Baerends, Vincenzo Barone, Patrizia Calaminici, Eric Cancès, Emily A. Carter, Pratim Kumar Chattaraj, Henry Chermette, Ilaria Ciofini, T. Daniel Crawford, Frank De Proft, John F. Dobson, Claudia Draxl, Thomas Frauenheim, Emmanuel Fromager, Patricio Fuentealba, Laura Gagliardi, Giulia Galli, Jiali Gao, Paul Geerlings, Nikitas Gidopoulos, Peter M. W. Gill, Paola Gori-Giorgi, Andreas Görling, Tim Gould, Stefan Grimme, Oleg Gritsenko, Hans Jørgen Aagaard Jensen, Erin R. Johnson, Robert O. Jones, Martin Kaupp, Andreas M. Köster, Leeor Kronik, Anna I. Krylov, Simen Kvaal, Andre Laestadius, Mel Levy, Mathieu Lewin, Shubin Liu, Pierre-François Loos, Neepa T. Maitra, Frank Neese, John P. Perdew, Katarzyna Pernal, Pascal Pernot, Piotr Piecuch, Elisa Rebolini, Lucia Reining, Pina Romaniello, Adrienn Ruzsinszky, Dennis R. Salahub, Matthias Scheffler, Peter Schwerdtfeger, Viktor N. Staroverov, Jianwei Sun, Erik Tellgren, David J. Tozer, Samuel B. Trickey, Carsten A. Ullrich, Alberto Vela, Giovanni Vignale, Tomasz A. Wesolowski, Xin Xu, Weitao Yang, Chemistry, General Chemistry, Vriendenkring VUB, Laboratoire de chimie théorique (LCT), Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL), CEntre de REcherches en MAthématiques de la DEcision (CEREMADE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Groupe Méthodes et outils de la chimie quantique (LCPQ) (GMO), Laboratoire de Chimie et Physique Quantiques Laboratoire (LCPQ), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Fédération de recherche « Matière et interactions » (FeRMI), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie Physique (ICP), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Systèmes de Fermions Finis - Agrégats (LPT), Laboratoire de Physique Théorique (LPT), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Fédération de recherche « Matière et interactions » (FeRMI), ANR-10-LABX-0026,CSC,Center of Chemistry of Complex System(2010), ANR-19-CE07-0024,Co-LAB,Acide/base de Lewis confinées(2019), and European Project: 863481,PTEROSOR
Subjects: [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, [PHYS.MPHY]Physics [physics]/Mathematical Physics [math-ph], Materials Science, ddc:540, General Physics and Astronomy, Humans, Physical and Theoretical Chemistry
Abstract: In this paper, the history, present status, and future of density-functional theory (DFT) is informally reviewed and discussed by 70 workers in the field, including molecular scientists, materials scientists, method developers and practitioners. The format of the paper is that of a roundtable discussion, in which the participants express and exchange views on DFT in the form of 300 individual contributions, formulated as responses to a preset list of 26 questions. Supported by a bibliography of 776 entries, the paper represents a broad snapshot of DFT, anno 2022.
Published: 2022
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50. Effect of air temperature on human births, preterm births and births associated with maternal hypertension

Author: Kurt Barbé, Sébastien Doutreloup, Florent Fuchs, Leonardo Gucciardo, Frederic Blavier, Gilles Faron, Malik Boukerrou, Obstetrics, Radiation Therapy, Artificial Intelligence supported Modelling in clinical Sciences, Biostatistics and medical informatics, Digital Mathematics, Public Health Sciences, Surgical clinical sciences, Mother and Child, CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Universitair Ziekenhuis [Brussels, Belgium], Vrije Universiteit Brussel (VUB), Université de Liège, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Université de La Réunion (UR), Centre d'Études Périnatales de l'Océan Indien (CEPOI), Université de La Réunion (UR)-Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Hôpital Arnaud de Villeneuve [CHRU Montpellier], and Fuchs, Florent
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, 010504 meteorology & atmospheric sciences, 010501 environmental sciences, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, 01 natural sciences, Heat waves, Pregnancy, Obstetrics and Gynaecology, medicine, Maternal hypertension, Humans, 0105 earth and related environmental sciences, Retrospective Studies, Medicine(all), Obstetrics, business.industry, Global warming, Infant, Newborn, Temperature, Parturition, Public Health, Environmental and Occupational Health, Obstetrics and Gynecology, Preterm Births, Heat wave, medicine.disease, humanities, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Hypertensive disease, Premature birth, Air temperature, Pediatrics, Perinatology and Child Health, Hypertension, Premature Birth, hypertensive disease, Female, business, Prematurity
Abstract: International audience; Objective: We studied potential effects of outdoor air temperatures or barometric pressure on births, preterm births and births associated with maternal hypertension.Methods: 12,269 births were retrospectively reviewed in Brussel and 25,880 in South Reunion Island. National Belgium and French weather reference centers provided outdoor air temperatures and barometric pressures from the nearest weather stations on the corresponding birthdays. Poisson regression models were used to assess if outdoor air temperatures or barometric pressure could be correlated, immediately and several days later, with the number of daily births, preterm births and births associated with hypertension.Results: Outdoor air temperature was significantly correlated to the number of daily births in Brussels. For each additional degree Celsius, overall births increased by 0.4% during the same day. Four days later, overall births increased by 1.8%, preterm births by 2.6% and births associated with hypertension by 5.7%. Similar observations on numbers of daily births were reported in South Reunion Island, without reaching statistical significance (p = .08).Conclusion: As previously demonstrated in recent studies, increased air temperature leads progressively to higher rates of births and preterm births. An even stronger delayed effect of air temperature was observed on births associated with hypertension. This would be worth further investigating.
Published: 2022
Full Text: View/download PDF

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