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1. Sensitivity of a Bayesian source-term estimation model to spatiotemporal sensor resolution

Author

Derek D. Jensen, Donald D. Lucas, Katherine A. Lundquist, and Lee G. Glascoe

Subjects
Environmental pollution, TD172-193.5, Meteorology. Climatology, QC851-999
Abstract

Source-term estimation (STE) methods attempt to calculate the most-likely source characteristics of an atmospheric release given concentration observations. The quality of the STE depends partially on the time and space scales of the observations, sensor locations, and release parameters. We quantify the sensitivity of a probabilistic STE algorithm that was previously validated using observational data collected during a controlled tracer release experiment to the spatiotemporal resolution of observing networks. We have also made many improvements to the STE algorithm, which extends applicability to coarser-resolution observational datasets. Improvements include the use of a fully-connected deep neural network model emulator with dynamically optimized architecture and better goodness-of-fit (GoF) metrics to measure the discrepancy between model and observational data. The GoF metrics, which are more robust and resilient than previous metrics, are the Spearman rank-based correlation coefficient and a variation of the binary f1 classification score adapted for regression problems. Using synthetically generated observations over East Asia, the skill of the improved algorithm is quantified over a broad range of sensor configurations and release scenarios. The evaluation is broken into three experiments. First, a validation study shows that the proposed GoF metrics perform more reliably than other possible candidates. Next, data-denial techniques are applied to a single release scenario over the Korean peninsula, where the skill of the inversion is shown to be highly sensitive to the number and location of deployed sensors but less sensitive to temporal resolution. Finally, the STE algorithm is tested for many release locations throughout the geographic model domain, where the STE algorithm performs well for all but a few cases. The results indicate that the STE algorithm provides informative source-parameter posterior probability distributions utilizing data collected by sparse sensor networks; however, the skill of the STE algorithm improves significantly for higher resolution networks. Keywords: Source-term estimation, Dispersion modeling, Bayesian inversion, Machine learning, Nuclear nonproliferation

Published
2019
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2. Deoxycholic acid modulates cell death signaling through changes in mitochondrial membrane properties[S]

Author

Tânia Sousa, Rui E. Castro, Sandra N. Pinto, Ana Coutinho, Susana D. Lucas, Rui Moreira, Cecília M.P. Rodrigues, Manuel Prieto, and Fábio Fernandes

Subjects
apoptosis, bile acids and salts, bile acids and salts/physical chemistry, fluorescence microscopy, membranes/fluidity, membranes, Biochemistry, QD415-436
Abstract

Cytotoxic bile acids, such as deoxycholic acid (DCA), are responsible for hepatocyte cell death during intrahepatic cholestasis. The mechanisms responsible for this effect are unclear, and recent studies conflict, pointing to either a modulation of plasma membrane structure or mitochondrial-mediated toxicity through perturbation of mitochondrial outer membrane (MOM) properties. We conducted a comprehensive comparative study of the impact of cytotoxic and cytoprotective bile acids on the membrane structure of different cellular compartments. We show that DCA increases the plasma membrane fluidity of hepatocytes to a minor extent, and that this effect is not correlated with the incidence of apoptosis. Additionally, plasma membrane fluidity recovers to normal values over time suggesting the presence of cellular compensatory mechanisms for this perturbation. Colocalization experiments in living cells confirmed the presence of bile acids within mitochondrial membranes. Experiments with active isolated mitochondria revealed that physiologically active concentrations of DCA change MOM order in a concentration- and time-dependent manner, and that these changes preceded the mitochondrial permeability transition. Importantly, these effects are not observed on liposomes mimicking MOM lipid composition, suggesting that DCA apoptotic activity depends on features of mitochondrial membranes that are absent in protein-free mimetic liposomes, such as the double-membrane structure, lipid asymmetry, or mitochondrial protein environment. In contrast, the mechanism of action of cytoprotective bile acids is likely not associated with changes in cellular membrane structure.

Published
2015
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3. Pulmonary macrophages and SARS-Cov2 infection

Author

Calum C. Bain, Adriano G. Rossi, Christopher D. Lucas, Mariani, Samanta A., Cassetta, Luca, and Galluzzi, Lorenzo

Subjects
SARS-CoV-2, coronavirus, macrophage, lung
Abstract

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the largest global pandemic in living memory, with between 4.5 and 15M deaths globally from coronavirus disease 2019 (COVID-19). This has led to an unparalleled global, collaborative effort to understand the pathogenesis of this devastating disease using state-of-the-art technologies. A consistent feature of severe COVID-19 is dys- regulation of pulmonary macrophages, cells that under normal physiological conditions play vital roles in maintaining lung homeostasis and immunity. In this article, we will discuss a selection of the pivotal findings examining the role of monocytes and mac- rophages in SARS-CoV-2 infection and place this in context of recent advances made in understanding the fundamental immunobiology of these cells to try to understand how key homeostatic cells come to be a central pathogenic component of severe COVID-19 and key cells to target for therapeutic gain.

Published
2022
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4. Novel Fluorinated Benzimidazole-Based Scaffolds and their Anticancer Activity in vitro

Author

Vladimír Kryštof, Mark R. J. Elsegood, Simon J. Teat, Mariam Mojally, Mark Edgar, George W. Weaver, Lynne Horsburgh, Paul D. Lucas, Fatemeh Zeinali, Thomas G. Warwick, and Avninder S. Bhambra

Subjects
Benzimidazole, Crystal structure, 010402 general chemistry, 01 natural sciences, Biochemistry, Inorganic Chemistry, chemistry.chemical_compound, Nucleophilic aromatic substitution, Environmental Chemistry, Physical and Theoretical Chemistry, Caspase, biology, 010405 organic chemistry, Drug discovery, Organic Chemistry, in vitro, Fluorine, Combinatorial chemistry, SNAR, In vitro, 0104 chemical sciences, Anticancer, chemistry, Apoptosis, Cell culture, biology.protein
Abstract

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link. A small library of twelve, structurally diverse, fluoroaryl benzimidazoles was prepared using a simple synthetic strategy employing SNAr reactions. This allowed rapid assembly of heterocyclic structures containing linked and tethered fluoroaryl benzimidazoles. X-ray crystal structures of seven compounds were obtained including those of two macrocyclic compounds containing 21- and 24-membered rings. Three tethered fluoroaryl benzimidazole derivatives demonstrated micromolar inhibition against K-562 and MCF-7 cell lines. These compounds, in addition to 1-tetrafluoropyrid-4-yl-2-tetrafluoropyrid-4-ylsulfanyl-1H-benzimidazole, also demonstrated micromolar inhibition against G361 and HOS cell lines. Two of the compounds were found to activate caspases leading to apoptosis.

Published
2016
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5. Contributors

Author

Seema S. Aceves, Ian M. Adcock, N. Franklin Adkinson, Cezmi A. Akdis, Mübeccel Akdis, Keith C. Allen, Andrea J. Apter, Claus Bachert, Katherine J. Baines, Mark Ballow, Peter J. Barnes, Neal P. Barney, Fuad M. Baroody, Heidrun Behrendt, Bruce G. Bender, M. Cecilia Berin, Paul J. Bertics, Thomas Bieber, Leonard Bielory, Judith Black, Bruce S. Bochner, Mark Boguniewicz, Larry Borish, Louis-Philippe Boulet, Jean Bousquet, Joshua A. Boyce, Peter Bradding, Christopher E. Brightling, David H. Broide, Simon G.A. Brown, Rebecca H. Buckley, Janette K. Burgess, A. Wesley Burks, Peter G.J. Burney, Robert K. Bush, William W. Busse, Jeroen Buters, Lien Calus, Carlos A. Camargo, Brendan J. Canning, Thomas B. Casale, Mario Castro, Gülfem E. Çelik, Christina Chambers, Javier Chinen, Anca Mirela Chiriac, Sandra C. Christiansen, Kian Fan Chung, Donald W. Cockcroft, Lauren Cohn, Ellen B. Cook, Jonathan Corren, Adnan Custovic, Pascal Demoly, Dhananjay Desai, Graham Devereux, Thomas Diepgen, Myrna B. Dolovich, David A. Dorward, Jo A. Douglass, Stephen R. Durham, Sandy R. Durrani, Mark S. Dykewicz, Ronald Eccles, Alan M. Edwards, Renata J.M. Engler, Robert E. Esch, Sean B. Fain, Reuben Falkoff, Matthew J. Fenton, Thomas A. Fleisher, Joseph R. Fontana, Michael M. Frank, Anthony J. Frew, Glenn T. Furuta, Holger Garn, Monica L. Gavala, Philippe Gevaert, Viviane Ghanim, Peter G. Gibson, David B.K. Golden, Matthew J. Greenhawt, Anete S. Grumach, Theresa W. Guilbert, Sudhir Gupta, Andrew J. Halayko, Teal S. Hallstrand, Robert G. Hamilton, Hamida Hammad, Trevor T. Hansel, Catherine Hawrylowicz, Michelle L. Hernandez, C. Garren Hester, Jeremy Hirota, Stephen T. Holgate, John W. Holloway, Charles G. Irvin, Richard S. Irwin, Elliot Israel, Daniel J. Jackson, Peter K. Jeffery, Diane F. Jelinek, Richard B. Johnston, Stacie M. Jones, H. William Kelly, John M. Kelso, Stephen F. Kemp, Hirohito Kita, Amy D. Klion, Darryl Knight, Marek L. Kowalski, Cynthia J. Koziol-White, Rakesh K. Kumar, Gideon Lack, Bart N. Lambrecht, Beth L. Laube, Heather K. Lehman, Robert F. Lemanske, Catherine Lemière, Donald Y.M. Leung, Ian P. Lewkowich, James T. Li, Xiu-Min Li, Phillip L. Lieberman, Andrew H. Liu, Clare Lloyd, Christopher D. Lucas, Andrew D. Luster, Eric Macy, J. Mark Madison, Elizabeth C. Matsui, Michael H. Mellon, Dean D. Metcalfe, Zamaneh Mikhak, E.N. Clare Mills, Harold S. Nelson, Sarah K. Nicholas, Rosemary L. Nixon, Anna Nowak-We˛grzyn, Paul M. O'Byrne, Hans C. Oettgen, Robyn E. O'Hehir, Brian G. Oliver, Jordan S. Orange, Dennis R. Ownby, C.P. Page, Reynold A. Panettieri, Hae-Sim Park, Mary E. Paul, Ian D. Pavord, Ruby Pawankar, David B. Peden, R. Stokes Peebles, Stephen P. Peters, Werner J. Pichler, Mark R. Pittelkow, Douglas A. Plager, Thomas A.E. Platts-Mills, Susan L. Prescott, Benjamin A. Raby, Hengameh H. Raissy, Cynthia S. Rand, Anuradha Ray, Harald Renz, Jonathan P. Richardson, Johannes Ring, Clive Robinson, Duncan F. Rogers, Lanny J. Rosenwasser, Adriano G. Rossi, Marc E. Rothenberg, Brian H. Rowe, Sejal Saglani, Sarbjit S. Saini, Hirohisa Saito, Hugh A. Sampson, Mario Sanchez-Borges, Alessandra Sandrini, Guy W. Scadding, Michael Schatz, John T. Schroeder, Malcolm R. Sears, Christine Seroogy, William T. Shearer, James H. Shelhamer, Scott H. Sicherer, F. Estelle R. Simons, Jodie L. Simpson, Jay E. Slater, Peter D. Sly, Philip H. Smith, Michael C. Sneller, Domenico Spina, P. Sriramarao, James L. Stahl, John W. Steinke, Geoffrey A. Stewart, Jeffrey R. Stokes, Kathleen E. Sullivan, Steve L. Taylor, Abba I. Terr, Euan Tovey, Thai Tran, Bradley J. Undem, Peter Valent, Olivier Vandenplas, Stephan von Gunten, Richard W. Weber, Peter F. Weller, Sally E. Wenzel, Gregory J. Wiepz, Marsha Wills-Karp, Robert A. Wood, Leman Yel, Robert S. Zeiger, Jihui Zhang, and Bruce L. Zuraw

Published
2014
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6. Resolution of Allergic Inflammation

Author

Adriano G. Rossi, David A. Dorward, Keith C. Allen, and Christopher D. Lucas

Subjects
business.industry, Immunology, Resolution (electron density), Medicine, business, Allergic inflammation
Published
2014
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7. Zeolites and Other Silicon-Based Promoters in Carbohydrate Chemistry

Author

Miguel M. Santos, Amélia P. Rauter, Susana D. Lucas, and Nuno M. Xavier

Subjects
inorganic chemicals, chemistry.chemical_compound, Silicon, chemistry, Carbohydrate chemistry, Silica gel, chemistry.chemical_element, Organic chemistry, Organic synthesis, Heterogeneous catalysis, Chemical reaction, Environmentally friendly, Catalysis
Abstract

Silicon-based materials, namely zeolites, clays, and silica gel have been widely used in organic synthesis, allowing mild reaction conditions and environmentally friendly methodologies. These heterogeneous catalysts are easy to handle, possess nontoxic and noncorrosive character and offer the possibility of recovery and reuse, thus contributing to clean and sustainable organic transformations. Moreover, they present shape-selective properties and provide stereo- and regiocontrol in chemical reactions. Herein, we survey the most significant applications of silicon-based materials as catalysts in carbohydrate chemistry, to mediate important transformations such as glycosylation, sugar protection and deprotection, and hydrolysis and dehydration. Emphasis is placed on their promising synthetic potential in comparison with conventional catalysts.

Published
2010
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8. Susceptibility and exposure biomarkers in people exposed to pahs from diesel exhaust

Author

P Ancic, Romina M. Riquelme, R Tapia, D Lucas, Lionel Gil, Victor D. Martinez, G González, Marta Adonis, François Berthou, and M Castro

Subjects
Adult, Male, Diesel exhaust, Genotype, Physiology, Urine, Toxicology, Diesel fuel, Genetic predisposition, Cytochrome P-450 CYP1A1, Humans, Polycyclic Aromatic Hydrocarbons, Chromatography, High Pressure Liquid, Glutathione Transferase, Vehicle Emissions, Air Pollutants, Principal Component Analysis, Polymorphism, Genetic, Pyrenes, Chemistry, Reverse Transcriptase Polymerase Chain Reaction, General Medicine, DNA, respiratory system, Biomarker (medicine), Female, Gene polymorphism, Seasons, Rural area, Biomarkers, Filtration, Mutagens
Abstract

Xenobiotic metabolizing enzymes, especially CYP1A1 and GSTM1, are involved in the activation and conjugation of PAHs and are controlled by polymorphic genes. PAHs released from diesel emissions in many cities of the world, especially in developing countries, contribute significantly to the toxic effects of airborne inhalable particles. We have evaluated the gene-environment interaction in Santiago of Chile, studying the contribution of CYP1A1 and GSTM1 polymorphisms on 1-OH-P urinary levels used as the PAHs exposure biomarker. The study was performed on 59 diesel exposed (38 diesel revision workers and 21 subjects working in an urban area as established street vendors) and 44 non-exposed subjects living in a rural area. The 1-OH-P urinary levels of the urban (P=0.043) and rural (P=0.040) populations showed, without considering the genotypes, significant differences between smokers and non-smokers, but no significant differences were found between smokers and non-smokers among the diesel plant workers (P=0.33). Non-smoking subjects of the diesel plants and the urban area showed similar 1-OHP levels (P=0.466) which were significantly higher than those of the subjects living in the rural area (P

Published
2003

9. Lithography

Author

Kevin D. Lucas, Sergei V. Postnikov, Scott Daniel Hector, and Cliff Henderson

Subjects
Engineering drawing, Engineering, Computational lithography, business.industry, Hardware_PERFORMANCEANDRELIABILITY, Integrated circuit, law.invention, Lens (optics), Resist, Optical proximity correction, law, Hardware_INTEGRATEDCIRCUITS, Electronic engineering, Miniaturization, Photolithography, business, Lithography
Abstract

Publisher Summary This chapter discusses that lithography is a key technology enabling the continued miniaturization of integrated circuits. An overview is presented of all the important aspects of lithography. Some basic scaling equations governing the theory of optical lithography are presented, but the chapter focuses on describing the practical challenges in applying lithography for integrated circuit manufacturing. Practical aspects of pattern layout, exposure tool design, masks, lens design, CD control, overlay control, resists, substrate control, simulation, optical proximity correction, phase shift masks, cost of ownership, and emerging lithographic techniques are described in detail.

Published
2003
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10. The role of natural color additives in food allergy

Author

Stephen L Taylor, Christine D. Lucas, and John B. Hallagan

Subjects
medicine.medical_specialty, Allergy, food.ingredient, business.industry, Food additive, medicine.disease, Dermatology, Food intolerance, medicine.anatomical_structure, food, Food allergy, Medicine, Ingestion, Food science, business, Adverse effect, Sensitization, Anaphylaxis
Abstract

A critical evaluation of the available information demonstrates that reactions to natural color additives are rare. Studies of turmeric and carotenoid pigments administered in mixtures with other food colorings failed to definitely identify reactions to either color additive. For carotenoids, the one case report of an adverse reaction was not conclusive. An anaphylactic reaction to saffron does suggest an IgE-mediated reaction, but the high use of saffron as compared with this single report of an adverse reaction suggests that sensitivity to saffron is extremely rare. Numerous reports of reactions to grapes or grape products have been reported in the literature, but no reports of sensitivities to grape skin extract or grape color extract were found. In rare cases, annatto dye may provoke a severe, adverse reaction in individuals with an uncommon hypersensitivity, and may aggravate the symptoms of patients suffering from recurrent urticaria. In its long history of use, there has been only one reported case of anaphylaxis resulting from the ingestion of annatto. Studies designed to investigate the role of annatto in recurrent urticaria sufferers were limited due to the absence of double-blind challenge and placebo controls. A number of cases of adverse reactions to carmine following ingestion have been reported in the literature. These adverse reactions suggest an IgE-mediated hypersensitivity. In many of the reported cases, the cause of sensitization to carmine was topical exposure from the use of carmine-containing cosmetics or occupational exposure to carmine and not from ingestion of carmine-containing foods and beverages. Following sensitization, affected individuals would be sensitive to carmine and the amounts present in foods and beverages could elicit allergic reactions. It is not known whether all individuals with carmine sensitivity induced through topical use are sensitive to the ingestion of carmine in foods. However, reactions to carmine solely because of ingestion are likely to be exceedingly rare due to the low use levels of carmine in foods and beverages. Despite their widespread use in food products, few reports of allergic reactions following ingestion have been reported for the majority of natural color additives. It is concluded that the ingestion of natural color additives presents a very low risk of provoking adverse reactions.

Published
2001
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13. Participants

Author

R.K. Aaran, A. Adam, E. Ades, M. Aker, R. Aksamit, P. Alexander, J.P. Allison, R.N. Apte, D. Armerding, R.F. Ashman, A. Astaldi, G.C.B. Astaldi, W. Augener, R. Averdunk, B. Axelsson, F.H. Bach, J.F. Bach, M.A. Bach, W.W. Bakker, J.J. Ballet, Y. Barak, R.F. Barth, J.R. Battisto, M. Becker, C. Bell, D. Belpomme, S. Ben-Ami, S. Ben-Efraim, Y. Ben Neriah, Z. Bentwich, S.L. Berger, B. Bergholtz, G. Berke, J. Bernheim, W. Bessler, M. Biniaminov, E. Blitzstein-Willinger, F. Blomberg, R.P. Blumenthal, W. Boersma, R.L.H. Bolhuis, G. Boltz-Nitulescu, C. Bona, B. Bonavida, G.D. Bonnard, B.A. Bradley, S. Bright, A. Castellani, R. Cesla, J. Charreire, F. Chattah, J.W. Chiao, J. Clot, J.D. Clough, D. Cohen, I.R. Cohen, M. Cohen, D-A. Cohn, K.M. Connolly, D.A. Cooper, H.L. Cooper, G. Cordier, J. Couderc, C. Cowing, A.S. Cross, C. Cunningham-Rundles, S. Cunningham-Rundles, C. Damais, M. Dardenne, J.R. David, W.A. Davies, de Baetselier, P. Debre, G. Delespresse, J.F. Delfraissy, T.L. Delovich, A. de Rey, B. Devens, T. Diamantstein, M.L. Dillner-Cinterlind, A. Dimitriu, T. Dishon, J.F.P. Dixon, J. Dornand, G. Drizlich, W. Droege, V. Duprez, R. Edelman, V.P. Eijsvoogel, T.K. Eisenstein, H.P. Ekre, K.D. Elgert, L. Ercolani, M. Escobar, A. Eshel, Z. Eshhar, A. Fagraeus, F. Falkenberg, A.S. Fauci, M. Feldman, M. Fellous, E.J. Field, F. Fish, Z. Fishelson, M. Fogel, K. Folkers, D.R. Forsdyke, O. Forster, C. Fournier, D.P. Fradelizi, K. Frank, M.H. Freedman, W.H. Fridman, A. Friedman, H. Friedman, E. Frisch, D. Gabison, A. Gabizon, null Gausset, M.E. Gershwin, H. Ginsburg, J.P. Girard, A. Globerson, J.C. Gluckman, T. Godal, H. Golan, N. Goldblum, D.W. Golde, A. Goldstein, G. Goldstein, P. Golstein, S.H. Golub, E. Gomard, R.M. Gorczynski, J. Gordon, E. Gorelik, R. Goren, E. Goulmy, J.M. Goust, Y. Gozes, E. Grimm, S. Gupta, L. Gurtler, M. Haas, M.R. Hadam, H. Hahn, T. Hahn, J. Haimovich, G. Hamers, J.D. Hamilton, S. Hammarstrom, T. Han, B.S. Handwerger, Z.T. Handzel, N. Hanna, N. Haran-Ghera, T.N. Harris, K. Havemann, C.S. Hawes, C.J. Heijnen, D. Heller, G.P. Hemstreet, M.P. Henkart, A. Henrikson, E.J. Hensen, R.B. Herberman, J. Hilgers, H. Hirschberg, M. Hirtenstein, R.J. Hodes, F. Hofman, H. Holden, N. Hollander, R.J. Hooghe, J. Horowitz, K. Huygen, R.M. Ikeda, D.N. Ilfeld, C. Irle, N. Isakov, E. Israel, B. Iszak, J. Ivanyi, L. Ivanyi, G. Izak, G. Joyce, A. Kaplan, J.G. Kaplan, S. Katzar, D.B. Kaufman, S.H.E. Kaufman, Y. Kaufman, H.D. Kay, J.E. Kay, E. Kedar, M.L. Kern, S. Kfir, J. Kieler, F. Kierszenbaum, J. Klein, R. Kleinman, W. Klinkert, W. Knapp, R. Kol, E. Kondracki, H.S. Korne, U. Koszinowski, L. Koulisher, K. Kozima, R.S. Krakauer, P. Krammer, A. Kruisbeek, O. Kuperman, B. Kupfer, P. Lake, Z. Landro, J.M. Lang, C. Leclerc, M. Leirisolo, F. Lemonnier, E.J. Leonard, R.H. Levin, W.R. Levis, J. Levy, R. Levy, W. Lichter, K. Lindahl-Kiessling, M. Linker-Israeli, T.J. Linna, P. Lonai, J. London, F. Loor, M. Lotker, G.H. Lowell, I. Lowy, C.J. Lucas, D. Lucas, M.L. Lukic, J.R. Lumb, S. Lustig, J.C. Mani, D.L. Manor, S. Mannheimer, M. Margalith, R. Maron, G. Matthyssens, M. Mayer, J.M. McCord, M.S. Meltzer, J. Mendelsohn, J.E. Merrill, R.G. Miller, J. Minowada, T. Moen, C. Moroni, C. Moroz, E. Mozes, P.F. Muhlradt, N. Naaktgeboren, D. Nachtigal, I. Nakamura, D. Naor, E. Naparstek, C. Néauport-Sautès, D. Nelken, Y. Nir, A. Nisonoff, F. Noonan, N. Novick, A. Novogrodsky, R.L. O'Brien, H. Oerkermann, J.J. Oppenheim, F.L. Owen, R.M.J. Palmer, G.R. Pape, M. Papiernik, M. Parant, B. Parhami, C.W. Parker, W.E. Paul, T.W. Pearson, A. Peled, R. Penny, H. Perlmann, J.H. Peters, A.I. Pick, E. Pick, J. Pitt, Y.M. Plesser, D.H. Pluznik, C. Present, A.M. Prieur, M.R. Quastel, R. Rabinovitz, T. Radaszkiewicz, J. Radnay, B. Ramot, A. Ravid, Y. Reisner, H. Repo, K. Resch, S. Reuveni, J.P. Revillard, E. Riklis, M. Rister, N. Robert, D. Roos, C. Rosenfeld, A. Rosenthal, V. Rotter, Y. Roy, A.L. Rubin, B. Rubin, L. Sachs, S.B. Salvin, G. Sandberg, G.P. Sandilands, I. Sarov, M. Sasportes, D. Sauder, G.F. Saunders, K.P. Schafer, B. Schechter, G.P. Schechter, P.Th.A. Schellekens, B. Schick, V. Schirrmacher, A.M. Schmitt-Verhulst, M. Schwartz, D.M. Segal, S. Segal, B.A. Sela, M. Sela, M.N. Sela, B.C. Serrou, S. Shaltiel, G.D. Shantz, G.M. Shearer, E.M. Shevach, T.A. Shiftan, A. Shneyour, J. Shoham, B. Shohat, M.M. Siegal, E. Silverstein, M. Simic, M.A. Simons, A. Singer, R.P. Siraganian, A. Skibin, S. Slavin, M. Small, A.I. Smievoll, R. Snyderman, C.P. Sodomann, C. Sorg, S. Sprecher-Goldgerger, S. Sorensesn, B. Sredni, S. Starobin, E.J. Steele, H.B. Steen, M. Steinitz, K.H. Stenzel, K. Stern, S.K. Storch, H. Stotter, J. Strausser, M. Stroun, Y. Stupp, D. Sulitzeanu, M. Suthanthiran, R.H. Swanborg, A. Szenberg, T. Tada, M. Talpaert-Borle, S. Targan, R. Tarrab-Hazdai, B. Tartakovsky, D. Teitelbaum, A. Termijtelen, M. Thomsen, K.J.I. Thorne, R. Toper, N. Trainin, V.J. Treves, D.G. Trist, M. Troye, E. Tzehoval, J. Uhr, T. Umiel, F. Uytdehaag, H. Valdimarsson, J.A. van Boxel, J.J. van der Poel, R. van Furth, P. Vassalli, I.M. Verma, L. Verschaeve, J.E. de Vries, B.U. von Specht, H. Wagner, G. Wagemaker, T. Waks, M.A. Wainberg, S.D. Waksal, H. Waldmann, H.A. Ward, K.N. Ward, W.T. Weber, R.S. Weening, Y. Weinstein, B. Wenzel, E.F. Wheelock, J. Wietzerbin, M. Wilchek, M. Wilton, J.H. Wissler, J. Wolfe, J.N. Woody, P. Wright, L. Wren, J. Wybran, Y. Yakir, E. Yefenof, R. Zaizov, I. Zan-Bar, A. Zeevi, W.P. Zeijlemaker, Y. Zick, J.B. Ziegler, K. Zier, and I.M. Zitron

Published
1979
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14. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Author

Sorin Hostiuc, Shaun Wen Huey Lee, Jorge R. Ledesma, Carsten Flohr, Masoumeh Sadeghi, João Mauricio Castaldelli-Maia, Behzad Karami Matin, Cyrus Alinia, Mehdi Bohluli, Félix Carvalho, Yun Jin Kim, Catalina Liliana Andrei, Seyyed Meysam Mousavi, Bernhard T. Baune, Ehsan Ahmadpour, Dinh-Toi Chu, Beatrix Haddock, Gianfranco Alicandro, Vasily Vlassov, Mohammad Taghi Khodayari, Gianna Gayle Herrera Amul, Arash Tehrani-Banihashemi, Govinda Prasad Dhungana, Fereshteh Ansari, Michael K. Hole, Azeem Majeed, Iman Halvaei, Saqib Ali, Arianna Maever L. Amit, Tomas Y. Yeheyis, John S. Ji, Martin McKee, Jamileh Shadid, Leonardo Roever, Peng Jia, Ettore Beghi, Pablo M. Lavados, Young Eun Kim, Vahid Alipour, Sowmya J. Rao, Ahmad Daryani, Cathleen Keller, Ibrahim Abdollahpour, Nicole K. DeCleene, Ebrahim Babaee, Saman Esmaeilnejad, Boris Bikbov, William M. Gardner, Lydia M. Haile, Luca Ronfani, Azalea M. Thomson, Irena Ilic, Ruth W. Kimokoti, Yingxi Zhao, Guoqing Hu, Mehran Shams-Beyranvand, Ilais Moreno Velásquez, Nathaniel J. Henry, Brijesh Sathian, Daniel Kim, Peter Memiah, Mohammad Hadi Abbasi, Andrea Farioli, Zahra Kamiab, Bolajoko O. Olusanya, Matthew C. Doxey, Tommi Vasankari, Hamideh Salimzadeh, Luisa Sorio Flor, Priya Rathi, Shanshan Li, Tanvir M. Huda, Dillon O Sylte, Rosario Cárdenas, Agegnehu Bante, Helen Ippolito, Alyssa Acebedo, Jeffrey D. Stanaway, Anwar Faraj, João Pedro Silva, Amin Mousavi Khaneghah, Pushpendra Kumar, Sangram Kishor Patel, Josephine W. Ngunjiri, Holly E. Erskine, Eugene Sobngwi, Filippo Ariani, Shane D. Morrison, Mohammad Aghaali, Meghan D. Mooney, Vera Marisa Costa, Palash Chandra Banik, Rupak Desai, Ken Takahashi, Maigeng Zhou, Morteza Oladnabi, Bogdan Oancea, Daniela Ribeiro, Mohammad Farahmand, Irmina Maria Michalek, Yetunde O. John-Akinola, Khem Narayan Pokhrel, Emilie R Maddison, Syed Mohamed Aljunid, Damian G. Hoy, Hosni Salem, V. 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L., Department of Public Health, Clinicum, Department of Neurosciences, HUS Comprehensive Cancer Center, Environmental Sciences, Public Health, Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Value, Affordability and Sustainability (VALUE), Microbes in Health and Disease (MHD), Sálfræðideild (HR), Department of Psychology (RU), Samfélagssvið (HR), School of Social Sciences (RU), Háskólinn í Reykjavík, Reykjavik University, GBD 2019 Diseases and Injuries Collaborator, Violante FS, Department of Earth Observation Science, Faculty of Geo-Information Science and Earth Observation, and UT-I-ITC-ACQUAL

Subjects
Male, Life expectancy, Disability-Adjusted Life Year, Diseases, Disease, communicable disease, systematic analysis, Global Burden of Disease, 0302 clinical medicine, 80 and over, Medicine, 10. No inequality, Child, 11 Medical and Health Sciences, injuries, Aged, 80 and over, education.field_of_study, Sjúkdómar, DEMENTIA, FALLS, General Medicine, Forvarnir, 3. Good health, Child, Preschool, Human, GBD, Population health, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Humans, Global Burden of Disease Study, education, Aged, Spatial Analysis, Global burden, Disability, Prevention, DISABILITY, Infant, Spatial Analysi, Mortality rate, Global Burden of Disease, Diseases, Injuries, Systematic analysis, PREVENTION, Years of potential life lost, Risk factors, Disease study, ITC-ISI-JOURNAL-ARTICLE, RISK-FACTORS, Clinical Medicine, RA, Demography, Fötlun, Dánartíðni, Áhættuþættir, 030204 cardiovascular system & hematology, Risk Factors, Cause of Death, Global health, 030212 general & internal medicine, 1. No poverty, Disability-Adjusted Life Years, Public Health, Global Health, Social Medicine and Epidemiology, Middle Aged, 3142 Public health care science, environmental and occupational health, Adolescent, Adult, Age Distribution, Female, Infant, Newborn, Young Adult, Lýðheilsa, CLINICAL-TRIALS, Population, Settore MED/01 - Statistica Medica, diseases, ITC-HYBRID, Heilbrigðisvísindi, General & Internal Medicine, Mortality, Preschool, Disease burden, business.industry, Risk Factor, Klinisk medicin, Newborn, purl.org/pe-repo/ocde/ford#3.02.00 [https], Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Áverkar, Systematic analysis, NA, business
Abstract

Publisher's version (útgefin grein), Background In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990-2010 time period, with the greatest annualised rate of decline occurring in the 0-9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10-24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10-24 years were also in the top ten in the 25-49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50-74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and development investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Copyright (C) 2020 The Author(s). Published by Elsevier Ltd., Research reported in this publication was supported by the Bill & Melinda Gates Foundation; the University of Melbourne; Queensland Department of Health, Australia; the National Health and Medical Research Council, Australia; Public Health England; the Norwegian Institute of Public Health; St Jude Children's Research Hospital; the Cardiovascular Medical Research and Education Fund; the National Institute on Ageing of the National Institutes of Health (award P30AG047845); and the National Institute of Mental Health of the National Institutes of Health (award R01MH110163). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders. The authors alone are responsible for the views expressed in this Article and they do not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated, the National Health Service (NHS), the National Institute for Health Research (NIHR), the UK Department of Health and Social Care, or Public Health England; the United States Agency for International Development (USAID), the US Government, or MEASURE Evaluation; or the European Centre for Disease Prevention and Control (ECDC). This research used data from the Chile National Health Survey 2003, 2009-10, and 2016-17. The authors are grateful to the Ministry of Health, the survey copyright owner, for allowing them to have the database. All results of the study are those of the authors and in no way committed to the Ministry. The Costa Rican Longevity and Healthy Aging Study project is a longitudinal study by the University of Costa Rica's Centro Centroamericano de Poblacion and Instituto de Investigaciones en Salud, in collaboration with the University of California at Berkeley. The original pre-1945 cohort was funded by the Wellcome Trust (grant 072406), and the 1945-55 Retirement Cohort was funded by the US National Institute on Aging (grant R01AG031716). The principal investigators are Luis Rosero-Bixby and William H Dow and co-principal investigators are Xinia Fernandez and Gilbert Brenes. The accuracy of the authors' statistical analysis and the findings they report are not the responsibility of ECDC. ECDC is not responsible for conclusions or opinions drawn from the data provided. ECDC is not responsible for the correctness of the data and for data management, data merging and data collation after provision of the data. ECDC shall not be held liable for improper or incorrect use of the data. The Health Behaviour in School-Aged Children (HBSC) study is an international study carried out in collaboration with WHO/EURO. The international coordinator of the 1997-98, 2001-02, 2005-06, and 2009-10 surveys was Candace Currie and the databank manager for the 1997-98 survey was Bente Wold, whereas for the following surveys Oddrun Samdal was the databank manager. A list of principal investigators in each country can be found on the HBSC website. Data used in this paper come from the 2009-10 Ghana Socioeconomic Panel Study Survey, which is a nationally representative survey of more than 5000 households in Ghana. The survey is a joint effort undertaken by the Institute of Statistical, Social and Economic Research (ISSER) at the University of Ghana and the Economic Growth Centre (EGC) at Yale University. It was funded by EGC. ISSER and the EGC are not responsible for the estimations reported by the analysts. The Palestinian Central Bureau of Statistics granted the researchers access to relevant data in accordance with license number SLN2014-3-170, after subjecting data to processing aiming to preserve the confidentiality of individual data in accordance with the General Statistics Law, 2000. The researchers are solely responsible for the conclusions and inferences drawn upon available data. Data for this research was provided by MEASURE Evaluation, funded by USAID. The authors thank the Russia Longitudinal Monitoring Survey, conducted by the National Research University Higher School of Economics and ZAO Demoscope together with Carolina Population Center, University of North Carolina at Chapel Hill and the Institute of Sociology, Russia Academy of Sciences for making data available. This paper uses data from the Bhutan 2014 STEPS survey, implemented by the Ministry of Health with the support of WHO; the Kuwait 2006 and 2014 STEPS surveys, implemented by the Ministry of Health with the support of WHO; the Libya 2009 STEPS survey, implemented by the Secretariat of Health and Environment with the support of WHO; the Malawi 2009 STEPS survey, implemented by Ministry of Health with the support of WHO; and the Moldova 2013 STEPS survey, implemented by the Ministry of Health, the National Bureau of Statistics, and the National Center of Public Health with the support of WHO. This paper uses data from Survey of Health, Ageing and Retirement in Europe (SHARE) Waves 1 (DOI:10.6103/SHARE. w1.700), 2 (10.6103/SHARE.w2.700), 3 (10.6103/SHARE.w3.700), 4 (10.6103/SHARE.w4.700), 5 (10.6103/SHARE.w5.700), 6 (10.6103/SHARE.w6.700), and 7 (10.6103/SHARE.w7.700); see Borsch-Supan and colleagues (2013) for methodological details. The SHARE data collection has been funded by the European Commission through FP5 (QLK6-CT-2001-00360), FP6 (SHARE-I3: RII-CT-2006-062193, COMPARE: CIT5-CT-2005-028857, SHARELIFE: CIT4-CT-2006-028812), FP7 (SHARE-PREP: GA N degrees 211909, SHARE-LEAP: GA N degrees 227822, SHARE M4: GA N degrees 261982) and Horizon 2020 (SHARE-DEV3: GA N degrees 676536, SERISS: GA N degrees 654221) and by DG Employment, Social Affairs & Inclusion. Additional funding from the German Ministry of Education and Research, the Max Planck Society for the Advancement of Science, the US National Institute on Aging (U01_AG09740-13S2, P01_AG005842, P01_AG08291, P30_AG12815, R21_AG025169, Y1-AG-4553-01, IAG_BSR06-11, OGHA_04-064, HHSN271201300071C), and from various national funding sources is gratefully acknowledged. This study has been realised using the data collected by the Swiss Household Panel, which is based at the Swiss Centre of Expertise in the Social Sciences. The project is financed by the Swiss National Science Foundation. The United States Aging, Demographics, and Memory Study is a supplement to the Health and Retirement Study (HRS), which is sponsored by the National Institute of Aging (grant number NIA U01AG009740). It was conducted jointly by Duke University and the University of Michigan. The HRS is sponsored by the National Institute on Aging (grant number NIA U01AG009740) and is conducted by the University of Michigan. This paper uses data from Add Health, a program project designed by J Richard Udry, Peter S Bearman, and Kathleen Mullan Harris, and funded by a grant P01-HD31921 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, with cooperative funding from 17 other agencies. Special acknowledgment is due to Ronald R Rindfuss and Barbara Entwisle for assistance in the original design. Information on how to obtain the Add Health data files is available on the Add Health website. No direct support was received from grant P01-HD31921 for this analysis. The data reported here have been supplied by the United States Renal Data System. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy or interpretation of the US Government. Collection of data for the Mozambique National Survey on the Causes of Death 2007-08 was made possible by USAID under the terms of cooperative agreement GPO-A-00-08-000_D3-00. This manuscript is based on data collected and shared by the International Vaccine Institute (IVI) from an original study IVI conducted. L G Abreu acknowledges support from Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (Brazil; finance code 001) and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, a Brazilian funding agency). I N Ackerman was supported by a Victorian Health and Medical Research Fellowship awarded by the Victorian Government. O O Adetokunboh acknowledges the South African Department of Science and Innovation and the National Research Foundation. A Agrawal acknowledges the Wellcome Trust DBT India Alliance Senior Fellowship. S M Aljunid acknowledges the Department of Health Policy and Management, Faculty of Public Health, Kuwait University and International Centre for Casemix and Clinical Coding, Faculty of Medicine, National University of Malaysia for the approval and support to participate in this research project. M Ausloos, C Herteliu, and A Pana acknowledge partial support by a grant of the Romanian National Authority for Scientific Research and Innovation, CNDS-UEFISCDI, project number PN-III-P4-ID-PCCF-2016-0084. A Badawi is supported by the Public Health Agency of Canada. D A Bennett was supported by the NIHR Oxford Biomedical Research Centre. R Bourne acknowledges the Brien Holden Vision Institute, University of Heidelberg, Sightsavers, Fred Hollows Foundation, and Thea Foundation. G B Britton and I Moreno Velasquez were supported by the Sistema Nacional de Investigacion, SNI-SENACYT, Panama. R Buchbinder was supported by an Australian National Health and Medical Research Council (NHMRC) Senior Principal Research Fellowship. J J Carrero was supported by the Swedish Research Council (2019-01059). F Carvalho acknowledges UID/MULTI/04378/2019 and UID/QUI/50006/2019 support with funding from FCT/MCTES through national funds. A R Chang was supported by National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases grant K23 DK106515. V M Costa acknowledges the grant SFRH/BHD/110001/2015, received by Portuguese national funds through Fundacao para a Ciencia e Tecnologia, IP, under the Norma Transitaria DL57/2016/CP1334/CT0006. A Douiri acknowledges support and funding from the National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care South London at King's College Hospital NHS Foundation Trust and the Royal College of Physicians, and support from the NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. B B Duncan acknowledges grants from the Foundation for the Support of Research of the State of Rio Grande do Sul (IATS and PrInt) and the Brazilian Ministry of Health. H E Erskine is the recipient of an Australian NHMRC Early Career Fellowship grant (APP1137969). A J Ferrari was supported by a NHMRC Early Career Fellowship grant (APP1121516). H E Erskine and A J Ferrari are employed by and A M Mantilla-Herrera and D F Santomauro affiliated with the Queensland Centre for Mental Health Research, which receives core funding from the Queensland Department of Health. M L Ferreira holds an NHMRC Research Fellowship. C Flohr was supported by the NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust. M Freitas acknowledges financial support from the EU (European Regional Development Fund [FEDER] funds through COMPETE POCI-01-0145-FEDER-029248) and National Funds (Fundacao para a Ciencia e Tecnologia) through project PTDC/NAN-MAT/29248/2017. A L S Guimaraes acknowledges support from CNPq. C Herteliu was partially supported by a grant co-funded by FEDER through Operational Competitiveness Program (project ID P_40_382). P Hoogar acknowledges Centre for Bio Cultural Studies, Directorate of Research, Manipal Academy of Higher Education and Centre for Holistic Development and Research, Kalaghatagi. F N Hugo acknowledges the Visiting Professorship, PRINT Program, CAPES Foundation, Brazil. B-F Hwang was supported by China Medical University (CMU107-Z-04), Taichung, Taiwan. S M S Islam was funded by a National Heart Foundation Senior Research Fellowship and supported by Deakin University. R Q Ivers was supported by a research fellowship from the National Health and Medical Research Council of Australia. M Jakovljevic acknowledges the Serbian part of this GBD-related contribution was co-funded through Grant OI175014 of the Ministry of Education Science and Technological Development of the Republic of Serbia. P Jeemon was supported by a Clinical and Public Health intermediate fellowship (grant number IA/CPHI/14/1/501497) from the Wellcome Trust-Department of Biotechnology, India Alliance (2015-20). O John is a recipient of UIPA scholarship from University of New South Wales, Sydney. S V Katikireddi acknowledges funding from a NRS Senior Clinical Fellowship (SCAF/15/02), the Medical Research Council (MC_UU_12017/13, MC_UU_12017/15), and the Scottish Government Chief Scientist Office (SPHSU13, SPHSU15). C Kieling is a CNPq researcher and a UK Academy of Medical Sciences Newton Advanced Fellow. Y J Kim was supported by Research Management Office, Xiamen University Malaysia (XMUMRF/2018-C2/ITCM/00010). K Krishan is supported by UGC Centre of Advanced Study awarded to the Department of Anthropology, Panjab University, Chandigarh, India. M Kumar was supported by K43 TW 010716 FIC/NIMH. B Lacey acknowledges support from the NIHR Oxford Biomedical Research Centre and the BHF Centre of Research Excellence, Oxford. J V Lazarus was supported by a Spanish Ministry of Science, Innovation and Universities Miguel Servet grant (Instituto de Salud Carlos III [ISCIII]/ESF, the EU [CP18/00074]). K J Looker thanks the NIHR Health Protection Research Unit in Evaluation of Interventions at the University of Bristol, in partnership with Public Health England, for research support. S Lorkowski was funded by the German Federal Ministry of Education and Research (nutriCARD, grant agreement number 01EA1808A). R A Lyons is supported by Health Data Research UK (HDR-9006), which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, NIHR (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation, and Wellcome Trust. J J McGrath is supported by the Danish National Research Foundation (Niels Bohr Professorship), and the Queensland Health Department (via West Moreton HHS). P T N Memiah acknowledges support from CODESRIA. U O Mueller gratefully acknowledges funding by the German National Cohort Study BMBF grant number 01ER1801D. S Nomura acknowledges the Ministry of Education, Culture, Sports, Science, and Technology of Japan (18K10082). A Ortiz was supported by ISCIII PI19/00815, DTS18/00032, ISCIII-RETIC REDinREN RD016/0009 Fondos FEDER, FRIAT, Comunidad de Madrid B2017/BMD-3686 CIFRA2-CM. These funding sources had no role in the writing of the manuscript or the decision to submit it for publication. S B Patten was supported by the Cuthbertson & Fischer Chair in Pediatric Mental Health at the University of Calgary. G C Patton was supported by an aNHMRC Senior Principal Research Fellowship. M R Phillips was supported in part by the National Natural Science Foundation of China (NSFC, number 81371502 and 81761128031). A Raggi, D Sattin, and S Schiavolin were supported by grants from the Italian Ministry of Health (Ricerca Corrente, Fondazione Istituto Neurologico C Besta, Linea 4-Outcome Research: dagli Indicatori alle Raccomandazioni Cliniche). P Rathi and B Unnikrishnan acknowledge Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal. A L P Ribeiro was supported by Brazilian National Research Council, CNPq, and the Minas Gerais State Research Agency, FAPEMIG. D C Ribeiro was supported by The Sir Charles Hercus Health Research Fellowship (#18/111) Health Research Council of New Zealand. D Ribeiro acknowledges financial support from the EU (FEDER funds through the Operational Competitiveness Program; POCI-01-0145-FEDER-029253). P S Sachdev acknowledges funding from the NHMRC of Australia Program Grant. A M Samy was supported by a fellowship from the Egyptian Fulbright Mission Program. M M Santric-Milicevic acknowledges the Ministry of Education, Science and Technological Development of the Republic of Serbia (contract number 175087). R Sarmiento-Suarez received institutional support from Applied and Environmental Sciences University (Bogota, Colombia) and ISCIII (Madrid, Spain). A E Schutte received support from the South African National Research Foundation SARChI Initiative (GUN 86895) and Medical Research Council. S T S Skou is currently funded by a grant from Region Zealand (Exercise First) and a grant from the European Research Council under the EU's Horizon 2020 research and innovation program (grant agreement number 801790). J B Soriano is funded by Centro de Investigacion en Red de Enfermedades Respiratorias, ISCIII. R Tabares-Seisdedos was supported in part by the national grant PI17/00719 from ISCIII-FEDER. N Taveira was partially supported by the European & Developing Countries Clinical Trials Partnership, the EU (LIFE project, reference RIA2016MC-1615). S Tyrovolas was supported by the Foundation for Education and European Culture, the Sara Borrell postdoctoral programme (reference number CD15/00019 from ISCIII-FEDER). S B Zaman received a scholarship from the Australian Government research training programme in support of his academic career., "Peer Reviewed"

Published
2020
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16. Host location by arthropod vectors: are microorganisms in control?

Author

Bourne ME, Lucas-Barbosa D, and Verhulst NO

Subjects
Animals, Vertebrates microbiology, Arthropod Vectors microbiology, Arthropods microbiology, Arthropods physiology
Abstract

Vector-borne microorganisms are dependent on their arthropod vector for their transmission to and from vertebrates. The 'parasite manipulation hypothesis' states that microorganisms are likely to evolve manipulations of such interactions for their own selective benefit. Recent breakthroughs uncovered novel ecological interactions initiated by vector-borne microorganisms, which are linked to different stages of the host location by their arthropod vectors. Therefore, we give an actualised overview of the various means through which vector-borne microorganisms impact their vertebrate and arthropod hosts to ultimately benefit their own transmission. Harnessing the directionality and underlying mechanisms of these interactions driven by vector-borne microorganisms may provide tools to reduce the spread of pathogenic vector-borne microorganisms., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2024
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17. [Protection of caregivers in a university hospital at the time of Covid-19: Between overprotection and underprotection or between abandonment and weakening of the vital forces?]

Author

Pougnet R, Pougnet L, Eniafe-Eveillard BM, Ouedraogo S, Lucas D, Dewitte JD, and Loddé B

Abstract

During the first months of the Sars-Cov-2 pandemic, French caregivers faced difficult situations, organizational changes, and rapidly changing recommendations. The occupational physicians of the hospital staff had to accompany the caregivers, both to answer their questions, both to better prevent the risks to their health in connection with the pandemic. Recommendations were quickly issued by the Société française de médecine du travail (French Society of Occupational Medicine). In our CHU, an evaluation of exposures was made by department. Occupational physicians advised agents and the institution to limit the risks to the health of agents. However, faced with the uncertainties linked to ignorance of the virus, how can we play both the role of protection of each agent, and that of a doctor registered in a health war? This article revisits from a distance the ethical tensions of the hospital occupational physician and the qualities necessary for the accomplishment of these missions., (© 2022 Elsevier Masson SAS. All rights reserved.)

Published
2022
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19. Early diagnosis of T2DM using high sensitive tests in the mandatory medical examinations for fishers, seafarers and other transport workers.

Author

Jensen OC, Flores A, Corman V, Canals ML, Lucas D, Denisenko I, Lucero-Prisno DE, Secher AEL, Andersen GS, Jørgensen ME, and Gyntelberg F

Subjects
Blood Glucose, Early Diagnosis, Fasting, Glucose Tolerance Test, Glycated Hemoglobin analysis, Humans, Diabetes Mellitus, Type 2 diagnosis
Abstract

Transport workers like seafarers, truck-, bus-, train- and taxi drivers and fishers have a known great inequity in health at work including high risk of developing type 2 diabetes. Their routine mandatory medical examinations use urine glucose for diabetes check with more than 50% false negatives, which should be replaced by high sensitive tests for diabetes-2, like A1C, Fasting Glucose (FPG) or Oral Glucose Tolerance Test (OGTT)., (Copyright © 2021 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

Published
2022
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21. Allosteric SHP2 inhibitors in cancer: Targeting the intersection of RAS, resistance, and the immune microenvironment.

Author

Kerr DL, Haderk F, and Bivona TG

Subjects
Allosteric Regulation drug effects, Animals, Antineoplastic Agents immunology, Antineoplastic Agents pharmacology, Cell Line, Tumor, Drug Resistance, Neoplasm, Enzyme Inhibitors immunology, Enzyme Inhibitors pharmacology, Humans, Immunotherapy, Molecular Docking Simulation, Protein Binding, Protein Conformation, Signal Transduction, Xenograft Model Antitumor Assays, Antineoplastic Agents chemistry, Enzyme Inhibitors chemistry, Mitogen-Activated Protein Kinases metabolism, Protein Tyrosine Phosphatase, Non-Receptor Type 11 antagonists & inhibitors, Receptor Protein-Tyrosine Kinases metabolism, ras Proteins metabolism
Abstract

The nonreceptor protein tyrosine phosphatase SHP2 (encoded by PTPN11) integrates growth and differentiation signals from receptor tyrosine kinases (RTKs) into the RAS/mitogen-activated protein kinase (MAPK) cascade. Considered 'undruggable' over three decades, SHP2 is now a potentially druggable target with the advent of allosteric SHP2 inhibitors. These agents hold promise for improving patient outcomes, showing efficacy in preclinical cancer models, where SHP2 is critical for either oncogenic signaling or resistance to current targeted agents. SHP2 inhibition may also produce immunomodulatory effects in certain tumor microenvironment cells to help cultivate antitumor immune responses. The first generation of allosteric SHP2 inhibitors is under clinical evaluation to determine safety, appropriate tolerability management, and antitumor efficacy, investigations that will dictate future clinical applications., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: T. G. B. is an advisor to Novartis, Astrazeneca, Revolution Medicines, Array/Pfizer, Springworks, Strategia, Relay, Jazz, Rain and receives research funding from Novartis and Revolution Medicines and Strategia. D. L. K. and F. H. declare that they have no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Published
2021
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22. Neutrophils as regulators of the hematopoietic niche.

Author

Cossío I, Lucas D, and Hidalgo A

Subjects
Animals, Cell Movement, Cell Proliferation, Cellular Senescence, Circadian Rhythm, Hematopoietic Stem Cells metabolism, Humans, Neutrophils metabolism, Hematopoiesis, Hematopoietic Stem Cells cytology, Neutrophils cytology, Stem Cell Niche
Abstract

The niche that supports hematopoietic stem and progenitor cells (HSPCs) in the bone marrow is a highly dynamic structure. It maintains core properties of HSPCs in the steady state, and modulates their proliferation and differentiation in response to changing physiological demands or pathological insults. The dynamic and environment-sensing properties of the niche are shared by the innate immune system. Thus, it is not surprising that innate immune cells, including macrophages and neutrophils, are now recognized as important regulators of the hematopoietic niche and, ultimately, of the stem cells from which they derive. This review synthesizes emerging concepts on niche regulation by immune cells, with a particular emphasis on neutrophils. We argue that the unique developmental, circadian, and migratory properties of neutrophils underlie their critical contributions as regulators of the hematopoietic niche., (© 2019 by The American Society of Hematology.)

Published
2019
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23. Multi-class multi-residue analysis of pesticides in edible oils by gas chromatography-tandem mass spectrometry using liquid-liquid extraction and enhanced matrix removal lipid cartridge cleanup.

Author

Zhao L, Szakas T, Churley M, and Lucas D

Subjects
Calibration, Pesticide Residues isolation & purification, Corn Oil chemistry, Gas Chromatography-Mass Spectrometry methods, Lipids chemistry, Liquid-Liquid Extraction methods, Olive Oil chemistry, Pesticide Residues analysis, Soybean Oil chemistry, Tandem Mass Spectrometry methods
Abstract

This study presents the development and validation of a method for the multi-class multi-residue analysis of pesticide residues in edible oils using liquid-liquid extraction followed by EMR-Lipid (enhanced matrix removal - lipid) cartridge cleanup, and then analyzed by gas chromatography tandem mass spectrometer (GC-MS/MS). The method was optimized for analyte recovery, matrix removal, and water removal during the sample extraction, sample cleanup and sample drying steps. The extraction efficiency of lipophilic pesticides (i.e. organochlorine) from the hydrophobic oil matrix was improved using a two-step liquid-liquid extraction with a mixture of ethyl acetate and acetonitrile. EMR-Lipid cartridges provided efficient and selective cleanup of the tested oil matrices. The developed method was verified by analyzing four edible oil matrices: olive oil, corn oil, soybean oil and canola oil. The results demonstrated that the method effectively removes unwanted matrix co-extractives better than conventional PSA/C18 dispersive solid phase extraction (dSPE) cleanup, while still delivering acceptable recovery results (recoveries of 60-120%) for the majority of pesticides tested. With the established quantification method, over 95% of the pesticides obtained for 70-120% accuracy, RSD < 20%, and calibration curves from 1 to 500 (400) ng/g in oil with R 2 > 0.99., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Published
2019
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24. Multi-class multi-residue analysis of veterinary drugs in meat using enhanced matrix removal lipid cleanup and liquid chromatography-tandem mass spectrometry.

Author

Zhao L, Lucas D, Long D, Richter B, and Stevens J

Subjects
Animals, Cattle, Chickens, Dimethyl Sulfoxide chemistry, Muscles metabolism, Reference Standards, Reproducibility of Results, Solvents chemistry, Sus scrofa, Chromatography, Liquid methods, Drug Residues analysis, Lipids analysis, Meat analysis, Tandem Mass Spectrometry methods, Veterinary Drugs analysis, Veterinary Drugs classification
Abstract

This study presents the development and validation of a quantitation method for the analysis of multi-class, multi-residue veterinary drugs using lipid removal cleanup cartridges, enhanced matrix removal lipid (EMR-Lipid), for different meat matrices by liquid chromatography tandem mass spectrometry detection. Meat samples were extracted using a two-step solid-liquid extraction followed by pass-through sample cleanup. The method was optimized based on the buffer and solvent composition, solvent additive additions, and EMR-Lipid cartridge cleanup. The developed method was then validated in five meat matrices, porcine muscle, bovine muscle, bovine liver, bovine kidney and chicken liver to evaluate the method performance characteristics, such as absolute recoveries and precision at three spiking levels, calibration curve linearity, limit of quantitation (LOQ) and matrix effect. The results showed that >90% of veterinary drug analytes achieved satisfactory recovery results of 60-120%. Over 97% analytes achieved excellent reproducibility results (relative standard deviation (RSD) < 20%), and the LOQs were 1-5 μg/kg in the evaluated meat matrices. The matrix co-extractive removal efficiency by weight provided by EMR-lipid cartridge cleanup was 42-58% in samples. The post column infusion study showed that the matrix ion suppression was reduced for samples with the EMR-Lipid cartridge cleanup. The reduced matrix ion suppression effect was also confirmed with <15% frequency of compounds with significant quantitative ion suppression (>30%) for all tested veterinary drugs in all of meat matrices. The results showed that the two-step solid-liquid extraction provides efficient extraction for the entire spectrum of veterinary drugs, including the difficult classes such as tetracyclines, beta-lactams etc. EMR-Lipid cartridges after extraction provided efficient sample cleanup with easy streamlined protocol and minimal impacts on analytes recovery, improving method reliability and consistency., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Published
2018
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25. The role of sorption processes in the removal of pharmaceuticals by fungal treatment of wastewater.

Author

Lucas D, Castellet-Rovira F, Villagrasa M, Badia-Fabregat M, Barceló D, Vicent T, Caminal G, Sarrà M, and Rodríguez-Mozaz S

Subjects
Biodegradation, Environmental, Bioreactors microbiology, Pharmaceutical Preparations analysis, Wastewater chemistry, Water Pollutants, Chemical analysis, Pharmaceutical Preparations metabolism, Waste Disposal, Fluid methods, Wastewater microbiology, Water Pollutants, Chemical metabolism
Abstract

The contribution of the sorption processes in the elimination of pharmaceuticals (PhACs) during the fungal treatment of wastewater has been evaluated in this work. The sorption of four PhACs (carbamazepine, diclofenac, iopromide and venlafaxine) by 6 different fungi was first evaluated in batch experiments. Concentrations of PhACs in both liquid and solid (biomass) matrices from the fungal treatment were measured. Contribution of the sorption to the total removal of pollutants ranged between 3% and 13% in relation to the initial amount. The sorption of 47 PhACs in fungi was also evaluated in a fungal treatment performed in 26days in a continuous bioreactor treating wastewater from a veterinary hospital. PhACs levels measured in the fungal biomass were similar to those detected in conventional wastewater treatment (WWTP) sludge. This may suggest the necessity of manage fungal biomass as waste in the same manner that the WWTP sludge is managed., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Published
2018
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26. The orphan nuclear receptor TR4 regulates erythroid cell proliferation and maturation.

Author

Lee MP, Tanabe O, Shi L, Jearawiriyapaisarn N, Lucas D, and Engel JD

Subjects
Anemia blood, Anemia genetics, Animals, Bone Marrow Cells cytology, Bone Marrow Cells metabolism, Cell Proliferation genetics, Erythropoiesis genetics, Gene Expression Regulation, Developmental, Genes, Lethal, Heterozygote, Homozygote, Lymphopoiesis genetics, Mice, Mice, Knockout, Mutation, Myelopoiesis genetics, Nuclear Receptor Subfamily 2, Group C, Member 2 metabolism, Cell Differentiation genetics, Erythroid Cells cytology, Erythroid Cells metabolism, Nuclear Receptor Subfamily 2, Group C, Member 2 genetics
Abstract

The orphan nuclear receptors TR4 (NR2C2) and TR2 (NR2C1) are the DNA-binding subunits of the macromolecular complex, direct repeat erythroid-definitive, which has been shown to repress ε- and γ-globin transcription during adult definitive erythropoiesis. Previous studies implied that TR2 and TR4 act largely in a redundant manner during erythroid differentiation; however, during the course of routine genetic studies, we observed multiple variably penetrant phenotypes in the Tr4 mutants, suggesting that indirect effects of the mutation might be masked by multiple modifying genes. To test this hypothesis, Tr4 +/- mutant mice were bred into a congenic C57BL/6 background and their phenotypes were reexamined. Surprisingly, we found that homozygous Tr4 null mutant mice expired early during embryogenesis, around embryonic day 7.0, and well before erythropoiesis commences. We further found that Tr4 +/- erythroid cells failed to fully differentiate and exhibited diminished proliferative capacity. Analysis of Tr4 +/- mutant erythroid cells revealed that reduced TR4 abundance resulted in decreased expression of genes required for heme biosynthesis and erythroid differentiation ( Alad and Alas2 ), but led to significantly increased expression of the proliferation inhibitory factor, cyclin dependent kinase inhibitor ( Cdkn1c) These studies support a vital role for TR4 in promoting erythroid maturation and proliferation, and demonstrate that TR4 and TR2 execute distinct, individual functions during embryogenesis and erythroid differentiation., (© 2017 by The American Society of Hematology.)

Published
2017
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27. Study of the effect of the bacterial and fungal communities present in real wastewater effluents on the performance of fungal treatments.

Author

Badia-Fabregat M, Lucas D, Tuomivirta T, Fritze H, Pennanen T, Rodríguez-Mozaz S, Barceló D, Caminal G, and Vicent T

Subjects
Biodegradation, Environmental, Bioreactors microbiology, Wastewater chemistry, Water Microbiology, Water Pollutants, Chemical analysis, Water Pollutants, Chemical toxicity, Waste Disposal, Fluid methods, Wastewater microbiology
Abstract

The use of the ligninolytic fungi Trametes versicolor for the degradation of micropollutants has been widely studied. However, few studies have addressed the treatment of real wastewater containing pharmaceutically active compounds (PhAC) under non-sterile conditions. The main drawback of performing such treatments is the difficulty for the inoculated fungus to successfully compete with the other microorganisms growing in the bioreactor. In the present study, several fungal treatments were performed under non-sterile conditions in continuous operational mode with two types of real wastewater effluent, namely, a reverse osmosis concentrate (ROC) from a wastewater treatment plant and a veterinary hospital wastewater (VHW). In all cases, the setup consisted of two parallel reactors: one inoculated with T. versicolor and one non-inoculated, which was used as the control. The main objective of this work was to correlate the operational conditions and traditional monitoring parameters, such as laccase activity, with PhAC removal and the composition of the microbial communities developed inside the bioreactors. For that purpose a variety of biochemical and molecular biology analyses were performed: phospholipid fatty acids analysis (PLFA), quantitative PCR (qPCR) and denaturing gradient gel electrophoresis (DGGE) followed by sequencing. The results show that many indigenous fungi (and not only bacteria, which were the focus of the majority of previously published research) can successfully compete with the inoculated fungi (i.e., Trichoderma asperellum overtook T. versicolor in the ROC treatment). We also showed that the wastewater origin and the operational conditions had a stronger impact on the diversity of microbial communities developed in the bioreactors than the inoculation or not with T. versicolor., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Published
2017
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28. Removal of pharmaceuticals from wastewater by fungal treatment and reduction of hazard quotients.

Author

Lucas D, Barceló D, and Rodriguez-Mozaz S

Subjects
Bioreactors, Water Pollutants, Chemical metabolism, Pharmaceutical Preparations analysis, Trametes metabolism, Waste Disposal, Fluid methods, Wastewater analysis, Water Pollutants, Chemical analysis
Abstract

The elimination of 81 pharmaceuticals (PhACs) by means of a biological treatment based on the fungus Trametes versicolor was evaluated in this work. PhAC removal studied in different types of wastewaters (urban, reverse osmosis concentrate, hospital, and veterinary hospital wastewaters) were reviewed and compared with conventional activated sludge (CAS) treatment. In addition, hazard indexes were calculated based on the exposure levels and ecotoxicity for each compound and used for the evaluation of the contaminants removal. PhAC elimination achieved with the fungal treatment (mean value 76%) was similar or slightly worse than the elimination achieved in the CAS treatment (85%). However, the fungal reactor was superior in removing more hazardous compounds (antibiotics and psychiatric drugs) than the conventional activated sludge in terms of environmental risk reduction (93% and 53% of reduction respectively). Fungal treatment can thus be considered as a good alternative to conventional treatment technologies for the elimination of PhACs from wastewaters., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Published
2016
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29. Suspect screening of emerging pollutants and their major transformation products in wastewaters treated with fungi by liquid chromatography coupled to a high resolution mass spectrometry.

Author

Llorca M, Lucas D, Ferrando-Climent L, Badia-Fabregat M, Cruz-Morató C, Barceló D, and Rodríguez-Mozaz S

Subjects
Chromatography, Liquid methods, Mass Spectrometry methods, Pharmaceutical Preparations analysis, Trametes, Wastewater analysis, Water Pollutants, Chemical analysis
Abstract

A new approach for the screening of 33 pharmaceuticals and 113 of their known transformation products in wastewaters was developed. The methodology is based on the analysis of samples by liquid chromatography coupled to high resolution mass spectrometry (HRMS) followed by data processing using specific software and manual confirmation. A home-made library was built with the transformation products reported in literature for the target pharmaceuticals after treatment with various fungi. The method was applied to the search of these contaminants in 67 samples generated along treatment of wastewaters with white-rot fungus Trametes versicolor. The screening methodology allowed the detection of different transformation products (TPs) generated from degradation of parent compounds after fungal treatment. This approach can be a useful tool for the rapid screening and tentative detection of emerging contaminants during water treatment in both full and batch-scale studies when pure standards are not available., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Published
2016
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30. Polycystin deficiency induces dopamine-reversible alterations in flow-mediated dilatation and vascular nitric oxide release in humans.

Author

Lorthioir A, Joannidès R, Rémy-Jouet I, Fréguin-Bouilland C, Iacob M, Roche C, Monteil C, Lucas D, Renet S, Audrézet MP, Godin M, Richard V, Thuillez C, Guerrot D, and Bellien J

Subjects
Adult, Cardiovascular Diseases etiology, Cardiovascular Diseases physiopathology, Case-Control Studies, Dopamine physiology, Endothelium, Vascular physiopathology, Female, Humans, Male, Mutation, Nitric Oxide physiology, Polycystic Kidney, Autosomal Dominant complications, Polycystic Kidney, Autosomal Dominant genetics, Radial Artery physiopathology, TRPP Cation Channels genetics, TRPP Cation Channels physiology, Vasodilation physiology, Young Adult, Hemodynamics physiology, Polycystic Kidney, Autosomal Dominant physiopathology, TRPP Cation Channels deficiency
Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a renal hereditary disorder associated with increased cardiovascular mortality, due to mutations in polycystin-1 and polycystin-2 genes. Endothelial polycystin-deficient cells have an altered mechanosensitivity to fluid shear stress and subsequent deficit in calcium-induced nitric oxide release, prevented by dopamine receptor stimulation. However, the impact of polycystin deficiency on endothelial function in ADPKD patients is still largely unknown. Here we assessed endothelium-dependent flow-mediated dilatation in 21 normotensive ADPKD patients and 21 healthy control subjects, during sustained (hand skin heating) and transient (postischemic hyperemia) flow stimulation. Flow-mediated dilatation was less marked in ADPKD patients than in controls during heating, but it was similar during postischemic hyperemia. There was no difference in endothelium-independent dilatation in response to glyceryl trinitrate. Local plasma nitrite, an indicator of nitric oxide availability, increased during heating in controls but not in patients. Brachial infusion of dopamine in a subset of ADPKD patients stimulated plasma nitrite increase during heating and improved flow-mediated dilatation. Thus, ADPKD patients display a loss of nitric oxide release and an associated reduction in endothelium-dependent dilatation of conduit arteries during sustained blood flow increase. The correction of these anomalies by dopamine suggests future therapeutic strategies that could reduce the occurrence of cardiovascular events in ADPKD.

Published
2015
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31. Identification of some factors affecting pharmaceutical active compounds (PhACs) removal in real wastewater. Case study of fungal treatment of reverse osmosis concentrate.

Author

Badia-Fabregat M, Lucas D, Gros M, Rodríguez-Mozaz S, Barceló D, Caminal G, and Vicent T

Subjects
Hot Temperature, Osmosis, Bioreactors microbiology, Pharmaceutical Preparations chemistry, Trametes metabolism, Waste Disposal, Fluid methods, Wastewater chemistry, Water Pollutants, Chemical chemistry
Abstract

Many technologies are being developed for the efficient removal of micropollutants from wastewater and, among them, fungal degradation is one of the possible alternative biological treatments. In this article, some factors that might affect pharmaceutically active compounds (PhACs) removal in a fungal treatment of real wastewater were identified in batch bioreactor treating reverse osmosis concentrate (ROC) from urban wastewater treatment plant (WWTP). We found that degradation of PhACs by Trametes versicolor was enhanced by addition of external nutrients (global removal of 44%). Moreover, our results point out that high aeration might be involved in the increase in the concentration of some PhACs. In fact, conjugation and deconjugation processes (among others) affect the removal assessment of emerging contaminants when working with real concentrations in comparison to experiments with spiked samples. Moreover, factors that could affect the quantification of micropollutants at lab-scale experiments were studied., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Published
2015
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32. Hospital wastewater treatment by fungal bioreactor: removal efficiency for pharmaceuticals and endocrine disruptor compounds.

Author

Cruz-Morató C, Lucas D, Llorca M, Rodriguez-Mozaz S, Gorga M, Petrovic M, Barceló D, Vicent T, Sarrà M, and Marco-Urrea E

Subjects
Fungi physiology, Wastewater chemistry, Bioreactors microbiology, Endocrine Disruptors analysis, Hospitals, Pharmaceutical Preparations analysis, Waste Disposal, Fluid methods, Water Pollutants, Chemical analysis
Abstract

Hospital effluents contribute to the occurrence of emerging contaminants in the environment due to their high load of pharmaceutical active compounds (PhACs) and some endocrine disruptor compounds (EDCs). Nowadays, hospital wastewaters are co-treated with urban wastewater; however, the dilution factor and the inefficiency of wastewater treatment plants in the removal of PhACs and EDCs make inappropriate the co-treatment of both effluents. In this paper, a new alternative to pre-treat hospital wastewater concerning the removal of PhACs and EDCs is presented. The treatment was carried out in a batch fluidized bed bioreactor under sterile and non-sterile conditions with Trametes versicolor pellets. Results on non-sterile experiments pointed out that 46 out of the 51 detected PhACs and EDCs were partially to completely removed. The total initial PhAC amount into the bioreactor was 8185 μg in sterile treatment and 8426 μg in non-sterile treatment, and the overall load elimination was 83.2% and 53.3% in their respective treatments. In addition, the Microtox test showed reduction of wastewater toxicity after the treatment. Hence, the good efficiency of the fungal treatment regarding removal of the wide diversity of PhACs and EDCs detected in hospital effluents is demonstrated., (Copyright © 2014. Published by Elsevier B.V.)

Published
2014
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33. Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy.

Author

Woyach JA, Smucker K, Smith LL, Lozanski A, Zhong Y, Ruppert AS, Lucas D, Williams K, Zhao W, Rassenti L, Ghia E, Kipps TJ, Mantel R, Jones J, Flynn J, Maddocks K, O'Brien S, Furman RR, James DF, Clow F, Lozanski G, Johnson AJ, and Byrd JC

Subjects
Adenine analogs & derivatives, Adult, Agammaglobulinaemia Tyrosine Kinase, Aged, Aged, 80 and over, CD40 Ligand metabolism, Disease-Free Survival, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell blood, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Lymphocytes drug effects, Lymphocytes immunology, Lymphocytes metabolism, Lymphocytosis blood, Lymphocytosis immunology, Male, Middle Aged, Phospholipase C gamma antagonists & inhibitors, Phosphorylation, Piperidines, Prognosis, Protein Kinase Inhibitors adverse effects, Protein-Tyrosine Kinases antagonists & inhibitors, Receptors, Antigen, B-Cell metabolism, Signal Transduction drug effects, ZAP-70 Protein-Tyrosine Kinase metabolism, Lymphocytosis etiology, Pyrazoles adverse effects, Pyrimidines adverse effects
Abstract

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has outstanding activity in patients with chronic lymphocytic leukemia. Most patients experience lymphocytosis, representing lymphocyte egress from nodal compartments. This resolves within 8 months in the majority of patients, but a subgroup has lymphocytosis lasting >12 months. Here we report a detailed characterization of patients with persistent lymphocytosis during ibrutinib therapy. Signaling evaluation showed that while BTK is inhibited, downstream mediators of B-cell receptor (BCR) signaling are activated in persistent lymphocytes. These cells cannot be stimulated through the BCR and do not show evidence of target gene activation. Flow cytometry for κ and λ expression, IGHV sequencing, Zap-70 methylation, and targeted gene sequencing in these patients are identical at baseline and later time points, suggesting that persistent lymphocytes do not represent clonal evolution. In vitro treatment with targeted kinase inhibitors shows that they are not addicted to a single survival pathway. Finally, progression-free survival is not inferior for patients with prolonged lymphocytosis vs those with traditional responses. Thus, prolonged lymphocytosis is common following ibrutinib treatment, likely represents the persistence of a quiescent clone, and does not predict a subgroup of patients likely to relapse early.

Published
2014
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34. Stability of AMH measurement in blood and avoidance of proteolytic changes.

Author

Fleming R, Fairbairn C, Blaney C, Lucas D, and Gaudoin M

Subjects
Blood Specimen Collection, Enzyme-Linked Immunosorbent Assay methods, Humans, Protein Stability, Proteolysis, Temperature, Time Factors, Anti-Mullerian Hormone blood, Blood Chemical Analysis methods
Abstract

The new Gen II assay for anti-Müllerian hormone (AMH) shows good stability and reliability in serum, but analyses of stability in whole blood are lacking. Testing the effects of storage of whole-blood samples at room temperature revealed significant increases in the measured value of AMH of 31% over 4 days (P<0.001). The effect is temperature dependent, with storage at 4°C showing markedly reduced increments. Further, samples collected into serum tubes with gel separators and centrifuged within 5h (blood cells and serum physically separated within the collection tube) showed reliable stability over a period of more than 5 days., (Copyright © 2012 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Published
2013
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35. Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia.

Author

Lapalombella R, Sun Q, Williams K, Tangeman L, Jha S, Zhong Y, Goettl V, Mahoney E, Berglund C, Gupta S, Farmer A, Mani R, Johnson AJ, Lucas D, Mo X, Daelemans D, Sandanayaka V, Shechter S, McCauley D, Shacham S, Kauffman M, Chook YM, and Byrd JC

Subjects
Acrylates chemistry, Acrylates metabolism, Active Transport, Cell Nucleus drug effects, Animals, Antineoplastic Agents chemistry, Antineoplastic Agents metabolism, Antineoplastic Agents pharmacology, Cell Line, Tumor, Cell Survival drug effects, Cells, Cultured, Crystallography, X-Ray, Humans, Immunoblotting, Interleukin-10 metabolism, Interleukin-6 metabolism, Karyopherins chemistry, Karyopherins genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Mice, Mice, SCID, Mice, Transgenic, Microscopy, Confocal, Models, Molecular, Molecular Structure, Protein Binding, Protein Structure, Tertiary, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, RNA Interference, Receptors, Cytoplasmic and Nuclear chemistry, Receptors, Cytoplasmic and Nuclear genetics, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocytes drug effects, T-Lymphocytes metabolism, Triazoles chemistry, Triazoles metabolism, Exportin 1 Protein, Acrylates pharmacology, Karyopherins metabolism, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Receptors, Cytoplasmic and Nuclear metabolism, Triazoles pharmacology
Abstract

The nuclear export protein XPO1 is overexpressed in cancer, leading to the cytoplasmic mislocalization of multiple tumor suppressor proteins. Existing XPO1-targeting agents lack selectivity and have been associated with significant toxicity. Small molecule selective inhibitors of nuclear export (SINEs) were designed that specifically inhibit XPO1. Genetic experiments and X-ray structures demonstrate that SINE covalently bind to a cysteine residue in the cargo-binding groove of XPO1, thereby inhibiting nuclear export of cargo proteins. The clinical relevance of SINEs was explored in chronic lymphocytic leukemia (CLL), a disease associated with recurrent XPO1 mutations. Evidence is presented that SINEs can restore normal regulation to the majority of the dysregulated pathways in CLL both in vitro and in vivo and induce apoptosis of CLL cells with a favorable therapeutic index, with enhanced killing of genomically high-risk CLL cells that are typically unresponsive to traditional therapies. More importantly, SINE slows disease progression, and improves overall survival in the Eμ-TCL1-SCID mouse model of CLL with minimal weight loss or other toxicities. Together, these findings demonstrate that XPO1 is a valid target in CLL with minimal effects on normal cells and provide a basis for the development of SINEs in CLL and related hematologic malignancies.

Published
2012
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36. Molecular inversion probe analysis detects novel copy number alterations in Ewing sarcoma.

Author

Jahromi MS, Putnam AR, Druzgal C, Wright J, Spraker-Perlman H, Kinsey M, Zhou H, Boucher KM, Randall RL, Jones KB, Lucas D, Rosenberg A, Thomas D, Lessnick SL, and Schiffman JD

Subjects
Adolescent, Adult, Bone Neoplasms pathology, Cell Adhesion Molecules, Neuronal genetics, Child, Child, Preschool, Chromosomal Proteins, Non-Histone genetics, DNA-Binding Proteins genetics, Extracellular Matrix Proteins genetics, Female, Gene Deletion, Humans, Immunohistochemistry, Infant, Loss of Heterozygosity, Male, Nerve Tissue Proteins genetics, Paraffin Embedding, Reelin Protein, SMARCB1 Protein, Sarcoma, Ewing pathology, Serine Endopeptidases genetics, Transcription Factors genetics, Young Adult, Bone Neoplasms genetics, Gene Dosage, Molecular Probes, Sarcoma, Ewing genetics
Abstract

Ewing sarcoma (ES) is the second most common bone tumor in children and young adults, with dismal outcomes for metastatic and relapsed disease. To better understand the molecular pathogenesis of ES and to identify new prognostic markers, we used molecular inversion probes (MIPs) to evaluate copy number alterations (CNAs) and loss of heterozygosity (LOH) in formalin-fixed paraffin-embedded (FFPE) samples, which included 40 ES primary tumors and 12 ES metastatic lesions. CNAs were correlated with clinical features and outcome, and validated by immunohistochemistry (IHC). We identified previously reported CNAs, in addition to SMARCB1 (INI1/SNF5) homozygous loss and copy neutral LOH. IHC confirmed SMARCB1 protein loss in 7-10% of clinically diagnosed ES tumors in three separate cohorts (University of Utah [N = 40], Children's Oncology Group [N = 31], and University of Michigan [N = 55]). A multifactor copy number (MCN)-index was highly predictive of overall survival (39% vs. 100%, P < 0.001). We also identified RELN gene deletions unique to 25% of ES metastatic samples. In summary, we identified both known and novel CNAs using MIP technology for the first time in FFPE samples from patients with ES. CNAs detected by microarray correlate with outcome and may be useful for risk stratification in future clinical trials., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Published
2012
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37. Norepinephrine reuptake inhibition promotes mobilization in mice: potential impact to rescue low stem cell yields.

Author

Lucas D, Bruns I, Battista M, Mendez-Ferrer S, Magnon C, Kunisaki Y, and Frenette PS

Subjects
Animals, Cells, Cultured, Fluorescent Antibody Technique, Granulocyte Colony-Stimulating Factor, Male, Mice, Mice, Inbred C57BL, Sympathetic Nervous System cytology, Sympathetic Nervous System metabolism, Cell Movement physiology, Hematopoietic Stem Cell Mobilization, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells metabolism, Norepinephrine metabolism
Abstract

The mechanisms mediating hematopoietic stem and progenitor cell (HSPC) mobilization by G-CSF are complex. We have found previously that G-CSF-enforced mobilization is controlled by peripheral sympathetic nerves via norepinephrine (NE) signaling. In the present study, we show that G-CSF likely alters sympathetic tone directly and that methods to increase adrenergic activity in the BM microenvironment enhance progenitor mobilization. Peripheral sympathetic nerve neurons express the G-CSF receptor and ex vivo stimulation of peripheral sympathetic nerve neurons with G-CSF reduced NE reuptake significantly, suggesting that G-CSF potentiates the sympathetic tone by increasing NE availability. Based on these data, we investigated the NE reuptake inhibitor desipramine in HSPC mobilization. Whereas desipramine did not by itself elicit circulating HSPCs, it increased G-CSF-triggered mobilization efficiency significantly and rescued mobilization in a model mimicking "poor mobilizers." Therefore, these data suggest that blockade of NE reuptake may be a novel therapeutic target to increase stem cell yield in patients.

Published
2012
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38. The effects of herbivore-induced plant volatiles on interactions between plants and flower-visiting insects.

Author

Lucas-Barbosa D, van Loon JJ, and Dicke M

Subjects
Adaptation, Physiological, Animals, Magnoliopsida physiology, Selection, Genetic, Behavior, Animal, Flowers chemistry, Insecta physiology, Magnoliopsida chemistry, Oils, Volatile metabolism, Plant Diseases, Pollination
Abstract

Plants are faced with a trade-off between on the one hand growth, development and reproduction and on the other hand defence against environmental stresses. Yet, research on insect-plant interactions has addressed plant-pollinator interactions and plant-attacker interactions separately. Plants have evolved a high diversity of constitutive and induced responses to attack, including the systemic emission of herbivore-induced plant volatiles (HIPVs). The effect of HIPVs on the behaviour of carnivorous insects has received ample attention for leaf-feeding (folivorous) species and their parasitoids and predators. Here, we review whether and to what extent HIPVs affect the interaction of plants in the flowering stage with mutualistic and antagonistic insects. Whereas the role of flower volatiles in the interactions between plants and insect pollinators has received increased attention over the last decade, studies addressing both HIPVs and pollinator behaviour are rare, despite the fact that in a number of plant species herbivory is known to affect flower traits, including size, nectar secretion and composition. In addition, folivory and florivory can also result in significant changes in flower volatile emission and in most systems investigated, pollinator visitation decreased, although exceptions have been found. Negative effects of HIPVs on pollinator visitation rates likely exert negative selection pressure on HIPV emission. The systemic nature of herbivore-induced plant responses and the behavioural responses of antagonistic and mutualistic insects, requires the study of volatile emission of entire plants in the flowering stage. We conclude that approaches to integrate the study of plant defences and pollination are essential to advance plant biology, in particular in the context of the trade-off between defence and growth/reproduction., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Published
2011
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39. ATF4 and the integrated stress response are induced by ethanol and cytochrome P450 2E1 in human hepatocytes.

Author

Magne L, Blanc E, Legrand B, Lucas D, Barouki R, Rouach H, and Garlatti M

Subjects
Activating Transcription Factor 4 genetics, Cells, Cultured, Eukaryotic Initiation Factor-2 metabolism, Gene Expression drug effects, Hep G2 Cells, Humans, Liver Diseases, Alcoholic etiology, Liver Diseases, Alcoholic genetics, Liver Diseases, Alcoholic metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Risk Factors, Signal Transduction drug effects, Stress, Physiological drug effects, Stress, Physiological genetics, Stress, Physiological physiology, Activating Transcription Factor 4 biosynthesis, Cytochrome P-450 CYP2E1 metabolism, Ethanol toxicity, Hepatocytes drug effects, Hepatocytes metabolism
Abstract

Background & Aims: Molecular mechanisms underlying alcoholic liver disease (ALD) are still not fully understood. Activating transcription factor-4 (ATF4) is the master coordinator of the integrated stress response (ISR), an adaptive pathway triggered by multiple stressors. which can promote cell death and induce metabolic dysregulation if the stress is intense or prolonged. The aim of this study was to assess the effect of alcohol on the ISR signaling pathway in human liver cells and to define the role of cytochrome P450 2E1 (CYP2E1) in this response., Methods: Primary cultured human hepatocytes and human HepG2 cells over-expressing CYP2E1 by adenoviral infection were exposed to ethanol (25-100mM) for 8-48h., Results: Ethanol treatment of both liver cells up-regulated ATF4 as well as the pro-survival and the pro-apoptotic transcriptional program of the ISR. Indeed, in CYP2E1-expressing HepG2 cells exposed to ethanol, the expression of ISR target genes (HMOX-1, GCLC, AsnS, IGFBP-1, GADD34,CHOP, ATF3, CHAC1) was induced. Up-regulation of ATF4 and the ISR transcriptional program was decreased by addition of the anti-oxidant glutathione. Several mechanisms mediated ATF4 protein induction, including, at early times, the phosphorylation of eIF2α which controls ATF4 translation, and, at later times, increased mRNA level and increased stability of the protein. A decrease in cell survival was also observed., Conclusions: This study demonstrates that both CYP2E1 and ethanol induce ATF4 and the integrated stress response, a pathway which coordinates signals from multiple stresses, as well as established risk factors for ALD, and can display detrimental cellular effects upon prolonged activation., (Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Published
2011
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40. Stereoselective epoxidation of the last double bond of polyunsaturated fatty acids by human cytochromes P450.

Author

Lucas D, Goulitquer S, Marienhagen J, Fer M, Dreano Y, Schwaneberg U, Amet Y, and Corcos L

Subjects
Humans, Isoenzymes metabolism, Protein Binding, Recombinant Proteins metabolism, Stereoisomerism, Substrate Specificity, Cytochrome P-450 Enzyme System metabolism, Epoxy Compounds chemistry, Fatty Acids, Unsaturated chemistry, Fatty Acids, Unsaturated metabolism
Abstract

Cytochromes P450 (CYPs) metabolize polyunsaturated long-chain fatty acids (PUFA-LC) to several classes of oxygenated metabolites. Through use of human recombinant CYPs, we recently showed that CYP1A1, -2C19, -2D6, -2E1, and -3A4 are mainly hydroxylases, whereas CYP1A2, -2C8, -2C9, and -2J2 are mainly epoxygenases of arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), respectively. It is worth noting that the last double bond of these PUFAs, i.e., omega6 in AA or omega3 in EPA and DHA, respectively, was preferentially epoxidized. In this study, we have characterized the stereoselectivity of this epoxidation reaction by comparison with the PUFA-LC epoxide stereoisomers obtained from the enantioselective bacterial CYP102A1 F87V. The stereoselectivity of the epoxidation of the last olefin of AA (omega6), EPA (omega3), or DHA (omega3) differed between the CYP isoforms but was similar for EPA and DHA. These data give additional insight into the PUFA-LC epoxide enantiomers generated by the hepatic CYPs.

Published
2010
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41. Subclinical rejection in stable positive crossmatch kidney transplant patients: incidence and correlations.

Author

Kraus ES, Parekh RS, Oberai P, Lepley D, Segev DL, Bagnasco S, Collins V, Leffell M, Lucas D, Rabb H, Racusen LC, Singer AL, Stewart ZA, Warren DS, Zachary AA, Haas M, and Montgomery RA

Subjects
Adult, Alleles, Biopsy, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes pathology, Creatinine blood, Cross-Sectional Studies, Female, Follow-Up Studies, HLA-DR Antigens genetics, HLA-DR Antigens immunology, HLA-DRB4 Chains, HLA-DRB5 Chains, Humans, Incidence, Kidney pathology, Kidney physiology, Male, Middle Aged, Retrospective Studies, Graft Rejection epidemiology, Graft Rejection immunology, Histocompatibility Testing adverse effects, Kidney Transplantation immunology
Abstract

We reviewed 116 surveillance biopsies obtained approximately 1, 3, 6 and 12 months posttransplantation from 50 +XM live donor kidney transplant recipients to determine the frequency of subclinical cell-mediated rejection (CMR) and antibody-mediated rejection (AMR). Subclinical CMR was present in 39.7% of the biopsies at 1 month and >20% at all other time points. The presence of diffuse C4d on biopsies obtained at each time interval ranged from 20 to 30%. In every case, where histological and immunohistological findings were diagnostic for AMR, donor-specific antibody was found in the blood, challenging the long-held belief that low-level antibody could evade detection due to absorption on the graft. Among clinical factors, only recipient age was associated with subclinical CMR. Clinical factors associated with subclinical AMR were recipient age, positive cytotoxic crossmatch prior to desensitization and two mismatches of HLA DR 51, 52 and 53 alleles. Surveillance biopsies during the first year post-transplantation for these high-risk patients uncover clinically occult processes and phenotypes, which without intervention diminish allograft survival and function.

Published
2009
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42. Determination of epoxyeicosatrienoic acids in human red blood cells and plasma by GC/MS in the NICI mode.

Author

Goulitquer S, Dréano Y, Berthou F, Corcos L, and Lucas D

Subjects
8,11,14-Eicosatrienoic Acid analogs & derivatives, 8,11,14-Eicosatrienoic Acid blood, Humans, Plasma chemistry, Reproducibility of Results, Sensitivity and Specificity, Solid Phase Extraction, Uncertainty, Eicosanoids blood, Erythrocytes chemistry, Gas Chromatography-Mass Spectrometry methods
Abstract

Epoxyeicosatrienoic acids (EETs) are cytochrome P450 metabolites of arachidonic acid involved in the regulation of vascular tone. Despite the importance of EETs in a variety of physiological effects, few methods have been developed to quantify them in human blood. This led us to develop a method by GC/MS with negative ion chemical ionization. As EETs are primarily located in phospholipids, red blood cells (RBCs) and plasma phospholipids were hydrolyzed with phospholipase A(2) after a solid phase extraction. Then, EETs were derivatized as pentafluorobenzyl esters, and [(2)H(8)]-arachidonic acid was used as internal standard for quantification. EETs were found to be at concentrations of 106+/-37ng mL(-1) in plasma and 33.4+/-8.5 ng/10(9) RBCs (mean+/-S.D.) in 10 healthy volunteers. Their amount in RBCs was 3-fold that in plasma; both parameters proved to be well correlated.

Published
2008
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44. Metabolism of eicosapentaenoic and docosahexaenoic acids by recombinant human cytochromes P450.

Author

Fer M, Dréano Y, Lucas D, Corcos L, Salaün JP, Berthou F, and Amet Y

Subjects
Aryl Hydrocarbon Hydroxylases chemistry, Aryl Hydrocarbon Hydroxylases metabolism, Biological Assay, Catalysis, Chromatography, High Pressure Liquid, Cytochrome P-450 CYP1A2 chemistry, Cytochrome P-450 CYP1A2 metabolism, Cytochrome P-450 CYP2C19, Cytochrome P-450 CYP2C9, Cytochrome P-450 Enzyme System chemistry, Docosahexaenoic Acids chemistry, Eicosapentaenoic Acid chemistry, Epoxy Compounds chemistry, Epoxy Compounds metabolism, Humans, Hydroxylation, Mixed Function Oxygenases chemistry, Mixed Function Oxygenases metabolism, Oxidation-Reduction, Recombinant Proteins chemistry, Stereoisomerism, Cytochrome P-450 Enzyme System metabolism, Docosahexaenoic Acids metabolism, Eicosapentaenoic Acid metabolism, Recombinant Proteins metabolism
Abstract

Epoxidation and hydroxylation of arachidonic acid (AA) are both catalyzed by cytochromes P450s (CYPs). The oxidized metabolites are known to be involved in the regulation of vascular tone and renal function. By using a panel of 15 human recombinant CYPs, this study demonstrates that other polyunsaturated long-chain fatty acids (PUFA-LC), especially the omega3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are also epoxidised. The regioselectivity of epoxidation of four PUFA-LC by CYPs was investigated. Among the several CYPs tested, CYP2C9/2C19 and 1A2 were the most efficient in EPA and DHA epoxidations. It ensued that 10muM of these two omega3 fatty acids decreased by more than 80% and 60%, respectively, the formation by CYP2C9 of AA-epoxidised derivatives. These findings suggest that some physiological effects of omega3 fatty acids may be due to a shift in the generation of active epoxidised metabolites of AA through CYP-mediated catalysis.

Published
2008
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45. Comparison of broiler performance and carcass parameters when fed diets containing soybean meal produced from glyphosate-tolerant (MON 89788), control, or conventional reference soybeans.

Author

Taylor M, Hartnell G, Lucas D, Davis S, and Nemeth M

Subjects
Animal Nutritional Physiological Phenomena, Animals, Body Composition, Glycine metabolism, Herbicides metabolism, Meat standards, Plants, Genetically Modified, Reference Standards, Glyphosate, Animal Feed analysis, Chickens growth & development, Diet veterinary, Glycine analogs & derivatives, Glycine max genetics
Abstract

A 42-d floor pen study was conducted to compare broiler (Ross x Ross 308) performance and carcass measurements when fed diets containing meal produced from glyphosate-tolerant soybeans (MON 89788) with those of broilers fed diets containing meal produced from control soybean (A3244) that has similar genetic background to MON 89788. Soybean meal produced from 6 conventional soybean varieties was included in the study to provide comparison measurements for broilers fed meal derived from conventional soybeans. It has been found that MON 89788 produces the 5-enolpyruvylshikimate-3-phosphate synthase protein from Agrobacterium sp. strain CP4 (cp4 epsps), which confers tolerance to glyphosate, the active ingredient in Roundup agricultural herbicides. Broilers were fed starter diets (approximately 33% wt/wt dehulled soybean meal) from d 0 to 21 and grower-finisher diets (approximately 30% wt/wt dehulled soybean meal) from d 21 to 42. The study utilized a randomized complete block design with 8 dietary treatments assigned randomly within 5 blocks of 16 pens each (8 male and 8 female) with 10 birds per pen. There were 10 pens per treatment group (5 male and 5 female). No treatment differences (P > 0.05) were detected among dietary treatments for feed intake, weight gain, adjusted feed conversion, or any measured carcass and meat quality parameters. Comparison of all performance, carcass, and meat quality parameters measured showed no differences (P > 0.05) between birds fed the MON 89788 soybean meal diet and the population of birds fed the control and 6 conventional reference soybean meal diets. It is concluded that the diets containing soybean meal produced from MON 89788 were nutritionally equivalent to diets containing soybean meal produced from the control and conventional reference soybean varieties when fed to broilers.

Published
2007
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46. Comparison of broiler performance when fed diets containing grain from second-generation insect-protected and glyphosate-tolerant, conventional control or commercial reference corn.

Author

Taylor M, Hartnell G, Nemeth M, Lucas D, and Davis S

Subjects
Animal Nutritional Physiological Phenomena, Animals, Body Composition, Genetic Engineering, Glycine pharmacology, Herbicides pharmacology, Plants, Genetically Modified, Glyphosate, Animal Feed, Chickens growth & development, Diet veterinary, Glycine analogs & derivatives, Lepidoptera physiology, Zea mays drug effects, Zea mays parasitology
Abstract

Two 42-d floor pen studies were conducted to compare broiler (Ross x Ross 308) performance and carcass measurements when broilers were fed diets containing grain from either second-generation lepidopteran insect-protected corn (MON 89034; study 1) or second-generation lepidopteran combined with second-generation corn rootworm-protected and glyphosate-tolerant corn (MON 89034 x MON 88017; study 2) with those of diets containing corn grain from the conventional control and 4 conventional corn hybrids. In both studies, broilers were fed starter diets (approximately 55%, wt/wt, corn grain) from d 0 to 21 and grower-finisher diets (approximately 59%, wt/wt, corn grain) from d 21 to 42. Each study used a randomized complete block design with 6 dietary treatments assigned randomly within 5 blocks of 12 pens each (6 male and 6 female) and 10 pens per treatment group (5 male and 5 female). In study 1 (MON 89034), no treatment differences were detected among dietary treatments for feed intake, weight gain, or any measured carcass parameter. A significant difference was noted for adjusted feed conversion between MON 89034 and control birds; however, no differences were detected in individual treatment comparisons between the MON 89034 and 3 of the 4 commercial corn diets. In study 2 (MON 89034 x MON 88017), no treatment differences were observed for feed intake and most carcass parameters. When significant treatment differences were detected, no differences were observed between MON 89034 x MON 88017, its control, and 2 or more of the commercial corn diets. In each study, comparison of all parameters measured showed no differences between birds fed the test diet and the population of birds fed the control and 4 commercial corn diets. In conclusion, the test diets were nutritionally equivalent to diets containing the control and corn grain from commercial hybrids.

Published
2007
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47. Comparison of broiler performance and carcass parameters when fed diets containing combined trait insect-protected and glyphosate-tolerant corn (MON 89034 x NK603), control, or conventional reference corn.

Author

Taylor M, Lucas D, Nemeth M, Davis S, and Hartnell G

Subjects
Animal Nutritional Physiological Phenomena, Animals, Body Composition, Body Weight, Genetic Engineering, Glycine pharmacology, Herbicides pharmacology, Plants, Genetically Modified, Glyphosate, Animal Feed, Chickens growth & development, Diet veterinary, Glycine analogs & derivatives, Lepidoptera physiology, Zea mays drug effects, Zea mays parasitology
Abstract

A 42-d floor pen study was conducted to compare broiler (Ross x Ross 308) performance and carcass measurements when fed diets containing lepidopteran-protected corn combined with glyphosate-tolerant corn (MON 89034 x NK603) with those of broilers fed diets containing corn grain from the conventional control (similar genetic background to the test corn) and 6 conventional corn hybrids. It has been found that MON 89034 produces the Cry1A.105 and Cry2Ab2 insecticidal proteins that protect corn plants from feeding damage caused by European corn borer (Ostrinia nubilalis) and other lepidopteran insect pests. In addition, NK603 produces the 5-enolpyruvylshikimate-3-phosphate synthase protein from Agrobacterium sp. strain CP4 (CP4 EPSPS), which confers tolerance to glyphosate, the active ingredient in Roundup agricultural herbicides. The traditional breeding of plants that express the individual traits produced MON 89034 x NK603. Broilers were fed starter diets (approximately 57% wt/wt corn grain) from d 0 to 21 and grower-finisher diets (approximately 59% wt/wt corn grain) from d 21 to 42. The study utilized a randomized complete block design with 8 dietary treatments assigned randomly within 5 blocks of 16 pens each (8 male and 8 female) with 10 birds per pen. There were 10 pens per treatment group (5 male and 5 female). Weight at d 0 and 42, feed intake, feed conversion, and all measured carcass and meat quality parameters were not different (P > 0.05) for birds fed MON 89034 x NK603 and control corn diets. In addition, comparisons of the MON 89034 x NK603 diet to the population of the control and 6 reference corn diets showed no difference (P > 0.05) in any performance, carcass, or meat quality parameter measured. In conclusion, the diets containing MON 89034 x NK603 were nutritionally equivalent to diets containing the control or conventional reference corn grain when fed to broilers.

Published
2007
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48. Ethanol oxidation into acetaldehyde by 16 recombinant human cytochrome P450 isoforms: role of CYP2C isoforms in human liver microsomes.

Author

Hamitouche S, Poupon J, Dreano Y, Amet Y, and Lucas D

Subjects
Catalysis, Cytochrome P-450 CYP2C19, Cytochrome P-450 CYP2C8, Cytochrome P-450 CYP2C9, Humans, Oxidation-Reduction, Recombinant Proteins pharmacology, Acetaldehyde metabolism, Aryl Hydrocarbon Hydroxylases physiology, Ethanol metabolism, Microsomes, Liver metabolism, Mixed Function Oxygenases physiology
Abstract

The involvement of cytochromes P450 (CYPs) in the oxidation of ethanol into acetaldehyde was investigated by using 16 recombinant human CYP isoforms. Apparent K(m) and V(m) were determined for CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9*1, CYP2C9*2, CYP2C9*3, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2J2, CYP3A4 and CYP4A11. All of the tested CYPs, except CYP2A6 and CYP2C18, metabolized ethanol into significant amounts of acetaldehyde and displayed K(m) values around 10mM. The significant correlation found between ethanol oxidation and CYP2E1, CYP3A4 and CYP1A2 catalytic activities in a panel of human liver microsomes confirmed the strong implication of these CYPs in ethanol metabolism. The contribution of CYP2C isoforms which are the most abundant in the liver after CYP3A4, was studied using selective inhibitors either with recombinant CYP2C isoforms or in human liver microsomes. Tienilic acid (100 microM) and ticlopidine (20 microM), mechanism-based inhibitors of CYP2C9 and CYP2C19, respectively, decreased ethanol oxidation by 8+/-1.2% and 7.6+/-1.6% in human liver microsomal samples while selective inhibitors of CYP2E1 (DEDTC 100 microM), CYP3A4 (TAO 50 microM) and CYP1A2 (furafylline 25 microM) decreased it by 11.9+/-2.1%, 19.8+/-1.9% and 16.3+/-3.9%, respectively. As ethanol can be metabolized by most of CYPs, it helps to explain or predict alcohol-xenobiotics interactions which are of high importance in medical prescription.

Published
2006
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49. SOCS up-regulation mobilizes autologous stem cells through CXCR4 blockade.

Author

Pello OM, Moreno-Ortiz Mdel C, Rodríguez-Frade JM, Martínez-Muñoz L, Lucas D, Gómez L, Lucas P, Samper E, Aracil M, Martínez C, Bernad A, and Mellado M

Subjects
Animals, Antigens, Differentiation biosynthesis, Bone Marrow metabolism, Bone Marrow Transplantation, Cattle, Cell Line, Chemokine CXCL12, Chemokines, CXC metabolism, Growth Hormone genetics, Growth Hormone metabolism, Hematopoietic Stem Cell Mobilization methods, Humans, Mice, Mice, Transgenic, Receptors, CXCR4 antagonists & inhibitors, Receptors, CXCR4 genetics, Suppressor of Cytokine Signaling Proteins genetics, Transplantation, Autologous, Cell Movement genetics, Hematopoietic Stem Cells metabolism, Receptors, CXCR4 metabolism, Suppressor of Cytokine Signaling Proteins biosynthesis, Up-Regulation
Abstract

The chemokine CXCL12 influences self-renewal and differentiation of hematopoietic stem cell precursors in bone marrow by directing them toward specific stromalcell components. CXCL12 up-regulates members of the SOCS family through JAK/STAT activation, a mechanism that attenuates chemokine responses. SOCS expression may thus modulate retention of hematopoietic precursors (Sca-1(+) c-Kit(+)Lin(-) cells) in bone marrow. We show that in bovine growth hormone transgenic mice and in growth hormone-treated mice, SOCS up-regulation correlated with a large number of Sca-1(+) c-Kit(+)Lin(-) cells in blood. Retroviral transduction of SOCSs blocked in vitro migration of Sca-1(+)c-Kit(+)Lin(-) cells, as well as their capacity to reconstitute lethally irradiated mice. Furthermore, in lethally irradiated mice reconstituted with bone marrow infected by a tetracycline-regulated, SOCS-expressing lentiviral vector, doxycycline treatment promoted rapid, extensive precursor mobilization to the periphery. The results indicate that by blocking CXCR4-mediated functions, SOCSs modulate hematopoietic precursor cell retention in bone marrow, and suggest the therapeutic interest of SOCS manipulation in several pathologic situations.

Published
2006
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50. High-throughput methods for measuring heparanase activity and screening potential antimetastatic and anti-inflammatory agents.

Author

Huang KS, Holmgren J, Reik L, Lucas-McGady D, Roberts J, Liu CM, and Levin W

Subjects
Animals, Anti-Inflammatory Agents pharmacology, Antineoplastic Agents pharmacology, Biotin metabolism, CHO Cells, Cattle, Cells, Cultured, Cloning, Molecular, Cricetinae, Escherichia coli genetics, Fibroblast Growth Factors metabolism, Fluorescein-5-isothiocyanate, Gene Expression, Glucuronidase analysis, Glucuronidase genetics, Heparitin Sulfate analysis, Heparitin Sulfate metabolism, Humans, Kidney enzymology, Staining and Labeling, Tritium, Anti-Inflammatory Agents isolation & purification, Antineoplastic Agents isolation & purification, Drug Evaluation, Preclinical methods, Glucuronidase metabolism
Abstract

Heparanase plays an important role in the degradation of the extracellular matrix. It is implicated in inflammation, tumor angiogenesis and metastasis. We have developed two high-throughput methods for measuring heparanase activity and screening potential inhibitors. The first method involves coating fibroblast growth factor (FGF) on microtiter plates and capturing fluorescein isothiocyanate (FITC)-labeled heparin sulfate (HS), which is used as a substrate for heparanase digestion. Labeled HS fragments are released into the medium and quantitated by fluorescence intensity measurement. We have implemented this assay method into a Zeiss uHTS system and screened compound libraries for heparanase inhibitors. The second method involves labeling HS with biotin followed by FITC to generate a dual-labeled HS. The labeled material is bound to streptavidin-coated plates and used as a substrate for heparanase digestion. Both methods are sensitive and easily applicable to robotic systems. In addition, we have labeled both HS and biotin-HS with Eu-chelate, a fluorophore that exhibits long decay fluorescence. Assays using Eu-labeled HS and Eu-labeled biotin-HS have been developed and show higher sensitivity than those using FITC-labeled material. Furthermore, assays using Eu-chelate HS (or biotin-HS) should eliminate the interference of fluorescence compounds.

Published
2004
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