Academic Profiles

Featured Stories

Research Interests

Systems Biology

Mycobacterial genetics

Pathogenicity of tuberculosis

Neisserial genetics

Pathogenicity of meningococcal meningitis

Quantum Biology - It has recently been recognized that non-trivial aspects of quantum mechanics play a major role in biology, see presentations from a recent workshop on this topic held at the University of Surrey:

http://www.ias.surrey.ac.uk/workshops/quantumbiology/

or read review in The Biologist (https://www.societyofbiology.org/biologist/158-biologist/features/541-making-the-quantum-leap)

Research Collaborations

Graham Stewart

Andrzej Kierzek

Danny Beste

Andrea Rocco

Mycobacterial research

The tubercle bacillus (Mycobacterium tuberculosis) infects approximately one quarter of the world's population and is responsible for three million deaths each year. The related pathogen, Mycobacterium bovis, causes disease in many mammals and is a major cause of economic loss in livestock, particularly cows.

Mycobacterial research within the Microbial Sciences Group is focussed on understanding the pathogenic mechanisms that allow Mycobacterium tuberculosis to cause about three million deaths each year, identification of new drug targets and development of new vaccines to treat the disease.

Most of our work utilises a systems biology modelling approach, particularly applied to metabolism. We constructed the first genome-scale metabolic model of the TB bacillus (http://genomebiology.com/2007/8/5/r89) and used the model to analyse the metabolism of the pathogen both in the laboratory (http://epubs.surrey.ac.uk/184899/) and in infected cells (http://www.sciencedirect.com/science/article/pii/S1074552113002457). The following projects are ongoing:

  • Identification of nitrogen source and metabolism of Mycobacterium tuberculosis during intracellular replication. BBSRC-funded.
  • Development of recombinant BCG vaccine and complementary diagnostics for TB control in cattle. BBSRC-funded
  • BBSRC Investigation of stochastic variations in growth rate as the mechanism of drug tolerance in Mycobacterium tuberculosis. BBSRC-funded.
  • Improving BCG vaccination to make it compatible with the skin test. Gates Foundation-funded.
  • Defining the metabolic phenotype of intracellular Mycobacterium tuberculosis.  (PI, Dany Beste) MRC-funded. 

SurreyFBA: Interactive tool for computer simulations of genome scale metabolic networks. (PI, Andrzej Kierzek), BBSRC-funded.  

Meningococcal research

Our work has been to investigate virulence mechanisms in Neisseria meningitidis with the aim of developing new vaccines capable of protecting against all strains. Recent successes of our laboratory include constructing a genome-scale metabolic model of the meningococcus (http://epubs.surrey.ac.uk/629934/) and performing an immunoproteomic study of the meningococcus (http://mic.sgmjournals.org/content/160/Pt_2/429).

Neisseria meningitidis cells as revealed by scanning electron microscopy. The cells tend to occur in pairs and are surrounded by a waxy capsule that protects them from immune attack. Most of the current meningococcal vaccines generate antibodies to the capsule that kills the pathogen. However, antibodies cannot be generated against Group B strains of the meningococcus, which is the most common cause of bacterial meningitis in the UK. Work in our laboratory aims to identify alternative targets of vaccine immunity.

  


When bacteria, such as Mycobacterium tuberculosis, are treated with an antibiotic a very small fraction survive, despite being genetically identical to the killed population. Persisters can be seen in this video which shows growth of Mycobacterium smegmatis and killing with an antibiotic (4 hours). Killed cells are revealed by their permeability to a fluorescent dye. However, one cell survives and, when the antibiotic is removed (at 14 hours), it is able to grow. The cell is not genetically resistant to the antibiotic as, when antibiotic is added again (at 24 hours), all its descendent cells are killed: it is a persister.
These ‘persisters’ are a major problem in treatment of bacterial infections, particularly in tuberculosis; and how they manage to survive exposure to antibiotics is a mystery that is being activity investigated here at the University of Surrey.

Mycobacterium smegmatis

Mycobacterium smegmatis

Contact Me

E-mail:
Phone: 01483 68 6494

Find me on campus
Room: 07 AX 01

Publications

Highlights

  • Beste DJ, Bonde B, Hawkins N, Ward JL, Beale MH, Noack S, Nöh K, Kruger NJ, Ratcliffe RG, McFadden J. (2011) '¹³C metabolic flux analysis identifies an unusual route for pyruvate dissimilation in mycobacteria which requires isocitrate lyase and carbon dioxide fixation.'. PLoS PLoS Pathog, United States: 7 (7)

    Abstract

    Mycobacterium tuberculosis requires the enzyme isocitrate lyase (ICL) for growth and virulence in vivo. The demonstration that M. tuberculosis also requires ICL for survival during nutrient starvation and has a role during steady state growth in a glycerol limited chemostat indicates a function for this enzyme which extends beyond fat metabolism. As isocitrate lyase is a potential drug target elucidating the role of this enzyme is of importance; however, the role of isocitrate lyase has never been investigated at the level of in vivo fluxes. Here we show that deletion of one of the two icl genes impairs the replication of Mycobacterium bovis BCG at slow growth rate in a carbon limited chemostat. In order to further understand the role of isocitrate lyase in the central metabolism of mycobacteria the effect of growth rate on the in vivo fluxes was studied for the first time using ¹³C-metabolic flux analysis (MFA). Tracer experiments were performed with steady state chemostat cultures of BCG or M. tuberculosis supplied with ¹³C labeled glycerol or sodium bicarbonate. Through measurements of the ¹³C isotopomer labeling patterns in protein-derived amino acids and enzymatic activity assays we have identified the activity of a novel pathway for pyruvate dissimilation. We named this the GAS pathway because it utilizes the Glyoxylate shunt and Anapleurotic reactions for oxidation of pyruvate, and Succinyl CoA synthetase for the generation of succinyl CoA combined with a very low flux through the succinate--oxaloacetate segment of the tricarboxylic acid cycle. We confirm that M. tuberculosis can fix carbon from CO₂ into biomass. As the human host is abundant in CO₂ this finding requires further investigation in vivo as CO₂ fixation may provide a point of vulnerability that could be targeted with novel drugs. This study also provides a platform for further studies into the metabolism of M. tuberculosis using ¹³C-MFA.

Journal articles

  • Newcombe J, Mendum TA, Ren CP, McFadden J. (2013) 'Identification of the immunoproteome of the meningococcus by cell surface immunoprecipitation and mass spectrometry (CSIP-MS).'. Microbiology,
  • Beste DJ, Nöh K, Niedenführ S, Mendum TA, Hawkins ND, Ward JL, Beale MH, Wiechert W, McFadden J. (2013) '(13)C-Flux Spectral Analysis of Host-Pathogen Metabolism Reveals a Mixed Diet for Intracellular Mycobacterium tuberculosis.'. Elsevier Chem Biol, 20 (8), pp. 1012-1021.
  • McFadden J. (2013) 'Making the Quantum Leap.'. The Biologist, 60 (2), pp. 13-16.
  • McFadden J. (2013) 'The CEMI Field Theory Gestalt Information and the Meaning of Meaning'. IMPRINT ACADEMIC JOURNAL OF CONSCIOUSNESS STUDIES, 20 (3-4), pp. 152-182.
  • Rocco A, Kierzek AM, McFadden J. (2013) 'Slow Protein Fluctuations Explain the Emergence of Growth Phenotypes and Persistence in Clonal Bacterial Populations'. Public Library of Science PLoS One, 8 (1) Article number e54272

    Abstract

    One of the most challenging problems in microbiology is to understand how a small fraction of microbes that resists killing by antibiotics can emerge in a population of genetically identical cells, the phenomenon known as persistence or drug tolerance. Its characteristic signature is the biphasic kill curve, whereby microbes exposed to a bactericidal agent are initially killed very rapidly but then much more slowly. Here we relate this problem to the more general problem of understanding the emergence of distinct growth phenotypes in clonal populations. We address the problem mathematically by adopting the framework of the phenomenon of so-called weak ergodicity breaking, well known in dynamical physical systems, which we extend to the biological context. We show analytically and by direct stochastic simulations that distinct growth phenotypes can emerge as a consequence of slow-down of stochastic fluctuations in the expression of a gene controlling growth rate. In the regime of fast gene transcription, the system is ergodic, the growth rate distribution is unimodal, and accounts for one phenotype only. In contrast, at slow transcription and fast translation, weakly non-ergodic components emerge, the population distribution of growth rates becomes bimodal, and two distinct growth phenotypes are identified. When coupled to the well-established growth rate dependence of antibiotic killing, this model describes the observed fast and slow killing phases, and reproduces much of the phenomenology of bacterial persistence. The model has major implications for efforts to develop control strategies for persistent infections.

  • Lofthouse EK, Wheeler PR, Beste DJV, Khatri BL, Wu H, Mendum TA, Kierzek AM, McFadden J. (2013) 'Systems-Based Approaches to Probing Metabolic Variation within the Mycobacterium tuberculosis Complex'. PUBLIC LIBRARY SCIENCE PLOS ONE, 8 (9) Article number ARTN e75913
  • Slayden RA, Jackson M, Zucker J, Ramirez MV, Dawson CC, Crew R, Sampson NS, Thomas ST, Jamshidi N, Sisk P, Caspi R, Crick DC, McNeil MR, Pavelka MS, Niederweis M, Siroy A, Dona V, McFadden J, Boshoff H, Lew JM. (2013) 'Updating and curating metabolic pathways of TB'. CHURCHILL LIVINGSTONE TUBERCULOSIS, 93 (1), pp. 47-59.
  • McFadden J. (2013) 'The CEMI Field Theory Closing the Loop.'. Journal of Consciousness Studies: controversies in science and the humanities, 20 (1-2), pp. 153-168.

    Abstract

    Several theories of consciousness first described about a decade ago, including the conscious electromagnetic information (CEMI) field theory, claimed that the substrate of consciousness is the brain's electromagnetic (EM) field. These theories were prompted by the observation, in many diverse systems, that synchronous neuronal firing, which generates coherent EM fields, was a strong correlate of attention, awareness, and consciousness. However, when these theories were first described there was no direct evidence that synchronous firing was actually functional, rather than an epiphenomenon of brain function. Additionally, any EM field-based consciousness would be a 'ghost in the machine' unless the brain's endogenous EM field is also able to influence neuron firing. Once again, when these theories were first described, there was only indirect evidence that the brain's EM field influenced neuron firing patterns in the brain. In this paper I describe recent experimental evidence which demonstrate that synchronous neuronal firing does indeed have a functional role in the brain; and also that the brain's endogenous EM field is involved in recruiting neurons to synchronously firing networks. The new data point to a new and unappreciated form of neural communication in the brain that is likely to have significance for all theories of consciousness. I describe an extension of the CEMI field theory that incorporates these recent experimental findings and integrates the theory with the 'communication through coherence' hypothesis.

  • Golchin SA, Stratford J, Curry RJ, McFadden J. (2012) 'A microfluidic system for long-term time-lapse microscopy studies of mycobacteria.'. Tuberculosis (Edinb), Scotland: 92 (6), pp. 489-496.
  • Neves V, Heister E, Costa S, Tîlmaciu C, Flahaut E, Soula B, Coley HM, McFadden J, Silva SR. (2012) 'Design of double-walled carbon nanotubes for biomedical applications.'. Institute of Physics Nanotechnology, England: 23 (36)

    Abstract

    Double-walled carbon nanotubes (DWNTs) prepared by catalytic chemical vapour deposition were functionalized in such a way that they were optimally designed as a nano-vector for the delivery of small interfering RNA (siRNA), which is of great interest for biomedical research and drug development. DWNTs were initially oxidized and coated with a polypeptide (Poly(Lys:Phe)), which was then conjugated to thiol-modified siRNA using a heterobifunctional cross-linker. The obtained oxDWNT-siRNA was characterized by Raman spectroscopy inside and outside a biological environment (mammalian cells). Uptake of the custom-designed nanotubes was not associated with detectable biochemical perturbations in cultured cells, but transfection of cells with DWNTs loaded with siRNA targeting the green fluorescent protein (GFP) gene, serving as a model system, as well as with therapeutic siRNA targeting the survivin gene, led to a significant gene silencing effect, and in the latter case a resulting apoptotic effect in cancer cells.

  • Heister E, Neves V, Lamprecht C, Silva SRP, Coley HM, McFadden J. (2012) 'Drug loading, dispersion stability, and therapeutic efficacy in targeted drug delivery with carbon nanotubes'. Elsevier Carbon, 50 (2), pp. 622-632.

    Abstract

    We have designed a drug delivery system for the anti-cancer drugs doxorubicin and mitoxantrone based on carbon nanotubes, which is stable under biological conditions, allows for sustained release, and promotes selectivity through an active targeting scheme. Carbon nanotubes are particularly promising for this area of application due to their high surface area, allowing for high drug loading, and their unique interaction with cellular membranes. We have taken a systematic approach to PEG conjugation in order to create a formulation of stable and therapeutically effective CNTs. The presented drug delivery system may be a means of improving cancer treatment modalities by reducing drug-related side effects.

  • Neves V, Gerondopoulos A, Heister E, McFadden J, Coley HM, Silva SRP, Tîlmaciu C, Flahaut E, Soula B. (2012) 'Cellular localization, accumulation and trafficking of double-walled carbon nanotubes in human prostate cancer cells'. Nano Research, 5 (4), pp. 223-234.

    Abstract

    Carbon nanotubes (CNTs) are at present being considered as potential nanovectors with the ability to deliver therapeutic cargoes into living cells. Previous studies established the ability of CNTs to enter cells and their therapeutic utility, but an appreciation of global intracellular trafficking associated with their cellular distribution has yet to be described. Despite the many aspects of the uptake mechanism of CNTs being studied, only a few studies have investigated internalization and fate of CNTs inside cells in detail. In the present study, intracellular localization and trafficking of RNA-wrapped, oxidized double-walled CNTs (oxDWNT-RNA) is presented. Fixed cells, previously exposed to oxDWNT-RNA, were subjected to immunocytochemical analysis using antibodies specific to proteins implicated in endocytosis; moreover cell compartment markers and pharmacological inhibitory conditions were also employed in this study. Our results revealed that an endocytic pathway is involved in the internalization of oxDWNT-RNA. The nanotubes were found in clathrin-coated vesicles, after which they appear to be sorted in early endosomes, followed by vesicular maturation, become located in lysosomes. Furthermore, we observed co-localization of oxDWNT-RNA with the small GTP-binding protein (Rab 11), involved in their recycling back to the plasma membrane via endosomes from the trans-golgi network. © 2012 Tsinghua University Press and Springer-Verlag Berlin Heidelberg.

  • Sanz V, Coley HM, McFadden J, Silva SRP. (2012) 'Modeling the binding of peptides on carbon nanotubes and their use as protein and DNA carriers'. Journal of Nanoparticle Research, 14 (2)

    Abstract

    An in-depth study of a novel functionalization of carbon nanotubes for their application as protein and DNA carriers is presented. First, the optimum conditions for the dispersion of singlewalled carbon nanotubes (SWCNTs) with amphiphilic polypeptides were obtained, and the SWCNT-polypeptide complexes were characterized by different techniques (UV-Vis-NIR, CD, and AFM). Based on the properties of the SWCNT-polypeptide complexes, a model that characterizes the adsorption of natural proteins onto SWCNT was described for the first time. This model predicts the adsorption of natural proteins on SWCNTs based on the protein structure and composition, and therefore, allows the design of methods for the preparation of SWCNT-protein complexes. Besides, the use of cationic-designed amphiphilic polypeptides to disperse SWCNTs is applied for subsequent and efficient binding of DNA to carbon nanotubes by a bilayer approach. Therefore, in this article, we develop procedures for the use of SWCNTs as protein and DNA carriers. The systems were delivered into cells showing that the efficiency of delivery is affected by the charge of the complexes, which has important implications in the use of SWCNT as platforms for protein and DNA binding and subsequent use as delivery systems. © Springer Science+Business Media B.V. 2012.

  • Sanz V, Coley HM, McFadden J, Silva SRP. (2012) 'Protamine and chloroquine enhance gene delivery and expression mediated by RNA-wrapped single walled carbon nanotubes'. Journal of Nanoscience and Nanotechnology, 12 (3), pp. 1739-1747.
  • Borsuk S, Seixas FK, Ramos DF, Mendum T, McFadden J, Dellagostin O. (2012) 'Rational design of diagnostic and vaccination strategies for tuberculosis.'. Braz J Infect Dis, Brazil: 16 (1), pp. 68-73.
  • Mendum TA, Newcombe J, Mannan AA, Kierzek AA, McFadden J. (2011) 'Interrogation of global mutagenesis data with a genome scale model of Neisseria meningitidis to assess gene fitness in vitro and in sera.'. BioMed Central Ltd Genome Biol, 12 (12)

    Abstract

    BACKGROUND: Neisseria meningitidis is an important human commensal and pathogen that causes several thousand deaths each year, mostly in young children. How the pathogen replicates and causes disease in the host is largely unknown, particularly the role of metabolism in colonization and disease. Completed genome sequences are available for several strains but our understanding of how these data relate to phenotype remains limited. RESULTS: To investigate the metabolism of N. meningitidis we generated and selected a representative Tn5 library on rich medium, a minimal defined medium and in human serum to identify genes essential for growth under these conditions. To relate these data to a systems-wide understanding of the pathogen's biology we constructed a genome-scale metabolic network: Nmb_iTM560. This model was able to distinguish essential and non-essential genes as predicted by the global mutagenesis. These essentiality data, the library and the Nmb_iTM560 model are powerful and widely applicable resources for the study of meningococcal metabolism and physiology. We demonstrate the utility of these resources by predicting and demonstrating metabolic requirements on minimal medium such as a requirement for PEP carboxylase, and by describing the nutritional and biochemical status of N. meningitidis when grown in serum, including a requirement for both the synthesis and transport of amino acids. CONCLUSIONS: This study describes the application of a genome scale transposon library combined with an experimentally validated genome-scale metabolic network of N. meningitidis to identify essential genes and provide novel insight to the pathogen's metabolism both in vitro and during infection.

  • Sanz V, Tilmacîu C, Soula B, Flahaut E, Coley HM, Silva SRP, McFadden J. (2011) 'Chloroquine-enhanced gene delivery mediated by carbon nanotubes'. Elsevier Carbon, 49 (15), pp. 5348-5358.

    Abstract

    Polyethyleneimine-coated double-walled carbon nanotubes (DWCNTs) were used for dual gene and drug delivery, after loading the DWCNTs with the drug chloroquine, a lysosomotropic compound that is able to promote escape from the lysosomal compartment. Different forms of functionalization of the DWCNTs were examined in order to optimize this system. They included the testing of different treatments on DWCNTs to optimize the loading and delivery of chloroquine and the selection of a cationic polymer for coating the DWCNTs for optimum DNA binding and delivery. An acid oxidation treatment of DWCNTs was selected for optimum chloroquine loading together with polyethyleneimine as optimum cationic coating agent for plasmid DNA binding. Optimization of the conditions for choroquine-enhanced gene delivery were developed using luciferase expression as a model system. We have demonstrated that chloroquine-loading increases the ability of polyethyleneimine-coated DWCNTs to deliver functional nucleic acid to human cells. Cell viability tests have shown no cytotoxicity of the functionalized DWCNTs at the concentrations needed for optimum gene delivery. These results support the potential applications of this methodology in gene therapy.

  • Beste DJ, Bonde B, Hawkins N, Ward JL, Beale MH, Noack S, Nöh K, Kruger NJ, Ratcliffe RG, McFadden J. (2011) '¹³C metabolic flux analysis identifies an unusual route for pyruvate dissimilation in mycobacteria which requires isocitrate lyase and carbon dioxide fixation.'. PLoS PLoS Pathog, United States: 7 (7)

    Abstract

    Mycobacterium tuberculosis requires the enzyme isocitrate lyase (ICL) for growth and virulence in vivo. The demonstration that M. tuberculosis also requires ICL for survival during nutrient starvation and has a role during steady state growth in a glycerol limited chemostat indicates a function for this enzyme which extends beyond fat metabolism. As isocitrate lyase is a potential drug target elucidating the role of this enzyme is of importance; however, the role of isocitrate lyase has never been investigated at the level of in vivo fluxes. Here we show that deletion of one of the two icl genes impairs the replication of Mycobacterium bovis BCG at slow growth rate in a carbon limited chemostat. In order to further understand the role of isocitrate lyase in the central metabolism of mycobacteria the effect of growth rate on the in vivo fluxes was studied for the first time using ¹³C-metabolic flux analysis (MFA). Tracer experiments were performed with steady state chemostat cultures of BCG or M. tuberculosis supplied with ¹³C labeled glycerol or sodium bicarbonate. Through measurements of the ¹³C isotopomer labeling patterns in protein-derived amino acids and enzymatic activity assays we have identified the activity of a novel pathway for pyruvate dissimilation. We named this the GAS pathway because it utilizes the Glyoxylate shunt and Anapleurotic reactions for oxidation of pyruvate, and Succinyl CoA synthetase for the generation of succinyl CoA combined with a very low flux through the succinate--oxaloacetate segment of the tricarboxylic acid cycle. We confirm that M. tuberculosis can fix carbon from CO₂ into biomass. As the human host is abundant in CO₂ this finding requires further investigation in vivo as CO₂ fixation may provide a point of vulnerability that could be targeted with novel drugs. This study also provides a platform for further studies into the metabolism of M. tuberculosis using ¹³C-MFA.

  • Bonde BK, Beste DJV, Laing E, Kierzek AM, McFadden J. (2011) 'Differential Producibility Analysis (DPA) of Transcriptomic Data with Metabolic Networks: Deconstructing the Metabolic Response of M. tuberculosis'. PUBLIC LIBRARY SCIENCE PLOS COMPUTATIONAL BIOLOGY, 7 (6) Article number ARTN e1002060
  • Sanz V, Borowiak E, Lukanov P, Galibert AM, Flahaut E, Coley HM, Silva SRP, McFadden J. (2011) 'Optimising DNA binding to carbon nanotubes by non-covalent methods'. PERGAMON-ELSEVIER SCIENCE LTD CARBON, 49 (5), pp. 1775-1781.
  • Sroka J, Bieniasz-Krzywiec L, Gwóźdź S, Leniowski D, Lącki J, Markowski M, Avignone-Rossa C, Bushell ME, McFadden J, Kierzek AM. (2011) 'Acorn: a grid computing system for constraint based modeling and visualization of the genome scale metabolic reaction networks via a web interface.'. BioMed Central BMC Bioinformatics, England: 12 (196)

    Abstract

    Constraint-based approaches facilitate the prediction of cellular metabolic capabilities, based, in turn on predictions of the repertoire of enzymes encoded in the genome. Recently, genome annotations have been used to reconstruct genome scale metabolic reaction networks for numerous species, including Homo sapiens, which allow simulations that provide valuable insights into topics, including predictions of gene essentiality of pathogens, interpretation of genetic polymorphism in metabolic disease syndromes and suggestions for novel approaches to microbial metabolic engineering. These constraint-based simulations are being integrated with the functional genomics portals, an activity that requires efficient implementation of the constraint-based simulations in the web-based environment.

  • Shi L, Sohaskey CD, Pfeiffer C, Datta P, Parks M, McFadden J, North RJ, Gennaro ML. (2010) 'Carbon flux rerouting during Mycobacterium tuberculosis growth arrest'. WILEY-BLACKWELL MOLECULAR MICROBIOLOGY, 78 (5), pp. 1199-1215.
  • Kadir TAA, Mannan AA, Kierzek AM, McFadden J, Shimizu K. (2010) 'Modeling and simulation of the main metabolism in Escherichia coli and its several single-gene knockout mutants with experimental verification'. BIOMED CENTRAL LTD MICROBIAL CELL FACTORIES, 9 Article number ARTN 88
  • Beste DJV, McFadden J. (2010) 'Systems biology of the metabolism of Mycobacterium tuberculosis'. PORTLAND PRESS LTD Biochemical Society Transactions, 38 (5), pp. 1286-1289.

    Abstract

    Despite decades of research, many aspects of the biology of Mycobacterium tuberculosis remain unclear, and this is reflected in the antiquated tools available to treat and prevent tuberculosis and consequently this disease remains a serious public health problem. Important discoveries linking the metabolism of M. tuberculosis and pathogenesis has renewed interest in this area of research. Previous experimental studies were limited to the analysis of individual genes or enzymes, whereas recent advances in computational systems biology and high-throughput experimental technologies now allows metabolism to be studied on a genome scale. In the present article, we discuss the progress being made in applying system-level approaches to study the metabolism of this important pathogen.

  • McFadden J. (2010) 'Physics and the mind Comment on 'Natural world physical-, brain operational-, and mind phenomenal-space-time' by Fingelkurts et al.'. ELSEVIER SCIENCE BV PHYSICS OF LIFE REVIEWS, 7 (2), pp. 250-251.
  • Heister E, Lamprecht C, Neves V, Tilmaciu C, Datas L, Flahaut E, Soula B, Hinterdorfer P, Coley HM, Silva SRP, McFadden J. (2010) 'Higher Dispersion Efficacy of Functionalized Carbon Nanotubes in Chemical and Biological Environments'. AMER CHEMICAL SOC ACS NANO, 4 (5), pp. 2615-2626.
  • Beste DJV, McFadden J. (2010) 'System-level strategies for studying the metabolism of Mycobacterium tuberculosis'. ROYAL SOC CHEMISTRY MOLECULAR BIOSYSTEMS, 6 (12), pp. 2363-2372.
  • Neves V, Heister E, Costa S, Tilmaciu C, Borowiak-Palen E, Giusca CE, Flahaut E, Soula B, Coley HM, McFadden J, Silva SRP. (2010) 'Uptake and Release of Double-Walled Carbon Nanotubes by Mammalian Cells'. WILEY-V C H VERLAG GMBH ADVANCED FUNCTIONAL MATERIALS, 20 (19), pp. 3272-3279.
  • Borsuk S, Newcombe J, Mendum TA, Dellagostin OA, McFadden J. (2009) 'Identification of proteins from tuberculin purified protein derivative (PPD) by LC-MS/MS'. Elsevier TUBERCULOSIS, 89 (6), pp. 423-430.

    Abstract

    The tuberculin purified protein derivative (PPD) is a widely used diagnostic antigen for tuberculosis, however it is poorly defined. Most mycobacterial proteins are extensively denatured by the procedure employed in its preparation, which explains previous difficulties in identifying constituents from PPD to characterize their behaviour in B- and T-cell reactions. We here described a proteomics-based characterization of PPD from several different sources by LC-MS/MS, which combines the solute separation power of HPLC, with the detection power of a mass spectrometer. The technique is able to identify proteins from complex mixtures of peptide fragments. A total of 171 different proteins were identified among the four PPD samples (two bovine PPD and two avium PPD) from Brazil and UK. The majority of the proteins were cytoplasmic (77.9%) and involved in intermediary metabolism and respiration (24.25%) but there was a preponderance of proteins involved in lipid metabolism. We identified a group of 21 proteins that are present in both bovine PPD but were not detected in avium PPD preparation. In addition, four proteins found in bovine PPD are absent in Mycobacterium bovis BCG vaccine strain. This study provides a better understanding of the tuberculin PPD components leading to the identification of additional antigens useful as reagents for specific diagnosis of tuberculosis.

  • Lamprecht C, Liashkovich I, Neves V, Danzberger J, Heister E, Rangl M, Coley HM, McFadden J, Flahaut E, Gruber HJ, Hinterdorfer P, Kienberger F, Ebner A. (2009) 'AFM imaging of functionalized carbon nanotubes on biological membranes'. IOP PUBLISHING LTD NANOTECHNOLOGY, 20 (43) Article number ARTN 434001
  • Heister E, Neves V, Tilmaciu C, Lipert K, Beltran VS, Coley HM, Silva SRP, McFadden J. (2009) 'Triple functionalisation of single-walled carbon nanotubes with doxorubicin, a monoclonal antibody, and a fluorescent marker for targeted cancer therapy'. PERGAMON-ELSEVIER SCIENCE LTD CARBON, 47 (9), pp. 2152-2160.
  • Beste DJV, Espasa M, Bonde B, Kierzek AM, Stewart GR, McFadden J. (2009) 'The Genetic Requirements for Fast and Slow Growth in Mycobacteria'. PUBLIC LIBRARY SCIENCE PLOS ONE, 4 (4) Article number ARTN e5349
  • Mendum TA, Newcombe J, McNeilly CL, McFadden J. (2009) 'Towards the Immunoproteome of Neisseria meningitidis'. PUBLIC LIBRARY SCIENCE PLOS ONE, 4 (6) Article number ARTN e5940
  • Senaratne RH, Sidders B, Sequeira P, Saunders G, Dunphy K, Marjanovic C, Reader JR, Lima P, Chan S, Kendall S, McFadden J, Riley LW. (2008) 'Mycobacterium tuberculosis strains disrupted in mce3 and mce4 operons are attenuated in mice'. SOC GENERAL MICROBIOLOGY JOURNAL OF MEDICAL MICROBIOLOGY, 57 (2), pp. 164-170.
  • Casey R, Newcombe J, McFadden J, Bodman-Smith KB. (2008) 'The acute-phase reactant C-reactive protein binds to phosphorylcholine-expressing Neisseria meningitidis and increases uptake by human phagocytes'. AMER SOC MICROBIOLOGY INFECTION AND IMMUNITY, 76 (3), pp. 1298-1304.
  • Borsuk S, Mendum TA, Fagundes MQ, Michelon M, Cunha CW, McFadden J, Dellagostin OA. (2007) 'Auxotrophic complementation as a selectable marker for stable expression of foreign antigens in Mycobacterium bovis BCG'. CHURCHILL LIVINGSTONE TUBERCULOSIS, 87 (6), pp. 474-480.
  • Beste DJV, Laing E, Bonde B, Avignone-Rossa C, Bushell ME, McFadden JJ. (2007) 'Transcriptomic analysis identifies growth rate modulation as a component of the adaptation of mycobacteria to survival inside the macrophage'. AMER SOC MICROBIOLOGY JOURNAL OF BACTERIOLOGY, 189 (11), pp. 3969-3976.
  • Santangelo MP, McIntosh D, Bigi F, Armoa GRG, Campos ASD, Ruybal P, Dellagostin OA, McFaddend J, Mendum T, Gicquel B, Winter N, Farber M, Cataldi A. (2007) 'Mycobacterium bovis BCG as a delivery system for the RAP-1 antigen from Babesia bovis'. ELSEVIER SCI LTD VACCINE, 25 (6), pp. 1104-1113.
  • Beste DJV, Hooper T, Stewart G, Bonde B, Avignone-Rossa C, Bushell M, Wheeler P, Klamt S, Kierzek AM, McFadden J. (2007) 'GSMN-TB: a web-based genome scale network model of Mycobacterium tuberculosis metabolism'. BIOMED CENTRAL LTD GENOME BIOLOGY, 8 (5) Article number ARTN r89
  • Michelon A, Conceicao FR, Binsfeld PC, da Cunha CW, Moreira AN, Argondizzo AP, McIntosh D, Armoa GRG, Campos AS, Farber M, McFadden J, Dellagostin OA. (2006) 'Immunogenicity of Mycobacterium bovis BCG expressing Anaplasma marginale MSP1a antigen'. ELSEVIER SCI LTD VACCINE, 24 (37-39), pp. 6332-6339.
  • Jeynes JCG, Mendoza E, Chow DCS, Watts PCR, McFadden J, Silva SRP. (2006) 'Generation of chemically unmodified pure single-walled carbon nanotubes by solubilizing with RNA and treatment with ribonuclease A'. WILEY-V C H VERLAG GMBH ADVANCED MATERIALS, 18 (12), pp. 1598-+.
  • Rustam T, McClean S, Newcombe J, McFadden J, Eales-Reynolds LJ. (2006) 'Reduced toxicity of lipo-oligosaccharide from a phoP mutant of Neisseria meningitidis: an in vitro demonstration'. MANEY PUBLISHING JOURNAL OF ENDOTOXIN RESEARCH, 12 (1), pp. 39-46.

Conference papers

  • Jenson JS, Casey R, Newcombe J, Smith M, McFadden JJ, Bodman-Smith K. (2008) 'Dendritic cell responses to C-reactive protein-opsonised Neisseria meningitidis'. WILEY-BLACKWELL PUBLISHING, INC IMMUNOLOGY, Glasgow, SCOTLAND: Annual Congress of the British-Society-of-Immunology 125, pp. 124-124.
  • Casey R, McFadden J, Newcombe J, Bodman-Smith M, Bodman-Smith K. (2007) 'C-reactive protein binds to Neisseria meningitidis and affects macrophage responses to infection'. BLACKWELL PUBLISHING IMMUNOLOGY, Glasgow, SCOTLAND: Annual Congress of the British-Society-of-Immunology 120, pp. 20-20.

Books

  • McFadden J, Beste DJV, Kierzek AM. (2012) Systems Biology of Tuberculosis. Springer

Book chapters

  • Beste DJV, McFadden J. (2013) 'Metabolism of Mycobacterium tuberculosis'. in (ed.) Systems biology of tuberculosis Article number 4
  • Beste DJV, McFadden J. (2012) 'System-level Strategies for Studying the Metabolism of Mycobacterium tuberculosis'. in Robertson BD, Wren BW (eds.) Systems Microbiology: Current Topics and Applications Article number 7

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