Assoc Prof Richard Ferrero - Researcher Profile

Richard Ferrero

Address

Monash Institute of Medical Research
27-31 Wright Street

Biography

How do host cells interact with bacteria?

The discovery of Helicobacter pylori debunked the long-held belief that stress and spicy food caused peptic ulcers. While more than 80 per cent of the carriers of this bacterium never have any symptoms, Associate Professor Richard Ferrero wants to understand why the remaining carriers develop peptic ulcers or gastric cancer. 

 

H. pylori lives in the human stomach and causes inflammation of the stomach lining. Richard is researching how the bacterium interacts with the host cells that line the stomach, as well as the inflammation that the bacterium triggers. Despite its relatively recent discovery (findings were first published in 1983), the two main severe diseases caused by H. pylori, peptic ulcer and gastric cancer, have long been known as mutually exclusive.

“There are common elements in both pathways, one of which is H. pylori infection, but what happens in the stomach is slightly different between the two,” Richard says. “People with more debilitating symptoms have peptic ulcer disease. This was thought to be caused solely by stress or acidity, but H. pylori is the critical element to the deregulation of acid production in the stomach. People with peptic ulcer disease will never develop gastric cancer. The problem cases are those who develop gastric cancer because the bug sits in their stomach throughout their lives, but they usually have no symptoms.”

Richard says he has learnt a lot about how H. pylori interacts with host cells, but applying this knowledge to treatment is still in the early stages. He thinks screening for the bacteria may be more important in the long-term.

“We’ve made a lot of progress, but there are still a lot of questions we can’t answer. Two key questions are why some people have H. pylori, and why some of those develop severe disease. Most people who have H. pylori will have inflammation but they won’t develop ulcers or cancer. Being able to screen and manage the disease may be more of a key than actually treating it per se. You might be able to identify biomarkers by doing a screen like they do for prostate cancer,” he says.  

Richard says the advent of next-generation sequencing will offer further unique insights into the points of difference among H. pylori carriers.

“In the last few years, there have been incredible advances in the technology that allows us to sequence the genomes of organisms. Sequencing the first human genome took many years and billions of dollars. Now, our machine allows us to sequence a human genome in a matter of days for a few thousand dollars. This allows us to study host susceptibility. For example, countries like Japan and South Korea have very high rates of gastric cancer, whereas in Africa, where H. pylori is supposedly rampant, there are very low rates of gastric cancer. So there are host factors, and the only way to understand these is with large-scale genome sequencing of individuals and, coupled with other technologies such as microarrays, trying to understand individual differences.” 

 

Qualifications

GRADUATE CERTIFICATE IN HIGHER EDUCATION
Institution: Monash University
Year awarded: 2009
PHD IN MICROBIOLOGY
Institution: University of NSW, Sydney
Year awarded: 1990
BACHELOR OF MICROBIOLOGY (HONS)
Institution: University of NSW, Sydney
Year awarded: 1985
BACH. OF APPLIED SCIENCE(MICROBIOLOGY & CHEMISTRY)
Institution: NSW Institute of Technology, Sydney
Year awarded: 1984

Publications

Book Chapters

Kaparakis, M., Allison, C., Hutton, M., Ferrero, R., 2010, Innate immune initiators and effectors in Helicobacter pylori infection, in Helicobacter pylori in the 21st Century, eds Philip Sutton and Hazel M. Mitchell, CABI, UK, pp. 142-166.

Ferrero, R.L., Jenks, P.J., 2001, In Vivo Adaptation to the Host, in Helicobacter pylori: Physiology and Genetics, eds H Mobley, G Mendz, S Hazell, ASM Press, Washington DC, pp. 583-592.

Ferrero, R.L., Fox, J.G., 2001, In Vivo Modeling of Helicobacter-associated Gastrointestinal Diseases, in Helicobacter pylori: Physiology and Genetics, eds H Mobley, G Mendz, S Hazell, ASM Press, Washington DC, pp. 565-582.

Journal Articles

Gorrell, R.J., Xin, Y., Guan, J., Anoushiravani Tafreshi, M., Hutton, M.L., McGuckin, M.A., Ferrero, R.L., Kwok-Scheulein, T., 2013, A novel NOD1- and CagA-independent pathway of interleukin-8 induction mediated by the Helicobacter pylori type IV secretion system, Cellular Microbiology [P], vol E-pub, Wiley-Blackwell Publishing Ltd, UK, pp. 1-43. View Publication

Andrews, P.C., Ferrero, R.L., Junk, P.C., Maclellan, J.G., Peiris, J.M.R., 2012, Bismuth(III) thiobenzoates and their activity against helicobacter pylori, Australian Journal of Chemistry [E], vol 65, issue 7, CSIRO Publishing, Collingwood Vic Australia, pp. 883-891. View Publication

Ferrero, R.L., Wilson, J.E., Sutton, P., 2012, Mouse models of Helicobacter-induced gastric cancer: use of cocarcinogens, Methods in molecular biology (Clifton, N.J.) [P], vol 921, Humana Press, Inc., USA, pp. 157-173. View Publication

Roure, S., Bonis, M., Chaput, C., Ecobichon, C., Mattox, A., Barriere, C., Geldmacher, N., Guadagnini, S., Schmitt, C., Prevost, M.C., Labigne, A., Backert, S., Ferrero, R.L., Boneca, I.G., 2012, Peptidoglycan maturation enzymes affect flagellar functionality in bacteria, Molecular Microbiology [P], vol 86, issue 4, Wiley-Blackwell Publishing Ltd., United Kingdom, pp. 845-856. View Publication

Andrews, P.C., Busse, M., Deacon, G.B., Ferrero, R.L., Junk, P.C., Maclellan, J.G., Vom, A., 2012, Remarkable in vitro bactericidal activity of bismuth(III) sulfonates against Helicobacter pylori, Dalton Transactions [P], vol 41, issue 38, Royal Society of Chemistry, Cambridge England, pp. 11798-11806. View Publication

Hutton, M., Liaskos, M., Ferrero, R., 2012, The use of AlbuMAX II[R] as a blood or serum alternative for the culture of helicobacter pylori, Helicobacter [E], vol 17, issue 1, Wiley-Blackwell Publishing Ltd, United Kingdom, pp. 68-76. View Publication

Andrews, P., Ferrero, R., Forsyth, C., Junk, P., Maclellan, J., Peiris, J., 2011, Bismuth(III) saccharinate and thiosaccharinate complexes and the effect of ligand substitution on their activity against Helicobacter pylori, Organometallics [P], vol 30, issue 22, American Chemical Society, USA, pp. 6283-6291. View Publication

Kennedy, C., Najdovska, M., Jones, G., McLeod, L., Hughes, N., Allison, C., Ooi, C., Tan, P., Ferrero, R., Jones, S., Dev, A., Sievert, W., Bhathal, P., Jenkins, B., 2011, The molecular pathogenesis of STAT3-driven gastric tumourigenesis in mice is independent of IL-17, Journal Of Pathology [P], vol 225, issue 2, John Wiley & Sons Ltd, United Kingdom, pp. 255-264. View Publication

Liaskos, M., Turnbull, L., Carneiro, L., Firth, S.D., Coleman, H.A., Parkington, H.C., Le Bourhis, L., Karrar, A., Viala, J., Mak J., Hutton, M.L., Davies, J.K., Crack, P.J., Hertzog, P.J., Philpott, D., Girardin, S.E., Whitchurch, C.B., Ferrero, R.L., 2010, Bacterial membrane vesicles deliver peptidoglycan to NOD1 in epithelial cells, Cellular Microbiology [P], vol 12, Wiley-Blackwell Publishing Ltd, UK, pp. 372-385. View Publication

Andrews, P.C., Ferrero, R.L., Junk, P.C., Kumar, I., Luu, Q., Nguyen, K., Taylor, J.W., 2010, Bismuth(III) complexes derived from non-steroidal anti-inflammatory drugs and their activity against Helicobacter pylori, Dalton Transactions [P], vol 39, issue 11, The Royal Society of Chemistry, England, pp. 2861-2868. View Publication

Foo, J.H., Culvenor, J., Ferrero, R.L., Kwok-Schuelein, T., Lithgow, T.J., Gabriel, K., 2010, Both the p33 and p55 subunits of the Helicobacter pylori VacA toxin are targeted to mammalian mitochondria, Journal of Molecular Biology [P], vol 401, issue 5, Academic Press, UK, pp. 792-798. View Publication

Gantier, M.P.M., Irving, A.T., Liaskos, M., Xu, D., Evans, V., Cameron, P.U., Bourne, J.A., Ferrero, R.L., John, M., Behlke, M.A., Williams, B.R.G., 2010, Genetic modulation of TLR8 response following bacterial phagocytosis, Human Mutation [P], vol 31, issue 9, John Wiley & Sons, Inc., USA, pp. 1069-1079. View Publication

Hutton, M., Liaskos, M., Turner, L., Cardona, A., Kwok-Schuelein, T., Ferrero, R., 2010, Helicobacter pylori exploits cholesterol-rich microdomains for induction of NF-kappaB-dependent responses and peptidoglycan delivery in epithelial cells, Infection And Immunity [P], vol 78, issue 11, American Society for Microbiology, United States, pp. 4523-4531. View Publication

Ding, S., Fischer, W., Kaparakis-Liaskos, M., Liechti, G., Merrell, D., Grant, P.A., Ferrero, R., Crowe, S., Hass, R., Hatakeyama, M., Goldberg, J., 2010, Helicobacter pylori-induced histone modification, associated gene expression in gastric epithelial cells, and its implication in pathogenesis, PLoS ONE [P], vol 5, issue 4 (e9875), Public Library of Science, United States, pp. 1-15. View Publication

Wee, J.L., Chionh, Y., Ng, G.Z., Harbour, S.N., Allison, C.C., Pagel, C.N., Mackie, E.J., Mitchell, H.M., Ferrero, R.L., Sutton, P., 2010, Protease-activated receptor-1 down-regulates the murine inflammatory and humoral response to Helicobacter pylori, Gastroenterology [P], vol 138, WB Saunders Co., USA, pp. 573-582. View Publication

Allison, C., Ferrero, R., 2010, Role of virulence factors and host cell signaling in the recognition of Helicobacter pylori and the generation of immune responses, Future Microbiology [P], vol 5, issue 8, Future Medicine Ltd, United Kingdom, pp. 1233-1255. View Publication

Andrews, P., Busse, M., Deacon, G., Ferrero, R., Junk, P., Huyhn, P., Kumar, I., MacLellan, J., 2010, Structural and solution studies of phenylbismuth(III) sulfonate complexes and their activity against Helicobacter pylori, Dalton Transactions [P], vol 39, issue 40, Royal Society of Chemistry, Cambridge England, pp. 9633-9641. View Publication

Grubman, A., Liaskos, M.(., Viala, J., Allison, C.C., Badea, L., Karrar, A., Boneca, I.G., Le Bourhis, L., Reeve, S.B., Smith, A.I., Hartland, E.L., Philpott, D.J., Ferrero, R.L., 2010, The innate immune molecule, NOD1, regulates direct killing of Helicobacter pylori by antimicrobial peptides, Cellular Microbiology [P], vol 12, Wiley-Blackwell Publishing Ltd, UK, pp. 626-639. View Publication

Grubman, A., Phillips, A., Thibonnier, M., Kaparakis-Liaskos, M., Johnson, C., Thiberge, J.-., Radcliffe, F.J., Ecobichon, C., Labigne, A., de Reuse, H., Mendz, G.L., Ferrero, R.L., 2010, Vitamin B 6 is required for full motility and virulence in Helicobacter pylori, mBio [E], vol 1, issue 3 (e00112-10), American Society for Microbiology, United States, pp. 1-9. View Publication

Chaouche-Drider, N., Kaparakis, M., Karrar, A., Fernandez, M., Carneiro, L.A.M., Viala, J., Boneca, I.G., Moran, A.P., Philpott, D.J., Ferrero, R.L., 2009, A commensal Helicobacter sp. of the rodent intestinal flora activates TLR2 and NOD1 responses in epithelial cells, PLoS ONE [P], vol 4, issue 4 (e5396), Public Library of Science, USA, pp. 1-10. View Publication

Andrews, P.C., Deacon, G.B., Ferrero, R.L., Junk, P.C., Karrar, A., Kumar, I., MacLellan, J., 2009, Bismuth(III) 5-sulfosalicylate complexes: structure, solubility and activity against Helicobacter pylori, Dalton Transactions [P], The Royal Society of Chemistry, UK, pp. 6377-6384. View Publication

Allison, C.C., Kufer, T.A., Kremmer, E., Liaskos, M.(., Ferrero, R.L., 2009, Helicobacter pylori induces MAPK phosphorylation and AP-1 activation via a NOD1-dependent mechanism, Journal Of Immunology [P], vol 183, issue 12, American Association of Immunologists, USA, pp. 8099-8109. View Publication

Badea, L., Beatson, S.A., Kaparakis, M., Ferrero, R.L., Hartland, E.L., 2009, Secretion of flagellin by the LEE-encoded type III secretion system of enteropathogenic Escherichia coli, BMC Microbiology, vol 9, issue 30, BioMed Central Ltd, UK, pp. 1-10. View Publication

Ferrero, R.L., Ave, P., Ndiaye, D., Bambou, J., Huerre, M.R., Philpott, D.J., Memet, S., 2008, NF-kappaB activation during acute Helicobacter pylori infection in mice, Infection And Immunity [P], vol 76, issue 2, American Society for Microbiology, United States, pp. 551-561. View Publication

Snider, J.L., Allison, C.C., Bellaire, B.H., Ferrero, R.L., Cardelli, J.A., 2008, The ?1 integrin activates JNK independent of CagA, and JNK activation is required for Helicobacter pylori CagA+-induced motility of gastric cancer cells, Journal of Biological Chemistry, vol 283, issue 20, American Society for Biochemistry and Molecular Biology, Inc., United States, pp. 13952-13963. View Publication

Kaparakis, M., Philpott, D., Ferrero, R.L., 2007, Mammalian NLR proteins; discriminating foe from friend, Immunology & Cell Biology, vol 85, issue 6, Nature Publishing Group, New York NY USA, pp. 495-502. View Publication

McGuckin, M., Every, A.L., Skene, C.D., Linden, S.K., Chionh, Y.T., Swierczak, A., McAuley, J., Harbour, S., Kaparakis, M., Ferrero, R.L., Sutton, P., 2007, Muc1 mucin limits both Helicobacter pylori colonization of the murine gastric mucosa and associated gastritis, Gastroenterology, vol 133, issue 4, WB Saunders Co-Elsevier Inc, Philadelphia, PA, USA, pp. 1210-1218. View Publication

Fritz, J.H., Le Bourhis, L., Sellge, G., Magalhaes, J.G., Fsihi, H., Kufer, T.A., Collins, C., Viala, J., Ferrero, R.L., Girardin, S.E., Philpott, D., 2007, Nod1-mediated innate immune recognition of peptidoglycan contributes to the onset of adaptive immunity, Immunity, vol 26, issue 4, Cell Press, Cambridge MA USA, pp. 445-459. View Publication

Fritz, J.H., Ferrero, R.L., Philpott, D.J., Girardin, S.E., 2006, Nod-like proteins in immunity, inflammation and disease, Nature Immunology, vol 7, issue 12, Nature Publishing Group, New York NY USA, pp. 1250-1257.

Ferrero, R.L., 2005, Innate immune recognition of the extracellular mucosal pathogen, Helicobacter pylori, Molecular Immunology, vol 42, issue 8, Pergamon, UK, pp. 879-885. View Publication

Gobert, A.P., Bambou, J.C., Werts, C., Balloy, V., Chignard, M., Moran, A.P., Ferrero, R.L., 2004, Helicobacter pylori heat shock protein 60 mediates interleukin-6 production by macrophages via a toll-like receptor (TLR)-2-, TLR-4-, and myeloid differentiation factor 88-independent mechanism, The Journal of Biological Chemistry, vol 279, issue 1, Japanese Biochemical Society, Tokyo Japan, pp. 245-250. View Publication

Viala, J., Chaput, C., Boneca, I.G., Cardona, A., Girardin, S.E., Moran, A.P., Athman, R., Memet, S., Huerre, M.R., Coyle, A.J., DiStefano, P.S., Sansonetti, P.J., Labigne, A., Bertin, J., Philpott, D.J., Ferrero, R.L., 2004, Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island, Nature Immunology, vol 5, issue 11, Nature Publishing Group, New York USA, pp. 1166-1174. View Publication

Ferrero, R.L., 2003, Vaccination against H. pylori: an achievable goal, Gastroenterologie Clinique et Biologique, vol 27, issue 3, Masson Editeur, Cedex France, pp. 488-493.

Innocenti, M., Thoreson, A.C., Ferrero, R.L., Stromberg, E., Bolin, I., Eriksson, L., Svennerholm, A.M., Quiding-Jarbrink, M., 2002, Helicobacter pylori-induced activation of human endothelial cells, Infection and immunity, vol 70, issue 8, American Society for Microbiology, Washington DC USA, pp. 4581-4590.

Philpott, D.J., Belaid, D., Troubadour, P., Thiberge, J., Tankovic, J., Labigne, A., Ferrero, R.L., 2002, Reduced activation of inflammatory responses in host cells by mouse-adapted Helicobacter pylori isolates, Cellular Microbiology, vol 4, issue 5, Blackwell Publishing, Oxford UK, pp. 285-296. View Publication

Crabtree, J.E., Ferrero, R.L., Kusters, J.G., 2002, The mouse colonizing Helicobacter pylori strain SS1 may lack a functional cag pathogenicity island, Helicobacter, vol 7, issue 2, Blackwell Science, Oxford England, pp. 139-141.

Radcliffe, F.J., Ferrero, R.L., 2001, Effect of low-dose antigen exposure on development of immunity to Helicobacter pylori infection in mice, Infection & Immunity, vol 69, issue 8, American Society for Microbiology, Washington DC USA, pp. 5186-5188.

Ferrero, R.L., Labigne, A., 2001, Helicobacter pylori vaccine development in the post-genomic era: can in silico translate to in vivo, Scandinavian Journal of Immunology, vol 53, Blackwell Publishing, Oxfrord England, pp. 443-448.

Jenks, P.J., Ferrero, R.L., Tankovic, J., Thiberge, J., Labigne, A., 2000, Evaluation of nitrofurantoin combination therapy of metronidazole-sensitive and -resistant Helicobacter pylori infections in mice, Antimicrobial Agents and Chemotherapy, vol 44, issue 10, American Society for Microbiology, Washington DC USA, pp. 2623-2629.

Ferrero, R.L., Ave, P., Radcliffe, F.J., Labigne, A., Huerre, M.R., 2000, Outbred mice with long-term Helicobacter felis infection develop both gastric lymphoid tissue and glandular hyperplastic lesions, Journal of Pathology, vol 191, John Wiley & Sons Ltd, Chichester UK, pp. 333-340.3.0.CO;2-H> View Publication

Conference Proceedings

Ferrero, R.L., Philpott, D.J., 2005, Nod1 signaling to extracellular mucosal bacteria in epithelial cells, International Congress Series, 11 July 2005 to 13 July 2005, Elsevier, Amsterdam Netherlands, pp. 68-77.

Grants

Title:
Bacterial outer membrane vesicles as immunomodulatory agents in Helicobacter pylori infection.
Investigators:
Ferrero, R
Funding:
(2008 - 2011). National Health & Medical Research Council (NHMRC).
(2009 - 2013). National Health & Medical Research Council (NHMRC).
Title:
Bio-inspired Chemistry of Novel Metal-Organic Bismuth Compounds.
Investigators:
Andrews, P, Junk, P, Ferrero, R, Kedzierski, L
Funding:
(2011 - 2014). Australian Research Council (ARC).
(2011 - 2014). Monash University.
(2011 - 2015). Australian Research Council (ARC).
(2011 - 2015). Walter & Eliza Hall Institute of Medical Research.
Title:
Cross-talk between cytokine and pathogen recognition receptor networks in the pathogenesis of gastric cancer.
Investigators:
Jenkins, B, Mansell, A, Ferrero, R
Funding:
(2008 - 2011). Cancer Council Victoria.
Title:
Cross-talk between cytokine and pathogen recognition receptor networks in the pathogenesis of gastric cancer.
Investigators:
Jenkins, B, Mansell, A, Ferrero, R
Funding:
(2008 - 2011). National Health & Medical Research Council (NHMRC).
Title:
Cross-talk between cytokines and pathogen rcognition receptor networks in the pathogenesis of gastric cancer.
Investigators:
Jenkins, B, Mansell, A, Ferrero, R
Funding:
(2008 - 2011). Association for International Cancer Research.
Title:
Epithelial cell signalling and host response to virulent helicobacter pylori strains.
Investigators:
Ferrero, R, Jenkins, B
Funding:
(2011 - 2015). National Health & Medical Research Council (NHMRC).
Title:
Helicobacter pylori acquisition of host cholesterol: its role in inflammation.
Investigators:
Ferrero, R, Croker, B
Funding:
(2012 - 2016). National Health & Medical Research Council (NHMRC).
Title:
Identification of novel colonisation factors in Helicobacter pylori ; ID: 384232.
Investigators:
Ferrero, R, Mendz, G, Labigne, A
Funding:
(2006 - 2010). National Health & Medical Research Council (NHMRC).
(2009 - 2013). National Health & Medical Research Council (NHMRC).
Title:
Modulation of anti-tumour and inflammatory signalling during gastric cancer.
Investigators:
Allison, C, Ferrero, R
Funding:
(2011 - 2015). Cancer Council Victoria.
Title:
NHMRC Research Fellowship.
Investigators:
Ferrero, R
Funding:
(2010 - 2014). National Health & Medical Research Council (NHMRC).
Title:
Novel regulation of inflammasomes by cytokine signalling pathways in gastric disease.
Investigators:
Jenkins, B, Ferrero, R, Latz, E
Funding:
(2013 - 2017). National Health & Medical Research Council (NHMRC).
Title:
Request for a POLARstar Optima - Fluorescence Microplate Reader.
Investigators:
Drummond, G, Summers, R, Widdop, R, Ricardo, S, Ferrero, R
Funding:
(2005 - 2009). Clive & Vera Ramaciotti Foundation.
Title:
The impact of virulence gene polymorphisms on helicobacter pylori pathogenesis.
Investigators:
Ferrero, R, Sutton, P
Funding:
(2011 - 2015). National Health & Medical Research Council (NHMRC).
Title:
The role of Helicobacter pylori membrane vesicles as mediators of host cell signalling in epithelial cells.
Investigators:
Ferrero, R
Funding:
(2006 - 2009). ANZ Charitable Trusts: Medical Research & Technology Grant.
Title:
The role of the intracellular pathogen-recognition molecule Nod1 in the host response to Helicobacter pylori infection I.
Investigators:
Ferrero, R
Funding:
(2005 - 2009). National Health & Medical Research Council (NHMRC).
Title:
Transport and innate immune properties of DNA in bacterial nano-sized vesicles.
Investigators:
Ferrero, R, Stacey, K
Funding:
(2012 - 2016). Australian Research Council (ARC).
(2012 - 2016). University of Queensland.
Title:
Understanding the molecular processes involved in Helicobacter pylori induced inflammation; a precursor of peptic ulceration and stomach cancer.
Investigators:
Ferrero, R
Funding:
(2007 - 2010). CASS Foundation Limited.
Title:
Protease-activated receptor-1 (PAR-1) and regulation of Helicobacter pylori induced mucosal inflammation.
Investigators:
Ferrero, R, Sutton, P, Mitchell, H
Funding:
(2008 - 2012). National Health & Medical Research Council (NHMRC).

Postgraduate Research Supervisions

Current Supervision

Program of Study:
(DOCTORATE BY RESEARCH).
Thesis Title:
The immunomodulatory roles of Helicobacter pylori outer membrane vesicles..
Supervisors:
Ferrero, R (Main), Kaparakis Liaskos, M (Associate).
Program of Study:
(DOCTORATE BY RESEARCH).
Thesis Title:
Transport and innate immune properties of DNA in bacterial nano-sized vesicles.
Supervisors:
Ferrero, R (Main).

Completed Supervision

Student:
Allison, C.
Program of Study:
The role of the pathogen recognition molecule, NOD1, in the induction of gastric epithelial cell signalling during Helicobacter pylori infection. (PHD) 2010.
Supervisors:
Davies, J (Main), Ferrero, R (Associate), Kaparakis Liaskos, M (Associate).
Student:
Grubman, A.
Program of Study:
The role of strain heterogeneity in Helicobacter pylori colonisation, virulence and host adaptation. (PHD) 2011.
Supervisors:
Ferrero, R (Main).
Student:
Hutton, M.
Program of Study:
The role of cholesterol in Helicobacter pylori interactions with host cells. (PHD) 2012.
Supervisors:
Ferrero, R (Main), Kaparakis Liaskos, M (Associate).