Arturo Casadevall

Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States

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Publications (670)3615.91 Total impact

  • Liise-anne Pirofski, Arturo Casadevall
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    ABSTRACT: Proof of the Germ theory of disease and acceptance of Koch's postulates in the late 1890's launched the fields of microbial pathogenesis and infectious diseases and provided the conceptual framework that has guided thought and research in these fields. A central tenet that emerged from studies with microbes that fulfilled Koch's postulates was that microbes that caused disease had characteristics that allowed them to do so, with the corollary that microbes that did not cause disease lacked disease-causing determinants. This observation, which held true for many diseases that were known to cause disease in the late 19th century, such as toxin-producing and encapsulated bacteria, led to the view that the ability to cause disease rested with microbes and reflected the activity of specific determinants, or virulence factors. With the dawn of the 20th century, efforts to neutralize virulence factors were under development and ultimately translated into anti-microbial therapy in the form of antibodies targeted to toxins and polysaccharide capsules. However, the 20th century progressed, antibiotics were identified and developed as therapy for infectious diseases while other medical advances, such as specialized surgeries, intensive care units, intravenous catheters, and cytotoxic chemotherapy became commonplace in resourced nations. An unintended consequence of many of these advances was that they resulted in immune impairment. Similarly, HIV/AIDS, which emerged in the late 1970's also produced profound immune impairment. Unexpectedly, the prevailing view that microbes were the sole perpetrators of virulence was untenable. Microbes that were rarely if ever associated with disease emerged as major causes of disease in people with impaired immunity. This phenomenon revealed that available explanations for microbial infectiveness and virulence were flawed. In this review, we discuss the question 'what is infectiveness' based on the tenets of the Damage-response framework.
    BMC Immunology 12/2015; 16(1). DOI:10.1186/s12865-015-0076-1 · 2.25 Impact Factor
  • Arturo Casadevall, Ferric C. Fang
    Microbe (Washington, D.C.) 06/2015; 10(6):224-225. DOI:10.1128/microbe.10.224.1
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    ABSTRACT: Microbial secretion is integral for regulating cell homeostasis as well as releasing virulence factors during infection. Phosphatidylserine synthase (CHO1) and phosphatidylserine decarboxylase (PSD1 and PSD2) are Candida albicans genes involved in phospholipid biosynthesis, and mutations in these genes affect mitochondrial function, cell wall thickness, and virulence in mice. We tested the role of these genes in several agar-based secretion assays and observed that the cho1Δ/Δ and psd1Δ/Δ psd2Δ/Δ strains manifested less protease and phospholipase activity. Since extracellular vesicles (EVs) are surrounded by a lipid membrane, we investigated the effects of these mutations on EV structure, composition, and biological activity. The cho1Δ/Δ mutant releases EVs comparable in size to wild-type EVs, but EVs from the psd1Δ/Δ psd2Δ/Δ strain are much larger than those from the wild-type, including a population of >100 nm EVs not observed in the EVs from wild type. Proteomic analysis revealed that EVs from both mutants had significantly different protein cargo than those from wild-type. EVs were tested for their ability to activate NFkB in bone marrow-derived macrophage cells. While wild-type and psd1Δ/Δ psd2Δ/Δ mutant-derived EVs activated NFkB, the cho1Δ/Δ mutant-derived EV did not. These studies indicate that the presence and absence of these C. albicans genes have qualitative and quantitative effects on EV size, composition, and immunostimulatory phenotypes that highlight a complex interplay between lipid metabolism and vesicle production. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Eukaryotic Cell 05/2015; DOI:10.1128/EC.00054-15 · 3.18 Impact Factor
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    ABSTRACT: The role of lymphatic vessels is to transport fluid, soluble molecules, and immune cells to the draining lymph nodes. Here, we analyze how the aging process affects the functionality of the lymphatic collectors and the dynamics of lymph flow. Ultrastructural, biochemical, and proteomic analysis indicates a loss of matrix proteins, and smooth muscle cells in aged collectors resulting in a decrease in contraction frequency, systolic lymph flow velocity, and pumping activity, as measured in vivo in lymphatic collectors. Functionally, this impairment also translated into a reduced ability for in vivo bacterial transport as determined by time-lapse microscopy. Ultrastructural and proteomic analysis also indicates a decrease in the thickness of the endothelial cell glycocalyx and loss of gap junction proteins in aged lymph collectors. Redox proteomic analysis mapped an aging-related increase in the glycation and carboxylation of lymphatic's endothelial cell and matrix proteins. Functionally, these modifications translate into apparent hyperpermeability of the lymphatics with pathogen escaping from the collectors into the surrounding tissue and a decreased ability to control tissue fluid homeostasis. Altogether, our data provide a mechanistic analysis of how the anatomical and biochemical changes, occurring in aged lymphatic vessels, compromise lymph flow, tissue fluid homeostasis, and pathogen transport.
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    [Show abstract] [Hide abstract]
    ABSTRACT: The role of lymphatic vessels is to transport fluid, soluble molecules, and immune cells to the draining lymph nodes. Here, we analyze how the aging process affects the functionality of the lymphatic collectors and the dynamics of lymph flow. Ultrastructural, biochemical, and proteomic analysis indicates a loss of matrix proteins, and smooth muscle cells in aged collectors resulting in a decrease in contraction frequency, systolic lymph flow velocity, and pumping activity, as measured in vivo in lymphatic collectors. Functionally, this impairment also translated into a reduced ability for in vivo bacterial transport as determined by time-lapse microscopy. Ultrastructural and proteomic analysis also indicates a decrease in the thickness of the endothelial cell glycocalyx and loss of gap junction proteins in aged lymph collectors. Redox proteomic analysis mapped an aging-related increase in the glycation and carboxylation of lymphatic's endothelial cell and matrix proteins. Functionally, these modifications translate into apparent hyperpermeability of the lymphatics with pathogen escaping from the collectors into the surrounding tissue and a decreased ability to control tissue fluid homeostasis. Altogether, our data provide a mechanistic analysis of how the anatomical and biochemical changes, occurring in aged lymphatic vessels, compromise lymph flow, tissue fluid homeostasis, and pathogen transport.
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    Michael J Imperiale, Arturo Casadevall
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    ABSTRACT: Michael Imperiale and Arturo Casadevall propose a path forward for life sciences research whose results could be misused to cause harm.
    PLoS Medicine 04/2015; 12(4):e1001813. DOI:10.1371/journal.pmed.1001813 · 14.00 Impact Factor
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    Arturo Casadevall, Liise-Anne Pirofski
    PLoS Pathogens 04/2015; 11(4):e1004717. DOI:10.1371/journal.ppat.1004717 · 8.06 Impact Factor
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    ABSTRACT: Melanin pigments protect against both ionizing radiation and free radicals and have potential soil remediation capabilities. Eumelanins produced by pathogenic Cryptococcus neoformans (CN) fungi are virulence factors that render the fungal cells resistant to host defenses and certain antifungal drugs. Because of their insoluble and amorphous characteristics, neither the pigment bonding framework nor cellular interactions underlying CN melanization have yielded to comprehensive molecular-scale investigation. The current study used the CN requirement of exogenous obligatory catecholamine precursors for melanization to produce isotopically enriched pigment 'ghosts' and applied 2D (13)C-(13)C correlation solid-state NMR to reveal the carbon-based architecture of intact natural eumelanin assemblies in fungal cells. We demonstrated that the aliphatic moieties of solid CN melanin ghosts include cell-wall components derived from polysaccharides and/or chitin that are associated proximally with lipid membrane constituents. Prior to development of the mature aromatic fungal pigment, these aliphatic moieties form a chemically resistant framework that could serve as the scaffold for melanin synthesis. The indole-based core aromatic moieties show interconnections that are consistent with proposed melanin structures consisting of stacked planar assemblies, which are associated spatially with the aliphatic scaffold. The pyrrole aromatic carbons of the pigments bind covalently to the aliphatic framework via glycoside or glyceride functional groups. These findings establish that the structure of the pigment assembly changes with time and provide the first biophysical information on the mechanism by which melanin is assembled in the fungal cell wall, offering vital insights that can advance the design of bioinspired conductive nanomaterials and novel therapeutics. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 03/2015; 290(22). DOI:10.1074/jbc.M114.618389 · 4.60 Impact Factor
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    ABSTRACT: In recent years several groups have shown that isotype switching from IgM to IgG to IgA can affect the affinity and specificity of antibodies (Abs) sharing identical variable (V) regions. However, whether the same applies to IgE is unknown. In this study we compared the fine specificity of V region identical IgE and IgA to Cryptococcus neoformans capsular polysaccharide and found that these differed in specificity from each other. The IgE and IgA paratopes were probed by nuclear magnetic resonance spectroscopy (NMR) with 15Nlabeled peptide mimetics of cryptococcal polysaccharide antigen (Ag). IgE was found to cleave the peptide at a much faster rate than V region-identical IgG subclasses and IgA, consistent with an altered paratope. Both IgE and IgA were opsonic for C. neoformans and protected against infection in mice. In summary, V region expression in the context of the epsilon constant (C) region results in specificity changes that are greater than observed for comparable IgG subclasses. These results raise the possibility that expression of certain V regions in the context of alpha and epsilon C regions affects their function and contributes to the special properties of those isotypes. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 03/2015; 290(19). DOI:10.1074/jbc.M114.618975 · 4.60 Impact Factor
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    Michael J Imperiale, Arturo Casadevall
    mBio 03/2015; 6(2). DOI:10.1128/mBio.00236-15 · 6.88 Impact Factor
  • Jacqueline M. Achkar, John Chan, Arturo Casadevall
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    ABSTRACT: Better understanding of the immunological components and their interactions necessary to prevent or control Mycobacterium tuberculosis (Mtb) infection in humans is critical for tuberculosis (TB) vaccine development strategies. Although the contributory role of humoral immunity in the protection against Mtb infection and disease is less defined than the role of T cells, it has been well-established for many other intracellular pathogens. Here we update and discuss the increasing evidence and the mechanisms of B cells and antibodies in the defense against Mtb infection. We posit that B cells and antibodies have a variety of potential protective roles at each stage of Mtb infection and postulate that such roles should be considered in the development strategies for TB vaccines and other immune-based interventions. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
    Immunological Reviews 03/2015; 264(1). DOI:10.1111/imr.12276 · 12.91 Impact Factor
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    ABSTRACT: Mycobacterium tuberculosis has evolved from a Mycobacterium canettii-like progenitor pool into one of the most successful and widespread human pathogens. The pathogenicity of M. tuberculosis is linked to its ability to secrete/export/release selected mycobacterial proteins, and it is also established that active release of mycobacterial antigens is a prerequisite for strong immune recognition. Recent research has enabled mycobacterial secretion systems and vesicle-based release of mycobacterial antigens to be elucidated, which together with host-related specificities constitute key variables that determine the outcome of infection. Here, we discuss recently discovered, novel aspects on the nature and the regulation of antigen release of the tuberculosis agent with particular emphasis on the biological characterization of mycobacteria-specific ESX/type VII secretion systems and their secreted proteins, belonging to the Esx, PE, and PPE categories. The importance of specific mycobacterial antigen release is probably best exemplified by the striking differences observed between the cellular events during infection with the ESX-1-deficient, attenuated Mycobacterium bovis BCG compared to the virulent M. tuberculosis, which are clearly important for design of more specific diagnostics and more efficient vaccines. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
    Immunological Reviews 03/2015; 264(1). DOI:10.1111/imr.12251 · 12.91 Impact Factor
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    Vincent Robert, Gianluigi Cardinali, Arturo Casadevall
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    ABSTRACT: From the viewpoint of fungal virulence in mammals, thermal tolerance can be defined as the ability to grow in the 35-40°C range, which is essential for inhabiting these hosts. We used archival information in a fungal collection to analyze the relationship between thermal tolerance and genetic background for over 4289 yeast strains belonging to 1054 species. Fungal genetic relationships were inferred from hierarchical trees based on pairwise alignments using the rRNA internal transcribed spacer (ITS) and large subunit rDNA (LSU) sequences. In addition, we searched for correlations between thermal tolerance and other archival information including antifungal susceptibility, carbon sources, and fermentative capacity. Thermal tolerance for growth at mammalian temperatures was not monophyletic with thermally tolerant species being interspersed among families that included closely related species that were not thermal tolerant. Thermal tolerance and resistance to antifungal drugs were not correlated suggesting that these two properties evolved independently. Nevertheless, the ability to grow at higher temperatures did correlate with origin from lower geographic latitudes, capacity for fermentation and assimilation of certain carbon sources. Thermal tolerance was significantly more common among ascomycetous than basidiomycetous yeasts, suggesting an explanation for the preponderance of ascomycetous yeasts among human pathogenic fungi. Analysis of strain maximum tolerable temperature as a function of collection time suggested that basidiomycetous yeasts are rapidly adapting to global warming. The analysis identified genera with a high prevalence of the thermal tolerant species that could serve as sources of emerging pathogenic fungi.
    BMC Biology 02/2015; 13(1):18. DOI:10.1186/s12915-015-0127-3 · 7.43 Impact Factor
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    ABSTRACT: Human infection with Cryptococcus neoformans, a common fungal pathogen, follows deposition of yeast spores in the lung alveoli. The subsequent host-pathogen interaction can result in eradication, latency, or extrapulmonary dissemination. Successful control of C. neoformans infection is dependent on host macrophages, but macrophages display little ability to kill C. neoformans in vitro. Recently, we reported that ingestion of C. neoformans by mouse macrophages induces early cell cycle progression followed by mitotic arrest, an event that almost certainly reflects host cell damage. The goal of the present work was to understand macrophage pathways affected by C. neoformans toxicity. Infection of macrophages by C. neoformans was associated with alterations in protein translation rate and activation of several stress pathways, such as hypoxia-inducing factor-1-α, receptor-interacting protein 1, and apoptosis-inducing factor. Concomitantly we observed mitochondrial depolarization in infected macrophages, an observation that was replicated in vivo. We also observed differences in the stress pathways activated, depending on macrophage cell type, consistent with the nonspecific nature of C. neoformans virulence known to infect phylogenetically distant hosts. Our results indicate that C. neoformans infection impairs multiple host cellular functions and undermines the health of these critical phagocytic cells, which can potentially interfere with their ability to clear this fungal pathogen. Copyright © 2015 by The American Association of Immunologists, Inc.
    The Journal of Immunology 02/2015; 194(5). DOI:10.4049/jimmunol.1402350 · 5.36 Impact Factor
  • Ferric C Fang, Arturo Casadevall
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    ABSTRACT: Science has always been a competitive undertaking. Despite recognition of the benefits of cooperation and team science, reduced availability of funding and jobs has made science more competitive than ever. Here we consider the benefits of competition in providing incentives to scientists and the adverse effects of competition on resource sharing, research integrity and creativity. The history of science shows that transformative discoveries often occur in the absence of competition, which only emerges once fields are established and goals are defined. Measures to encourage collaboration and ameliorate competition in the scientific enterprise are discussed. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Infection and Immunity 01/2015; 83(4). DOI:10.1128/IAI.02939-14 · 4.16 Impact Factor
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    Arturo Casadevall, Jo Handelsman
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    ABSTRACT: ABSTRACT We investigated the hypothesis that the gender of conveners at scientific meetings influenced the gender distribution of invited speakers. Analysis of 460 symposia involving 1,845 speakers in two large meetings sponsored by the American Society for Microbiology revealed that having at least one woman member of the convening team correlated with a significantly higher proportion of invited female speakers and reduced the likelihood of an all-male symposium roster. Our results suggest that inclusion of more women as conveners may increase the proportion of women among invited speakers at scientific meetings. IMPORTANCE The proportion of women entering scientific careers has increased substantially, but women remain underrepresented in academic ranks. Participation in meetings as a speaker is a factor of great importance for academic advancement. We found that having a woman as a convener greatly increased women's participation in symposia, suggesting that one mechanism for achieving gender balance at scientific meetings is to involve more women as conveners.
    mBio 12/2014; 5(1). DOI:10.1128/mBio.00846-13 · 6.88 Impact Factor
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    W Paul Duprex, Arturo Casadevall
    mBio 12/2014; 5(6). DOI:10.1128/mBio.02421-14 · 6.88 Impact Factor
  • Arturo Casadevall, Liise-anne Pirofski
    Nature 12/2014; 516(7530):165-6. DOI:10.1038/516165a · 42.35 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The role of lymphatic vessels is to transport fluid, soluble molecules, and immune cells to the draining lymph nodes. Here, we analyze how the aging process affects the functionality of the lymphatic collectors and the dynamics of lymph flow. Ultrastructural, biochemical, and proteomic analysis indicates a loss of matrix proteins, and smooth muscle cells in aged collectors resulting in a decrease in contraction frequency, systolic lymph flow velocity, and pumping activity, as measured in vivo in lymphatic collectors. Functionally, this impairment also translated into a reduced ability for in vivo bacterial transport as determined by time-lapse microscopy. Ultrastructural and proteomic analysis also indicates a decrease in the thickness of the endothelial cell glycocalyx and loss of gap junction proteins in aged lymph collectors. Redox proteomic analysis mapped an aging-related increase in the glycation and carboxylation of lymphatic's endothelial cell and matrix proteins. Functionally, these modifications translate into apparent hyperpermeability of the lymphatics with pathogen escaping from the collectors into the surrounding tissue and a decreased ability to control tissue fluid homeostasis. Altogether, our data provide a mechanistic analysis of how the anatomical and biochemical changes, occurring in aged lymphatic vessels, compromise lymph flow, tissue fluid homeostasis, and pathogen transport. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
    Aging Cell 12/2014; DOI:10.1111/acel.12330 · 5.71 Impact Factor
  • Arturo Casadevall, Liise-Anne Pirofski
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    ABSTRACT: Since proof of the germ theory of disease in the late 19(th) century a major focus of the fields of microbiology and infectious diseases has been to seek differences between pathogenic and non-pathogenic microbes and the role that the host plays in microbial pathogenesis. Remarkably, despite the increasing recognition that host immunity plays a role in microbial pathogenesis, there has been little discussion about what constitutes a host. Historically, hosts have been viewed in the context of their fitness or immunological status, and characterized by adjectives such as immune, immunocompetent, immunosuppressed, immunocompromised, or immunologically impaired. However, in recent years it has become apparent that the microbiota has profound effects on host homeostasis and susceptibility to microbial diseases in addition to its effects on host immunity. This raises the question of how to incorporate the microbiota into defining a host. This definitional problem is further complicated because neither host nor microbial properties are adequate to predict the outcome of host-microbe interaction because this outcome exhibits emergent properties. In this essay we revisit the 'damage-response framework' (DRF) of microbial pathogenesis and demonstrate how it can incorporate the rapidly accumulating information being generated by the microbiome revolution. We use the tenets of the DRF to put forth the following definition of a host: a host is an entity that houses an associated microbiome/microbiota and interacts with microbes such that the outcome results in damage, benefit, or indifference thus resulting in the states of symbiosis, colonization, commensalism, latency and disease.
    Infection and Immunity 11/2014; 83(1). DOI:10.1128/IAI.02627-14 · 4.16 Impact Factor

Publication Stats

22k Citations
3,615.91 Total Impact Points

Institutions

  • 2015
    • Johns Hopkins Bloomberg School of Public Health
      • W. Harry Feinstone Department of Molecular Microbiology and Immunology
      Baltimore, Maryland, United States
  • 2006–2015
    • Yeshiva University
      • • Albert Einstein College of Medicine
      • • Department of Microbiology & Immunology
      • • Division of Infectious Diseases
      • • Division of Nuclear Medicine
      New York, New York, United States
    • Institute for Transuranium Elements
      Carlsruhe, Baden-Württemberg, Germany
  • 1990–2015
    • Albert Einstein College of Medicine
      • • Department of Microbiology & Immunology
      • • Department of Pediatrics
      • • Infectious Diseases
      • • Department of Nuclear Medicine
      • • Department of Medicine
      • • Department of Cell Biology
      New York, New York, United States
  • 2007–2014
    • Federal University of Rio de Janeiro
      • • Instituto de Biofísica Carlos Chagas Filho (IBCCF)
      • • Institute of Biomedical Sciences
      • • Instituto de Microbiologia Professor Paulo de Góes (IMPPG)
      • • Instituto de Biologia (IB)
      Rio de Janeiro, Rio de Janeiro, Brazil
    • Trinity University of Asia
      Alfonso XIII, Mimaropa, Philippines
  • 2012
    • University of Coimbra
      • Faculty of Medicine
      Coímbra, Coimbra, Portugal
    • Istituto Superiore di Sanità
      Roma, Latium, Italy
    • AECOM
      Sandy, Utah, United States
  • 2008–2012
    • University of Washington Seattle
      Seattle, Washington, United States
    • University of Pittsburgh
      • Division of Infectious Diseases
      Pittsburgh, Pennsylvania, United States
    • Wayne State University
      • Department of Chemistry
      Detroit, Michigan, United States
    • City University of New York - Bronx Community College
      New York City, New York, United States
  • 2011
    • City University of New York - Bernard M. Baruch College
      • Department of Natural Sciences
      New York City, NY, United States
  • 2010
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
    • Albert Einstein Medical Center
      Filadelfia, Pennsylvania, United States
    • The Commonwealth Medical College
      • Department of Basic Sciences
      Scranton, PA, United States
  • 2009
    • Stony Brook University
      • Department of Medicine
      Stony Brook, NY, United States
  • 2004–2008
    • Cornell University
      • Department of Biological and Environmental Engineering
      Ithaca, New York, United States
    • All India Institute of Medical Sciences
      • Department of Microbiology
      New Delhi, NCT, India
  • 2006–2007
    • Department of Nuclear Medicine
      Nyitra, Nitriansky, Slovakia
  • 2005
    • Massachusetts General Hospital
      • Division of Infectious Diseases
      Boston, Massachusetts, United States
    • Worcester Polytechnic Institute
      • Department of Chemical Engineering
      Worcester, Massachusetts, United States
  • 2000–2003
    • Duke University Medical Center
      • • Department of Molecular Genetics and Microbiology
      • • Division of Infectious Diseases
      Durham, NC, United States
    • Venezuelan Institute for Scientific Research
      Caracas, Distrito Federal, Venezuela
    • Università degli studi di Parma
      Parma, Emilia-Romagna, Italy
  • 2001
    • The University of Manchester
      Manchester, England, United Kingdom
    • Long Island University
      • Department of Biology
      New York City, NY, United States
  • 1999
    • New York State
      New York City, New York, United States
  • 1995–1999
    • Georgia State University
      • Department of Chemistry
      Atlanta, Georgia, United States
  • 1998
    • University of Nevada School of Medicine
      Reno, Nevada, United States