Biomedical subjects

Gordon D Brown

Publications and source records attributed to Gordon D Brown.

At least 37 records · Page 2Linked to original sources

PubMed2005

Dectin-2 is predominantly myeloid restricted and exhibits unique activation-dependent expression on maturing inflammatory monocytes elicited in vivo.

Dectin-2 is a recently described dendritic-cell-associated receptor, suggested to be involved in the initiation and maintenance of UV-induced tolerance. To understand the physiological relevance of the proposed functions of this C-type lectin-like receptor, we have generated monoclonal antibodies against its extracellular domain and performed a detailed study of its expression. In naive mice, Dectin-2 has a novel distribution pattern compared with other myeloid markers, but is predominantly expressed by a wide variety of tissue macrophages. Its expression was limited on dendritic cells and notably absent from brain microglia and choroid plexus or meningeal macrophages. On peripheral blood monocytes, Dectin-2 expression was very low on the surface but was transiently and markedly up-regulated on induction of inflammation in vivo using a variety of stimuli. This change in Dectin-2 expression occurs on 'inflammatory' monocytes after arrival at the inflammatory lesion as demonstrated by adoptive cell-transfer studies, and is independent of whether the macrophages elicited by the stimuli ultimately expressed Dectin-2. These observations show Dectin-2 expression to be characteristic of monocyte activation/maturation at an inflammatory lesion and provide a new perspective on the interpretation of Dectin-2 function in vivo.

Adoptive Transfer↗

PubMed2005

Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins.

Pattern-recognition receptors (PRRs) detect molecular signatures of microbes and initiate immune responses to infection. Prototypical PRRs such as Toll-like receptors (TLRs) signal via a conserved pathway to induce innate response genes. In contrast, the signaling pathways engaged by other classes of putative PRRs remain ill defined. Here, we demonstrate that the beta-glucan receptor Dectin-1, a yeast binding C type lectin known to synergize with TLR2 to induce TNF alpha and IL-12, can also promote synthesis of IL-2 and IL-10 through phosphorylation of the membrane proximal tyrosine in the cytoplasmic domain and recruitment of Syk kinase. syk-/- dendritic cells (DCs) do not make IL-10 or IL-2 upon yeast stimulation but produce IL-12, indicating that the Dectin-1/Syk and Dectin-1/TLR2 pathways can operate independently. These results identify a novel signaling pathway involved in pattern recognition by C type lectins and suggest a potential role for Syk kinase in regulation of innate immunity.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Dectin-1 escape by fungal dimorphism.

Candida albicans, a medically important fungus, exists primarily as yeast and filamentous forms. Its cell wall is rich in beta-glucans, which are recognized by a lectin-like innate immune receptor, Dectin-1. A recent study shows that exposure of glucan, by yeasts but not filaments, determines Dectin-1-dependent uptake by macrophages, and thus represents a novel immune evasion mechanism. Here, we discuss the insights these results provide in relation to macrophage interactions with C. albicans and pathogen entry.

Animals↗

PubMed2005

Immune recognition of fungal beta-glucans.

The recognition of conserved microbial structures is a key aspect of metazoan immunity, and beta-glucans are emerging as a major target for the recognition of fungal pathogens. A number of receptors for these carbohydrates have been identified, which upon recognition, trigger a variety of immune responses. In contrast to many other systems, there is little apparent conservation in these mechanisms between vertebrates and invertebrates. In this review, we will highlight all the known receptors for beta-glucans and will discuss the various immune responses they can initiate, with reference to fungal infection, in both vertebrates and invertebrates.

Animals↗

PubMed2005

Innate immunity to the pathogenic fungus Coccidioides posadasii is dependent on Toll-like receptor 2 and Dectin-1.

Coccidioides posadasii is a pathogenic fungus that causes endemic and epidemic coccidioidomycosis in the deserts of North, Central, and South America. How the innate immune system responds to the organism is not well understood. Here we show that elicited mouse peritoneal macrophages respond to spherules (the tissue form of the fungus) by producing proinflammatory cytokines as measured by quantitative PCR of cellular transcripts and by enzyme-linked immunosorbent assay (ELISA) assays for secreted protein. We examined the contribution of Toll-like receptors (TLR) and MyD88 in macrophage responses to formalin-killed spherules (FKS) by comparing cytokine responses of elicited macrophages from different knockout mice. FKS were added to elicited mouse peritoneal macrophages from wild-type, TLR2-/-, and MyD88-/- cells, and wild-type cells made more tumor necrosis factor alpha, MIP-2, and interleukin 6 than did the mutant macrophages. In contrast, the C3H/HeJ mice, which have a point mutation in TLR4, and TLR4-/- B6 mice exhibited no defect in cytokine production compared to the control mice. We also investigated the role of the macrophage beta-glucan receptor, Dectin-1. RAW 264.7 macrophages overexpressing Dectin-1 produced more cytokines in respond to FKS, live spherules, and purified beta-glucan than did control RAW cells. Blockage of Dectin-1 with antibodies inhibited cytokine production in elicited mouse peritoneal macrophages. Taken together, these results show that cytokine responses in mouse peritoneal macrophages to C. posadasii spherules are dependent on TLR2, MyD88, and Dectin-1.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Executive management studies: the application of real-time science in health administration education.

While sound scientific research, such as randomized controlled trials (RCTs), has produced findings leading to significant gains in healthcare, real-time science learning gives administrators and providers a way of responding to immediate need and rapid change while improving performance and the quality of care delivered. Real-time science learning is a cycle of team reflection on and exchange of theory and practical knowledge that produces many benefits for the individual, the organization, and the healthcare field. By questioning principles and analyzing information, teams generate recommendations for organizational improvement as well as develop their individual abilities to address other unforeseen demands in differentcontexts. All of this serves as a foundation for more rigorous scientific research that leads to the advancement of the healthcare field. This article shows how the Department of Health Management and Informatics at the University of Missouri-Columbia adapted real-time science into the Executive Management Study (EMS) requirement of the Master of Health Administration (M.H.A.) and the Master of Science in Health Informatics (M.S.) curriculums. The process is represented by a cycle of Health Administration Education, experienced through a Practical Application, which leads to the creation and dissemination of information and Research Advancing the Field.

Curriculum↗

PubMed2005

Assessing communications effectiveness in meeting corporate goals of public health organizations.

Much evaluation of health communications in public health is considered from a program perspective of smoking cessation, weight reduction, education on sexually transmitted diseases, etc. These studies have advanced the knowledge base of communications theory and evaluation and have contributed to program effectiveness. In program-based evaluation the communications process is structured as part of the program itself. This article extends program-based communications evaluation to view communications from the perspective of the consumer and how effectively public health departments respond to consumer expectations. It develops a conceptual model for evaluating elements of communications such as its importance in defining mission and goals within the community, managing strategic constituencies, and enlisting individuals and groups as customers and co-producers of health. It gives a broader perspective on how communications in public heath organizations are managed and a basis for assessing whether they are being managed effectively.

Communication↗

PubMed2004

A comprehensive survey of the genes involved in maturation and development of the rainbow trout ovary.

Development and maturation of the ovary requires precisely coordinated expression of specific gene classes to produce viable oocytes. We undertook identification of some of the genes involved in these processes by creating ovary-specific cDNA libraries by suppression subtractive hybridization and by microarray-based analyses. We present 5778 tissue- and sex-specific genes from subtracted ovary and testis libraries, many of which remain unidentified. A microarray containing 3557 salmonid cDNAs was used to compare the transcriptomes of precocious ovary at three different stages during the second year of life with a reference (normal ovary) transcriptome. On average, approximately 240 genes were developmentally regulated during the study period from June to October. Classes of genes maintaining relatively steady-state levels of expression, such as those controlling tissue remodeling, immunoregulation, cell-cycle progression, apoptosis, and growth also were identified. Concurrent expression of various cell division and ubiquitin-mediated proteolysis regulators revealed the utility of microarray analysis to monitor important maturation events. We also report unequivocal evidence for expression of the transcripts that encode the common glycoprotein alpha, LH beta, FSH beta, thyroid-stimulating hormone beta, and retinol-binding protein in both the ovary and testis of trout.

Age Factors↗

PubMed2004

Microarray analyses identify molecular biomarkers of Atlantic salmon macrophage and hematopoietic kidney response to Piscirickettsia salmonis infection.

Piscirickettsia salmonis is the intracellular bacterium that causes salmonid rickettsial septicemia, an infectious disease that kills millions of farmed fish each year. The mechanisms used by P. salmonis to survive and replicate within host cells are not known. Piscirickettsiosis causes severe necrosis of hematopoietic kidney. Microarray-based experiments with QPCR validation were used to identify Atlantic salmon macrophage and hematopoietic kidney genes differentially transcribed in response to P. salmonis infection. Infections were confirmed by microscopy and RT-PCR with pathogen-specific primers. In infected salmon macrophages, 71 different transcripts were upregulated and 31 different transcripts were downregulated. In infected hematopoietic kidney, 30 different transcripts were upregulated and 39 different transcripts were downregulated. Ten antioxidant genes, including glutathione S-transferase, glutathione reductase, glutathione peroxidase, and cytochrome b558 alpha- and beta-subunits, were upregulated in infected macrophages but not in infected hematopoietic kidney. Changes in redox status of infected macrophages may allow these cells to tolerate P. salmonis infection, raising the possibility that treatment with antioxidants may reduce hematopoietic tissue damage caused by this rickettsial infection. The downregulation of transcripts involved in adaptive immune responses (e.g., T cell receptor alpha-chain and C-C chemokine receptor 7) in infected hematopoietic kidney but not in infected macrophages may contribute to infection-induced kidney tissue damage. Molecular biomarkers of P. salmonis infection, characterized by immune-relevant functional annotations and high fold differences in expression between infected and noninfected samples, may aid in the development of anti-piscirickettsial vaccines and therapeutics.

Animals↗

PubMed2004

Dectin-1 uses novel mechanisms for yeast phagocytosis in macrophages.

The phagocytosis of pathogens is a critical event in host defense, not only for clearance of the invading microorganism, but also for the subsequent immune response. We have examined Dectin-1, a proinflammatory nonopsonic receptor for beta-glucans, and show that it mediates the internalization of beta-glucan-bearing ligands, including yeast particles. Although requiring tyrosine phosphorylation and the cytoplasmic immunoreceptor tyrosine-based activation motif (ITAM)-like motif, uptake mediated by Dectin-1 was different from any previously reported phagocytic receptor and was not dependent on Syk-kinase in macrophages. Furthermore, intracellular trafficking of this receptor was influenced by the nature of the beta-glucan ligand, which has significance for the biologic activity of these immunomodulatory carbohydrates.

3T3 Cells↗

PubMed2004

Loss of cell wall mannosylphosphate in Candida albicans does not influence macrophage recognition.

The outer layer of the cell wall of the human pathogenic fungus Candida albicans is enriched with heavily mannosylated glycoproteins that are the immediate point of contact between the fungus and cells of the host, including phagocytes. Previous work had identified components of the acid-labile fraction of N-linked mannan, comprising beta-1,2-linked mannose residues attached via a phosphodiester bond, as potential ligands for macrophage receptors and modulators of macrophage function. We therefore isolated and disrupted the CaMNN4 gene, which is required for mannosyl phosphate transfer and hence the attachment of beta-1,2 mannose oligosaccharides to the acid-labile N-mannan side chains. With the mannosylphosphate eliminated, the mnn4Delta null mutant was unable to bind the charged cationic dye Alcian Blue and was devoid of acid-labile beta-1,2-linked oligomannosaccharides. The mnn4Delta mutant was unaffected in cell growth and morphogenesis in vitro and in virulence in a murine model of systemic C. albicans infection. The null mutant was also not affected in its interaction with macrophages. Mannosylphosphate is therefore not required for macrophage interactions or for virulence of C. albicans.

Alcian Blue↗

PubMed2004

Expression of the beta-glucan receptor, Dectin-1, on murine leukocytes in situ correlates with its function in pathogen recognition and reveals potential roles in leukocyte interactions.

Dectin-1 is a pathogen-recognition receptor on macrophages (MPhis), neutrophils, and dendritic cells (DCs). On MPhis and bone marrow-derived DCs, it has been shown to mediate the nonopsonic recognition of and response to soluble and particulate yeast beta-glucans. We have optimized the immunohistochemical detection of Dectin-1 and demonstrated its expression on neutrophils, subpopulations of MPhis in splenic red and white pulp, alveolar MPhis, Kupffer cells, and MPhis and DCs in the lamina propria of gut villi. This is consistent with its role in pathogen surveillance. A significant proportion of CD11c(+) splenic DCs expressed Dectin-1, but expression was not restricted to any one subset. Dectin-1 expression was low on resident MPhis and DCs of skin and was not detected on resident MPhis or DCs in kidney, heart, brain, or eye. The proposed, additional role of Dectin-1 as a coreceptor for T cell activation is supported by its expression on DCs in the T cell areas of the spleen and lymph nodes. Strong expression of Dectin-1 on subpopulations of MPhis and DCs in the medullary and corticomedullary regions of the thymus suggests a role distinct from pathogen recognition. Tissue localization thus revealed potential roles of Dectin-1 in leukocyte interactions during innate immune responses and T cell development.

Age Factors↗

PubMed2004

Development and application of a salmonid EST database and cDNA microarray: data mining and interspecific hybridization characteristics.

We report 80,388 ESTs from 23 Atlantic salmon (Salmo salar) cDNA libraries (61,819 ESTs), 6 rainbow trout (Oncorhynchus mykiss) cDNA libraries (14,544 ESTs), 2 chinook salmon (Oncorhynchus tshawytscha) cDNA libraries (1317 ESTs), 2 sockeye salmon (Oncorhynchus nerka) cDNA libraries (1243 ESTs), and 2 lake whitefish (Coregonus clupeaformis) cDNA libraries (1465 ESTs). The majority of these are 3' sequences, allowing discrimination between paralogs arising from a recent genome duplication in the salmonid lineage. Sequence assembly reveals 28,710 different S. salar, 8981 O. mykiss, 1085 O. tshawytscha, 520 O. nerka, and 1176 C. clupeaformis putative transcripts. We annotate the submitted portion of our EST database by molecular function. Higher- and lower-molecular-weight fractions of libraries are shown to contain distinct gene sets, and higher rates of gene discovery are associated with higher-molecular weight libraries. Pyloric caecum library group annotations indicate this organ may function in redox control and as a barrier against systemic uptake of xenobiotics. A microarray is described, containing 7356 salmonid elements representing 3557 different cDNAs. Analyses of cross-species hybridizations to this cDNA microarray indicate that this resource may be used for studies involving all salmonids.

Animals↗

PubMed2004

Identification and characterization of a novel human myeloid inhibitory C-type lectin-like receptor (MICL) that is predominantly expressed on granulocytes and monocytes.

Inhibitory and activatory C-type lectin-like receptors play an important role in immunity through the regulation of leukocytes. Here, we report the identification and characterization of a novel myeloid inhibitory C-type lectin-like receptor (MICL) whose expression is primarily restricted to granulocytes and monocytes. This receptor, which contains a single C-type lectin-like domain and a cytoplasmic immunoreceptor tyrosine-based inhibitory motif, is related to LOX-1 (lectin-like receptor for oxidized low density lipoprotein-1) and the beta-glucan receptor (Dectin-1) and is variably spliced and highly N-glycosylated. We demonstrate that it preferentially associates with the signaling phosphatases SHP-1 and SHP-2, but not with SHIP. Novel chimeric analyses with a construct combining MICL and the beta-glucan receptor show that MICL can inhibit cellular activation through its cytoplasmic immunoreceptor tyrosine-based inhibitory motif. These data suggest that MICL is a negative regulator of granulocyte and monocyte function.

Alternative Splicing↗

PubMed2004

The role of SIGNR1 and the beta-glucan receptor (dectin-1) in the nonopsonic recognition of yeast by specific macrophages.

We recently demonstrated that the beta-glucan receptor Dectin-1 (betaGR) was the major nonopsonic beta-glucan receptor on macrophages (Mphi) for the yeast-derived particle zymosan. However, on resident peritoneal Mphi, we identified an additional mannan-inhibitable receptor for zymosan that was distinct from the Mphi mannose receptor (MR). In this study, we have studied the mannose-binding potential of murine Mphi and identified the dendritic cell-specific ICAM-3-grabbing nonintegrin homolog, SIGN-related 1 (SIGNR1), as a major MR on murine resident peritoneal Mphi. Both SIGNR1 and betaGR cooperated in the nonopsonic recognition of zymosan by these Mphi. When SIGNR1 was introduced into NIH3T3 fibroblasts or RAW 264.7 Mphi, it conferred marked zymosan-binding potential on these cells. However, in the nonprofessional phagocytes (NIH3T3), SIGNR1 was found to be poorly phagocytic, suggesting that other receptors such as betaGR may play a more dominant role in particle internalization on professional phagocytes. Binding of zymosan to RAW 264.7 Mphi expressing SIGNR1 resulted in TNF-alpha production. Treatment of RAW 264.7 Mphi expressing SIGNR1, which express low levels of betaGR, with beta-glucans had little effect on binding or TNF-alpha production, indicating that there was no absolute requirement for betaGR in this process. These studies have identified SIGNR1 as a major MR for fungal and other pathogens present on specific subsets of Mphi.

Animals↗

PubMed2004

Dectin-1 and its role in the recognition of beta-glucans by macrophages.

beta-Glucans are well known leukocyte activators that have shown protective benefits in a variety of animal disease models, yet the mechanism of action of these carbohydrates remains unknown. We have shown that Dectin-1, a murine type II C-type lectin-like receptor, was able to non-opsonically recognize beta-1,3 and beta-1,6 linked glucan rich particles and intact yeast. Dectin-1 is widely expressed in murine tissues, particularly on the monocyte/macrophage and neutrophil lineages, on dendritic cells (DC) and at a lower level on a sub-population of T cells. The human homologue of Dectin-1 was identified and is functionally similar to the murine molecule. Human Dectin-1 differs from the murine molecule in that it is expressed as two major splice variants that are selectively expressed in particular leukocyte populations. In addition to beta-glucans, Dectin-1 also recognizes an endogenous ligand on T cells. The ligand and the immunological role of Dectin-1 mediated T cell interactions remain to be described.

Animals↗

PubMed2004

Design of a peer-to-peer telerehabilitation model.

PURPOSE: To describe the design and development process for an information network that meets the complex needs for information exchange by persons with disabilities. This paper describes the needs assessment and design processes that drove the selection of specific system features, and discusses the range of entities with whom persons with disabilities must exchange information. The authors delineate the design goals and their associated specifications for a network of local resource information that serves the needs of persons with disabilities. A model program has been specified and is currently under development. It will enable users to exchange personal, health, and resource information with service entities and with other members of the disability community who depend on detailed information to support their performance of everyday tasks. As an outcome this activity, a highly portable, replicable, sustainable, scalable, and secure model of consumer-driven information exchange will become available to persons with disabilities and to those who provide services to them. The impact of this system will be amplified when it is launched and replicated in interested communities nationwide.

Persons with Disabilities↗

PubMed2004

The potential for Toll-like receptors to collaborate with other innate immune receptors.

Cells of the innate immune system express a large repertoire of germ-line encoded cell-surface glycoprotein receptors including Toll-like receptors (TLRs). TLRs recognize conserved motifs on microbes and induce inflammatory signals. Evidence suggests that individual members of the TLR family or other non-TLR surface antigens either physically or functionally interact with each other and cumulative effects of these interactions instruct the nature and outcome of the immune response to a particular pathogen.

Humans↗