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ItemAn interactive visualization tool and data model for experimental design in systems biology(Georgia Institute of Technology, 2008-08) Kapoor, Shray ; Quo, Chang Feng ; Merrill, Alfred H. ; Wang, May DongmeiExperimental design is important, but is often under-supported, in systems biology research. To improve experimental design, we extend the visualization of complex sphingolipid pathways to study biosynthetic origin in SphinGOMAP. We use the ganglio-series sphingolipid dataset as a test bed and the Java Universal Network / Graph Framework (JUNG) visualization toolkit. The result is an interactive visualization tool and data model for experimental design in lipid systems biology research. We improve the current SphinGOMAP in terms of interactive visualization by allowing (i) choice of four different network layouts, (ii) dynamic addition / deletion of on-screen molecules and (iii) mouse-over to reveal detailed molecule data. Future work will focus on integrating various lipid-relevant data systematically i.e. SphinGOMAP biosynthetic data, Lipid Bank molecular data (Japan) and Lipid MAPS metabolic pathway data (USA). We aim to build a comprehensive and interactive communication platform to improve experimental design for scientists globally in high-throughput lipid systems biology research.
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ItemComputational modeling of a metabolic pathway in ceramide de novo synthesis(Georgia Institute of Technology, 2007-08) Dhingra, Shobhika ; Freedenberg, Melissa ; Quo, Chang Feng ; Merrill, Alfred H. ; Wang, May DongmeiStudies have implicated ceramide as a key molecular agent in regulating programmed cell death, or apoptosis. Consequently, there is significant potential in targeting intracellular ceramide as a cancer therapeutic agent. The cell’s major ceramide source is the ceramide de novo synthesis pathway, which consists of a complex network of interdependent enzyme-catalyzed biochemical reactions. To understand how ceramide works, we have initiated the study of the ceramide de novo synthesis pathway using computational modeling based on fundamental principles of biochemical kinetics. Specifically, we designed and developed the model in MATLAB SIMULINK for the behavior of dihydroceramide desaturase. Dihydroceramide desaturase is one of three key enzymes in the ceramide de novo synthesis pathway, and it converts a relatively inert precursor molecule, dihydroceramide into biochemically reactive ceramide. A major issue in modeling is parameter estimation. We solved this problem by adopting a heuristic strategy based on a priori knowledge from literature and experimental data. We evaluated model accuracy by comparing the model prediction results with interpolated experimental data. Our future work includes more experimental validation of the model, dynamic rate constants assessment, and expansion of the model to include additional enzymes in the ceramide de novo synthesis pathway.
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ItemLMSD: LIPID MAPS structure database(Georgia Institute of Technology, 2006-11-10) Sud, Manish ; Fahy, Eoin ; Cotter, Dawn ; Brown, Alex ; Dennis, Edward A. ; Glass, Christopher K. ; Merrill, Alfred H. ; Murphy, Robert C. ; Raetz, Christian R. H. ; Russell, David W. ; Subramaniam, ShankarThe LIPID MAPS Structure Database (LMSD) is a relational database encompassing structures and annotations of biologically relevant lipids. Structures of lipids in the database come from four sources: (i) LIPID MAPS Consortium’s core laboratories and partners; (ii) lipids identified by LIPID MAPS experiments; (iii) computationally generated structures for appropriate lipid classes; (iv) biologically relevant lipids manually curated from LIPID BANK, LIPIDAT and other public sources. All the lipid structures in LMSD are drawn in a consistent fashion. In addition to a classification-based retrieval of lipids, users can search LMSD using either textbased or structure-based search options. The textbased search implementation supports data retrieval by any combination of these data fields: LIPID MAPS ID, systematic or common name, mass, formula, category, main class, and subclass data fields. The structure-based search, in conjunction with optional data fields, provides the capability to perform a substructure search or exact match for the structure drawn by the user. Search results, in addition to structure and annotations, also include relevant links to external databases. The LMSD is publicly available at www.lipidmaps.org/data/structure/
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ItemGlucosylceramide synthase is an essential regulator of pathogenicity of Cryptococcus neoformans(Georgia Institute of Technology, 2006-06) Rittershaus, Philipp C. ; Kechichian, Talar B. ; Allegood, Jeremy C. ; Merrill, Alfred H. ; Hennig, Mirko ; Luberto, Chiara ; Del Poeta, MaurizioThe pathogenic fungus Cryptococcus neoformans infects humans upon inhalation and causes the most common fungal meningoencephalitis in immunocompromised subjects worldwide. In the host, C. neoformans is found both intracellularly and extracellularly, but how these two components contribute to the development of the disease is largely unknown. Here we show that the glycosphingolipid glucosylceramide (GlcCer), which is present in C. neoformans, was essential for fungal growth in host extracellular environments, such as in alveolar spaces and in the bloodstream, which are characterized by a neutral/alkaline pH, but not in the host intracellular environment, such as in the phagolysosome of macrophages, which is characteristically acidic. Indeed, a C. neoformans mutant strain lacking GlcCer did not grow in vitro at a neutral/alkaline pH, yet it had no growth defect at an acidic pH. The mechanism by which GlcCer regulates alkali tolerance was by allowing the transition of C. neoformans through the cell cycle. This study establishes C. neoformans GlcCer as a key virulence factor of cryptococcal pathogenicity, with important implications for future development of new antifungal strategies
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ItemExposure to fumonisins and the occurrence of neural tube defects along the Texas-Mexico border(Georgia Institute of Technology, 2005-09-25) Missmer, Stacey A. ; Suarez, Lucina ; Felkner, Marilyn ; Wang, Elaine ; Merrill, Alfred H. ; Rothman, Kenneth J. ; Hendricks, Katherine A.Along the Texas-Mexico border, the prevalence of neural tube defects (NTDs) among Mexican-American women doubled during 1990-1991. The human outbreak began during the same crop year as epizootics attributed to exposure to fumonisin, a mycotoxin that often contaminates corn. Because Mexican Americans in Texas consume large quantities of corn, primarily in the form of tortillas, they may be exposed to high levels of fumonisins. We examined whether or not maternal exposure to fumonisins increases the risk of NTDs in offspring using a population-based casecontrol study. We estimated fumonisin exposure from a postpartum sphinganine:sphingosine (sa:so) ratio, a biomarker for fumonisin exposure measured in maternal serum, and from maternal recall of periconceptional corn tortilla intake. After adjusting for confounders, moderate (301400) compared with low 100) consumption of tortillas during the first trimester was associated with increased odds ratios (ORs) of having an NTD-affected pregnancy (OR = 2.4; 95% confidence interval, 1.15.3). No increased risks were observed at intakes higher than 400 tortillas (OR = 0.8 for 401800, OR = 1.0 for > 800). Based on the postpartum sa:so ratio, increasing levels of fumonisin exposure were associated with increasing ORs for NTD occurrences, except for the highest exposure category (sa:so > 0.35). Our findings suggest that fumonisin exposure increases the risk of NTD, proportionate to dose, up to a threshold level, at which point fetal death may be more likely to occur. These results also call for population studies that can more directly measure individual fumonisin intakes and assess effects on the developing embryo.
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ItemDynamic pathway modeling of sphingolipid metabolism(Georgia Institute of Technology, 2004-09) Henning, Peter A. ; Merrill, Alfred H. ; Wang, May DongmeiWe report our research results on computational metabolome study. The goal of this research is to extend the integrated experimental modeling methodologies in sphingolipid metabolism study to other complex biological process studies such as signal transduction or gene regulation. Another feature of this work is that the 3-D information representation enables the user orchestrate the simulated pathways in real time.