I have participated in a drug discovery program designed to screen marine algae for inhibitors of cancer-related enzymes, antitumor compounds, antiinflammatory substances, and other agents of potential pharmaceutical utility. Over 1,500 lipid and aqueous extracts of marine plants and animals were surveyed for biomedical potential. Assays designed to screen extracts for new types of marine toxins have served to guide the isolation and identification of biologically active compounds. Extracts of the Oregon marine alga Constantinea simplex were found to contain a mixture of constanolactones, and lactonized cyclopropyl-containing oxylipin metabolites that logically derive from arachidonic and eicosapentaenoic acids. Spectroscopic analysis and chiroptical measurements of the natural products and various synthetically produced derivatives afforded the structures of seven structurally related compounds. Nakienones A-C and nakitriol, a series of reactive cytotoxic metabolites, were isolated from dead and necrotic branches of stony coral (Acropora sp.) which were completely covered with a gray-black mat of cyanobacteria (Synechocystis sp.). Their structures were determined spectroscopically by interpretation of 2D-NMR experiments, including heteronuclear multiple-bond coherence spectroscopy (HMBC) and 2-D nuclear Overhauser exchange spectroscopy (NOESY), and by comparison with model compounds. Bioassay-guided fractionation of the organic extract of a Curacao Lyngbya majuscula organic extract led to the isolation of an extremely potent brine shrimp toxin with antiproliferative activity. The structure of this new thiazoline ring-containing lipid, curacin A, was deduced from spectroscopic information and comparison of products obtained from chemical degradation of the natural product with the same substances prepared by synthesis. Curacin A is an antimitotic agent that inhibits microtubule assembly and the binding of colchicine to tubulin. In addition to curacin A, a potent new ichthyotoxic depsipeptide (antillatoxin), a new malyngamide derivative, and an unusual molluscicidal compound have been isolated from this alga. / Graduation date: 1995

Physiological traits that are biologically associated with feed efficiency may be useful indicator traits residual feed intake (RFI). The objective of this study was to examine the relationships between RFI, temperament, serum hormones and serum metabolites in growing heifers. A 4 yr study (n = 114-119 heifers/yr) was conducted with Brangus heifers (Initial BW = 271 ± 26 kg) that were weaned for 25.5 ± 8.6 d prior to high roughage diet adaptation (ME = 2.0 Mcal/kg DM). Individual dry matter intakes (DMI) were measured using Calan gate feeders and BW measured at 7-d intervals during the 70-d studies. RFI was calculated as the residual from the linear regression of DMI on mid-test BW0.75 and average daily gain (ADG). Temperament scores and exit velocity (EV) were taken at 0-d. Temperament index (TI) was calculated as the average of EV and chute score. On 0-d, blood samples were collected and assayed for partial blood counts (WBC, RBC, hemoglobin, HB), metabolites (total protein, TP; glucose; creatinine; blood urea nitrogen, BUN; β-hydroxybutyrate, BHB) and hormones (cortisol; insulin-like growth hormone I, IGF-I). Across all heifers, RFI was positively correlated with DMI (0.70) and feed:gain (0.59). Heifers with low RFI (< 0.5 SD from mean RFI 0.00 ± 0.71 kg/d) consumed 16 percent less DMI and had 16 percent lower feed:gain than heifers with high RFI (> 0.50 SD from mean RFI). RFI was weakly correlated (P < 0.05) with WBC (0.15), HB (-0.11), total protein (-0.10), BUN (0.10), creatinine (-0.11) and BHB (0.13). Hemoglobin and BHB were weakly correlated with all feed efficiency traits except feed conversion ratio (FCR). No phenotypic correlation was found between cortisol and IGF-I with RFI. Temperament was not correlated with RFI. Cortisol, creatinine and glucose were moderately correlated with all temperament traits. Low TI heifers (calm) had significantly higher Final BW, ADG and DMI than high TI heifers. Calm animals had significantly lower cortisol, HB, creatinine and glucose and higher BHB. These results suggest that the temperament and serum metabolites evaluated in this study have limited utility as indicator traits for RFI in growing heifers.

<p>Type 2 diabetes is characterized by insufficient insulin secretion to maintain euglycemia in the setting of peripheral insulin resistance. The majority of insulin-resistant diabetics are obese, yet not all insulin-resistant obese individuals develop diabetes. This obesity/diabetes dichotomy suggests that genetic factors play a pivotal role in disease pathogenesis.</p><p>Gene mapping has identified genetic quantitative trait loci (QTL) influencing disease-related phenotypes. To uncover molecular pathways leading from genotype to clinical trait, we classify phenotypes in greater depth and identify QTL that influence combinations of physiological traits, mRNA levels, and metabolite abundance. A major challenge then becomes deciphering the causal interrelationships among correlated phenotypes. </p><p>In this dissertation, we develop methods for building causal direction into an undirected network by including QTLs for each phenotype. We then apply and validate these methods in an F2 intercross between the diabetes-resistant C57BL/6 leptinob/ob (B6ob/ob) and the diabetes-susceptible BTBR leptinob/ob (BTBRob/ob) mouse strains. We show that genomic analysis can be integrated with liver transcriptional and metabolite profiling data to construct causal networks for specific metabolic processes in liver. This causal network construction led to the discovery of a pathway by which glutamine induces Phosphoenolpyruvate carboxykinase (Pck1) expression.</p><p>To investigate glutamine induction of Pck1 in the context of diabetes, we perform mRNA expression analysis and metabolic profiling in liver of the parental strains. We find glutamine is decreased with obesity in both strains; in the diabetes-resistant B6 strain, liver Pck1 expression parallels glutamine abundance, but in the diabetes-susceptible BTBR strain, Pck1 is elevated with obesity. Follow-up in vitro studies indicate that α-ketoglutarate, which is elevated nearly two fold in the livers of BTBR relative to B6 mice in vivo, may mediate the glutamine effect. We hypothesize that hepatic Pck1 is regulated by glutamine abundance in the liver of B6 animals, but in the presence of high α-ketoglutarate, Pck1 becomes uncoupled from glutamine regulation in the livers of diabetes-susceptible BTBR mice.</p><p>Our method of causal network construction led to the discovery of glutamine induction of a key hepatic gluconeogenic enzyme, a pathway potentially disrupted in the diabetes-susceptible BTBR mouse. Future studies will include identifying hepatic mediators of the glutamine effect, and applying QTL-directed networks to multiple organs to ultimately define causal relationships between tissues involved in diabetes progression.</p> / Dissertation

Many bacterial diseases were controlled by antibiotics since mid 1900s. However, over use of the drugs leads to the prevalence of resistant strains, some of them are resistant to essentially all of the commercial antibiotics except for one or two. Therefore, new drugs are needed to combat the die-hard resistant pathogens. This study is aimed at isolating bacteria with antimicrobial activities from the intertidal soils of Taiwan. A total of 25 samples were collected from 5 locations, including Peng-Hu, Da-Peng Bay, Ken-ding, Gueishan Island and Little Liu-chiu. Marine Agar 2216 and Actinomycete Isolation Agar were used for cultivation. Of 313 bacterial isolated, 47 of them showed antimicrobial activities against at least one of the 7 indicators (Bacillus cereus, Staphylococcus aureus, Klebsiella pneumonia, Salmonella typhimurium, Pseudomonas aeruginosa, Vibrio harveyi, Escherichia coli). The 47 strains were classified based on 16S rRNA phylogeny. The majority of them are Pseudoalteromonas spp. (31) and Bacillus spp. (9) as well as Virgibacillus sp. (1), Vibrio sp. (1), Streptomyces sp. (1) and Microbulbifer spp. (4). Over all, 10/47 are Gram positive and 37/47 require added salts for growth. The titers of antimicrobial substances as judged by ethyl acetate extraction were influenced by cultivation conditions, such as: growth temperature, types of media and time.

Thesis (Ph. D.)--University of Hawaii at Manoa, 2003. / Includes bibliographical references (leaves 190-210). Also available via World Wide Web.

Thesis (Ph. D.)--University of Hawaii at Manoa, 2003. / Includes bibliographical references (leaves 190-210).

Thesis (M.S.)--University of North Carolina at Wilmington, 2003. / Includes bibliographical references (leaves : 63-66).

Not available / text

The project focused on the isolation, characterization and synthesis of secondary metabolites of Gunnera perpensa L. (Gunneraceae), a South African medicinal plant used by many South African women to induce or augment labour and as an antenatal medication to tone the uterus. From the methanol extracts of the rhizomes we have isolated the compounds Z-venusol, methyl lespedezate, 4-6>-/?-D-glucopyranosyl-3,3',4'-tri-0- methylellagic acid and punicallagin. Structural elucidation of the compounds was performed using NMR spectroscopy. The presence of ellagic acid derivatives and hydrolysable tannins have not previously been reported from the family Gunneraceae. The study also focuses on the development of an HPLC analytical method to fingerprint the crude extracts of G perpensa. This method was used to determine the chemical composition of the rhizomes of the G. perpensa collected in different parts of South Africa. It is clear from the HPLC study that the rhizomes contain large concentrations of the hydrolysable tannin punicalagin and the second most abundant metabolite was Z-venusol. However, it was observed from plants collected in different regions that the ratio between punicalagin and Z-venusol differs substantially in the different extracts. An ellagic acid derivative isolated from G. perpensa contains a biaryl structure derived from gallic acid. The synthesis described in this thesis focused on reaction methods to access unsymmetrical biaryls and two synthetic routes were investigated - one that relies on the Ullmann reaction and the second that uses the Heck coupling reaction. Success of this coupling reaction towards the formation of ellagic acid derivatives was accomplished by the Heck coupling reaction method. One of the most important considerations towards the synthesis was the manipulation of hydroxyl groups of gallic acid by selective protection reactions that provide entry to the aforementioned preparation of unsymmetrical ellagic acid derivatives. / Thesis (Ph.D.)-University of KwaZulu-Natal, Pietermaritzburg, 2007.

The work undertaken explored the potential for discovery of new bioactive metabolites from soil fungi. The research developed selective mycological isolation techniques and maximised metabolite production from active selected fungi by application of the OSMAC approach and concept of hormesis. Novel active compounds were discovered and many other known compounds characterised.