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Biomedical subjects

David Savage

Publications and source records attributed to David Savage.

10 recordsLinked to original sources
PubMed2006

SSRPrimer and SSR Taxonomy Tree: Biome SSR discovery.

Simple sequence repeat (SSR) molecular genetic markers have become important tools for a broad range of applications such as genome mapping and genetic diversity studies. SSRs are readily identified within DNA sequence data and PCR primers can be designed for their amplification. These PCR primers frequently cross amplify within related species. We report a web-based tool, SSR Primer, that integrates SPUTNIK, an SSR repeat finder, with Primer3, a primer design program, within one pipeline. On submission of multiple FASTA formatted sequences, the script screens each sequence for SSRs using SPUTNIK. Results are then parsed to Primer3 for locus specific primer design. We have applied this tool for the discovery of SSRs within the complete GenBank database, and have designed PCR amplification primers for over 13 million SSRs. The SSR Taxonomy Tree server provides web-based searching and browsing of species and taxa for the visualisation and download of these SSR amplification primers. These tools are available at http://bioinformatics.pbcbasc.latrobe.edu.au/ssrdiscovery.html.

Classification↗
PubMed2006

Non-DNA binding, dominant-negative, human PPARgamma mutations cause lipodystrophic insulin resistance.

PPARgamma is essential for adipogenesis and metabolic homeostasis. We describe mutations in the DNA and ligand binding domains of human PPARgamma in lipodystrophic, severe insulin resistance. These receptor mutants lack DNA binding and transcriptional activity but can translocate to the nucleus, interact with PPARgamma coactivators and inhibit coexpressed wild-type receptor. Expression of PPARgamma target genes is markedly attenuated in mutation-containing versus receptor haploinsufficent primary cells, indicating that such dominant-negative inhibition operates in vivo. Our observations suggest that these mutants restrict wild-type PPARgamma action via a non-DNA binding, transcriptional interference mechanism, which may involve sequestration of functionally limiting coactivators.

DNA↗
PubMed2005

Activation of the farnesoid X receptor improves lipid metabolism in combined hyperlipidemic hamsters.

The transcription factor farnesoid X receptor (FXR) has recently been implicated in the control of hepatic triglyceride production. Activation of FXR may ameliorate hypertriglyceridemia, a cardinal feature of the metabolic syndrome. Because hamsters share many characteristic features of human lipid metabolism, we used a high-fructose-fed hamster model to study the impact of FXR activation with chenodeoxycholic acid (CDCA) on plasma lipoprotein metabolism. Male Syrian hamsters fed a diet containing 60% kcal from fructose for 2 wk developed hypertriglyceridemia and hypercholesterolemia (+120 and +60%, P = 0.005 and 0.0004 vs. controls) due to increased hepatic lipoprotein production. This could be largely attributed to enhanced hepatic de novo lipogenesis, as indicated by increased expression of sterol regulatory element-binding protein-1, fatty acid synthase, and steaoryl-CoA desaturase-1. Lipoprotein analysis demonstrated that the increase in plasma triglycerides occurred in the VLDL density range, whereas increases in VLDL, IDL/LDL, and HDL cholesterol accounted for the elevated plasma cholesterol concentrations. Addition of 0.1% CDCA to the high-fructose diet decreased hepatic de novo lipogenesis and consequently triglyceride production and prevented the increases in plasma triglycerides and cholesterol (-40 and -18%, P = 0.03 and 0.03 vs. high fructose-fed animals). CDCA-treated animals had lower VLDL triglycerides and decreased VLDL and IDL/LDL cholesterol plasma concentrations. These data demonstrate that activation of FXR with CDCA effectively lowers plasma triglyceride and cholesterol concentrations, mainly by decreasing de novo lipogenesis and hepatic secretion of triglyceride-rich lipoproteins. Our studies identify activators of FXR as promising new tools in the therapy of hypertriglyceridemic states, including the insulin resistance syndrome and type 2 diabetes.

Animals↗
PubMed2005

SNPServer: a real-time SNP discovery tool.

SNPServer is a real-time flexible tool for the discovery of SNPs (single nucleotide polymorphisms) within DNA sequence data. The program uses BLAST, to identify related sequences, and CAP3, to cluster and align these sequences. The alignments are parsed to the SNP discovery software autoSNP, a program that detects SNPs and insertion/deletion polymorphisms (indels). Alternatively, lists of related sequences or pre-assembled sequences may be entered for SNP discovery. SNPServer and autoSNP use redundancy to differentiate between candidate SNPs and sequence errors. For each candidate SNP, two measures of confidence are calculated, the redundancy of the polymorphism at a SNP locus and the co-segregation of the candidate SNP with other SNPs in the alignment. SNPServer is available at http://hornbill.cspp.latrobe.edu.au/snpdiscovery.html.

Internet↗
PubMed2004

Cardiac toxicity observed in association with high-dose cyclophosphamide-based chemotherapy for metastatic breast cancer.

INTRODUCTION: Cyclophosphamide is an alkylating agent given frequently as a component of many conditioning regimens. In high doses, its nonhematological dose-limiting toxicity is cardiomyopathy. STUDY DESIGN: We combined paclitaxel, melphalan and high-dose cyclophosphamide, thiotepa, and carboplatin in a triple sequential high-dose regimen for patients with metastatic breast cancer. Analysis was performed on 61 women with chemotherapy-responsive metastatic breast cancer receiving 96-h infusional cyclophosphamide as part of a triple sequential high-dose regimen to assess association between presence of peritransplant congestive heart failure (CHF) and the following pretreatment characteristics: presence of electrocardiogram (EKG) abnormalities, age, hypertension, prior cardiac history, smoking, diabetes mellitus, prior use of anthracyclines, and left-sided chest irradiation. RESULTS: Six of 61 women (10%) developed clinically reversible grade 3 CHF following infusional cyclophosphamide with a median percent decline in ejection fraction of 31%. Incidence of transient cyclophosphamide-related cardiac toxicity (10%) is comparable to previous recorded literature. Older age was significantly correlated with the CHF development; with median ages for the entire group and for patients developing CHF of 45 and 59, respectively. No association was found with other pretreatment characteristics. CONCLUSIONS: As a result of these findings, oncologists should carefully monitor fluid balance in older patients. Routine EKG monitoring during infusional cyclophosphamide did not predict CHF development.

Adult↗
PubMed2003

Water and glycerol permeation through the glycerol channel GlpF and the aquaporin family.

The 2.2 A resolution crystal structure of GlpF, an E. coli aquaporin that facilitates the flow of glycerol, water and other small solutes, provides much insight into the molecular function and selectivity of aquaporins. Using GlpF and its atomic structure as a paradigm for the ten highly conserved human aquaporins, site-directed mutagenesis has been used to mutate residues that are possibly integral to the structure and function of different aquaporins. X-ray crystallography and other biophysical and molecular simulation methods allows for assessment of these changes at the structural and functional level. Initial attempts to convert the glycerol specific properties of GlpF towards a water specific aquaporin resulted in the shifting of GlpF channel properties towards that of the water aquaporins. This result reveals the great possibility of emulating and deciphering the function of other aquaporins with GlpF via mutagenesis and investigation of structure and function.

Aquaporins↗
PubMed2003

Selectivity and conductance among the glycerol and water conducting aquaporin family of channels.

The atomic structures of a transmembrane water plus glycerol conducting channel (GlpF), and now of aquaporin Z (AqpZ) from the same species, Escherichia coli, bring the total to three atomic resolution structures in the aquaporin (AQP) family. Members of the AQP family each assemble as tetramers of four channels. Common helical axes support a wider channel in the glycerol plus water channel paradigm, GlpF. Water molecules form a single hydrogen bonded file throughout the 28 A long channel in AqpZ. The basis for absolute exclusion of proton or hydronium ion conductance through the line of water is explored using simulations.

Amino Acid Sequence↗
PubMed2002

Ethyl and isopropyl 4-ferrocenyl-benzoate.

The title compounds, [Fe(C(5)H(5))(C(14)H(13)O(2))] and [Fe(C(5)H(5))(C(15)H(15)O(2))], respectively, contain the ferrocenyl eta(5)(C(5)H(4)) and phenylene -C(6)H(4)- rings in a nearly coplanar arrangement, with interplanar angles of 6.88 (12) and 10.5 (2) degrees, respectively. Molecules of the ethyl ester form dimers through eta(5)(C(5)H(5))C-H...O=C hydrogen bonds, with graph set R(2)(2)(20), and, together with Csp(3)-H.pi(C(5)H(5)) interactions, generate a one-dimensional column (irregular ladder). Molecules of the isopropyl ester aggregate through eta(5)(C(5)H(5))C-H.pi(C(6)H(4)) interactions.

Journal Article↗
PubMed2002

Isomer-dependent metabolic effects of conjugated linoleic acid: insights from molecular markers sterol regulatory element-binding protein-1c and LXRalpha.

Conjugated linoleic acid (CLA) is a heterogeneous group of positional and geometric isomers of linoleic acid. This study demonstrates the divergent effects of the cis-9 trans-11 (c9,t11-CLA) and trans-10 cis-12 (t10,c12-CLA) isomers of CLA on lipid metabolism and nutrient regulation of gene expression in ob/ob mice. The c9, t11-CLA diet decreased serum triacylglycerol (P = 0.01) and nonesterified fatty acid (NEFA) (P = 0.05) concentrations, and this was associated with reduced hepatic sterol regulatory element-binding protein-1c (SREBP-1c; P = 0.0045) mRNA expression, coupled with reduced levels of both the membrane-bound precursor and the nuclear forms of the SREBP-1 protein. C9,t11-CLA significantly reduced hepatic LXRalpha (P = 0.019) mRNA expression, a novel regulator of SREBP-1c. In contrast, c9,t11-CLA increased adipose tissue SREBP-1c mRNA expression (P = 0.0162) proportionally to the degree of reduction of tumor necrosis factor alpha (TNF-alpha) mRNA (P = 0.012). Recombinant TNF-alpha almost completely abolished adipose tissue SREBP-1c mRNA expression in vivo. The t10,c12-CLA diet promoted insulin resistance and increased serum glucose (P = 0.025) and insulin (P = 0.01) concentrations. T10, c12-CLA induced profound weight loss (P = 0.0001) and increased brown and white adipose tissue UCP-2 (P = 0.001) and skeletal muscle UCP-3 (P = 0.008) mRNA expression. This study highlights the contrasting molecular and metabolic effect of two isomers of the same fatty acids. The ameliorative effect of c9,t11-CLA on lipid metabolism may be ascribed to reduced synthesis and cleavage of hepatic SREBP-1, which in turn may be regulated by hepatic LXRalpha expression.

Animals↗