Dean Billheimer

Abstract:

Receptor models apportion an ambient mixture of pollutants to the contributing pollution sources. Often, neither the number of sources nor their chemical profiles are known precisely. The dual goals of modeling are to estimate the chemical 'signature' of the sources, and to characterize the mixing process. The author develops a novel modeling approach for receptor data where all model components are compositions (i.e. vectors of proportions). This approach maintains positivity and summation constraints for source contributions and chemical profiles. Further, it incorporates available prior knowledge regarding the source chemical profiles. Including prior knowledge allows parameter estimation while avoiding restrictive assumptions regarding presence or absence of chemical tracers. This approach is illustrated by modeling air pollution data collected from a receptor near Juneau, Alaska. The compositional model produces point estimates of source profiles and mixing proportions similar to those obtained in a previous study. However, interval estimates for mixing proportions are roughly 30 per cent shorter than those found previously. Copyright © 2001 John Wiley & Sons, Ltd.

PMID: 21737566;PMCID: PMC3186211;Abstract:

Nonalcoholic fatty liver disease (NAFLD) is characterized by a series of pathological changes that range from simple fatty liver to nonalcoholic steatohepatitis (NASH). The objective of this study is to describe changes in global gene expression associated with the progression of human NAFLD. This study is focused on the expression levels of genes responsible for the absorption, distribution, metabolism, and elimination (ADME) of drugs. Differential gene expression between three clinically defined pathological groups - normal, steatosis, and NASH - was analyzed. Genome-wide mRNA levels in samples of human liver tissue were assayed with Affymetrix GeneChip Human 1.0ST arrays. A total of 11,633 genes exhibited altered expression out of 33,252 genes at a 5% false discovery rate. Most gene expression changes occurred in the progression from steatosis to NASH. Principal component analysis revealed that hepatic disease status was the major determinant of differential ADME gene expression rather than age or sex of sample donors. Among the 515 drug transporters and 258 drug-metabolizing enzymes (DMEs) examined, uptake transporters but not efflux transporters or DMEs were significantly over-represented in the number of genes down-regulated. These results suggest that uptake transporter genes are coordinately targeted for down-regulation at the global level during the pathological development of NASH and that these patients may have decreased drug uptake capacity. This coordinated regulation of uptake transporter genes is indicative of a hepatoprotective mechanism acting to prevent accumulation of toxic intermediates in disease- compromised hepatocytes. Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics.

Abstract:

Aim: Rapidly evolving pathogens may exert diversifying selection on genes involved in host immune defence including those encoding antimicrobial peptides (AMPs). Amphibian skin peptides are one important defence against chytridiomycosis, an emerging infectious disease caused by the chytrid fungus Batrachochytrium dendrobatidis (Bd). We examined the population-level variation in this innate immune defence to understand its relationship with disease dynamics. Location: Queensland, Australia. Methods: We examined skin peptide defences in five geographically distinct populations of Australian green-eyed treefrogs, Litoria genimaculata. Skin peptide samples were collected from 52 frogs from three upland populations that previously declined as chytridiomycosis emerged, but subsequently recovered, and from 34 frogs in two lowland populations that did not decline. Historical samples of skin peptides preceding Bd emergence were not available from any population. Results: In general, lowland populations had more effective peptide defences than upland populations. Peptide profiles were similar among populations, although relative amounts of peptides expressed differed significantly among populations and were more variable in the uplands. Infected frogs in upland populations carried a significantly higher infection burden compared to lowland populations. The presence of effective AMPs in the skin of L. genimaculata does not eliminate infection; however, more effective peptide defences may limit infection intensity and the progression of disease. Main conclusions: The population bottleneck in upland populations caused by chytridiomycosis emergence did not appear to produce responses to selection for more effective peptide defences against chytridiomycosis compared to lowland populations of L. genimaculata. This does not exclude the possibility that current peptide defences have adapted in response to disease emergence. A suggestive (P 0.10) interaction between infection status and population indicates that in lowland populations, infected individuals tend to be those with lower relative intensities of AMPs, whereas in the upland populations, infected and uninfected individuals are similar. Thus, both the AMPs and the environment may act to mediate resistance to Bd infection. © 2010 Blackwell Publishing Ltd.

PMID: 17910796;Abstract:

Raman spectroscopy has been shown to have the potential for providing differential diagnosis in the cervix with high sensitivity and specificity in previous studies. The research presented here further evaluates the potential of near-infrared Raman spectroscopy to detect cervical dysplasia in a clinical setting. Using a portable system, Raman spectra were collected from the cervix of 79 patients using clinically feasible integration times (5 seconds on most patients). Multiple Raman measurements were taken from colposcopically normal and abnormal areas prior to the excision of tissue. Data were processed to extract Raman spectra from measured signal, which includes fluorescence and noise. The resulting spectra were correlated with the corresponding histopathologic diagnosis to determine empirical differences between different diagnostic categories. Using histology as the gold standard, logistic regression discrimination algorithms were developed to distinguish between normal ectocervix, squamous metaplasia, and high-grade dysplasia using independent training and validation sets of data. An unbiased estimate of the accuracy of the model indicates that Raman spectroscopy can distinguish between high-grade dysplasia and benign tissue with sensitivity of 89% and specificity of 81%, while colposcopy in expert hands was able to discriminate with a sensitivity and specificity of 87% and 72%. © 2007 Society for Applied Spectroscopy.