Thesis (Ph.D.)--University of Texas at Dallas, 2008. / Includes vita. Includes bibliographical references (leaves 101-107)

Uric acid is a nitrogenous compound that is produced as an end product of the deamination of amino acids. Many insects and all reptiles and birds excrete the majority of excess nitrogen as solid uric acid granules that are suspended in the urine. However, the solid uric acid is not in crystalline form, but is packaged into small, spherical structures that are usually 3 - 15 μm in diameter. Further, the uric acid that is dissolved in the urine exceeds its aqueous solubility limit and the solubility limits of the potassium and sodium urate salts. Thus, a factor(s) in the urine is facilitating urate in exceeding its solubility limits and in causing urate to form spheres rather than crystals. I have reported that avian urine contains unusually high amounts of protein (1-3 mg/ml), and that the uric acid spheres also contain protein. Linear regression analysis shows that the amount of uric acid and protein in urine are positively correlated (r = 0.80, p<0.005), suggesting a functional relationship between the two. Equilibrium dialysis of urine before and after its treatment with protease shows the urinary protein capable of binding urate (and calcium). After isolating and purifying a sphere protein, I was able to generate sheep anti-sphere protein antibodies. By using these and commercially obtained anti-chicken serum albumin antibodies in a series of western blot analyses, I have identified serum albumin as the sphere protein and as a major urinary protein in birds. In summary, my data show serum albumin to playa significant role in the excretion of uric acid in birds. Because urine from all uricotelic species I have examined contains similar spheres, I am suggesting that all uricoteles may use like, or analogous, proteins to facilitate the excretion of urates.

The aim of this dissertation is to provide an analysis of central concepts in philosophy of science from the perspective of current molecular and developmental research. Each chapter explores the ways in which particular phenomena or discoveries in molecular biology influences our philosophical understanding of the nature of scientific knowledge. The introductory prologue draws some general connections between the various threads, which revolve around two central themes: causation and explanation. Chapter Two identifies a particular type of causal relation which is widespread across the sciences, but cannot be straightforwardly accommodated by extant accounts of causation and causal explanation. Chapter Three explores how the form of redundant causality identified in the previous chapter plays an important role in causal explanation, by making the effect stable and robust. Chapter Four offers a novel perspective on the debate over biological reductionism by distinguishing between different paradigms of molecular explanation. Chapter Five provides a philosophical analysis of the so-called "Developmental Synthesis" of evolutionary and developmental biology, and suggests a general account of scientific unification grounded in the notion of explanatory relevance. Chapter Six offers an account of dispositional properties inspired by mechanisms of gene regulation, according to which dispositions are not properties of entities, but properties that describe the behavior of abstract idealized models. Finally, Chapter Seven scrutinizes the concept of the molecular ecosystem, a metaphor frequently employed by biologists to describe cellular interactions, but seldom articulated in detail.

Hemorrhagic shock is a clinical syndrome involving widespread cellular dysfunction and resulting in injury to many organs. Resuscitation from hemorrhagic shock is similar to reperfusion after ischemia, but differs in that some blood flow persists during shock. Ischemia-reperfusion produces oxygen radicals in many organs, including the liver of the rat and the human. The hypothesis of this project was that oxygen radicals are produced and cause hepatic injury during resuscitation from hemorrhagic shock. The production of oxygen radicals within the liver should cause lipid peroxidation and tissue injury. Manipulation of defenses against oxygen radicals should decrease the hepatic injury caused by hemorrhagic shock and resuscitation. The blood pressure of Sprague-Dawley rats was reduced to 35-40 mm Hg by blood withdrawal for two hours, followed by reinfusion of withdrawn blood. Plasma alanine aminotransferase (ALT) levels rose and injury to hepatocytes and non-parenchymal cells was found on transmission electron microscopy. The presence of lipid peroxidation was determined by quantitation of ethane exhalation and hepatic content of thiobarbituric acid reactive substances (TBARS). Ethane exhalation was elevated during the hypotensive phase and after resuscitation. Hepatic TBARS levels were elevated after resuscitation only. The same hemorrhagic shock protocol was used to determine the effect of antioxidant manipulation on hepatic injury. The antioxidants superoxide dismutase, catalase, or deferoxamine produced no reduction in hepatic injury. The administration of phorone reduced hepatic non-protein sulfhydryl content and increased plasma ALT levels nine fold at 24 hours after resuscitation. The development of lipid peroxidation and the exacerbation of liver injury by the administration of phorone suggest that oxygen radicals are produced in the liver during hemorrhagic shock and resuscitation. However, the administration of antioxidants provided no protection. Therefore, it seems unlikely the oxygen radicals are involved in the pathogenesis of liver injury in this model. It is possible that the lipid peroxidation occurs after the cell is irreversible injured.

Lu, Yao. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Caenorhabditis elegans is arguably the best understood animal on the planet. Used for over 50 years to study development, we have a vast amount of knowledge of the inner workings of this worm. Our knowledge is incomplete, however, without placing this organism in its evolutionary and ecological context. In this body of work, I focused on examining the evolutionary forces shaping Caenorhabditis nematodes, with a particular emphasis on C. briggsae. In the first part, I examined the evolution of mitochondrial genomes throughout the genus. I tested for signatures of selection and examined the evolution of mitochondrial genome architecture. Through this, I have shown that the mitochondrial genomes of Caenorhabditis nematodes appear to be primarily influenced by purifying selection and that molecular evolutionary inference is greatly limited by mutational saturation. The evolutionary forces acting on mitochondrial genomes have been examined before, however, this study, extensively examining this within a single genus, provides a much better characterization than any of the studies to date. In the second part, I characterized the evolutionary dynamics of mitochondrial pseudogenes in C. briggsae and its closest relatives. I showed that these elements, while they might not evolve under strictly neutral terms, are still quite useful in uncovering cryptic diversity and population structure. I also observed that they appear/disappear in a manner that appears inconsistent with one commonly held model for mitochondrial pseudogene evolution. In the final part, I examined the evolution of C. briggsae in response to a biotic environment. I showed that fitness in a parasite-containing environment incurs a trade-off with fitness in the absence of parasites. Together, the chapters of this dissertation demonstrate the strength of Caenorhabditis, and in particular C. briggsae, for examining evolutionary questions and advances this system as a tool for evolutionary biology research. / Graduation date: 2013

Zero-inflated data are common in biomedical research. In cluster analysis, the heuristic approach fails to provide inferential properties to the outcome while the existing model-based approach only works in the case of a mixture of multivariate normal. In this dissertation, I developed two new model-based clustering algorithms- the multivariate zero-inflated log-normal and the multivariate zero-inflated Poisson clustering algorithms. I then applied these methods to the questionnaire data and compare the resulting clusters to the ones derived from assuming multivariate normal distribution. Associations between clustering results and clinical outcomes were also investigated.

No description available.

The effectiveness of estrogen replacement therapy in the prevention of postmenopausal osteoporosis has led to its current widespread use throughout the United States and much of Western Europe, and recently, clinical correlations between circulating androgen levels and structural bone integrity have been presented. Nevertheless, the biochemical mechanism through which estrogens and androgens act to protect and maintain bone has remained unclear. One possibility is that these hormones directly modulate the activity of cells responsible for bone formation. Therefore, studies were conducted to examine the effects of sex steroids on human osteoblast-like cells. In the first set of experiments, a finite human cell line was established from trabecular bone explants obtained from a 48 year-old woman. These cells, designated BG688, were characterized as osteoblast-like in phenotype using several independent criteria. In addition to classical osteoblast markers, BG688 cells also possess approximately 2400 high affinity (K(d) = 0.45nM) 17-β estradiol (E₂) binding sites per cell. The binding of E₂ to a subset of these sites was specific. BG688 cells were also shown to respond to a physiological concentration (10nM) of E₂, which elicits pleiotropic changes in several mRNA levels including a 2-fold increase in the steady state concentration of α₁(I)-procollagen mRNA. These results indicate that human osteoblast-like cells respond to E₂ via a receptor mediated mechanism, but that, unlike the reproductive tissues, osteoblasts are a less sensitive target. In the second series of experiments, the effects of androgenic hormones on the osteoblast-like, human osteosarcoma cell line, HOS TE85 were evaluated. Employing radiolabelled dihydrotestosterone (DHT), 2800 saturable, high-affinity (K(d) = 0.66nM) androgen binding sites were detected per HOS TE85 cell. Androgen binding was specific. The expression of androgen receptors in HOS TE85 cells was further substantiated by Northern analysis. Physiological concentrations of DHT and testosterone decreased HOS TE85 cell proliferation. This finding suggests that androgens may also play a role in osteoblast differentiation. In support of this hypothesis, treatment with testosterone enhanced the abundance of both α₁ (I)-procollagen mRNA and transforming growth factor- β mRNA. The non-aromatizable androgen DHT also elicited an increase in the steady state concentration of α₁(I)-procollagen mRNA. The findings presented herein are significant within the field of bone cell biology in that they demonstrate that osteoblasts are a target cell for the action of sex steroids, via their cognate, high-affinity receptors. These results also have important implications within the broader context of bone pathophysiology in that they suggest a direct modulation of bone forming and bone remodeling activity by sex steroids.

This chapter presents the Infobiotics Workbench (IBW), an integrated software suite developed for computational systems biology. The tool is built upon stochastic P systems, a probabilistic extension of P systems, as modelling framework. The platform utilises computer-aided modelling and analysis of biological systems through simulation, verification and optimisation. IBW allows modelling and analysing not only cell level behaviour, but also multi-compartmental population dynamics. This enables comparing be tween macroscopic and mesoscopic interpretations of molecular interaction networks and investigating temporo-spatial phenomena in multicellular systems. These capabilities make IBW a useful, coherent and comprehensive in silico tool for systems biology research.