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This thesis is primarily concerned with oesophageal motility, but certain aspects of the mechanism of deglutition were also studied in detail, either deliberately or by chance. · All dissections, experiments and microscopical and other examinations were conducted by the author and some specimens personally blocked, Out and stained. The liberal use of illustrations clarifies many points which otherwise would not have been so convincingly described; they also ,emphasise strongly the wide variation of normal, which unfortunately we only too often lose sight of in medicine. The literature on this wide subject is so vast that it cannot be completely covered or referred to in a thesis of this nature. The references at the end of this thesis are mainly recent and should, give the·reader·some indication of the divergence of opinion and current concepts on this complex subject.

Marine microbes support global carbon cycling by sequestration and metabolizing of marine carbon. Understanding how these microbes use unique motility modalities to navigate the physicochemical environment of the ocean is crucial to understanding microbial carbon metabolism. Motility in several marine Rhodobacter strains exhibit dendritic motility, but underlying genetic mechanisms remain poorly characterized. To lay groundwork for future study of genetic mechanisms for dendritic motility in novel Rhodobacter strains HOT5_B8 and HOT5_C3, we use timelapse microscopy to qualitatively and quantitatively characterize patterns in dendrite formation. Preliminary results determine that dendritic motility is faster than non-dendritic motility in HOT5_B8 and HOT5_C3. Further, key differences in HOT5_B8 and HOT5_C3 behaviors are used as evidence to posit putative density-dependent mechanisms in the formation and behaviors of dendrites. / 2023-09-10T00:00:00Z

This thesis investigates bacterial motility from the mechanism permitting individual selfpropulsion to the complex collective flocking motility in Escherichia coli and Bacillus subtilis cells. Understanding bacterial swimming has intrigued scientists for decades and recently there has been a growing interest in collective swimming behaviour. The first part of this thesis reviews the characteristics of E. coli and B. subtilis cells subsequently describing the governing physics and constraints of self-propulsion in the low Reynolds regime. The second part of this thesis presents three self-contained experimental sections, examining individual swimming in non-conventional body shaped cells and subsequently focusing on concentrated bacterial swimming in normal cells. We first investigated motility in mutant spherical E. coli cells KJB24 motivated by simulations, which often model bacteria as self-propelled spheres. Somewhat unexpectedly these spherical cells do not exhibit runs and tumbles but diffuse slower than expected. As an introduction to working with microbiology and to familiarise with microbiology techniques we investigated why these spherical cells do not swim. Secondly we investigated how cellular motility varies as a function of body length by inhibiting cell division in wild-type E. coli with cephalexin; which remained motile despite body elongation. Fluorescent flagella visualization provided evidence of multiple bundle formations along the lateral walls as a mechanism to sustain motility. The average swimming velocity, body and flagella rotation rates, the number of flagella and number of flagella bundles were extracted experimentally as a function of length. The extracted experimental parameters for normal sized cells were consistent with Purcell’s model. We explored simple adaptations and scaling of this model to describe motility for filamentous cells, which agrees with experimental values. The main focus is on collective behaviour of B. subtilis by examining the onset from individual swimming to collective motility using time-lapse microscopy. Results demonstrated a smooth transition where cells self-organize into domains expanding rapidly by recruiting cells. We present advancements in B. subtilis fluorescent flagella staining which revealed unexpected multiple flagella bundle arrangements during runs, contradictory to general conjectures. Novel visualisation of flagella filaments during reversal events is presented in both E. coli and B. subtilis cells, providing experimental evidence for complex flagella ‘flipping’. Cellular reversal is hypothesized as a mechanism for quorum polarity facilitating collective swimming. We present novel flagella imaging in the setting of collective behaviour showing evidence to support quorum polarity. Subsequently we extracted the run length distributions of cells as a function of concentration, yielding a decreasing trend with increasing concentration. Using particle tracking we quantitatively extracted the mean squared displacement of swimming cells versus passive tracers at different concentrations during collective swimming, these novel results are discussed in respect to recent simulations. These presented experiments provide new insights into collective behaviour improving current understanding of this phenomenon.

The human stomach is a complex organ with sophisticated function. – The control of delivery of nutrients to the small intestine is tightly regulated, and the patterns and determinants of the associated processes are numerous, complex and interrelated. The presence of nutrients in the small intestine stimulates the release of a number of gastrointestinal hormones, including glucagon-like peptide-1 (GLP-1). Exogenous GLP-1 reduces fasting and postprandial glucose concentrations, and this is thought to be via a slowing of gastric emptying (GE). The effects of endogenous GLP-1 on GE and glycaemia were evaluated using exendin(9-39), a GLP-1 antagonist, in healthy subjects, in a randomised, placebo-controlled study, in Chapter 5. Exendin(9-39) increased postprandial glycaemia through an acceleration of GE; these findings support the putative role of GLP-1 as an enterogastrone. The capacity to measure GE has greatly increased the understanding of normal and disordered gastric physiology. 30 – 50 % of patients with longstanding diabetes have delayed GE. Scintigraphy remains the ‘gold standard’ in the measurement of GE, however, it is associated with a radiation burden. Recently, three-dimensional (3D) ultrasonography was validated against scintigraphy in healthy subjects. In Chapter 6, GE was measured concurrently by 3D ultrasonography and scintigraphy in patients with diabetic gastroparesis, and good correlation and agreement was found between both techniques. Glycaemic control represents one of the main pathogenetic factors of diabetic gastroparesis. Hyperglycaemia slows, while hypoglycaemia accelerates, GE in healthy subjects and patients with uncomplicated type 1 diabetes. Chapter 7 reports a study investigating the effects of insulin-induced hypoglycaemia vs. euglycaemia on GE in longstanding type 1 diabetes. Hypoglycaemia accelerated GE of a mixed solid/liquid meal; the magnitude of this acceleration was greater when GE during euglycaemia was slower. In contrast to glucose, the effects of intravenous (iv) fructose (used widely in the diabetic diet) on GE are less well understood. The comparative effects of iv fructose, glucose and saline on GE and antropyloroduodenal motility in healthy males are reported in Chapter 8. Compared with saline, fructose infusion was associated with a slowing of GE and suppression of antral waves, the magnitude of which was comparable to glucose. Treatment for the management of gastroparesis is currently suboptimal and there is a need for novel prokinetic agents. Itopride has demonstrated prokinetic activity in dogs. The effects of itopride on GE, glycaemia and upper gastrointestinal symptoms were studied in patients with longstanding diabetes in a randomised, placebo-controlled trial (Chapter 9). There was a trend for itopride to accelerate both solid and liquid GE. 48 % of patients had delayed solid and/or liquid GE on placebo, and in this group, itopride accelerated liquid, but not solid, GE. Autonomic neuropathy represents another pathogenetic factor of diabetic gastroparesis, and delayed GE is more prevalent in patients with autonomic dysfunction. There is evidence that C-peptide improves autonomic nerve function (ANF) in type 1 diabetes. The effects of C-peptide on GE and ANF were studied in patients with longstanding type 1 diabetes in randomised, placebo-controlled design, in Chapter 10. C-peptide had no effect on solid or liquid GE, or ANF. Gastroparesis, particularly in patients with diabetes, represents an important clinical problem. The studies presented in this thesis have provided fundamental insights into the measurement and determinants of gastric motor function and postprandial glycaemia, and treatment of gastroparesis, however, further studies which assess the complex pathogenesis and pathophysiology of gastroparesis, and which include a larger cohort of patients, are warranted. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1456472 / Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2009

The human stomach is a complex organ with sophisticated function. – The control of delivery of nutrients to the small intestine is tightly regulated, and the patterns and determinants of the associated processes are numerous, complex and interrelated. The presence of nutrients in the small intestine stimulates the release of a number of gastrointestinal hormones, including glucagon-like peptide-1 (GLP-1). Exogenous GLP-1 reduces fasting and postprandial glucose concentrations, and this is thought to be via a slowing of gastric emptying (GE). The effects of endogenous GLP-1 on GE and glycaemia were evaluated using exendin(9-39), a GLP-1 antagonist, in healthy subjects, in a randomised, placebo-controlled study, in Chapter 5. Exendin(9-39) increased postprandial glycaemia through an acceleration of GE; these findings support the putative role of GLP-1 as an enterogastrone. The capacity to measure GE has greatly increased the understanding of normal and disordered gastric physiology. 30 – 50 % of patients with longstanding diabetes have delayed GE. Scintigraphy remains the ‘gold standard’ in the measurement of GE, however, it is associated with a radiation burden. Recently, three-dimensional (3D) ultrasonography was validated against scintigraphy in healthy subjects. In Chapter 6, GE was measured concurrently by 3D ultrasonography and scintigraphy in patients with diabetic gastroparesis, and good correlation and agreement was found between both techniques. Glycaemic control represents one of the main pathogenetic factors of diabetic gastroparesis. Hyperglycaemia slows, while hypoglycaemia accelerates, GE in healthy subjects and patients with uncomplicated type 1 diabetes. Chapter 7 reports a study investigating the effects of insulin-induced hypoglycaemia vs. euglycaemia on GE in longstanding type 1 diabetes. Hypoglycaemia accelerated GE of a mixed solid/liquid meal; the magnitude of this acceleration was greater when GE during euglycaemia was slower. In contrast to glucose, the effects of intravenous (iv) fructose (used widely in the diabetic diet) on GE are less well understood. The comparative effects of iv fructose, glucose and saline on GE and antropyloroduodenal motility in healthy males are reported in Chapter 8. Compared with saline, fructose infusion was associated with a slowing of GE and suppression of antral waves, the magnitude of which was comparable to glucose. Treatment for the management of gastroparesis is currently suboptimal and there is a need for novel prokinetic agents. Itopride has demonstrated prokinetic activity in dogs. The effects of itopride on GE, glycaemia and upper gastrointestinal symptoms were studied in patients with longstanding diabetes in a randomised, placebo-controlled trial (Chapter 9). There was a trend for itopride to accelerate both solid and liquid GE. 48 % of patients had delayed solid and/or liquid GE on placebo, and in this group, itopride accelerated liquid, but not solid, GE. Autonomic neuropathy represents another pathogenetic factor of diabetic gastroparesis, and delayed GE is more prevalent in patients with autonomic dysfunction. There is evidence that C-peptide improves autonomic nerve function (ANF) in type 1 diabetes. The effects of C-peptide on GE and ANF were studied in patients with longstanding type 1 diabetes in randomised, placebo-controlled design, in Chapter 10. C-peptide had no effect on solid or liquid GE, or ANF. Gastroparesis, particularly in patients with diabetes, represents an important clinical problem. The studies presented in this thesis have provided fundamental insights into the measurement and determinants of gastric motor function and postprandial glycaemia, and treatment of gastroparesis, however, further studies which assess the complex pathogenesis and pathophysiology of gastroparesis, and which include a larger cohort of patients, are warranted. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1456472 / Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2009

Myxococcus xanthus, referred to as a 'social bacterium', demonstrates unique behaviors such as coordinated motility, cooperative feeding, and multicellular structure formation. Its complex social behaviors and developmental processes make M. xanthus a model organism for studying bacterial social behaviors and their underlying mechanisms. Much of the social behavior of M. xanthus hinges on coordination of cell motility among bacteria in close proximity. M. xanthus moves on moist solid surfaces, using its Adventurous (A)-motility and Social (S)-motility systems. A striking feature of M. xanthus motility is the periodic reversal of its direction of movement. The reversal frequency is influenced by chemical and mechanical cues in the surrounding environment. The modulation of the reversal frequency upon physical contact between cells is believed to be a key factor in the bacterium's social behaviors, especially in the formation of complex patterns and structures within the cell population. Here I utilized mathematical modeling to study the motility regulation in M. xanthus, focusing on contact-dependent reversal control, mechanosensing response and impact of motility regulation in solitary (single-cell) predation. My goal is to provide experiment-guiding theories and hypotheses for M. xanthus motility regulation, which is essential to fully understand the social behaviors in this bacterium. In Chapter 2, I developed a single-cell model based on a hypothesis that the motility regulation in M. xanthus is mediated by the interplay between the cell polarity regulation pathway and the A-motility machinery. The aim of this model is to elucidate the cellular mechanism governing contact-dependent motility coordination among cells and to understand how contact-dependent responses at the single-cell level contribute to population-level patterns. This model suggests that the A-motility machinery of M. xanthus potentially serves as a 'mechanosensor' that transduces mechanical cues in the environment into a reversal modulation signal. Chapter 3 addresses a puzzling observation: cells with A-motility alone (A+S−) show a dependence of reversal frequency on substrate stiffness that is opposite to what is observed in wild-type cells that possess both motility systems. Specifically, A+S− cells reverse less frequently on harder substrates, whereas wild-type cells reverse more frequently. To elucidate this perplexing phenomenon, I refined the single-cell model developed in Chapter 2 to study the mechanosensing behaviors with or without S-motility. The base model was sufficient to explain the mechanosensing response in A+S− cells. I then proposed possible interactions between the A-motility and S-motility systems that could explain the contrasting responses to substrate stiffness when S-motility is present or absent. This provides a testable prediction for future experimental investigations. The model suggests that the A-motility system in M. xanthus functions as a central hub of mechanosensing-based reversal control, modulating cell reversal in response to environmental mechanical cues. In Chapter 4, I constructed an agent-based model to investigate the optimal motility strategies for nutrient consumption by M. xanthus during its solitary predation. For different nutrient source types and their uptake latencies, the model identifies 'explore', 'inch', and 'fast explore' as the three most effective motility strategies. Variability in velocity and cell reversal period changes the optimal strategies from 'explore' mode to 'revisit' mode and to 'speed-controlled explore' mode, respectively, for massive remains of prey nutrient sources with moderate uptake latency. The experimental observation that solitary M. xanthus cells combined the 'revisit' and 'inch' mode—as predicted by the model for nutrient acquisition respectively from prey remains and macromolecules—suggests that some of the dead preys may not release its cellular contents immediately and that release of molecular nutrients may require multiple digestion cycles. This model provides insights into the functional role of complex motility regulation in M. xanthus during solitary predation. / Doctor of Philosophy / A fundamental question in biology is how a cell responds to physical, chemical and biological stimuli. Such responses are usually mediated by complex coupling between multiple cellular processes. Bacterial motility and its regulation present many excellent examples of this kind. This dissertation focuses on Myxococcus xanthus, a model organism for bacterial social behavior due to the highly coordinated motility of cells in M. xanthus colonies and their functional cooperation. In this dissertation, I built theoretical models to study the motility regulation in M. xanthus, which is essential for understanding the social behaviors and survival in this bacterium. The specific focuses are to comprehend how environmental mechanical cues regulate M. xanthus's motility, and how the observed motility regulation in M. xanthus facilitates its predatory behavior at the single-cell level. The key aspect of this work is to construct a modeling framework to provide coherent explanations for the experimental observations. It is anticipated that the hypotheses generated through modeling will guide new experiments in the field of myxobacterial biology. The findings offer general insights into how bacterial cells sense, respond, and adapt to the chemical, physical, and biological cues.

Typescript (photocopy). / Digitized by Kansas Correctional Industries

This work explores bacterial motility from the mechanisms of propulsion of an individual cell to the complex behavior of collective motility. The shear modulus of bacterial flagella was measured by stretching isolated flagella with an optical trap and by measuring force extension curves of the stretched flagella shedding light onto the me-chanics involved in the motility of single micro-organisms. Experiments in concentrated suspensions of bacteria show collective behavior with large scale mixing on a time and length scale greater than can be understood from the standard model of "run and tumble" motility of a single organism are reported. To further understand the transition from individual to collective motility a novel form of motility where an individual bacterium can reverse direction without changing cell orientation is reported here. These experiments further the understanding of bacterial motility.

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