The members of the genus Streptomyces are well-known for their capacity to synthesize a vast repertoire of secondary metabolites, including many useful antibiotics and proteins. Streptomyces clavuligerus is the producer of the medically important &amp / #946 / -lactam antibiotics such as cephamycin C and the potent &amp / #946 / -lactamase inhibitor clavulanic acid. The aspartate pathway of S. clavuligerus is an important primary metabolic pathway providing substrates for &amp / #946 / -lactam synthesis. This pathway uses L-aspartic acid as the precursor for the biosynthesis of the amino acids L-lysine, L-methionine, L-isoleucine, L-threonine and several important metabolic intermediates. L-&amp / #945 / -aminoadipic acid (&amp / #945 / -AAA) required for &amp / #946 / -lactam synthesis is a catabolic product of L-lysine produced from the lysine branch of the aspartate pathway. The carbon flow through the L-lysine-specific branch of aspartate pathway is limiting for the formation of cephamycin C. Formation of L-homoserine from aspartate semialdehyde (ASA) is the first step of the other branch of the aspartate pathway leading to L-threonine, L-isoleucine and L-methionine synthesis and is catalyzed by homoserine dehydrogenase (HSD, EC 1.1.1.3). Regulation of the activity or biosynthesis of the HSD of S. clavuligerus determines the availability of ASA for the biosynthesis of L-lysine and &amp / #945 / -AAA. The gene encoding for homoserine dehydrogenase (hom) was previously cloned from S. clavuligerus NRRL 3585 and characterized in our laboratory. In this study, the hom gene was disrupted via insertion of a kanamycin resistance cassette into this gene which was subsequently transferred to S. clavuligerus cells using the Streptomyces plasmid vector pIJ486. A hom mutant of S. clavuligerus (AK39) was formed through integration into the chromosome by double crossing over and the effects of hom disruption on cephamycin C yields were investigated. Disruption of hom gene resulted in a 1.7 to 2.0 fold increase in specific cephamycin C production in chemically defined medium (CDM).

Machiavelli&rsquo / s uniqueness and originality renders his educational direction as pertinent for times and conditions that are similar to and prevalent in ours. On the grand scale, his thought process disrupts the classical sense of philosophy, metaphysics, and religion. This disruption of the classical Western consciousness is an aim in the contemporary realm of political thought, which, starting with the extensive criticism of modernity found in the works of Nietzsche, has been developed in the realm of political thought throughout the twentieth and onto the twenty-first century. Therefore, Machiavelli &ndash / who lived 500 years ago &ndash / is nevertheless the source for productive knowledge, analysis, and prognosis for the contemporary political crisis, a crisis due to the downfall of modernity. The presupposition of latter-day modernity, as being considered the best of all possible worlds, is no longer believable. Modernity, what was once considered as being utterly unique and superior in human history, is responded to today by critiques on class domination, Western imperialism, the dissolution of community and tradition, the rise of alienation, and the impersonality of bureaucratic power. Machiavelli supplants the dominant modern consciousness through being a source for a new artistic revolution, a revolution of consciousness through a humane call for strength in facing reality, in order to re-constitute a divergent set of epistemological and ontological discoveries, which are better aligned to the condition of the present-day than those formulated by the dominant Western modern consciousness.

Lean distribution networks have been facing an increased exposure to the risk of unpredicted disruptions causing significant economic forfeitures. At the same time, the existing literature contains very few studies that examine the impact of fortification of facilities for improving network reliability. This dissertation presents three related classes of models that support the design of reliable distribution networks. The models extend the uncapacitated P-median and fixed-charge location models by considering heterogeneous facility failure probabilities, supplier backups, and facility fortification within a finite budget. The first class of models considers binary fortification via linear fortification functions. The second class of models extends binary fortification to partial (continuous) reliability improvement with linear fortification. This extension allows a more efficient utilization of limited fortification resources. The third class of models generalizes linear fortification to nonlinear to reflect the effect of diminishing marginal reliability improvement from fortification investment. For each of the models, we develop solution algorithms and demonstrate their computational efficiency. We present a detailed discussion on the novelty of the proposed models. The models are intended to support corporate decisions on the design of robust distribution networks using limited fortification resources.

There have been many theories on why we forget. One of the recent approaches to this phenomenon is retrieval induced forgetting (RIF). The present study investigated RIF and different kinds of disruptions and their effects by using extra-list cued recall task. Some participants studied two additional word lists after the target list and some participants studied and were tested from these interpolated lists before their final recall of target list. Relatedness of the interfering lists was also manipulated. There were two control groups that either got an immediate test or got a math task before memory test. The particular interest was on the target competitor effect. The results of the study indicated that all the disruption conditions reduced the effects of competitors. However, there was no effect of retrieval-induced forgetting and also no effect of relatedness. The importance of retention interval on forgetting was discussed.

The impact on the UK recorded music industry of digital music files distributed via the Internet has been studied using Clayton M. Christensen's Disruptive Innovation Theory. The study has identified that the recent innovation of Internet retail and distribution of digital music files was indeed disruptive (rather than sustaining) in nature in its impact on the established UK record manufacturers and retailers. Furthermore, Christensen's theories have been used to investigate the factors (assets, culture and capabilities) that impeded the established UK recorded music manufacturers from adopting and promoting the new technology to create a digital consumer proposition. The reluctance of the established record manufacturers to embrace and therefore control the new technology of digital music files distributed via the Internet allowed new retailers like Apple's iTunes to become the dominant providers to the new digital consumers. The study therefore considers and identifies the organisational assets, culture and capabilities that created the most successful Internet retailing operation for digital music and in so doing reveals how to incorporate and harness disruptive technology for commercial gain within the established recorded music industry. Finally, the study proposes a strategic framework for UK recorded music companies so that they can respond successfully to disruptive technologies that will in future alter their market sector, including consumer attitudes and music usage. This framework will give the record companies the opportunity to manage the impact of disruptive technologies, enabling them to adapt their business strategies and tactics to provide a service that meets consumer needs the next time an innovative technology impacts the established manufacturing and retailing paradigm.

Inanga (Galaxias maculatus) are a culturally and economically important fish species in New Zealand and abroad. However, very little is known about their ability to deal with trace element contamination. As a scaleless fish with the ability to survive in relatively extreme environments, they may not fit toxicity models (such as the biotic ligand model; BLM) based on other fish species. The aim of this study was to determine how this fish responds to elevated trace elements in both the laboratory and field in order to determine the applicability of these toxicity models. In order to determine the impacts of stress on ion transport and subsequent metal toxicity, inanga were exposed to handling stress and measures of ion uptake were collected. Handling stress was shown to result in increased ventilation rates, resulting in stimulated sodium (Na+) efflux. A compensatory increase in Na+ influx was also measured as a result of this stress. Inanga largely recovered from this ionoregulatory stress within 2 hours, with full recovery after 24 hours. This was indicative of a rapid homeostatic response for maintaining ion balance. Enhanced Na+ uptake in response to this stress resulted in increased copper (Cu) uptake in Cu-contaminated water, suggesting stressed fish will accumulate more Cu (and likely other Na+ mimics) than an unstressed fish. These results suggest a heightened vulnerability of inanga to this type of contaminant as a result of exercise stress during migrations. A combination of field and laboratory studies was used in order to measure trace element accumulation in inanga. In situ field studies showed changes to aluminum (Al) and iron (Fe) body burdens when inanga were placed in streams of varying trace element concentrations along the West Coast of the South Island. However, other trace elements measured did not alter over the period of exposure (9-10 days). Biochemical biomarker analysis showed no changes in the activity of Na+/K+-ATPase (NKA), but a marker of lipid peroxidation (thiobarbituric acid reactive substances; TBARS) was elevated in one stream. Analysis suggested that stream pH was the major driver of this effect, whether directly or via changes to metal bioavailability. Subsequent laboratory exposures (96 h) of inanga to 1.2, 2.7, 10.8, and 44 µg L-1 dissolved Fe and 5.6, 23.3, 60.7, and 128.7 µg L-1 dissolved zinc (Zn) showed no difference in whole body trace element accumulation, ammonia excretion, ion influx (Ca2+ and Na+), and TBARS. There were significant differences in oxygen consumption (MO2) after Fe exposures, with increases in the 2.7 and 44 µg L-1 dissolved Fe exposures. Laboratory exposure results suggest inanga are relatively insensitive to short-term Fe and Zn exposures. Both in vivo (whole body partitioning) and in vitro (Ussing chamber) techniques were used to determine the influence of cutaneous ion transport on preventing trace element accumulation. Results suggest inanga use their skin as an additional site of calcium (Ca2+) and Na+ uptake. This is the first study to confirm these ion transport capabilities in inanga, and revealed that up to 48% of Na+ uptake may occur across the skin. Pharmacological inhibition of Ca2+ uptake was achieved by known Ca2+ channel blockers (verapamil and lanthanum). Furthermore Fe and Zn impaired cutaneous Ca2+ transport, indicating that ion transport pathways in the skin modulate in response to these metals.

Sitosterolemia (STSL) is a sterol storage disorder characterized by very high plasma plant sterol (PS) and 5α-stanol levels, and leads to premature atherosclerosis, xanthomas, macrothrombocytopenia and endocrine disruption. Ezetimibe (EZE), a sterol absorption inhibitor, reduces plasma PS levels in STSL but its effect on tissue pool of sterols has not been investigated yet. The research objectives were to assess if EZE reduces whole body sitosterol and cholesterol pool sizes, improves cholesterol homeostasis, enhance hematologic profile and reduce endocrine disruption in STSL. EZE effects on circulating levels of cholestanol and its precursors (cholesterol and bile acid derivative 7α-hydroxy-4-cholesten-3-one, 7α-H-C4) relative to exogenous stanols (sitostanol) were also studied. Eight STSL patients were taken off EZE for 14 wks. After 4 wks off EZE they received intravenous doses of D7-sitosterol and 18O-cholesterol for sterol pool sizes assessments, and oral doses of 13C-cholesterol and deuterium oxide to measure fractional cholesterol absorption and synthesis rates. EZE (10 mg/d) was resumed and stable isotopes testing repeated. Measurement parameters included isotopic sterol enrichments, blood cell count, plasma and red blood cell (RBC) PS, cholesterol and its precursor (lathosterol), 5α-stanols and plasma 7α-H-C4, and thyroid hormones levels. EZE reduced plasma levels of sitosterol and total cholesterol, whole body sitosterol and cholesterol pool sizes and fractional cholesterol absorption rate while increasing cholesterol synthesis, production and clearance rates. EZE increased platelet count and decreased platelet size without affecting RBC indices of size or mass. A substantial decrease in circulating sitostanol but moderate decrease of cholestanol was noted with EZE. EZE increased lathosterol but not 7α-H-C4, suggesting increases in cholesterol biosynthesis and thus precursor availability for synthesis of cholestanol. In summary, EZE reduces body stores of PS and cholesterol, and increases cholesterol turnover by reducing cholesterol absorption and enhancing its synthesis and clearance. EZE reduces circulating PS and 5α-stanol levels, and improves macrothrombocytopenia and thyroid disruption. Endogenous cholestanol in STSL is mainly derived from cholesterol but not bile acid synthesis pathway. These data suggest that EZE may reduce the risks of developing premature atherosclerosis, bleeding and hormone disruption, thereby reinforcing the rationale for the use of EZE in treatment of STSL. / February 2015

This thesis presents theoretical results on the tidal disruption of stars by supermassive black holes (SMBHs). The multiwavelength ares produced by tidal disruption events (TDEs) have supernova-like luminosities, and associated relativistic jets can be visible to cosmological distances. TDEs probe the demography of quiescent SMBHs, and are natural laboratories for jet launching mechanisms and super-Eddington accretion. The first chapter broadly surveys TDE physics. The second and third chapters estimate the TDE rate following gravitational wave (GW) recoil of a SMBH (after a SMBH binary merger). Immediately after GW recoil, the TDE rate increases, sometimes to \(~10^{-1}\) TDEs per year. This "burst" of TDE flares can provide an electromagnetic counterpart to low frequency GW signals, localizing sources and measuring cosmological parameters. Millions of years later, recoiled SMBHs wandering through their host galaxies will produce spatially offset TDEs at a rate which is likely detectable with the LSST. In the fourth chapter, we show that standard estimates for \(\Delta\epsilon\), the energy spread of TDE debris, are wrong, sometimes by orders of magnitude. Correcting this error reduces the observability of many TDEs. We introduce a new analytic model for tidal disruption, calculate \(\Delta\epsilon\)'s dependence on stellar spin, estimate general relativistic corrections to \(\Delta\epsilon\), and quantify the GW signal generated from tidal compression. The fifth chapter presents hydrodynamical simulations of TDE debris circularization, focusing on eccentric, rather than parabolic, orbits. General relativistic precession drives debris circularization, in contrast to past simulations using smaller black holes. In the sixth chapter, we show that TDE light curves can constrain or measure SMBH spins, as Lense-Thirring torques produce quasiperiodic variability in disk emission. Precession of a relativistic jet could also measure SMBH spin, and we apply our model to the relativistic Swift 1644+57 TDE. The seventh chapter considers the disruption of neutron stars (NSs) by stellar mass black holes (BHs) or other NSs. Jet precession in associated short-hard gamma ray bursts is uniquely possible for NS-BH (not NS-NS) mergers. We quantify typical precession amplitudes and periods, and calculate their time evolution. If disk viscosities are relatively low, electromagnetic observations alone could distinguish NS-BH from NS-NS mergers. / Astronomy

Transport networks have to provide carriers with time-efficient alternative routes in case of disruptions. It is, therefore, essential for transport network planners and operators to identify sections within the network which, if broken, have a considerable negative impact on the networks performance. Research on transport network analysis provides lots of different approaches and models in order to identify such critical sections. Most of them, however, are only applicable to mono-modal transport networks and calculate indices which represent the criticality of sections by using aggregated data. The model presented, in contrast, focuses on the analysis of intermodal transport networks by using a traffic micro simulation. Based on available, real-life data, our approach models a transport network as well as its actual traffic participants and their individual decisions in case of a disruption. The resulting transport delay time due to a specific disruption helps to identify critical sections and critical networks, as a whole. Therefore, the results are a valuable decision support for transport network planners and operators in order to make the infrastructure less vulnerable, more attractive for carriers and thus more economically sustainable. In order to show the applicability of the model we analyse the Austrian intermodal transport network and show how critical sections can be evaluated by this approach. (authors' abstract)

This thesis compares actual and perceived travel times and presents a model for predicting traffic flows when there is a network disruption. The goal of this research is to demonstrate the necessity of accounting for possible differences in travel time perception and actual travel times, and also to show trends in how the route choices change based on the transformation of the perceived travel times. A pilot test was done to determine actual travel time perceptions, and the results provided the foundation for the tests presented in this thesis and the model framework. The model is separated into three phases: equilibrium assignment, link travel time transform, and logit assignment. The transform of the link travel times is best represented by an inverse cumulative Normal distribution, and the corresponding values provide quantifiable measure of the severity of a traffic network disruption. The methodology is presented and applied to two test networks to demonstrate the resulting route choice patterns. Both networks are tested for three severity levels and three levels of demand. / text