Intercepting Cyclic Dinucleotide Signaling with Small Molecules

Bacterial infections, especially the ones that are caused by multidrug-resistant strains, are becoming increasingly difficult to treat and put enormous stress on healthcare systems. Recently President Obama announced a new initiative to combat the growing problem of antibiotic resistance. New types of antibiotic drugs are always in need to catch up with the rapid speed of bacterial drug-resistance acquisition. Bacterial second messengers, cyclic dinucleotides, play important roles in signal transduction and therefore are currently generating great buzz in the microbiology community because it is believed that small molecules that inhibit cyclic dinucleotide signaling could become next-generation antibacterial agents. The first identified cyclic dinucleotide, c-di-GMP, has now been shown to regulate a large number of processes, such as virulence, biofilm formation, cell cycle, quorum sensing, etc. Recently, another cyclic dinucleotide, c-di-AMP, has emerged as a regulator of key processes in Gram-positive and mycobacteria. C-di-AMP is now known to regulate DNA damage sensing, fatty acid synthesis, potassium ion transport, cell wall homeostasis and host type I interferon response induction. Due to the central roles that cyclic dinucleotides play in bacteria, we are interested in small molecules that intercept cyclic dinucleotide signaling with the hope that these molecules would help us learn more details about cyclic dinucleotide signaling or could be used to inhibit bacterial viability or virulence. This dissertation documents the development of several small molecule inhibitors of a cyclic dinucleotide synthase (DisA from B. subtilis) and phosphodiesterases (RocR from P. aeruginosa and CdnP from M. tuberculosis). We also demonstrate that an inhibitor of RocR PDE can inhibit bacterial swarming motility, which is a virulence factor.

Parsing, Generation and Grammar

Humans use their grammatical knowledge in more than one way. On one hand, they use it to understand what others say. On the other hand, they use it to say what they want to convey to others (or to themselves). In either case, they need to assemble the structure of sentences in a systematic fashion, in accordance with the grammar of their language. Despite the fact that the structures that comprehenders and speakers assemble are systematic in an identical fashion (i.e., obey the same grammatical constraints), the two ‘modes’ of assembling sentence structures might or might not be performed by the same cognitive mechanisms. Currently, the field of psycholinguistics implicitly adopts the position that they are supported by different cognitive mechanisms, as evident from the fact that most psycholinguistic models seek to explain either comprehension or production phenomena. The potential existence of two independent cognitive systems underlying linguistic performance doubles the problem of linking the theory of linguistic knowledge and the theory of linguistic performance, making the integration of linguistics and psycholinguistic harder. This thesis thus aims to unify the structure building system in comprehension, i.e., parser, and the structure building system in production, i.e., generator, into one, so that the linking theory between knowledge and performance can also be unified into one. I will discuss and unify both existing and new data pertaining to how structures are assembled in understanding and speaking, and attempt to show that the unification between parsing and generation is at least a plausible research enterprise. In Chapter 1, I will discuss the previous and current views on how parsing and generation are related to each other. I will outline the challenges for the current view that the parser and the generator are the same cognitive mechanism. This single system view is discussed and evaluated in the rest of the chapters. In Chapter 2, I will present new experimental evidence suggesting that the grain size of the pre-compiled structural units (henceforth simply structural units) is rather small, contrary to some models of sentence production. In particular, I will show that the internal structure of the verb phrase in a ditransitive sentence (e.g., The chef is donating the book to the monk) is not specified at the onset of speech, but is specified before the first internal argument (the book) needs to be uttered. I will also show that this timing of structural processes with respect to the verb phrase structure is earlier than the lexical processes of verb internal arguments. These two results in concert show that the size of structure building units in sentence production is rather small, contrary to some models of sentence production, yet structural processes still precede lexical processes. I argue that this view of generation resembles the widely accepted model of parsing that utilizes both top-down and bottom-up structure building procedures. In Chapter 3, I will present new experimental evidence suggesting that the structural representation strongly constrains the subsequent lexical processes. In particular, I will show that conceptually similar lexical items interfere with each other only when they share the same syntactic category in sentence production. The mechanism that I call syntactic gating, will be proposed, and this mechanism characterizes how the structural and lexical processes interact in generation. I will present two Event Related Potential (ERP) experiments that show that the lexical retrieval in (predictive) comprehension is also constrained by syntactic categories. I will argue that the syntactic gating mechanism is operative both in parsing and generation, and that the interaction between structural and lexical processes in both parsing and generation can be characterized in the same fashion. In Chapter 4, I will present a series of experiments examining the timing at which verbs’ lexical representations are planned in sentence production. It will be shown that verbs are planned before the articulation of their internal arguments, regardless of the target language (Japanese or English) and regardless of the sentence type (active object-initial sentence in Japanese, passive sentences in English, and unaccusative sentences in English). I will discuss how this result sheds light on the notion of incrementality in generation. In Chapter 5, I will synthesize the experimental findings presented in this thesis and in previous research to address the challenges to the single system view I outlined in Chapter 1. I will then conclude by presenting a preliminary single system model that can potentially capture both the key sentence comprehension and sentence production data without assuming distinct mechanisms for each.

FABRICATION, CHARACTERIZATION, AND IRRADIATION OF AN AUSTENITIC OXIDE DISPERSION STRENGTHENED STEEL SUITED FOR NEXT GENERATION NUCLEAR APPLICATIONS

As nuclear energy systems become more advanced, the materials encompassing them need to perform at higher temperatures for longer periods of time. In this Master’s thesis we experiment with an oxide dispersion strengthened (ODS) austenitic steel that has been recently developed. ODS materials have a small concentration of nano oxide particles dispersed in their matrix, and typically have higher strength and better extreme temperature creep resistance characteristics than ordinary steels. However, no ODS materials have ever been installed in a commercial power reactor to date. Being a newer research material, there are many unanswered phenomena that need to be addressed regarding the performance under irradiation. Furthermore, due to the ODS material traditionally needing to follow a powder metallurgy fabrication route, there are many processing parameters that need to be optimized before achieving a nuclear grade material specification. In this Master’s thesis we explore the development of a novel ODS processing technology conducted in Beijing, China, to produce solutionized bulk ODS samples with ~97% theoretical density. This is done using relatively low temperatures and ultra high pressure (UHP) equipment, to compact the mechanically alloyed (MA) steel powder into bulk samples without any thermal phase change influence or oxide precipitation. By having solutionized bulk ODS samples, transmission electron microscopy (TEM) observation of nano oxide precipitation within the steel material can be studied by applying post heat treatments. These types of samples will be very useful to the science and engineering community, to answer questions regarding material powder compacting, oxide synthesis, and performance. Subsequent analysis performed at Queen’s University included X-ray diffraction (XRD) and inductively coupled plasma optical emission spectrometry (ICP-OES). Additional TEM in-situ 1MeV Kr2+ irradiation experiments coupled with energy dispersive X-ray (EDX) techniques, were also performed on large (200nm+) non-stoichiometric oxides embedded within the austenite steel grains, in an attempt to quantify the elemental compositional changes during high temperature (520oC) heavy ion irradiation.

Best after rain : waterfall discharges and the tourist experience

Waterfalls attract tourists because they are aesthetically appealing landscape features that are not part of everyday experience. It is generally understood that falls are usually seen at their best when there is a copious flow of water, especially after heavy rain. Guidebooks often contain this observation when referring to waterfalls, sometimes warning readers that the flow may be severely reduced during dry periods. Indeed, many visitors are disappointed when they see falls at such times. Some are saddened when the discharge of a waterfall has been depleted by the abstraction of water upstream for power generation or other purposes. While, for those in search of the Sublime or merely the superlative, size is often important, small waterfalls can give great pleasure to lovers of landscape beauty. According to guidebooks, however, even these falls are usually best seen after rain. Drawing on tourist and travel literature and personal journals from the eighteenth century to the present, and with reference to examples from different parts of the world, this paper discusses the importance of discharge in the tourist experience of waterfalls.

Evolutions of an Online Generation: Education, Industry and IMC

This paper traces the evolutions of a new generation of students who are predominantly the ‘online generation’; explores the emerging impact of this generation on industry; identifies the changing role of education from traditional classroom to an online environment; and explores the contribution related to integrated marketing communications (IMC). Educational requirements from a business perspective must incorporate global business demands; virtual learning environments progress the online generation towards a post-modern learning state. The central proposition of this paper is that the emergence of IMC in evolving industry practices is influenced by student generations who are producing a new paradigm of alignment between education and industry. This is purely a conceptual exploration using limited examples to provide some context and illustrate the questions raised for consideration.