Fungal diseases, Pythium ultimum (Pythium leak) and Helminthosporium solani (silver scurf) have detrimental effects on potato tuber (Solanum tuberosum) quality and yield. Tubers are the world’s fourth largest agricultural food crop and are crucial for feeding a growing population. Bacteria from the genus Streptomyces are known for producing a wide variety of secondary metabolites with antifungal properties. Isolates of Streptomyces have recently shown inhibitory effects towards P. ultimum and H. solani in Petri dish assays. These data suggest that Streptomyces may work as a biocontrol to protect tubers from P. ultimum and H. solani. We tested talc-based powder formulas for their ability to maintain viable Streptomyces spores in storage. The formula that maintained spores the longest was then used to coat varying Streptomyces isolates onto a tuber surface that contained, or would be exposed to P. ultimum or H. solani. Tests were conducted in a lab, greenhouse, and field setting. We found a powder formula that kept 50% of the added Streptomyces spores viable for a period of three to six months depending on the isolate. Isolates with inhibitory effects towards H. solani were applied as a powder on seed tubers infected with H. solani and grown in a greenhouse. Upon completion of the experiment, we found that progeny tubers from neither the treatment nor the control groups contained H. solani. Instead, we found a similar surface pathogen, Colletotrichum coccodes (Black dot), on many of the progeny tubers. While not the target pathogen of this study, some isolates significantly limited C. coccodes compared to the control. This experiment was repeated in a field setting where C. coccodes was again the primary disease found on the progeny tubers. In the field, isolates showed no inhibitory effect towards C. coccodes. Isolates with inhibitory effects towards P. ultimum were applied as a powder onto wounded tubers. One hour later the tubers were exposed to P. ultimum. Isolates did not limit P. ultimum compared to the control after a week of incubation. A follow up experiment revealed that the Streptomyces isolate used needed at least 24 hours of growth to produce antifungal secondary metabolites. Our data suggest that Streptomyces bacteria can easily be stored in a powder and that there are beneficial effects as a biocontrol against C. coccodes. Our data also suggest that timing Streptomyces application for maximum secondary metabolite production may improve its efficacy as a biocontrol.

abstract: Water is one of, if not the most valuable natural resource but extremely challenging to manage. According to old research in the field, many Water Distribution Systems (WDSs) around the world lose above 40 percent of clean water pumped into the distribution system because of unfortune leaks before the water gets anywhere from the fresh water resources. By reducing the amount of water leaked, distribution system managers can reduce the amount of money, resources, and energy wasted on finding and repairing the leaks, and then producing and pumping water, increase system reliability and more easily satisfy present and future needs of all consumers. But having access to this information pre-amatively and sufficiently can be complex and time taking. For large companies like SRP who are moving tonnes of water from various water bodies around phoenix area, it is even more crucial to efficiently locate and characterize the leaks. And phoenix being a busy city, it is not easy to go start digging everywhere, whenever a loss in pressure is reported at the destination. Keeping this in mind, non-invasive methods to geo-physically work on it needs attention. There is a lot of potential in this field of work to even help with environmental crisis as this helps in places where water theft is big and is conducted through leaks in the distribution system. Methods like Acoustic sensing and ground penetrating radars have shown good results, and the work done in this thesis helps us realise the limitations and extents to which they can be used in the phoenix are. The concrete pipes used by SRP are would not be able to generate enough acoustic signals to be affectively picked up by a hydrophone at the opening, so the GPR would be helpful in finding the initial location of the leak, as the water around the leak would make the sand wet and hence show a clear difference on the GPR. After that the frequency spectrum can be checked around that point which would show difference from another where we know a leak is not present. / Dissertation/Thesis / Masters Thesis Mechanical Engineering 2019

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21016号 / 医博第4362号 / 新制||医||1028(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 小西 靖彦, 教授 福田 和彦, 教授 松村 由美 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Large-scale distributed computing systems such as data centers are hosted on heterogeneous and networked servers that execute in a dynamic and uncertain operating environment, caused by factors such as time-varying user workload and various failures. Therefore, achieving stringent quality-of-service goals is a challenging task, requiring a comprehensive approach to performance control, fault diagnosis, and failure recovery. This work presents a model-based approach for fault management, which integrates limited lookahead control (LLC), diagnosis, and fault-tolerance concepts that: (1) enables systems to adapt to environment variations, (2) maintains the availability and reliability of the system, (3) facilitates system recovery from failures. We focused on memory leak errors in this thesis. A characterization function is designed to detect memory leaks. Then, a LLC is applied to enable the computing system to adapt efficiently to variations in the workload, and to enable the system recover from memory leaks and maintain functionality.

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Concurrent software has been widely utilizing in computer systems owing to the highly efficient computation. However, testing and verifying concurrent software remain challenging tasks. This matter is not only because of the non-deterministic thread interferences which are hard to reason about but also because of the large state space due to the simultaneous path and interleaving explosions. That is, the number of program paths in each thread may be exponential in the number of branch conditions, and also, the number of thread interleavings may be exponential in the number of concurrent operations. This dissertation presents a set of new methods, built upon symbolic execution, a program analysis technique that systematically explores program state space, for testing concurrent programs. By modeling both functional and non-functional properties of the programs as assertions, these new methods efficiently analyze the viable behaviors of the given concurrent programs. The first method is assertion guided symbolic execution, a state space reduction technique that identifies and eliminates redundant executions w.r.t the explored interleavings. The second method is incremental symbolic execution, which generates test inputs only for the influenced program behaviors by the small code changes between two program versions. The third method is SYMPLC, a technique with domain-specific reduction strategies for generating tests for the multitasking Programmable Logic Controller (PLC) programs written in languages specified by the IEC 61131-3 standard. The last method is adversarial symbolic execution, a technique for detecting concurrency related side-channel information leaks by analyzing the cache timing behaviors of a concurrent program in symbolic execution. This dissertation evaluates the proposed methods on a diverse set of both synthesized programs and real-world applications. The experimental results show that these techniques can significantly outperform state-of-the-art symbolic execution tools for concurrent software. / Doctor of Philosophy / Software testing is a technique that runs software as a black-box on computer hardware multiple times, with different inputs per run, to test if the software behavior conforms to the designed functionality by developers. Nowadays, programmers have been increasingly developing multithreaded and multitasking software, e.g., web browser and web server, to utilize the highly efficient multiprocessor hardware. This approach significantly improves the software performance since a large computing job can now decompose to a set of small jobs which can then distribute to concurrently running threads (tasks). However, testing multithreaded (multitask) software is extremely challenging. The most critical problem is the inherent non-determinism. Typically, executing sequential software with the same input data always results in the same output. However, running a multithreaded (multitask) software multiple times, even under the same input data, may yield different output in each run. The root reason is that concurrent threads (tasks) may interleave their running progress at any time; thus the internal software execution order may be altered unexpectedly, causing runtime errors. Meanwhile, finding such faults is difficult, since the number of all possible interleavings can be exponentially growing in the number of concurrent thread (task) operations. This dissertation proposes four methods to test multithreaded/multitask software efficiently. The first method summarizes the already-tested program behaviors to avoid future testing runs that cannot lead to new faults. The second method only tests program behaviors that are impacted by program changes. The third method tests multitask Programmable Logic Controller (PLC) programs by excluding infeasible testing runs w.r.t the PLC semantics. The last method tests non-functional program properties by systematic concurrency analysis. This dissertation evaluates these methods upon a diverse set of benchmarks. The experimental results show that the proposed methods significantly outperform state-of-the-art techniques for concurrent software analysis.

Due to the lack of effective techniques for detecting and mitigating property violations, existing approaches to ensure the safety and security of software systems are often labor intensive and error prone. Furthermore, they focus primarily on functional correctness of the software code while ignoring micro-architectural details of the underlying processor, such as cache and speculative execution, which may undermine their soundness guarantees. To fill the gap, I propose a set of new methods and tools for ensuring the safety and security of software systems. Broadly speaking, these methods and tools fall into three categories. The first category is concerned with static program analysis. Specifically, I develop a novel abstract interpretation framework that considers both speculative execution and a cache model, and guarantees to be sound for estimating the execution time of a program and detecting side-channel information leaks. The second category is concerned with static program transformation. The goal is to eliminate side channels by equalizing the number of CPU cycles and the number of cache misses along all program paths for all sensitive variables. The third category is concerned with runtime safety enforcement. Given a property that may be violated by a reactive system, the goal is to synthesize an enforcer, called the shield, to correct the erroneous behaviors of the system instantaneously, so that the property is always satisfied by the combined system. I develop techniques to make the shield practical by handling both burst error and real-valued signals. The proposed techniques have been implemented and evaluated on realistic applications to demonstrate their effectiveness and efficiency. / Doctor of Philosophy / It is important for everything around us to follow some rules to work correctly. That is the same for our software systems to follow the security and safety properties. Especially, softwares may leak information via unexpected ways, e.g. the program timing, which makes it more difficult to be detected or mitigated. For instance, if the execution time of a program is related to the sensitive value, the attacker may obtain information about the sensitive value. On the other side, due to the complexity of software, it is nearly impossible to fully test or verify them. However, the correctness of software systems at runtime is crucial for critical applications. While existing approaches to find or resolve properties violation problem are often labor intensive and error prone, in this dissertation, I first propose an automated tool for detecting and mitigating the security vulnerability through program timing. Programs processed by the tool are guaranteed to be time constant under any sensitive values. I have also taken the influence of speculative execution, which is the cause behind recent Spectre and Meltdown attack, into consideration for the first time. To enforce the correctness of programs at runtime, I introduce an extra component that can be attached to the original system to correct any violation if it happens, thus the entire system will still be correct. All proposed methods have been evaluated on a variety of real world applications. The results show that these methods are effective and efficient in practice.

Trimethylamine N-oxide (TMAO) is a metabolite derived from dietary choline, betaine, and carnitine via intestinal microbiota metabolism. In several recent studies, TMAO has been shown to directly induce inflammation and reactive oxygen species (ROS) generation in numerous cell types, resulting in cell dysfunction. However, whether TMAO will impact stem cell properties remains unknown. This project aims to explore the potential impact of TMAO on mouse embryonic stem cells (mESCs), which serve as an in vitro model of the early embryo and of other potent stem cell types. Briefly, mESCs were cultured in the absence (0mM) or presence of TMAO under two different sets of treatment conditions: long-term (21 days), low-dose (20µM, 200µM, and 1000µM) treatment or short-term (5 days), high-dose (5mM, 10mM, 15mM) treatment. Under these treatment conditions, mESC viability, proliferation, and stemness were analyzed. mESC properties were not negatively impacted under long-term, low-dose TMAO treatment; however, short-term, high-dose treatment resulted in significant reduction of mESC viability and proliferation. Additionally, mESC stemness was significantly reduced when high-dose treatment was extended to 21 days. To investigate an underlying cause for TMAO-induced loss in mESC stemness, metabolic activity of the mESCs under short-term, high-dose TMAO treatment was measured with a Seahorse XFe96 Analyzer. TMAO treatment significantly decreased the rate of glycolysis, and it increased the rate of compensatory glycolysis upon inhibition of oxidative phosphorylation (OxPHOS). It also significantly increased the rate of OxPHOS, maximal respiratory capacity, and respiratory reserve. These findings indicate that TMAO induced a metabolic switch of mESCs from high glycolytic activity to greater OxPHOS activity to promote mESC differentiation. Additionally, TMAO resulted in increased proton leak, indicating increased oxidative stress, and elucidating a potential underlying mechanism for TMAO-induced loss in mESC stemness. Altogether, these findings indicate that TMAO decreases stem cell potency potentially via modulation of metabolic activity. / Master of Science / Trimethylamine N-oxide (TMAO) is a metabolite that is produced by the bacteria in the gut after the consumption of specific dietary ingredients (e.g., choline, carnitine, betaine). These ingredients are commonly found in meat and dairy products, and thus make up a large part of the average American diet. Recently, it was discovered that high TMAO levels in the bloodstream put people at an increased risk for heart disease, neurodegenerative diseases (e.g., Alzheimer's Disease), diabetes, stroke, and chronic kidney disease. At the cellular level, there is evidence that TMAO increases inflammation and the production of oxygen radicals, which causes cells to lose their function and promotes the onset of disease. TMAO has been well studied in adult cell types; however, no one has investigated whether TMAO will impact cells of the early embryo. This project aims to explore the impact of TMAO on mouse embryonic stem cells (mESCs), which are cells that represent the early stage of embryonic development and are critical for proper development of the final offspring. In addition, mESCs may also help to provide insight into how TMAO impacts other stem cell types, some of which are present throughout the entire human lifespan and play an important role in the body's ability to repair itself and maintain overall health. My project demonstrated that TMAO does not impact the overall health of mESCs under normal conditions, which signifies that TMAO generated by a pregnant mother may not directly impact the early embryonic stage of development. Further studies should be conducted to determine the potential impact of TMAO on late stages of embryonic and fetal development. Next, to simulate diseased conditions, the mESCs were treated with extremely high concentrations of TMAO in order to determine what concentration of TMAO will negatively impact these cells. It was found that at 5mM TMAO, mESCs begin to lose their basic properties and become dysfunctional. They are impaired in their viability, growth, ability to become other cell types, and in their metabolic activity. These mESC properties are shared with several types of adult stem cells, and therefore, these findings help to provide insight into how TMAO may impact stem cells found in the adult body which are exposed to a lifetime of high TMAO levels. In the future, we would like to further explore the impact of TMAO on mESCs at the molecular level as well as examine the direct impact of TMAO on other stem cell types.