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End date: 2016 × Start date: 2010 × search.filters.applied.f.resourcesubtype: Dissertation ×

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The influence of wheelchair mechanical parameters and human physical fitness on propulsion effort

2016-11-15 , Lin, Jui-Te

The majority of wheelchair studies that attempt to evaluate propulsion efforts across wheelchair configurations examines long and steady propulsion. However, the results of these studies cannot represent performance during daily maneuvers, which include changes in speed and direction. Although each component of wheelchair configuration was widely studied, the knowledge has a limitation to describe the mechanical properties of wheelchairs systematically. Physical fitness was proved to be related to health status and exercise performance. In addition, the biomechanical characteristics of the user were shown to influence wheelchair maneuvers. However, it is still unknown how these human factors would influence wheelchair propulsions together. Therefore, the overall objective of the study is to define the relative influence of mechanical wheelchair parameters as well as individual physical and biomechanical variables on propulsion efforts during over-ground maneuvers. The first aim is to develop and validate a test that quantifies the impact of wheelchair configurations on frictional energy loss, particularly loss related to turning trajectories. The second aim is to develop and validate a testing protocol designed to measure maximum propulsion strength, which will test subjects in a realistic condition – while seated in their wheelchairs. The third aim is to identify the impact of the mechanical parameters of wheelchairs as well as the physical and biomechanical variables of operators on propulsion efforts during over-ground maneuvers. Mechanical parameters include both inertial and frictional measurements. Operator factors include shoulder position, propulsion strength, and aerobic capacity. To evaluate the performance of daily maneuvering, we designed a repeatable maneuver consisting of several momentum changes. Because of the breadth of wheelchair configurations and variance in user physical capacity, it is necessary to define the effects of wheelchair configurations and user fitness on propulsion with a systematic approach. The study results demonstrated that shoulder position and weight distribution had a significant influence on the frictional energy loss and propulsion efforts. However, aerobic capacity and muscle strength had less influence on daily wheelchair maneuver. Clinicians can use our finding, which covers wheelchair designs and human fitness, to select equipment and prescribe exercise to wheelchair users. Manufacturers can also improve their wheelchair design by understanding the importance of shoulder position and weight distribution.

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Environmental niche partitioning of microbial community genomic diversity, gene expression, and metabolism in a marine oxygen minimum zone

2016-11-14 , Ganesh, Sangita

Oxygen Minimum Zones (OMZs) serve as habitats to diverse assemblages of microorganisms that play an important role in mediating global biogeochemical cycles. OMZ microbial communities have not been extensively characterized, and the linkages between microbial community structure, and ecological and biogeochemical processes are still unclear. OMZs act as model systems to study partitioning of microbial niches and biogeochemical transformations owing to their steep vertical gradients of oxygen, nutrient, and redox substrates. This thesis combined genomic tools with environmental measurements of nitrogen transformation rates to characterize how microbial community structure, function and ecological diversity vary at the microscale between free-living (planktonic) and particle-associated microbial communities and over vertical and longitudinal gradients in two of the world’s largest permanent OMZs. The results show an important role for particle-association as a major driver of OMZ microbial community metabolic potential and genome content, and identify wide variation in nitrogen transformation rates in the presence versus absence of particles. These results highlight the dependence of free-living microorganisms on particles for substrates and nutrients, as well as selective partitioning of genes facilitating key steps of an important nitrogen loss pathway, denitrification, in the particle-associated microbial fraction. Finally, this thesis describes the genomic composition and gene expression variation of an important OMZ bacterium, Candidatus Scalindua sp., responsible for anaerobic ammonia oxidation (anammox), the second major nitrogen loss pathway in OMZs. Combining single cell genomics, transcriptome profiling, and rate measurements, this study identifies high metabolic plasticity of OMZ anammox bacteria in different niches along the OMZ redoxcline, including a potential for use of diverse nitrogen substrates to drive anammox. Collectively, these studies enhance our understanding of the environmental determinants of microbial diversity and biochemical activity in low oxygen marine systems.

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Scalable mapping-free algorithms and K-mer data structures for genomic analysis

2016-07-19 , Audano, Peter Anthony

An organism’s DNA sequence is a virtual cornucopia of information, and sequencing technology is the key to unlocking it. The past few decades have been witness to meteoric growth of these technologies and the volume of data they produce. New industries are forming around it, existing ones are changing as a result of it, and modern medicine is on the precipice of a genomic revolution. Turning this deluge of data into useful information is already a challenging task with advances in sequencing technology far outstripping advances in semiconductors, and this trend shows no signs of stopping. Incremental advances are being made in sequence analysis techniques, but progress is far too slow to keep up with the volume of data delivered by modern sequencing platforms. This gap is often filled by allocating more computing resources in the form of distributed computing platforms, and this can quickly become prohibitive. Because medicine requires a quick answer and science often has limited funding, the analysis bottleneck is a major concern. Instead of finding new ways to dedicate more computing resources to the problem, I am interested in streamlining the process. In this dissertation, I explore methods to make the analysis faster and more efficient. My ultimate goal is to create algorithms that can run on a standard computer workstation, and when necessary, make the most of expensive distributed and cloud computing resources. Many analysis pipelines start by aligning sequence reads to a reference or assembling them into long consensus sequences, but it can take several hours to analyze a single sample on a workstation computer. Instead aligning or assembling sequence reads, the approaches described in this dissertation transform and analyze the sequence data without alignments. These alignment-free approaches often improve performance by an order of magnitude or more. The first step for many alignment-free approaches involves transforming the sequence reads into k-mers, which are short overlapping fragments of uniform size. If the size, k, is 48, then all substrings of length 48 are extracted from each sequence read and counted. The resulting frequency of each k-mer can then be used as evidence for genomic analysis techniques. When I started as graduate student, I began by working on a program to transform sequence data to k-mer frequencies. The resulting software, KAnalyze, was incredibly flexible because of its software architecture and approach to solving the k-mer counting problem. This became the foundation for the rest of my graduate work because it was possible to test new ideas that required data structures and transformations not commonly used today. After my initial work with k-mers, I was connected with the Centers for Disease Control and Prevention (CDC) Mycobacterium tuberculosis (M. tuberculosis) science team. They were interested in replacing existing software with an alignment-free approach based on k-mers. The new software significantly reduced analysis time, and it reduced errors. K-mers are more rigid than sequence aligments, so I had to find a way to correct for mutations in the samples. This resulted in a novel algorithm that could identify single nucleotide polymorphism (SNP) and insertion/deletion (indel) mutations, and it still took far less time than the alignment approach. I am not aware of an error correction algorithm with k-mers that does not employ a simple hamming distance calculation, and therefore, is capable of handling indel variants. The CDC M. tuberculosis project solved this problem in a naı̈ve way; when a variant was detected, it took 4 paths and assumed that it might be a SNP, insertion, deletion, or no variant. The result is an algorithm that runs with a computational time complexity of O(4n ). Although this worked well on the short reference sequences analyzed for this project, it would never scale to larger references. After some thought and experimentation, I realized that the reconstruction algorithm I had created was generating a sequence that was ostensibly related to the reference, and comparing two sequences to determine how well they match is the fundamental task of alignments. Instead of taking multiple paths for each base mismatch, could it be possible to guide the rebuilding algorithm by aligning the dynamically constructed sequence with the reference? Although it is not 100% alignment-free, this approach would significantly reduce the computational burden of modern methods, which aligns each of the sequence reads to the reference. What was more exciting is that it might be able to pick out variants blind to sequence read alignments, such as dense SNP loci or large insertions. This work culminated in Kestrel, which is a novel first-in-class variant caller application that uses this idea. The chapters that follow tell this story from the current state of the art to novel applications of this new technology that are under development today.

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Acclimating across healthy and degraded reefs

2016-05-31 , Dell, Claire Louise Alice

As a result of human activities, many environments are becoming fragmented into areas with different community compositions and selective regimes. The coral reefs of Fiji for example, are divided into ‘fished areas’ (fragments subjected to fishing and trampling) and ‘protected areas’ (fragments with little human pressure) that occur in close proximity and now have differing community compositions and selective regimes. Theory predicts that the species able to survive in such conditions should have highly plastic genotypes allowing them to acclimatise to diverse habitats without the time lag required for local adaptation. Here we use two species -Epinephelus merra (a small grouper) and Sargassum polycystum C. Agardh (a brown macroalga)- which are found in both fished and protected reefs, to investigate this plastic response and understand how these species cope in healthy versus degraded environments. We found that the fish E. merra exhibits plasticity in diet and feeds lower in the food chain in fished reefs than similarly sized conspecifics in protected reefs. The seaweed S. polycystum exhibits plasticity in defensive traits and is able to induce increased defenses in response to being partially consumed. In addition, we found that dense stands of S. polycystum increased the survival and growth of both recruit-sized and mature-sized S. polycystum ramets, suggesting that Sargassum beds protect conspecifics from grazing by herbivorous fishes and construct conditions that facilitate their growth. Implications for management are discussed.

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Population genomics of human polymorphic transposable elements

2016-11-15 , Rishishwar, Lavanya

Transposable element (TE) activity has had a major impact on the human genome; more than two-thirds of the sequence is derived from TE insertions. Several families of human TEs – primarily Alu, L1 and SVA – continue to actively transpose, thereby generating insertion polymorphisms between individuals. Until very recently, it has not been possible to characterize the genetic variation generated by the activity of these TE families at the scale of whole genomes for multiple individuals within and between human populations. For this reason, the impact of recent TE activity on human evolution has yet to be fully appreciated. My dissertation research leverages novel technologies in data science to investigate the role that recent TE activity has played in shaping human population genetic variation. Specifically, my dissertation addresses three problems: 1) evaluation of the computational techniques used to characterize human polymorphic TE insertion sites from whole genome, next-generation sequence data, 2) characterization of the population genomic variation of human polymorphic TEs and evaluation of their effectiveness as markers of human genetic ancestry and admixture, and 3) analysis of the effects that natural selection (negative and positive) has exerted on human polymorphic TE insertions. I close by presenting a broad prospectus on the implications of genome-scale analyses of human polymorphic TE insertions for population and clinical genetic studies. The results reported in this dissertation represent the dawn of the population genomics era for human TEs.

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Gene expression profiling approach towards enhancement of malaria vaccine development

2016-08-24 , Rojas Pena, Monica Lisseth

Malaria continues to be one of the highest morbidity and mortality infectious diseases in the world, posing an enormous public health burden with significant economic consequences. The development of vaccines that provide sterile protection against pathogenic infection by the Plasmodium parasites that cause malaria is thus a major global public health priority. This dissertation describes three gene expression profiling experiments using RNA sequencing technology (RNASeq) applied to samples collected during clinical trials performed at the CAUCASECO research center in Cali, Colombia. In each case, peripheral blood samples from volunteers and patients enrolled in studies addressing different aspects of immunity against P. vivax malaria were studied, namely the effect of prior exposure, the efficacy of an attenuated parasite vaccine, and resolution of complicated disease. The results presented explore how gene expression profiling of the complex mixture of cells present in whole blood can nevertheless reveal the cellular nature and duration of the immune response to P. vivax infection, while also highlighting subsets of genes that may mediate adaptive immunity. These results demonstrate the potential value of RNASeq for studying the response of the host transcriptome of a malaria infection, and represent a step toward genomic profiling as a component of personalized clinical diagnostics for malaria treatment.

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Understanding the systemic roles of exosomes in innate immunity

2016-07-13 , Srinivasan, Swetha

Cell-cell communication is critical for rapidly spreading the message of infection and enabling the innate immune system to mount a broad response against the pathogen. Exosomes are nanovesicles (~50nm in diameter) that are released extracellularly by all cell types. Their ability to transmit messages between cells at a distance and their rapid transport through the body makes them ideal messengers for establishing innate immune responses. However, their utilization of transport pathways in vivo was uncharacterized. The central role of lymphatic transport in trafficking exosomes in vivo was established for the first time in this thesis. Furthermore, differential distribution of exosomes in the draining lymph nodes that is dependent on the lymphatic flow has been established and macrophages and B-cells were identified as key players in exosome uptake. The distal recapitulation of the local toll-like receptor response via exosomes definitively established their ability to disseminate innate immune information in vitro. This is the first delineation of the kinetics of the response accompanied with abrogation of the action-at-a-distance signaling of exosomes by UV irradiation, demonstrating that RNA is crucial for their effector function. The impact of exosome uptake in whole lymph node and macrophages uptake is elucidated to show reprogramming of the node to a pro-inflammatory state and M1 macrophage polarization. Therefore, this work characterized the role of exosomes in initiating an innate immune response comprehensively in the context of a viral infection both in vitro and in vivo.

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Bioinformatic tools for testing microbial ecology theory in natural environments through metagenomics

2016-11-14 , Rodriguez Rojas, Luis Miguel

Metagenomics offers unique opportunities to close the gaps that exist between theory and empirical testing in microbial ecology given the windows it can provide into the large fraction of yet-unculturable organisms and species-level resolution. However, realizing the full potential of metagenomics requires the advancement of computational and statistical techniques for data analyses. In the first part of this dissertation I will present a general overview of the current state of quantitative methods for comparative metagenomics and introduce novel algorithms developed for these purposes. Particular emphasis will be placed on the issue of metagenomic coverage, i.e., what fraction of the microbial community was characterized by the sequencing effort, discussing its practical impact on metagenomic analyses and study design, and proposing a novel method for its accurate estimation, Nonpareil (Rodriguez-R and Konstantinidis, Bioinformatics 2014; –, ISME J 2014). Further, the Nonpareil approach can be leveraged for the estimation of extant diversity using a novel metric of sequence diversity, Nd, independent of databases, and with little impact of sequencing effort. In the second part of this dissertation, I will apply the computational and statistical toolbox described above to the characterization of community assembly processes in natural environments. First, I will describe the post-disturbance successional patterns following the deposition of large amounts of hydrocarbons in the shoreline of Florida following the 2010 Macondo Oil Spill in the Gulf of Mexico. We demonstrated that this secondary succession had only minor lasting effects in community composition post-recovery, and was mainly driven by hydrocarbon degradation and nutrient scavenging metabolic potentials in concert with the degree of specialization of community members (Rodriguez-R et al., ISME 2015). I will discuss these results as evidence in support of the specialization-disturbance ecologic hypothesis. Finally, I’ll describe variations within the meta-community of a freshwater interconnected system without recent major documented disturbances composed of five lakes and two estuarine locations along the Chattahoochee River (Southeast USA) monitored for a span of six years. Our results revealed strong seasonal patterns together with significant distance decay and minor landscape effects, indicating that both historic and contemporary factors shape the community assembly within this system in similar proportions. I will discuss these results in the framework of classic (macro-organismal) biogeographic theory, and illustrate in which ways they contradict the contemporary view of the now classic Baas-Becking dictum: “everything is everywhere, and the environment selects”.

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Natural competence and Type VI secretion in Vibrio cholerae

2016-07-22 , Bernardy, Eryn

The waterborne bacterium Vibrio cholerae, responsible for epidemics of cholera diarrhea, associates with the human gut and with chitinous surfaces in aquatic reservoirs. Prior studies of two clinical V. cholerae isolates revealed that natural competence for genetic transformation, a horizontal gene transfer mechanism, requires the chitin-induced TfoX regulator, and quorum sensing transcription factor HapR made at high cell density. To further understand this regulation, I helped identify, in a genetic screen, CytR, a new positive regulator required for competence gene expression and natural transformation. Recently, this complex regulatory network in V. cholerae was shown to also control a type VI secretion system (T6SS) that allows contact-dependent killing of other bacteria by injecting toxic proteins. I characterized a diverse set of sequenced V. cholerae isolates, revealing that transformation was rare in all isolates, while constitutive type VI killing was common among environmental but not clinical isolates. These latter results were consistent with a “pathoadaptive” model that tight regulation is beneficial in a host, while constitutive killing is advantageous in the environment. We hypothesized that two sequenced V. cholerae isolates with distinct T6SSs could generate structured populations from initially well-mixed conditions by killing competitors, but not kin. Indeed, when both isolates were rendered T6SS-, a well-mixed population was observed via fluorescence microscopy. In contrast, mutual killing generated clonal patches with each isolate segregating into distinct groups. Structural dynamics were recapitulated with three mathematical models and a cooperation model developed supports that this assortment promotes cooperation among kin. My work in V. cholerae has helped elucidate a complex regulatory network controlling multiple important phenotypes, diversity of these phenotypes among species members, and ecological consequences of antagonistic microbial interactions in the environment.

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Changes in leg and joint coordination during locomotor adaptation in amputees and able-bodied controls

2016-06-06 , Selgrade, Brian Paul

Activities of daily life require humans to locomote in unfamiliar environments. We respond to these new environments through adaptation, a gradual change in movement parameters in response to a sensory error caused by altered environmental conditions. I investigated changes in coordination at the joint and leg level as subjects adapted to split-belt treadmill walking and altered visual feedback in hopping. As subjects adapted to increase leg force, they preferentially reduced deviations in joint torque that affected leg force. Once peak leg force reached a steady level, subjects reduced all joint torque deviations, regardless of relevance to leg force, suggesting that when subjects achieved the task goal, they switched from a minimal intervention strategy to a total noise reduction strategy. As subjects adapt to split-belt walking, they reduce hip work and shift to doing more ankle work in the step-to-step transition. Because ankle work in the step-to-step transition is more efficient, this ankle timing strategy likely contributes to the reduction in metabolic power during split-belt walking. Both amputees and controls gradually adapted step length symmetry in split-belt walking, demonstrating an aftereffect when the split-belt condition was removed. This result is consistent with previous studies of intact subjects and indicates that interlimb coordination is changed using feedforward control. Subjects also adapt to split-belt walking by moving farther backward in single support on the fast belt and less backward on the slow belt. This center of mass displacement strategy persists in amputees and controls, when the split-belt condition is introduced gradually or suddenly, and no matter which belt the prosthetic foot is on. This work suggests that mechanical changes that improve efficiency underlie the reduction in metabolic power during split-belt walking adaptation.

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