Decoding function through comparative genomics: from animal evolution to human disease

Deciphering the functionality encoded in the genome constitutes an essential first step to understanding the context through which mutations can cause human disease. In this dissertation, I present multiple studies based on the use or development of comparative genomics techniques to elucidate function (or lack of function) from the genomes of humans and other animal species. Collectively, these studies focus on two biological entities encoded in the human genome: genes related to human disease susceptibility and those that encode microRNAs - small RNAs that have important gene-regulatory roles in normal biological function and in human disease. Extending this work, I investigated the evolution of these biological entities within animals to shed light on how their underlying functions arose and how they can be modeled in non-human species. Additionally, I present a new tool that uses large-scale clinical genomic data to identify human mutations that may affect microRNA regulatory functions, thereby providing a method by which state-of-the-art genomic technologies can be fully utilized in the search for new disease mechanisms and potential drug targets. The scientific contributions made in this dissertation utilize current data sets generated using high-throughput sequencing technologies. For example, recent whole-genome sequencing studies of the most distant animal lineages have effectively restructured the animal tree of life as we understand it. The first two chapters utilize data from this new high-confidence animal phylogeny - in addition to data generated in the course of my work - to demonstrate that (1) certain classes of human disease have uncommonly large proportions of genes that evolved with the earliest animals and/or vertebrates, and (2) that canonical microRNA functionality - absent in at least two of the early branching animal lineages - likely evolved after the first animals. In the third chapter, I expand upon recent research in predicting microRNA target sites, describing a novel tool for predicting clinically significant microRNA target site variants and demonstrating its applicability to the analysis of clinical genomic data. Thus, the studies detailed in this dissertation represent significant advances in our understanding of the functions of disease genes and microRNAs from both an evolutionary and a clinical perspective

Effect of sediment slurry application on selected aspects of sulfur, iron, and manganese biogeochemistry in a coastal Louisiana marsh

Coastal wetlands, long recognized to be among the most productive ecosystems on the planet, are being lost at a disturbingly high rate in coastal Louisiana due to both eustatic sea-level rise and land subsidence. A number of approaches have been proposed for reducing wetland loss and restoring deteriorated wetlands, among which the addition of sediment to increase marsh surface elevation is promising. However, little is known about how the added sediment affects the biogeochemistry of marsh sediment. The objective of this study was to determine the effects of sediment slurry addition on sulfur, iron, and manganese biogeochemistry in a subsiding Spartina patens dominated marsh in coastal Louisiana. The study site was located inside the Paul J. Rainey Wildlife Sanctuary in Vermillion Parish, Louisiana where low, medium, or high levels of sediment slurry were added to each study plot in July of 2008. Sediment and porewater samples were collected from the control (i.e. no sediment addition), low, medium, and high sediment treatment plots approximately on a seasonal basis from February 2009 to June 2011. Laboratory incubation of sediment using the radioisotope 35S technique showed that there was no significant difference (p=0.2201) among the treatments in the rate of sulfate reduction 3 years after sediment slurry addition. However, significant increases (p=0.0007) in average concentrations of sulfate in sediment and decreases (p\u3c0.0001) in sulfide in porewater with sediment addition over the 3 years’ measurements indicate that there likely was a decrease in sulfate reduction rate with increasing sediment addition during the preceding 3 years. Concentrations of sediment and porewater iron and manganese significantly increased when sediment addition increased, which was primarily attributed to the high levels of these two elements in the added sediment. The increased iron and manganese concentrations could, in part, explain the lower level of sulfide observed in the sediment-treated plots over the 3 year study. Additionally, average pH and redox increased significantly with sediment addition (p\u3c0.0001 and p=0.0084, respectively). More samplings are needed to better understand the long-term impacts of sediment slurry addition on the rate of sulfate reduction in marsh sediment

Tiny Groups Tackle Byzantine Adversaries

A popular technique for tolerating malicious faults in open distributed systems is to establish small groups of participants, each of which has a non-faulty majority. These groups are used as building blocks to design attack-resistant algorithms. Despite over a decade of active research, current constructions require group sizes of $O(\log n)$, where $n$ is the number of participants in the system. This group size is important since communication and state costs scale polynomially with this parameter. Given the stubbornness of this logarithmic barrier, a natural question is whether better bounds are possible. Here, we consider an attacker that controls a constant fraction of the total computational resources in the system. By leveraging proof-of-work (PoW), we demonstrate how to reduce the group size exponentially to $O(\log\log n)$ while maintaining strong security guarantees. This reduction in group size yields a significant improvement in communication and state costs.Comment: This work is supported by the National Science Foundation grant CCF 1613772 and a C Spire Research Gif

A comparison of stage-specific all-cause mortality between testicular sex cord stromal tumors and germ cell tumors: results from the National Cancer Database.

BackgroundTesticular sex cord stromal tumors (SCSTs) are managed similarly to germ cell tumors (GCTs); however, few studies have directly compared outcomes between these tumor types. Using the National Cancer Database (NCDB), we sought to compare overall and stage-specific all-cause mortality (ACM) between SCSTs versus GCTs.MethodsNCDB was queried for patients diagnosed with SCSTs and GCTs between 2004 and 2013. Descriptive statistics were used to compare sociodemographic and clinical characteristics between groups. Univariable and multivariable Cox proportional hazards regression analyses were used to assess associations with ACM.ResultsWe identified 42,192 patients diagnosed with testicular cancer between 2004 and 2013, with 280 having SCSTs and 41,912 patients having GCTs. Median age for SCSTs and GCTs was 45 (interquartile range [IQR] 34-59) and 34 (IQR 27-43), respectively (p < 0.001). Median follow-up was 39 and 52 months, respectively. Overall, patients with SCSTs had greater risk of ACM compared to those with GCTs (HR 1.69, 95% CI 1.14-2.50). Private insurance, greater education, and fewer comorbidities were associated with reduced risk of ACM (p < 0.05 for all). Among those with stage I disease, tumor type was not associated with ACM on multivariable analysis. Among those with stage II/III disease, patients with SCSTs had increased risk of ACM compared to patients with GCTs (HR 3.29, 95% CI 1.89-5.72).ConclusionsPatients with advanced SCSTs had worse survival outcomes compared to those with advanced GCTs. These data suggest a need for further investigation to ascertain effective management recommendations for SCSTs

Isostaticity of Constraints in Jammed Systems of Soft Frictionless Platonic Solids

The average number of constraints per particle $$ in mechanically stable systems of Platonic solids (except cubes) approaches the isostatic limit at the jamming point ($\rightarrow 12$), though average number of contacts are hypostatic. By introducing angular alignment metrics to classify the degree of constraint imposed by each contact, constraints are shown to arise as a direct result of local orientational order reflected in edge-face and face-face alignment angle distributions. With approximately one face-face contact per particle at jamming chain-like face-face clusters with finite extent form in these systems.Comment: 4 pages, 3 figures, 4 tabl

Self-handicapping mediates between impulsiveness and self-discipline

Self-handicapping, while not a very acknowledged tendency, is very prevalent today. Especially among students of any grade level, the behavior prevents many from reaching their full potential. The purpose of this experiment was to see how Selfhandicapping mediated between Impulsiveness and Self-discipline which can later be used by teachers to help students with this phenomenon. A short survey was given to psychology undergraduate students at the University of Tennessee-Chattanooga whose age ranged from 18-44 and were predominantly Caucasian. Self-handicapping was found to mediate between Impulsiveness and Self-discipline (r = .512) compared to Impulsiveness and Self-discipline (r= .288) without using self-handicapping as a mediator. The implications that can be taken from this study include using the results in an educational setting to pinpoint selfhandicapping tendencies. Despite limitations in the study, it was conducted in an environment that was cohesive to the environment in which it would be applied

Dashing away hypertension: Evaluating the efficacy of the dietary approaches to stop hypertension diet in controlling high blood pressure

The dietary approaches to stop hypertension (DASH) diet has been developed and popularized as a non-pharmaceutical intervention for high blood pressure reduction since 1995. However, to date, a comprehensive description of the biochemical rationale behind the diet’s principal guidelines has yet to be compiled. With rising interest for healthy and reliable life-style modifications to combat cardiovascular disease, this review aims to compile the most recent and relevant studies on this topic and make an informed assessment as to the efficacy of and underlying mechanisms operant in the DASH diet. Specifically, the merits of lowering dietary intake of sodium and saturated fat, as well as increasing the intake of fruits, vegetables, fiber, and dairy, have been shown to attenuate hypertension individually. Upon review of this evidence, we conclude that the combination of dietary patterns proposed in the DASH diet is effective in attenuating high blood pressure. We also suggest that efforts to more widely implement adoption of the DASH diet would be beneficial to public health

The ocean’s role in the transient response of climate to abrupt greenhouse gas forcing

We study the role of the ocean in setting the patterns and timescale of the transient response of the climate to anthropogenic greenhouse gas forcing. A novel framework is set out which involves integration of an ocean-only model in which the anthropogenic temperature signal is forced from the surface by anomalous downwelling heat fluxes and damped at a rate controlled by a ‘climate feedback’ parameter. We observe a broad correspondence between the evolution of the anthropogenic temperature (T[subscript anthro]) in our simplified ocean-only model and that of coupled climate models perturbed by a quadrupling of CO[subscript 2]. This suggests that many of the mechanisms at work in fully coupled models are captured by our idealized ocean-only system. The framework allows us to probe the role of the ocean in delaying warming signals in the Southern Ocean and in the northern North Atlantic, and in amplifying the warming signal in the Arctic. By comparing active and passive temperature-like tracers we assess the degree to which changes in ocean circulation play a role in setting the distribution and evolution of T[subscript anthro]. The background ocean circulation strongly influences the large-scale patterns of ocean heat uptake and storage, such that T[subscript anthro] is governed by an advection/diffusion equation and weakly damped to the atmosphere at a rate set by climate feedbacks. Where warming is sufficiently small, for example in the Southern Ocean, changes in ocean circulation play a secondary role. In other regions, most noticeably in the North Atlantic, changes in ocean circulation induced by T[subscript anthro] are central in shaping the response.United States. National Aeronautics and Space Administration. Modeling, Analysis, and Prediction ProgramMassachusetts Institute of Technology. Joint Program on the Science & Policy of Global ChangeJames S. McDonnell Foundation (Postdoctoral Fellowship

pNaKtide inhibits Na/K-ATPase reactive oxygen species amplification and attenuates adipogenesis

Obesity has become a worldwide epidemic and is a major risk factor for metabolic syndrome. Oxidative stress is known to play a role in the generation and maintenance of an obesity phenotype in both isolated adipocytes and intact animals. Because we had identified that the Na/K-ATPase can amplify oxidant signaling, we speculated that a peptide designed to inhibit this pathway, pNaKtide, might ameliorate an obesity phenotype. To test this hypothesis, we first performed studies in isolated murine preadipocytes (3T3L1 cells) and found that pNaKtide attenuated oxidant stress and lipid accumulation in a dose-dependent manner. Complementary experiments in C57Bl6 mice fed a high-fat diet corroborated our in vitro observations. Administration of pNaKtide in these mice reduced body weight gain, restored systemic redox and inflammatory milieu, and, crucially, improved insulin sensitivity. Thus, we propose that inhibition of Na/K-ATPase amplification of oxidative stress may ultimately be a novel way to combat obesity, insulin resistance, and metabolic syndrome

Clinical Study The Effect of Withdrawal and Intake of Nicotine on Smokers' Ability to Ignore Distractors in a Number Parity Decision Task

Nicotine's attention enhancing effects are often attributed to enhancement of stimulus filtering by the attention networks. We investigated distractibility in 20 abstinent cigarette smokers (9 hours overnight; phase 1) and tested them again after smoking one cigarette (phase 2). Their performance was compared to 20 nonsmokers (no nicotine intake). In an auditory number parity decision task, participants had to make a forced choice "odd" or "even" decision about centrally presented numbers between 2 and 9, while ignoring laterally presented preceding or simultaneous novel distractors. In phase 1, distractors that preceded goal stimuli slowed reaction times (RTs) more than simultaneously presented distractors in both groups. In phase 2, nicotine intake speeded RTs in smokers in all conditions and reduced RT variability for simple number decisions and simultaneous distractors. Overall, there was a nonsignificant trend for smokers to be less accurate than nonsmokers. Accuracy in the simultaneous distractor condition decreased in both groups in phase 2. We argue that the observed nicotine-induced improvements on behavioral performance primarily reflect enhancement of top-down control of attention