Microsatellites, or simple tandem repeat sequences, occur naturally in the human genome and have important roles in genome evolution and function. However, the expansion of microsatellites is associated with over two dozen neurological diseases. A common denominator among the majority of these disorders is the expression of expanded tandem repeat-containing RNA, referred to as xtrRNA, which can mediate molecular disease pathology in multiple ways. Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are two fatal neurodegenerative diseases with significant clinical, neurological and genetic overlap thus referred to as C9FTD/ALS. Currently, gaps in the study of the underlying disease mechanisms persist, which can aid in the identification of promising therapeutic approaches. Access to simple models of neurological repeat expansion disease is critical for investigating biochemical mechanisms and for early therapeutic discovery. To better understand the molecular pathology of C9FTD/ALS repeat expansion disorder, we cloned GGGGCC repeats, which are the leading genetic cause of C9FTD/ALS. We employed a recursive directional ligation (RDL) technique to build multiple GGGGCC repeat-containing vectors and validated the cloning to facilitate step-by-step characterization of disease mechanisms at the cellular and molecular level using these vectors. In this study, we also differentiated C9FTD/ALS patient-derived induced pluripotent stem cells (iPSCs) to neural stem cells (NSCs) to be used as model systems. The use of iPSCs and NSCs to reveal important insights into the pathogenic mechanisms and to generate multiple neural cell types presents an excellent opportunity for researchers to model neurodegenerative diseases for cell therapy and drug discovery. We further investigated potential nuclear export mechanisms for C9FTD/ALS xtrRNA. The nuclear export mechanisms of xtrRNA in C9FTD/ALS are not well studied. ASOs and siRNAs were employed to knockdown genes of interest to study their involvement in the nuclear export of xtrRNA. We saw promising results on knockdown of TorsinA involved in nuclear export of xtrRNAs, corroborated by a substantial increase in the average number of xtrRNA foci in the nucleus. Our initial study provides evidence that TOR1A may be involved in the nuclear export of aberrant C9FTD/ALS repeat-containing RNAs. Due to the lack of reliable and robust assays to detect RAN translation products, the effect of the knockdown of TorsinA in these cell lines still remains to be explored. But the current study lays the groundwork for a deeper understanding of the less-studied nuclear export mechanisms in C9FTD/ALS and could reveal new therapeutic approaches to selectively block the nuclear export of xtrRNA through the use of RNAi and ASOs. The insights gained from this study will help us understand future events in the xtrRNA life cycle such as repeat translation mechanisms.

During the last decade, relay networks have attracted a lot of interest due to their numerous benefits. The relaying technique allows extending the coverage zone of wireless networks and offers a higher reliability for communication systems. The performance of relay networks can be improved further by the use of automatic repeat request (ARQ) and hybrid automatic repeat request (HARQ) techniques. ARQ and HARQ are retransmission mechanisms that ensure a good quality of service even in absence of channel state information at the transmitter. We, firstly, study the spectral and energy efficiency of ARQ in Nakagami-m block-fading channels. We maximize both spectral efficiency and energy efficiency with respect to the transmitted power. We derive exact expressions as well as compact and tight approximation for the solutions of these problems. Our analysis shows that the two problems of maximizing spectral efficiency and energy efficiency with respect to the transmitted power are completely different and give different solutions. Additionally, operating with a power that maximizes energy efficiency can lead to a significant drop in the spectral efficiency, and vice versa. Next, we consider a three node relay network comprising a source, a relay, and a destination. The source transmits the message to the destination using HARQ with incremental redundancy (IR). The relay overhears the transmitted message, amplifies it using a variable gain amplifier, and then forwards the message to the destination. This latter combines both the source and the relay message and tries to decode the information. In case of decoding failure, the destination sends a negative acknowledgement. A new replica of the message containing new parity bits is then transmitted in the subsequent HARQ round. This process continues until successful decoding occurs at the destination or a maximum number M of rounds is reached. We study the performance of HARQ-IR over the considered relay channel from an information theoretic perspective. We derive exact expressions and bounds for the information outage probability, the average number of transmissions, and the average transmission rate. Moreover, we evaluate the delay experienced by Poisson arriving packets over the considered relay network. We also provide analytical expressions for the expected waiting time, the sojourn time, and the energy efficiency. The derived exact expressions are validated by Monte Carlo simulations. Finally, we consider a relay network consisting of a source, K relays, and a destination. The source transmits a message to the destination using HARQ-IR. We study the performance of HARQ-IR over dualhop multibranch amplify-and-forward relay channels. We derive exact expression for outage probability of the considered network. We investigate the benefit of relaying and the effect of changing the rate and the maximum number M of rounds on the outage probability.

No description available.

Our knowledge discovery algorithm employs a combination of association rule mining and graph mining to identify frequent spatial proximity relationships in genomic data where the data is viewed as a one-dimensional space. We apply mining techniques and metrics from association rule mining to identify frequently co-occurring features in genomes followed by graph mining to extract sets of co-occurring features. Using a case study of ab initio repeat finding, we have shown that our algorithm, ProxMiner, can be successfully applied to identify weakly conserved patterns among features in genomic data. The application of pairwise spatial relationships increases the sensitivity of our algorithm while the use of a confidence threshold based on false discovery rate reduces the noise in our results. Unlike available defragmentation algorithms, ProxMiner discovers associations among ab initio repeat families to identify larger more complete repeat families. ProxMiner will increase the effectiveness of repeat discovery techniques for newly sequenced genomes where ab initio repeat finders are only able to identify partial repeat families. In this dissertation, we provide two detailed examples of ProxMiner-discovered novel repeat families and one example of a known rice repeat family that has been extended by ProxMiner. These examples encompass some of the different types of repeat families that can be discovered by our algorithm. We have also discovered many other potentially interesting novel repeat families that can be further studied by biologists.

International Telemetering Conference Proceedings / October 25-28, 1993 / Riviera Hotel and Convention Center, Las Vegas, Nevada / Soft-decision correlation decoding with retransmission requests for block codes is proposed and the resulting performance is analyzed. The correlation decoding rule is modified to allow retransmission requests when the received word is rendered unreliable by the channel noise. The modification is realized by a reduction in the volume in Euclidean space of the decoding region corresponding to each codeword. The performance analysis reveals the typical throughput - reliability trade-off characteristic of error control systems which employ retransmissions. Performance comparisons with hard-decision decoding reveal performance improvements beyond those attainable with hard-decision decoding algorithms. The proposed soft-decision decoding rule permits the use of a simplified codeword searching algorithm which reduces the complexity of the correlation decoder to the point where practical implementation is feasible.

Polyadenylation is an essential post-transcriptional modification resulting in a mature mRNA in eukaryotes. Three cis-elements the Far Upstream Element (FUE), Near Upstream Element (NUE), and Cleavage Site (CS) - guide the process of cleavage and polyadenylation with the help of multi-subunit protein complexes cleavage and polyadenylation specificity factor (CPSF), cleavage stimulation factor (CstF) along with cleavage factors and poly(A) polymerase. Protein-protein interactions play an important role in the cleavage and polyadenylation process. WD repeat proteins play an important role in protein-protein interactions and have diverse functions in plant system. In the present study WD repeat proteins AtCstF50 and AtFY were studied for their role in polyadenylation process. Mammalian CstF50 is a WD repeat protein that is one of the subunit of CstF that aids in the cleavage step by associating with CPSF and cleavage factors. AtCstF50 was functionally characterized using T-DNA knock-out lines and by identifying the proteins that interacts with it in the process. Results shows that AtCstF50 is essential and was identified as part of CPSF complex, which is different from its mammalian counter part. CPSF was known to interact with Fip (factor interacting with PAP), Poly(A) polymerase and Poly(A) binding protein and AtCstF50 also interacts with these complexes. AtFY is a 3’ end processing factor which contains WD repeats is one of the subunits of the CPSF complex in Arabidopsis polyadenylation machinery. The AtFY interacts with FCA and promotes the alternative polyadenylation and also plays a role in polyadenylation site choice of FCA mRNA. We characterized the FY expression and localization of FY in the cell by fusing with RFP reporter. Results show that FY accumulates in the nucleus while FY with deleted calmodulin binding domain localizes both to the nucleus and outside the nucleus. The individual N-terminal and C-terminal domains also localized in the nucleus suggesting that they are multiple nuclear localization signals in FY and calmodulin might play a direct or indirect role in FY localization. Using a tethering assay we proved that AtFY is able to recruit the 3’ end processing complex in the proximal polyadenylation site choice of the reporter mRNA.

CAG/CTG repeat instability is associated with at least 14 neurological disorders, including Huntington’s disease and Myotonic dystrophy type 1. In vitro and in vivo studies have showed that CAG/CTG repeats form a stable hairpin that is believed to be the intermediate for repeat expansion and contraction. Addition of extra DNA is essential for repeat expansion, so DNA synthesis is one of the keys for repeat expansion. In vivo studies reveal that 3’ CTG slippage with subsequent hairpin formation (henceforth called the 3’ CTG slippage hairpin) occurs during DNA synthesis. It is proposed that hairpin tolerance machinery is activated because prolonged stalling of DNA polymerase triggers severe DNA damage. As a means toward studying the hairpin-mediated expansion, we created a special hairpin substrate, mimicking the 3’ CTG slippage hairpin, to determine which polymerase promotes hairpin bypass. Our studies reveal polymerase β (pol β) is involved in the initial hairpin synthesis while polymerase δ (pol δ) is responsible for the resumption of DNA synthesis beyond the hairpin (extension step). Surprisingly, we also found that the pol δ can remove the short CTG hairpin by excision of the hairpin with its 3’ to 5’ exonuclease activity. Besides repairing the hairpin directly, resolving the hairpin is an alternative pathway to maintain CAG/CTG repeat stability. With limited understanding of which human helicase is responsible for resolving CAG/CTG hairpins, we conducted a screening approach to identify the human helicase involved. Werner Syndrome Protein (WRN) induces the hairpin repair activity when (CTG)35 hairpin is formed on the template strand. Primer extension assay reveals that WRN stimulates pol δ synthesis on (CAG)35/(CTG)35 template and such induction was still found in the presence of accessory factors. Helicase assay confirms that WRN unwinds CTG hairpin structures. Our studies provide a better understanding of how polymerases and helicases play a role in CAG/CTG repeat instability. Considering CAG/CTG repeat instability associated disorders are still incurable, our studies can provide several potential therapeutic targets for treating and/or preventing CAG/CTG repeat associated disorders.

Scouring is the process of soil or sediment erosion due to flowing water, which can lead to bed degradation and compromised transportation infrastructure. In the decade before 2000, over half of the 500 bridge failures in the United States were caused by flooding or scouring. To gain a better grasp of the effects of extreme weather events, such as Tropical Storm Irene, on the scouring process, this work is focused on a first principle understanding of the mechanism(s) of scour. The field of Computational Fluid Dynamics (CFD) is particu larly well suited to this task. Utilizing a Direct Numerical Simulation (DNS) code, the repeated impacts of a vortex dipole on a particle bed are simulated. The resulting scour characteristics and flow dynamics are investigated as a function of the Shields number. The vortex dipole propagates perpendicularly to the particle bed, resulting in the scouring of the bed and dissipation of the dipole. After completion of the scour event, the simulation is repeated four more times, where subsequent simulations use the scoured bed from the previous simulation as the initial bed form. This simulation series is conducted over a Shields number parameter space. The fluid phase is treated as a continuum and the discretized Navier-Stokes equations are solved down to the smallest scales of the flow on an Eulerian grid. The particles comprising the bed are represented by the Discrete Particle Model (DPM), whereby each individual particle is tracked in a Lagrangian framework. Particle-particle and particle-wall collisions are calculated using a soft-sphere model. The fluid phase and the solid phase are coupled through a forcing term in the fluid conservation of momentum equation, and a drag force in the particle equation of motion, governed by Newton's Second Law. Above the critical Shields number, the scour hole topography is not fundamentally altered with subsequent impacts until the scale of the scour hole reaches a critical value. At which point, the shape and scale of the scour hole significantly alters the behavior of the vortex dipole and results in strongly asymmetric scour topographies. This two-way coupling between the bed scour and the vortex dipole dynamics is the focus of this work.

The purpose of this dissertation is to better understand the role of repeated-sprint ability (RSA) and resulting fatigue in cyclists; how it relates to measures of aerobic power and strength and power performance indices- due to the nature of cycling competitions and the necessity of RSA for success. The first part of this dissertation attempted to elucidate the relationship between RSA and aerobic power and strength/ power measures in competitive cyclists. The purpose was to potentially illustrate the importance of the inclusion of strength and power training in the training regimen of cyclists. The findings showed several statistically significant relationships between variables of RSA and aerobic power or the isometric squat test. The second part of the dissertation examined the effects of fatigue induced from the acute bout of repeat sprint exercise on strength and power measures in three different recovery periods. It is commonplace for cyclists to have several heats in one day of racing. Examining the effects of fatigue on strength measures such as peak force and rate of force development could begin to delineate how an individual experiences fatigue based on their own characteristics, enabling them to design a training program to address these strengths/ weaknesses to optimize performance and decrease fatigue. The results from a repeated measures analysis of variance found no statistically significant effect on PF or RFD. Additional comparisons showed moderate effects of fatigue on RFD throughout the three post-RSE trials. There was also a moderate correlation between the RSE fatigue % decrement score and the isometric RFD fatigue % decrement score. What we may conclude from this dissertation is that fatigue has various causes and can vary with an individuals’ unique physiology and how they respond to performance variables on any specific day can vary. Development of increased strength and subsequent power, or “explosive strength”, may have advantages in competitive cycling. Coupling proper strength and power training with an aerobic training regimen, may greatly benefit the athlete by increasing their peak power output, economy of movement, delaying fatigue, improving anaerobic capacity, and overall enhancing their maximal speed.

Thesis advisor: Hideo Konishi / Becker (1968) provides a formal framework for analyzing various policies in criminal law. Within this framework there are potential criminals, who have varying benefits from committing an illegal act. They are subject to sanctions when they are caught and are found guilty for committing such acts. Accordingly, increased expected sanctions lead to greater deterrence. There are also costs associated with achieving such deterrence. Hence, there are optimal policy variables which balance costs and gains associated with increased deterrence. In my dissertation, in five independent but closely related essays, I address various issues related to criminal law by making use of optimal crime and deterrence models, which are similar to Becker (1968). First, I analyze the standard of proof in criminal trials and extend a justification as to why there are higher standards of proof in criminal trials versus civil trials. Next, I introduce the concept of mixed warning strategies, and justify the use of mixed as well as pure warning strategies in law enforcement. In a related essay, I show that it is optimal to punish repeat offenders more severely than first time offenders, provided that offenders gain experience in evading detection by committing offenses. In my fourth essay, I identify reasons as to why it is welfare improving to allow individuals to self-report conduct crimes. Finally, I propose a simple framework to incorporate the concept of remorse in the economic analysis of criminal law, and show that the Beckerian maximal fine result need not hold when some individuals feel remorse. / Thesis (PhD) — Boston College, 2010. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Economics.