Practical Approaches to Biological Network Discovery

This dissertation addresses a current outstanding problem in the field of systems biology, which is to identify the structure of a transcriptional network from high-throughput experimental data. Understanding of the connectivity of a transcriptional network is an important piece of the puzzle, which relates the genotype of an organism to its phenotypes. An overwhelming number of computational approaches have been proposed to perform integrative analyses on large collections of high-throughput gene expression datasets to infer the structure of transcriptional networks. I put forth a methodology by which these tools can be evaluated and compared against one another to better understand their strengths and weaknesses. Next I undertake the task of utilizing high-throughput datasets to learn new and interesting network biology in the pathogenic fungus Cryptococcus neoformans. Finally I propose a novel computational method for mapping out transcriptional networks that unifies two orthogonal strategies for network inference. I apply this method to map out the transcriptional network of Saccharomyces cerevisiae and demonstrate how network inference results can complement chromatin immunoprecipitation: ChIP) experiments, which directly probe the binding events of transcriptional regulators. Collectively, my contributions improve both the accessibility and practicality of network inference methods

Roadmap Analysis of Protein-Protein Interactions. Master\u27s Thesis, August 2007

The ability to effectively model the interaction between proteins is an important and open problem. In molecular biology it is well accepted that from sequence arises form and from form arises function but relating structure to function remains a challenge. The function of a given protein is defined by its interactions. Likewise a malfunction or a change in protein-protein interactions is a hallmark of many diseases. Many researchers are studying the mechanisms of protein-protein interactions and one of the overarching goals of the community is to predict whether two proteins will bind, and if so what the final conformation will be. Attention is seldom paid to the association pathways that allow two proteins to bind. Evidence has shown that the information in the association pathways can play a vital role in understanding the interaction itself. This thesis presents a novel and scalable approach to computing association pathways between two proteins using the Probabilistic Roadmap (PRM) framework. We will discuss the challenges in extending PRM to the domain of protein-protein interactions such as performing structural mappings in a reduced space of flexibility, and sampling high dimensional conformation spaces. We will present analysis of individual association pathways as well as methods for estimating collective properties of the energy landscape. Our results indicate that these methods can discriminate between true and false protein binding interfaces. Finally, we will present condensing methods such as pathway clustering and visualization using dimensionality reduction that can be be applied to create compact representations of the interaction space

Optimal search strategies for identifying mental health content in MEDLINE: an analytic survey

OBJECTIVE: General practitioners, mental health practitioners, and researchers wishing to retrieve the best current research evidence in the content area of mental health may have a difficult time when searching large electronic databases such as MEDLINE. When MEDLINE is searched unaided, key articles are often missed while retrieving many articles that are irrelevant to the search. The objectives of this study were to develop optimal search strategies to detect articles with mental health content and to determine the effect of combining mental health content search strategies with methodologic search strategies calibrated to detect the best studies of treatment. METHOD: An analytic survey was conducted, comparing hand searches of 29 journals with retrievals from MEDLINE for 3,395 candidate search terms and 11,317 combinations. The sensitivity, specificity, precision, and accuracy of the search strategies were calculated. RESULTS: 3,277 (26.8%) of the 12,233 articles classified in the 29 journals were considered to be of interest to the discipline area of mental health. Search term combinations reached peak sensitivities of 98.4% with specificity at 50.0%, whereas combinations of search terms to optimize specificity reached peak specificities of 97.1% with sensitivity at 51.7%. Combining content search strategies with methodologic search strategies for treatment led to improved precision: substantive decreases in the number of articles that needed to be sorted through in order to find target articles. CONCLUSION: Empirically derived search strategies can achieve high sensitivity and specificity for retrieving mental health content from MEDLINE. Combining content search strategies with methodologic search strategies led to more precise searches

The parish churches of Norwich north of the River Wensum: city, community, architecture and antiquarianism

Norwich Ultra Aquam (‘over the water’) formed a discrete leet or administrative area within the medieval city. At its heart was an Anglo-Scandinavian defensive enclosure, with Coslany lying to the west, and later suburban developments to the north and east. Evidence from topographic, dedicatory, archaeological and inter-parochial relationships, suggests that the pattern of church foundation was both complex and distinctive. Unlike several parishes south of the river, there are no indications that the early phases of Ultra Aquam church foundations were the initiative of senior ecclesiastics, or had specifically royal connections. Rather, they were local projects responding to the manner in which the city was developing. Later in the Middle Ages monastic interest on the north bank increased but several of the churches remained in secular hands. Patronage, whether lay or ecclesiastical, played a key part in their architectural development; St Michael Coslany and St George Colegate in particular received considerable burgess investment. The rich antiquarian tradition in the city provides a record of attitudes to the churches in the post-Reformation period which has to be understood in terms of priorities that changed over time

NGC 4254: An Act of Harassment Uncovered by the Arecibo Legacy Fast ALFA Survey

We present an HI map constructed from the Arecibo Legacy Fast ALFA (ALFALFA) survey of the surroundings of the strongly asymmetric Virgo cluster Sc galaxy NGC 4254. Noted previously for its lopsided appearance, rich interstellar medium, and extradisk HI emission, NGC 4254 is believed to be entering the Virgo environment for the first time and at high speed. The ALFALFA map clearly shows a long HI tail extending ~250 kpc northward from the galaxy. Embedded as one condensation within this HI structure is the object previously identified as a "dark galaxy": Virgo HI21 (Davies et al. 2004). A body of evidence including its location within and velocity with respect to the cluster and the appearance and kinematics of its strong spiral pattern, extra-disk HI and lengthy HI tail is consistent with a picture of "galaxy harassment" as proposed by Moore et al. (1996a,b; 1998). The smoothly varying radial velocity field along the tail as it emerges from NGC 4254 can be used as a timing tool, if interpreted as resulting from the coupling of the rotation of the disk and the collective gravitational forces associated with the harassment mechanism.Comment: accepted for publication in Ap.J.(Lett.). higher resolution figure available at http://egg.astro.cornell.edu/alfalfa/pubs/figs/n4254_f1.ep

Physiological and molecular changes in Oryza meridionalis Ng., a heat-tolerant species of wild rice

Oryza meridionalis Ng. is a wild relative of Oryza sativa L. found throughout northern Australia where temperatures regularly exceed 35 °C in the monsoon growing season. Heat tolerance in O. meridionalis was established by comparing leaf elongation and photosynthetic rates at 45 °C with plants maintained at 27 °C. By comparison with O. sativa ssp. japonica cv. Amaroo, O. meridionalis was heat tolerant. Elongation rates of the third leaf of O. meridionalis declined by 47% over 24 h at 45 °C compared with a 91% decrease for O. sativa. Net photosynthesis was significantly higher in O. sativa at 27 °C whereas the two species had the same assimilation rates at 45 °C. The leaf proteome and expression levels of individual heat-responsive genes provided insight into the heat response of O. meridionalis. After 24 h of heat exposure, many enzymes involved in the Calvin Cycle were more abundant, while mRNA of their genes generally decreased. Ferredoxin-NADP(H) oxidoreductase, a key enzyme in photosynthetic electron transport had both reduced abundance and gene expression, suggesting light reactions were highly susceptible to heat stress. Rubisco activase was strongly up-regulated after 24 h of heat, with the large isoform having the largest relative increase in protein abundance and a significant increase in gene expression. The protective proteins Cpn60, Hsp90, and Hsp70 all increased in both protein abundance and gene expression. A thiamine biosynthesis protein (THI1), previously shown to act protectively against stress, increased in abundance during heat, even as thiamine levels fell in O. meridionalis

An overview of the design and methods for retrieving high-quality studies for clinical care

BACKGROUND: With the information explosion, the retrieval of the best clinical evidence from large, general purpose, bibliographic databases such as MEDLINE can be difficult. Both researchers conducting systematic reviews and clinicians faced with a patient care question are confronted with the daunting task of searching for the best medical literature in electronic databases. Many have advocated the use of search filters or "hedges" to assist with the searching process. The purpose of this report is to describe the design and methods of a study that set out to develop optimal search strategies for retrieving sound clinical studies of health disorders in large electronics databases. OBJECTIVE: To describe the design and methods of a study that set out to develop optimal search strategies for retrieving sound clinical studies of health disorders in large electronic databases. DESIGN: An analytic survey comparing hand searches of 170 journals in the year 2000 with retrievals from MEDLINE, EMBASE, CINAHL, and PsycINFO for candidate search terms and combinations. The sensitivity, specificity, precision, and accuracy of unique search terms and combinations of search terms were calculated. CONCLUSION: A study design modeled after a diagnostic testing procedure with a gold standard (the hand search of the literature) and a test (the search terms) is an effective way of developing, testing, and validating search strategies for use in large electronic databases

Technology Candidates for Air-to-Air and Air-to-Ground Data Exchange

Technology Candidates for Air-to-Air and Air-to-Ground Data Exchange is a two-year research effort to visualize the U. S. aviation industry at a point 50 years in the future, and to define potential communication solutions to meet those future data exchange needs. The research team, led by XCELAR, was tasked with identifying future National Airspace System (NAS) scenarios, determining requirements and functions (including gaps), investigating technical and business issues for air, ground, & air-to-ground interactions, and reporting on the results. The project was conducted under technical direction from NASA and in collaboration with XCELAR's partner, National Institute of Aerospace, and NASA technical representatives. Parallel efforts were initiated to define the information exchange functional needs of the future NAS, and specific communication link technologies to potentially serve those needs. Those efforts converged with the mapping of each identified future NAS function to potential enabling communication solutions; those solutions were then compared with, and ranked relative to, each other on a technical basis in a structured analysis process. The technical solutions emerging from that process were then assessed from a business case perspective to determine their viability from a real-world adoption and deployment standpoint. The results of that analysis produced a proposed set of future solutions and most promising candidate technologies. Gap analyses were conducted at two points in the process, the first examining technical factors, and the second as part of the business case analysis. In each case, no gaps or unmet needs were identified in applying the solutions evaluated to the requirements identified. The future communication solutions identified in the research comprise both specific link technologies and two enabling technologies that apply to most or all specific links. As a result, the research resulted in a new analysis approach, viewing the underlying architecture of ground-air and air-air communications as a whole, rather than as simple "link to function" paired solutions. For the business case analysis, a number of "reference architectures" were developed for both the future technologies and the current systems, based on three typical configurations of current aircraft. Current and future costs were assigned, and various comparisons made between the current and future architectures. In general, it was assumed that if a future architecture offers lower cost than the current typical architecture, while delivering equivalent or better performance, it is likely that the future solution will gain industry acceptance. Conversely, future architectures presenting higher costs than their current counterparts must present a compelling benefit case in other areas or risk a lack of industry acceptance. The business case analysis consistently indicated lower costs for the proposed future architectures, and in most cases, significantly so. The proposed future solutions were found to offer significantly greater functionality, flexibility, and growth potential over time, at lower cost, than current systems. This was true for overall, fleet-wide equipage for domestic and oceanic air carriers, as well as for single, General Aviation (GA) aircraft. The overall research results indicate that all identified requirements can be met by the proposed solutions with significant capacity for future growth. Results also illustrate that the majority of the future communication needs can be met using currently allocated aviation RF spectrum, if used in more effective ways than it is today. A combination of such optimized aviation-specific links and commercial communication systems meets all identified needs for the 50-year future and beyond, with the caveat that a new, overall function will be needed to manage all information exchange, individual links, security, cost, and other factors. This function was labeled "Delivery Manager" (DM) within this research. DM employs a distributed client/server architecture, for both airborne and ground communications architectures. Final research results included identifying the most promising candidate technologies for the future system, conclusions and recommendations, and identifying areas where further research should be considered