Copyright (c) 2009 University of Pennsylvania All rights reserved. http://repository.upenn.edu Recent documents in ScholarlyCommons en-us Fri, 20 Nov 2009 06:12:55 PST 3600 http://repository.upenn.edu/edissertations/38 http://repository.upenn.edu/edissertations/38 Wed, 18 Nov 2009 07:21:57 PST This dissertation exploits phylogenomic approaches to identify genes and gene families likely to be important in the biology of apicomplexan parasites, including Plasmodium (the causative agent of malaria) and Toxoplasma (a leading source of congenital neurological birth defects, and a prominent opportunistic infection in immunosuppressed individuals). In particular, we have explored the significance of lateral gene transfer and gene duplication as sources of evolutionary novelty . Genomic-scale phylogenetic tree comparison identifies surprisingly extensive lateral gene transfer (LGT), including plant-like genes presumably acquired from the algal source of the apicomplexan plastid (apicoplast), and animal-like genes that may have been acquired from these parasites' host species. Studies on apicomplexan-specific expanded gene families indicate that kinases are a probable source of functional innovation. The T. gondii kinome displays previously under-appreciated diversity in parasite-specific secreted kinases associated with the rhoptry organelles required for host cell invasion. Evolutionary analysis points to the importance of this 'ROPK' family, and functional genomics datasets were employed to prioritize family members for further investigation, including subcellular localization and overexpression in transgenic parasites. Transcriptional profiling of host-cell responses to infection, coupled with functional clustering, reveals pathways likely to be regulated by the parasite, and a role for ROP38 in controlling this process. Our studies highlight the potential of combining phylogenetics with genome-scale analysis and experimental manipulation to elucidate biological function; similar strategies should be generally useful in integrating the diverse range of genomic-scale datasets that increasingly characterizes modern biomedical research. Lucia Peixoto http://repository.upenn.edu/cis_reports/910 http://repository.upenn.edu/cis_reports/910 Tue, 17 Nov 2009 13:26:13 PST In recent years, data management has begun to consider situations in which data access is closely tied to network routing and distributed acquisition: sensor networks, in which reachability and contiguous regions are of interest; declarative networking, in which shortest paths and reachability are key; distributed and peer-to-peer stream systems, in which we may monitor for associations among data at the distributed sources (e.g., transitive relationships). In each case, the fundamental operation is to maintain a view over dynamic network state; the view is frequently distributed, recursive and may contain aggregation, e.g., describing transitive connectivity, shortest paths, least costly paths, or region membership. Surprisingly, solutions to this problem are often domain-specific, expensive to compute, and incomplete. In this paper, we recast the problem as one of incremental recursive view maintenance in the presence of distributed streams of updates to tuples: new stream data becomes insert operations and tuple expirations become deletions. We develop a set of techniques that maintain information about tuple derivability--a compact form of data provenance. We complement this with techniques to reduce communication: aggregate selections to prune irrelevant aggregation tuples, provenance-aware operators that can determine when tuples are no longer derivable and remove them from their state, and shipping operators that greatly reduce the tuple and provenance information being propagated while still maintaining correct answers. We validate our work in a distributed setting with sensor and network router queries, showing significant gains in bandwidth consumption without sacrificing performance. Mengmeng Liu http://repository.upenn.edu/ese_papers/520 http://repository.upenn.edu/ese_papers/520 Tue, 17 Nov 2009 07:53:30 PST Distributed routing algorithms may give rise to transient loops during path recomputation, which can pose significant stability problems in high-speed networks. We present a new algorithm, Distributed Path Computation with Intermediate Variables (DIV), which can be combined with any distributed routing algorithm to guarantee that the directed graph induced by the routing decisions remains acyclic at all times. The key contribution of DIV, besides its ability to operate with any routing algorithm, is an update mechanism using simple message exchanges between neighboring nodes that guarantees loop-freedom at all times. DIV provably outperforms existing loop-prevention algorithms in several key metrics such as frequency of synchronous updates and the ability to maintain paths during transitions. Simulation results quantifying these gains in the context of shortest path routing are presented. In addition, DIV's universal applicability is illustrated by studying its use with a routing that operates according to a non-shortest path objective. Specifically, the routing seeks robustness against failures by maximizing the number of next-hops available at each node for each destination. Saikat Ray http://repository.upenn.edu/edissertations/37 http://repository.upenn.edu/edissertations/37 Fri, 13 Nov 2009 12:43:26 PST Immune activation through Toll-like receptors (TLRs) has historically been considered to be a characteristic of cells of the innate, rather than adaptive immune system. Recent studies have challenged this paradigm by demonstrating that TLRs are also expressed on T lymphocytes and that TLR ligands can directly co-stimulate T cell responses in vitro. However, the physiological relevance of these findings during in vivo immune responses was unclear. Mice lacking the critical TLR-adapter protein, myeloid differentiation protein 88 (MyD88), have increased susceptibility to numerous pathogens, highlighting the importance of TLRs in host defense. While the immune impairments associated with MyD88-deficiency have generally been attributed to the importance of MyD88 in regulating innate immune responses, in light of the studies showing that TLRs can directly stimulate T cells, we hypothesized that they may also reflect a direct role for MyD88 in T cells. In this work, we use lymphocytic choriomeningitis virus (LCMV) as a model infection to examine the role of MyD88 in regulating antiviral T cell responses. Using a series of adoptive cell transfer and bone marrow chimera experiments, we identify a critical, but previously unappreciated, T-cell intrinsic role for MyD88 in regulating the survival and expansion of LCMV-specific effector T cells during acute viral infection. Using a system to inducibly delete MyD88 we also show that, while naïve T cells critically depend on MyD88-dependent signals for their expansion, virus-specific memory T cells do not require MyD88 for their differentiation, maintenance or reactivation in response to secondary infection. Overall, our findings broaden the importance of MyD88 in T cells, support a shift in the dogma that restricts the role MyD88 to cells of the innate immune system, and may have significant implications for understanding the signals that control T cell survival during inflammatory immune responses. Adeeb H. Rahman http://repository.upenn.edu/ircs_reports/202 http://repository.upenn.edu/ircs_reports/202 Thu, 12 Nov 2009 07:56:14 PST I demonstrate the application of hierarchical regression modeling, a state-of-the-art technique for statistical inference, to language research. First, a stable sociolinguistic variable in Philadelphia (Labov, 2001) is reconsidered, with attention paid to the treatment of collinearities among socioeconomic predictors. I then demonstrate the use of hierarchical models to account for the random sampling of subjects and items in an experimental setting, using data from a study of word-learning in the face of tonal variation (Quam and Swingley, forthcoming). The results from these case studies demonstrate that modeling sampling from the population has empirical consequences. Kyle Gorman http://repository.upenn.edu/edissertations/36 http://repository.upenn.edu/edissertations/36 Wed, 11 Nov 2009 13:14:10 PST The literature on organizational niche suggests that competition between firms that have overlapping niches tends to elevate exit risks. Thus, firms tend to enter markets that are relatively uncrowded in order to minimize direct competition with other firms. Although this research has focused on organizational "micro-niches," it has not been applied to organizational populations occupying different "macro-niches" and possessing different organizational forms. We apply niche overlap theory to the market for outpatient surgical procedures in order to compare the entry and exit patterns of firms in a mature population of general hospitals to those of firms within a growing population of ambulatory surgery centers (ASCs). By manipulating patient-level datasets from the state of Florida, we were able to measure competition, market demand, and firm entry/exit with a high level of precision. We broke down our explanatory variables by facility type (ASC vs. hospital), and utilized Cox proportional hazard and negative binomial models to evaluate the impact of niche density on market entry/exit among ASCs and hospitals.Although hospitals tend to exit markets with high levels of ASC density, ASCs appear to be unaffected by the presence of nearby hospitals. This finding confirms the presence of asymmetric competition between these two organizational forms since specialized organizational forms representing "focused factories" are unaffected by generalist forms while generalists are hurt by the presence of competing specialists. We also find that hospitals display low entry rates in markets with overlapping ASCs while ASCs display high entry rates in markets with overlapping ASCs. These results are consistent with the notion that firms in growing populations tend to seek out crowded markets as they compete to occupy the most desirable market segments while firms in mature populations avoid direct competition as they compete on the basis of efficiency. Taken together, our results extend niche overlap theory to settings in which two different organizational forms compete and demonstrate that several key predictions are actually reversed in the case of these industries. Michael G. Housman http://repository.upenn.edu/edissertations/35 http://repository.upenn.edu/edissertations/35 Wed, 11 Nov 2009 12:20:50 PST Life history traits are critical components of fitness and frequently reflect adaptive responses to environmental pressures. Natural populations of Drosophila melanogaster exhibit patterns of lifespan, fecundity, development time, body size and stress resistance that vary predictably along environmental gradients. Artificial selection studies, genetic correlation analyses, and quantitative trait mapping efforts have demonstrated a genetic basis for the observed phenotypic variation, but few genes have been identified that contribute to natural life history variation. This work employs a candidate gene approach to discover genes and specific polymorphisms that contribute to genetic variance for D. melanogaster life history. Three aging genes, which have been characterized to mediate longevity, reproduction and stress tolerance, have been evaluated for natural genetic variation from samples derived from the wild. Allelic variation at one gene, methuselah (mth), shows functional effects on lifespan, lifetime fecundity and resistance to oxidative stress. A polymorphism in the mth promoter has been identified which may contribute to variation in these traits by affecting levels of gene expression. Natural genetic variation at two genes in the insulin signaling pathway reveals a history of positive selection at the Insulin-like Receptor (InR), but evidence of neutral evolution at the InR substrate, chico. Furthermore, an indel polymorphism in the first exon of InR shows striking, nonrandom distributions on two continents, a sign that it may contribute to the observed patterns of phenotypic variation across these same habitats. Functional evaluation of alternate InR alleles demonstrates predictable effects on phenotype and levels of insulin signaling, which implicates this polymorphism in the adaptive evolution of wild D. melanogaster populations. These findings provide novel examples of how allelic variation underlies adaptive changes in life history evolution, and contribute complementary characterization of genetic function to the biology of aging. Annalise B. Paaby http://repository.upenn.edu/edissertations/34 http://repository.upenn.edu/edissertations/34 Wed, 11 Nov 2009 11:34:28 PST Rhythmic motor patterns, which underlie behaviors such as mastication, respiration and locomotion, are generated by specialized neural circuits called central pattern generators (CPGs). Although CPGs can generate their rhythmic motor output in the absence of rhythmic input, these motor patterns are modified by rhythmic sensory feedback in vivo. Furthermore, although the importance of sensory feedback in shaping CPG output is well known, most systems lack the experimental access needed to elucidate the mechanisms underlying sensorimotor integration at the cellular and synaptic level. I am therefore examining this issue using the gastric mill CPG, a circuit which generates the rhythmic retraction and protraction motor activity that drives chewing by the teeth in the gastric mill compartment of the crustacean stomach. The gastric mill CPG is well defined and very accessible at the cellular level. Specifically, I am examining the mechanism by which the gastropyloric receptor (GPR), a phasically active proprioceptor, selectively prolongs one phase (retraction) of the gastric mill rhythm in the isolated nervous system when it is activated in a pattern that mimics its in vivo activity. I first demonstrate that GPR regulation of the gastric mill rhythm relies on its presynaptic inhibition of modulatory commissural neuron 1 (MCN1), a projection neuron that activates and drives this rhythm. I also demonstrate that the GPR inhibition of MCN1 regulates the gastric mill rhythm by selectively regulating peptidergic cotransmission by MCN1. Lastly, I demonstrate that a peptide hormone (crustacean cardioactive peptide) that only modestly modifies the gastric mill rhythm, strongly gates the GPR regulation of this rhythm. Mechanistically, it acts not by influencing GPR or MCN1, but by activating the same excitatory current in the CPG neuron LG (lateral gastric) that is activated by MCN1-released peptide. This novel gating mechanism reduces GPR control over the amplitude of this excitatory current in LG. Thus, I have identified specific cellular mechanisms by which (a) phase-specific regulation of an ongoing motor pattern by a sensory input is accomplished, and (b) hormonal modulation gates that sensory input. These events are likely to reflect comparable ones occurring in the larger and less accessible vertebrate CNS. Nicholas D. DeLong http://repository.upenn.edu/asc_papers/147 http://repository.upenn.edu/asc_papers/147 Tue, 10 Nov 2009 09:21:07 PST My purpose in this chapter is to suggest a particular mode of thinking about media and global civil society: ways in which major groups that seek to mould opinion around the world interact with each other, with states and corporations, with domestic regulatory systems and with international organisations and structures. I start with an approach I developed in a book called Television, Ihe Public Sphere, and National Identity (Price 1995) and expanded in Media and Sovereignty: The Global Information Revolution and its Challenge to State Power (Price 2002). There I described the existence of a 'market for loyalties', in which large-scale competitors for power, in a shuffle for allegiances, often use the regulation of communications to organise a cartel of imagery and identity among themselves. In the retrospectively simple state centred version of a market for loyalties, government is usually not only the mechanism that allows the cartel to operate, but is often part of the cartel itself. Management of the market yields the mix of ideas and narratives employed by a dominant group or coalition to maintain power. For fulfilling that process - or attempting to do so - control over participation in the market has been, for many countries, a condition of political stability. Monroe E. Price http://repository.upenn.edu/cis_papers/422 http://repository.upenn.edu/cis_papers/422 Tue, 10 Nov 2009 09:19:00 PST Medical devices are pervasive throughout modern healthcare, but each device works on its own and in isolation. Interoperable medical devices would lead to clear benefits for the care provider and the patient, such as more accurate assessment of the patient's health and safety interlocks that would enable error-resilient systems. The Center for Integration of Medicine & Innovative Technology (www.CIMIT.org) sponsors the Medical Device Plug-and-Play Interoperability program (www.MDPnP.org), which is leading the development and adoption of standards for medical device interoperability. Such interoperable medical devices will lead to increased patient safety and enable new treatment options, and the aim of this project is to show the benefits of interoperable and interconnected medical devices. David Arney