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Kosmos
Astronomia Astrofizyka
Inne

Kultura
Sztuka dawna i współczesna, muzea i kolekcje

Metoda
Metodologia nauk, Matematyka, Filozofia, Miary i wagi, Pomiary

Materia
Substancje, reakcje, energia
Fizyka, chemia i inżynieria materiałowa

Człowiek
Antropologia kulturowa Socjologia Psychologia Zdrowie i medycyna

Wizje
Przewidywania Kosmologia Religie Ideologia Polityka

Ziemia
Geologia, geofizyka, geochemia, środowisko przyrodnicze

Życie
Biologia, biologia molekularna i genetyka

Cyberprzestrzeń
Technologia cyberprzestrzeni, cyberkultura, media i komunikacja

Działalność
Wiadomości | Gospodarka, biznes, zarządzanie, ekonomia

Technologie
Budownictwo, energetyka, transport, wytwarzanie, technologie informacyjne

ScholarlyCommons, University of Pennsylvania

W Filadelfii.

Despite decades of research, the function of sleep remains controversial. One theory is that sleep plays a role in consolidating plasticity induced during prior waking. Ocular dominance plasticity (ODP) in the cat visual cortex is induced during waking monocular deprivation (MD) and consolidated during subsequent sleep. Extracellular signal-regulated kinase (ERK) signaling is required for ODP and is elevated during post-MD sleep, but its requirement during sleep is unknown. In Chapter 2, we investigated whether ERK activity is required during sleep for ODP consolidation by inhibiting the upstream activator of ERK (MEK) with intracortical infusions of U0126 into V1 during post-MD sleep. ERK inhibition abolished ODP consolidation, as measured by extracellular single unit recording. Furthermore, ERK inhibition reduced phosphorylation of eukaryotic initiation factor 4E (eIF4E) and post-synaptic density protein 95 (PSD-95) levels. MAP kinase-interacting kinase 1 (Mnk1) is activated by ERK and directly phosphorylates eIF4E; inhibition of Mnk1 mimicked the effects of ERK inhibition. These results show that activation of the ERK-Mnk1 pathway during post-MD sleep is required for ODP consolidation, and that this pathway promotes the synthesis of plasticity-related proteins such as PSD-95. However, sleep can be broadly subdivided into rapid eye movement (REM) and non-REM (NREM) sleep, but the relative contributions of these states to ODP and the ERK pathway are unknown. In Chapter 3, we examined whether REM sleep is required for ODP consolidation and ERK activation by depriving animals of REM sleep following six hours of waking MD. REM sleep deprivation (RSD) abolished ODP consolidation, as measured by optical imaging of intrinsic cortical signals, and reduced ERK phosphorylation in V1. These effects were not seen in a group that received NREM-fragmented sleep (as a control for the nonspecific effects of RSD). Furthermore, ODP and ERK phosphorylation correlated with the degree of beta-gamma activity in V1 during REM sleep, suggesting that neuronal activity patterns during REM promote ERK activation and ODP consolidation. Together, the findings in the following chapters suggest that, following the induction of cortical plasticity during waking, the ERK-Mnk1 pathway is activated during REM sleep, promoting the synthesis of plasticity-related proteins to consolidate cortical plasticity.

http://repository.upenn.edu/edissertations/852 2014/10/01 - 21:58

Mutations in the gene CEP290 cause an array of debilitating and phenotypically distinct human diseases, ranging in severity from the devastating blinding disease Leber congenital amaurosis (LCA) to Senior Løken Syndrome, Joubert syndrome, and the embryonically lethal Meckel-Grüber syndrome. The pathology observed in these diseases is thought to be due to CEP290's essential role in the development and maintenance of the primary cilium, but despite its critical role in biology and disease we know only little about CEP290's function. Here we identify four novel functional domains of the protein, showing that CEP290 directly binds to cellular membranes through an N-terminal domain that includes a highly conserved amphipathic helix motif, and to microtubules through a domain located within its myosin-tail homology domain. Furthermore, CEP290 activity was found to be regulated by two novel autoinhibitory domains within its N- and C-termini, both of which were also found to play critical roles in regulating ciliogenesis. Disruption of the microtubule-binding domain in the rd16 mouse LCA model was found to be sufficient to induce significant deficits in cilium formation leading to retinal degeneration. Taking these findings into account, we developed a novel model that accurately predicts patient CEP290 protein levels in a mutation-specific fashion. Predicted CEP290 protein levels were found to robustly correlate with disease severity for all reported CEP290 patients. All these data implicate CEP290 as an integral structural and regulatory component of the primary cilium and provide insight into the pathological mechanisms of LCA and related ciliopathies. Our findings also suggest novel strategies for therapeutic intervention in the treatment of CEP290-based disease that, if fully realized, would be the first treatment available for the many patients suffering the devastating effects of CEP290 dysfunction.

http://repository.upenn.edu/edissertations/851 2014/10/01 - 21:58

SUSTAINABLE EMERGENCIES: THE PARADOX OF COMMUNITY
MANAGEMENT OF ACUTE MALNUTRITION PROGRAMS
Kelly Delaney, RN, MS, PHD
Alison Buttenheim, PHD, MBA
In 2008, the World Health Organization (WHO) formally endorsed the community management of acute malnutrition protocol as the preferred method of treatment for the approximately 13 million acutely malnourished children in the world (Collins, 2007; WHO, 2008). This protocol reflected a change in treatment strategies from the hospital to the community. Health care providers who respond to nutrition emergencies (referred to as emergency nutrition workers for the purpose of this study) were tasked with understanding the complex nature of a community's structure and culture, in addition to providing medical treatment for acutely malnourished children. To implement the WHO protocols successfully, emergency nutrition workers must be able to translate international standards into a culturally and contextually appropriate emergency nutrition program. This qualitative descriptive study describes the experience of emergency nutrition workers regarding community participation in program assessment, design, and implementation following declaration of a nutrition emergency.
There is a lack of understanding concerning what personal and professional beliefs and structures influence how emergency nutrition workers interpret their environment and define the community structure they are working within when developing assessment and implementation strategies. Bronfrenbrenner's (1977) social ecology theoretical framework was utilized to guide a review of literature concerning environmental influences that may affect community participation during emergency nutrition programs. In the study, a cross-sectional qualitative descriptive design was utilized in a deterritorialized setting. English speaking emergency nutrition workers who responded to a nutrition emergency as an employee of an international non-governmental organization in the previous twelve months were recruited through a maximum variation, purposeful sampling technique. Participants were recruited through professional networks, NGO headquarters, and an online professional forum until saturation is reached. Semi-structured interviews conducted by the researcher were the primary form of data collection for this study. Interviews were conducted over the Internet using voice over Internet protocol (VOIP) technology. Directed content analysis was utilized for data analysis.
The study results included an identification of five themes that influence the ways in which an emergency nutrition worker engages with local communities during Community Management of Acute Malnutrition (CMAM) programs: (1) Dimensions of Community in CMAM; (2) Learning Through Field Experience; (3) Partnerships for Success; (4) Disconnects in Funding Priorities; and (5) Sustainability in Emergencies.

http://repository.upenn.edu/edissertations/850 2014/10/01 - 21:58

LABORS OF REPRESENTATION: CULTIVATING LAND, SELF, AND COMMUNITY AMONG MUSLIMS IN LATE COLONIAL BENGAL
Ananya Dasgupta
Lisa Mitchell
This dissertation studies how the specificity of regional practices of cultural productions, ideological strands, forms and practices of civil associations, and styles of literary expressions among Muslims inflected the Pakistan movement in late colonial Bengal. Using wide-ranging sources that include vernacular religious tracts, the popular genre of Muslim improvement texts, pamphlets of tenant-peasant associations, journals, diaries, autobiographies, and literary archives, I trace historical transformations in practices and ideas about religion and political representation among the Muslims of Bengal from the mid-nineteenth century to the late colonial period. In so doing, I examine key shifts in Islamic theological concepts, Muslim forms of civil associations, social movements and Muslim literary cultures to argue that by the inter-war period (in the 1920s and 1930s) these altered the meaning of being Muslim, in the context of Bengal, in very critical ways by, at one level, linking up notions of cultivation of self and community to ideas of cultivating land, thus valorizing labor as a positive repository of value, while positing sites and actors engaged in the spheres of exchange and circulation as full of deceit and dubiousness, and at another level, by conjoining the meaning of cultivating land and Islamic moral community to the land of Bengal, thereby creating new kinds of claims of ethnic belonging rooted in a regionalism. I show how such transformations were critical in instantiating subjectivities that could inhabit modalities of organized politics, which, in an era of expanding franchise, became available to mobilization and manipulation by political players and parties who championed the primacy of the producer in a claim to politically represent them. Broadly speaking, my dissertation traces the rise of an ideology of labor as the touchstone of Bengali Muslim politics in the late colonial period for our understanding of the conjunction between leftist populism and religious nationalism rooted in a regional identity.

http://repository.upenn.edu/edissertations/849 2014/10/01 - 21:58

This dissertation focuses on publics and the public sphere to argue that communication theory should investigate connections across discourse, space, and practice in the creation and maintenance of publics. I chose antebellum Philadelphia as my test case for two reasons. First, theorists such as Jurgen Habermas have identified the antebellum period as the time when the public sphere ceased to be maintained through face-to-face relations and became connected by means of the news media. Second, tremendous social and political conflict also characterized this period when categories considered by communications theory to be discursively constructed, such as "race" and "nation," were contested and revised. The majority of archival evidence tells a different story, one in which spatial relations and material conditions defined the public, and the act of being in public was a contested mode of political communication. Antebellum Philadelphians attempted to define, shape, and communicate public opinion through the development of the material city and the spatial practices of its inhabitants.

http://repository.upenn.edu/edissertations/848 2014/10/01 - 21:58

How are object features and knowledge-fragments represented and bound together in the human brain? Distributed patterns of activity within brain regions can encode distinctions between perceptual and cognitive phenomena with impressive specificity. The research reported here investigated how the information within regions' multi-voxel patterns is combined in object-concept networks. Chapter 2 investigated how memory-driven activity patterns for an object's specific shape, color, and identity become active at different stages of the visual hierarchy. Brain activity patterns were recorded with functional magnetic resonance imaging (fMRI) as participants searched for specific fruits or vegetables within visual noise. During time-points in which participants were searching for an object, but viewing pure noise, the targeted object's identity could be decoded in the left anterior temporal lobe (ATL). In contrast, top-down generated patterns for the object's specific shape and color were decoded in early visual regions. The emergence of object-identity information in the left ATL was predicted by concurrent shape and color information in their respective featural regions. These findings are consistent with theories proposing that feature-fragments in sensory cortices converge to higher-level identity representations in convergence zones. Chapter 3 investigated whether brain regions share fluctuations in multi-voxel information across time. A new analysis method was first developed, to measure dynamic changes in distributed pattern information. This method, termed "informational connectivity" (IC), was then applied to data collected as participants viewed different types of man-made objects. IC identified connectivity between object-processing regions that was not apparent from existing functional connectivity measures, which track fluctuating univariate signals. Collectively, this work suggests that networks of regions support perceptual and conceptual object processing through the convergence and synchrony of distributed pattern information.

http://repository.upenn.edu/edissertations/847 2014/10/01 - 21:58

Boiling, evaporation, and liquid-vapor phase change are inherently multiscale processes. Current continuum-based numerical models fail to capture the atomistic nature of the local density fluctuations that lead to vapor nucleation. Atomistic methods, such as molecular dynamics (MD) simulations, are capable of fully resolving the effects of individual atomic interactions and nanoscale surface structure on the incipience of liquid-vapor phase change. Macroscopic problems, however, are still well beyond the reach of MD simulations due to the prohibitively large computational expense of modeling discrete particles. Hybrid atomistic-continuum (HAC) models offer a solution. HAC models limit the use of MD simulations to only a small region where atomistic-level resolution is necessary, such as near a wall or heater surface, and use continuum methods away from this region.
In this work a fully parallelized hybrid atomistic-continuum model is developed to resolve nanoscale features of liquid-vapor phase change. The domain is decomposed into an atomistic domain, where individual atomic interactions are computed, and a continuum domain, where the Navier-Stokes equations are solved. The two domains are coupled through an overlap region in which the solutions in both domains are consistent. The accuracy of the HAC model is demonstrated through the simulation of sudden start Couette flow, unsteady heat transfer, and the bulk flow of a liquid-vapor interface. The new HAC model is used to model vapor nucleation at a heater surface and compares well to analytic solutions for evaporation. Unlike continuum-only methods, the new HAC model is able to nucleate vapor from liquid naturally, given the correct thermodynamic conditions, without any assumptions on the nucleation location or frequency. The new highly-parallelized HAC model is shown to reduce computation time by a factor of five for Couette flow in a 78 nm channel as compared to a fully-atomistic simulation. This speedup is expected to become even greater for larger systems. A general discussion on the performance of the new HAC model is included along with a discussion of the advantages and disadvantages, specific to HAC models, of the volume-of-fluid (VOF) method used to track interfaces within the continuum domain.

http://repository.upenn.edu/edissertations/846 2014/10/01 - 21:58

Intertemporal choices, or decisions that involve tradeoffs between rewards and time, are ubiquitous in our daily lives. The tendency to devalue, or discount, future rewards has been linked to maladaptive long-term health and financial outcomes. Despite their broad clinical relevance, individual differences in discounting preferences are poorly understood. In this thesis, we make progress on the understanding of the neural basis of these decisions and factors that affect individual differences. The first two chapters focus on neurobiology. Chapter 2 investigates the decision-related variables that best explain the observed patterns of BOLD activity in ventromedial prefrontal cortex (VMPFC) and ventral striatum (VS) during intertemporal choice. We find that these regions carry different signals and likely contribute to different stages of the choice process. Across the brain, we find four kinds of value-responsive regions, each carrying different combinations of value-related signals. Next, we examine whether we can predict participants' choices from any or all of these groups of regions, and find that we can predict choice from most value-responsive regions, with interesting exceptions. In Chapter 3, we identify a novel brain predictor of individual differences in discounting. When participants are making judgments about how far away some number of days feels, discount rates, measured a week later, can be predicted from how VMPFC and VS respond as a function of temporal distance. This difference in the basic response to delayed time intervals could be a target for interventions aiming to reduce discount rates. In the final chapter, we find several behavioral manipulations that are able to reduce discount rates persistently and to a significant degree. We find that there is a general lack of knowledge about the normative strategy in the monetary discounting task, and that providing information about this strategy - to accept all delayed offers that provide higher interest rates than one could obtain elsewhere - reduces discounting significantly, for at least one month. Information about peers' strategies for making these decisions also reduces discounting. Taken together, this work advances our understanding of individual differences in discounting and further suggests interventions that could be used to reduce discounting.

http://repository.upenn.edu/edissertations/845 2014/10/01 - 21:58

Images of urban conflagration had a powerful hold on the ancient Roman literary imagination. This phenomenon represents a unique confluence between literary tradition and urban reality: Greco-Roman literature offers a wide array of poetic, philosophical and historiographic reflections of cities destroyed by fire, yet daily life in ancient Rome was haunted by the very real fear of conflagration. The major investigative goal of this project is the exploration of the ways in which Romans authors used powerful images of fiery destruction, often drawn from the broader literary tradition, to address contemporary moments of political crisis in the early imperial period. In three chapters, I follow the intersection of urban fires and claims to power, as expressed both in urban space and in the literary city of Rome, during three critical periods from early imperial history: Augustan, Neronian, and post-Neronian Rome. In each period, a distinct set of fire-related problems arose for the current leader: in the aftermath of disaster, each leader in different ways, attempted to configure himself as protector of and provider for the urban population, with varying outcomes. Augustus faced the task of renewing Rome after the defining rupture of the triumviral conflicts and the fall of the republic; Nero came to power after generations of jeopardized successions and often-violent transitions had produced significant civic anxiety and suspicion of new leadership, a precarious dynamic even before the unprecedented destruction of 64 CE; and Vespasian, founder of the Flavian dynasty, came to power in 69 CE, after Rome had been ravaged by the violent (and incendiary) Year of Four Emperors. Each ruler, in his own way, worked to equate his restoration of Rome after disaster, which included efforts to prevent future fires, with his larger claims to political control and even mastery of the cosmos. Likewise, authors working in an increasingly repressive environment found in images of urban destruction a productive set of metaphors and figures for addressing the fears and tensions attached to contemporary ideology.

http://repository.upenn.edu/edissertations/844 2014/10/01 - 21:58

Alternative splicing is a key step in gene regulation and involves the differential selection of splice sites to generate different pre-mRNA transcripts. It has been shown that 90-95% of pre-mRNAs are alternatively spliced in human cells. Pre-mRNA splicing is catalyzed the spliceosome, which consists mainly of the U1, U2, U4, U5 and U6 snRNP, and about a hundred of non-snRNP proteins. Splicing regulators that bind to enhancer or silencer elements on the pre-mRNA can alter assembly of these spliceosome components. Understanding how splicing regulators control spliceosome assembly will bring insights to the prediction of splice site choices. In our lab, we used CD45 as a model gene for studying alternative splicing and spliceosome assembly. The exonic silencer sequence (ESS1) within CD45 exon 4 is bound by hnRNP L to induce its skipping. HnRNP L represses spliceosome assembly at a step after the binding of U1 and U2 snRNP on either side of the exon. My goal is to understand how hnRNP L perturbs U1 snRNP binding at the 5' splice site (5' ss) to cause the skipping of CD45 exon 4.
Using psoralen- and UV-crosslinking analysis, U1 snRNP and other protein components that associate with the sequences around the 5' ss within the hnRNP L-repressed spliceosome complexes were compared with the control complexes. These studies revealed that hnRNP L recruits hnRNP A1 to the 3' end of exon 4 to induce an extended pairing interaction between the U1 snRNA and the 5' ss. Splicing assays in vitro and in cells further demonstrated that hnRNP A1 and the U1 snRNA binding at the 3'end of exon 4 are required for hnRNP L-mediated skipping of exon 4. Further analysis of other exons repressed by hnRNP L or A1 suggests the potential for the extended U1 pairing interactions with these exons. These data imply that induction of U1 interactions with the exonic region nearby a 5' ss could be a widespread mechanism in inducing the skipping of exon. To further determine how the extended U1 binding affects the subsequent spliceosome assembly steps, hnRNP L-repressed spliceosome complexes were purified. This analysis revealed that association of U6 snRNP with the 5'ss, and recruitment of NTC components, are blocked in the hnRNP L-repressed complexes. Moreover, enhancing binding of U6 to the 5'ss overcomes the effect of the extended U1 interaction, thereby increasing the splicing of the hnRNP L-repressed substrate. These results provide the first example showing that the U1/U6 switch, a structural rearrangement during the catalytic activation of the spliceosome, is a naturally occurring point for regulating alternative splicing. This study also suggests that splicing regulators that alter U1 binding, or spliceosome components that associate with the 5' ss after U1 binding, are important factors for determining the usage of the 5'ss.

http://repository.upenn.edu/edissertations/843 2014/10/01 - 21:58

Plasma cells are the immune system cells responsible for producing antibodies, the key mediators of protective humoral immunity. Long-lived plasma cells (PC) are thought to be responsible for maintaining antibody titers and are believed to populate unique survival niches in the bone marrow (BM). Current models predict that bone marrow plasma cells (BM PC) consist chiefly of long-lived, slowly renewing cells. In chapter 2, we show the turnover rate of the BM PC pool to be much higher than predicted by these models; in fact, more than 50% of BM PC exhibit characteristics of recently formed PC. Intriguingly, these B220+ PC do not appear to be cycling and are depleted upon ablation of peripheral B cell pools. In chapter 3, we extend our studies to antigen-induced responses. We find that very long-term maintenance of the antigen-specific BM PC pool is dependent on a CD40-independent B cell precursor. Despite the rapid turnover rate exhibited by B220+ BM PC, antigen-induced antibody secreting cells are found within this population for more than 100 days post-immunization. These cells secrete exclusively low affinity, unswitched, κ type antibodies in sharp contrast to the high affinity, isotype switched cells found within the slowly renewing BM PC pool. Finally, we identify a population of rapidly renewing memory B cells that appear to be the precursors of the B220+ BM PC. Together these data suggest that BM niches are continuously repopulated by newly generated plasma cells long after antigenic exposure and identify
the memory B cell precursors of BM PC.

http://repository.upenn.edu/edissertations/842 2014/10/01 - 21:58

Mechanical instability and large deformation are pervasive occurrences on stressed soft material surface patterns, which are normally detrimental to device performance. In this dissertation we show that these phenomena can be harnessed on structured polymeric thin films for surface patterning, strong dry adhesion and guided wettability. On dyed SU-8 photoresist films with graded depth-wise crosslinking density, we study the swelling-induced wrinkling. We demonstrate that isotropic surface wrinkles can be aligned with low aspect ratio 1-D channel-type pre-patterns. By varying the pitch and height ratios, defined as the pre-pattern pitch and height of the channels to the wrinkle wavelength and amplitude, respectively, we construct a morphological diagram of the confined wrinkles. For pitch ratios much larger than 1, the wrinkle morphology is predominantly isotropic. As pitch ratio decreases to ~ 1, the wrinkles arrange to out-of-phase 1-D bumps along the mountain regions of the channels. For pitch ratio much smaller than 1, the wrinkles evolve from in-phase perpendicular (to the channels) wrinkles, coexisting perpendicular wrinkles and localized patterns back to isotropic wrinkles in the order of decreasing height ratios.
In a separate material system, we utilize the buckling of high aspect ratio shape memory polymer (SMP) pillars to develop a strong interlocking dry adhesive. We engage the two identical pillar arrays together above the glass transition temperature of SMP (80 °C), where the SMP modulus drops by 3 orders of magnitude, leading to mutual buckling and deformation of the pillars when interlocked. Our finite element analysis and comparison of the calculated adhesion versus experimental data suggest that the adhesion force originates primarily from the pillar interweaving and secondarily from pillar indentation. The resultant pillar-to-pillar adhesion forces in normal (~ 54 N/cm2) and shear (~ 72 N/cm2) direction are found much larger than the pillar-to-flat (~ 12 N/cm2 in normal and ~ 15 N/cm2 in shear) and flat-to-flat contacts (~ 7 N/cm2 in normal and ~ 16 N/cm2 in shear). We further tune the adhesion anisotropy, designated by the ratio of shear to normal adhesion, by changing the pillar spacing. In spite of the strong adhesion, we show that the engaged adhesive can be easily separate on demand by heating to 80 °C.
Using similar SMP pillars, we design a reconfigurable surface to control surface wettability. Specifically, we report that the water droplets convert from low adhesion Cassie state on the original (or recovered) straight pillars to fully pinned Wenzel state on deformed pillars. Potentially, surface with both straight and deformed pillars can be utilized as a reprogrammable water collecting surface. Employing the deformed pillars, we present an advanced patterning method based on the deformed SMP pillars to transfer nanoparticle assemblies from donor substrates onto selected locations of pillars. Finally, we show a new approach to precisely control the tilting angle of the SMP pillars by coating the deformed pillars with a layer of metal, which hinders the full recovery of SMP pillars. On the composite surface, we observe strong anisotropic liquid spreading behavior, where the liquid propagates predominantly in the opposite direction of the pillar tilting.

http://repository.upenn.edu/edissertations/841 2014/10/01 - 21:58

Recent experiments have demonstrated that thermal properties of semiconductor nanostructures depend on nanostructure boundary geometry. Phonons are quantized mechanical vibrations that are the dominant carrier of heat in semiconductor materials and their aggregate behavior determine a nanostructure's thermal performance. Phonon-geometry scattering processes as well as waveguiding effects which result from coherent phonon interference are responsible for the shape dependence of thermal transport in these systems. Nanoscale phonon-geometry interactions provide a mechanism by which nanostructure geometry may be used to create materials with targeted thermal properties. However, the ability to manipulate material thermal properties via controlling nanostructure geometry is contingent upon first obtaining increased theoretical understanding of fundamental geometry induced phonon scattering processes and having robust analytical and computational models capable of exploring the nanostructure design space, simulating the phonon scattering events, and linking the behavior of individual phonon modes to overall thermal behavior. The overall goal of this research is to predict and analyze the effect of nanostructure geometry on thermal transport. To this end, a harmonic lattice-dynamics based atomistic computational modeling tool was created to calculate phonon spectra and modal phonon transmission coefficients in geometrically irregular nanostructures. The computational tool is used to evaluate the accuracy and regimes of applicability of alternative computational techniques based upon continuum elastic wave theory. The model is also used to investigate phonon transmission and thermal conductance in diameter modulated silicon nanowires. Motivated by the complexity of the transmission results, a simplified model based upon long wavelength beam theory was derived and helps explain geometry induced phonon scattering of low frequency nanowire phonon modes.

http://repository.upenn.edu/edissertations/840 2014/10/01 - 21:58

Each mammalian cell type has a unique gene expression pattern that supports its specialized function. Mutations in factors that regulate gene expression can disrupt normal function and cause human disease, though the mechanistic consequences of these defects are often unknown. Here, we address how alterations in the transcription factor GATA1 lead to distinct hematologic disorders by combining structural, biochemical, and genomic approaches with gene complementation systems that examine GATA1 function in biologically relevant cellular contexts. We first investigated missense mutations in the GATA1 N-terminal zinc finger (NF) and found that NF mutations impair association with essential GATA1 cofactors. Several NF mutations diminish FOG1 binding, resulting in greatly reduced transcriptional activation and repression. This severely impairs erythroid and megakaryocyte maturation and correlates with pronounced clinical phenotypes. Notably, clinical severity parallels the degree of FOG1 disruption. Unexpectedly, NF mutations shown to disrupt DNA binding of GATA1 in vitro did not measurably affect target gene occupancy in vivo. Rather, one of these falls into a subset of mutations that diminish TAL1 complex binding. Reduced association with the TAL1 complex moderately impairs transcriptional activation, resulting in subtle defects in erythroid and megakaryocyte development that correlate with relatively mild disease presentations. Remarkably, different substitutions at the same amino acid position can selectively inhibit TAL1 complex or FOG1 binding, producing distinct cellular and clinical phenotypes. We next examined splice site mutations in the second exon of GATA1 that lead to the expression of an amino-truncated protein called GATA1 short (GATA1s). We found that GATA1s was significantly impaired in binding to erythroid-specific target genes, while occupancy at megakaryocyte-specific genes was normal. This results in a strongly diminished erythroid gene expression program and inhibits erythroid maturation, similar to the phenotype observed in patients. In concert, our findings uncover novel molecular mechanisms that link genetic defects in GATA1 to cellular and human phenotypes. Applying this knowledge to the clinic should improve patient diagnosis, classification, and treatment. More broadly, this work highlights the power of gene complementation assays for elucidating the underlying basis of disease, and serves as a model for the study of other disease-causing mutations.

http://repository.upenn.edu/edissertations/839 2014/10/01 - 21:58

Medieval music is difficult. When performed, its harmonies are often pretonal, its rhythms obscure, and its language frequenly Latin and religious. Its theoretical framework is an abstract language of geometric proportions and arithmetic ratios. When Boethius articulated his taxonomy of music - a system that undergirded all Medieval musicological writing - he divided it into three types, and the first two made no sound at all: musica mundana was the music of the spheres, a harmony produced by the motion of celestial bodies so rarified that human ears did not have the ability to perceive it; musica humana was also phenomenally silent, referring to the continuous musical performance of the human soul as it resonated with the body. Only the third and final type, musica instrumentalis, was what we might consider "music" proper: sung or played melodies and harmonies. This dissertation argues for a fourth type of music implied, but almost never explicitly named, by Medieval thinkers, and one which generates much of Late Medieval English devotional and mystical literature. This is musica celestis, or, as I have chosen to call it, mystical song. Mystical song is produced by God and his angels in heaven - beings without corporeal bodies - and exists beyond the world of material being. However, beginning in the early fourteenth century, a number of English authors claimed to hear it during mystical experience. This dissertation charts the wide-ranging effects of musica celestis in devotional, mystical, liturgical, and literary writing from the beginning of the fourteenth century to the beginning of the Reformation in England.

http://repository.upenn.edu/edissertations/838 2014/10/01 - 21:58

This study tests the hypothesis that increased rugosity (the ratio between urban perimeter and farmland area) of the rural-urban fringe allows farms to create greater value for their regions through greater access to urban markets. Findings show that increased rugosity is not associated with farmland loss despite correlating with greater population growth. Rugosity is, instead, associated with higher agricultural sales per acre and more farm-to-city networks. Using the urban interface as a variable to understand farm production and stabilization, this paper includes a spatial statistical analysis of county-level metro-area farm products, farmland loss, and demographics in relation to the concentricity of urban morphology in the United States. Four case studies reveal spatial and social network patterns of direct farm sales and donations of raw product. Farm-to-city market director interviews ground-truth these farm-city functions in relation to county and state-level policies that govern urban and farmland morphologies and function.

http://repository.upenn.edu/edissertations/837 2014/10/01 - 21:58

While the English-speaking tradition has dominated the production of Arthurian-themed materials since the nineteenth-century Arthurian Revival, there is evidence that the publication of modern Arthurian fiction in French has enjoyed a major upswing over the past few decades. Notable contributions include Michel Rio's Merlin-Morgane-Arthur trilogy, Jacques Roubaud and Florence Delay's ten-volume cycle Graal théâtre, a half-dozen fantasy novels about the origins of the Arthurian world by Jean-Louis Fetjaine, and medievalist Michel Zink's young adult novel Déodat, ou la transparence. Such texts are deeply anchored in the medieval tradition, invested in co-opting the flavor of medieval source texts at the level of narration as well as plot. Textual genealogies are frequently thematized in modern French Arthuriana by authors who credit a medieval parentage, whether through a narratorial intervention or paratexual references. As modern texts seek their own ground--whether as parodies, pastiches, entirely new adventures, or retellings of familiar stories from new perspectives--they continually draw upon the dozens of Arthurian works produced centuries before, presenting themselves as heirs to a literary tradition. With this implicit authorization, they continue its evolution. This paradigm replicates that which is already found in the medieval source material, whether in the Vulgate Cycle's transformation of the Grail Quest from the romance conceived by Chrétien de Troyes into a Christian work exhorting scriptural exegesis, or in Wace's appropriation of Geoffrey of Monmouth's Historia Regum Brittaniae. Modern authors engage with the same process in ways that reflect a canny understanding of Arthurian literature, both its early iterations and its ongoing trajectory. Intertwined threads of genealogy, authority, legacy, and tradition in modern French Arthurian texts reveal an affinity between medieval and postmodern literary practice. As authors of the late twentieth- and early twenty-first centuries appropriate Arthurian material, they adopt techniques and textual strategies closely associated with medieval literature, recycling them to advance postmodern agendas.

http://repository.upenn.edu/edissertations/836 2014/10/01 - 21:58

Treatment options for mesalamine-refractory ulcerative colitis (UC) include chronic immunosuppressive medications or colectomy surgery. Current treatment paradigms presume the patients' foremost desire is to avoid surgery and therefore view surgery as a consequence of medication failure. However, immunosuppressive therapy may not be ideal for all patients due to unclear durable efficacy and potential lethal serious adverse events (SAEs). We sought to quantify UC patients' risk tolerance of chronic immunosuppression to avoid colectomy.
We first conducted a meta-analysis of all-cause and cause-specific mortality in both Crohn's disease (CD) and UC, and examined the effect of study design on this outcome. We found elevated all-cause and cause-specific mortality in both UC and CD including colorectal-, pulmonary- and non-alcoholic liver disease-related relative mortality. We further found little evidence that study design impacted all-cause relative mortality summary estimates.
We next conducted a study examining the reliability of the 6-Point Mayo score, a simple two-item non-invasive non-physician driven index, for measuring UC disease activity. We found the 6-Point Mayo to strongly correlate with more extensive disease assessment tools, with a similar sensitivity, specificity and ROC area under the curve for patient-defined clinical remission.
With these insights, we conducted a discrete choice experiment to quantify the UC patients' mean maximum acceptable risk for life-threatening SAEs associated with immunosuppressant therapy to avoid colectomy surgery with various outcomes. We found that UC patient tolerance for medical and surgical risks do not conform to conventional preference-elicitation methodology assumptions. UC patients were willing to accept very high levels of fatal SAEs to avoid an ostomy. However, if a durable medication-induced remission could not be achieved, patients were equally satisfied with J-pouch surgery. Several important clinical phenotypes impacted patient risk tolerances. This is the first empirical demonstration that UC patients view a well-functioning J-pouch as equivalent to mild clinical disease. It further demonstrates that patients value medication efficacy and suggests that clinical remission, rather than response, be the preferred outcome for therapy trials and treatment algorithms. Our findings underline the need for rigorous methodologies to accurately measure patient-preferences; and suggest potential avenues to enhance UC patient autonomy and facilitate shared decision-making.

http://repository.upenn.edu/edissertations/835 2014/10/01 - 21:58

The three main goals of the research discussed in this dissertation were (1) to expand and characterize the first extensive series of half-sandwich metallatricarbadecaborane complexes, (2) to synthesize and explore the reactivity of 5-TfO-B10H13, and (3) to investigate metal-catalyzed hydrogen release from ammonia borane in ionic liquids. The major achievements are outlined below.
Chapter 1 describes the synthesis and structural characterization of the first series of group 9 tricarbadecaboranyl half-sandwich complexes. The tricarbadecaboranyl ligands in these complexes exhibit properties distinct from their cyclopentadienyl analogs, including (1) strong electron-withdrawing properties, (2) the ability to readily form slipped-cage structures, and (3) the ability to stabilize lower metal oxidation states. The unique properties of these complexes mean they could find potential applications as, for example, catalysts for alkyne oligomerizations, polymer and dendrimer building blocks, and synthetic precursors for medicinal therapies.
Chapter 2 discusses the development of several high yield pathways to 5-TfO-B10H13. The new routes to 5-TfO-B10H13 allowed for a systematic exploration of its reactivity and potential use as a starting material for the syntheses of other important polyboranes. The combined reactions of the synthesis of 5-TfO-B10H13, the formation of its Lewis acid-base adduct, 5-TfO-6,9-(Me2S)2-B10H11, and the alkyne-insertion and base-promoted cage closure reactions of 5-TfO-6,9-(Me2S)2-B10H11, now provide the first pathways to B-triflate-substituted ortho-carboranes and decaborates.
Chapter 3 reports that the metal-catalyzed hydrogen release from ammonia borane (AB) in an ionic liquid produces a significant increase in initial H2-release. However, the metal-catalysts affect only the rate of loss of the first H2-equivalent, with the uncatalyzed and catalyzed rates becoming equal following that point. NMR studies indicate that the mechanism of AB H2-release of these metal-catalyzed systems in ionic liquids appears to be similar to that observed in organic solvents, but differs from that observed in only ionic liquids.

http://repository.upenn.edu/edissertations/834 2014/10/01 - 21:58

CHALLENGING THE ASSUMPTION OF RATIONALITY IN PERFORMANCE-BASED ACCOUNTABILITY SYSTEMS: A COMPARATIVE CASE STUDY OF SCHOOL AND DISTRICT DECISION-MAKING APPROACHES
Jessica K. Beaver
Richard M. Ingersoll
Performance-based accountability systems provide schools and districts with detailed student performance data on the front end and demand that schools meet rigorous minimum proficiency thresholds on the back end or face a set of sanctions that ratchet up year after year. The process by which schools and districts make decisions for improvement in order to meet these requirements, however, is opaque at best. Each district is like an island unto itself, with its own political context, financial constraints, demographic and economic makeup, human capital, and social dynamics. Especially given the immense amount of money spent every year in improvement grants to districts, as well as the plethora of vendors touting new products, there is a clear imperative to understand how schools and districts select particular programs or strategies for improvement above other options.
In this dissertation study, I apply the literature on search and decision-making in other disciplines to the field of public elementary and secondary education, paying particular attention to schools and districts under pressure to improve from performance-based accountability systems. I employ a comparative case study approach, using three consecutive years of data from a stratified random sample of eight schools (nested within their districts) in Pennsylvania. I find that schools and districts are under immense pressure to demonstrate student achievement gains, and that this pressure extends to all phases of the decision-making process, including problem identification, search, and the decision point. Despite this pressure, I find that schools do not descend into chaos when making decisions for improvement - they generally approach the decision-making process in a linear manner and let building-level administrators employ a "middle-out" approach to decision-making. But on the other hand, schools are far from purely rational organizations, as there are forces internal and external to the school or district that constrain decision-making processes. Although these constraints affect all stages of the decision-making process, they have the most severe influence on the search phase. Finally, I create a framework that advances the literature on decision-making in education by establishing four distinct typologies of decision-making approaches.

http://repository.upenn.edu/edissertations/833 2014/10/01 - 21:58

This research focuses on the forms of exclusion that democratizing processes have historically facilitated. The dynamics of democratization often lead political coalitions to change electoral rules to simultaneously extend and constrict the right to vote across different categories of persons, as well as to reinforce existing exclusions. This pattern occurred in all the 'exemplary models' of early democratization, and yet the historical narratives relied on by the comparative democratization literature neglect its exclusionary dimension, and thereby misinform comparative theory building. The dissertation
empirically documents the "dark side of democratization" in the three paradigmatic cases of the United States, the United Kingdom, and France, and develops and tests a theory explaining cross-national and cross-time variation. At key moments in a country's development, political entrepreneurs advance ideas of community belonging for the purpose of securing a governing coalition. When successful the ideas of political community are embedded in new institutions and in public opinion, shaping the expectations of political agents across the political spectrum and resulting in higher costs of coalition-building and political mobilization across categories of people. The exclusions were thereby made resilient to subsequent democratizing processes. The dissertation advances research the role of ideas in social science by focusing on the micro-foundations of democratic exclusion. The model predicts various of political behavior that are integrally important to democratization, and is tested against debates, voting behavior, and correspondence in and outside of parliaments, legislatures, and constitutional conventions. The data draws on archival field work research, multiple datasets of legislator behavior, constituency demographics, and institutional change. These allow for the identification of stable patterns as well as change across time, and supplement a process tracing research design.

http://repository.upenn.edu/edissertations/832 2014/10/01 - 21:58

Reentry programs for persons with serious mental illness (SMI) leaving jails or prisons have produced mixed results (Chandler & Spicer, 2006), including those for evidence-based treatments (EBT). These interventions occur in the complex nexus of the mental health and criminal justice systems and the effects of the intervention can be facilitated or constrained by the environment in which they operate (Smith, Jennings, Cimino, 2010; Solomon and Draine, 1995; Weisman, Lamberti, & Price, 2004). This dissertation explores how the economic, social, physical, and political factors that comprise the risk environment interact with an EBT for persons with SMI and contribute to poor outcomes for this population. Utilizing a multi-informant, multi-perspective framework, in-depth interviews were conducted with 28 participants and 6 staff members involved in a randomized field trial testing the effectiveness of Critical Time Intervention (CTI) for men with mental illnesses leaving prison in New Jersey. Participants completed between one and five interviews (total, 38 interviews) in order to capture the different stages of reentry. Other data collection methods included observation through attending team meetings and conducting go-along interviews and document analysis through reviewing team meeting notes and client progress notes. The risk environment posed significant challenges for participants in acquiring basic needs, including income and housing, as punitive public and social policies excluded resources to individuals based on their criminal history. These policies played within an environment with multiple opportunities to engage in illegal activities under heightened criminal justice scrutiny, but few prosocial opportunities. Case managers were also challenged to provide resources under this context and relied on emotional support as a primary component of their work. A combination of individual, interpersonal, and environmental factors combined to produce risk for reincarceration and also impinged on the intervention possibly undermining its effectiveness. As EBTs are disseminated widely, adapted to different settings, and applied to new populations, there are more opportunities for their effectiveness to be undermined by the noise of real-world settings. The risk environment in certain high-risk communities needs to be addressed or else they little chance of improving the lives of those we seek to help.

http://repository.upenn.edu/edissertations/831 2014/10/01 - 21:58

Antibody responses are one of the major defense mechanisms that mammals employ against microbial infections. As such, these responses have been targeted by most vaccine regimens used to prevent infections. However, in spite of the success of current vaccines, our understanding of how humoral immune responses develop is incomplete. A better understanding of the immunology behind humoral immunity will help in the future design of effective vaccine regimens. Much of the work done toward understanding humoral immunity has focused on the germinal center (GC) reaction. GC reactions are initiated after infections and vaccinations when B cells are activated through the B cell receptor (BCR) and interact with the other members of the responding immune system, including helper T cells. GC B cells proliferate while improving their BCR, and ultimately go on to differentiate into plasma cells that secrete protective antibodies and memory B cells that can respond to re-infection in the future. The extrinsic mechanisms by which GC B cells adopt these mutually exclusive fates have been extensively researched, but we considered that GC B cells may exercise cell-intrinsic control over their differentiation. Specifically, we hypothesized that GC B cells use asymmetric cell division to accomplish the multiple tasks set before them. Using confocal microscopy we examined dividing GC B cells and observed that two drivers of GC B cell differentiation, Bcl6 and the receptor for the cytokine IL-21 (IL-21R), are asymmetrically segregated during mitosis and unequally inherited by the resulting daughter B cells. This process is dependent on the evolutionarily conserved regulator of polarity, aPKC, and GC B cells are stimulated to divide asymmetrically by contacts made with helper T cells. By examining humoral immune responses in mice in which GC B cells do not divide asymmetrically, we have shown that asymmetric division is not required for B cell differentiation, while cell-cell contacts are absolutely critical to their differentiation. These data suggest that, in addition to signals from the environment of the GC reaction, diversity of GC B cell function may be supported by cell-cell interactions in the GC reaction.

http://repository.upenn.edu/edissertations/830 2014/10/01 - 21:58

Objective: Increased parent-child communication has been found to strengthen family relationships and reduce adolescent sexual risk behaviors. These processes, however, have not been studied in the sex worker population. Given the fact that the children of sex workers often do not leave the sexual risk environments inhabited by their mothers, the manner in which sex worker mothers shape their children's sexual risk behaviors is crucial to their health and well-being. Family-based sexual health communication interventions (FSHCI) have the potential to change adolescent sexual risk behaviors within the sex work community.
Methods: Utilizing a sequential mixed-methods design, this study 1) explored sex worker mothers' normative, behavioral, and control beliefs about sexual health communication with their adolescent children by conducting in-depth qualitative interviews with 34 sex worker mothers, 2) utilized the results of this analysis to design a FSHCI collaboratively with Durbar, a sex worker collective in Kolkata, India, and 3) tested the feasibility and preliminary efficacy of the FSHCI in improving the frequency of mother-children communication about sexual health with a small sample of sex worker mothers.
Results: Durbar's collectivizing processes were instrumental in shaping participants' orientation to sexual health communication with their children. FSHCI was successful in changing participants' attitudes and comfort about sexual health communication and the frequency of sexual risk reduction communication. Furthermore, participants' attitudes and perceived behavioral control were significantly correlated with the frequency and comfort of sexual health communication.
Conclusion: This is the first study to explore mother-child sexual health communication and test a FSHCI in the sex worker community. Findings support the importance of understanding both community and family level processes in developing and implementing interventions. Findings also support the feasibility of a FSHCI in the sex worker community.

http://repository.upenn.edu/edissertations/829 2014/10/01 - 21:58

Daxx, a multifunctional protein with a diverse set of proposed functions, is ubiquitously expressed and highly conserved through evolution. A primarily nuclear protein, Daxx is able to regulate apoptosis, transcription, and cellular proliferation. Despite many studies into the function of Daxx, its precise role in the cell remains enigmatic. Herein, evidence is presented to expand upon the known anti-apoptotic function of Daxx, to establish Daxx as a novel molecular chaperone, and to further its repertoire of transcriptional targets. As an apoptotic inhibitor, Daxx is known to regulate p53 by stabilizing its main negative regulator, Mdm2, via formation of a ternary complex between Daxx, Mdm2, and Hausp. The present study reveals that DNA damage-induced phosphorylation of Daxx is an important step in the disruption of the Daxx-Mdm2-Hausp complex, allowing for p53 activation. A novel activity for Daxx is presented whereby it is able to modulate protein folding in vitro and in vivo. Daxx can refold and reactivate denatured substrates using its paired amphipathic helical and acid-rich domains. This finding was extended to p53, where Daxx was able to solubilize misfolded p53 both in vitro and in vivo. Further, this finding may provide a biochemical rationale as to the varied functionality of Daxx in the cell. Finally, a novel transcriptional target, Cdk6, is described for Daxx. Microarray analysis indicated that Cdk6 is a strongly downregulated gene upon Daxx silencing. Depletion of Daxx in various cancer and primary cell lines led to a decrease in Cdk6 protein levels. Additionally, Daxx can affect transcription of Cdk6, and chromatin immunoprecipitation reveals that Daxx binds to the Cdk6 promoter. Together, these results indicate that Daxx has potential functional plasticity and is involved in an array of cellular functions; in fact, cellular homeostasis relies on the proper execution of multiple biological processes. Elucidation of the biology of Daxx would not only provide insight into the regulation of these processes, but may also establish Daxx as a relevant therapeutic target.

http://repository.upenn.edu/edissertations/828 2014/10/01 - 21:58

Coordinated smooth muscle contraction is critical for force production and proper functioning of numerous organ systems. Activation at the myosin motor domain via phosphorylated myosin light chain (phospho-MLC) remains the primary signal to initiate contraction, but it is now appreciated that there are additional force modulators also present in smooth muscle. One particularly well studied modulatory protein is Caldesmon (CaD), which has been implicated in controlling contractile force in vascular smooth muscle, however little is known of CaD's physiological role in vivo. Studies in vitro have shown that CaD inhibits actomyosin interactions and that this effect is reversed after phosphorylation, allowing for greater force propagation. Since a number of gastrointestinal (GI) tract and vascular disorders are known to be a result of aberrant force production, closely monitoring CaD's functional properties may provide insight into common contractile defects. We took advantage of the transparent nature of the intestine in larval zebrafish to study CaD's effect on smooth muscle contraction in a vertebrate model. We initiated these studies by examining propulsive peristalsis in the larval intestine after knockdown of endogenous smooth muscle CaD protein. We next measured the role of CaD in the absence of phospho-MLC to better understand its function in disease states where myosin activation is perturbed. Using extensive live imaging analysis, we show that disrupting CaD function within intestinal smooth muscle can significantly increase GI motility, with and without phospho-MLC, highlighting CaD's ability to independently modulate contractile force. In addition, previous work on a mutant, meltdown (mlt), in our lab has uncovered a smooth muscle myosin (myh11) mutation leading to increased contractile force and premature CaD phosphorylation. Interestingly, in the mlt mutant intestinal epithelial invasion was observed pointing to the unique role for force propagation in initiating cell invasion. We show that CaD is necessary for mlt epithelial invasion to occur, as knockdown of CaD causes the invasive phenotype in heterozygous mlt, which otherwise appear wild type. To gain a better understanding of the crosstalk between muscle contraction and epithelial invasion, we performed a genetic screen for modifier mutants of the mlt phenotype. From the screen, we discovered two enhancer mutants of mlt that contained missense mutations in unique protein domains of MYH11 that alter the contractile function of smooth muscle. These mutations (S237Y and L1287M) occur in both the motor domain and helical tail domain of the protein, suggesting that alterations in distinct regions of myosin can result in abnormal contraction and potentially lead to invasion in underlying cells. Since a number of myosin mutations have been implicated in vascular disease and colon cancer, these studies provide insight into the diversity and mechanistic consequences of mutated myosin in altering smooth muscle contraction and epithelial cell invasion.

http://repository.upenn.edu/edissertations/827 2014/10/01 - 21:58

Decision making is a necessary and integral part of life. This paper examines several specific concepts related to decision making and attempts to demonstrate how to create a positively charged culture that embraces change, attracts talent and improves decision making. First we will discuss how leveraging our personal strengths instead of focusing on our weaknesses can lead to a culture that emboldens people to take appropriate risks and encourages them to focus on the opportunities in change. Second we will discuss how having positive, high quality relationships creates a supportive workplace that attracts and retains talent and fosters collaboration. Third, we will explain how being engaged in what we do, finding meaning in our work and recognizing and acknowledging the role emotions play in our lives can all positively affect our decision making abilities. Fourth, we will discuss how all of us utilize decision making short cuts called heuristics that often serve us well but can sometimes lead to unhelpful biases. We will describe some of the most common heuristics people use and the potential biases they produce and offer some suggestions on how we can overcome these biases, when appropriate, to make the best decisions possible. Finally, we will discuss how positive emotions affect decisions as well as result from the decision making concepts discussed.

http://repository.upenn.edu/mapp_capstone/67 2014/10/01 - 21:58

Many Baby Boomers are finding (or may be finding) themselves in a difficult transition, as they lose their jobs in this listless economy. For most of them, not yet ready to retire, finding a new, equally well-paying job in their field will be extremely difficult. How can they go through the initial disbelief, anger, sadness and fear that come with losing their jobs; and rediscover their sense of direction, purpose, security and identity? As 8,000 Baby Boomers turn 60 each day for the next ten years, this question takes on enormous proportions. Positive psychology offers many insights and interventions for individuals who are facing such a challenging time. By identifying and focusing on their inherent strengths; developing ways to reflect more deeply; amplifying their optimism; enhancing their resilience; and connecting more genuinely with others, they may open themselves up to new possibilities – discovering a new sense of purpose and meaning in their next chapter. From there, they will be able to craft a compelling new vision of themselves, connecting who they are with what happened, where they are going, and how they plan to get there. The intention of this work is to provide hope, solace, insights, and direction for individuals who are feeling lost – helping them find their own compass, pointing in a new, more positive direction.

http://repository.upenn.edu/mapp_capstone/66 2014/10/01 - 21:58

This dissertation describes the electrical properties of metal nanowire-polymer hybrid systems. The first part of the thesis discusses electrical percolation of metal nanowire networks in bulk polymer nanocomposites (3D) and nanowire films (quasi-2D). Specifically, we integrate simulations of rod networks and experiments of model metal nanowire systems to establish the dependence of their electrical properties on the nanowire aspect ratio (L/D) and network structure. For bulk polymer nanocomposites, we find that narrow Gaussian distributions in filler size do not impact the electrical percolation threshold, while mixing small fractions of high-L/D rods with modest-L/D rods significantly reduces the threshold. We also generalize the widely used excluded volume model of percolation, which was originally formulated for infinite-L/D, monodisperse rod networks, to account for both finite-L/D and arbitrary distribution in the rod dimensions. Next, we adapt our 3D simulation approach to model the electrical properties quasi-2D rod networks, which are relevant to nanowire films that are being pursued for flexible, transparent conductors. We present the first quantitative predictions of the dependence of the sheet resistance in nanowire films on the aspect ratio and areal density of mono- and poly-disperse nanowires. Moreover, by combining our simulations of sheet resistance and an empirical diameter-dependent expression for the optical transmittance, we produced a fully calculated plot of optical transmittance versus sheet resistance, the primary performance criteria for transparent conductors. Further, by fitting simulation results to experimental data, we obtain an effective average contact resistance, Rc_effective, between two nanowires. Rc_effective extracted using our integrated approach enables direct comparisons between nanowires of different compositions or networks fabricated by distinct means. We also report the critical area fraction of rods required to form a percolated network in nanowire films and provide a semi-empirical analytical expression for the critical area fraction as a function of L/D for mono- and poly-disperse rods. Our simulations of electrical percolation in quasi-2D and 3D rod networks, coupled with our extensions of existing analytical models, provide critical guidance for engineering bulk conducting nanocomposites and nanowire films with well-defined properties that are optimized for specific applications.
In the second part of this thesis, we demonstrate reversible resistive switching in silver/polystyrene/silver nano-gap devices comprised of Ag nano-strips separated by a nanoscale gap and encapsulated in polystyrene (PS). These devices show highly reversible switching behavior with high on-off ratios during cyclic switching tests over many cycles. We also observe evolution of the gap after extensive testing, which is consistent with metal filament formation as the switching mechanism in Ag/PS/Ag nano-gap devices. The reversible electrical bistability demonstrated here was accomplished with an electrically inactive polymer, thereby extending the range of polymers suitable for organic digital memory applications.

http://repository.upenn.edu/edissertations/902 2014/09/28 - 12:08

Innate immunity is the first line of defense against viral infection and depends on the use of germline-encoded pattern recognition receptors (PRRs) that detect pathogen-associated molecular patterns (PAMPs). Virus recognition subsequently triggers an assortment of effector responses that are critical for clearing the invading pathogen. Among known antiviral pathways, autophagy, a biological process that mediates the degradation of cytoplasmic components, may be one of the most ancient. We previously demonstrated that autophagy is essential for resistance to the Rhabdovirus Vesicular stomatitis virus (VSV) in flies. However, the mechanism by which autophagy is triggered during VSV infection remained unclear. Through a targeted RNAi screen, I discovered that a previously uncharacterized Drosophila Toll receptor, Toll-7, is essential for restricting VSV replication in cells and adult flies. Moreover, Toll-7 was required to activate antiviral autophagy both in vitro and in vivo. Toll-7 interacted with VSV virions at the cell surface, demonstrating that Toll-7 is a bona fide PRR and the only known Toll receptor that physically associates with a pathogen. Taken together, these data have revealed Toll-7 as the link between VSV recognition and activation of antiviral autophagy.
To investigate the range of Toll receptor-mediated antiviral immunity, I next challenged Toll receptor mutant flies with a panel of arthropod-borne viruses (arboviruses). These studies revealed a critical in vivo role for Toll-7 in restricting infection with Rift Valley fever virus (RVFV), a medically relevant pathogen in the bunyavirus family that causes disease in humans and livestock. Toll-7 mutant flies showed increased viral replication and mortality after RVFV infection due to impaired antiviral autophagy activation. Remarkably, autophagy was also required to restrict RVFV infection in mouse and human cells, demonstrating an evolutionarily conserved role for antiviral autophagy in flies and mammals. Autophagy activation using pharmacologic inducers of autophagy potently inhibited RVFV infection in flies and mammalian cells. Collectively, these data suggest that modulation of this conserved antiviral pathway may be a promising strategy for controlling RVFV infection, which lacks effective therapeutics and vaccines, in both mammals and the vector insect.

http://repository.upenn.edu/edissertations/901 2014/09/28 - 12:08

Foxp3 is a transcription factor required for the development and function of regulatory T cells (Treg). Humans lacking functional Foxp3 are afflicted with uncontrolled systemic autoimmunity. How the Foxp3 protein is regulated post-translationally is unclear. Our previous studies demonstrate cyclin-dependent kinase 2 (CDK2) controls Foxp3+Treg function, but the mechanism by which this occurred was not identified. The CDKs are primarily thought to control cell cycle progression. However, recent studies suggest only CDK1 is required for normal mammalian cell cycle, raising questions about the biological role of the other CDKs. Specifically, mice genetically deficient in CDK2 are viable with no significant defects in cell cycle. We probed the Foxp3 sequence for the presence of CDK motifs, finding four such sites in the amino terminus. We confirmed that Foxp3 is phosphorylated by CDK2 using an in vitro kinase assay and mass spectrometry, as well as a phospho-specific antibody that recognizes one of the phosphorylated Foxp3-CDK motifs. We generated a mutant of Foxp3 lacking all four CDK motifs, which has increased half-life compared to wild-type Foxp3. CD4+ T cells transduced with a Foxp3-CDK motif mutant have increased function compared to cells transduced with wild-type Foxp3 as measured by induction and repression of canonical Foxp3 target genes, as well as the ability to suppress conventional T cell proliferation. These data suggest CDKs negatively regulate Foxp3 protein stability, which has an impact on Foxp3 function. To determine when the CDK cascade was actively regulating Foxp3 in vivo we investigated the role of the CDK2 inhibitor, p27kip1. Recent data shows TGFβ signaling drives expression of p27kip1 in B cells. TGFβ is also required for extrathymic induction of Foxp3 in conventional CD4+ T cells. We show that conventional T cells, which have high CDK2 activity and minimal p27kip1 expression, induce large amounts of p27kip1 along with Foxp3 in the presence of TGFβ. Additionally, T cells lacking p27kip1 have defective TGFβ-dependent Foxp3 induction. We hypothesize that TGFβ signaling is required to activate p27kip1 and stabilize Foxp3 protein levels in developing iTreg by repressing CDK2.

http://repository.upenn.edu/edissertations/900 2014/09/28 - 12:08

Over the past few years, online social networks have become nearly ubiquitous, reshaping our social interactions as in no other point in history. The preeminent aspect of this social media revolution is arguably an almost complete transformation of the ways in which we acquire, process, store, and use information. In view of the evolving nature of social networks and their increasing complexity, development of formal models of social learning is imperative for a better understanding of the role of social networks in phenomena such as opinion formation, information aggregation, and coordination. This thesis takes a step in this direction by introducing and analyzing novel models of learning and coordination over networks. In particular, we provide answers to the following questions regarding a group of individuals who interact over a social network: 1) Do repeated communications between individuals with different subjective beliefs and pieces of information about a common true state lead them to eventually reach an agreement? 2) Do the individuals efficiently aggregate through their social interactions the information that is dispersed throughout the society? 3) And if so, how long does it take the individuals to aggregate the dispersed information and reach an agreement? This thesis provides answers to these questions given three different assumptions on the individuals' behavior in response to new information. We start by studying the behavior of a group of individuals who are fully rational and are only concerned with discovering the truth. We show that communications between rational individuals with access to complementary pieces of information eventually direct everyone to discover the truth. Yet in spite of its axiomatic appeal, fully rational agent behavior may not be a realistic assumption when dealing with large societies and complex networks due to the extreme computational complexity of Bayesian inference. Motivated by this observation, we next explore the implications of bounded rationality by introducing biases in the way agents interpret the opinions of others while at the same time maintaining the assumption that agents interpret their private observations rationally. Our analysis yields the result that when faced with overwhelming evidence in favor of the truth even biased agents will eventually learn to discover the truth. We further show that the rate of learning has a simple analytical characterization in terms of the relative entropy of agents' signal structures and their eigenvector centralities and use the characterization to perform comparative analysis. Finally, in the last chapter of the thesis, we introduce and analyze a novel model of opinion formation in which agents not only seek to discover the truth but also have the tendency to act in conformity with the rest of the population. Preference for conformity is relevant in scenarios ranging from participation in popular movements and following fads to trading in stock market. We argue that myopic agents who value conformity do not necessarily fully aggregate the dispersed information; nonetheless, we prove that examples of the failure of information aggregation are rare in a precise sense.

http://repository.upenn.edu/edissertations/899 2014/09/28 - 12:08

PDT for the thoracic cavity provides a promising cancer treatment modality, but improvements in treatment planning, particularly in PDT dosimetry, can be made to improve uniformity of light delivery. When a cavity of arbitrary geometry is illuminated, the fluence increases due to multiple-scattered photons, referred to as the Integrating Sphere Effect (ISE). Current pleural PDT treatment protocol at the University of Pennsylvania monitors light fluence (hereafter simply fluence, measured in W/cm2) via seven isotropic detectors sutured at different locations in thoracic cavity of a patient. This protocol monitors light at discrete locations, but does not provide a measurement of fluence for the thoracic cavity as a whole. Current calculation of light fluence includes direct light only and thus does not account for the unique optical properties of each tissue type present, which in turn affects the accuracy of the calculated light distribution in the surrounding tissue and, in turn, the overall cell death and treatment efficacy.
Treatment planning for pleural PDT can be improved, in part, by considering the contribution of scattered light, which is affected by the two factors of geometry and in vivo optical properties. We expanded the work by Willem Star in regards to the ISE in a spherical cavity. A series of Monte Carlo (MC) simulations were run for semi-infinite planar, spherical, and ellipsoidal geometries for a range of optical properties. The results of these simulations are compared to theory and numerical solutions for fluence in the cavity and at the cavity-medium boundary. The development via MC simulations offers a general method of calculating the required light fluence specialized to each patient, based on the treatment surface area.
The scattered fluence calculation is dependent on in vivo optical properties (μa and μs') of the tissues treated. Diffuse reflectance and fluorescence spectroscopy methods are used to determine the optical properties and oxygenation (reflectance measurements) and drug concentration (fluorescence measurements) of different tissues in vivo, before and after treatment, in patients enrolled the Phase I HPPH study ongoing at the University of Pennsylvania.
This work aims to provide the building blocks essential to pleural PDT treatment planning by more accurately calculating the required fluence using a model that accounts for the effects of treatment geometry and optical properties measured in vivo.  

http://repository.upenn.edu/edissertations/898 2014/09/28 - 12:08

Control over dynamics of excited states of molecules is fundamental to utilization of these states in all areas of technologies, including optical microscopy and tomography. We explored the possibility of magnetically controlling molecular emissivity by influencing spin dynamics in radical pairs (RPs) and triplet-triplet pair. We envisioned that by including RPs into a pathway leading to the formation (or decay) of an emissive triplet state, magnetic influence on phosphorescence could be realized via modulation of the RP's spin dynamics. RPs can initially be produced in their singlet or triplet spin state. These two cases were explored in the studies of electron and energy dynamics in series of donor-acceptor systems, comprising phosphorescent platinum (II) porphyrins (PtP) and rhodamine B (RhB+) derivatives.
In one series, the phosphorescent triplet state of PtP is generated by way of photo-excitation of RhB+, followed by photoinduced electron transfer with formation of a singlet-born RP, RP intersystem crossing, and subsequent recombination of the triplet RP. Similarly, singlet-born RPs were included into a pathway leading to PtP triplet state in a triad system comprising PtP, anthracene, and boron dipyrromethene.
Using another series, we have demonstrated that visible room-temperature phosphorescence can be modulated by weak magnetic fields (<1T). In this case, the RP is initially born in its triplet state upon direct excitation of PtP, followed by electron transfer originating in the PtP triplet state. External magnetic field modulates spin dynamics in the RP, affecting contribution of the singlet charge recombination channel and thereby influencing the phosphorescence.
Spin dynamics of triplet-triplet pair is also susceptible to magnetic field. Triplet-triplet pair can undergo triplet-triplet annihilation (TTA) process leading to photon upconversion, which is typically observed as p-type delayed fluorescence. We have demonstrated TTA-sensitized delayed fluorescence and delayed phosphorescence, mediated by near-infrared absorbing metalloporhyrins as sensitizers in solution at room temperature, can be magnetically modulated.
These studies present unusual and interesting examples of magnetic field effects on molecular emission and set the stage for rational design of optical imaging probes with magnetically controlled emissivity.

http://repository.upenn.edu/edissertations/897 2014/09/28 - 12:08