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IQCB1 and PDE6B Mutations Cause Similar Early Onset Retinal Degenerations in Two Closely Related Terrier Dog Breeds

Fri, 20 Apr 2018 09:00:49 PDT

Purpose.: To identify the causative mutations in two early-onset canine retinal degenerations, crd1 and crd2, segregating in the American Staffordshire terrier and the Pit Bull Terrier breeds, respectively.

Methods.: Retinal morphology of crd1- and crd2-affected dogs was evaluated by light microscopy. DNA was extracted from affected and related unaffected controls. Association analysis was undertaken using the Illumina Canine SNP array and PLINK (crd1 study), or the Affymetrix Version 2 Canine array, the “MAGIC” genotype algorithm, and Fisher's Exact test for association (crd2 study). Positional candidate genes were evaluated for each disease.

Results.: Structural photoreceptor abnormalities were observed in crd1-affected dogs as young as 11-weeks old. Rod and cone inner segment (IS) and outer segments (OS) were abnormal in size, shape, and number. In crd2-affected dogs, rod and cone IS and OS were abnormal as early as 3 weeks of age, progressing with age to severe loss of the OS, and thinning of the outer nuclear layer (ONL) by 12 weeks of age. Genome-wide association study (GWAS) identified association at the telomeric end of CFA3 in crd1-affected dogs and on CFA33 in crd2-affected dogs. Candidate gene evaluation identified a three bases deletion in exon 21 of PDE6B in crd1-affected dogs, and a cytosine insertion in exon 10 of IQCB1 in crd2-affected dogs.

Conclusions.: Identification of the mutations responsible for these two early-onset retinal degenerations provides new large animal models for comparative disease studies and evaluation of potential therapeutic approaches for the homologous human diseases.




Pharmacological Modulation of Photoreceptor Outer Segment Degradation in a Human iPS Cell Model of Inherited Macular Degeneration

Fri, 20 Apr 2018 09:00:43 PDT

Degradation of photoreceptor outer segments (POS) by retinal pigment epithelium (RPE) is essential for vision, and studies have implicated altered POS processing in the pathogenesis of some retinal degenerative diseases. Consistent with this concept, a recently established hiPSC-RPE model of inherited macular degeneration, Best disease (BD), displayed reduced rates of POS breakdown. Herein we utilized this model to determine (i) if disturbances in protein degradation pathways are associated with delayed POS digestion and (ii) whether such defect(s) can be pharmacologically targeted. We found that BD hiPSC-RPE cultures possessed increased protein oxidation, decreased free-ubiquitin levels, and altered rates of exosome secretion, consistent with altered POS processing. Application of valproic acid (VPA) with or without rapamycin increased rates of POS degradation in our model, whereas application of bafilomycin-A1 decreased such rates. Importantly, the negative effect of bafilomycin-A1 could be fully reversed by VPA. The utility of hiPSC-RPE for VPA testing was further evident following examination of its efficacy and metabolism in a complementary canine disease model. Our findings suggest that disturbances in protein degradation pathways contribute to the POS processing defect observed in BD hiPSC-RPE, which can be manipulated pharmacologically. These results have therapeutic implications for BD and perhaps other maculopathies.




Transient Photoreceptor Deconstruction by CNTF Enhances rAAV-Mediated Cone Functional Rescue in Late Stage CNGB3-Achromatopsia

Fri, 20 Apr 2018 09:00:37 PDT

Achromatopsia is a genetic disorder of cones, and one of the most common forms is a channelopathy caused by mutations in the β-subunit, CNGB3, of the cone cyclic nucleotide-gated (CNG) channel. Recombinant adeno-associated virus of serotype 5 (rAAV5)-mediated gene transfer of human CNGB3 cDNA to mutant dog cones results in functional and structural rescue in dogs <0.5 years of age, but treatment is minimally effective in dogs >1 year. We now test a new therapeutic concept by combining gene therapy with the administration of ciliary neurotrophic factor (CNTF). Intravitreal CNTF causes transient dedifferentiation of photoreceptors, a process called deconstruction, whereby visual cells become immature with short outer segments, and decreased retinal function and gene expression that subsequently return to normal. Cone function was successfully rescued in all mutant dogs treated between 14 and 42 months of age with this strategy. CNTF-mediated deconstruction and regeneration of the photoreceptor outer segments prepares the mutant cones optimally for gene augmentation therapy.




Successful Arrest of Photoreceptor and Vision Loss Expands the Therapeutic Window of Retinal Gene Therapy to Later Stages of Disease

Fri, 20 Apr 2018 09:00:30 PDT

Inherited retinal degenerations cause progressive loss of photoreceptor neurons with eventual blindness. Corrective or neuroprotective gene therapies under development could be delivered at a predegeneration stage to prevent the onset of disease, as well as at intermediate-degeneration stages to slow the rate of progression. Most preclinical gene therapy successes to date have been as predegeneration interventions. In many animal models, as well as in human studies, to date, retinal gene therapy administered well after the onset of degeneration was not able to modify the rate of progression even when successfully reversing dysfunction. We evaluated consequences of gene therapy delivered at intermediate stages of disease in a canine model of X-linked retinitis pigmentosa (XLRP) caused by a mutation in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene. Spatiotemporal natural history of disease was defined and therapeutic dose selected based on predegeneration results. Then interventions were timed at earlier and later phases of intermediate-stage disease, and photoreceptor degeneration monitored with noninvasive imaging, electrophysiological function, and visual behavior for more than 2 y. All parameters showed substantial and significant arrest of the progressive time course of disease with treatment, which resulted in long-term improved retinal function and visual behavior compared with control eyes. Histology confirmed that the human RPGR transgene was stably expressed in photoreceptors and associated with improved structural preservation of rods, cones, and ON bipolar cells together with correction of opsin mislocalization. These findings in a clinically relevant large animal model demonstrate the long-term efficacy of RPGR gene augmentation and substantially broaden the therapeutic window for intervention in patients with RPGR-XLRP.




Restoration of Visual Function by Expression of a Light-Gated Mammalian Ion Channel in Retinal Ganglion Cells or ON-Bipolar Cells

Fri, 20 Apr 2018 09:00:24 PDT

Most inherited forms of blindness are caused by mutations that lead to photoreceptor cell death but spare second- and third-order retinal neurons. Expression of the light-gated excitatory mammalian ion channel light-gated ionotropic glutamate receptor (LiGluR) in retinal ganglion cells (RGCs) of the retina degeneration (rd1) mouse model of blindness was previously shown to restore some visual functions when stimulated by UV light. Here, we report restored retinal function in visible light in rodent and canine models of blindness through the use of a second-generation photoswitch for LiGluR, maleimide-azobenzene-glutamate 0 with peak efficiency at 460 nm (MAG0460). In the blind rd1 mouse, multielectrode array recordings of retinal explants revealed robust and uniform light-evoked firing when LiGluR-MAG0460 was targeted to RGCs and robust but diverse activity patterns in RGCs when LiGluR-MAG0460 was targeted to ON-bipolar cells (ON-BCs). LiGluR-MAG0460 in either RGCs or ON-BCs of the rd1 mouse reinstated innate light-avoidance behavior and enabled mice to distinguish between different temporal patterns of light in an associative learning task. In the rod-cone dystrophy dog model of blindness, LiGluR-MAG0460 in RGCs restored robust light responses to retinal explants and intravitreal delivery of LiGluR and MAG0460 was well tolerated in vivo. The results in both large and small animal models of photoreceptor degeneration provide a path to clinical translation.




Reply to Townes-Anderson: RPE65 Gene Therapy Does Not Alter the Natural History of Retinal Degeneration

Fri, 20 Apr 2018 09:00:19 PDT

We appreciate the interest shown by TownesAnderson in our article examining the natural history of retinal degeneration in Leber congenital amaurosis caused by retinal pigment epithelium-specific protein 65kDa (RPE65) mutations and evaluating the consequences of gene augmentation therapy. Townes-Anderson’s remarks focused on the final phrase of the last sentence of the Discussion of our article. In the full sentence, we suggested that in the future, agents to reduce cell death could be delivered in combination with a more advanced version of the gene augmentation therapy that reaches not only remaining rods and extrafoveal cones but also foveal cone photoreceptors.




Improvement in Vision: A New Goal for Treatment of Hereditary Retinal Degenerations

Fri, 20 Apr 2018 09:00:13 PDT

Introduction: Inherited retinal degenerations (IRDs) have long been considered untreatable and incurable. Recently, one form of early-onset autosomal recessive IRD, Leber congenital amaurosis (LCA) caused by mutations in RPE65 (retinal pigment epithelium-specific protein 65 kDa) gene, has responded with some improvement of vision to gene augmentation therapy and oral retinoid administration. This early success now requires refinement of such therapeutics to fully realize the impact of these major scientific and clinical advances.

Areas covered: Progress toward human therapy for RPE65-LCA is detailed from the understanding of molecular mechanisms to preclinical proof-of-concept research to clinical trials. Unexpected positive and complicating results in the patients receiving treatment are explained. Logical next steps to advance the clinical value of the therapeutics are suggested.

Expert opinion: The first molecularly based early-phase therapies for an IRD are remarkably successful in that vision has improved and adverse events are mainly associated with surgical delivery to the subretinal space. Yet, there are features of the gene augmentation therapeutic response, such as slowed kinetics of night vision, lack of foveal cone function improvement and relentlessly progressive retinal degeneration despite therapy, that still require research attention.




Human Retinal Gene Therapy for Leber Congential Amaurosis Shows Advancing Retinal Degeneration Despite Enduring Visual Improvement

Fri, 20 Apr 2018 09:00:07 PDT

Leber congenital amaurosis (LCA) associated with retinal pigment epithelium-specific protein 65 kDa (RPE65) mutations is a severe hereditary blindness resulting from both dysfunction and degeneration of photoreceptors. Clinical trials with gene augmentation therapy have shown partial reversal of the dysfunction, but the effects on the degeneration are not known. We evaluated the consequences of gene therapy on retinal degeneration in patients with RPE65-LCA and its canine model. In untreated RPE65-LCA patients, there was dysfunction and degeneration of photoreceptors, even at the earliest ages. Examined serially over years, the outer photoreceptor nuclear layer showed progressive thinning. Treated RPE65-LCA showed substantial visual improvement in the short term and no detectable decline from this new level over the long term. However, retinal degeneration continued to progress unabated. In RPE65-mutant dogs, the first one-quarter of their lifespan showed only dysfunction, and there was normal outer photoreceptor nuclear layer thickness retina-wide. Dogs treated during the earlier dysfunction-only stage showed improved visual function and dramatic protection of treated photoreceptors from degeneration when measured 5–11 y later. Dogs treated later during the combined dysfunction and degeneration stage also showed visual function improvement, but photoreceptor loss continued unabated, the same as in human RPE65-LCA. The results suggest that, in RPE65 disease treatment, protection from visual function deterioration cannot be assumed to imply protection from degeneration. The effects of gene augmentation therapy are complex and suggest a need for a combinatorial strategy in RPE65-LCA to not only improve function in the short term but also slow retinal degeneration in the long term.




Concepts and Strategies in Retinal Gene Therapy

Fri, 20 Apr 2018 08:59:59 PDT

Genetic defects of the retina or retinal pigment epithelium (RPE) cause a substantial number of sight-impairing or blinding disorders, many of which eventually cause the degeneration and death of the visual cells. Previously considered incurable, some of these retinal diseases can now be treated, at least experimentally, by gene therapy.




BEST1 Gene Therapy Corrects a Diffuse Retina-Wide Microdetachment Modulated by Light Exposure

Fri, 20 Apr 2018 08:59:50 PDT

Mutations in the BEST1 gene cause detachment of the retina and degeneration of photoreceptor (PR) cells due to a primary channelopathy in the neighboring retinal pigment epithelium (RPE) cells. The pathophysiology of the interaction between RPE and PR cells preceding the formation of retinal detachment remains not well-understood. Our studies of molecular pathology in the canine BEST1 disease model revealed retina-wide abnormalities at the RPE-PR interface associated with defects in the RPE microvillar ensheathment and a cone PR-associated insoluble interphotoreceptor matrix. In vivo imaging demonstrated a retina-wide RPE-PR microdetachment, which contracted with dark adaptation and expanded upon exposure to a moderate intensity of light. Subretinal BEST1 gene augmentation therapy using adeno-associated virus 2 reversed not only clinically detectable subretinal lesions but also the diffuse microdetachments. Immunohistochemical analyses showed correction of the structural alterations at the RPE-PR interface in areas with BEST1 transgene expression. Successful treatment effects were demonstrated in three different canine BEST1 genotypes with vector titers in the 0.1-to-5E11 vector genomes per mL range. Patients with biallelic BEST1 mutations exhibited large regions of retinal lamination defects, severe PR sensitivity loss, and slowing of the retinoid cycle. Human translation of canine BEST1 gene therapy success in reversal of macro- and microdetachments through restoration of cytoarchitecture at the RPE-PR interface has promise to result in improved visual function and prevent disease progression in patients affected with bestrophinopathies.




Acute and Protracted Cell Death in Light-Induced Retinal Degeneration in the Canine Model of Rhodopsin Autosomal Dominant Retinitis Pigmentosa

Fri, 20 Apr 2018 08:59:42 PDT

Purpose

To characterize a light damage paradigm and establish structural and immunocytochemical measures of acute and protracted light-induced retinal degeneration in the rhodopsin (RHO) T4R dog model of RHO–autosomal dominant retinitis pigmentosa (ADRP).

Methods

Retinal light damage was induced in mutant dogs with a 1-minute exposure to various light intensities (0.1–1.0 mW/cm2) delivered with a Ganzfeld stimulator, or by fundus photography. Photoreceptor cell death was assessed by TUNEL assay, and alterations in retinal layers were examined by histology and immunohistochemistry 24 hours and 2 weeks after light exposure. Detailed topographic maps were made to document changes in the outer retinal layers of all four retinal quadrants 2 weeks post exposure.

Results

Twenty-four hours post light exposure, the severity of photoreceptor cell death was dose dependent. Immunohistochemical analysis revealed disruption of rod outer segments, focal loss of the RPE integrity, and an increase in expression of endothelin receptor B in Müller cells with the two highest doses of light and fundus photography. Two weeks after light exposure, persistence of photoreceptor death, thinning of the outer nuclear layer, and induction of Müller cell gliosis occurred with the highest doses of light.

Conclusions

We have characterized outcome measures of acute and continuing retinal degeneration in the RHO T4R dog following light exposure. These will be used to assess the molecular mechanisms of light-induced damage and rescue strategies in this large animal model of RHO-ADRP.




Assessment of Visual Function and Retinal Structure Following Acute Light Exposure in the Light Sensitive T4R Rhodopsin Mutant Dog

Fri, 20 Apr 2018 08:59:34 PDT

The effect of acute exposure to various intensities of white light on visual behavior and retinal structure was evaluated in the T4R RHO dog, a naturally-occurring model of autosomal dominant retinitis pigmentosa due to a mutation in the Rhodopsin gene. A total of 14 dogs (ages: 4–5.5 months) were used in this study: 3 homozygous mutant RHOT4R/T4R, 8 heterozygous mutant RHOT4R/+, and 3 normal wild-type (WT) dogs. Following overnight dark adaptation, the left eyes were acutely exposed to bright white light with a monocular Ganzfeld dome, while the contralateral right eye was shielded. Each of the 3 homozygous (RHOT4R/T4R) mutant dogs had a single unilateral light exposure (LE) to a different (low, moderate, and high) dose of white light (corneal irradiance/illuminance: 0.1 mW/cm2 , 170 lux; 0.5 mW/cm2 , 820 lux; or 1 mW/cm2 , 1590 lux) for 1min. All 8 heterozygous (RHOT4R/+) mutant dogs were exposed once to the same moderate dose of light. The 3 WT dogs had their left eyes exposed 1, 2, or 3 times to the same highest dose of light. Visual function prior to LE and at 2 weeks and 33 weeks after exposure was objectively assessed in the RHOT4R/T4R and WT dogs by using an obstacle-avoidance course. Transit time through the obstacle course was measured under different scotopic to photopic ambient illuminations. Morphological retinal changes were evaluated by non-invasive in vivo cSLO/sdOCT imaging and histology before and at several time-points (2–36 weeks) after light exposure. The analysis of the transit time through the obstacle course showed that no differences were observed in any of mutant or WT dogs at 2 weeks and 33 weeks post LE. The RHOT4R/T4R retina exposed to the lowest dose of white light showed no obvious changes in ONL thickness at 2 weeks, but mild decrease was noted 36 weeks after LE. The RHOT4R/T4R retina that received a moderate dose (showed an obvious decrease in ONL thickness along the superior and temporal meridians at 2 weeks post LE with more severe damage at 36 weeks post LE in all four meridians. The RHOT4R/T4R retina exposed to the high dose showed at 2 weeks after LE extensive ONL damage in all four meridians. This light intensity did not cause any retinal damage in WT dogs even after repeated (up to 3) LE. Analysis of ONL thickness in heterozygous mutant dogs exposed to the moderate dose of light confirmed the increased sensitivity to light damage of the superior/ tapetal retina, and the occurrence of an ongoing cell death process several weeks after the acute LE. In conclusion, a short single exposure to a dose of white light that is not retinotoxic in WT dogs causes in the T4R RHO retina an acute loss of ONL in the central to mid peripheral region that keeps progressing over the course of several weeks. However, this severe retinal damage does not affect visual behavior presumably because of islands of surviving photoreceptors found in the area centralis including the newly discovered canine fovea-like area, and the lack of damage to peripheral photoreceptors.




"Too Blue to Talk about Sex": Exploring the Relationship between Depression and Sexual Behavior among Black Women - A Study for HIV Prevention

Fri, 20 Apr 2018 05:36:44 PDT

Compared to women of all racial categories within the United States, Black women continue to have higher incidence rates for contracting HIV/AIDS. Black women contract HIV at more than 10x the rate of their White and minority counterparts (CDC, 2014). Among Black women diagnosed with HIV, over 80% reported contracting it through unprotected heterosexual intercourse (Institute, 2012). Research on sexual behavioral risks for contracting HIV/AIDS has contributed to targeted racial and gender-based HIV prevention programs that provide education and skills training in utilizing risk-reduction methods during heterosexual intercourse (CDC, 2015). However, the continued disproportionality of HIV incidence among Black women necessitates further examination of why this difference persists. Although research has shown the impact of depression on various health outcomes, understanding depression symptomatology relationally with high risk sexual behaviors, and the underlying reasons behind those behaviors, has been an underexplored area within HIV prevention research of Black women. To increase knowledge of the lived experiences of Black women, this quantitative research study explored the following question: Is there a relationship between risky sexual behaviors and depression symptomatology among adult Black women who engage in heterosexual intercourse? The aims of the study were to better understand: 1) the sexual behavioral practices of Black women; 2) depression experiences among Black women; and 3) the relationship between depression symptomatology and sexual behavioral practices as an indicator of HIV risk. To achieve these aims, the study tested the following hypothesis: Adult Black women who report depressive symptoms will be more likely to engage in high risk sexual behaviors than Black women who are not depressed. A non-probability convenience sample of 48 Black women (n=48) from urban communities in the northeast completed two questionnaires measuring depressive symptoms and sexual behaviors. Findings revealed that the presence of depression symptomatology was positively associated with high-risk sexual behaviors among Black women in the sample. Additionally, age was found to be a factor in both depression and sexual risk behavior. This study is recognized as a beginning towards understanding how mental health impacts sexual risk for Black women. To address the disproportionately higher rate of HIV infections among Black women, it may be prudent to apply culturally-relevant mental health interventions that consider the psychological experiences of Black women at all stages of their emotional and sexual development. While not commonly implemented in existing HIV prevention programs, identifying strategies for integrating mental health interventions may have significance towards eliminating the disproportionately high HIV incidence rate among Black women in the United States.










Lower Postsurgical Mortality for Individuals with Dementia with Better-Educated Hospital Workforce

Tue, 17 Apr 2018 08:14:22 PDT

Surgical patients age 65 and over with Alzheimer’s disease and related dementias (ADRD) were more likely to die within 30 days of admission and to die after a complication than those without ADRD. Having better-educated nurses in the hospital improved the likelihood of good outcomes for all surgical patients, but had a much greater effect in individuals with ADRD. Specifically, a 10% increase in the proportion of nurses with a Bachelor of Science in Nursing (BSN) degree or higher was associated with 10% lower odds of death and 10% lower odds of dying after a complication for surgical patients with ADRD.




The creative destruction of New York City: Landscape, memory, and the politics of place, 1900--1930

Mon, 16 Apr 2018 19:40:20 PDT

This dissertation is a study of the process and experience of destruction and rebuilding in early-twentieth century New York City. By examining debates surrounding aspects of citybuilding such as private real estate development, slum clearance, the demolition of historic buildings, and the elimination of street trees, I describe an urban development process whose central dynamic was not defined by simple expansion and growth but rather by a vibrant and often chaotic "creative destruction." I apply the concept of economic creative destruction to the literal, physical destruction and creation of buildings and natural landscapes, and thereby show how capitalism inscribed its economic and social processes into the physical landscape of the city, and then into the minds of city people. It was this process--celebrated and decried, encouraged and resisted--that defined the experience of the city and posed in the most jarring manner the dilemmas of modernity.^ One of these central dilemmas was the role the past would play in the modern world. Contrary to the sense of New York as an ahistorical city, I show how central the past--as recalled, invented, and manipulated by powerful New Yorkers--was to defining how the city would henceforth be built. Collective memories were fashioned and used with abandon by the city's builders, in complex and sometimes contradictory ways: by real estate developers hoping to enhance the prestige of Fifth Avenue; by historic preservation advocates seeking moral inspiration and assimilationist lessons by saving and promoting historic landmarks; by tenement reformers eager to expunge deplorable memories of slums; and by street tree advocates who saw in nature a link to a more stable pace of change which would serve as a palliative for the ills of the modern city. The "politics of place," that is, the centrality of the nature and sense of place in urban development debates, was the product of citybuilders setting the tool of memory to the substance of landscape in order to transform the metropolis. ^




*Design through drawing: Eero Saarinen's design in the Jefferson National Expansion Memorial Competition

Mon, 16 Apr 2018 19:40:08 PDT

Drawing has the power to generate design. It is not only the depiction of an image in the architect's mind, but also, more importantly, drawing, either the act or the product, can contribute to design as a physical counterpart to architectural imagination. Many architects might agree with this proposition, based on their daily practice. This research is an attempt to cast light on this phenomenon, offering a rigorous analysis and concrete proofs. The study begins with an attempt to define architectural drawing, which leads to an extensive investigation of the characteristics of representation in architectural drawings. Eero Saarinen's winning entry in the Jefferson National Expansion Memorial Competition of 1947-48 was chosen for examination. A total of twenty-one drawings, ranging from early sketches to the four submission sheets, have survived to be studied. Contemporaneous comments by the architect and team members are also examined. With the limited interaction between the architect and client during the competition, it was possible to identify and set aside external design influences. That done, the study examines changes that occurred in the evolution of the design and traces many of them to the effects of drawing. Five ways in which drawing generates design development are proposed and related to the case. Drawing suggests a specific way in which an ambiguous design may become more concrete. Multiple interpretation of a drawing, either conflicting with the original or not, offers a particular design development. Drawing may suggest design alternatives, sometimes by clarifying the particular problems of the design, other times by helping the architect exhaust the possibilities of design. Drawing sometimes brings an unforeseen issue to light and forces an architect to consider it. Drawing may concretize an accidental, unintended form before an architect's eyes. Seen in all its possibilities, drawing becomes more than a mere means of communication, it is a generator of creativity. Through the production of physical objects, architects are able to formulate, change, and elaborate such complex mental images as architectural designs. In the realm of architecture, imagination grows out of the experience of making. ^




Time and architecture: Problems of duration and sequence in architectural design

Mon, 16 Apr 2018 19:39:50 PDT

The outlook to and value man places on time affects every aspect of human activity, including architecture. The current heightened sense of time-awareness can be witnessed in the emergence of such practices as fast-tracking. Such unconventional methods associated with speed have been the subject of much criticism and controversy on the assumption that they adversely affect the quality of architectural design. Yet the ties between time and architecture are multifold, and go much deeper than their being a problem of speed alone. They involve the interrelationship of such issues as the notion of time of an entire age, as well as the specific architectural parameters of sequence and duration. The understanding and evaluation of current architectural practices can only be achieved in view of a broader historical perspective. The intricacies of this relationship are examined by tracing the major historical developments in time conception and tying them to architectural practices of the time. Duration and sequence are themselves functions of broader influences of technology, economic conditions, weather, myth, magic, custom and tradition and human values. Through the study of specific buildings as well as general principles of architectural design and construction the impact of the temporal aspects of duration and sequence on the ensuing design, tempered by the aforementioned influences are identified and analyzed. Several fast-track designs, representative of short duration and overlapped sequence in current practice are investigated. By tying the historical analysis to contemporary practice key aspects of the intricate interrelationship between time and architecture are uncovered. It becomes apparent that duration (long and short) and sequence (linear or overlapped) affect architectural design in precise ways, some beneficial and some adverse. Ultimately, the study also reveals that the current and much maligned practice of fast-tracking, rather than being an invention of this century is simply a reversal to design and construction methods of pre-industrial eras, but under a new set of circumstances. Moreover, it becomes evident through historical and contemporary example that each of the sequential and overlapped processes has its possibilities and limitations and that by understanding the innate qualities of each system, creative design is attainable using either method. ^




Organizational policy, organizational support systems, computer education, and attitudes toward the computer as they relate to computer usage in private industry

Mon, 16 Apr 2018 19:39:44 PDT

Research studies have suggested that computer education, attitudes toward the computer, and organizational policy relate to computer usage in business environments. Systems theory has suggested that for a system within an organization to change, a change in management policy must be conveyed, and the system must be able to incorporate this information, manage its own change, stabilize this change, and obtain feedback on the effectiveness of this change. Therefore, this author hypothesized that in order for managers to use computers, they must sense that the organization expects computers to be used, learn how to use them, and maintain this change through feedback and support mechanisms.^ The purpose of this study was to investigate the relationship between computer usage in private businesses and (1) the organizational policies and supports that are available to the individual and (2) the amount and kind of computer education that the individual has experienced. Attitudes toward the computer were also investigated. In addition, this investigation examined the interaction between two organizational variables (Organizational Policy, Use of Support Systems), the variable Computer Education, four individual variables (Computer Anxiety, Computer Experience, Age, Gender) and the variable Computer Usage.^ Ninety-five managers completed the questionnaire battery and 18 of these managers were interviewed. Analysis consisted of correlation, discriminant analysis, one way analysis of variance, forward-selection regression analysis, and path analysis as well as content analysis of interviews. Results indicated that Lack of Computer Anxiety and Computer Experience affect Computer Usage directly. Youth affects Computer Usage both directly and indirectly through its effect on Lack of Anxiety. The effect Computer Education has on Computer Usage is mediated by Computer Experience. Providing support systems aids and facilitates usage. The results have implications for schools and businesses that are planning to introduce computers or to increase computer usage in their organizations. Through an understanding of which variables contribute positively to computer usage, educators and executives may be aided in formulating policies and planning courses, workshops, and programs to encourage computer usage. ^




Cadmium block of squid calcium currents

Mon, 16 Apr 2018 19:39:40 PDT

The mechanism of Cd$\sp{2+}$ block of Ca$\sp{2+}$ currents was explored in squid giant fiber lobe (GFL) neurons using the whole-cell patch clamp.^ Control calcium currents activated sigmoidally, more rapidly at more positive potentials and did not inactivate significantly. 10 to 250 $\mu$M external Cd$\sp{2+}$ blocked the currents reversibly in a voltage- and time-dependent fashion. For Vm $\leq$ 0 mV, the time course for a step of 10 ms resembled that of the control; but for Vm $>$ 0 mV, the currents "inactivated" rapidly (within 5 ms in 125 $\mu$M Cd$\sp{2+}$) to a nonzero level. Final block was greater for larger depolarizations. Block increased with Cd$\sp{2+}$ concentration, and at 0 mV the half-blocking concentration was 125 $\mu$M.^ Tail currents in cadmium had an initial "hook"--upon hyperpolarization, the currents increased transiently, then decreased. This suggests that Cd$\sp{2+}$ escapes from some channels before they close. Superimposed tail traces recorded in the presence and absence of Cd$\sp{2+}$ did not cross one another. This shows that Cd$\sp{2+}$ does not slow channel closing.^ Many of described features can be explained if Cd$\sp{2+}$ is a permeant blocker of Ca$\sp{2+}$ channels: Cd$\sp{2+}$ permeates the channels, but binds transiently to an intrapore site, obstructing the passage of other (e.g. calcium) ions. The dwell time depends on the transmembrane potential, becoming shorter for steeper potential gradients.^ A 5-state model simulates the steady state and kinetic features. It combines a Hodgkin-Huxley m$\sp2$ gating scheme and a one-site Woodhull ionic blockage model for a permeant blocker and includes a closed blocked state. To fit the data, the binding site for cadmium had to be near the outer side of the pore ($\delta$ = 0.1), with a well depth of about $-$12.2 RT. The site was flanked by a barrier at each end of the channel. The model predicts that the Cd$\sp{2+}$ entry rate is nearly voltage independent, whereas the exit rate is steeply voltage dependent (e-fold/$-$16 mV). The channel closes at a normal rate with cadmium inside. ^




CONTENT ANALYSIS OF VIDEOTAPED INTERVIEWS OF CHILDREN IDENTIFIED AS SEXUALLY EXPLOITED

Mon, 16 Apr 2018 19:39:36 PDT

The purpose of this study was to develop methodology to analyze responses from suspected sexually exploited children contained in videotaped interviews with a clinician. The content was analyzed using predetermined categories developed from the competency requirements of the Federal Rules of Evidence to determine the value of the tapes as admissible evidence.^ Fifty videotaped interviews were analyzed by the process of content analysis. Through the use of written coding instructions the content of each videotaped interview was coded according to four competency categories: personal, interpersonal, academic and truthfulness competency. Content that indicated sexual exploitation was coded according to a separate category for abuse. The method of questioning by the clinician and the clinician's response to the child were also coded for their leading, suggestive and reinforcing nature.^ Analysis of the videotaped interviews for the legal requirement of competency revealed the clinician's application of the competency categories to be inconsistent.^ The videotapes provided a clear illustration of the child's presentation of self, verbal and nonverbal behaviors as well as the child's defensive style.^ Verbal statements from the child that would support sexual victimization were present in one third of the videotaped interviews. However, because the children's answers were obtained through leading questions they mitigated the competency categories, thus limiting the utility of the videotaped content for legal purposes. ^




VEHICLE ROUTING AND SCHEDULING WITH TIME WINDOW CONSTRAINTS: MODELS AND ALGORITHMS (HEURISTICS)

Mon, 16 Apr 2018 19:39:18 PDT

The effective and efficient management of the distribution of goods or services is becoming increasingly important in both the private and public sectors.^ A key element of many distribution systems is the routing and scheduling of vehicles through a set of customers. This thesis is concerned with the design and analysis of models and algorithms for the vehicle routing and scheduling problem with time window constraints. These allowable service time constraints arise naturally in problems faced by business organizations which work on fixed time schedules.^ Given the intrinsic difficulty of this problem class, approximation methods seem to offer the most promise for practical size problems. After describing a variety of heuristics, an extensive computational study of their performance is conducted. The problem set includes routing and scheduling environments which differ in terms of the type of data being used to generate the problems, the percentage of time windows, their tightness and positioning, and the sechduling horizon. Our results indicate that heuristics are very effective and efficient in solving a wide range of large-scale problems. Several heuristics performed well in different problem environments; among them, the behavior of one heuristic was consistently very good. A parametric analysis of the best heuristic is conducted, and the effect of factors, such as time windows' density, tightness, and positioning, on the behavior of heuristics is analyzed and found to be very strong.^ Analytical results concerning the behavior of approximation methods are then derived through worst-case analysis. For a variety of heuristics, it is shown that their worst-case behavior on n customer problems is (OMEGA)(n), for the number of vehicles used and the total distance traveled.^ Time window constraints alter the computational complexity of even "easy" problems involving routing components. It is shown that the spanning tree problem with time windows is NP-hard. We then analyze alternative model formulations and present new possibilities for developing branch and bound algorithms which exploit the structure of the time window constraints for this and more general problems with time windows. Approximate methods are also presented, and their performance is assessed theoretically. ^




AN INVESTIGATION INTO THE NATURE OF THE RELATIONSHIP BETWEEN THE PARTS AND THE WHOLE IN ARCHITECTURAL COMPOSITION

Mon, 16 Apr 2018 19:39:10 PDT

The scope of this study is a theoretical investigation into the nature of the relationship between the parts and the whole in architectural composition. Implicit in this choice of theme is the assumption that this relationship is an essential component of the process of design. The aim of the study is to show that, rather than proceeding from the whole to the parts, the process of architectural design is characterized by a constant interaction between parts and compositional principles, and that the character of the resulting artefact is essentially determined by the parts of which it is composed.^ The fundamental importance of the parts in the generation of architectural wholes is established in three ways: (1) The process of architectural design is described as happening on two planes, one conceptual, the other material. The architectural artefact--or constructed whole--is presented as the result of the interaction between a 'conceptual whole'--abstract and general--and material parts--which are formal interpretations of various functional demands--in such a way that they mutually influence each other; (2) analogy is shown to be the basic tool used in the generation of architectural form. The fact that analogy proceeds from part to part determines one of the basic characteristics of the process of architectural design, namely that of proceeding from the parts to the whole. (3) The study of the possible ways in which the parts of a whole can be organized shows: (i) that only an artefact conceived as a complex of parts can embody the hierarchy of different functions always present in any object; (ii) that the character of a whole is determined by the material properties of its parts.^




INFORMATION AND PRICING OF ASSETS

Mon, 16 Apr 2018 19:39:05 PDT

Continuous time financial models assume that the state vector which characterizes the instantaneous motion of the economy, is perfectly known. Observable quantities however are unlikely to constitute the state. They should be viewed as messages which signal about an unknown underlying state variable. This research takes explicit account of information processing on behalf of agents, in order to construct a dynamic theory of asset pricing. Both the case of public and heterogeneous information are investigated, in Gaussian structures.^ In a multiperiod economy with CARA tastes, fixed supply of the risky asset, and where agents value terminal wealth, the rational expectations equilibrium (R.E.E.), when information is homogeneous, is linear in the conditional mean and variance of the uncertainty, given the common observation. When traders have differing observations, there exists a fully revealing R.E.E. which is unique in the class of linear price functions.^ These results are generalized in an equilibrium model with profit maximizing firms. In the full communication economy, there exists a continuous, positive and bounded equilibrium pricing function. Its arguments are wealth, and the conditional mean and variance. It is unique in stationary as well as non stationary function spaces. When information is heterogeneous, a R.E.E. exists if the solution to the pooling economy is invertible.^ In continuous time economies, separation, Merton's multibeta model, and Breeden's consumption based model hold. The mutual funds are the portfolios with highest correlation with the conditional mean processes. Betas are impacted not only by observations, but also by the precision of the information structure which has deterministic incremental motion.^ In a continuous time general equilibrium setting, valuation formulas in the form of partial differential equations are developed. In two specific cases, a fully revealing R.E.E. is exhibited.^ Finally equilibrium in capital markets is reexamined, when constant stochastic returns to scale technologies are available. Breeden's relationships between the interest rate, consumption and production are generalized to the informational case. ^




A DESCRIPTIVE MODEL OF THE ORGANIZATIONAL STRUCTURE OF ARCHITECTURAL DESIGN BEHAVIOR

Mon, 16 Apr 2018 19:39:01 PDT

This dissertation is to be classified as an effort of developing design theories in architecture. A rationalized descriptive model of the organizational structure of architectural design behavior is developed and argued in this effort. The proposed design systems model describes the four basic activities of designing--information-processing, value-judgment, decision-making, and document-production, and their designated roles and systematic interrelationship. The main purpose of the model is to increase the quality of communication in design by clarifying the basic elements and rules of organization of the behavior.^ Existing descriptive theories are analysed in order to develop collaborating evidences for the argument. For the purpose of the argument, existing theories are classified into three categories: "paradigms of design" explaining the ways of looking at design behavior, "micro-theories" describing the individual activities involved in the problem-solving efforts, and "macro-theories" illustrating the operational patterns of actual design behavior. These three levels of descriptions are analysed and integrated in this study in order to elaborate and verify the ideas involved in the proposed model.^ Based on the three categories of descriptive theories, three issues of argument are developed: validity of the axioms employed to develop the model, comprehensive description of componential activities of design by means of the model; and empirical evidences connoted in the model. Design theories of the three categories are identified and investigated to develop the arguments for the corresponding issues. In addition to the analysis of theories, the arguments are supplemented by the author's introspective analysis of daily design activities.^ For the result of this dissertation, the design systems model is elaborated on the various levels of description. This provides a comprehensive review of the inter-relationship between existing design theories and the organizational structure of design behavior. This will help architects and researchers clarify what individual theories are about in reference to the organization of design behavior. This dissertation, therefore, provides a way of improving the accessibility and utility of the findings of existing theoretical efforts to the practice of design by proposing an explicit system of inter-relationship. ^










Optochemical Tools for Protein Dimerization in Living Cells

Mon, 16 Apr 2018 19:36:38 PDT

Fundamental biological processes including cell division, migration, and death, are driven by protein interactions. Regulation of protein localization is one of the mechanisms cells utilize to control cellular events with high spatial and temporal precision. Therefore, several techniques have been developed to provide control of protein interactions and localization. A number of elegant approaches employ naturally light-responsive proteins, also known as optogenetics, to reversibly induce protein? protein binding interactions with subcellular precision. However, the application of these light-inducible protein systems to various intracellular locations beyond the plasma membrane has been limited. Moreover, to achieve sustained interactions in some applications, most of these optogenetic systems require continuous illumination, increasing the risk of phototoxicity. Another robust and widely utilized technique to control protein interactions via small molecules is the chemically-induced dimerization (CID) of proteins; the most classic example of this technique being rapamycin-induced dimerization. However, the lack of spatiotemporal control and reversibility in this system has necessitated the development of new dimerizers in the past two decades. By combining light-inducible features with the CID technique, we have created a novel platform to rapidly and reversibly induce protein dimerization using light with high specificity in living cells. This is accomplished with subcellular spatiotemporal resolution using a series of novel, cell-permeable, photoactivatable, and photocleavable chemical dimerizers. The modular design of our system has allowed us to tailor the properties of our molecules for studying various protein functions and biological pathways inside living cells. Furthermore, we demonstrate the utility of our system by applying it to manipulate dynamic biological events including organelle transport and spindle assembly checkpoint. This work establishes a foundation for optogenetic control over protein function and highlights the advantages of a hybrid chemical and genetic approach. We envision our tools to be readily adapted to experimentally probe complex signaling networks and other cellular processes that depend upon spatiotemporal regulation of protein localization on biologically-relevant timescales. ^




Diverging Paths: Three Essays on the Transitions of Working-Class Young People in South Korea

Mon, 16 Apr 2018 19:36:32 PDT

Despite the egalitarian ideal of "college-for-all," research shows that working-class young people remain disadvantaged in the transition to college and work. However, while some experience upward mobility, most go to work. Yet, scholars have paid scant attention to these variant pathways to adulthood within the working-class young individuals. Particularly, they have not fully recognized varying roles that teachers play in the transition of working-class students to college and work. Moreover, working-class young people's understanding of the transition to adulthood has been discussed only insufficiently in the literature. Therefore, this dissertation, consist of three independent but complementary essays, investigates various transitional experiences of the working-class young people. The results draw on a one-year of ethnography in a South Korean high school as well as the broader community which serves young individuals from working-class homes. The first article of the dissertation shows how teachers, as "mobility sponsors," selectively help working-class students to go to college. Whereas teachers provide sponsorship for the college admissions of those working-class students with academic excellence, they take a "laissez-faire" approach for ordinary working-class students without helping them directly. The second article illustrates how teachers stigmatize working-class students who seek to become working-class workers. Teachers stereotype working-class work and criticize vocational aspirations. I also find that work-bound students report that teachers' negative comments create emotional distress for them. The third article explores young workers' subjective understanding of their status in the college-for-all society focusing particularly on gender differences. The study finds that female workers are pessimistic about their status because they believe that their lack of college education might adversely affect their transition to adult roles. On the other hand, male workers are optimistic as they believe that their future compulsory military service will help them to become a respectable male adult. Overall, the dissertation discusses the social implications of the college-for-all society by showing various struggles of working-class young people. It also calls for policy efforts to provide institutional support for their diverging pathways to adulthood.^




Learning and Decision Making in Groups

Mon, 16 Apr 2018 19:36:26 PDT

Many important real-world decision-making problems involve group interactions among individuals with purely informational interactions. Such situations arise for example in jury deliberations, expert committees, medical diagnoses, etc. We model the purely informational interactions of group members, where they receive private information and act based on that information while also observing other people's beliefs or actions. ^ In the first part of the thesis, we address the computations that a rational (Bayesian) decision-maker should undertake to realize her optimal actions, maximizing her expected utility given all available information at every decision epoch. We use an approach called iterated eliminations of infeasible signals (IEIS) to model the thinking process as well as the calculations of a Bayesian agent in a group decision scenario. Accordingly, as the Bayesian agent attempts to infer the true state of the world from her sequence of observations, she recursively refines her belief about the signals that other players could have observed and beliefs that they would have hold given the assumption that other players are also rational. We show that IEIS algorithm runs in exponential time; however, when the group structure is a partially ordered set the Bayesian calculations simplify and polynomial-time computation of the Bayesian recommendations is possible. We also analyze the computational complexity of the Bayesian belief formation in groups and show that it is NP-hard. We investigate the factors underlying this computational complexity and show how belief calculations simplify in special network structures or cases with strong inherent symmetries. We finally give insights about the statistical efficiency (optimality) of the beliefs and its relations to computational efficiency. ^ In the second part, we propose the "no-recall" model of inference for heuristic decision-making that is rooted in the Bayes rule but avoids the complexities of rational inference in group interactions. Accordingly to this model, the group members behave rationally at the initiation of their interactions with each other; however, in the ensuing decision epochs, they rely on heuristics that replicate their experiences from the first stage and can be justified as optimal responses to simplified versions of their complex environments. We study the implications of the information structure, together with the properties of the probability distributions, which determine the structure of the so-called "Bayesian heuristics'' that the agents follow in this model. We also analyze the group decision outcomes in two classes of linear action updates and log-linear belief updates and show that many inefficiencies arise in group decisions as a result of repeated interactions between individuals, leading to overconfident beliefs as well as choice-shifts toward extreme actions. Nevertheless, balanced regular structures demonstrate a measure of efficiency in terms of aggregating the initial information of individuals. Finally, we extend this model to a case where agents are exposed to a stream of private data in addition to observing each other's actions and analyze properties of learning and convergence under the no-recall framework.^ [...]



Metagenomic Methods in Idiopathic and Immune Diseases

Mon, 16 Apr 2018 19:36:20 PDT

Microbial involvement in disease has been long-established, but only recently has metagenomics—the study of entire microbial communities—been leveraged in disease research. Powered by advancements in sequencing technologies, metagenomics has been used to better understand a wide variety of diseases, especially in the gastrointestinal tract and other areas with high microbial activity. However, the extreme sensitivity of modern sequencing and lack of established best practices yields high error rates when used in settings with low microbial involvement. To realize the potential of metagenomic sequencing in disease research, we need new high-precision experimental and statistical methods that reach clinical standards of confidence. In this thesis, I describe our search for microbial signatures in sarcoidosis, an idiopathic disease with suspected microbial involvement. Through the use of novel experimental and statistical methods, we were able to eliminate confounding environmental factors and identify the enrichment of Cladosporiaceae fungi in sarcoidosis. I next describe a computational method to recover pathogen genomes from a sample containing mostly host DNA without the use of over-sequencing or culturing. This method enables study of cryptic pathogen genomes and the ability to track genetic variants that may affect virulence or antibiotic resistance. Finally, I demonstrate the integration of metagenomic sequencing with immune repertoire sequencing in patients with severe combined immunodeficiency after gene therapy. This study is the first to describe the changes in an immune-naïve microbiome that occur during the development of a new immune system. We see that the microbiome of these children shift from an abnormal state to one resembling healthy children in conjunction with their restored immunities. These studies lay out methods that improve the precision and utility of metagenomic sequencing for investigating idiopathic and immune disorders.^




Exploring the Universe with the Atacama Cosmology Telescope: Polarization-Sensitive Measurements of the Cosmic Microwave Background

Mon, 16 Apr 2018 19:36:17 PDT

Over the past twenty-five years, observations of the Cosmic Microwave Background (CMB) temperature fluctuations have served as an important tool for answering some of the most fundamental questions of modern cosmology: how did the universe begin, what is it made of, and how did it evolve? More recently, measurements of the faint polarization signatures of the CMB have offered a complementary means of probing these questions, helping to shed light on the mysteries of cosmic inflation, relic neutrinos, and the nature of dark energy. A second-generation receiver for the Atacama Cosmology Telescope (ACT), the Atacama Cosmology Telescope Polarimeter (ACTPol), was designed and built to take advantage of both these cosmic signals by measuring the CMB to high precision in both temperature and polarization. The receiver features three independent sets of cryogenically cooled optics coupled to transition-edge sensor (TES) based polarimeter arrays via monolithic silicon feedhorn stacks. The three detector arrays, two operating at 149 GHz and one operating at both 97 and 149 GHz, contain over 1000 detectors each and are continuously cooled to a temperature near 100 mK by a custom-designed dilution refrigerator insert. Using ACT's six meter diameter primary mirror and diffraction limited optics, ACTPol is able to make high-fidelity measurements of the CMB at small angular scales (l ~ 9000), providing an excellent complement to Planck. The design and operation of the instrument are discussed in detail, and results from the first two years of observations are presented. The data are broadly consistent with /\CDM and help improve constraints on model extensions when combined with temperature measurements from Planck.^




Simulation & Experiment Learning From Kinases in Cancer

Mon, 16 Apr 2018 19:36:14 PDT

The decreasing cost of genome sequencing technology has lead to an explosion of information about which mutations are frequently observed in cancer, demonstrating an important role in cancer progression for kinase domain mutations. Many therapies have been developed that target mutations in kinase proteins that lead to constitutive activation. However, a growing body of evidence points to the serious dangers of many kinase ATP competitive inhibitors leading to paradoxical activation in non-constitutively active proteins. The large number of observed mutations and the critical need to only treat patients harboring activating mutations with targeted therapies raises the question of how to classify the thousands of mutations that have been observed. We start with an in depth look at the state of knowledge of the distribution and effects of kinase mutations. We then report on computational methods to understand and predict the effects of kinase domain mutations. Using molecular dynamics simulations of mutant kinases, we show that there is a switch-like network of labile hydrogen bonds that are often perturbed in activating mutations. This is paired with a description of a software platform that has been developed to streamline the execution and analysis of molecular dynamics simulations. We conclude by examining a machine learning method to demonstrate what kinds information derived from protein sequence alone have the most value in distinguishing activating and non-activating mutations.^




Role and Impact of the Gut Microbiota in a Drosophila Model for Parkinsonism

Mon, 16 Apr 2018 19:36:11 PDT

Current studies suggest a relationship between microbes in the gut and the brain, including an impact on brain disease development, severity, and progression. However, exploring this relationship is hindered by the intricacies of mammalian models. Drosophila has the potential to be an excellent model organism for studies of the gut-brain axis due to the relative simplicity of its microbiome, similarity to mammals, and efficient methods to rear germ-free flies. To take advantage of this potential, I examined the gut-brain axis in Drosophila models of autosomal recessive parkinsonism and observed a five-fold increase in the gut microbial load of aged parkin animals. The microbial load of pink1 animals was unchanged, suggesting a Pink1-independent role for parkin in maintaining microbial load numbers within normal range. Conditional RNAi showed that parkin is required in gut enterocytes and not in neurons or muscle to maintain microbial load homeostasis. Germ-free parkin flies exhibited improved resistance to paraquat, suggesting an impact of the gut microbiome on toxin sensitivity in parkin flies. Sequencing of 16S rDNA revealed microbial species with altered relative abundance in parkin null flies compared to controls. These data reveal a role for parkin activity in maintaining microbial composition and abundance in the gut, suggesting a relationship between parkin function and the gut microbiome, and deepening our understanding of parkin and its mutant effects.^




From a "Strong Town of War" to the "Very Heart of the Country": The English Border Town of Berwick-upon-Tweed, 1558-1625

Mon, 16 Apr 2018 19:35:07 PDT

The English border town of Berwick-upon-Tweed provides the perfect case study to analyze early modern state building in the frontiers. Berwick experienced two seismic shifts of identity, instituted by two successive monarchs: Elizabeth I (1558–1603) and James I (1603–1625). Both sought to expand state power in the borders, albeit in different ways. Elizabeth needed to secure her borders, and so built up Berwick's military might with expensive new fortifications and an enlarged garrison of soldiers, headed by a governor who administered the civilian population as well. This arrangement resulted in continual clashes with Berwick's traditional governing guild. Then, in 1603, Berwick's world was turned upside-down when James VI, king of Scotland, ascended the English throne. The turbulent borders were rechristened the “Middle Shires” of his united realm. Berwick was stripped of its border garrison, and relevance, by 1604; now, it was merely a regional market center. Its townspeople regained their pre-Elizabethan autonomy, but they faced the challenge of redefining their urban identity, so tied as it had been to the town's militarized status. While Berwick's leaders developed creative solutions to cope with the loss of employment and crown funds resulting from the garrison's dissolution, ultimately the town declined without the border line to give it international significance. ^ Across early modern Europe, states engaged in concerted efforts of consolidation and centralization of their power. These efforts proved particularly difficult in the frontiers, which were often distant from the crown and near a hostile neighboring state. We cannot understand the process of state formation from the state's perspective alone. This work tracks the changes in governance, economy, and identity of a town that found itself directly in the orbit of an expanding state. Crown policy as it was enacted on the ground elicited local responses, both cooperative and combative, that in turn shaped how the townspeople understood their community and themselves, and the power of the state.^




Credit Ratings with Endogenous Assets

Mon, 16 Apr 2018 19:35:04 PDT

The market prices of securities are heavily dependent on their credit ratings, which can in turn influence the issuers' incentives to invest in asset generation, resulting in inefficiencies. We provide a model with a strategic credit rating agency (CRA) and issuers with endogenous set of assets. Specifically, we consider two ways by which issuers generate assets: (1) bundling assets into securities of varying qualities (securitization) (2) investing in projects funded by issuing corporate bonds (investment). We then analyze the equilibrium of these models and derive the conditions under which ratings can result in over or under investments. Next, we perform comparative statics analysis on the impact of market and macro factors on inefficiency by way of influencing credit ratings. Finally, we show that how ratings models with endogenous assets can explain different ratings performances across different asset classes.^




Synaptic Mechanisms and Network Architecture Underlying Spatiotemporal Properties of Simple Cell Receptive Fields in Primary Visual Cortex In Vivo

Mon, 16 Apr 2018 19:34:58 PDT

Neurons in sensory cortex represent information about the environment and relay this information to other cells in the network using electrical and chemical signals. The study of neuronal receptive fields—descriptions of the sensory stimuli that best drive a neuron to fire—can yield insights into how different groups of cells transform sensory information. In layer 4 (L4) of primary visual cortex (V1), neurons called simple cells are responsive to the specific orientation and spatial phase of an edge-like stimulus. Relatedly, simple cell receptive fields are characterized by elongated, non-overlapping, spatially restricted subregions in which visual stimuli can either increase or decrease the cell’s firing rate, depending on contrast. ^ In this dissertation, we examine the synaptic and network mechanisms underlying the generation of simple cell receptive fields and their response characteristics to visual stimuli within their receptive fields. Our experimental data from in vivo, intracellular recordings provides a characterization of the spatiotemporal distribution of visually-evoked excitatory and inhibitory synaptic conductances. In contrast with a popular theory of functional connectivity in primary visual cortex, but consistent with anatomical studies of inhibitory neurons, we present evidence supporting unbiased connectivity arising from inhibitory simple cells in L4 of V1. In addition to our experimental findings, we provide two different network models of V1 L4 that combine anatomical and experimental data. Together, these models account for apparent discrepancies in experimental findings and offer mechanistic explanations for the characteristic delay between the onset of excitation and inhibition that has been observed across sensory cortex. The work here provides the most complete description to date of the spatial and temporal distribution of inhibition as it relates to simple cells in layer 4 of primary visual cortex.^




Rotorcraft Blade Pitch Control Through Torque Modulation

Mon, 16 Apr 2018 19:34:55 PDT

Micro air vehicle (MAV) technology has broken with simple mimicry of manned aircraft in order to fulfill emerging roles which demand low-cost reliability in the hands of novice users, safe operation in confined spaces, contact and manipulation of the environment, or merging vertical flight and forward flight capabilities. These specialized needs have motivated a surge of new specialized aircraft, but the majority of these design variations remain constrained by the same fundamental technologies underpinning their thrust and control. This dissertation solves the problem of simultaneously governing MAV thrust, roll, and pitch using only a single rotor and single motor. Such an actuator enables new cheap, robust, and light weight aircraft by eliminating the need for the complex ancillary controls of a conventional helicopter swashplate or the distributed propeller array of a quadrotor. ^ An analytic model explains how cyclic blade pitch variations in a special passively articulated rotor may be obtained by modulating the main drive motor torque in phase with the rotor rotation. Experiments with rotors from 10 cm to 100 cm in diameter confirm the predicted blade lag, pitch, and flap motions. We show the operating principle scales similarly as traditional helicopter rotor technologies, but is subject to additional new dynamics and technology considerations. Using this new rotor, experimental aircraft from 29 g to 870 g demonstrate conventional flight capabilities without requiring more than two motors for actuation. In addition, we emulate the unusual capabilities of a fully actuated MAV over six degrees of freedom using only the thrust vectoring qualities of two teetering rotors. Such independent control over forces and moments has been previously obtained by holonomic or omnidirection multirotors with at least six motors, but we now demonstrate similar abilities using only two. Expressive control from a single actuator enables new categories of MAV, illustrated by experiments with a single actuator aircraft with spatial control and a vertical takeoff and landing airplane whose flight authority is derived entirely from two rotors.^




Influence of Acetyl-CoA Metabolism in Histone Acetylation and Cancer

Mon, 16 Apr 2018 19:34:51 PDT

Cancer cells increase nutrient uptake to support viability and proliferation. The influx of nutrients alters intermediary metabolite levels, and compelling evidence shows that metabolite availability impacts cell functions through altering chromatin modifications and downstream gene expression. One such metabolic intermediate is acetyl-CoA, as the concentration of acetyl-CoA is positively correlated with histone and non-histone protein acetylation. Histone acetylation is emerging as a nutrient-sensitive process, conferring gene expression changes in response to nutrient availability. In this thesis, we examined the impact of acetyl-CoA metabolism on the epigenome. We established that histone acetylation is sensitive to acetyl-CoA concentrations, which are dynamically regulated by glucose availability. This dynamic increase in histone acetylation induces the expression of cancer-promoting genes. We hypothesized that oncogene activation could lead to increased histone acetylation through reprogrammed metabolism. In two mouse models of cancer, histone acetylation increased upon oncogene activation. Additionally, histone acetylation was positively correlated with phosphorylated AKT in human prostate tumors and glioma. To test whether AKT regulates histone acetylation through metabolic changes, we utilized glioblastoma cell lines expressing constitutively active AKT and found that AKT promotes histone acetylation in nutrient-limited conditions. Mechanistically, this occurs partly through AKT-mediated phosphorylation of ACLY at serine 455, increasing ACLY activity. These studies reveal a novel role for AKT-driven metabolic changes on global histone acetylation in cancer cells. To better understand how concentrations of acetyl-CoA could lead to differential gene expression, we investigated a subset of acetyl-CoA regulated genes. Under conditions in which intracellular acetyl-CoA is abundant, glioma cells upregulate expression of adhesion and migration genes, increase transwell migration, adhere better to ECM, and are efficient in wound healing. Genetic deletion or biochemical inhibition of acetyl-CoA generating enzyme, ACLY, abrogates nutrient-dependent adhesion and migration. We postulated that specificity for regulation of migration related gene expression would be achieved through regulation of transcription factors. Using computational analysis of our acetyl-CoA gene set, NFAT1 was predicted as the top transcription factor in promoting these genes. Through fluorescent single cell analyses, we find that acetyl-CoA triggers calcium oscillations that allow for NFAT1 nuclear localization. These findings suggest that that acetyl-CoA availability is differentially regulated in cancer cells and contributes to malignant phenotypes.^




The Writing on the Wall: Inscriptions and Memory in the Temples of Late Antique Greece and Asia Minor

Mon, 16 Apr 2018 19:34:46 PDT

This dissertation documents late antique (fourth to seventh century CE) Christian responses to earlier, pagan inscriptions at sanctuaries, as seen in the archaeological record. I argue that Christians in Greece and Asia Minor neither ignored nor unthinkingly destroyed older inscriptions, but rather were generally tolerant toward these legible reminders of the pagan past, selectively editing them only occasionally. In order to clarify the types of inscriptions that Christians encountered on temple walls and architraves, I have assembled the first catalog of inscriptions on temples, which reveals that the majority of texts inscribed on sacred structures between the seventh century BCE and the third century CE were, counterintuitively, not about religion, but rather civic matters: political privileges, economic/territorial rights, and elite social structures. This data further reveals regional variations and chronological trends in the ancient practice of inscribing temples, including a proclivity for the practice in Caria and a break in the Roman imperial period from the Hellenistic habit of inscribing important documents on temples. Christian reception of these inscribed texts is explored in depth at six sites: Ankara, Sagalassos, Labraunda, the Corycian Cave (Cilicia) Clifftop Temple, Aizanoi, and Aphrodisias. Inscriptions on temples at these sites have been overlooked in late antique scholarship because of disciplinary biases. Art historical/archaeological studies have traditionally fixated on the original appearance of monuments rather than their full lifespan, while epigraphic publications often treat texts as historical data rather than elements of larger, trans-temporal architectural settings. Each of these sites shows a different approach toward the older inscriptions, including preservation in place, reuse, modification, and erasure. I argue that the civic-focused nature of the majority of inscribed texts on temple walls inflected late antique conceptualization of temples and provided a counterbalance to the negative, polemical depiction of temples presented in hagiographical texts. This study therefore adds a new facet to our understanding of Christianization between the ancient Roman and early Byzantine periods. ^




Seeing Things as We Do: Ecological Psychology and the Normativity of Visual Perception

Mon, 16 Apr 2018 19:34:41 PDT

In virtue of what is perception successful? In philosophy and psychology, we sometimes assume that visual accuracy amounts to a correspondence between percepts and subject-independent, physical properties. In this dissertation, I argue that we should reject this assumption in favor of norms grounded in the action-guiding nature of perception. ^ Recent theories of perception purport to cast off the intellectualist baggage of twentieth-century thinking, and to address perception in its own distinctive terms. I show that these approaches are unified in aiming to reduce spatial aspects of the percept to subject-independent geometrical facts about the object-perceiver relation. In doing so, these views remain guilty of an unwarranted assimilation of perception to cognition. ^ Perceptual constancy, the capacity to encounter a relatively stable world of object properties despite variation in sensory stimulation, is measured using a metric that has percept-physical property correspondence at one extreme, and retinal match at the other. Advocates of the correspondence norm freely redeploy this metric as gauging accuracy in perception, so that the closer a percept comes to invariantly matching the distal property, the closer it comes to veridically presenting the environment. ^ Yet, correspondence views are committed to widespread misperception that cannot be accounted for in terms of evolutionary complexity. I distinguish between descriptive and normative enterprises in cognitive science, and suggest that we reinterpret the constancy metric as an empirically useful, descriptive quantificational tool—one that does not straightforwardly entail normative facts. ^ With the correspondence norm undercut, I develop a more viable framework for understanding accuracy, one that draws on James Gibson's ecological theory. Accordingly, accuracy is best understood pragmatically, in ecological terms such as usefulness. Partial constancy is often sufficient for an organism to act effectively in its environment, a result that suggests surprising consequences for what is seen in perception. ^ In color ontology, there is some theoretical attention to descriptive facts about constancy. However, because of a worry about stipulating perceiver and context standards, theorists continue to reject ecological approaches to color. I resolve the worry by appealing to pluralism about scientific objects. The resulting framework is ecologically sensible, empirically useful, and deeply interdisciplinary.^




Quantitative Modeling of Oxygen Precipitation in Silicon

Mon, 16 Apr 2018 19:34:36 PDT

The vast majority of modern microelectronic devices are fabricated on single-crystal silicon wafers, which are produced predominantly by the Czochralski (CZ) melt-growth process. Important metrics that ultimately influence the quality of the silicon wafers include the concentration of impurities and the distribution of lattice defects (collectively known as microdefects). This thesis provides a multiscale quantitative modeling framework for describing physics of microdefects formation in silicon crystals, with particular emphasis on oxide precipitates. ^ Among the most prevalent microdefects found in silicon crystals are nanoscale voids and oxide precipitates. Oxide precipitates, in particular, are critically important because they provide gettering sites for highly detrimental metallic atoms introduced during wafer processing and also enhance the mechanical strength of large-diameter wafers during high-temperature annealing. On the other hand, like any other crystalline defect species, they are undesirable in the surface region of the wafer where microelectronic devices are fabricated. Although much progress has been made with regards to oxide precipitate prediction and optimization, it has been surprisingly difficult to generate a robust, quantitative model that can accurately predict the distribution and density of precipitates over a wide range of crystal growth and wafer annealing conditions. ^ In the first part of this thesis, a process scale model for oxide precipitation is presented. The model combines continuum mass transport balances, continuum thermodynamic and mechanical principles, and information from detailed atomic-scale simulations to describe the complex physics of coupled vacancy aggregation and oxide precipitation in silicon crystals. Results for various processing situations are shown and comparisons are made to experimental data demonstrating the predictive capability of the model. ^ In the second part of this thesis, atomistic simulations are performed to study the stress field and strain energy of oblate spheroidal precipitates in silicon crystals as a function of precipitate shape and size. Although the stress field of a precipitate in silicon crystals may be studied within a continuum mechanics framework, atomic scale modeling does not require the idealized mechanical properties (and precipitate shapes) assumed in continuum models and therefore provides additional valuable insight. The atomistic simulations are based on a Tersoff empirical potential framework for silicon, germanium and oxygen. Stress distributions and stress energies are computed for coherent germanium precipitates and for incoherent, amorphous silicon dioxide precipitates in a crystalline silicon matrix. The impacts of precipitate size and shape are considered in detail, and for the case of oxide precipitates, special emphasis is placed on the role of interfacial relaxation. Whenever possible[...]



The Ethics of Meaning

Mon, 16 Apr 2018 19:34:30 PDT

This dissertation develops an ethics of meaning. In the first chapter, I offer an account of meaning that comprehends its many varieties—natural, cultural, linguistic, literary, and ethical meaning, for example—by appeal to the structural role meaning plays in the practice of interpretation. In Chapter 2, I develop a distinctive account of the concept of ethical meaning ("meaning" as it's used in the phrase "the meaning of life"). In Chapter 3, I develop a new account of irony on the basis of the comprehensive-interpretive account of meaning introduced in Chapter 1.^




Medial Temporal Lobe Does Not Tell the Whole Story: Episodic Memory in 'Atypical' Variants of Alzheimer's Disease

Mon, 16 Apr 2018 19:34:23 PDT

Alzheimer's disease is the most common form of dementia, which is globally epidemic and well-known by the general public. Episodic memory, a conscious recollection of a particular event in spatial and temporal context, is the most prominent deficit in the early stage of clinical amnestic AD, and reflected by the shrinkage of structures in medial temporal lobe (MTL), including the hippocampus. According to Braak staging, tangles begin in the transentorhinal cortex of the MTL, which then spreads to hippocampal subfields, and later to neocortical areas. Cases that are less recognized by the general public are patients with the atypical variants of AD. Interestingly, many of the atypical cases of AD appear to share the same histopathological features with clinical amnestic AD. According to the diagnostic criteria for these atypical variants of AD, episodic memory should be relatively preserved. However, inconsistent reports on the episodic memory performance and the hippocampal involvement in these atypical cases pose challenges for accurately diagnosing these patients. The two kinds of atypical variants of AD that I focused here are logopenic variant of Primary Progressive Aphasia (lvPPA) and posterior cortical atrophy (PCA). The overarching theme of my thesis is to examine 1) whether the atypical cases of AD have episodic memory difficulty, and if so, 2) what brain areas are responsible for this difficulty. Chapter 2 and 3 of the current thesis show that 1) episodic memory difficulty is observed in lvPPA and PCA cases and 2) this impairment is modulated by deficit in other cognitive domains and associated with disease in non-MTL brain regions. This would be consistent with the 'hippocampal-sparing' hypothesis that not all AD histopathology begins in the MTL, and these hippocampal-sparing conditions suggest that additional mechanisms must be considered in the genesis of spreading pathology in AD. ^




Molecular Dynamics Simulation Study of Water-Soluble Cryptophane Binding a Variety Guest Objects

Mon, 16 Apr 2018 19:34:18 PDT

Given their signicance to chemical sensing and molecular recognition, host-guest interactions are of broad interest in molecular science. Cryptophanes, which are a kind of spherical cage molecules, are one of the most applicable host molecules. Herein computer simulation is used to address the binding of cryptophanes to monatomic guest species in aqueous environments. Water soluble cryptophanes have high binding anity to Xe-129, which is a powerful contrast agent for magnetic resonance imaging and can be used as an NMR-based biosensor. Molecular details of Xe-cryptophane binding are hard to obtain from experiment, however. Extensive molecular dynamics simulation are carried out to understand the underlying molecular features of the Xe-cryptophane system. Free energy perturbation and adaptive biasing force methods are used to obtain the energetic aspects of cryptophane-Xe interactions: binding anities of individual cryptophanes to Xe and potentials of mean force for Xe to entry the cavity. Additionally, the structure adjustments cryptophane undergoes as it accommodates Xe are investigated in depth. From the simulations, the hydrophobicity of cryptophane interior and the kinetics of water enter the cavity are found to be correlated with the Xe binding anity. These ndings shed light on the design of Xe-binding cryptophanes. A related cryptophane is considered for the selective binding of alkali metal ions. The cryptophane has particularly high binding anities with the large cesium cation. The Cs-137 isotope is a common, problematic radioactive nuclear ssion byproduct. The simulations provide insight on the relative anities of alkali cations and the roles of water molecules that enter the cavity along with ions. The simulations reveal that the high bind- ing anity of cryptophane to Cs+ may result from the comparatively low solvation energy of Cs+ and its geometric t to the cryptophane cavity.^




Optimal Adaptation Principles in Neural Systems

Mon, 16 Apr 2018 19:34:13 PDT

Animal brains are remarkably efficient in handling complex computational tasks, which are intractable even for state-of-the-art computers. For instance, our ability to detect visual objects in the presence of substantial variability and clutter surpasses any algorithm. This ability seems even more surprising given the noisiness and biophysical constraints of neural circuits. This thesis focuses on understanding the theoretical principles governing how neural systems, at various scales, are adapted to the structure of their environment in order to interact with it and perform informa- tion processing tasks efficiently. Here, we study this question in three very different and challenging scenarios: i) how a sensory neural circuit the olfactory pathway is organised to efficiently process odour stimuli in a very high-dimensional space with complex structure; ii) how individual neurons in the sensory periphery exploit the structure in a fast-changing environment to utilise their dynamic range efficiently; iii) how the auditory system of whole organisms is able to efficiently exploit temporal structure in a noisy, fast-changing environment to optimise perception of ambiguous sounds. We also study the theoretical issues in developing principled measures of model complexity and extending classical complexity notions to explicitly account for the scale/resolution at which we observe a system.^




The Reproduction of Citizenship: How the U.S. Government Shaped Citizenship During the 20th Century by Regulating Fertility, Procreation, and Birth Across Generations

Mon, 16 Apr 2018 19:34:09 PDT

Who qualifies, with full status, as an American citizen? Like all modern nation-states, the United States erects and maintains various types of legal and geographic boundaries to demarcate citizens from noncitizens. The literature in political science tends to focus on the ways in which immigration law structures citizenship over time, but this is only half the story. As this dissertation demonstrates, governments also regulate the birth of citizens from one generation to the next. The concept of a 'civic lineage regime' is introduced as the domestic counterpart to the 'immigration regime,' when it comes to structuring civic membership in the United States (and other nations). To bring visibility to this deeply constitutive yet largely unexamined dimension of American political development, the project engages in a close analysis of U.S. Supreme Court cases targeting civic lineage during the twentieth century. Examining eugenic sterilization laws, birth control, abortion, and welfare reform, the dissertation maintains that the federal and state governments regulate the intimate lives of Americans for many of the same reasons governments seek to control immigration. In both realms, the state makes legal distinctions between who can and cannot become a member by coercively privileging certain visions of American identity over others. This often entrenches hierarchies of citizenship based on race, gender, ethnicity, class, disability, religion, and sexuality. These state-building policies, involving the regulation of reproduction and birth, have the ability to define and redefine the meaning and scope of U.S. citizenship across time by shaping the future "face" of the American polity. Finally, although many older inegalitarian conceptions of civic membership are now discredited, the dissertation concludes with evidence that the conflictual politics involved in constructing an American civic lineage regime continue today in the form of the rise of a new 'neoliberal ideal of citizenship.'^




Constitutive Modeling of Viscoplastic Porous Single Crystals and Polycrystals: Macroscopic Response and Evolution of the Microstructure

Mon, 16 Apr 2018 19:34:06 PDT

Porosity can have a significant effect on the overall constitutive behavior of many materials, especially when it serves to relax kinematic constraints imposed by the underlying matrix behavior. In this study, we investigate the multiscale, finite-strain response of viscoplastic porous single crystals and porous polycrystals. For these materials, the presence of voids leads to highly nonlinear dilatational behavior for loads with a large hydrostatic component, even though the matrix material itself is essentially incompressible. ^ In this study, we employ the recently developed "fully optimized second-order" homogenization approach, along with an iterated homogenization procedure, to obtain accurate estimates for the effective behavior of porous single crystals and porous polycrystals with fixed states of the microstructure. The method makes use of the effective properties of a "linear comparison composite," whose local properties are chosen according to a suitably designed variational principle, to generate the corresponding estimates for the actual nonlinear porous materials. Additionally, consistent homogenization estimates for the average strain-rate and spin fields in the phases are used to develop approximate evolution equations for the microstructures. The model is quite general, and applies for viscoplastic porous single crystals and polycrystals with general crystallographic texture, general ellipsoidal voids, and general ellipsoidal grains, which are subjected to general loading conditions. The model is used to study both the instantaneous response and the evolution of the microstructure for porous FCC and HCP single crystals and polycrystals. It is found that the intrinsic anisotropy of the matrix phase—either due to the local crystallography in single crystals or to the texture of polycrystals—has significant effects on the porosity evolution, as well as on the overall hardening/softening behavior of the porous materials. In particular, the predictions of the model for porous single crystals are found to be in fairly good agreement with the full-field, numerical results available in the literature. The results for porous polycrystals suggest that the macroscopic behavior is controlled by porosity growth at high stress triaxialities, while it is controlled by texture evolution of the underlying matrix at low triaxialities.^




Worker Mobilization in Twenty-First Century Liberalism

Mon, 16 Apr 2018 19:34:02 PDT

Over the past decades, capitalist democracies across the OECD have transitioned from manufacturing to models for growth based on dynamic services. In many countries, the transition to the knowledge economy has been accompanied by a process of liberalization, whereby market forces are disembedded from institutions for social protection. As a result, inequality has risen and insecurity has spread. While some scholars suggest that liberalization is an unavoidable structural characteristic of the knowledge economy, this dissertation offers an alternative. ^ I argue that rising inequality and spreading insecurity are the result of a shift in the discourse surrounding production, and that this shift has restructured the balance of power between employers and workers. This discursive approach captures the threat that workers face in the knowledge economy by illustrating the connection between employers' orientation to shareholder value and their adoption of new strategies to control the workplace. Focusing on discursive contests in the workplace sheds light on the strategies that workers can develop to protect their rights despite their distance from labor's traditional power resources, particularly unions. ^ I trace workers' responses to downsizing at four sites of multinational technology firms in the US and Germany in order to uncover the causal mechanisms that explain why workers acquiesce to dismissals in some cases but resist in others. In the knowledge economy, managers justify dismissals in a primarily financial discourse that disposes workers to believe that downsizing is the unavoidable consequence of global market forces. Workers can redeploy this discourse to critique management's justification and motivate workers to pressure management into considering alternatives to downsizing. I find that workers mobilize against downsizing when they develop counterhegemonic strategies that credibly demonstrate that collective action can be effective. National institutions do not automatically protect workers from employer discretion, but with enough creativity, workers can find ways to activate them. ^ By illustrating the causal mechanisms that shape power relations in the knowledge economy, this dissertation develops a theoretical framework for explaining variation in workers' rights in twenty-first century liberalism. ^




Isolating the Effects of Body Mass and Energy Balance on Sleep and Metabolic Health

Mon, 16 Apr 2018 19:33:59 PDT

Obesity is associated with numerous metabolic and behavioral abnormalities, including excessive daytime sleepiness independent of sleep disorders (e.g., sleep apnea). In humans, obesity is traditionally classified by weight metrics such as body mass index (BMI); over one-third of Americans are obese based on BMI. The most common cause of obesity is chronic positive energy balance due to overconsumption of calorically-dense diets. However, it is difficult to isolate the independent effects of 'overnutrition/positive energy balance' and 'excess body weight' on metabolic and behavioral parameters since the former causes the latter. Therefore, the focus of this dissertation is to discover how diet/energy balance, independent from body weight, affect sleep/wake behavior and metabolic health using the high-fat diet (HFD)-induced obese mouse model. In Chapter 2, I introduce the Diet Switch (DS) feeding paradigm which generates two groups of mice of similar body weight by divergent energy balance. Using the DS protocol, I show that diet-induced changes to energy balance can affect sleep and wakefulness independent of actual body weight. In Chapter 3, I explore the role of a central regulator of energy balance, peroxisome proliferator-activated receptor gamma (PPARg), on HFD-induced sleep abnormalities; our results indicate that central PPARg does not influence sleep/wake behavior. In Chapter 4, I again use the DS feeding paradigm, but instead measure various molecular (blood biomarkers and hypothalamic gene expression), behavioral (spontaneous activity), and metabolic (indirect calorimetry) outcomes. Using linear regression modeling, I quantify the relative influence of body weight and diet/energy balance on these parameters, and relate these key findings to the results from Chapter 2. Taken together, these studies offer novel insights into the pathogenesis and reversibility of obesity-related sleep and metabolic disorders.^




A Methodology for Micro-Policies

Mon, 16 Apr 2018 19:33:55 PDT

This thesis proposes a formal methodology for defining, specifying, and reasoning about micro-policies—security policies based on fine-grained tagging that include forms of access control, memory safety, compartmentalization, and information-flow control. Our methodology is based on a symbolic machine that extends a conventional RISC-like architecture with tags. Tags express security properties of parts of the program state ("this is an instruction," "this is secret," etc.), and are checked and propagated on every instruction according to flexible user-supplied rules. We apply this methodology to two widely studied policies, information-flow control and heap memory safety, implementing them with the symbolic machine and formally characterizing their security guarantees: for information-flow control, we prove a classic notion of termination-insensitive noninterference; for memory safety, a novel property that protects memory regions that a program cannot validly reach through the pointers it possesses—which, we believe, provides a useful criterion for evaluating and comparing different flavors of memory safety. We show how the symbolic machine can be realized with a more practical processor design, where a software monitor takes advantage of a hardware cache to speed up its execution while protecting itself from potentially malicious user-level code. Our development has been formalized and verified in the Coq proof assistant, attesting that our methodology can provide rigorous security guarantees.^




Probabilistic Couplings for Probabilistic Reasoning

Mon, 16 Apr 2018 19:33:52 PDT

This thesis explores proofs by coupling from the perspective of formal verification. Long employed in probability theory and theoretical computer science, these proofs construct couplings between the output distributions of two probabilistic processes. Couplings can imply various probabilistic relational properties, guarantees that compare two runs of a probabilistic computation. ^ To give a formal account of this clean proof technique, we first show that proofs in the program logic PRHL (probabilistic Relational Hoare Logic) describe couplings. We formalize couplings that establish various probabilistic properties, including distribution equivalence, convergence, and stochastic domination. Then we deepen the connection between couplings and PRHL by giving a proofs-as-programs interpretation: a coupling proof encodes a probabilistic product program, whose properties imply relational properties of the original two programs. We design the logic ×PRHL (product PRHL) to build the product program, with extensions to model more advanced constructions including shift coupling and path coupling. ^ We then develop an approximate version of probabilistic coupling, based on approximate liftings. It is known that the existence of an approximate lifting implies differential privacy, a relational notion of statistical privacy. We propose a corresponding proof technique— proof by approximate coupling—inspired by the logic APRHL, a version of PRHL for building approximate liftings. Drawing on ideas from existing privacy proofs, we extend APRHL with novel proof rules for constructing new approximate couplings. We give approximate coupling proofs of privacy for the Report-noisy-max and Sparse Vector mechanisms, well-known algorithms from the privacy literature with notoriously subtle privacy proofs, and produce the first formalized proof of privacy for these algorithms in APRHL. ^ Finally, we enrich the theory of approximate couplings with several more sophisticated constructions: a principle for showing accuracy-dependent privacy, a generalization of the advanced composition theorem from differential privacy, and an optimal approximate coupling relating two subsets of samples. We also show equivalences between approximate couplings and other existing definitions. These ingredients support the first formalized proof of privacy for the Between Thresholds mechanism, an extension of the Sparse Vector mechanism. ^




Genetics and Retinal Degeneration: Challenges in Optogenetic Therapy and Indentifying Pathogenic Variants

Mon, 16 Apr 2018 19:33:48 PDT

Inherited retinal degenerative diseases are one of the leading causes of childhood blindness. While over 200 causative genes have been identified, many cases still have an unknown underlying genetic cause. With the advent of next generation sequencing (NGS), it should be possible to identify the genetic cause in almost every case, provided enough relatives are willing to participate. However, the massive amount of data generated by NGS can make identifying the pathogenic variant challenging. It is necessary to filter the data in order to create a manageable candidate list, but overly strict filtering or erroneous assumptions can result in filtering out the pathogenic variant. Identifying the genetic cause of retinal degeneration in each patient will allow us to better identify candidate genes for gene therapy and bring us a step closer to precision medicine. Here we developed an efficient screening system to find candidate mutations with minimal assumptions to avoid screening out pathogenic variants and better identify good candidates for novel gene discovery. Out of an initial cohort of 69 patients we identify the pathogenic variant(s) in 44 of them and identified 11 subjects as good candidates for novel gene discovery. ^ We also need a broad treatment for retinal degeneration to help those who have mutations in genes that are poor candidates for gene therapy or who have an unknown genetic cause. We tested the efficacy of using the GRM6 minimal promoter as a bipolar cell specific promoter to express channelrhodopsin in bipolar cells after photoreceptor degeneration to make the bipolar cells directly respond to light. Surprisingly, we found that unlike in the wildtype mouse retina, the GRM6 promoter is not bipolar cell specific in multiple mouse models of retinal degeneration. This suggests that the genetic profiles of the cells in the inner retina change during retinal degeneration. Understanding these fundamental changes in cell specific gene expression during retinal degenerative processes will be critical in order to develop effective therapeutic strategies for late stage retinal degeneration. ^




Modular Hopping and Running via Parallel Composition

Mon, 16 Apr 2018 19:33:43 PDT

Though multi-functional robot hardware has been created, the complexity in its functionality has been constrained by a lack of algorithms that appropriately manage flexible and autonomous reconfiguration of interconnections to physical and behavioral components. ^ Raibert pioneered a paradigm for the synthesis of planar hopping using a composition of "parts'': controlled vertical hopping, controlled forward speed, and controlled body attitude. Such reduced degree-of-freedom compositions also seem to appear in running animals across several orders of magnitude of scale. Dynamical systems theory can offer a formal representation of such reductions in terms of "anchored templates,'' respecting which Raibert's empirical synthesis (and the animals' empirical performance) can be posed as a parallel composition. However, the orthodox notion (attracting invariant submanifold with restriction dynamics conjugate to a template system) has only been formally synthesized in a few isolated instances in engineering (juggling, brachiating, hexapedal running robots, etc.) and formally observed in biology only in similarly limited contexts. ^ In order to bring Raibert's 1980's work into the 21st century and out of the laboratory, we design a new family of one-, two-, and four-legged robots with high power density, transparency, and control bandwidth. On these platforms, we demonstrate a growing collection of {body, behavior} pairs that successfully embody dynamical running / hopping "gaits'' specified using compositions of a few templates, with few parameters and a great deal of empirical robustness. We aim for and report substantial advances toward a formal notion of parallel composition—embodied behaviors that are correct by design even in the presence of nefarious coupling and perturbation—using a new analytical tool (hybrid dynamical averaging). ^ With ideas of verifiable behavioral modularity and a firm understanding of the hardware tools required to implement them, we are closer to identifying the components required to flexibly program the exchange of work between machines and their environment. Knowing how to combine and sequence stable basins to solve arbitrarily complex tasks will result in improved foundations for robotics as it goes from ad-hoc practice to science (with predictive theories) in the next few decades.^




Flexible, Photopatterned, Colloidal CdSe Semiconductor Nanocrystal Integrated Circuits

Mon, 16 Apr 2018 19:33:37 PDT

As semiconductor manufacturing pushes towards smaller and faster transistors, a parallel goal exists to create transistors which are not nearly as small. These transistors are not intended to match the performance of traditional crystalline semiconductors; they are designed to be significantly lower in cost and manufactured using methods that can make them physically flexible for applications where form is more important than speed. One of the developing technologies for this application is semiconductor nanocrystals. ^ We first explore methods to develop CdSe nanocrystal semiconducting “inks” into large-scale, high-speed integrated circuits. We demonstrate photopatterned transistors with mobilities of 10 cm2/Vs on Kapton substrates. We develop new methods for vertical interconnect access holes to demonstrate multi-device integrated circuits including inverting amplifiers with ~7 kHz bandwidths, ring oscillators with <10 µs stage delays, and NAND and NOR logic gates. In order to produce higher performance and more consistent transistors, we develop a new hybrid procedure for processing the CdSe nanocrystals. This procedure produces transistors with repeatable performance exceeding 40 cm2/Vs when fabricated on silicon wafers and 16 cm 2/vs when fabricated as part of photopatterned integrated circuits on Kapton substrates. ^ In order to demonstrate the full potential of these transistors, methods to create high-frequency oscillators were developed. These methods allow for transistors to operate at higher voltages as well as provide a means for wirebonding to the Kapton substrate, both of which are required for operating and probing high-frequency oscillators. Simulations of this system show the potential for operation at MHz frequencies. Demonstration of these transistors in this frequency range would open the door for development of CdSe integrated circuits for high-performance sensor, display, and audio applications. ^ To develop further applications of electronics on flexible substrates, procedures are developed for the integration of polychromatic displays on polyethylene terephthalate (PET) substrates and a commercial near field communication (NFC) link. The device draws its power from the NFC transmitter common on smartphones and eliminates the need for a fixed battery. This allows for the mass deployment of flexible, interactive displays on product packaging.^




Rate and State Friction Laws for Interfacial Chemical Bond-Induced Friction at the Nanoscale

Mon, 16 Apr 2018 19:33:31 PDT

Rate and state friction (RSF) laws are widely-used empirical relationships that describe macroscale frictional behavior of a broad range of materials, including rocks. Conventional RSF laws entail a linear combination of the direct effect (friction increasing with sliding velocity) and evolution effect (evolution of the state of the contact). One manifestation of evolution effect is "ageing", where static friction increases logarithmically with contact time. In order to understand the physical origins of RSF laws, we use atomic force microscope (AFM) to study nanoscale friction of silica, which is one important component of rocks. Overall, we observe RSF behavior, due to interfacial chemical bond-induced (ICBI) friction, which is manifested in several ways. The first aspect is the load and time dependence of ageing, whereby ageing magnitude increases approximately linearly with the product of the normal load and the log of the hold time. The second aspect is a physically-based RSF law we establish for single asperity contact, which we call the Prandtl-Tomlinson with temperature and evolution effect (PTTE) model. In PTTE model, the velocity for the direct effect is loading point velocity rather than tip velocity. Also, the combination of direct effect and evolution effect is nonlinear. The third aspect is the velocity dependence of kinetic friction, which reflects the competition of direct effect and evolution effect. Kinetic friction first decreases and then increases logarithmically with sliding velocity (the increase corroborates PTTE model). We explain the logarithmic decreasing by assuming that during low-velocity sliding, after an interfacial bond breaks, the resulting dangling bond can easily bond with other dangling bonds on the opposing surface. The fourth aspect is stick-slip, which could be better understood with PTTE model. We observe quasi-periodic stick-slip at lower velocities and uncover the velocity dependence of stick-slip. We also observe partial dropping of lateral force in some slip events in the transition regime between quasi-periodic stick-slip and smooth sliding, which corroborates the physical picture of dangling bonds forming interfacial bonds. In conclusion, these four aspects together demonstrate the nature of RSF behavior for nanoscale single-asperity contacts, and establish new, physically-based frictional laws for nanoscale contacts.^




Sleep and Activity Problems in Mouse Models of Neurodevelopmental Disorders

Mon, 16 Apr 2018 19:33:26 PDT

Adequate sleep is important for long-term health and day-to-day function. Compared to the general population, patients diagnosed with neurodevelopmental disorders have substantially higher prevalence of sleep, activity, and circadian problems, dramatically affecting their quality of life, and potentially exacerbating other adverse symptomologies. Despite this, the neurobiological underpinnings of sleep problems in neurodevelopmental disorders remain unknown, and accurate rodent models capable of recapitulating human sleep and activity problems are lacking. In this dissertation, I investigate sleep, activity, and circadian rhythms in genetic mouse models of human neurodevelopmental disorders, with a focus on autism spectrum disorder (ASD). In Chapter 1, I review the importance of—and mechanisms contributing to—sleep/wake regulation, sleep problems in neurodevelopmental disorders, and the utility of rodent genetic models to address these problems. In Chapter 2, I investigate hyperactivity and male-specific sleep deficits found in the 16p11.2 del/+ chromosomal copy number variation mouse model of neurodevelopmental disorders (Angelakos et al., 2016). In Chapter 3, I highlight REM sleep reductions and altered electroencephalography (EEG) spectra in the SYGNAP1 +/– mouse model of intellectual disability and ASD. In Chapter 4, I discuss home-cage hypoactivity observed in four different mouse models of ASD.^




Applied Dynamic Factor Modeling in Finance

Mon, 16 Apr 2018 19:33:20 PDT

In this dissertation, I study model misspecification in applications of dynamic factor models to finance. In Chapter 1, my co-author Jacob Warren and I examine factors for volatility of equities. Historical literature on the subject decomposes volatility into a factor component and an idiosyncratic remainder. Recent work has suggested that idiosyncratic volatility of US equities data has a factor structure, with the factor highly correlated with, and possibly precisely the market volatility. In this paper we attempt to characterize the underlying factor and find that it can be decomposed into a statistical (PCA) and structural (market volatility) factor. We also show that this feature is not unique to equities, appearing in diverse sets of financial data. Lastly, we find that this dual-factor approach is slightly dominated in forecasting environments by a single statistical factor, suggesting that accurate measurement of the factors provides a direction for future work. In Chapter 2, I explore the use of dynamic factor models in yield curve forecasting and an exploration of the spanning hypothesis—that is, whether all information necessary for forecasting yields is contained in the current yield curve. Only linear tests of the spanning hypothesis are typically conducted in the literature, and the results are subject to substantial disagreement. In this paper, I explore a key modern nonlinearity, namely the zero lower bound (ZLB). I first demonstrate in simulation that only very small nonlinearities in the measurement equation are necessary to break down the assumed linear spanning relationship. Because bond yields are determined by forward-looking behavior of investors, the effect of the ZLB affects spanning results as early as 1995. New nonlinear spanning tests are found to behave appropriately. Using the full set of yields instead of truncating to a small number of principal components is quantitatively important but does not eliminate the omitted nonlinearity effect.^




Investigation of Metabolism and Mitochondrial Function in a Drosophila Model of Fragile X Syndrome

Mon, 16 Apr 2018 19:33:15 PDT

As early as 1943, reports first emerged of sex-linked transmission of intellectual disability. Several decades later, a cytogenetic variant found to segregate with intellectual impairment allowed for the localization and identification a pathogenic lesion in the fragile X mental retardation 1 (FMR1) gene. Subsequently, it was determined that loss-of-function mutations in the FMR1 gene result in the aptly named Fragile X Syndrome (FXS). The landmark discovery of FXS etiology engendered a plethora of advances in the field of intellectual disability and autism. Notably, as the most common heritable form of intellectual disability and the leading monogenetic cause of autism, FXS is an ideal genetic paradigm for the study of the cellular and molecular underpinnings of the multifarious forms of intellectual impairment and autism. Moreover, the generation of animal models of FXS has greatly facilitated progress in the field. One such model, Drosophila melanogaster, is uniquely suited to rapid genetic and biochemical approaches to probe the processes and pathways involved in FXS pathogenesis. ^ Recently, work from our laboratory implicated brain insulin signaling dysregulation in the development of behavioral and cognitive deficits in the Drosophila model of FXS. This finding, along with reports that FXS patients with metabolic disturbances have a higher prevalence of clinically defined autism, prompted me to explore the metabolic implications of loss of FMR1 expression. In my thesis, I uncovered striking differences in metabolism in the Drosophila model of FXS. The metabolic alterations that I revealed provide clues about the biochemical pathways that are perturbed in FXS. Further, my efforts to elucidate the mechanism underlying the observed metabolic changes precipitated the exciting discovery of a novel, clinically relevant phenotype in feeding behavior. I also uncovered new evidence that aberrant mitochondrial function and morphology are involved in FXS pathophysiology. My findings provide a solid foundation for future dissection of the precise mechanistic links between metabolism, mitochondria, and behavioral and cognitive output in the context of FXS.^




Constitutionalizing Health: Rights, Democracy and the Political Economy of Health Policy

Mon, 16 Apr 2018 19:33:11 PDT

In recent decades there has been an increasing trend toward “constitutionalizing” health—identifying health as a right in national constitutions. Today more than half of written constitutions in the world contain such a right. Whether that is good, bad, or immaterial for the production of population health, however, is much debated. Does constitutionalization improve wellbeing or might it simply distract from or distort good health policy? This dissertation uses a nested analysis that pairs a large-N statistical analysis of 40 years of global health data with in-depth interviews with over 165 policymakers, activists, elected officials, lawyers, and judges in South Africa, India, Malawi, and Thailand. Empirical evidence shows that constitutionalizing health is a significant development in the institutions of health governance and can contribute to improved wellbeing. Over forty years of global health data, we can observe a small but significant health dividend for countries that have adopted the right to health, when controlling for the major alternative explanations of cross-national variation in mortality. Tracing health policy issues in South Africa and India reveals a right that operates as a “policy anchor”—tying health to the fundamental national political bargain and providing an innovation in the institutions of governance that helps policy entrepreneurs gain a foothold from which to drive policy to expand health capabilities. Shadow cases in Thailand and Malawi show that this shift can matter even without judicial intervention but depends on sufficient support structure to enable the full institutionalization of health as a right. These findings contribute to literature on law and rights, sharpen models of the public policy process, and respond to the need to better understanding the broader set of institutions in the political economy of development that drive improvements in population health. In a broader context, this study suggests that constitution-writing is health policymaking. Greater attention to constitutions and the process of institutionalizing rights is warranted for those engaged in global health, with implications for the U.S. and other countries of the global North as well.^




Branding the Muisca-Self: Indigenous Sincerity Amidst Colombian Multicultural Coloniality

Mon, 16 Apr 2018 19:33:08 PDT

This dissertation has two aims. First, it explores the historical, political and legal apparatuses that have facilitated the formation of contemporary indigenous groups in the proximity of Bogota, Colombia and their recent transformation into branded products of indigenous spirituality. With this framework, it then focuses on how group members attempt to produce indigenous personas who seem to comply with the expectations of their branded form while remaining true to their indigenous-selves; which I found out can be partially revealed as glimpses of sincerity. The two indigenous groups under study are the officially recognized Muisca of the locality of Bosa, an impoverished area in the outskirts of the city of Bogota, and the Muisca of the town of Sesquile, located 45km north of Bogota. Despite the program of ethnic and cultural assimilation towards mestizaje that took place alongside the independence of the country in 1810, the members of these groups have recently claimed to be descendants of the Muisca people who inhabited the area in the pre-Hispanic period, gaining recognition on the basis of an already diluted cultural alterity. Hence, appearing “different enough” from the mestizo majorities to deserve special treatment from a state that embraces multiculturalism has become their priority, and indigenous spirituality has served this purpose by becoming the widely accepted, branded expression of Muisca alterity. Through fourteen months of ethnographic fieldwork, during which I engaged in dialogical interactions and shared affect-charged experiences with Muisca members, I have retrieved various moments of indigenous sincerity and analysed them from a decolonial perspective that uses well-known theoretical frameworks as border theories. By doing so, I have been able to unveil, on the one hand, the apparatuses of colonial domination behind the Colombian multicultural policy towards indigenous people and, on the other, the multiple Muisca-selves that remain concealed behind the brand, and which are constantly re-shaped as members navigate the contradictions between a recently incorporated spirituality and their own approach to indigeneity. ^




A World of Our Own: Climate Change Advocacy in the Anthropocene

Mon, 16 Apr 2018 19:33:04 PDT

The effects of human impacts on the environment are often not comprehensible to people and have to be given meaning through communication. Such impacts, most prominently climate change, have increased to the extent that human actions are the dominant force in planetary biophysical systems. Yet these impacts are for the most part unintentional and not subject to democratic control. A critical discourse analysis of campaign material and media content examines how three advocacy groups – 350, a climate activist organization, The Breakthrough Institute, a think-tank, and The Nature Conservancy, an established conservation organization – discursively construct climate change. The three groups acknowledge the need to more consciously or deliberatively manage environmental impacts, and yet all have very different assumptions, objectives and tactics in their advocacy. Analysis of the communication activities of the organizations and how their ideas are represented and contested in other media shows not only how they construct the particular issue of climate change but their relationship to societal power relationships. How the organizations build their case for action involves discursive acts which define or re-define the boundaries between nature and society and what (and who) is to be included or excluded from political concern. Unless directly challenged, these new formations will reproduce existing power structures and inequalities.^




Functionalization of 2-Azaallyl Anions, Radicals and Benzylic Chloromethyl-Coupling Polymerization

Mon, 16 Apr 2018 19:33:00 PDT

C-C bond forming reactions, under either metal catalyzed or metal free conditions, are mainstay in the construction of functionalized molecules in organic synthesis. Disubstituted methylamines are highly valuable small molecule pharmaceuticals which are widely applied in the treatment of human disease. To date, traditional synthesis of such amines requires significant effort of synthesizing pre-functionalized reagents. This dissertation describes an innovation in the construction of disubstituted methylamines via the umpolung functionalization of 2-azaallyl anions and radicals.^ In chapter 1, umpolung synthesis of diarylmethylamines via palladium-catalyzed arylation of 2-azaallyl anion intermediates is introduced. 2-Azaallyl anion coupling partners include 1,1,3-triaryl-2-azaallyl anions and 1,3-diaryl-2-azaallyl anions. The key to success is the advancement of NIXANTPHOS-based catalysts that enabled the arylation of aryl bromides and more challenging aryl chlorides to be conducted under mild conditions. Moreover, the identification of hindered silylamide bases ensures that products of the arylation were not deprotonated or isomerized.^ In chapter 2, we address the regioselectivities in the α- and γ-arylation of azapentadienyl anions. The regioselectivity was achieved by controlling the reductive elimination of the Pd-azapentadienyl intermediates using two distinct catalysts. These methods provide the first divergent synthesis of allylic amine and enamine derivatives.^ In chapter 3, we presented an innovative concept that 2-azaallyl anions could behave as organic super-electron-donors. Such unique behavior was illustrated in (i) generation of 2-azaallyl radicals from single-electron-transfer (SET) between 2-azaallyl anions and neutral ketimines, which then coupled with vinyl bromides; (ii) generation of 2-azaallyl radicals from SET of 2-azaallyl anions with aryl and alkyl electrophiles, which then captured aryl and alkyl radicals to form C–C bonds. The transition-metal-free vinylation, arylation and alkylation of 2-azaallyls make possible the synthesis of high-value functionalized amine derivatives in good to excellent yields.^ In chapter 4, a new polymerization method named benzylic-chloromethyl-coupling polymerization (BCCP) is introduced. BCCP is catalyzed by sulfenate anions, which promote an umpolung polycondens[...]



Synthetic Efforts Toward Irciniastatin Analogues and Nahuoic Acids; Development of Anion Relay Chemistry Tactic

Mon, 16 Apr 2018 19:32:55 PDT

Polyketides constitute a group of highly structurally diverse and biologically active natural products. Synthetic efforts toward two families of polyketides, namely irciniastatins and nahuoic acids, are represented in this thesis, in conjunction with the development of Anion Relay Chemistry (ARC) tactic as a useful tool for polyketide construction.^ Chapter one describes the design and synthesis of seven novel irciniastatin analogues, achieved by structural simplification of the tetrahydropyran core as well as by functional group variation of the C(11) substituent of irciniastatin A. These analogues are in turn evaluated against several cancer cell lines; all possess antiproliferative activity in nanomolar range.^ Chapter two describes the extension of the ARC tactic to achieve effective [1,5]-vinyl Brook rearrange via incorporation of conformational constraints. Three types of restrained linchpins are designed, synthesized and validated for both alkylation and cross coupling reactions. Density Functional Theory (DFT) calculation also provides insight into the mechanism of such reactions. ^ Chapter three presents the first total synthesis of a member of the nahuoic acid family, namely Ci(Bii), in a longest linear sequence of 16 steps. Nahuoic acids are highly hydroxylated and cis-decalin-scaffold-containing polyketides. These acids are the first series of natural products isolated to date that exhibit S-adenosylemethionine (SAM) competitive inhibition activity against SETD8 enzyme. Our synthesis highlights a titanium-catalyzed asymmetric Diels–Alder reaction to generate the cis-decalin skeleton, Type II ARC tactic to construct the polyol chain, and a late-stage strategic large fragment union via a Micalizio alkoxide-directed alkyne-alkene coupling.^




Genetic Regulators of Toxicity in a Mouse Model of Amyotrophic Lateral Sclerosis and a Worm Model of Anoxic Injury

Mon, 16 Apr 2018 19:32:49 PDT

The equilibrium between energy consumption and energy production defines the metabolic rate of an organism. This homeostatic balance is tightly regulated by a variety of sophisticated processes that occur within and between cells and tissues. These processes also allow animals to tolerate some deviation from baseline by recruiting adaptive mechanisms to bring cells and organisms back to homeostasis. Temporary changes in the organism’s environment, such as alterations in ambient temperature, oxygen levels and infections are examples of conditions where animals must have a healthful adaptive metabolic response, allowing them to sustain the duration of the stress. However, in conditions of chronic disease or long-term stress, these adaptive mechanisms can no longer be protective and may even contribute to the damage incurred by the animal. Therefore, metabolism can either be healthful and adaptive to stressors, or stressors can induce pathogenic metabolic changes in an organism. In this body of work, I explore this bidirectional relationship between external stresses and organismal metabolism. In chapter 2, I investigate the contribution of hypermetabolism (energy production > energy consumption) in a mouse model of the disease amyotrophic lateral sclerosis (ALS). While hypermetabolism is a feature of ALS, it is not known if it contributes to disease pathogenesis. In a mouse model of ALS, I genetically induce hypometabolism to determine if this change alters disease progression. In chapter 3, I study the role of neuropeptides in regulating hypometabolic tolerance to extreme oxygen deprivation. Here, I employ C. elegans, a genetically tractable soil-dwelling nematode, as a model. Worms can tolerate long durations of anoxia by lowering their metabolic rate, and loss of neuropeptide signaling can further increase its ability to tolerate this stress. I investigate various aspects of neuropeptide regulation of this phenotype. Together, these projects demonstrate the role of metabolism in health, disease and stress, and suggest that inter-cellular and inter-tissue communication is a critical aspect of metabolic homeostasis.^




Defining Multi-Scale Relationships Between Biomechanics and Neuronal Dysfunction in Ligament Pain Using Integrated Experimental and Computational Approaches

Mon, 16 Apr 2018 19:32:46 PDT

Capsular ligaments can encode the mechanical state of joints owing to their innervation. For example, the spinal facet capsular ligament that encloses the facet joint is innervated by mechanoreceptors and nociceptors, and is a major source of neck and low back pain from aberrant spinal motions. The cervical facet capsule is commonly injured by its excessive stretch during neck trauma. Although supraphysiologic deformation of the facet capsular ligament can activate its afferents and induce pain, the local biomechanical and neuronal mechanisms underlying sensory transduction for pain from mechanical inputs remain unclear. The studies in this thesis use integrated in vitro, in vivo and in silico methods to investigate the interplay between the mechanical and nociceptive functions of the cervical facet capsular ligament. Tissue-level mechanics, collagen network restructuring and neuronal dysfunction are all assessed across length scales using a neuron collagen construct (NCC) system as well as animal and computational modeling. Afferent activation, nociception and dysfunction are found to depend on the macro-scale tissue strains. Yet, relationships between macroscopic stretch and micro-scale pathophysiology in the facet capsule is confounded by its heterogeneous fibrous architecture. Studies in this thesis show that localized collagen disorganization is associated with excessive network-level reorganization and fiber-level stretch using network analysis and finite element-based modeling. Integrated imaging of the extracellular matrix structure and neuronal dysfunction in the NCC system provides evidence for collagen network organization and local fiber kinematics as mediators of pain-related neuronal signaling. Stretch-induced production of nociceptive neuropeptides in NCCs is prevented by inhibiting collagen-binding integrins, supporting a role of cell-matrix adhesion in converting noxious mechanical stimuli in to pain signals. Further, neuronal mechanotransduction that initiates pain is found to involve the intracellular RhoA/Rho kinase ROCK. In vivo studies in the rat suggest that intra-articular ROCK likely contributes to the development of central sensitization and facet joint pain, possibly via neuropeptide-mediated synaptic transmission and spi[...]



Analyzing Heterogeneity in Neuroimaging with Probabilistic Multivariate Clustering Approaches

Mon, 16 Apr 2018 19:32:42 PDT

Automated quantitative neuroimaging analysis methods have been crucial in elucidating normal and pathological brain structure and function, and in building in vivo markers of disease and its progression. Commonly used methods can identify and precisely quantify subtle and spatially complex imaging patterns of brain change associated with brain diseases. However, the overarching premise of these methods is that the disease group is a homogeneous entity resulting from a single, unifying pathophysiological process that has a single imaging signature. This assumption ignores ample evidence for the heterogeneous nature of neurodegenerative diseases and neuropsychiatric disorders, resulting in incomplete or misleading descriptions. Accurate characterization of heterogeneity is important for deepening our understanding of neurobiological processes, thus leading to improved disease diagnosis and prognosis.^ In this thesis, we leveraged machine learning techniques to develop novel tools that can analyze the heterogeneity in both cross-sectional and longitudinal neuroimaging studies. Specifically, we developed a semi-supervised clustering method for characterizing heterogeneity in cross-sectional group comparison studies, where normal and patient populations are modeled as high-dimensional point distributions, and heterogeneous disease effects are captured by estimating multiple transformations that align the two distributions, while accounting for the effect of nuisance covariates. Moreover, toward dissecting the heterogeneity in longitudinal cohorts, we proposed a method which simultaneously fits multiple population longitudinal multivariate trajectories and clusters subjects into subgroups. Longitudinal trajectories are modeled using spatiotemporally regularized cubic splines, while clustering is performed by assigning subjects to the subgroup whose population trajectory best fits their data.^ The proposed tools were extensively validated using synthetic data. Importantly, they were applied to study the heterogeneity in large clinical neuroimaging cohorts. We identified four disease subtypes with distinct imaging signatures using data from Alzheimer’s Disease Neuroimaging Initiative, and revealed two subgroups with differe[...]



Nanoparticle Diffusion in Polymer Networks

Mon, 16 Apr 2018 19:32:36 PDT

The incorporation of nanoparticles into polymer networks can lead to improvements in current technologies and solutions for global challenges. For example, mechanical properties can be enhanced while maintaining processability, controlled release of drugs can be enabled, and desalinization membrane capabilities can be improved. Inherent to these applications is controlling the localization and mobility of nano-scale diffusants. To improve the functionality of polymer nanocomposite materials, a fundamental understanding of how polymer parameters affect nanoparticle diffusion is required. For this dissertation, I studied nanoparticle diffusion within heterogeneous, homogenous, and biological polymer networks. Using single particle tracking, I investigated the role of confinement, heterogeneity, extent of gelation, and swelling on nanoparticle mobility. For each study, nanoparticles were integrated into the polymer network, hundreds of trajectories were followed in fast frame rate videos, and then these trajectories were analyzed to yield quantitative information such as mean-squared displacement, displacement distributions, and diffusion coefficients. From quantitative analysis of nanoparticle dynamics, insight into the impact of various polymer properties on mobility were obtained. Specifically, in two environmentally responsive, heterogeneous hydrogels, polyacrylamide and poly(N-isopropylacrylamide) gels, confinement, dynamic heterogeneity, and enthalpic interactions impacted nanoparticle mobility, which varied from diffusive to localized. Solvents and temperature were used to elicit collapse of these heterogeneous networks, which resulted in drastically decreased nanoparticle mobility. In these studies, displacement distributions revealed the extent of Gaussian behavior which was found to be a marker of environmental heterogeneity or cage size. For gelation of tetra-poly(ethylene glycol) networks, a proposed homogeneous network, polymer concentration and extent of gelation impacted nanoparticle diffusion. Using analytical tools developed for synthetic polymer networks, nanoparticle diffusion within the cell cytoplasm was studied, revealing that nanoparticles moved further and faster in cancerou[...]



El estado como problema conceptual: Escritura, religion y politica en guerrillas latinoamericanas 1950--1980

Mon, 16 Apr 2018 19:32:31 PDT

El surgimiento de los gobiernos de tendencia de izquierda usualmente agrupados bajo el nombre de marea rosada durante la primera decada del siglo 21 ha vuelto a poner en cuestion el problema del Estado como agente revolucionario. Si en una epoca el establecimiento y consolidacion del neoliberalismo y del capitalismo transnacional han permitido suponer que la capacidad del Estado ha sido reducida, estos gobiernos representan un reto teorico para evaluar la capacidad que todavia tienen o no los gobiernos. En este trabajo tomo una aproximacion historica a ese problema centrandome en como las personas que combatieron al Estado en distintos momentos (Cuba, Peru, Venezuela) conceptualizaron el Estado a traves del analisis de textos producidos por los mismos combatientes, y tambien peliculas, documentales y novelas que representan y critican o juzgan esos intentos insurgentes centrandome siempre en el concepto del Estado. A partir del analisis he descubierto como los movimientos sociales estudiados han tenido una relacion conflictiva con el Estado como concepto; en un principio, mirandolo como un ente integral, monolitico y cerrado, basado en una concepcion religiosa del poder bajo el cual el Estado ocupaba el lugar de dios; posteriormente, busco momentos en que puede entenderse que esa vision integral del Estado como enemigo a combatir presenta fisuras, al ya no ser visto como ente integral. Lo que llamare secularizacion de la actividad politica termina siendo de esa manera en un proceso de des-secularizacion que nos lleva a pensar que la actividad politica ya no se encuentra en el Estado por si mismo, pero si al avance hacia nuevas formas de politica que encuentran ejecucion en espacio y acciones determinadas.




The Art of Dying Every Second: On the Representations, Publishing Legacy, and Posthumous Writings of Roberto Bazlen

Mon, 16 Apr 2018 19:32:26 PDT

My dissertation aims to describe and investigate the influence and legacy of the intellectual and cultural work of Roberto Bazlen. Interlocutor and consultant of many of the major writers and intellectuals of his time, highly valued publishing adviser, and author of few posthumously published writings, Bazlen, as Eugenio Montale recalled, “spent his life with the desire of leaving no tangible traces of his own transit”. He is nevertheless regarded today as a key figure of twentieth-century Italian literature. Still, because of the very nature of his intellectual activity, his figure and work have been studied only recently, and partially. In the first part of my dissertation I analyze the critical and novelistic representations of Bazlen, whose persona, in spite of his notorious discretion about his life, rose to a legendary status while he was still alive. In the second part of my study I focus on Bazlen’s collaborations with writers such as Italo Svevo, Pier Antonio Quarantotti Gambini, and Eugenio Montale, and I analyze the nature of his work and interventions in their writings. I subsequently address Bazlen’s publishing activity and the criteria and praxis behind his editorial opinions. In the third and final section of my dissertation I finally examine Bazlen’s writings as posthumously collected fragments of a post-humanistic thought deliberately and necessarily articulated in a non-organic fashion. Through the study of the traces collected in the partial and inevitably unfaithful realizations of Bazlen’s legacy, I aim to better comprehend the reasons behind his refusal of literary production and the characteristics of his primarily maieutic intellectual activity.^




Efficient Methods for Large-Scale Empirical Risk Minimization

Mon, 16 Apr 2018 19:32:18 PDT

Empirical risk minimization (ERM) problems express optimal classifiers as solutions of optimization problems in which the objective is the sum of a very large number of sample costs. An evident obstacle in using traditional descent algorithms for solving this class of problems is their prohibitive computational complexity when the number of component functions in the ERM problem is large. The main goal of this thesis is to study different approaches to solve these large-scale ERM problems.^ We begin by focusing on incremental and stochastic methods which split the training samples into smaller sets across time to lower the computation burden of traditional descent algorithms. We develop and analyze convergent stochastic variants of quasi-Newton methods which do not require computation of the objective Hessian and approximate the curvature using only gradient information. We show that the curvature approximation in stochastic quasi-Newton methods leads to faster convergence relative to first-order stochastic methods when the problem is ill-conditioned. We culminate with the introduction of an incremental method that exploits memory to achieve a superlinear convergence rate. This is the best known convergence rate for an incremental method.^ An alternative strategy for lowering the prohibitive cost of solving large-scale ERM problems is decentralized optimization whereby samples are separated not across time but across multiple nodes of a network. In this regime, the main contribution of this thesis is in incorporating second-order information of the aggregate risk corresponding to samples of all nodes in the network in a way that can be implemented in a distributed fashion. We also explore the separation of samples across both, time and space, to reduce the computational and communication cost for solving large-scale ERM problems. We study this path by introducing a decentralized stochastic method which incorporates the idea of stochastic averaging gradient leading to a low computational complexity method with a fast linear convergence rate.^ We then introduce a rethinking of ERM in which we consider not a par[...]



Widespread Use of CXCR6 for Entry by Natural Host SIVs: Implications for Cell Targeting and Infection Outcome

Mon, 16 Apr 2018 19:32:15 PDT

Natural hosts of simian immunodeficiency virus (SIV) are African primates that have coevolved with species-species SIVs and do not progress to AIDS despite high viral loads. This is in stark contrast to the immunodeficiency observed in infection of “non-natural” hosts of SIV/HIV, Asian macaques and humans. Certain critical CD4+ T cell subsets and anatomic niches that are required for maintaining immune system homeostasis and function are infected less frequently in natural hosts than in non-natural hosts, suggesting that the determinants of virus target cells contribute to the outcome of infection. SIV and HIV target cells are largely defined by the expression of the receptor CD4 and a coreceptor. Our lab recently discovered that the entry coreceptor CCR5 is dispensable for SIV infection of the natural host sooty mangabey (SM), and then identified CXCR6 as an additional coreceptor for this SIV. In this thesis, I defined entry coreceptors of a second natural host virus, SIVagmSab that infects sabaeus African green monkeys and found that CXCR6 was a robust coreceptor for this virus as well. I also investigated coreceptor use by the HIV-1 forerunners: the natural host virus SIVmus that infects mustached monkeys and crossed into chimpanzees; and SIVcpz that infects chimpanzees and causes AIDS-like disease and crossed into humans to found HIV-1. SIVmus infected cells expressing CXCR6 and CCR5, while SIVcpz was restricted to use of CCR5, indicating that loss of CXCR6 use coincided with the emergence of pathogenesis in this lineage. Lastly, I defined expression of CXCR6 on SM lymphocytes, and found little or no CXCR6 expression on CD4+ T cell subsets that are critical in lymphocyte homeostasis, but enrichment on replenishable effector memory CD4+ T cells. CXCR6+ CD4+ T cells were largely distinct from CCR5+ CD4+ T cells, thus forming a previously unappreciated SIV target cell population in SM. These data support a model where use of CXCR6 is a common feature among natural host SIVs that targets the virus towards more expendable cell subsets, and away from critical subsets and anatomic niche[...]



A Return to the Oikos: The Transformation of the Home in Modern Spain

Mon, 16 Apr 2018 19:32:10 PDT

Urban space has increasingly become a topic that has spawned intellectual debate across academic disciplines. In Spain, the cityscape, from the nineteenth century onward, has provided a pivotal backdrop for understanding the configuration of social networks represented in cultural production. At the same time, the city has always been a foundational site of contention: while communities gathered and formed in the realm of the urban center, spaces that consequently settled in the periphery breached deeper notions of exclusion. One of the most depicted spaces of such exclusion has been the urban home. A Return to the Oikos: The Transformation of the Home in Modern Spain considers cultural production of the mid-nineteenth through mid-twentieth century in Spain that analyzes the home as the exception to the visible domain of politics and labor and, simultaneously, the condition of the production of these categories. This four- chapter study argues that figures such as the mother, the prostitute, the unemployed hetero-normative male, the housekeeper, and the cook bring to bear the invisible functions of capitalist production and national construction that permit and maintain the bourgeois home and material culture in modern Spain. A Return to the Oikos historically transverses the Revolution of 1868, la Gloriosa, the Restoration (1875-1923), Primo de Rivera's regime (1923-1930), the Second Republic (1931-1939), The Civil War (1936-1939), and the isolating years of hunger under the Francoist dictatorship. In doing so, it posits that the home space and the domesticated figures that maintain this space are central and critical components to the possibilities of urbanization, modernization, and ideological shifts, specifically in the Spanish national imaginary from the late nineteenth century to the mid-twentieth century. Through analysis of their representation in literature and film, A Return to the Oikos places the home at the center of a general social conflict in the larger period of Spanish modernization as deeply intercalated in economic and political fabric. [...]



Dancehall Diaspora: Roots, Routes and Reggae Music in Ghana

Mon, 16 Apr 2018 19:32:06 PDT

The recent explosion of Ghanaian Reggae Dancehall reflects the longstanding and still growing influence of Jamaican-inspired popular culture in Ghana today. This emerging genre has been nurtured by local Rastafarian communities and championed by youth from the zongos—sprawling internal migrant and largely Islamic unplanned neighborhoods. Suffering similar forms of economic and political alienation from mainstream Ghanaian society, emerging Reggae Dancehall artists from these groups have adopted similar socio cultural and politically rebellious postures as their counterparts in Jamaica—mirroring Jamaican Patois, 'Dread Talk' and Rasta, ‘rudebwoy’ and ‘rudegyal’ identities as counter hegemonic ways of being and knowing in Ghana today. ^ Neoliberal structural adjustment, patron-clientelism and state corruption follow histories of slavery and colonialism in both these spaces. Subject populations in these locations have now, largely through entertainment media and internet technology come to see similar plights in each other’s experiences. Popular youth cultures in these locations have to come to mirror each other; resounding extant socio-linguistic and cultural retentions that tie African Jamaicans to Ghana through the Atlantic Slave Trade. Novel iterations of diaspora inhere in these processes. On the one hand Jamaican musicians hail ‘Africa’ as source of inspiration, site of return and escape from ‘Babylon’. Across the Atlantic Ghanaian artists and audiences look to Rastafari, Reggae, and Dancehall for strategies in culturally, politically and commercially mobilizing their increasingly urban African identities. Drawing heavily on Jamaican pop tropes which themselves owe a debt to the continent, Ghanaian artists reclaim Reggae Dancehall as broadly African and hence legitimately their own; brushing off charges of mimicry as they endeavor to uniquely indigenize the art form.^




Why We Help the Wronged: Emotional and Evolutionary Determinants of Victim Compensation

Mon, 16 Apr 2018 19:32:03 PDT

Why do third parties choose to help the victims of norm violations? In Chapter 1, we address this question at the emotional level. We show a relationship between environment and motivating emotion, in which moral outrage motivates the compensation of norm violation victims, whereas empathic concern drives compensation in other situations, at both the trait (Study 1) and state (Studies 2 and 3) levels. This finding presents a novel question for evolutionary psychology. Differing emotional drivers are taken to represent distinct underlying cognitive systems. While previous evolutionary models based on social insurance through indirect reciprocity can account for domain-general empathically driven compensation, they fail to address morally outraged compensation of norm violation victims. In Chapter 2, we extend two evolutionary models of punishment, showing how those same selection pressures may also account for victim compensation. We first propose the reputation-signaling hypothesis, under which compensators signal their community status and knowledge of local norms, making observers more likely to select them as future interaction partners. We also develop the norm stabilization hypothesis, in which compensators broadcast their endorsement of the violated norm, leading conditional conformists to continue to comply, thereby stabilizing the norm within the group. In Chapter 3, we develop and test empirical predictions of both hypotheses. In Study 4, we find support for the joint prediction of both the reputation-signaling and norm stabilization hypotheses that compensation is increased when observed by others. In Study 5, we show that, consistent with the norm stabilization hypothesis, those who observe compensation of a victim of a norm violation are more likely to conform to that norm. In Study 6, we test the prediction of the reputation-signaling hypothesis that those who compensate are preferred as interaction partners to those who act similarly pro-socially, but not through compensation. Here we find mixe[...]



Russia Eternal: Recalling the Imperial Era in Late- and Post- Soviet Literature and Culture

Mon, 16 Apr 2018 19:31:59 PDT

The return of Tsarist buildings, narratives and symbols has been a prominent facet of social life in post-Soviet Russia. My dissertation aims to explain this phenomenon and its meaning by tracking contemporary Russia’s cultural memory of the Imperial era. By close-reading both popular and influential cultural texts, as well as analyzing their conditions of production and reception, I show how three generations of Russian cultural elites from the 1950s until today have used Russia’s past to fight present-day political battles, and outline how the cultural memory of the Imperial epoch continues to inform post-Soviet Russian leaders and their mainstream detractors.^ Chapters One and Two situate the origin of Russian culture’s current engagement with the pre-Revolutionary era in the social dynamic following Stalin’s death in 1953. I first discuss how the pre-Soviet past was inherited by the post-Stalin liberal elites and amplified by the expansion of a mass ‘technical intelligentsia’, the burgeoning of media, and the growth of political and affective links between the educated masses and the cultural elites who would represent them. I then examine how late Soviet conservatives used the pre-Soviet past to dispute the liberal hegemony and to forge anti-liberal alliances with state power.^ Chapter Three shows how the memory of the late Imperial era and its Revolutionary terminus has informed the capitalist, liberal-conservative ‘homo faber’ rhetoric of the anti-Soviet intelligentsia coalition that brought first Yeltsin and then Putin to power, and legitimated an undemocratic and increasingly repressive post-Soviet state.^ Chapter Four examines several vectors of a more thoroughly liberal humanist counter-discourse on the pre-Soviet past. I claim that this counter-discourse was always productively skeptical of Soviet liberal and conservative models of historical inheritance, and that it arose simultaneously with the Perestroika and proceeded to reappear for two decad[...]



Equilibrium Field Theoretic and Dynamic Mean Field Simulations of Inhomogeneous Polymeric Materials

Mon, 16 Apr 2018 19:31:56 PDT

Inhomogeneous polymeric materials is a large family of promising materials including but limited to block copolymers (BCPs), polymer nanocomposites (PNCs) and microscopically confined polymer films. The promising application of the materials originates from the materials' unique microstructures, which offer enhanced mechanical, thermal, optical and electrical properties to the materials. Due to the complex interactions and the large parameter space, behaviors of the microstructures formed by grafted nanoparticles and nanorods in PNCs are difficult to understand. Separately, because of relatively weak interactions, the microstructures are typically achieved through rapid processing that are kinetically controlled and beyond equilibrium. However, efficient simulation framework to study nonequilbrium dynamics of the materials is currently not available. To attack the first difficulty, I extended an efficient simulation framework, polymer nanocomposite field theory (PNC-FT), to incorporate grafted nanoparticles and nanorods. This extended framework is demonstrated against existing experimental studies and implemented to study how the nanoparticle design affects the nanoparticle distribution in binary homopolymer blends. The grafted nanoparticle model is also used as a platform to adopt an advanced optimization method to inversely design nanoparticles which are able to self-assemble into targeted two dimensional lattices. The nanorod model under PNC-FT framework is used to investigate the design of nanorod and block copolymer thin films to control the nanorod distribution. To attack the second difficulty, I established an efficient framework (SCMF-LD) based on a recently proposed dynamic mean field theory and used SCMF-LD to study how to kinetically control the nanoparticle distribution at the end of solvent annealing block copolymer thin films. The framework is then extended to incorporate hydrodynamics (SCMF-DPD) and the extended framework is implemented to[...]



Depolarization in Nanowires, Tribo-Chemistry, and Negative Electrocaloric Effect

Mon, 16 Apr 2018 19:31:50 PDT

This thesis contains investigations about several technologically--important scientific problems: depolarization process in BaTiO3 nanowires, tribopolymer formation on metal surfaces, and negative electrocaloric effect in prototype ferroelectrics. Spontaneous electric polarization makes perovskite–based oxides of great interest for application to nonvolatile memory devices. However, the polarization of ferroelectric materials may not be infinitely stable. For successful technology application, the depolarization processes of nanoscale ferroelectric oxides must be better understood. Here, we report a combined experimental and theoretical investigation of the depolarization process of single--crystalline BaTiO3 nanowires. By building an Modified Schottky emission model, we explain the both temperature and nanowire thickness dependent polarization decay rates successfully. Besides, Micro--electro--mechanical system and nano--electro--mechanical system (MEMS and NEMS) transistors are considered promising for size--reducing and power--maximizing electronic devices. However, the tribopolymer which forms due to the mechanical load to the surface contacts affects the conductivity between the contacts dramatically. This is one of the challenging problems that prevent widespread practical use of these otherwise promising devices. Here, we use density functional theory (DFT) to investigate the mechanisms of tribopolymer formation, including normal mechanical loading, the catalytic effect, as well as the electrochemical effect of the metal contacts. Our study illustrates the underlying mechanisms of tribopolymer formation clearly, which has great significance in designing tribopolymerization–suppressing strategies. The last work is about electrocaloric effect. The electrocaloric effect (ECE) refers to the phenomenon in which the temperature of a material changes reversibly under the application and removal of electric field. Here, we [...]