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Lefschetz Theorem for Holomorphic One-Forms on Weakly 1-Complete Manifolds
No full textPh.D.For a holomorphic one-form on a weakly 1-complete manifold with certain properties, we discussed the connectivity of the pair , where is a covering map and . We also discussed the criteria about when such a manifold admits a proper holomorphic mapping onto a Riemann surface.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
Out of the Realm of Sentiment: Infant Mortality, Single Mothers, and the Formation of the American Welfare State, 1883-1924
No full textPh.D."Out of the Realm of Sentiment: Infant Mortality, Single Mothers, and the Formation of the American Welfare State, 1883-1924," examines state building at the turn-of-the-century with special attention to infant mortality, grief, and how those elements shaped private and state support for white and Black single mothers and their children. This dissertation argues that an emphasis on sex and sexuality, through either mothers or "fallen" women, drove a women's welfare network to actively undertake state building. Its subjects are women reformers who worked to bridge private charity for single mothers with state funded public welfare, while navigating the racial and gendered elements of turn-of-the-century America. It shows how sentiment and emotion wove a thread through the associational growth of state-sponsored social policy by exploring the early National Florence Crittenton Mission, a network of maternity homes for single mothers and its leader, Kate Waller Barrett. It also examines "Race Betterment" campaigns spearheaded by Black women reformers Sarah Malone in Topeka, KA and Lugenia Burns Hope in Atlanta, GA. Lastly, it analyzes the U.S. Children's Bureau and what historian Robyn Muncy terms "the female dominion" in the Progressive Era U.S. government through the lens of women charity reformers working on the local and national level. This work explores how late nineteenth, early twentieth century women reformers harnessed sentimentality to create political action in the formation of the American welfare state.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
The Effect of Cardiovascular Health on Multiple Sclerosis Disease Outcomes
No full textPh.D.Due to increasingly improved long-term disease outcomes of the multiple sclerosis (MS) population, new questions regarding healthy aging and cardiovascular comorbidities emerge. Furthermore, epidemiological data suggests that MS patients are at a greater risk for developing cardiovascular disease (CVD). Currently there is a substantial lack of cross-sectional and longitudinal studies that investigate the effect of CVDs and lipid dyshomeostasis on the clinical and MRI-derived MS outcomes. This Ph.D. work aims at demonstrating and quantifying the effect of CVDs and cardiovascular-based behavior on MRI-derived measures of brain atrophy and lesion accrual in a heterogeneous population of MS patients. Moreover, it aims at determining the state of the extracranial vascular anatomy and function of MS patients in relation to the MS disability and cognition. Lastly, perfusion-weighted imaging (PWI) was utilized to understand the relationship between cardiovascular-based health and intracranial circulation. Total of 194 MS patients and 43 age-matched healthy controls (HCs) underwent 3T MRI imaging at both baseline and approximately 5-years follow-up visits. Specific sequences included high-resolution 3D-T1 weighted imaging (WI), fluid-attenuated inverse recovery (FLAIR), magnetic resonance angiography (MRA), and dynamic susceptibility contrast (DSC) PWI. Quantitative measures of brain volumes, brain atrophy and lesion accrual were calculated. The MS cohort was characterized using MS-based clinical scores like Expanded Disability Status Scale (EDSS), Multiple Sclerosis Severity Score (MSSS) and with the Brief International Cognitive Assessment for MS (BICAMS) battery. Serum samples were utilized for determining the respective lipid profile measures. Data regarding the cardiovascular diseases was collected and calculation of cardiovascular-based score of Healthy Heart Score (HHS) and the Framingham Coronary Heart Disease Risk Score were performed. For statistical analysis, a set of parametric and non-parametric comparative methods, correlation analyses, and linear regression models were utilized. The sample utilized for each analysis varied based on available data.MS patients with diagnosis of hypertension and heart disease had accelerated rate of central and whole brain atrophy. Furthermore, lifestyle-based behavior contributing towards CVDs was associated with greater central rain atrophy. Poorer dietary habits were also associated with greater longitudinal T2 lesion accrual. MS patients also presented with significantly narrower major extracranial vessels and lower amount of secondary collaterals when compared to age-, sex- and body mass index (BMI)-matched HCs. The MS patients also demonstrated significant narrowing of the arterial vessels and concurrent loss of the number and size of secondary vessels. Both age and levels of lipoprotein (a) may be important factors that affect the extracranial arterial lumen. The overall arterial blood flow was further associated with poorer cognitive performance in the MS population. Similarly, poorer intracranial perfusion measures were associated with poorer cognitive and physical performance in MS patients. The rate of cerebral perfusion measured as mean transit time was associated with greater levels of high-density lipoprotein (HDL) cholesterol and HDL-associated apolipoproteins. In conclusion, the cardiovascular health represents a significant modulator of the physical and neurological outcomes in MS patients. Future studies should determine the benefit of aggressive cardiovascular disease management in providing better long-term MS disease outcomes.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
Characterizing ΔNp63α Binding Sites Based on Nucleosome Organization and Histone Modifications
No full textM.S.p63 is an essential transcription factor required for stratified epithelial development and also overexpressed in different squamous cell carcinomas. Our broader goal is to define the biological rules dictating p63 binding on chromosomal DNA. For approaching that we aimed to determine the nucleosome organization and histone modifications at p63 binding sites before and after p63 binding. The wild type and DNA binding mutant of predominant isoform of p63, ΔNp63α was ectopically induced in p63 naïve cells, K562. 1040 sites among 1427 common p63 binding sites identified by different p63 ChIP-seq datasets were found to contain 1214 p63 motifs using FIMO. We discovered that these p63 binding sites have higher nucleosome occupancy by assessing MNase-seq data for K562 cells. Also, before p63 binding the targeted sites lack H3K27ac signal indicating the capability of p63 to bind to unmodified chromatin. After p63 binding, regions surrounding the binding sites acquired H3K27ac, but the binding site itself lacked H3K27ac indicating the capability of p63 to recruit an enzyme responsible for acetylation and the depletion of nucleosome at the p63 binding site after binding respectively. Whereas, there was no difference in the nucleosome occupancy or H3K27ac signal at transcription start sites between before and after p63 binding. Then we found that 109 p63 binding sites among those 1040 motif containing sites are repressed or heterochromatin in K562 but enhancers in p63 native cell line NHEK indicating the ability of p63 to bind to inaccessible chromatin state. 13 among 109 sites were chosen based on ChIP-seq p-value and validated by ChIP-qPCR for characterization. All of these sites fall within or at the edges of nucleosomes, lacking H3K27ac in mutant ΔNp63α expressing K562 cell and obtaining H3K27ac on flanking regions with a depletion of signal at the motif site in wild-type ΔNp63α expressing K562 cells. We checked the nucleosome position at one individual p63 binding site using MNase digestion-qPCR in both wild-type and mutant ΔNp63α expressing K562 cells. Fold enrichment of the region covering the nucleosome center is higher in mutant cells compared to that of wild type cells indicating the displacement of nucleosome from that position. ChIP-qPCR for nucleosome subunit H4 for five p63 binding sites and two control sites positioned approximately 400 base pairs right and left to each of those five sites was performed. Two sites show lower fold enrichment for wild type K562 compared to that of the mutant K562 cells which again suggests the loss of nucleosomes from those p63 binding sites upon ΔNp63α binding, though the fold enrichment for the control sites in wild type and mutant cells did not show any consistency. ChIP-qPCR for chromatin remodeler BAF subunit brg1 for those 5 selected p63 binding sites were also executed to check the occupancy of BAF complex on those sites after p63 binding. Three sites exhibited slightly higher brg1 occupancy in wild type ΔNp63α expressing K562 compared to that of the mutant one. Finally, to know the occupancy of histone acetyl transferase on 13 p63 binding sites in K562 cells, histone acetyl transferase-p300 ChIP-qPCR was performed in wild type and mutant K562 cells. But no conclusion could be inferred from the experiment due to the unreliability of the data. In future, more comprehensive studies can be done to know the detailed mechanism of nucleosome repositioning and chromatin modification at p63 binding sites by the combinatorial actions of different factors upon p63 binding.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
Reprogramming Stem Cell Rejuvenation for Restoring Muscle Regeneration after Aging
No full textPh.D.The regeneration capacity of adult organisms decreases after aging or chronic diseases. One of the pivotal factors in regeneration is the stem cells that are resident in the tissues. These stem cells are evolutionarily inherited from embryonic development to regenerate our tissue after injury or aging. Unfortunately, stem cells are also subjected to cellular senescence as we age. Senescent stem cells lose their capacity to proliferate and regenerate in response to degeneration. Interestingly, in the first stages of life when the embryo develops, a circuit of transcription factors are active to maintain the self-renewal and pluripotency of embryonic stem cells (ESC). In the core of these factors are the master regulators of pluripotency "NANOG, OCT4, and SOX2." The expression of NANOG is essential to maintaining pluripotency and an undifferentiated state of ESC as well as induced pluripotent stem cells (iPSC) that are generated from reprogramming somatic cells. Indeed the process of reprogramming resets the aging clock in the somatic cells and as long as NANOG is present in iPSC, these cells maintain their proliferation and differentiation capacity overtime. Recent studies have shown that the ectopic expression of NANOG in somatic cells can improve proliferation and differentiation of mesenchymal stem cells (MSC) and fibroblasts without reprogramming these cells to iPSC. In line with these studies, I initially assessed the myogenic differentiation of mesenchymal stem cells toward smooth muscle cells (SMC) upon addition of TGF-β in the media. These MSC-SMC cells were then encapsulated in engineered microtissues that are under tension and recapitulate the microenvironment of smooth muscle tissues in our body. Similar to senescent smooth muscle, the contractile capacity of MSC-SMC tissues significantly decreased after cellular senescence due to decline in actomyosin contractile machinery, and overexpression of NANOG in senescent tissues could reinstate the actomyosin contractile machinery and restore the contractile function to the young levels. The restoration of myogenic differentiation and contractile function of MSC encouraged me to assess the effect of NANOG on the myogenic progenitors of skeletal muscle (Myoblasts)...**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
The Role of Moraxella catarrhalis Biofilms in the Pathogenesis of Otitis Media
No full textPh.D.Otitis media (OM) is a common childhood illness that presents a significant healthcare and financial burden worldwide. In the United States, OM affects 60% of children by 3 years of age, resulting in severe ear pain. The three primary causative agents of this disease are Moraxella catarrhalis, nontypeable Haemophilus influenzae, and Streptococcus pneumoniae. Collectively referred to as otopathogens, these bacterial species reside in the nasopharynx asymptomatically, providing a reservoir for opportunistic infection. Although the transition from asymptomatic colonization to active infection is not fully characterized, it is widely accepted that changes induced by viral upper respiratory infection are linked to the concurrent onset of OM. Complexities in this dynamic infection have led to poor treatment outcomes. Current standard of care is likely suffering due primarily to polymicrobial infections and biofilm-associated otopathogens. The work herein focuses on the polymicrobial interactions that occur during nasopharyngeal colonization. Extensive analysis was completed using an in vitro nasopharyngeal colonization model adapted to assess the primary otopathogens in various co-culture environments. This work provides insight into OM pathogenesis by dissecting the dual species and triple species relationships and characterizing the "protective effect," a phenomenon that results in the persistence of the three primary otopathogens in a polymicrobial biofilm. This concept has important implications in recurrent infections and treatment susceptibility. We further sought to demonstrate the feasibility of antimicrobial photodynamic therapy (aPDT) as a treatment strategy for polymicrobial OM. The photosensitizer chlorin e6 was used in conjunction with a 405nm laser to treat polymicrobial biofilms in vitro. Treatment was able to significantly reduce polymicrobial biofilms with minimal drug incubation and laser exposure times, and photosensitizer concentrations as low as 10 μM. Parameters were further optimized using a double treatment approach. These data suggest that aPDT is a promising antimicrobial strategy that warrants further assessment in the future for treatment of OM.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
Towards Privacy-Preserving and Secure Crowd Sensing in the Internet of Things
No full textPh.D.Recent years have witnessed the rise of Internet of Things (IoT), a newly emergent networking paradigm that connects humans and the physical-world through ubiquitous sensing, computing, and communicating devices. Driven by the ubiquitous and interconnected sensing devices in the Internet of Things, crowd sensing has emerged as a new way of collecting information from the physical world. Recently, a large variety of crowd sensing systems have been developed, serving a wide spectrum of applications that have significant impact on our daily lives, including urban sensing, smart transportation, environment monitoring, localization, health-care, and many others. However, the sensory data provided by the participating users are usually not reliable, due to various reasons such as poor sensor quality, incomplete observations, and background noise. To identify truthful values from the crowd sensing data, a lot of reliability-aware data aggregation mechanisms have been developed and they can automatically capture user reliability in the data aggregation process. Though able to improve the aggregation accuracy, existing reliability-aware data aggregation mechanisms fail to take into consideration the privacy and security issues in their design. On one hand, the sensory data provided by each individual user may contain sensitive information, which may be disclosed to others during the data aggregation process, resulting in the leakage of users' privacy. On the other hand, there may exist malicious users in crowd sensing systems who conduct the data poisoning attacks for the purpose of sabotage or financial rewards, and the effectiveness of the crowd sensing systems can be largely degraded by these malicious users. In this thesis, we take steps to study and address the privacy and security issues when conducting reliability-aware data aggregation in crowd sensing systems. Specifically, we first consider a widely adopted reliability-aware data aggregation mechanism named truth discovery and propose a series of privacy-preserving truth discovery frameworks for crowd sensing systems. These frameworks can not only accurately calculate the final aggregated results but also provide strong privacy protection for the users' sensitive information. Then, we investigate crowd sensing in adversarial environments and study the data poisoning attacks against the crowd sensing systems employing the truth discovery mechanism. We develop an optimal attack framework in which the attacker can not only maximize his attack utility but also disguise the introduced malicious users as normal ones such that they cannot be detected easily. Following a similar design philosophy, we also successfully attack the crowd sensing systems empowered with the Dawid-Skene model, another widely adopted reliability-aware data aggregation algorithm. The desirable performance of the proposed frameworks is verified through extensive experiments conducted on real-world crowd sensing systems.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
The Interplay Between Individual and Regional Factors in Access and Care Utilization Among Rural Patients
No full textPh.D.The overarching aim of this 3-study research project is to understand the mechanisms through which regional social and economic factors impact the utilization of health services among individuals living in resource-poor communities. In this dissertation, we tested our hypotheses among populations of patients living in rural Michigan (studies 1 & 2) and rural New York (study 3). Studies 1 & 2 focused on access to routine primary medical care, while study 3 examined the interplay between primary and specialty medical care using one of the most complex and resource-intensive diagnosis as an example (cancer)...**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
CD28 Promotes Mitochondrial Metabolism to Support Myeloma Cell Survival
No full textM.S.Multiple myeloma (MM) is a malignancy of bone marrow plasma cells (BMPCs). Despite advances in treatments, MM remains incurable due to the development of therapy resistant cells. The bone marrow (BM) microenvironment not only produces important soluble pro-MM survival factors, but also directly interacts with MM cells via cell-cell contact to upregulate pro-tumorigenesis pathways to support MM survival and therapy resistance. We previously described the critical role of CD28-CD80/CD86 interaction between MM cells and bone marrow dendritic cells. Despite the well-recognized central involvement of CD28 in supporting MM survival, the intrinsic molecular functions of CD28 remain to be delineated. In this study, we reveal preliminary data underlying CD28's function in promoting mitochondrial respiration capacity through the upregulation of the mitochondria biogenesis master regulator PGC1-β. We further defined fatty acids as essential fuels for CD28-mediated mitochondrial metabolism and that inhibition of fatty acid oxidation diminishes CD28's pro-survival effect in vitro. Taken together, our study suggests PGC1-β is a novel downstream signal mediating CD28's pro-metabolic functions and that inhibition of fatty acid metabolism could be applied in anti-MM treatment.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
Monumental Foundations: An Investigation of the Preclassic Development of Civic-Ceremonial Plazas in the Cival Region, Guatemala
No full textPh.D.This dissertation investigates the role of civic-ceremonial plazas in the formation and maintenance of the Preclassic period Maya centers of Cival, Holmul, and Witzna located in the Cival region in northern Guatemala. Ancient Maya public plazas are largely understudied by archaeologists, despite filling a critical role in the understanding of community formation and interaction through the practices associated with the commemorative and ceremonial rituals held in these locations. These public plazas were places of interaction that ranged from public, open places to restricted spaces. The theories of practice, structuration, place, social memory, and communities of practice are utilized here to critically examine the types of interactions and This examination of civic-ceremonial plazas in the Cival region draws upon excavations, GIS data, proxemics, estimated plaza capacity, and archaeological evidence of ritual activities to understand practices, which resulted in the emergence and continued occupation of public plazas. Lime plaster samples acquired from plaza floors are used to provide insight into the interaction and exchange of practices between the sites of Cival, Holmul, and Witzna. Thin section petrography, SEM-EDS, and x-ray fluorescence spectrometry (pXRF) are used to analyze the mineralogical and elemental composition of lime plaster, which is subsequently used to determine the quality of the plaster and in the identification of communities of practice. Findings from this study confirm the strong connection between Cival and Holmul during the Late Preclassic period by demonstrating the existence of multiple communities of practice involving the addition of barite to lime plaster production and the semi-standardization of E-Groups in the region. Additionally, it was discovered that the centers of Cival, Holmul, and Witzna each experienced a distinct trajectory regarding the construction and spatial positioning of public and private plazas. Despite these differences, public plazas remained essential focal points of community activity and as locations for commemorative and ceremonial rituals for each of these three sites throughout the Preclassic and Classic periods. Private plazas were also essential locations for ceremonial and ritual events conducted among a more restricted community, such as seen at the Watchtower plaza in East Witzna. The practices associated with the ritual events in these plazas were preserved in the material remains of lime plaster surfaces, caches, and stelae. These physical remains are used to provide insight into the types of rituals conducted in these plazas.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*