Advanced analytical strategies to determine biomedical parameters for medical diagnostics, drug delivery, and therapy

Biomedical parameters are critical for diseases prognosis, diagnosis and therapy. Many research groups have dedicated their studies to develop analytical instrumentation and apply analytical methods to determine biomedical parameters that have the potential to help with disease control and increase public health. This dissertation focuses on three major aspects of analytical strategies development and applications: 1) detection of pH changes caused by nanotoxicity (induced by TiO2 nanoparticles) using newly developed micro-pH sensor, 2) quantification of renal cell carcinoma (RCC) biomarkers by high-performance liquid chromatography - tandem mass spectrometry (HPLC-MS/MS), and 3) nuclear magnetic resonance (NMR) studies of porous wall hollow glass microspheres (PWHGMs) that have the potential to be used as drug delivery carriers. Firstly, a dual-core fiber-optic pH micro-probe was developed which can be used within the biologically relevant pH range from 6.20 - 7.92 (R2 = 0.9834). Secondly, a targeted HPLC-MS/MS protocol was developed to simultaneously monitor four urinary biomarkers for RCC and applied to human urine specimen analysis. Thirdly, a vacuum-based loading system was developed to charge PWHGMs with specific materials followed by a washing procedure. Immiscible binary model systems (n-dodecane/water and chloroform/water) as well as isopropanol- acetic acid esterification and the hydrolysis of isopropyl acetate were investigated to obtain NMR evidence for material loading into PWHGMs and their subsequent release into the surrounding solutions. In addition, microspheres loaded with H2O were suspended in D2O to obtain quantitative information about the release kinetics from PWHGMs. The results demonstrate that NMR is a particularly useful tool to study developments and applications of PWHGMs in the targeted and controlled drug delivery --Abstract, page iv

Mutant P53 in pre-leukemic hematopoietic stem cells and the pathogenesis of Myelodysplastic Syndrome

Indiana University-Purdue University Indianapolis (IUPUI)Myelodysplastic syndrome (MDS) is a clonal disease arising from mutated hematopoietic stem cells (HSCs). MDS stem cells originate from pre-leukemic HSCs, which have enhanced competitive advantage over wild-type (WT) HSCs but normal differentiation capacity. Recently, acquired somatic gain-of-function (GOF) TP53 mutations were identified in the blood of aged healthy individuals as well as in patients with MDS. However, the role of GOF TP53 mutations in clonal hematopoiesis and the pathogenesis of MDS is largely unknown. Based upon our previous studies and clinical findings, I hypothesized that GOF mutant p53 drives the development of pre-leukemic HSCs with enhanced competitive advantage, leading to clonal expansion and the pathogenesis of MDS. To test my hypothesis, I examined HSC behaviors in young p53+/+ and p53R248W/+ mice. I discovered that p53R248W enhances the repopulating potential of HSCs without affecting terminal differentiation. I also found that GOF mutant p53 protects HSCs from genotoxic stress and promotes their expansion. To investigate the role of mutant p53 in the pathogenesis of hematological malignancies, I monitored disease development in p53+/+ and p53R248W/+ mice and observed that some mutant p53 mice develop MDS during aging. Therefore, I demonstrated that GOF mutant p53 enhances the repopulating potential of HSCs and drives the development of pre-leukemic HSCs, predisposing aged mutant p53 mice to MDS development. Mechanistically, I found that mutant p53 increases the chromatin accessibility to genes important for HSC maintenance, including pluripotent gene Sox2 and chemokine gene Cxcl9. By performing biochemical experiments, I discovered that GOF mutant p53, but not WT p53, interacts with histone methyltransferase EZH2 and enhances histone H3 lysine 27 trimethylation (H3K27me3) at genes, including Mef/Elf4 and Gadd45g, that negatively regulate HSC self-renewal. Collectively, these findings demonstrated that GOF mutant p53 drives pre-leukemic HSC development through modulating epigenetic pathways. Thus, our studies have uncovered novel mechanistic and functional links between GOF mutant p53 and epigenetic regulators in pre-leukemic HSCs. This research may identify epigenetic regulator EZH2 as a novel target for the prevention and treatment of MDS patients with TP53 mutations

Parallel Toolkit for Measuring the Quality of Network Community Structure

Many networks display community structure which identifies groups of nodes within which connections are denser than between them. Detecting and characterizing such community structure, which is known as community detection, is one of the fundamental issues in the study of network systems. It has received a considerable attention in the last years. Numerous techniques have been developed for both efficient and effective community detection. Among them, the most efficient algorithm is the label propagation algorithm whose computational complexity is O(|E|). Although it is linear in the number of edges, the running time is still too long for very large networks, creating the need for parallel community detection. Also, computing community quality metrics for community structure is computationally expensive both with and without ground truth. However, to date we are not aware of any effort to introduce parallelism for this problem. In this paper, we provide a parallel toolkit to calculate the values of such metrics. We evaluate the parallel algorithms on both distributed memory machine and shared memory machine. The experimental results show that they yield a significant performance gain over sequential execution in terms of total running time, speedup, and efficiency.Comment: 8 pages; in Network Intelligence Conference (ENIC), 2014 Europea

Earnings management surrounding CEO turnover: evidence from Chinese listed firms

This paper examines the effects of CEO turnovers on earnings quality of Chinese listed firms. CEO turnover can be classified into two types that are respectively routine and non-routine CEO change and external and internal successors. After various selection procedures, modified Jones model and a multivariate regression are respectively applied to calculate the discretionary accruals and test hypothesis proposed. According to empirical results, non-routine CEO change is associated with more earning management and lower earnings quality, and external successors are associated with less earning manipulation thus higher earnings quality. In addition, more earning management in the transition year can be found than that in the following year

Developing a Gini Coefficient for Distributed Instructional Leadership (GDIL): How Distributed Instructional Leadership (DIL) Impacts Instructional Reform Implementation and Professional Community in Elementary Schools.

This dissertation examines the notion of school distributed instructional leadership (DIL). Most discussions about distributed leadership focus on the “average leadership” exercised by multiple roles or individuals to conceptualize and measure the construct. However, scant attention has been paid to “dispersed leadership,” which estimates the degree to which leadership is equalized (or decentralized) across multiple roles or individuals. Nor does previous research provide a robust theory or empirical evidence regarding the effects of “dispersed leadership,” either on instructional improvement directly or conditional on certain features of school context. To address these gaps, I developed a quantitative measure for the “dispersed leadership” of DIL — the Gini Coefficient for Distributed Instructional Leadership (GDIL). The GDIL measures the degree of “equality” to which instructional leadership functions are distributed across multiple roles or individuals. Then, using contingency theory as a guiding framework, I developed a theory about the effects of DIL on two school outcomes (i.e. “fidelity” to instructional regime and strength of professional community), contingent upon four features of school context: average instructional leadership [AIL], task, leader-leader interaction, and leader-teacher interaction. Finally, I tested the theory empirically in a series of longitudinal, multilevel models. My empirical inquiry regarding DIL was based on four-year longitudinal data on 109 elementary schools that adopted one of three Comprehensive School Reform (CSR) programs (i.e. America’s Choice [AC], Successful For All [SFA] or the Accelerated Schools Project [ASP]). The findings indicated that the influences of DIL on the two outcomes were conditional on the four school contingencies. However, the conditional effects of DIL not only varied across the four contingencies but also varied between the two outcomes.PhDEducational StudiesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/120809/1/chsisi_1.pd

Human Cytomegalovirus Encoded miR-US25-1-5p Attenuates CD147/EMMPRIN-Mediated Early Antiviral Response.

Cellular receptor-mediated signaling pathways play critical roles during the initial immune response to Human Cytomegalovirus (HCMV) infection. However, the involvement of type-I transmembrane glycoprotein CD147/EMMPRIN (extracellular matrix metalloproteinase inducer) in the antiviral response to HCMV infection is still unknown. Here, we demonstrated the specific knockdown of CD147 significantly decreased HCMV-induced activation of NF-κB and Interferon-beta (IFN-β), which contribute to the cellular antiviral responses. Next, we confirmed that HCMV-encoded miR-US25-1-5p could target the 3 UTR (Untranslated Region) of CD147 mRNA, and thus facilitate HCMV lytic propagation at a low multiplicity of infection (MOI). The expression and secretion of Cyclophilin A (sCyPA), as a ligand for CD147 and a proinflammatory cytokine, were up-regulated in response to HCMV stimuli. Finally, we confirmed that CD147 mediated HCMV-triggered antiviral signaling via the sCyPA-CD147-ERK (extracellular regulated protein kinases)/NF-κB axis signaling pathway. These findings reveal an important HCMV mechanism for evading antiviral innate immunity through its encoded microRNA by targeting transmembrane glycoprotein CD147, and a potential cause of HCMV inflammatory disorders due to the secretion of proinflammatory cytokine CyPA

Designing signaling environments to steer transcriptional diversity in neural progenitor cell populations

Stem cell populations within developing embryos are diverse, composed of many different subpopulations of cells with varying developmental potential. The structure of stem cell populations in cell culture remains poorly understood and presents a barrier to differentiating stem cells for therapeutic applications. In this paper we develop a framework for controlling the architecture of stem cell populations in cell culture using high-throughput single cell mRNA-seq and computational analysis. We find that the transcriptional diversity of neural stem cell populations collapses in cell culture. Cell populations are depleted of committed neuron progenitor cells and become dominated by a single pre-astrocytic cell population. By analyzing the response of neural stem cell populations to forty distinct signaling conditions, we demonstrate that signaling environments can restructure cell populations by modulating the relative abundance of pre-astrocyte and pre-neuron subpopulations according to a simple linear code. One specific combination of BMP4, EGF, and FGF2 ligands switches the default population balance such that 70% of cells correspond to the committed neurons. Our work demonstrates that single-cell RNA-seq can be applied to modulate the diversity of in vitro stem cell populations providing a new strategy for population-level stem cell control

How SaaS Application Led To Cloud Enabled Business Innovation: A Case Study from China

Although cloud computing is increasingly viewed as a catalyst for business innovation, many executives wonder whether and how it can enable the emergence of new business opportunities. This research-inprogress case study presents the business drivers and implementation of a leading telecommunication carrier from China in revolutionizing its SaaS application to a cloud enabled service platform in its innovation to develop a multisided platform business model. The preliminary implicatons from the case reveal that to gain value from cloud enabled business innovation, firms need to develop business strategies based on four key elements: customer needs probing, value proposition positioning, cloud enabled platform construction, and ecosystem development