Thesis (M.A.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / This paper is divided into five sections. It is concerned with the derivation and application of a formula known as Quadrature by Differentiation. Section One derives the basic formula by applying integration by parts to a suitably chosen 2n^th. degree polynomial. By applying this method to a polynomial of degree m + n, Hummel and Seebeck's Generalized Taylor Expansion is obtained and shown identical with the Quadrature Formula when m is set equal to n. Finally the quadrature approximation is proved convergent if f(x) is analytic in a certain domain of the complex plane. Section Two deals with the representation of certain elementary functions using quadrature methods. These expansions, because they have integer coefficients and appear in a rational form, are far easier to compute than the corresponding Maclaurin Series with the same degree of accuracy. Section Three uses quadrature methods to solve ordinary differential equations whose boundary data are given at a single point. The method that is devoloped is a variation of the predictor corrector type. It is very accurate and is easily extended to solve almost every type of initial value problem. Section Four treats the linear "Two Point" and eigenvalue problem. This is accomplished by transforming the given differential equation into a system of linear algebraic relationships between the known and unknown boundary conditions. This section also deals briefly with the non linear "Two Point Problem" suggesting a iterative method, based on the results of Section Three, to obtain the missing boundary data. Section Five improves on something that Quadrature by Differentiation already is; an accurate integration formula. This is achieved by replacing derivatives with central differences. The final result is three integration formulas based only on the tabular values of the function being integrated. Since these formulas are derived using the basic interval, xg< x < xg + h, integration can be extended into s successive intervals using the same or different values of h. / 2999-01-01

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Indiana University-Purdue University Indianapolis (IUPUI) / SIRT1 (Sirtuin 1) is a founding member of a family of seven proteins and histone deacetylases. It is involved in cellular resistance to stress, metabolism, differentiation, aging, and tumor suppression. SIRT1-/- mice demonstrate embryonic and postnatal development defects. We examined hematopoietic and endothelial cell differentiation of SIRT1-/- mouse embryonic stem (mES) cells in vitro, and hematopoietic progenitors in SIRT1+/+, SIRT1+/-, and SIRT1-/- mice. SIRT1-/- ES cells exhibited markedly delayed/immature formation of blast colony-forming cells (BL-CFCs). When individual blast colonies were analyzed for hematopoietic and endothelial potential, replated SIRT1-/- BL-CFC possessed limited hematopoietic potential, whereas endothelial potential was essentially unaltered. The ability of SIRT1-/- ES cells to form primitive erythroid progenitors was not only delayed but greatly decreased. Moreover, after differentiation of SIRT1-/- mES cells, there were also significant decreases in granulocyte-macrophage (CFU-GM) and multipotential (CFU-GEMM) progenitor cells. Differentiation delay/defects were associated with delayed capacity to switch off Oct4, Nanog and Fgf5, decreased β-H1 globin, β-major globin, and Scl gene expression and reduced activation of the Erk1/2 pathway upon SIRT1-/- ES cell commitment. Reintroduction of WT SIRT1 into SIRT1-/- cells partially rescued the primitive erythroid progenitor formation of SIRT1-/- cells and the expression of hemoglobin genes, Hbb-bh1 and Hbb-b1, suggesting that the defect of hematopoietic commitment is due to deletion of SIRT1, and not to genetic drifting of SIRT1-/- cells. To confirm the requirement for SIRT1 for normal development of hematopoietic progenitor cells, we assessed embryonic and adult hematopoiesis in SIRT1+/+, SIRT1+/- and SIRT1-/- mice. Yolk sacs from SIRT1 mutant embryos generated fewer primitive erythroid precursors compared to wild-type (WT) and heterozygous mice. Moreover, knockout of SIRT1 decreased primary bone marrow hematopoietic progenitor cells (HPCs) in 5 week and 12 month old mice, which was especially notable at lower (5%) O2 tension. In addition these progenitors survived less well in vitro under conditions of delayed growth factor addition. Taken together, these results demonstrate that SIRT1 plays a role in ES cell hematopoietic differentiation and mouse hematopoiesis.

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During embryo development, extracellular matrix (ECM) remodeling by matrix metalloproteinases (MMPs) and promotes downstream cell specifications. Pluripotent stem cell (PSC) aggregates can recapitulate various aspects of embryogenesis in vitro, and incorporation of biomaterial microparticles also provides an ideal platform to study cell-biomaterial interactions. Stem cell interactions with ECM-based biomaterials can impact tissue remodeling and differentiation propensity via modulation of MMP activity. This work investigated the MMP activity and subsequent mesenchymal differentiation of embryonic stem cell (ESC) aggregates with incorporated gelatin methacrylate (GMA) MPs with either low (20%) or high (90%) cross-linking densities, corresponding to faster or slower degradation rate, respectively. GMA MP incorporation increased total MMP and MMP-2 levels within 3D ESC aggregates in a substrate-dependent manner. GMA MP-incorporated aggregates also expressed higher levels of epithelial-to-mesenchymal transition markers and displayed enhanced mesenchymal morphogenesis than aggregates without MPs, and the MP-mediated effects were completely abrogated with MMP inhibitor treatment. This work predicts that control of proteolytic responses via introducing ECM-based MPs may offer a novel avenue to engineer the ECM microenvironment to modulate stem cell differentiation.

published_or_final_version / Medicine / Master / Master of Philosophy

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This study elucidates the temporal expression and regulation of transglutaminase (TGase) and ornithine decarboxylase (ODCase) during cell proliferation and differentiation. In synchronized CHO cells, there were two peaks of TGase activity expressed in G₁ and a smaller peak of activity in mid S phase. ODCase exhibited a single peak of expression in mid G₁ which was inhibited by the administration of both cycloheximide and actinomycin D. In contrast, the increase in TGase activity was not inhibited at any time measured by administration of either cycloheximide or actinomycin D to these cells. TGase activity in CHO cells was not affected by the addition of analogs of cyclic AMP, whereas ODCase activity was increased at all times measured. Retinol administration increased TGase activity 1 hr after release in CHO cells and the activity remained elevated for 4 hr. Retinol administration resulted in the inhibition of ODCase expression in these cells. The administration of α-melanocyte-stimulating hormone (MSH) to mouse melanoma cells resulted in a biphasic increase of TGase activity and a single peak of ODCase activity within 7 hr. In melanoma cells, addition of cycloheximide abolished the first peak of TGase activity but not the second peak. Actinomycin D did not inhibit either peak of TGase expression. The administration of both cycloheximide and actinomycin D inhibited ODCase activity after MSH stimulation. Analogs of cyclic AMP, when added to log phase mouse melanoma cells, increased ODCase but not TGase activity at all points measured. In these cells, retinoic acid plus MSH markedly enhanced the activity of the initial TGase peak compared to MSH alone. ODCase expression was attenuated with retinoic acid plus MSH. Dexamethasone (DEX) induced the first peak of TGase activity but not the second peak seen with MSH administration alone. Administration of DEX resulted in a peak expression of ODCase activity approximately 30% of that seen with MSH alone. In general, chelation of extracellular calcium with EGTA totally blocked ODCase expression with MSH, retinoic acid or DEX. Partial or total ablation of TGase expression was seen with addition of MSH or retinoic acid, but very little inhibition of this enzyme was evident when EGTA was added with DEX or DEX plus MSH. Addition of calcium after all CA⁺⁺-blocks restored the expression of both enzymes.