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The secant method is applied to an iterative algorithm of electromagnetic scattering from planar surfaces with periodic structure. The theory of convergent solutions for iterative techniques is discussed and examined. The Secant method is applied to the spectral iteration approach to accelerate and assure convergence of the basic iterative scheme. The derivation of the method as applied to surfaces containing parallel thin wire gratings is presented, and the conditions for achieving convergence are explored. This new method is also applied to gratings made of coated wires. The reflection characteristics of the grating as a function of wire spacing, wire conductivity, and polarization of the incident field are computed, and the results are compared with those of previous works. Suggestions and recommendations for applying the method to more complicated structures are also included.

Cyclic-3',5 '-adenosine monophosphate (cAMP) is an ancient signaling molecule that is found in a variety of species from prokaryotes to eukaryotes and translates extra-cellular stimuli into tightly controlled intra-cellular responses. The two major mammalian cAMP sensors are protein kinase A (PKA), for the phosphorylation of the downstream effectors, and the exchange protein directly activated by cAMP (Epac ), for the guanine nucleotide exchange in the small GTPase Rap proteins. In this study, we investigated the intra-molecular cAMP dependent allosteric network of Epac cyclic nucleotide binding domain (CBD) via solution NMR spectroscopy. Epac proteins have been shown to employ an auto-inhibition strategy in the control of the equilibrium between the active and the inactive states. In the absence of cAMP, the periphery of the Rap recognition site is masked via an ionic interface provided by the N-terminus of the CBD. Binding of cAMP at the distal Phosphate Binding Cassette (PBC), results in weakening of this interface. Here we show that the cAMP binding signal is propagated to the sites important in Epac activation, i.e. the ionic interface, via two key allosteric spots within the CBD. We have also determined the dynamics as a key carrier of cAMP effects to the region forming the ionic interface (ionic latch). Hence entropic enhancements emerged as a key effector in the cAMP mediated ionic latch weakening. We have also provided initial evidence of a negative allosteric contribution from the C-terminal Hinge-Lid region (CHLR) on the cAMP induced Epac activation. In addition to these findings, we also observed critical differences in the mode of cAMP recognition and inter-subdomain communication between the Epac and PKA. A detailed understanding of these two ubiquitous systems, will aid in the development of agonists and antagonists that are relevant in the drug lead development for related diseases, such as Alzheimer's and diabetes. / Thesis / Master of Science (MSc)

Yes / We combine single molecule force spectroscopy measurements with all-atom metadynamics simulations to investigate the cross-materials binding strength trends of DNA fragments adsorbed at the aqueous graphite C(0001) and Au(111) interfaces. Our simulations predict this adsorption at the level of the nucleobase, nucleoside, and nucleotide. We find that despite challenges in making clear, careful connections between the experimental and simulation data, reasonable consistency between the binding trends between the two approaches and two substrates was evident. On C(0001), our simulations predict a binding trend of dG > dA ≈ dT > dC, which broadly aligns with the experimental trend. On Au(111), the simulation-based binding strength trends reveal stronger adsorption for the purines relative to the pyrimadines, with dG ≈ dA > dT ≈ dC. Moreover, our simulations provide structural insights into the origins of the similarities and differences in adsorption of the nucleic acid fragments at the two interfaces. In particular, our simulation data offer an explanation for the differences observed in the relative binding trend between adenosine and guanine on the two substrates.

Current dogma suggests modulating or preventing amyloid assembly will prove critical to the armamentarium of therapeutic interventions that will likely be required to overcome the multifaceted pathology associated with amyloid diseases. The work described in this dissertation reveals substantial gains in understanding key aspects relating to the anti-amylin amyloid activities associated with both individual and broad groups of small molecule amyloid inhibitors. A main observation was the important role that the catechol functional group plays in modulating and preventing amyloid formation. In this context, each chapter provides unique yet complementary mechanistic insight that delineates a wide range of anti-amyloid activities associated with preventing amylin amyloid formation by mainly catechol-containing structural scaffolds. Structure activity studies show that the catechol moiety present within baicalein, oleuropein and rosmarinic acid are critical for their anti-amyloid functions, including exerting cell rescue effects against amylin induced cytotoxicity. We also demonstrate that in general, autoxidation enhances the anti-amyloid potency associated with many catechol containing amyloid inhibitors that may be mechanistically linked to a covalent mode of action. For example, we demonstrate that the O-quinone form of baicalein conjugates with amylin via a Schiff base mechanism. In contrast, we also show that catechol mediated formation of protein denaturant resistant aggregates, which requires autoxidation and that also stems from a predicted covalent mode of action, does not necessarily correlate with the enhanced anti-amyloid activities that occur upon catechol autoxidation. Regardless of the chemical mechanism(s) that drive catechol mediated anti-amyloid activity in vitro, the observed cell rescue effects exhibited by catechol containing molecules against amylin amyloid induced cytotoxicity is congruent with several recent in vivo studies that indicate polyphenols prevent toxic amyloid deposition as well as decades of population based studies that show regular consumption of diets rich in polyphenols are linked to a reduce incidence of age-related neurodegenerative amyloid disease. Indeed, advances in structure based drug discovery against amyloid formation may provide new avenues to optimize various catechol containing scaffolds that could be readily leveraged into improving diagnostic tools or perhaps accelerate the effort of discovering anti-amyloid therapeutics. / Ph. D. / From causing dementia in diseases like Alzheimer’s disease (AD) to potentiating type 2 diabetes (T2D), amyloid diseases represent some of the most devastating and increasingly more common human diseases. Amyloids themselves mainly consist of an aggregated mass of a specific type of protein that is believed to be either directly or indirectly toxic. Currently, there are no known cures for preventing amyloid diseases, and so far, efforts to discover anti-amyloid therapeutics have been largely unsuccessful. Many studies indicate regular consumption of plant-based diets, like the Mediterranean diet, that includes foods such as olives, vegetables and red wine leads to reduced incidence of age related amyloid diseases. Guided by these data, scientists have begun to uncover specific molecules within these diets that are able to prevent amyloid formation. A main emphasis in this dissertation was to understand the details of how these molecules prevent toxic amyloid formation. The insights gained from these studies have elucidated key chemical structural features present within these molecules that convey unique effects on perturbing amyloid formation. Excitingly, we also found that the presence of oxygen within the air we breathe, interacts with and enhances the ability of these compounds to exhibit stronger anti-amyloid functions! These data can be used to engineer better amyloid inhibitors that could lead to drugs.

A new family of molecule-based magnets related to the V[PTCE]x · yCH2Cl2 magnet (PTCE = phenyltricyanoethylene, x = ~2, y = ~0.2) was synthesized utilizing new reversible one-electron acceptors with the general form MexPTCE (PTCE = phenyltricyanoethylene, x is the number of methyl groups on the phenyl ring, Me = -CH3). These new acceptors were synthesized for the purpose of studying electronic and steric effects of the substitution of the phenyl ring with electron donating groups on the overall magnetic properties of the solid, specifically to contrast their behavior with materials that contain similar trifluoromethyl (-CF3) substituted acceptors. These electron-poor olefins react with V(CO)6 in dichloromethane (CH2Cl2) under N2 to yield air-sensitive, amorphous magnetic coordination polymers that exhibit ordering temperatures ranging from 160 K to 250 K and display anhysteretic behavior at all temperatures. The magnets synthesized in this project were all characterized and studied using magnetic measurements, infrared spectroscopy, and elemental analysis. The neutral acceptors used were characterized using NMR spectroscopy, infrared spectroscopy, mass spectrometry, cyclic voltammetry, and modeled using density functional theory (DFT) calculations. / Master of Science

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