Efficient and Accurate Characterization of the Bergman Cyclization for an Expanded Substructure of Esperamicin A1

Incorporation of enediynes into anticancer drugs remains an intriguing yet elusive strategy for the design of therapeutically active agents. Density functional theory was used to locate reactants, products, and transition states along the Bergman cyclization pathways connecting enediynes to reactive para-biradicals. Sum method correction to low-level calculations confirmed B3LYP/6-31G(d,p) as the method of choice in investigating enediynes. Herein described as MI:Sum, calculated reaction enthalpies differed from experiment by an average of 2.1 kcal·mol−1 (mean unsigned error). A combination of strain energy released across the reaction coordinate and the critical intramolecular distance between reacting diynes explains reactivity differences. Where experimental and calculated barrier heights are in disagreement, higher level multireference treatment of the enediynes confirms lower level estimates. Previous work concerning the chemically reactive fragment of esperamcin, MTC, is expanded to our model system MTC2.

The Relationship of Antipsychotic Drug Use, Resident Behavior, and Diagnoses Among Nursing Home Residents

Nursing homes have been criticized for frequent use and possible misuse of psycho-active agents. These issues are of clinical concern and policy relevance, especially since the passage of the Omnibus Budget Reconciliation Act (OBRA) of 1987. Using a sample of 419 residents, the authors examined the relationships among antipsychotic drug (AP) use, behavior, and mental health diagnoses. Only 23.2% of the residents were administered APs on a routine and/or "as-needed" basis. Based on the Multidimensional Observation Scale for Elderly Subjects (MOSES) ratings, AP users were more irritable, disoriented, and withdrawn than were nonusers. Also, AP users demonstrated agitated behaviors more frequently. Notably, AP users and nonusers differed significantly in terms of documented mental health diagnoses. Among AP users, 70.1% had documented dementia, 8.3% were psychotic or had other psychiatric disorders, and 21.6% had no mental health diagnoses. In contrast, the majority of nonusers had no mental health disorders. Logistic regression revealed that diagnostic factors, frequency of agitation, level of withdrawal, and marital status were significant predictors of AP use.

Active processes, morphology, and dynamics of icy debris fans: Landform evolution along rapidly degrading escarpments in alpine regions undergoing recent deglaciation

In the past few decades the impacts of climate warming have been significant in alpine glaciated regions. Many valley glaciers formerly linked as distributary glaciers to high-level icecaps have decoupled at their icefalls, exposing major escarpments and generating a suite of dynamic landforrns dominated by mass wasting. Ice-dominated landforms, here termed icy debris fans, develop rapidly by ice avalanching, rockfall, and icy debris flow. Field-based reconnaissance studies at two alpine settings, the Wrangell Mountains of Alaska and the Southern Alps of New Zealand, provide a preliminary morphogenetic model of spatial and temporal evolution of icy debris fans in a range of alpine settings. The influence of these processes on landform evolution is largely unrecognized in the literature dealing with post-glacial landform adjustment known as the paraglacial. A better understanding of these dynamic processes will be increasingly important because of the extreme geohazards characterizing these areas. Our field studies show that after glacier decoupling, icy debris fans begin to form along the base of bedrock escarpments at the mouths of catchments and prograde over valley glaciers. The presence of a distinct catchment, apex, and fan morphology distinguishes these landforms from other landforms common in periglacial hillslope settings receiving abundant clastic debris and ice. Ice avalanching is the most abundant process involved in icy debris fan formation. Fans developed below weakly incised catchments are dominated by ice avalanching and are composed primarily of ice with minor lithic detritus. Typically, avalanches fall into the fan catchments where sediments transform into grainflows that flow onto the fans. Once on the fans, avalanche deposits ablate rapidly, flattening and concentrating lithic fragments at the surface. Icy debris fans may become thick enough to become glaciers with splay crevasse systems. Fans developed below larger, more complex catchments are composed of higher proportions of lithic detritus resulting from temporary storage of ice and lithic detritus deposits within the catchment. Episodic outbursts of meltwater from the icecap may mix with the stored sediments and mobilize icy debris flows (mixture of ice and lithic clasts) onto the fans. Our observations indicate that the entire evolutionary cycle of icy debris fans probably occurs during an early paraglacial interval (i.e., decades to 100 years). Observations comparing avalanche frequency, volume, and fan morphologic evolution at the Alaska site between 2006 and 2010 illustrate complex response between icy debris fans even within the same cirque - where one fan may be growing while others are downwasting because of differences in ice supply controlled by their respective catchments and icecap contributions. As ice supply from the icecap diminishes through time, icy debris fans rapidly downwaste and eventually evolve into talus cones that receive occasional but ephemeral ice avalanches.

Probing The Active And Allosteric Binding Sites Of Soybean Lipoxygenase-1

Soybean lipoxygenase-1 is a model for lipoxygenase activity. While the mechanism of oxygenation is understood, the substrate binding mechanism has not yet been elucidated. Two putative binding mechanisms are the ¿head-first¿ and ¿tail-first¿ models, in which the carboxy-terminus or the methyl terminus of the fatty acid substrate is inserted into the active site while the remainder of the molecule protrudes from the surface, respectively. Previous work has demonstrated that derivatization of fatty acid substrates with D-tryptophan increases active site affinity. It has also been shown that while polyunsaturated fatty acids are the natural substrates of lipoxygenases, monounsaturated fatty acids can be oxygenated at a much slower rate. Starting with a monounsaturated fatty acid, oleic acid, as a platform, the molecule N-oleoyl-D-tryptophan (ODT) was synthesized with the anticipation of it being a potent competitive substrate-analogue inhibitor that could be used to discern the substrate binding mechanism. Inhibition kinetics demonstrated that this molecule functions as a partially competitive inhibitor, through an unknown mechanism. The implication behind partially competitive inhibition is that substrate and inhibitor molecules can bind simultaneously to the enzyme, which alludes to the presence of an allosteric binding domain. To investigate the possibility of an inhibitor binding site on the non-catalytic subunit, limited proteolysis was used to cleave the subunits apart which should have eliminated inhibition. Interestingly, it was observed that at high substrate concentrations the inhibitor was completely ineffective, but at low substrate concentrations the inhibitor maintained its standard efficacy. A satisfactory explanation for these results has not yet been determined.

Continuous Formation and Separation of Calcium-Alginate Capsules Containing Viable Mammalian Cells in Microfluidic Devices

Microfluidic devices can be used for many applications, including the formation of well-controlled emulsions. In this study, the capability to continuously create monodisperse droplets in a microfluidic device was used to form calcium-alginate capsules.Calcium-alginate capsules have many potential uses, such as immunoisolation of cells and microencapsulation of active drug ingredients or bitter agents in food or beverage products. The gelation of calcium-alginate capsules is achieved by crosslinking sodiumalginate with calcium ions. Calcium ions dissociated from calcium carbonate due to diffusion of acetic acid from a sunflower oil phase into an aqueous droplet containing sodium-alginate and calcium carbonate. After gelation, the capsules were separated from the continuous oil phase into an aqueous solution for use in biological applications. Typically, capsules are separated bycentrifugation, which can damage both the capsules and the encapsulated material. A passive method achieves separation without exposing the encapsulated material or the capsules to large mechanical forces, thereby preventing damage. To achieve passiveseparation, the use of a microfluidic device with opposing channel wa hydrophobicity was used to stabilize co-laminar flow of im of hydrophobicity is accomplished by defining one length of the channel with a hydrogel. The chosen hydrogel was poly (ethylene glycol) diacrylate, which adheres to the glass surface through the use of self-assembled monolayer of 3-(trichlorosilyl)-propyl methacrylate. Due to the difference in surface energy within the channel, the aqueous stream is stabilized near a hydrogel and the oil stream is stabilized near the thiolene based optical adhesive defining the opposing length of the channel. Passive separation with co-laminar flow has shown success in continuously separating calcium-alginatecapsules from an oil phase into an aqueous phase. In addition to successful formation and separation of calcium alginate capsules,encapsulation of Latex micro-beads and viable mammalian cells has been achieved. The viability of encapsulated mammalian cells was determined using a live/dead stain. The co-laminar flow device has also been demonstrated as a means of separating liquid-liquidemulsions.

Synthesis and Surface Modification of CdSe and CdS Quantum Dots Exhibiting High Quantum Yield

The thesis investigates the effect of surface treatment with various reducing and oxidizing agents on the quantum yield (QY) of CdSe and CdS quantum dots (QDs). The QDs, as synthesized by the organometallic method, contained defect sites on their surface that trapped photons and prevented their radiative recombination, therefore resulting in adecreased QY. To passivate these defect sites and enhance the QY, the QDs were treated with various reducing and oxidizing agents, including: sodium borohydride (NaBH4), calcium hydride (CaH2), hydrazine (N2H4), benzoyl peroxide (C14H10O4), and tert-butylhydroperoxide (C4H10O2). It was hypothesized that the reducing/oxidizing agents reduced the ligands on the QD surface, causing them to detach, thereby allowing oxygen from atmospheric air to bind to the exposed cadmium. This cadmium oxdide (CdO) layeraround the QD surface satisfied the defect sites and resulted in an increased QY. To correlate what effect the reducing and oxidizing agents were having on the optical properties of the QDs, we investigated these treatments on the following factors:chalcogenide (Se vs. S), ligand (oleylamine vs. OA), coordinating solvent (ODE vs.TOA), and dispersant solvent (chloroform vs. toluene) on the overall optical properties of the QDs. The QY of each sample was calculated before and after the various surface treatments from ultra-violet visible spectroscopy (UV-Vis) and fluorescence spectroscopy data to determine if the treatment was successful.From our results, we found that sodium borohydride was the most effective surface treatment, with 10 of the 12 treatments resulting in an increased QY. Hydrazine, on the other hand, was the least effective treatments, as it quenched the QD fluorescence in every case. From these observations, we hypothesize that the effectiveness of the QD surface treatments was dependent on reaction rate. More specifically, when the surface treatment reaction happened too quickly, we hypothesize that the QDs began to aggregate, resulting in a quenched fluorescence. Furthermore, we believe that the reactionrate is dependent on concentration of the reducing/oxidizing agents, solubility of the agents in each solvent, and reactivity of the agents with water. The quantum yield of the QDs can therefore be maximized by slowing the reaction rate of each surface treatment toa rate that allows for the proper passivation of defect sites.