Tissue transglutaminase (TG2) is a calcium-dependent enzyme that natively catalyses the formation of isopeptidic bonds between protein- or peptide-bound glutamine and lysine residues. Physiologically, it is ubiquitously expressed in tissues, with roles in cellular differentiation, extracellular matrix stabilisation, and apoptosis, among others. However, its unregulated activity has been associated with various pathologies including fibrosis, cancer and celiac disease. Since most pathologies are associated with an increased transamidation activity, efforts have been directed towards the development of TG2 inhibitors. In this context, the work described in this thesis is centred on reversible inhibitors, building on recent work done within the Keillor group in two directions, namely localisation and potency. In a localisation-driven approach, we developed a photolabile derivative of a known reversible inhibitor, in order to form a covalent bond with the enzyme and determine the inhibitor’s binding site. In tandem, we optimised a protocol for the expression of TG2 incorporating ArgΔ10 and LysΔ8, amino acids that are 13C- and 15N-labelled to provide a mass shift of 10 and 8 Da, respectively, compared to the corresponding unlabelled amino acids. This “heavy” TG2 was developed as a tool for reference in the analysis of the tryptic digest of labelled protein. In a potency-driven approach, based on the observation that previous trans cinnamoyl inhibitor scaffolds were susceptible to nucleophilic attack by glutathione, we developed a bis(triazole) scaffold with reduced electrophilicity. The preparation of a small library of compounds showed that this scaffold demonstrates a preference for electron-withdrawing substituents, such as nitro groups. Continuing in a potency-driven approach, and inspired by work done in the identification of glutathione-resistant scaffolds, we studied a new alkynyl scaffold. While still susceptible to glutathione addition, these compounds showed a marked improvement in potency, with the lead compound having an IC50 of 930 nM and being established as a competitive inhibitor with a Ki of 420 nM, our most potent reversible inhibitor to date. Furthermore, this scaffold also produced an inhibitor lacking nitro groups (to limit eventual cellular toxicity), but maintaining good potency, with an IC50 value of 3.03 μM.

abstract: In the first chapter, I study the two-sided, dynamic matching problem that occurs in the United States (US) foster care system. In this market, foster parents and foster children can form reversible foster matches, which may disrupt, continue in a reversible state, or transition into permanency via adoption. I first present an empirical analysis that yields four new stylized facts related to match transitions of children in foster care and their exit through adoption. Thereafter, I develop a two-sided dynamic matching model with five key features: (a) children are heterogeneous (with and without a disability), (b) children must be foster matched before being adopted, (c) children search for parents while foster matched to another parent, (d) parents receive a smaller per-period payoff when adopting than fostering (capturing the presence of a financial penalty on adoption), and (e) matches differ in their quality. I use the model to derive conditions for the stylized facts to arise in equilibrium and carry out predictions regarding match quality. The main insight is that the intrinsic disadvantage (being less preferred by foster parents) faced by children with a disability exacerbates due to the penalty. Moreover, I show that foster parents in high-quality matches (relative to foster parents in low-quality matches) might have fewer incentives to adopt. In the second chapter, I study the Minnesota's 2015 Northstar Care Program which eliminated the adoption penalty (i.e., the decrease in fostering-based financial transfers associated with adoption) for children aged six and older, while maintaining it for children under age six. Using a differences-in-differences estimation strategy that controls for a rich set of covariates, I find that parents were responsive to the change in direct financial payments; the annual adoption rate of older foster children (aged six to eleven) increased by approximately 8 percentage points (24% at the mean) as a result of the program. I additionally find evidence of strategic adoption behavior as the adoption rate of younger children temporarily increased by 9 percentage points (23% at the mean) while the adoption rate of the oldest children (aged fifteen) temporarily decreased by 9 percentage points (65% at the mean) in the year prior to the program's implementation. / Dissertation/Thesis / Doctoral Dissertation Economics 2019

Posterior reversible encephalopathy syndrome (PRES) is associated with seizures, visual disturbances, headache, and altered mental status. Given its presentation, the diagnosis can be mistaken for other severe conditions. Palliative medicine consultants should be aware of PRES and be prepared to counsel families on the treatment and prognosis of this syndrome.

Posterior reversible encephalopathy syndrome (PRES) is a clinical-radiographic syndrome that presents with neurological manifestations, including seizures, headache, or confusion, and is associated with posterior cerebral white matter edema on imaging. PRES is typically a benign and reversible condition. However, PRES can be fatal or associated with permanent deficits. Numerous conditions are associated with PRES, including hypertensive encephalopathy, renal diseases, and cytotoxic or immunosuppressant drugs. Recently, many case reports described the association between PRES and chemotherapeutic agents. However, trastuzumab-associated PRES is rarely reported. Herein, we report a case of a 51-year-old female with a history of metastatic gastric cancer who developed seizures while being treated with trastuzumab, and neuroimaging confirmed the diagnosis of PRES.

In this thesis, we apply a recently developed technique to comprehensively categorize all possible families of solitary wave solutions in two models of topical interest. The models considered are: a) the Generalized Pochhammer-Chree Equations, which govern the propagation of longitudinal waves in elastic rods, and b) a generalized microstructure PDE. Limited analytic results exist for the occurrence of one family of solitary wave solutions for each of these equations. Since, as mentioned above, solitary wave solutions often play a central role in the long-time evolution of an initial disturbance, we consider such solutions of both models here (via the normal form approach) within the framework of reversible systems theory. Besides confirming the existence of the known family of solitary waves for each model, we find a continuum of delocalized solitary waves (or homoclinics to small-amplitude periodic orbits). On isolated curves in the relevant parameter region, the delocalized waves reduce to genuine embedded solitons. For the microstructure equation, the new family of solutions occur in regions of parameter space distinct from the known solitary wave solutions and are thus entirely new. Directions for future work, including the dynamics of each family of solitary waves using exponential asymptotics techniques, are also mentioned.

No description available.

We are entering an exciting era, rich in the availability of data via sources such as the Internet, satellites, particle colliders, telecommunication networks, computer simulations, and the like. The confluence of increasing computational resources, volumes of data, and variety of statistical procedures has brought us to a modern enlightenment. Within the next century, these tools will combine to reveal unforeseeable insights into the social and natural sciences. Perhaps the largest headwind we now face is our collectively slow-moving imagination. Like a car on an open road, learning is limited by its own rate. Historically, slow information dissemination and the unavailability of experimental resources limited our learning. To that point, any methodological contribution that helps in the conversion of data into knowledge will accelerate us along this open road. Furthermore, if that contribution is accessible to others, the speedup in knowledge discovery scales exponentially. Markov chain Monte Carlo (MCMC) is a broad class of powerful algorithms, typically used for Bayesian inference. Despite their variety and versatility, these algorithms rarely become mainstream workhorses because they can be difficult to implement. The humble goal of this work is to bring to the table a few more highly versatile and robust, yet easily-tuned algorithms. Specifically, we introduce weighted particle tempering, a parallelizable MCMC procedure that is adaptable to large computational resources. We also explore and develop a highly practical implementation of reversible jump, the most generalized form of MetropolisHastings. Finally, we combine these two algorithms into reversible jump weighted particle tempering, and apply it on a model and dataset that was partially collected by the author and his collaborators, halfway around the world. It is our hope that by introducing, developing, and exhibiting these algorithms, we can make a reasonable contribution to the ever-growing body of MCMC research. / Ph. D.

The first chapter of this dissertation reports the synthesis of highly fluorinated Diels-Alder polyphenylenes. The first section of this chapter describes the three-pot synthesis of a perfluoroarylated bis(cyclopentadienone) monomer. The synthesis begins with the previously reported substitution reaction of decafluorobiphenyl and sodium cyclopentadienide. To the resulting 4,4'-octafluorobiphenylene-linked bis(cyclopentadiene), six perfluoro-4-tolyl groups (three on each of the two cyclopentadienyl moieties) are attached by nucleophilic aromatic substitution (SNAr) reactions. The remaining ring methylenes are subjected to a selenium dioxide-catalyzed oxidation to obtain the desired bis(cyclopentadienone) monomer. The next part of this chapter describes the polymerization of the perfluoroarylated bis-(cyclopentadienone) monomer and bis(4-ethynylphenyl) ether. The reaction affords an oligomer (Mn ~ 14,000 g/mol according to size-exclusion chromatographic analysis) that is soluble in several solvents and that decomposes above about 300°C according to thermogravimetric analysis. The second chapter of this dissertation describes a novel method to oxidize per-fluoroarylated cyclopentadiene compounds to the corresponding ketones using catalytic selenium dioxide and stoichiometric hydrogen peroxide. The first part of this chapter shows the synthesis of some perfluoroarylated cyclopentadiene substrates, while the second part of the chapter explores the oxidation of these compounds along with other perfluoroarylated cyclopentadienes already available within our research group. This chapter also explains how the reactivity of the perfluoroarylated cyclopentadienes under the oxidation conditions depends on their structure. Generally more electron-deficient cyclopentadienes react more readily, while sterically crowded cyclopentadienes react more reluctantly. This third chapter of this dissertation describes the synthesis and characterization of a reversible Diels-Alder polymer from an octafluorobiphenylene-linked bis(cyclopentadiene). In the first section, the synthesis of a reversible homopolymer of the bis(cyclopentadiene) monomer is described. The polymer reaches an optimized molecular weight of 11,000 g/mol (degree of polymerization is 20) under the reaction conditions because there is an equilibrium between polymerization and depolymerization even at the mild polymerization temperature (65°C). The TGA trace of the polymer shows that chain degradation takes place beyond 300°C. The thermal reversibility of the polymer was examined by bulk thermolysis, and flash-vacuum thermolysis. The second section describes the synthesis of a methylated bis(cyclopentadiene) that does not undergo self-polymerization at comparatively lower temperature but instead reacts with a second bis(maleimide) monomer. The resulting polymer typically shows a number-average molecular weight of 15,400 g/mol. This polymerization also is limited by the attainment of steady-state end group concentrations. The reversibility of the polymerization is demonstrated by solution thermolysis experiments in which unmasked cyclopentadiene groups are trapped by a monofunctional maleimide. / Ph. D.

For the first time, triblock copolymers of novel styrenic-based macromolecules were investigated in detail and examined for structure-morphology-performance relationships. We were able to design novel imidazolium- and phosphonium-containing styrenic macromolecules using controlled radical polymerization and conventional free radical polymerization strategies, for a variety of potential applications including electromechanical devices, ionic liquids, adhesives, and lithium-ion batteries. Block copolymers have a unique architecture providing physical crosslinking to behave as thermoplastic elastomers. We preferred ABA triblock copolymers as compared to random and diblock copolymers for improved mechanical performance. ABA triblock copolymers synthesized using nitroxide-mediated polymerization (NMP) of polystyrene external blocks and a charged imidazolium-containing central block, exhibited sufficient modulus and ionic conductivity for electromechanical transducers. We successfully reported the actuation behavior of triblock copolymers in the presence of added ionic liquid for the first time. We proposed that diluting the ion concentration of the ion-rich phase with neutral polymer comonomers that reduces Tg, increases ion dissociation, and potentially maximizes ionic conductivity. Tendency of ethylene-oxide units to coordinate cations, forming stable crown ether-like, multi-nuclear coordination complexes, promotes solvation and dissociation of ionic aggregates. In situ Fourier transform infrared spectroscopy (FTIR) was used to monitor the thermal polymerization in various acrylate and methacrylate monomers. It was found that acrylates have lower activation energy than methacrylates. The copolymerizations of poly(ethylene glycol)methyl ether acrylate (EG9MEA) and imidazole-containing monomer (VBIm) resulted in controlled polymerization kinetics with narrow molecular weight distributions. The control behavior of the copolymerizations is likely attributed to the observed decrease in calculated apparent rate constants for the copolymerizations with addition of VBIm as comonomer. Reversible addition fragmentation transfer (RAFT) successfully synthesized well-defined A-BC-A triblock copolymers containing a synergy of pendant ether and imidazolium sites. We demonstrated that electromechanical transducers derived from these triblock copolymer membranes with added ionic liquid showed superior actuation performance compared to a benchmark Nafion® membrane, suggesting potential for ionic polymer device applications. This was attributed to optimum modulus, improved ionic conductivity, and microphase-separated morphology of triblock copolymers. Conventional free radical polymerization and anion metathesis of 4-(diphenylphosphino)styrene (DPPS) successfully generated high molecular weight triaryl phosphine-containing copolymers. These macromolecules have no -CH2 group at the benzylic position increasing the thermal stability of the DPPS-containing polymers. Counterion exchange to fluorinated, bulkier anions broadened the library of polyelectrolytes, led to improved thermal stabilities, lower glass transition temperatures, and tunable wetting behavior. We also reported the synthesis of salt-responsive copolymers using conventional free radical polymerization. Adhesive performance measurements such as peel tests and probe tack enforced the application of these polymers as pressure sensitive adhesives. We also demonstrated the synthesis and subsequent neutralization of novel, well-defined A-BC-A triblock copolymers containing a soft central 'BC' block consisting of Sty-Tf2N and DEGMEMA with polystyrene external blocks. Sty-Tf2N monomer enables an important delocalization of the negative charge. Li+ has weak interactions with this anionic structure, consequently enabling a high dissociation level. Li+ ions are associated to the polymer chain to produce high transport numbers. Furthermore, incorporating DEGMEMA lowers the Tg of the charged block copolymers, thereby increasing the segmental mobility and thus ionic conductivity. Finally, the structure-property-morphology study of these triblock copolymers will be helpful for their use in potential applications such as ion-containing membranes, lithium-ion batteries. / Ph. D.

This dissertation describes a new platform for the synthesis of thermally reversible polymers, based on Diels-Alder reactions of bis-cyclopentadienes (bis-CPDs) and bis-maleimides (bis-MIs), that meets two main objectives. First, the bis-CPD must resist characteristic self-coupling. Second, the CPD-MI adducts should undergo the retro-Diels-Alder (rDA) reaction (i.e., thermal depolymerization) in a temperature regime that is comparable or slightly higher than that of the freely reversible bis-furan/bis-MI polymers (rDA between 80 °C and 130 °C) but much lower than that of bis-CPD homopolymers (rDA above 160 °C). Structure-reactivity relationships gleaned from the literature and from related but as yet unpublished work in our own laboratories led to our main hypothesis that a CPD moiety bearing one sterically encumbering substituent such as isopropyl (𝑖Pr) or tert-butyl (𝑡Bu) and one electronwithdrawing substituent such as perfluoroaryl would have the desired reactivity and adduct stability in combination with an 𝑁-substituted maleimide. Synthetic considerations led to a bisCPD monomer design in which two alkylcyclopentadiene groups (alkyl = 𝑖Pr or 𝑡Bu) are connected by an octafluorobiphenylene linker. As an initial fundamental step (Chapter 3), 1-(nonafluorobiphenyl-4’-yl)-4-tertbutylcyclopentadiene (1) was synthesized to provide a monofunctional model for the proposed difunctional CPD monomer. Reactions of 1 and 𝑁-(4-fluorophenyl)maleimide (FMI) afforded up to five regio- and stereo-isomeric adducts (of fourteen possible). Variable-temperature reactivity studies combined with NMR spectroscopic analysis, X-ray crystallography, and computational modeling enabled product distributions to be understood according to a conventional kinetic-vs- iii thermodynamic framework. These studies also predicted the microstructure of polymers derived from the proposed bis-CPD monomer, which is structurally analogous to 1, and bis-MIs. Moreover, 1 does not undergo DA self-coupling under ordinary conditions (T < 180 °C). Thermolysis studies of the major adducts revealed that the rDA becomes observable on a laboratory timescale (hours) at about 140 °C, which is at the upper end of the temperature range reported for furan+MI adducts but well below that of CPD+CPD adducts. In contrast, adducts formed from either of the analogous monosubstituted cyclopentadienes (𝑡BuC₅H₅ and C₆F₅C₅H₅) do not undergo rDA below 180 °C. These results strongly support the proposed bis-CPD monomer design. In a second fundamental step (Chapter 4), the hypothesis that an electron-withdrawing CPD substituent would destabilize a CPD-MI adduct was further tested by reacting 𝑁-(4- fluorophenyl)maleimide with a series of triarylated cyclopentadienes (1,2,3-Ar₃C₅H₃ and 1,2,4- Ar₃C₅H₃, Ar = C₆F₅, C₆F₄CF₃, and Ar = C₅F₄N). The perfluorophenyl- and perfluorotolylsubstituted compounds were previously reported, but the perfluoropyridyl-substituted cyclopentadienes were prepared for this study using SNAr reactions of pentafluoropyridine and sodium cyclopentadienide. The least electron deficient cyclopentadiene in each series (Ar = C₆F₅) reacted the most quickly and with the highest ultimate equilibrium binding constant, confirming the electron-effects hypothesis as well as the underlying presumption that DA reactions of even relatively electron-poor CPDs with MI would behave according to normal-electron-demand principles. In the main section of this dissertation (Chapter 5) the proposed bis(cyclopentadiene)s reacted with a series of previously reported bis(maleimides) to form linear polymers having molecular weights (Mn) up to 40 kDa. Relationships among the length and flexibility of the bis-MI linker (C₆H₁₂, C₁₂H₂₄, C₆H₄OC₆H₄, and (C₂H₄O)₂), the identity of the CPD alkyl substitutent (CHMe₂, CMe₃ and CMe₂Ph) and the glass transition temperature (Tg) as measured by differential scanning calorimetry (DSC) were understood in terms of a general model of local segmental mobility and free volume. Solution thermolysis of a model polymer system (bis-MI linker = C₆H₁₂ (7), CPD alkyl substituent = 𝑡Bu) showed a rapid decrease in molecular weight at 160 °C as determined by size exclusion chromatography (SEC). Solution thermolysis in the presence of excess FMI (as a trap for free CPD moieties) revealed that the onset temperature for rDA on a laboratory time scale (hours) was as low as 120 °C. In the bulk, thermolysis above 250 °C under vacuum led to recovery of a small portion of the bis-CPD monomer, but bulk thermolysis at 200 °C did not reveal a change in molecular weight as determined by SEC. The current interpretation of these observations is that limited mobility in these glassy polymers prohibits retro-DA decoupling. These findings largely validate the main hypothesis of this dissertation. / Ph. D.