Protein therapeutics are available as cytokines, clotting factors, enzymes, hormones, growth factors, antibodies et al. They have been shown to be effective in treating a variety of important human diseases. Since human insulin was approved as the first recombinant protein therapeutic, this field has experienced rapid growth. One of the biggest challenges for protein therapeutics in clinical application is their short half-life. Except for monoclonal antibodies, which have serum half-life for weeks, most of the protein therapeutics have half-lives ranging from minutes to hours. Kidney filtration, proteasome degradation and liver metabolism are the main factors that attribute to their short half-lives. The short half-life of protein therapeutics requires a higher dose or frequent application to maintain therapeutic concentration over a certain period. However, higher dose is easy to cause large plasma concentration fluctuation, which is easy to cause side effects. Most of protein therapeutics are not orally bioavailable. Frequent application will increase the burden of patients, affect their life quality, and reduce patient compliance. Thus, it is important to generate long-lasting therapeutics with improved pharmacokinetic properties. The current half-life extension approaches for protein therapeutics include PEGylation, albumin fusion or binding and fusion to an immunoglobulin Fc region. Their primary aim is to increase the size of biotherapeutics or to implement recycling by the neonatal Fc receptor (FcRn). However, the half-life extension by PEGylation, albumin fusion or Fc fusion is at the cost of binding affinity reduction. And the increase of size has limited their application in the field of anticancer agents where tumor penetration is required. Noncovalent albumin binding using albumin binding ligands such as fatty acids could maintain the small size and binding affinity. However, it would increase hydrophobicity, therefore is not suitable for protein therapeutics with low solubility. Here, we present a new approach for half-life extension for biotherapeutics. Human interleukin 2 (IL-2), a low solubility cytokine, was used as a model protein. By conjugating IL-2 with a hydrophilic small molecule that binds reversibly to the serum protein transthyretin, we enhanced its circulation half-life in rodents while maintained its in vitro bioactivity. To the best of our knowledge, this is the first demonstration of a successful approach that harnesses a small molecule in extending the circulation half-life of a protein while at the same time maintains the small size and hydrophilicity.

<p>The shallow soils of a former orchard area in Point Pelee National Park, near Leamington, Ontario, Canada have elevated concentrations of chlorinated pesticides above the regulatory limits. Previous studies in this area have shown that the DDT, DOE and ODD are highly persistent with an estimated half-life of DDT in the range of 15-30 years. In 2002 a pilot-scale field remediation experiment involving the application of cyclodextrin was conducted. This experiment resulted in substantial decrease of DDT, DDE and DDD concentrations in the upper soil layer within the remediation grid. Soil samples were collected within the treatment plots a year after the cyclodextrin application was completed to assess any further changes in concentrations of DDT, DDE and DDD. Groundwater samples were collected in the vicinity of the soil remediation grid which provided DDT, DDE and DDD concentrations in groundwater to assess the vertical mobilization of the compounds. Mass balance of the "soil - groundwater" system was calculated in order to estimate the degradation rate of DDT within the remediation zone. The 2-D unsaturated/saturated flow and solute transport numerical model "HYDRUS 2-D" was used to gain a better estimation of DDT, DDE and DDD mass and distribution in groundwater. The effectiveness of cyclodextrin application for remediation of DDT contaminated soils was assessed. After remediation treatments had stopped, there was no indication of further degradation of DDT and its metabolites in the upper layer of soil. The groundwater concentration of DDT, DDE and DDD near the remediation grid was 10-100 times higher than background value. This increase in groundwater concentration is a direct indication of DDT, DDE and DDD mobilization by cyclodextrin. The estimates of total mass of DDT in groundwater are less than 1% of mass leached from the soil. It was concluded that the application of cyclodextrin promoted enhanced co-metabolic biodegradation of DDT and it metabolites DDE and DDD. The estimated half-life for the displaced DDT was less than 2 months. This work demonstrates that cyclodextrin can be a highly effective agent for remediation of DDT contaminated soils.<p> / Thesis / Master of Science (MSc)

Alzheimer’s disease accounts for up to 80% of the cases of dementia making it the most common type of dementia. As of 2015, 46.8 million people are suffering from Alzheimer’s disease worldwide with an alarming rate of increase in the onset of the disease. Despite the ongoing research, the true cause of Alzheimer’s disease remains unknown. Aluminum is one of the major environmental toxins linked to the etiology of Alzheimer’s disease. A pilot clinical study for non-invasive measurement of bone aluminum was performed at the in vivo neutron activation analysis facility at McMaster University including 15 Alzheimer’s and 15 control subjects. A significant difference in bone aluminum, relative to calcium, was found between the two groups. Multiple methods of analysis were investigated to determine the method with the lowest minimum detection limit. The method of in vivo neutron activation analysis allows for the simultaneous activation of multiple elements. As such, it was possible to measure the magnesium levels, which has been shown to be involved in Alzheimer’s disease, in the study subjects. The results of bone measurements did not show a significant association between bone magnesium levels and Alzheimer’s disease. Moreover, the short-term kinetic behaviours of sodium and chlorine, both essential for the human body, were studied. The outcome of this study revealed an increase in the biological half-lives of sodium and chlorine with age and a higher variability in Alzheimer’s patients compared to control subjects. Finally, bone samples from parenteral nutrition patients were analyzed to determine their aluminum content for comparison and benchmarking purposes. The present results suggest a possible association between bone aluminum and the presence of Alzheimer’s disease. No such association was found for magnesium or the biological half-lives of sodium and chlorine. The technique of in vivo neutron activation analysis was shown to be a promising tool for measuring bone aluminum and magnesium; however, a better detection limit is required to strengthen the current results. / Dissertation / Doctor of Philosophy (PhD) / Alzheimer’s disease is the most common form of dementia. The cause of Alzheimer’s disease is unknown, but both genetic and environmental factors are known to be involved. Different elements have been studied for their possible role in this disease. Aluminum and to a lesser extent magnesium have been linked to the etiology of Alzheimer’s disease. The current thesis presents the results of a clinical study that utilizes the method of in vivo neutron activation analysis to measure aluminum and magnesium in the hand bone of Alzheimer’s disease and control subjects. In vivo neutron activation analysis is a non-invasive method that uses neutrons to activate elements in the human body and measures the radiation emitted. Different methods of analyzing the resulting data were investigated to find the most suitable analysis approach. The biological half-lives of sodium and chlorine were also measured to investigate their short-term kinetic behaviour and pattern with age.

The investigation of isomeric states in neutron-rich nuclei provides useful insights into the underlying nuclear configurations, and understanding their occurrence along an isotopic chain can inform about shell evolution. Recent studies on neutron-rich Si isotopes near the magic number N = 20 and approaching N = 28 have revealed the presence of low-lying states with intruder configurations, resulting from multiple-particle, multiple-hole excitations across closed shell gaps. The characterization of these states involves measuring their half-lives and transition probabilities. In this study, a new low-energy (7/2−1) isomer at 68 keV in 37Si was accessed via beta decay and characterized. To achieve this, radioactive 37Al and 38Al ions were produced through the projectile fragmentation reaction of a 48Ca beam and implanted into a CeBr3 detector, leading to the population of states in 37Si. The 68-keV isomer was directly populated in the beta-delayed one neutron emission decay of implanted 38Al ions. Ancillary detector arrays comprising HPGe and LaBr3(Ce) detectors were employed for the detection of beta-delayed gamma rays. The choice of detectors was driven by their excellent energy and timing resolutions, respectively. The beta-gamma timing method was utilized to measure the half-life of the new isomeric state in 37Si. This dissertation also discusses other timing techniques employed to search for and characterize isomeric states following beta decay of implanted ions. Notably, the half-life of the newly observed (7/2−1) isomeric state in 37Si was measured to be 9.1(7) ns. The half-life of the previously observed closely-lying (3/2−1) state at 156 keV was determined to be 3.20(4) ns, consistent with previously reported values. Reduced ground-state transition probabilities associated with the gamma-ray decay from these excited states were in agreement with results obtained from shell model calculations. In addition to the investigation of isomeric states in 37Si, isomeric 0+ states in 34Si and 32Mg nuclei belonging to the N = 20 “island of inversion” were characterized and searched for, respectively. The isomeric 0+ state in 34Si was populated following the beta decay of implanted 34Mg ions and its 34Al daughter nucleus. Similarly, the 0+ state in 32Mg was searched for via the beta-delayed one neutron emission decay of implanted 33Na ions.

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Ring-opening metathesis polymerization (ROMP) is a robust synthetic technique for synthesizing complex polymer architectures (topologies). To achieve complex architectures, specifically bottlebrush polymers, using ROMP, attaining the highest degree of living character is essential. As the molecular weight of the side chain or backbone increases, the "livingness" of the polymerization suffers due to premature catalyst degradation. Attaining large, well-defined, bottlebrush polymers requires precision so it was our goal to determine how seemingly simple reaction variables could affect the rates of propagation and achievable conversion, as well as why these variables have these effects. We tested several reaction parameters to understand how they affect the rate of polymerization, the rate of catalyst degradation, and the conversion that can be reached. We performed a systematic study using six organic solvents to determine the propagation rate of three macromonomers (MMs), one polystyrene and two poly(n-butyl acrylate) MMs, in ROMP with varying side chain chemistries and end groups, as well as rate of catalyst degradation in each of the solvents. We determined that solvent affected that rate of propagation primarily by interacting with the catalyst, while there was some evidence of polymer sidechain chemistry affecting the rate. We found that ethyl acetate (EtOAc) and CH2Cl2 had the highest rates of propagation compared to the other solvents, while DMF and THF were the slowest. UV-Vis testing on the catalyst in each solvent revealed that DMF and THF had fast rates of catalyst decomposition, while toluene was much slower to decompose. From these experiments we learned that toluene, despite its slower propagation rate, has the most living character, due to its slower rate of decomposition. We also learned that purification greatly affects the propagation rate, with THF requiring purification to have any conversion to bottlebrush polymer, while purification of EtOAc slows the rate of propagation almost 2-fold. From the decrease in rate after purification, and the conclusion that it was due to an acetic acid impurity in the impure EtOAc, we decided to systematically test small molecule additives and found that acids can increase the propagation rate and the conversion of the polynorbornene backbone achievable in ROMP reactions. Notably, in reactions performed in DMF with added CF3COOH we were able to polymerize a norbornene-functionalized unprotected peptide, which was insoluble in most organic solvents, to a higher conversion than in DMF without the added acid. We learned from our research that changing reaction variables can lead to substantial changes in the rate of propagation as well as the achievable conversion in bottlebrush polymer synthesis. By understanding this we can further test other reaction variables and do systematic studies on atmosphere and temperature. We hope this research and future fundamental research can guide scientists toward synthesizing large, well-defined, complex polymer architectures using ROMP. / Doctor of Philosophy / Nature has shown that complex molecular architectures lead to unique material properties. This has inspired scientists to synthetically mimic nature to create these polymer architectures in an effort to obtain novel material properties. Ring-opening metathesis polymerization (ROMP) has become a powerful synthetic method for synthesizing complex polymer architectures. Specifically, ROMP has been used to synthesize bottlebrush polymers, so named due to the polymer backbone with long, densely grafted, polymer side chains attached. These materials exhibit very interesting properties compared to their linear polymer counterparts. Using ROMP to synthesize bottlebrush polymers is not uncommon; however, difficulties can arise if trying to use sidechains that are very long or bulky. We have worked to understand how manipulating some of the reaction parameters can allow us, and other researchers, to synthesize bottlebrush polymers that contain long and/or bulky polymer side chains. We tested the purity and type of solvent that the reaction was performed in on one polystyrene macromonomer and two poly(n-butyl acrylate) macromonomers, as well as adding small molecules, including acids, bases, and salts, to determine if these variables could improve the synthesis of bottlebrush polymers. What we found was that all of the tested variables, solvent, purity, additives, and combinations of all of these variables, did have an effect on the synthesis of these materials. This fundamental information will assist our lab, and many others, in efficiently synthesizing complex architectures, thus achieving unique material properties.

In this thesis the enriched stable isotope marking technique was examined to determine its validity and effectiveness in marking of Lake Sturgeon fin rays. The enriched stable isotope marking technique uses stable isotopes of elements that replace calcium in boney tissue, which are fixed in nature, however in laboratory settings can be easily manipulated. Manipulated ratios of naturally occurring isotopes can be determined from a small sample of the fin ray, thus allowing for the discrimination of fish stocks. Further, the thesis examined the underlying assumptions for strontium and barium into the Lake Sturgeon. For the marking technique to work, strontium and barium must be taken up from the environment and accumulated long-term in boney tissue. Net flux and tissue retention of strontium is reported and the research has demonstrated that enriched stable isotopes can be successfully used to mark the fin ray of Lake Sturgeon for long-term stock discrimination. / October 2015

This thesis examines the topic of representation of totalitarianism in videogames. It aims to show how the totalitarianism is depicted in selected games and whether the videogame as a medium has some influence on this depiction. Theoretical part introduces and examines all sorts of different approaches, based on which one can study videogame as a medium. An argument about the videogames as a medium of control is presented further on and is also discussed in relation with totalitarianism. Second half of theoretical chapter focuses on definition of totalitarianism which is used in the case studies later on. Empirical part analyzes four games - Half-life 2, Papers, please, Wolfenstein: the New Order and BioShock with focus on representation of totality or dystopia. The games are analyzed both with regards to their rules and fiction. The conclusion shows that totalitarianism was represented mostly by its outer activities rather than ideology which were usually represented rather marginally. However, in all cases there could be found some examples of how was the representation of totalitarianism used to merge with system of control in games.