This dissertation has been devoted to the syntheses and studies of novel chiral, helical cyclophanes and their corresponding metal complexes. The subsequent part of the project involves the use of the copper complex of the chiral cyclophane 1 as an asymmetric catalyst in enantioselective organic transformation reactions. There are three chapters in this thesis. Chapter 1 describes the synthesis of chiral cyclophanes and their metal complexes. Racemic spirobiindanol (±)-6 was initially synthesized and resolved using literature methods. Metal-binding ligands were synthesized from each enantiomer, and Williamson ether synthetic method was used to obtain desired helical cyclophanes 1-5. Metal ions, such as silver(I), copper(I), mercury(II), zinc(II), and palladium(II), were used to form metal complexes of these cyclophanes. Chapter 2 discusses structures and properties of both cyclophanes and their metal complexes using spectral data from NMR, MS, UV, CD and X-ray crystallography. Lastly, Chapter 3 describes the use of a copper complex of the cyclophane 1 as an asymmetric catalyst for cyclopropanation of styrene with diazoester and for allylic oxidation of cycloalkenes, otherwise known as the Kharash-Sosnovsky reaction. The cyclopropanation reaction favored the formation of trans- phenylcyclopropane carboxylate in ̃ 20 % ee (68-87 % yield), and the allylic oxidation reactions produced the (R)-allylic carboxylate with ̃16 % ee (< 80 % yield)

Theme: Deer virus. I choose the theme word "deer". The whole story is related to "Deer virus". It works as a zombie virus. Goal: I wanted the game to make the player feel the tension. Player has to decide how to solve the problem, and also imagine the scene. This is the reason why I choose the background of the game as our college.

Our game “The curse of the Deer” is based on an adventure platformer game. And it has a base story. Therefore, I expected the players understand our story and think about how to solve the problem. This story is about pizza and deer so it can be a new story for the players. Form the story, we make our stages are continuous steps to make pizza. So it is familiar to the players because it is a common one. Everyone knows they should put pizza toppings and bake it. About art things, the first stage is about collecting toppings for the pizza. So we wanted to make items like more realistic to make players feel that they are pizza toppings. And for the second stage, we thought about how to express it as baking. So we use the concept of the oven, and collecting fires to bake it. From the class, we learned that it is important that make what we are interested in, and what we want to make. So, we thought about the main topics for the story at first. And we choose pizza and deer, and thought about the story. It was very fun because we knew many stories related to deer like “Adventure Time”, and make imaginary stories from it. We thought it was crazy to make the game with pizza and deer, but I think it is a success story today. Also, we think about our gameplay style. And I like platformer game style and also rhythm games. So I suggested it and thought about how to apply these things with our topics. Therefore, our game design consisted of this game. We thought that it would be more fun if it had multiple endings according to the player’s choice. So, we made the story first, and how to make different endings from the story. It is a very short-time project and the game project is also small, so we thought about how to deliver our stories to the player. Finally, we made pickup items can be the choices for the player. So, in our game, picking items are not the score, they are choices for the endings.   Also, we cannot find some assets using pizza and deer at the same time. So we should draw our characters and items. It was hard work, because we should draw most of them, and we are not the artist! But we wanted to give more proper design to the player. So, we draw the main player character looks like a pizza delivery man because our whole story is related to pizza. And also draw deer looks like a vicious king, so that the player can think that it is a villain. I also got feedback from other students, and I think it works well.    In this game, the player can be a hero just making a delicious pizza. However, it might be difficult for someone because they should guess deer’s favorite things. I think players feel fun with that. Also, it has 2 stages but different gameplay. And it makes the players have various experiences by playing one game. At first, we use different keys for each stage. In the platformer stage, it uses arrow keys to move. But in the oven stages looks like rhythm games, it uses 4 different alphabet keys. We got feedback it is difficult for users, and also we thought it is not good to explain how to play this. So, we modify it to use arrow keys. However, it is too difficult using 4 arrow keys at the same time, so we also modify it to use only 3 keys: up, left, and right. At the final testing, I got feedback we had improvement compare with the previous section. And we had some strange mechanics at the first stage. But we had feedback that it was fine because some players feel fun with that. And someone told us it passed too quickly between two stages. So, we changed the portal (oven) smaller, and give instructions to the player to prepare the next stage. Also, it has audio only for 2 stages, so we add some audios for the ending. We have some difficulties to implement our design. Because we want to make it be polished, and we have two stages, so they need different events. Our number of events is limited, and we should delete some events for this. I also discussed this in the TA section, but we had a response that we cannot add additional events. So we should delete some features. I think it can be more improved if we can have more events.

Objective

To examine the relationship between cognitive impairment and functional limitations and disability in persons with rheumatoid arthritis (RA).

Methods

Individuals from a longitudinal cohort study of RA participated in study visits that included physical, psychosocial, and biological metrics. Cognitive function was assessed using a battery of 12 standardized neuropsychological measures yielding 16 indices covering a range of cognitive domains. On each test, subjects were classified as "impaired" if they performed 1 SD below age-based population norms. Total cognitive function scores were calculated by summing the number of tests on which individuals were classified as "impaired" (higher scores = greater impairment). Performance-based and self-reported functional limitations were assessed with the Short Physical Performance Battery (SPPB) and the Health Assessment Questionnaire (HAQ), respectively. Self-reported disability was measured with the Valued Life Activities (VLA) scale. Multiple regression analyses controlling for sex, race, education, cardiovascular comorbidity, disease duration, disease severity, and depression were conducted to identify whether cognitive impairment was independently associated with physical function difficulties.

Results

There were 122 subjects with mean (SD) age of 58.4 (± 10.8) years; 62% were female and 80% were white. In multivariate regression models, total cognitive function score was significantly associated with greater functional limitations (SPPB: β = -0.24, p = 0.014; HAQ: β = 0.24, p = 0.003) but not with disability (VLA: β = 0.10, p = 0.207).

Conclusion

Cognitive impairment was significantly associated with greater functional limitations in patients with RA, suggesting that cognitive impairment may play a role in poor functional status in persons with RA.

Objective

Research shows a gap between perceived cognitive dysfunction and objective neuropsychological performance in persons with chronic diseases. We explored this relationship in persons with rheumatoid arthritis (RA).

Methods

Individuals from a longitudinal cohort study of RA participated in a study visit that included physical, psychosocial, cognitive, and biologic metrics. Subjective cognitive dysfunction was assessed using the Perceived Deficits Questionnaire (PDQ; range 0-20, where higher scores = greater perceived impairment). Objective cognitive impairment was assessed using a battery of 12 standardized neuropsychological measures yielding 16 indices. On each test, subjects were classified as impaired if they performed 1 SD below the age-based population norms. Total cognitive function scores were calculated by summing the transformed scores (range 0-16, where higher scores = greater impairment). Multiple linear regression analyses determined the relationship of the total cognitive function score with the PDQ score, controlling for sex, race, marital status, income, education, disease duration, disease severity, depression, and fatigue.

Results

One hundred twenty subjects (mean ± SD age 58.5 ± 11.0 years) were included. Mean ± SD scores of total cognitive function and the PDQ were 2.5 ± 2.2 (range 0-10) and 5.8 ± 3.8 (range 0-16), respectively. In multivariate analysis, there was no significant relationship between the total cognitive function score and the PDQ score. However, depression and fatigue (β = 0.32, P < 0.001 and β = 0.31, P = 0.001, respectively) were significantly associated with the PDQ score.

Conclusion

The findings emphasize the gap between subjective and objective measures of cognitive impairment and the importance of considering psychological factors within the context of cognitive symptoms in clinical settings.

Objective

To explore the prevalence and possible predictors of cognitive impairment in persons with rheumatoid arthritis (RA).

Methods

Individuals from a longitudinal cohort study of RA participated in a study visit that included a range of physical, psychosocial, and biologic metrics. Cognitive function was assessed using a battery of 12 standardized neuropsychological measures yielding 16 indices. Subjects were classified as "impaired" if they performed 1 SD below age-based population norms on at least 4 of 16 indices. Logistic regression analyses were conducted to identify which of the following were significant predictors of cognitive impairment: sex, race, income, education, depression, disease duration, disease severity, C-reactive protein (CRP) level, glucocorticoid use, and cardiovascular disease (CVD) risk factors.

Results

A total of 115 subjects with a mean ± SD age of 58.6 ± 10.8 years were included; 64% were women and 81% were white. The proportion of persons who were classified as cognitively impaired was 31%. Education, income, glucocorticoid use, and CVD risk factors independently predicted cognitive impairment, controlling for sex, race, disease duration, disease severity, CRP level, and depression. Individuals with cognitive impairment were more likely to have low education (odds ratio [OR] 6.18, 95% confidence interval [95% CI] 1.6-23.87), have low income (OR 7.12, 95% CI 1.35-37.51), use oral glucocorticoids (OR 2.92, 95% CI 1.05-8.12), and have increased CVD risk factors (OR 1.61, 95% CI 1.19-2.17 per risk factor).

Conclusion

The findings of this study suggest that the burden of cognitive impairment in RA is significant, and future studies identifying specific etiologic contributors to cognitive impairment are warranted.

Developing materials that are effective against sexually transmitted pathogens such as Chlamydia trachomatis (Ct) and HIV-1 is challenging both in terms of material selection and improving bio-membrane and cellular permeability at desired mucosal sites. Here, we engineered the prokaryotic bacterial virus (M13 phage) carrying two functional peptides, integrin binding peptide (RGD) and a segment of the polymorphic membrane protein D (PmpD) from Ct, as a phage-based material that can ameliorate Ct infection. Ct is a globally prevalent human pathogen for which there are no effective vaccines or microbicides. We show that engineered phage stably express both RGD motifs and Ct peptides and traffic intracellularly and into the lumen of the inclusion in which the organism resides within the host cell. Engineered phage were able to significantly reduce Ct infection in both HeLa and primary endocervical cells compared with Ct infection alone. Polyclonal antibodies raised against PmpD and co-incubated with constructs prior to infection did not alter the course of infection, indicating that PmpD is responsible for the observed decrease in Ct infection. Our results suggest that phage-based design approaches to vector delivery that overcome mucosal cellular barriers may be effective in preventing Ct and other sexually transmitted pathogens.

While recent research points to the importance of glycans in cancer immunity, knowledge on functional mechanisms is lacking. In lung carcinoma among other tumors, anti-tumor immunity is suppressed; and while some recent therapies boost T-cell mediated immunity by targeting immune-checkpoint pathways, robust responses are uncommon. Augmenting tumor antigen-specific immune responses by endogenous dendritic cells (DCs) is appealing from a specificity standpoint, but challenging. Here, we show that restricting a heparan sulfate (HS) loss-of-function mutation in the HS sulfating enzyme Ndst1 to predominantly conventional DCs (Ndst1f/f CD11cCre+ mutation) results in marked inhibition of Lewis lung carcinoma growth along with increased tumor-associated CD8+ T cells. In mice deficient in a major DC HS proteoglycan (syndecan-4), splenic CD8+ T cells showed increased anti-tumor cytotoxic responses relative to controls. Studies examining Ndst1f/f CD11cCre + mutants revealed that mutation was associated with an increase in anti-tumor cytolysis using either splenic CD8+ T cells or tumor-infiltrating (TIL) CD8+ T cells purified ex-vivo, and tested in pooled effector-to-target cytolytic assays against tumor cells from respective animals. On glycan compositional analysis, HS purified from Ndst1f/f CD11cCre + mutant DCs had reduced overall sulfation, including reduced sulfation of a tri-sulfated disaccharide species that was intriguingly abundant on wildtype DC HS. Interestingly, antigen presentation in the context of major histocompatibility complex class-I (MHC-I) was enhanced in mutant DCs, with more striking effects in the setting of HS under-sulfation, pointing to a likely regulatory role by sulfated glycans at the antigen/MHC-I - T-cell interface; and possibly future opportunities to improve antigen-specific T cell responses by immunologic targeting of HS proteoglycans in cancer.

The importance of biogenic volatile organic compounds (BVOCs) in understanding of air-quality and climate on regional to global scales has been highlighted in a number of modeling and observational studies. At the same time, another important emerging research topic in atmospheric chemistry is the regional and global impacts of fast growing East Asian megacities. These two research topics must be integrated in order to adequately understand and address air quality challenges emerging from Eastern Asian megacities surrounded by planted or natural forest areas. We present initial measurement results for May, June and September 2011 from the Taehwa Research Forest (TRF) which has been developed to serve as a long term observatory for investigating biosphere-atmosphere interactions at the edge of the Seoul Metropolitan Area (population of ∼23.5 million). The comprehensive measurement datasets of ozone and its precursors such as CO, NOx, SO2 and VOCs shows that high ozone episodes in the suburban site could not be explained by just anthropogenic pollutants alone. In addition, isoprene (C5H8) and monoterpenes (C10H16) were observed as two of the most important OH chemical sinks inside of the forest canopy. In order to understand the impacts of these BVOCs on ozone and related photochemistry, we conducted model sensitivity simulations using a coupled meteorology-chemistry model (WRF-Chem) for conditions including with and without BVOC emissions. The modeling results suggest that BVOC emissions could enhance regional daytime ozone production from 5 to 20 ppbv. The observed temporal variations in ozone correspond well with the variations in BVOCs, which likely reflects the influence of BVOCs on ozone formation. These findings strongly suggest that interactions between anthropogenic pollutants and BVOCs must be understood and quantified in order to assess photochemical ozone formation in the regions surrounding East Asian megacities. © 2012 Elsevier Ltd.