Terpene Syntheses Employing Aromatic Precursors

The thesis comprises two parts. In Part I, a review, complete to March, 1963, is given of all known aromatic diterpenes having an octahydrophenanthrene ring system and in particular of the compound totarolone. Aspects of their biogenesis and synthesis are discussed. An account is given of an investigation of a number of naphthalene derivatives which could function as precursors for a synthesis of totarolone. In an attempt to prepare 1,2,3,4-tetrahydro-5-isopropyl-2-keto-6-methoxy-l-methylnaphthalene, 2,6-dimethoxynaphthalene, 1-isonropyl-2-methoxy-naphthalene and l-isopropyl-2,6-dimethoxynaphbhalene were synthesised. 2,6-Dimethoxynaphthalene could be reduced to the 1,4-dihydro-derivative but attempts to methylate this product at the 1-position failed. l-Isopropyl-2-methoxynaphthalene underwent an abnormal nitration reaction giving an a-nitroketone with loss of the O-methyl group. 5-Bromo-6-hydroxytetralin was converted to 5-isopropyl-6-methoxytetralin which has now been converted, elsewhere to totarolone. Methyl 2-hydroxy-1-naphthoate was converted to l-isopropenyl-2-naphthol and 1-isopropyl-2-naphthol. The latter, however, proved to be much more readily available by direct alkylation of sodium 2-naphthoxide. The mechanism, of this process is discussed. l-Isopropyl-2-naphthol showed a remarkable propensity for oxygen absorption, being rapidly converted in air to 1,2-dihydro-1-h-ydropsroxy-l-isoprooyl- 2-keto-naphthalene. Since an autoxidation is possibly a key step in the biogenesis of totarol, this reaction was studied in some detail and comparison made of the reactivity of l-isopropyl-2-naphthol with that of 1-methyl-2-naphthol and 3-isopropyl-2-naphthol, the latter being prepared from 2-hydroxy-3-naphthoic acid. In Part II, the structures, biogenesis and published syntheses of all known iridoid monoterpenes are reviewed. An account is given of a reinvestigation of a synthetic approach to these substances from suitably substituted indanes. Condensation of para-cresol with ethyl acetoacetate gave 4,6-dimethyl-coumarin which was converted to 3-(2-methoxy-5-methylphenyl)butyric acid. Oyclisation of this with polyphosphoric acid gave a methoxyindanone which on Clemmensen reduction and demethylation gave 7-hydroxy-1,4-dimethylindane. This phenol was also obtained by rearrangement of the 3,4-dihydro-derivative of the above coumarin to a hydroxyindanone and reductive removal of the carbonyl group of the latter by the Clemmensen procedure. The degradation of this phenol to nepetalinic acid has been investigated. By a route similar to the first one above, 5,7-dihydroxy-1,4-bimethylindane has been prepared from 4-methylresorcinol and ethyl acetoacetate. It should be possible to convert this relatively simply to nepetalinic acid and research on this subject is continuing

A Systems Approach to Dissecting Immune Gene Regulatory Networks in the Modulation of Brain Function

Although the central nervous system was long perceived as the ivory tower without immune entities, there is growing evidence that the immune and nervous systems are intimated connected. These two systems have been shown to communicate both cellularly and molecularly under physiological and pathological conditions. Despite our increasing understanding of the interplay between these two systems, there are still numerous open questions. In this thesis, I address such unanswered questions related to: the role of microglia and their mechanism in contributing to pathologies in Rett syndrome; the beneficial effects of T-cell secreted cytokines in supporting social brain function; the evolutionary link of the interactions between the nervous and immune systems; the transcription regulation of a subset of microglia population in common neurodegenerative diseases. Collectively, the current thesis is focused on the joint frontier of bioinformatics and experimental work in neuroimmunology. A multifaceted approach, that includes transcriptomics, genomics and other biomolecular modules, was implemented to unearth signaling pathways and mechanisms underlying the presenting biological phenomena. The findings of this thesis can be summarized as follows: 1) MeCP2 acts as a master regulator in the transcriptional repression of inflammatory stimuli in macrophages; 2) T-cell secreted IFN-γ supports social brain function through an evolutionally conserved interaction between the immune and nervous systems; 3) The APOE-TREM2 pathway regulates the microglia phenotype switch in neurodegenerative diseases. Provided that recent technologies allow for readily manipulating the immune system, the findings presented herein may create new vistas for therapeutic interventions in various neurological disorders

The Effect of a Paired Lab on Course Completion and Grades in Nonmajors Introductory Biology

This paper explores the effect of a paired lab course on students’ course outcomes in nonmajors introductory biology at the University of Alaska Anchorage. We compare course completion and final grades for 10,793 students (3736 who simultaneously enrolled in the lab and 7057 who did not). Unconditionally, students who self-select into the lab are more likely to complete the course and to earn a higher grade than students who do not. However, when we condition on observable course, academic, and demographic characteristics, we find much of this difference in student performance outcomes is attributable to selection bias, rather than an effect of the lab itself. The data and discussion challenge the misconception that labs serve as recitations for lecture content, noting that the learning objectives of science labs should be more clearly articulated and assessed independent of lecture course outcomes. This paper explores the effect of a paired lab course on students’ course outcomes in introductory biology for nonmajors at the University of Alaska Anchorage (UAA), a large, open-enrollment, 4-year university. We compare outcomes for 10,793 students, 3736 who simultaneously enrolled in the lab and 7057 who did not, and analyze the degree to which they select into the lab on observable characteristics to explore the following research questions: 1. Are students who take a paired lab more likely to complete the lecture component (i.e., receive a final grade as opposed to withdrawing or receiving an Incomplete)? 2. Are students who take a paired lab more likely to receive a higher grade in the lecture component? 3. Does the laboratory experience differently affect course outcomes for students in specific demographic subgroups (e.g., gender, race, high school urbanicity, age, prior academic performance, and socioeconomic status)

Analytical thinking, analytical action: using prelab video demonstrations and e-quizzes to improve undergraduate preparedness for analytical chemistry practical classes

This project utilizes visual and critical thinking approaches to develop a higher-education synergistic prelab training program for a large second-year undergraduate analytical chemistry class, directing more of the cognitive learning to the prelab phase. This enabled students to engage in more analytical thinking prior to engaging in the analytical action in the laboratory, motivating students to arrive at classes prepared to engage in the material rather than the mechanics (physical processes) of the practical exercises. This reduced the likelihood of cognitive overload at the beginning of the class. Video demonstrations were developed providing both visual demonstrations with audio explanations to reinforce each concept, and students were guided to these through compulsory prelab e-quizzes. The effectiveness of the program was evaluated by academic performance and an attitudinal survey. Attitudes toward the prelab program were very positive, particularly for the e-quizzes. There was no improvement on academic performance in laboratory reports; however, students reported that the prelab material had a positive effect on their learning, and that they were able to enter the laboratory with high levels of perceived preparedness. Given that student experiences in the laboratory are arguably as important as assessable outcomes, an attitudinal study such as this is extremely important