MacSphere Collection:http://hdl.handle.net/11375/278062024-03-19T01:45:25Z2024-03-19T01:45:25ZTotal Asymmetric Synthesis of Ring-A Derivatives of (+)-Trans-DihydronarciclasineScattolon, Jonhttp://hdl.handle.net/11375/262892021-04-07T20:24:28Z2021-01-01T00:00:00ZTitle: Total Asymmetric Synthesis of Ring-A Derivatives of (+)-Trans-Dihydronarciclasine
Authors: Scattolon, Jon
Abstract: Significant attention from the medicinal and pharmaceutical communities has been pushed towards the design and development of natural products for defence against many forms of illnesses. The Amaryllidaceae plant family has shown their prevalence over time aiding towards our needs and becoming viable sources of alkaloids due to their wide variety of bioactivities presented. The low availability towards these often-complex structures with at times comprising up to six contiguous chiral centers have made practical testing scarce. More dominantly the isocarbostyrils are well recognized, being hydroxylated phenanthridones providing increased activities making them model targets to test and develop new synthetic strategies towards. These compounds represent a subset of the Amaryllidaceae alkaloids that lack a basic nitrogen center.
This thesis describes the total synthesis of four derivatives of the antiviral natural product (+)-trans-dihydronarciclasine from α-azidoacetone and m-anisaldehyde. Herein we demonstrate constructive routes towards ring-A modified, fully functionalized rings-B/C derivatives synthesized via asymmetric chemical syntheses providing further insight into SAR studies. This thesis expands on the organocatalytic [3+3]-cycloaddition sequence to produce aminocyclitol cores providing effective routes towards the development of five stereogenic centers in all targeted ring-C structures. Such studies were attributed to the enal adducts isolated from the Wittig reaction towards four natural product derivatives gaining knowledge related to the targeted molecules mode of action. One additional (+)-transdihydrolycoricidine analogue will be communicated, that enables the imaging while inside live cells with use of alkyne-tag Raman imaging.
Limitations of the alkaloids include the toxicity that accompanies these agents and the poor aqueous solubilities they provide, eliciting an increased need for new antiviral agents. The syntheses communicated provide effective routes towards unnatural alkaloids and can be pushed towards alternative chiral aminocyclitol targets for future studies. All
compounds have been sent away for screening including against coronavirus at Johns Hopkins.2021-01-01T00:00:00ZPerceptual grouping, motion discrimination, and shape completion of four-sided figures in younger and older adultsCali, Jessica N.http://hdl.handle.net/11375/251462020-01-03T16:35:50Z2019-01-01T00:00:00ZTitle: Perceptual grouping, motion discrimination, and shape completion of four-sided figures in younger and older adults
Authors: Cali, Jessica N.
Abstract: The present dissertation investigates perceptual grouping and shape completion in motion in younger and older observers. The first set of experimental results, Chapter 2, provides a set of exploratory experiments which characterize the nature of a motion grouping task, uncovering accurate direction discrimination when the stimulus contains a cue for global grouping, but compelling illusory motion when the stimulus does not contain that cue. Chapter 3 builds on the findings of Chapter 2 by measuring biases in motion integration that lead to the illusory motion. Chapter 3 extends this paradigm into older adult observers, and explores various stimulus variants and tasks to add to the characterization of this effect. In Chapter 4 the concepts of grouping and motion perception are examined in the context of shape completion by measuring the accuracy of aspect ratio, size, and area discrimination in younger and older adults. Chapter 4 concludes that older adults are worse at discriminating characteristics of shapes, but are similarly affected by incomplete or occluded stimuli as younger adults. On the whole, the dissertation demonstrates several novel findings in the perceptual organization literature, and investigates many of these phenomena into older adults populations. Throughout the dissertation, a central theme concerns the concept of behavioural measurement of perceptual processes, and consequently many of the phenomena are studied using several types of measurements and tasks to ensure a complete picture of the perceptual experience. The current dissertation presents a novel and important addition to the current literature in perceptual grouping and shape completion.2019-01-01T00:00:00ZDemographic patterns in Medieval London inferred from wills probated in the Court of Husting, 1259-1688Bushby, Alexandra S.http://hdl.handle.net/11375/242672019-04-29T20:24:19Z2019-01-01T00:00:00ZTitle: Demographic patterns in Medieval London inferred from wills probated in the Court of Husting, 1259-1688
Authors: Bushby, Alexandra S.
Abstract: The Calendar of Wills Proved and Enrolled in the Court of Husting, London, 1258--1688 (Husting wills) is exploited (i) to characterize, using statistics, the social and demographic characteristics of Medieval London and (ii) to analyze the temporal patterns of the four plague epidemics that occurred in London between 1348 and 1376.
The Husting wills were digitized by British History Online (BHO) in 2017. We created an R package that uses the BHO version of the Husting wills and provides tools for analysis of these wills.
Statistical analyses performed on the 4110 Husting wills reveal that 10.9% of testators were women. There is no clear evidence of bias of writing wills on particular weekdays. However, wills were least and most commonly written on Thursdays (11.72%) and Saturdays (16.18%), respectively. 51.2% of wills mention the career of the testator. By categorizing careers into one of four classes (business, church, city or nobility), we were able to determine that most testators were in the business category (80.2%). Among these individuals, the five most common occupations were fishmonger, merchant, goldsmith, draper and skinner.
Further analyses of the Husting wills strongly suggest that the temporal patterns of plague epidemics can be estimated more accurately from the dates wills were written rather than the dates they were probated. We identify two probable factors that make probate dates harder to interpret: First, the Court of Husting probated wills only on Mondays. Second, highly varying lags between the writing and probating of wills adds noise to statistics based on probate dates. The observed lags for the Husting wills are well approximated by a lognormal distribution.2019-01-01T00:00:00ZRole of the GABARAP Tumor Suppressor in the Control of E.R. Stress and Cell ApoptosisAssee, Samanthahttp://hdl.handle.net/11375/227472018-04-23T16:46:46Z2018-01-01T00:00:00ZTitle: Role of the GABARAP Tumor Suppressor in the Control of E.R. Stress and Cell Apoptosis
Authors: Assee, Samantha
Abstract: In response to starvation, mis-folded proteins accumulate in the endoplasmic reticulum (E.R.) causing E.R. stress. This triggers a series of signaling pathways known as the unfolded protein response (UPR). The response helps to both enhance protein folding capacity and initiate mis-folded protein degradation, reducing E.R. stress. Alternatively, misfolded proteins are degraded and nutrients are recycled through autophagy. Thus, E.R. homeostasis depends on both UPR and autophagy. However, if E.R. stress is not resolved, UPR and autophagy can also cause apoptosis by mechanisms that are not fully understood. In chicken embryo fibroblasts, gamma-aminobutyric acid receptor-associated protein or GABARAP (a protein involved in autophagy) can promote apoptosis in conditions of prolonged starvation (Maynard et al. 2015). In these conditions, the down-regulation of GABARAP by shRNA/RNA interference reduces the expression of the pro-apoptotic CHOP (CAAT-enhancer-binding protein homologous protein) transcription factor (a marker of E.R. stress) and enhances cell survival. This suggests that elevated levels of autophagy compromises E.R. homeostasis and promotes the expression of CHOP in UPR lethal pathways. While GABARAP induction and processing/activation has been linked to the expression of CHOP upon prolonged starvation (Maynard et al. 2015), nothing is known about the pathway mediating CHOP expression and the relationship with other pathways of the UPR in cells with GABARAP mis-expression. Understanding these pathways will allow us to determine if GABARAP is a general determinant of E.R. stress or acts specifically on the expression of CHOP to control cell survival.
Elucidating mechanisms which are involved in E.R. stress and the cellular transition between pro-survival to pro-apoptotic roles can allow understanding of processes associated with several pathological conditions like cancer and neuro-degenerative diseases. Additionally, establishing a role for GABARAP tumor suppressor in the control of the UPR and cell fate is also important.2018-01-01T00:00:00Z