Ring-closing metathesis (RCM) has proven to be a valuable tool for constructing alkaloid-like, poly-cyclic compounds. The syntheses of alkaloid structures we were interested in developing, could utilize RCM to construct a spirocyclic structure for the immunosuppressant FR901483 and the tetracyclic framework of lundurines A-C asymmetrically. The azaspirane core of FR901483 was obtained via an addition of an allylsilane to an N-acyl iminium ion, and a RCM. Other key functional group manipulations were a stereoselective hydroboration and a subsequent lactonization that provided a precursor for a lactone-lactam rearrangement. This rearrangement provided the azatricyclic core of FR901483. In the enantioselective approach to FR901483 a new mildly cleavable protecting group was developed. Addition of a zinc nucleophile to a chiral N-acyl iminium ion, and a RCM provided the desired precursor for the hydroboration/lactone-lactam rearrangement sequence but without a sufficient stereoselection. A novel approach toward the total synthesis of lundurines A-C has been developed. The key features of the approach involve an intramolecular cyclopropanation of the indole C(2)-C(3) double bond, an enantioselective tandem RCM to construct the tetracyclic core and a concise synthesis to access the RCM precursor. An Ugi reaction was utilized with both cyclic and acyclic ketones, 2-vinyltryptamine derivative, a carboxylic acid and an isocyanide to access diverse compounds, including RCM precursors. An alternative reductive amination route to construct the RCM precursor for the lundurines was found to be more efficient and high yielding than the Ugi approach. An RCM was utilized to affect the closure of the five-and eight-membered rings of the tetracyclic core. This constitutes as the first example of RCM of a 2-vinylindole derivative to give an indole-fused eight-membered ring. / text

published_or_final_version / Pharmacology and Pharmacy / Master / Master of Medical Sciences

Influenza epidemics have always been a constant public health threat to human populations. Recent societal developments and demographics changes have put us at increased risk of a widespread and potentially deadly influenza epidemic. Antiviral prophylaxis may provide an important epidemic intervention measure especially against influenza epidemic caused by novel influenza viruses where there will be no effective epidemic-specific vaccines available at the initial phase of the epidemic. Antiviral prophylaxis is listed as a fundamental component of the Hong Kong Preparedness Plan for Influenza Pandemics, however the rationale of such plan is not supported by public presentation of scientific evidence and no details of the actual antiviral prophylaxis plan are provided. With a majority of its stockpile set to expire in the very near future, we would like to know if antiviral prophylaxis is an effective intervention strategy against influenza epidemic and should antiviral stockpiling be continued. We identified relevant studies and reviewed the effectiveness of antiviral prophylaxis in preventing influenza infections at the individual, household and population level. We found that prophylactic treatment with Oseltamivir or Zanamivir are both effective in preventing influenza infections at the individual and household level. Both antivirals are well tolerated and neither is associated with major adverse events. Antiviral prophylaxis is effective in mitigating the public health impact of an influenza epidemic such as number of clinical influenza infections, hospitalization and deaths. However, antiviral prophylaxis alone may not be sufficient to contain or avert an influenza epidemic or delay the epidemic progress long enough for public health resources such as epidemic-specific vaccines to be acquired. In addition, the emergence of antiviral resistance and various logistics constraints will hamper the effectiveness of antiviral prophylaxis in containing influenza epidemics. We suggest the use of antiviral prophylaxis as the key intervention to mitigate influenza epidemics, however, with special considerations taken into hedging antiviral resistance and fulfilling the logistics requirements in order to make antiviral prophylaxis effective. In addition, we recommend public health authorities to take a multi-factorial approach in tackling highly transmissible influenza epidemics by incorporating other non-pharmaceutical interventions such as quarantine, school closures and boarder restrictions into the their antiviral prophylaxis-based containment plan. / published_or_final_version / Public Health / Master / Master of Public Health

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

This dissertation investigates several business cycle relationships when economic agents are heterogeneous. The particular focus is on the interactions between the cross-section of agents and the aggregate state of the economy. The first chapter shows that, when occasionally binding capacity constraints limit the production of heterogeneous firms, demand shocks can endogenously generate a number of important business cycle regularities: recessions are deeper than booms are high, firm-level volatility is countercyclical, the aggregate Solow residual is procyclical and the fiscal multiplier is countercyclical. A baseline calibration of a basic New Keynesian DSGE model with capacity constraints shows that this mechanism can explain more than a quarter of the empirically observed asymmetry in output, and matches the cyclicality of firm-level profitability dispersion and of the measured Solow residual. The model implies fluctuations in the fiscal multiplier of around 0.12 between expansions and recessions. Chapter two takes a different approach to firm level uncertainty, exploring how recessions can cause an endogenous rise in firm risk. If heterogeneous firms face real and financial frictions, then a shock to the mean of aggregate productivity endogenously leads to countercyclical profitability risk through firms' heterogeneous responses in price setting. Additionally, the mechanism endogenously generates countercyclical credit spreads and credit spread dispersion. The model explains a large share of the observed fluctuations in profitability dispersion (69%) and in credit spreads (40%) through fluctuations in aggregate TFP holding productivity risk constant. This suggests that the scope for uncertainty shocks to explain recessions may be smaller than previously thought. The third chapter focuses on distributional effects of oil price shocks on the household side. In the model, household behavior replicates two patterns found in household-level data which show that gas consumption increases with income, but on the intensive margin gasoline consumption as a share of the household's budget decreases with income. The model includes gas consumption in household utility on top of a fixed minimum level of gas consumption. Calibrated simulations suggest that a shock to the gas price is almost twice as costly for relatively poor households than for relatively rich households. / text

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It is important for designers, developers, and end-users to comprehend (or explain) why a software agent acts in a particular way when situated in its operating environment. Comprehending agent behaviors in an agent-based system is a challenging task due to environmental uncertainty and the dynamics and multitude of agent interactions, which must be captured, processed, and analyzed by the human user. While traditional software comprehension answers "what is happening in the implementation?", this research takes a step further to facilitate comprehension by answering "why is the behavior happening in the implementation?". To explain agent behaviors in the implemented system, this research takes the model-checking approach for representing abstracted software behavior and the reverse engineering approach for verifying the expected behavior model against the implementation's actual behavior, while assimilating the terminology and framework from abductive reasoning. This research empirically shows that maintaining accurate background knowledge of how the implementation is expected to behave is crucial in generating accurate explanations of agent behavior. The resulting Tracing Method and accompanying Tracer Tool build on ideas from existing approaches and extend the state-of-the-art to better assist human users (of various skill levels) in comprehending agent-based software by automating many reasoning tasks. The Tracing Method is applied to two domains to demonstrate the capabilities of the Tracer Tool in (1) suggesting background knowledge updates, (2) interpreting actual behaviors from implementation executions, and (3) explaining observed agent behaviors. This research aims to help designers who want to improve agent behavior; developers who need to debug and verify agent behavior; and end-users who want to comprehend agent behaviors. / text

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