Organophosphorus cholinesterase inhibitors (OPs) are a class of toxic chemicals that includes both pesticides and nerve agent chemical weapons. Every year accidental or intentional exposure to OPs accounts for millions of poisonings globally. Current standard of care (SOC) for treatment of acute OP intoxication improves survival if administered promptly following intoxication but does not prevent development of chronic neuropathology or neurological sequelae in survivors of such intoxications. While acute OP-induced status epilepticus (SE) is known to be a critical driver of subsequent neuropathology and adverse neurological consequences following intoxication, treatment of acute OP intoxication is likely to be delayed beyond the optimal therapeutic window for SOC intervention. This dissertation addresses two limitations in the treatment of acute OP intoxication: 1) identification of biomarkers for identification of populations at-risk of chronic neurological outcomes, and 2) assessment and targeting of the downstream process of neuroinflammation to mitigate adverse neurological consequences following OP poisoning. In Chapter 2, we identify acute and delayed electrophysiologic signatures following acute intoxication with the OP pesticide diisopropylfluorophosphate (DFP) that correlate with the frequency of spontaneous recurrent seizures (SRS). These findings present novel and translatable electrophysiologic biomarkers with potential to assist in triage following a mass casualty OP exposure incident. Chapter 3 characterizes the microglial and astrocytic neuroinflammatory responses following acute DFP intoxication, providing novel information regarding the spatiotemporal progression of glial phenotypes up to 28 days post exposure (DPE). These data point to early targeting of pro-inflammatory microglial activation as a potential strategy to improve outcomes following acute DFP intoxication. Chapter 4 builds upon the findings of Chapter 3 through transient depletion of microglia via administration of the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to female rats following acute DFP intoxication. We identify a time-dependent anti-epileptogenic effect of CSF1R inhibition post-DFP intoxication; PLX5622 administration 1-3 DPE prevented the development of SRS while PLX5622 from 4-6 DPE did not reduce the incidence of SRS relative to animals intoxicated with DFP and not provided PLX5622. Animals treated with PLX5622 1-3 DPE displayed attenuated chronic microglial and astrocytic activation and a greater density of neurons at 28 DPE. Collectively, Chapters 3 and 4 provide a natural history of glial inflammatory responses and identify the time-dependent epileptogenic effect of microglial activation following acute DFP intoxication. In Chapter 5, we assess the pleiotropic anti-seizure/anti-inflammatory neurosteroid allopregnanolone (ALLO) in a translatable model of acute soman intoxication. ALLO provides dose-dependent control of soman-induced seizures and mitigates acute neurodegeneration and neuroinflammation following soman intoxication. The findings of this dissertation offer tangible, clinically relevant improvements to acute and delayed treatment of OP poisoning, while also highlighting the time-dependency of microglial-targeted anti-inflammatory interventions post-intoxication.

En route to a total synthesis of tetrapetalone A, we have discovered an unexpected steric facilitation of the Nazarov cyclization of aryl dienyl ketones. Chapter 1 describes the success of the Nazarov cyclization of substrates possessing substituents at both the &alpha- and &gamma-positions of the acyclic dienone. Substrates possessing only one substituent at either the &alpha- or &gamma-position proceed much more slowly, or not at all. Density functional theory calculations on the Lewis acid-bound substrates and their respective transition states were performed by Rebecca Davis in the research group of Prof. Dean Tantillo at the University of California, Davis. The computations correlate closely with the observed reactivity. The effect is observed across a series of aryl dienyl ketones with an electron-rich arene portion. Further evidence for this effect was shown by the difficulty of effecting the Nazarov cyclization of a cyclic aryl dienone at room temperature.

Chapter 2 describes the application of the findings of the Nazarov study to the synthesis of the indanone portion of tetrapetalone A. Difficulties in differentiation of the C-12 and C-14 positions (tetrapetalone numbering) of the indanone led to the investigation of a meta-bromo-containing aryl dienone, which successfully underwent the Nazarov cyclization with 13:1 regioselectivity. Formation of the C-N bond was achieved by performing a lithium-halogen exchange on the aryl bromide and quenching with tosyl azide, the product of which was then reduced to the free amine using lithium aluminum hydride.

Chapter 3 describes the elaboration of the aniline intermediate to a late-stage tetracycle en route to tetrapetalone A. Closure of the tetracycle was achieved by Friedel-Crafts acylation onto a pyrrole in a double oxidation cascade. This sequence is promoted by Dess-Martin periodinane as both the oxidant and the activating agent for the carbonyl moiety. Installation of the angular ethyl group at C-4 was achieved by Birch reduction of the resulting 2-ketopyrrole followed by quenching with iodomethane. The correct substitution pattern on the tetramic acid was achieved following oxidation to the &alpha,&beta-unsaturated lactam and subsequent copper-mediated conjugate addition of bis(pinacolato)diboron, followed by further oxidation.

In 2011 Lick Observatory carried out a 2.5 month reverberation mapping campaign using the 3 meter Shane telescope monitoring 15 low redshift galaxies. The goal was to determine the black hole mass for each of these galaxies. My job was to use the JAVELIN software package to determine the size of the Broad Line Region around each of these objects and compare the results to those calculated using other methods. Here I present my findings for the 6 targets that JAVELIN found lag times for at least one of the emission lines. I also include the results using CCF which are in the process of being published.

In this work we develop a framework to detect structural variants (SVs) in the genomes of related individuals. In particular, we consider low-coverage regimes that are more inexpensive than in high-coverage settings but are more susceptible to sequencing errors. To improve our ability to accurately predict SVs, we incorporate statistical models with familial relationship constraints and sparsity promoting penalties. We use simulated data to run experiments. Previous detection methods have used Poisson statistical models. The main contribution of this thesis is the use of the more general negative binomial distribution model in one-parent/one-child and two-parent/one-child frameworks. We extend the existing SPIRAL algorithm, which uses a Poisson log-likelihood objective function, and implement a negative binomial log-likelihood objective function. The genomes tested are haploid, meaning there is only one copy of each chromosome.