Several qualitative models have been proposed to explain significant historical shifts in both societal and technological domains. Despite advancements in modeling, certain transitions remain enigmatic, such as the early shift from hunter-gatherer to agriculture-dependent societies, marked by a substantial increase in effort. Another perplexity involves the coordination of agricultural activities into cities and civilizations, despite the larger overhead effort and loss of independence. The exploration of simplified models featuring aggregate, dynamic, and nonlinear processes holds the potential to uncover distinctive facets of each transition. The transitions under consideration span from hunter-gatherer societies to agricultural societies and then to early civilizations.  Other analogies are suggested for further exploration for transitions to market systems, capitalism, industrialization, and sustainable societies, incorporating factors like land pressures, economies of scale, suppressed growth, and chain reactions.

Diverse modeling approaches can be employed for these transitions. Initially, fundamental characteristics, such as the width and midpoint of transitions, are deduced by analyzing historical events influencing the transition. However, this approach offers limited insights into the dynamics or parameters of the transition. For a more comprehensive understanding, two historical transitions are examined using a simple phenomenological model. These simplified models do not aim to quantitatively address the intricate details of actual historical mechanisms; instead, they leverage analogies to natural systems to gain insights.

The androgen testosterone (T) and its metabolite, dihydrotestosterone (DHT), are released from the gonads and act in the brain and periphery to control many male-typical traits, including male sexual behavior (MSB). The classical model of androgenic action asserts that T, or DHT binds to a single species of intracellular androgen receptor (AR), that acts as a transcription factor to induce transactivation of androgen-regulated genes. Accordingly, androgens may take hours or days to assert their full influence and transcriptional activity of the AR may persist long after circulating androgens decline. Despite decades of research on testicular factors that control MSB there are still major gaps in our knowledge of how androgens exert their effects on MSB via the AR; most related cellular and molecular data are derived from studies of prostate cancer cell lines grown on cell culture plates--the applicability of these data to other AR positive cell-types and to regulation of behavior is unknown. Consequently the pattern of endogenous gonadal release and its actions on the genome to control MSB requires more research.

In the present dissertation I tested the hypothesis that discontinuous hormone replacement paradigms that maintain endogenous-like hormone release profiles are more effective than constant release regimens at maintaining MSB in castrated male hamsters. Further, by employing a discontinuous T replacement regimen I developed a paradigm by which to investigate many general aspects of T action, including its interaction with the AR, and its efficacy in maintaining and restoring MSB.

Experiments 1 and 2 establish that endogenous-like T replacement regimens require a lower total concentration and duration of circulating androgen availability to effectively maintain and restore MSB than T replacement via other commonly employed regimens. I injected hamsters daily with T dissolved in an aqueous vehicle that raises circulating concentrations for only 7h per day; hamsters that received only 15 μg T in this manner maintained pre-operative- like MSB even though much higher doses are insufficient when administered in a long-lasting oil vehicle (Experiments 1 and 2). Additionally, a majority of hamsters injected with the low-dose of 50 μg T as infrequently as once per 7 days maintained the ejaculatory reflex despite having supraphysiological concentrations of circulating T for only 7 hours per week.

A follow-up study (experiment 3) suggests a more complex and potentially interesting regulation of the AR by its ligands than is typically appreciated. DHT does not maintain MSB in Syrian hamsters. I implanted 30 mm of DHT in Silastic tubing subcutaneously into hamsters, to generate circulating DHT concentrations an order of magnitude greater than those present endogenously, concurrent with daily T injections of 25 μg in aqueous solution. The high doses of constantly circulating DHT failed to inhibit the restoration of MSB by low-dose T treatment, instead surprisingly enhancing T's restoration of the behavior, suggesting that DHT and T do not compete for the same binding sites and the possibility of multiple AR species with different affinities for T and DHT or differential uptake of these hormones in the MSB neural circuit.

Discontinuous, low dose androgen treatment to castrated Syrian hamsters was then used to probe the timing of protein synthesis required for the expression of MSB (experiment 4). Hamsters were injected with 100 μg T once per week, while also being injected with the protein synthesis inhibitor anisomycin at varying times relative to the T injection. Anisomycin treatment from 6 to 12 hours after T injection blocked the maintenance of MSB, whereas injections before and up to 3 hours after T treatment were without significant effect. By taking into account the time course of anisomycin inhibition of protein synthesis, a time period of T-induced protein synthesis necessary for the maintenance of MSB was identified--12-15 h post-injection.

Finally, photoperiod markedly affects T and MSB in Syrian hamsters. Dopamine and norepinephrine are two critical neurotransmitter systems necessary for the expression of MSB: norepinephrine induces generalized arousal of the CNS necessary for motivated behavior, whereas dopamine must be released into the medial preoptic area (mPOA) to induce MSB. Experiment 5 tested whether upregulation of dopamine or norepinephrine signaling could bypass short-photoperiod induced sexual quiescence. Apomorphine and yohimbine were administered just prior to MSB tests to photoregressed hamsters, but failed to increase sexual behavior, suggesting that upregulation of these two systems is not sufficient to restore MSB during the season of reproductive quiescence.

Overall, the research herein demonstrates that T replacement therapy that more closely mimics endogenous T profiles is more effective at maintaining MSB and possibly other traits controlled by androgens. Exploitation of this paradigm may enhance understanding of hormone signaling of motivated behavior. Additionally, the present paradigm will facilitate specification of the genomic and proteomic underpinnings of MSB as well as molecular and cellular research into this complex social behavior.

Projection neuron subtype identities in the cerebral cortex are established through the expression of pan-cortical and subtype-specific effector genes, which execute terminal differentiation programs that bestow neurons with a glutamatergic neuron phenotype and subtype-specific morphology, physiology, and axonal projections. Whether pan-cortical glutamatergic and subtype-specific characteristics are regulated by the same genes or controlled by distinct programs remains largely unknown. Here, I show that the transcriptional corepressor, TLE4, is expressed specifically in postmitotic corticothalamic projection neurons, where it functions to regulate the molecular, dendritic, and electrophysiological characteristics unique to corticothalamic neurons. I also demonstrate that TLE4 directly interacts with the forebrain embryonic zinc finger protein, FEZF2, within corticothalamic projection neurons to facilitate the transcriptional repression of subcerebral projection neuron identity. Through the utilization of our novel Fezf2-Bac-EnR transgenic mouse line, I was then able rescue the molecular defects of corticothalamic neurons in the cortex of Tle4 knockout mice and restore the dendritic and electrophysiological characteristics of theses neurons. Overall, the work presented provides an in-depth investigation into the transcriptional regulation of subtype-specific cortical projection neuron identity by Tle4 and Fezf2, thereby contributing novel insight into our current understanding of mammalian cortical development.

Many natural products, including fatty acids, polyketides, and non-ribosomal peptides have pharmacologically valuable properties. These products are biosynthesized using diverse pathways, but they employ very similar machineries and chemical transformations. Central to these pathways are carrier proteins, which covalently tether a growing intermediate. Small, dynamic carrier proteins facilitate transport of intermediates to subsequent reaction partners within the biosynthetic pathway, and protect them from unfavorable reactions in the cytosol. This dissertation focuses on these carrier proteins, characterizing them both structurally and biophysically. Solution state protein NMR methods are ideal for studying carrier proteins, given their small size and high flexibility.

Several studies of the Escherichia coli fatty acid synthase (FAS) pathway yielded significant information about the structure and dynamics of the acyl carrier protein (ACP). Increasing the basic understanding of how modular synthases function, interact, and maintain product specificity has been a driving goal; such information is critical to engineering de novo modular pathways. Identification of the proteins in the pathways is essential, but understanding how they move and interact remains an intellectual bottleneck. Using mechanism-based crosslinking, the E. coli ACP was trapped in functional interaction with the cognate dehydratase protein, FabA. Structures were determined crystallographically in collaboration with the Tsai lab at the University of California, Irvine and by NMR in collaboration with the Opella lab at the University of California, San Diego. Residual Dipolar Couplings from NMR, together with Accelerated Molecular Dynamics studies in collaboration with the McCammon lab at the University of California, San Diego led to the identification of key residues necessary for this protein-protein interaction, and quantification of the ACP's dynamics both as a free protein and during interaction with a partner.

Furthermore, studies of the actinorhodin polyketide synthase (PKS) pathway led to insights into the sequestration and cyclization of polyketide intermediates. To prevent unwanted side-reactions of polyketide intermediates, geometrically appropriate atom replacement mimetic probes were synthesized and loaded onto the actinorhodin ACP. Chemical shift perturbations of the protein amide resonances allowed monitoring of sequestration, as probes of longer length demonstrated larger perturbation of more residues than shorter polyketide probes.

Additionally, studies of the prodigiosin and pyoluteorin pathways give new information about sequestration. Traditional NOE methods were employed to solve the solution NMR structure of the pyoluteorin carrier protein, PltL, in multiple cargo states. For the first time, sequestration of intermediates was observed in a non-ribosomal peptide synthetase (NRPS) system. Further studies are underway to determine if sequestration is observed in other NRPS systems.

Finally, a follow-up to the ACP FabA project is in an early manuscript stage, detailing the E. coli ACP interaction with another partner, the ketosynthase FabB. NMR titration experiments, demonstrating key residues in the ACP FabB interaction are reported. In vivo complementation of the wt ACP with mutated ACPs showed that perturbing the ACP FabB interaction reduces E. coli's ability to produce unsaturated fatty acids at lower temperatures, connecting in vivo observations to in vitro effects.

While challenges and unknowns remain, the work of this dissertation provides significant progress towards the possibilities of engineering novel pathways to produce pharmaceutically relevant or biochemically valuable products.

High pressure turbine blades in gas turbine engines rely on thermal barrier coating (TBC) systems for protection from the harsh combustion environment. These coating systems consist of a ceramic topcoat for thermal protection, a thermally grown oxide (TGO) for oxidation passivation, and an intermetallic bond coat to provide compatibility between the substrate and ceramic over-layers while supplying aluminum to sustain Al2O3 scale growth. As turbine engines are pushed to higher operating temperatures in pursuit of better thermal efficiency, the strength of industry-standard bond coats limits the lifetime of these coating systems. Bond coat creep deformation during thermal cycling leads to a failure mechanism termed rumpling. The interlayer thermal expansion differences, combined with TGO-imposed growth stresses, lead to the development of periodic undulations in the bond coat. The ceramic topcoat has low out-of-plane compliance and thus detaches and spalls from the substrate, resulting in a loss of thermal protection and subsequent degradation of mechanical properties. New creep resistant Ni3Al bond coats were designed with improved high-temperature strength to inhibit this type of premature failure at elevated temperatures. These coatings resist rumpling deformation while maintaining compatibility with the other layers in the system. Characterization methods are developed to quantify rumpling and assess the TGO-bond coat interface toughness of experimental systems.

Cyclic oxidation experiments at 1163 °C show that the Ni3Al bond coats do not ex- perience rumpling but have faster oxide growth rates and are quicker to spall TGO than the (Pt,Ni)Al benchmark. However, the Ni3Al coatings outperformed the benchmark by over threefold in TBC system life due to a higher resistance to rumpling (mechanical degradation) while maintaining adequate oxidation passivation. The Ni3Al coatings eventually grow spinel NiAl2O4 on top of the protective Al2O3 layer, which leads to the detachment of the ceramic topcoat. Furthermore, bilayer Ni3Al+NiAl architectures have been investigated to improve the oxidation performance of the monolithic Ni3Al coatings while maintaining their high strength. These bilayer architectures are shown to improve the cyclic oxidation performance of the monolithic layers and increase the TBC system life. The design, characterization, and experimentation of these coatings is discussed and related to the development of high-strength coatings.

"Greek Historiography, Roman Society, Christian Empire: the Ecclesiastical History of Eusebius of Caesarea" addresses a major shift in Roman social, political, and religious history at the pivotal turn of the fourth century AD. When Christianity was legalized in 313, the Christian church of the eastern Roman Empire, where the pagan Licinius ruled as emperor until the Christian Constantine defeated him in 324, remained in an insecure position. The Greek-speaking eastern Roman elite of this period only admitted outsiders to their circles who displayed a civilized manner of life inculcated in the elite Greek educational curriculum (paideia), the kind of life embodied by Greek philosophers. It was, I argue, to depict this newly legalized Christianity as the models of the philosophical life that Eusebius of Caesarea wrote the first history of the church in the 310s AD. Whereas Eusebius' Ecclesiastical History is usually studied for its intra-Christian discourse, this study considers the History as a Greek text aimed at Roman elites. I demonstrate that the History's reconfiguration of Greek historiographical genres constructed Christianity as a civilized and educated institution whose leaders were worthy to educate and advise the Roman ruling classes.

The first three chapters present a reading of the Ecclesiastical History within the rich variety of Greek historiographical genres. The first chapter applies genre theory to show that Eusebius' History was a combination of the Greek genres of national history and philosophical biography. This combination of genres presented the church as a nation of philosophers ready to assume the standard role of philosophers in the Roman Empire, of teaching Roman elites a civilized manner of life and of advising Roman emperors. The second chapter scrutinizes the character of Eusebius' Christianity by studying eighty mini-biographies embedded into the History that echo Diogenes Laertius', Philostratus', and Porphyry's philosophical biographies. By highlighting Christians' homogeneous and universal intellectual prowess, these profiles represent the church as reliable educators and advisors. The third chapter argues that, in a riposte to the grand genre of Greek war history that valorized other nations' pasts, Eusebius transformed persecution and martyrdom from an orderly legal procedure into a violent struggle told in the manner of the great Greek historian Thucydides. As the church's enemy in the struggle martyrdom was Satan and not the Roman persecutors of Christianity, Eusebius could call martyrdoms "wars contested for peace in the soul," critiquing Greek war history with Greek philosophical discourse. His church emerges victorious by remaining steadfastly loyal to God, surpasses the warriors in Greek literature by its virtuous conduct of the wars, and, by scapegoating the demons, absolves the Roman Empire of any systemic flaw that would discourage Christians from supporting it.

The next three chapters complement my analysis of the Ecclesiastical History's genres by locating Eusebius' Christianity in the social structures of the early fourth-century Roman Empire. The fourth chapter introduces Eusebius' experience of living under Rome through a thick description of the archaeological remains of his home city, Caesarea Maritima. Caesarea was unmistakably a Roman creation, as the governor of Palestine resided there and the city's topography featured numerous monuments to Roman power, including monuments to philosophers who were respected in the city. The peaceful, prosperous and well-connected life that a wealthy man such as Eusebius could live there solidified Eusebius' loyalty to the Roman Empire. The fifth chapter shows how Eusebius integrated the church into the Empire: he delineated networks of bishops and intellectuals that stretched across the Empire from Mesopotamia to Gaul and Carthage. The geographically diffused church displays a variety of mechanisms for maintaining long-distance cohesion, and the cohesive and homogeneous philosophical church bound together by these ties attracts favor from Roman leaders throughout the History. Through these encounters Eusebius patterned the church's relationship with the Empire after that of Greek philosophers: philosophers typically stayed in contact with emperors and governors while maintaining a critical distance from imperial power, so as to provide impartial advice for imperial officials. Eusebius placed Christians into the beneficial imagined relationship that philosophers had held with the Empire, from which they would strengthen imperial governance. The sixth chapter contextualizes the History in Eusebius' larger literary oeuvre. He published the History when he was writing his long magnum opus, the Gospel Preparation and Gospel Demonstration, a comprehensive exposition and defense of Christian doctrine. Eusebius' simultaneous publication of the Preparation-Demonstration with the History emulated the combination of expository works with biographical narratives in Greek philosophical curricula. Eusebius' forging of a comprehensive program for training Christians to think and act as philosophers positioned the church to displace Greek philosophical schools as the premier intellectual institution of the Empire. From this position, the church could then reinforce the Empire's mission to civilize the inhabited world.

The History articulated a central role for Eusebius' church in Rome's imperial regime. Where the most prominent role of Greek philosophers was to educate imperial elites and advise Roman emperors, Eusebius' assertion of Christians' intellectual prowess claimed the church's superiority as a philosophical institution. Eusebius published his vision at a fortuitous moment, for when the Christian emperor Constantine conquered the eastern Roman Empire in 324, the History had already advertised church leaders' competence in the philosophical profession. By telling the church's history within the Greek historiographical tradition stretching back to Herodotus and Thucydides, therefore, Eusebius' History became a catalyst for the church's integration into the power structures of the Roman Empire in the fourth century.