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Japan has often been cited as an example of a nation which is achieving the objectives of'sustainable development' as advocated by the Brundtland Commission. Various commentators believe that Japan attained rapid economic growth (at least until the current economic crisis which began in the early 1990s) while simultaneously protecting its environment, particularly after the oil crisis in 1973. However, this perspective ignores the fact that Japan's economic 'miracle' still involves the consumption of large quantities of low-entropy natural resources, and makes heavy use of the ecosphere's assimilative capacity for high-entropy wastes. Monetary analyses are excessively abstracted from biophysical reality and are therefore incapable of providing ecologically meaningful indices of sustainable development. Various biophysical approaches to assessment of sustainability have been proposed to fill the gap. In this dissertation, I use one of these, 'ecological footprint analysis,' to reassess the Japanese success story. The ecological footprint (EF) of a specified population has been defined as "the aggregate area of land and water ecosystems required continuously to produce the resource inputs and to assimilate the resource outputs of that population wherever on earth the land/water may be located." It provides a useful sustainability indicator in the form of the difference between a given country's ecological footprint and its domestic area of ecologically productive land/water. The gap between the two represents that country's 'ecological deficit' or 'sustainability gap.' Data from 1880 indicate that the per capita Japanese EF in the pre-industrial era was about 0.4 hectares (ha). By 1991 it had risen to 4.7 ha per person. Far from 'decoupling from nature,' the historic trend has seen a ten-fold increase in Japan's per capita load on the ecosphere. Japan is running a massive ecological deficit with the rest of the world. Moreover, since there are only about 1.5 ha of ecologically productive land and 0.5 ha of ecologically productive ocean per capita on Earth, Japanese material standards cannot be extended to the entire world population without depleting natural resource stocks. I conclude that the current level and form of Japanese resource consumption would be unsustainable if every country tried to do the same. Global society needs to consider alternative development paths that will reduce resource consumption by the inhabitants of high-income countries while enhancing their quality of life. / Applied Science, Faculty of / Community and Regional Planning (SCARP), School of / Graduate

Histological methods to estimate skeletal age at death, in forensic cases, are an alternative to the more traditional gross morphological methods. Most histological methods utilize counts of bone type within a given field for their estimation. The method presented in this paper uses the percentage area occupied by unremodeled bone to estimate age. The percentage area occupied by unremodeled bone is used in a linear regression model to predict skeletal age at death. Additionally, this method uses digital software to measure area rather than the traditional technique in which a gridded microscope is used to estimate area. The clavicle was chosen as a sample site since it is not a weight bearing bone and has little muscular insertion. These factors reduce the variation seen as a result of differences in lifestyle or activity pattern.

Wuthering Heights was significantly shaped by the pre-Darwinian scientific debate in ways that look ahead to Darwin's evolutionary theory more than a decade later. Wuthering Heights represents a cultural response to new and disturbing ideas. Darwin's enterprise was scientific; Emily Brontë's poetic. Both, however, were seeking to find ways to express their vision of the nature of human beings. The language and metaphors of Wuthering Heights suggest that Emily Brontë's vision was, in many ways, similar to Darwin's.

Body weight in mammals is defended so that small changes in weight evoke neuroendocrine and metabolic responses that encourage a return to one’s previous weight. While these homeostatic responses have been more commonly studied in the case of weight loss, our lab has developed a mouse model of overfeeding to study the physiology of defense against weight gain. In response to overfeeding-induced weight gain, the return to previous body weight is mediated primarily by a striking reduction in food intake, which persists until pre-overfeeding body weight is restored. However, preliminary data do not suggest activation of anorectic POMC neurons which reduce food intake or inhibition of the appetite stimulating AgRP or NPY neurons in the arcuate nucleus of the hypothalamus. Furthermore, we found that adipose tissue from overfed mice does not show the same inflammatory response as mice that have become obese slowly due to ad libitum high-fat diet (HFD) consumption. Paradoxically, despite the existence of mammalian systems that defend against weight gain, average body weight in humans has been on the rise over the last half century. Concomitant with the rise in obesity rates, has been increasing availability and consumption of processed and fast foods which are generally high in sugar, salt, and fat making them extremely palatable and calorically dense. Both the caloric density and enticing taste of the foods have been implicated in causing overconsumption and contributing to a rise in average body weight and prevalence of obesity. Thus, while controlling for caloric density we have investigated whether diet palatability can increase body weight and suppress defense against weight gain in mice. We designed our studies so that all diets were of the same caloric density and therefore varied only proportion of calories derived from fats, carbohydrates, and protein. Palatability is the relative subjective preference of one food over another; in our mouse studies we equated preference, when given, a choice with palatability. We confirmed that liquid diets sweetened with sucrose or the non-nutritive sweeteners sucralose and saccharin were preferred over non-sweetened diets. In 12 day feeding studies, although we found that sweetened diets were more palatable than unsweetened diets, they did not increase caloric intake or body weight. Next, we tested whether increasing percent calories from fat leads to increases in palatability or caloric intake. In a similar 12 day feeding preference study, we found diets higher in percent calories from fat (high-fat diet = HFD) were preferred to diets with lower percent calories from fat (low-fat diet = LFD) and that the access to a HFD increased caloric intake and body weight. Employing a four-week single diet feeding study, we also found a linear relationship between percent calories from fat and caloric intake consistent with our hypothesis that percent calories from fat is sensed and modulates caloric intake. To test whether HFD can suppress defense of body weight, we used an overfeeding paradigm which I help develop, to test whether ad libitum access to a HFD prevented a return to the original body weight following overfeeding. HFD did attenuate the hypophagic response to overfeeding and prevented a return to each mouse’s initial weight with the mice having access to the HFD mice stabilizing at a higher body weight. Palatability has traditionally been ascribed to sensing of smell and taste, however, macronutrients can also be sensed within intestinal tract. To determine whether the effects of percent calories from fat require naso-oral sensing to modulate feeding behavior, we used an intragastric feeding system to bypass taste and smell and deliver HFD directly into the stomach of mice. Even in the absence of oropharyngeal sensing, HFD in the gut was sufficient to increase ad libitum caloric intake of a low-fat diet and increase body weight. Finally, based on our findings of post-oral fat sensing driving caloric intake, we tested whether post-oral sensing of percent calories from fat was sufficient to condition a flavor preference. However, we found that when caloric density was controlled, a high percent calories from fat was not sufficient to condition a flavor preference.

The ability to generate cardiomyocytes from human induced pluripotent stem cells (hiPSCs) provides unprecedented opportunities in the study and treatment of cardiac diseases. The objective of this dissertation is the development of novel methods of utilizing hiPSC-derived cardiomyocytes (hiPSC-CMs). First, we leveraged the potential of hiPSC-CMs to model congenital heart disease caused by mutations in the transcription factor ZIC3. We developed a method to directly explore the effect of ZIC3 inhibition using hiPSCs at a molecular, cellular, and functional level through utilization of CRISPR interference. Our results identified the role of ZIC3 in regulating Nodal signaling, Wnt signaling, and cell structure and motility processes during cardiac development, suggesting that ZIC3 mutation leads to congenital heart disease in humans by the abnormal regulation of multiple steps during left-right axis establishment. Next, we leveraged the potential of hiPSC-CMs to treat myocardial infarction. We demonstrated that the extended delivery of extracellular vesicles secreted by hiPSC-CMs could attenuate injury and promote recovery of the heart after infarction by regulating apoptosis and inflammatory pathways. These results suggest that hiPSC-CM secreted extracellular vesicles represent a novel cell free tool in the treatment of myocardial infarction and the understanding of heart recovery.

Memory serves an integral function in every aspect of human life. Losing that function can be adevastating consequence of disease, dementia, and trauma. In order to develop treatments or prophylactics for memory disorders we must identify the neural basis of memory. Animal research has made prominent strides studying the neural correlates of memory by examining the more easily observable and manipulable neural correlates of spatial context, since the brain regions necessary for declarative memory intersect profoundly with those needed for spatial navigation. My research has two main goals. My first two studies, in Chapters 2 and 3, translate animal research relating the neural correlates of space to memory processes, and go beyond animal work to explore how internal features of experience such as goal states influence these conjunctive representations of space and memory. In Chapter 4, I expand my scope to examine how another internal feature, emotional context, affects the same brain regions on a network level to influence memory representations in the human brain. To perform these studies I recorded directly from the human brain in epilepsy patients performing a variety of memory tasks. First, I measured single-neuron activity as subjects navigated a virtual environment, encountering various objects at unique locations. As subjects moved through the environments, they were instructed to recall the locations of specific objects they encountered—I identified neurons in the human entorhinal cortex, called “memory-trace cells”, which selectively activated near the object-location that people were instructed to retrieve from memory. This is the first evidence that neurons in the brain can be tuned to the spatial context of an event for memory, and demonstrated a direct link between memory retrieval and the spatial tuning properties of neurons. For my second study, I examined whether spatially-tuned neurons in the MTL discharge at intervals organized by theta (2–10 Hz) oscillations (which represent network level brain-activity). I identified a particular pattern that is prominent in rodents, called “phase precession”, during which spatially-tuned neurons spike slightly faster than the network oscillation, and which is theorized to hold great value throughout the brain for learning and memory. In addition to discovering this pattern for spatial sequences, I discovered that phase precession was also present during more abstract features of experience, like the specific goal a person was seeking. These findings suggest that principles of network-level brain activity for organizing spatial navigation may extend to humans, and to broader forms of cognition and memory. Finally, I examined the role of the amygdala in memory encoding during a verbal episodic memory task, finding that the emotional context of a word influenced the probability of its subsequent recall. By measuring the prevalence and coordination of brain oscillations in the amygdala-hippocampal circuit, I found that gamma oscillations (30–120 Hz) increased in both regions as a function of word arousal and encoding success, and connectivity within the amygdala-hippocampal circuit also showed significant theta-gamma coupling as a function of memory and high arousal. Furthermore, direct 50 Hz stimulation impaired memory for high arousal words. These findings suggest a causal relationship between gamma oscillations in the amygdala-hippocampal circuit for memory as a function of emotional context during encoding. My work generalizes important neuronal principles from animal studies to humans (such as spatially-tuned neurons and phase precession), but also extends those findings more deeply to memory, and to internal/subjective aspects of memory that are difficult to directly measure in animals. Overall this work represents an important step towards understanding how the human brain enables declarative memory.

We hypothesized that bone evolved, in part, to enable bony vertebrates to escape danger in the wild. In support of this notion we show here that a bone-derived signal is necessary to develop an acute stress response (ASR). Indeed, exposure to various types of stressors in mice, rats (rodents) and humans leads to a rapid and selective surge of circulating bioactive osteocalcin because stressors favor the uptake by osteoblasts of glutamate, which prevents inactivation of osteocalcin prior to its secretion. Osteocalcin permits manifestations of the ASR to unfold by signaling in post-synaptic parasympathetic neurons to inhibit their activity, thereby leaving the sympathetic tone unopposed. Osteocalcin is also engaged in a complex cross talk with the other principal endocrine regulator of the ASR, the hypothalamic-pituitary-adrenal axis. Exogenous osteocalcin stimulates an increase in circulating adrenal steroids and Ocn-/- mice born of Ocn-/- mothers exhibit a severe developmental defect in adrenal steroidogenesis of corticosterone and aldosterone. Like wild-type animals, adrenalectomized rodents and adrenal-insufficient patients can develop an ASR, and genetic studies suggest that this is due to their high circulating osteocalcin levels. We propose that osteocalcin defines a bony vertebrate specific endocrine mediation of the ASR. Together these results demonstrate a role for bone in the physiology of danger.

This dissertation consists of three essays in the field of applied environmental economics. The first two essays study the effect of daily ambient temperature on police officer behavior. Police officers often exercise substantial discretion when making highly consequential decisions, which can lead to unfair and arbitrary law enforcement. In the first chapter, I exploit daily ambient temperature as a source of transitory, high-frequency shocks and examine how it affects an officer’s decision whether to discount a driver’s speeding penalty in Florida. I find that a 1-standard-deviation increase in temperature lowers the driver’s probability of receiving a lenient ticket by 2%. In addition, using traffic monitoring data and crash reports, I do not find evidence of decreased police effort or increased reckless driving on hot days. I show that the reduction in leniency is disproportionally borne by white drivers, who on average benefit more from officer leniency. In addition, I find that newly hired officers become less affected by temperature as they accumulate more experience on the job. The first chapter shows that daily ambient temperature has a significant effect on police officers’ professional performance. Inspired by this result, in the second chapter I study the effect of temperature on officers’ online expressed sentiment. Mood changes caused by temperature could be a potential mechanism for officers’ behavioral changes observed in the first chapter. To study this question, I obtained messages posted on an online police forum that is popular among Florida police departments. I find that a 1-standard-deviation increase in temperature leads to a 3.5% increase in the use of profanity. In addition, higher temperature has a negative but nonlinear relationship with expressed sentiment. I also find limited evidence of a change in forum activity or discussion topics on relatively hot days, which suggests that these results are likely to be driven by temperature’s effect on officers’ mood. Taken together, the first two chapters highlight the sensitivity of law enforcement behavior to transitory shocks such as environmental conditions. The third chapter, which is joint work with Xinming Du, explores the impact of the 2018 China- U.S. trade war on air pollution in China. Since the Chinese economic data is heavily censored, we take air pollution as a proxy for measuring economic activity. Using city-industry level trade data, we construct a Bartik-style trade war exposure measure for cities in China and compare the pollution trajectory of cities in the top quartile of our measure to those in the bottom quartile under a difference-in-difference design. In addition, to test whether local governments relaxed their enforcement of environmental policies in response to the trade war, we look at whether firms changed their tendency of polluting in the dark during the trade war. Our analysis finds a negative but small and not robust effect of the U.S. tariffs on China’s air quality and no effect of the Chinese retaliatory tariffs. In addition, we find no impact on disguised pollution behaviors of local firms. We conclude that the trade war had minimal effect on China’s economic activity.

The question of how we form memories has fascinated scientists for decades. The hippocampus and surrounding medial-temporal-lobe (MTL) structures are critical for both memory and spatial navigation, yet we do not fully understand the neuronal representations used to support these behaviors. Much research has examined how the MTL neurally represents spatial information, such as with “place cells” that represent an animal’s current location or “head-direction cells” that code for an animal’s current heading. In addition to attending to current spatial locations, navigating to remote destinations is a common part of daily life. In this dissertation I investigate how the human MTL represents the relevant information in a goal-directed spatial-memory task. Specifically, I analyze single-neuron and local field potential (LFP) data from neurosurgical patients with respect to their spatial navigation and memory behavior, with a focus on probing the link between neuronal firing, oscillations, and memory. In Chapter 2, I find that the firing rates of many MTL neurons during navigation significantly change depending on the position of the current spatial target. In addition, I observe neurons whose firing rates during navigation are tuned to specific heading directions in the environment, and others whose activity changes depending on the timing within the trial. By showing that neurons in our task represent remote locations rather than the subject’s own position, my results suggest that the human MTL can represent remote spatial information according to task demands. In Chapter 3, I find that during encoding the left hippocampus exhibits greater low theta power for subsequently recalled items compared to unrecalled items. I also find that high frequency activity and neuronal firing in the hippocampus distinguish between item-filled compared to empty chests. Finally, I find that MTL cells’ firing rates and the differential timing of spikes relative to low frequency oscillations in the LFP distinguish between subsequent recall conditions. These results provide evidence for a distinct processing state during the encoding of successful spatial memory in the human MTL. Overall, in this thesis I show new aspects of the neural code for spatial memories, and how the human MTL supports these representations.