Browsing by Subject "Development"

Following World War II, in the estimate of the Congress of Industrial

Organizations (CIO), one out of every six people in the city of Gadsden, Alabama

belonged to the union, making it the “best organized CIO city in the US.” At

midcentury, as most southern communities were growing more antiunion and more

conservative, workers in this city of 60,000 in northeastern Alabama insisted that they

had the same interests as union workers elsewhere and looked to a liberal Democratic

Party and robust federal government to bolster them. In the late 2010s, little evidence

remains that Gadsden and Etowah County were once so different from the rest of the

South. White people here often vote for Republicans. Unions have all but vanished. Development officials openly brag that 94 percent of

industry in the county operates unorganized.

A visitor to Gadsden today might find it hard to believe that the community was

once perhaps the most pro-CIO city the world has ever known. Yet those who came to

study Gadsden in the late 1940s and early 1950s, to see it as a union town, like the

famous American author John Dos Passos, had to reckon with a transformation even

more difficult to conceive: just a few years before their arrival, the city was perhaps the

most anti-CIO town in the country. In the mid-to-late 1930s, it was dangerous to give

even tacit support to the federation. On more than one occasion, workers joined with

police and civic leaders to literally run organizers out of Alabama. But this antiunionism

represented even yet another sea change: in the late 1910s and early 1920s, Gadsden had

also been something like a union town.

The purpose of this dissertation is to use Gadsden as a case study to come to

terms with the historical forces that have turned its feeling about unions upside down

and inside out. When the residents of Gadsden changed their minds

about unionism, for the most part, they did so as a community. This consensus was not

the result of shared values; neither was it compelled by the dominance of local elites. It

was, to the contrary, an outcome of Gadsden’s relationship to the out-of-town capitalists

who sustained it. For all but a few exceptional years in the twentieth century (when

Gadsden could be a union town), residents here have had to fight for capital against

people from communities like their own. In both of the cases in which this working class

city has forsaken unionism, it was because, and only because, that was what American capitalism demanded of it.

The evolution of reproductive strategies involves a complex calculus of costs and benefits to both parents and offspring. Many marine animals produce embryos packaged in tough egg capsules or gelatinous egg masses attached to benthic surfaces. While these egg structures can protect against environmental stresses, the packaging is energetically costly for parents to produce. In this series of studies, I examined a variety of ecological factors affecting the evolution of benthic development as a life history strategy. I used marine gastropods as my model system because they are incredibly diverse and abundant worldwide, and they exhibit a variety of reproductive and developmental strategies.

The first study examines predation on benthic egg masses. I investigated: 1) behavioral mechanisms of predation when embryos are targeted (rather than the whole egg mass); 2) the specific role of gelatinous matrix in predation. I hypothesized that gelatinous matrix does not facilitate predation. One study system was the sea slug Olea hansineensis, an obligate egg mass predator, feeding on the sea slug Haminoea vesicula. Olea fed intensely and efficiently on individual Haminoea embryos inside egg masses but showed no response to live embryos removed from gel, suggesting that gelatinous matrix enables predation. This may be due to mechanical support of the feeding predator by the matrix. However, Haminoea egg masses outnumber Olea by two orders of magnitude in the field, and each egg mass can contain many tens of thousands of embryos, so predation pressure on individuals is likely not strong. The second system involved the snail Nassarius vibex, a non-obligate egg mass predator, feeding on the polychaete worm Clymenella mucosa. Gel neither inhibits nor promotes embryo predation for Nassarius, but because it cannot target individual embryos inside an egg mass, its feeding is slow and inefficient, and feeding rates in the field are quite low. However, snails that compete with Nassarius for scavenged food have not been seen to eat egg masses in the field, leaving Nassarius free to exploit the resource. Overall, egg mass predation in these two systems likely benefits the predators much more than it negatively affects the prey. Thus, selection for environmentally protective aspects of egg mass production may be much stronger than selection for defense against predation.

In the second study, I examined desiccation resistance in intertidal egg masses made by Haminoea vesicula, which preferentially attaches its flat, ribbon-shaped egg masses to submerged substrata. Egg masses occasionally detach and become stranded on exposed sand at low tide. Unlike adults, the encased embryos cannot avoid desiccation by selectively moving about the habitat, and the egg mass shape has high surface-area-to-volume ratio that should make it prone to drying out. Thus, I hypothesized that the embryos would not survive stranding. I tested this by deploying individual egg masses of two age classes on exposed sand bars for the duration of low tide. After rehydration, embryos midway through development showed higher rates of survival than newly-laid embryos, though for both stages survival rates over 25% were frequently observed. Laboratory desiccation trials showed that >75% survival is possible in an egg mass that has lost 65% of its water weight, and some survival (<25%) was observed even after 83% water weight lost. Although many surviving embryos in both experiments showed damage, these data demonstrate that egg mass stranding is not necessarily fatal to embryos. They may be able to survive a far greater range of conditions than they normally encounter, compensating for their lack of ability to move. Also, desiccation tolerance of embryos may reduce pressure on parents to find optimal laying substrata.

The third study takes a big-picture approach to investigating the evolution of different developmental strategies in cone snails, the largest genus of marine invertebrates. Cone snail species hatch out of their capsules as either swimming larvae or non-dispersing forms, and their developmental mode has direct consequences for biogeographic patterns. Variability in life history strategies among taxa may be influenced by biological, environmental, or phylogenetic factors, or a combination of these. While most prior research has examined these factors singularly, my aim was to investigate the effects of a host of intrinsic, extrinsic, and historical factors on two fundamental aspects of life history: egg size and egg number. I used phylogenetic generalized least-squares regression models to examine relationships between these two egg traits and a variety of hypothesized intrinsic and extrinsic variables. Adult shell morphology and spatial variability in productivity and salinity across a species geographic range had the strongest effects on egg diameter and number of eggs per capsule. Phylogeny had no significant influence. Developmental mode in Conus appears to be influenced mostly by species-level adaptations and niche specificity rather than phylogenetic conservatism. Patterns of egg size and egg number appear to reflect energetic tradeoffs with body size and specific morphologies as well as adaptations to variable environments. Overall, this series of studies highlights the importance of organism-scale biotic and abiotic interactions in evolutionary patterns.

The bone morphogenetic protein (BMP) signaling pathways have important roles in embryonic development and homeostasis. BMPs have been shown to pattern the dorsoventral axis in zebrafish (Danio rerio) early during embryonic development by establishing a dorsal-to-­ventral ligand gradient. During tumorigenesis, BMPs primarily function as tumor promoters, as an increase in BMP expression is associated with an increase in invasion, migration, epithelial-­to-­mesenchymal transition (EMT), proliferation and angiogenesis.

Although it is clear that BMPs play multiple roles in these biological events, the precise mechanism by which BMPs mediate these functions is not fully understood. Canonically, BMP ligands signal through cell surface receptor complexes that phosphorylate transcription factors, Smad1, Smad5 and Smad8, which mediate BMP-­ specific gene transcription. While studying BMP signaling during cancer progression, we determined that BMPs unexpectedly signal through the canonical TGF-β-­responsive transcription factors, Smad2 and Smad3.

We determined that BMP-­induced Smad2/3 signaling occurs preferentially in embryonic cells and transformed cells. BMPs signal to Smad2/3 by stimulating complex formation between the BMP binding TGF-­β superfamily receptors, ALK3/6, and the Smad2/3 phosphorylating receptors, ALK5/7. BMP signaling through Smad1/5/8 induces MET, while Smad1/5 and Smad2 mediate dorsoventral axis patterning in zebrafish embryos and Smad3 facilitates invasion.

Taken together, our data provides evidence that BMP-­induced Smad2 and Smad3 phosphorylation occurs through a non-­canonical signaling mechanism to mediate multiple biological events. Thus, the signaling mechanisms utilized by BMPs and TGF-­β superfamily receptors are broader than previously appreciated.

This dissertation examines the politics of industry and industrialization in Ethiopia. I analyze how multinational alcohol companies and the Ethiopian state are brewing development, meaning spurring the creation of industrial linkages through the production, distribution, sale, and consumption of commercial beer as well as their corresponding socio-cultural consequences as the Ethiopian people respond to such processes. An ethnography at the nidus of corporate supply and value chain management and the state’s industrialization policy, the following pages examine how state and companies are making industry to meet the developmentalist goals of an Ethiopian ruling party and the needs of capital, respectively, albeit not without local collaboration and resistance.

This study uses the data from the National Institute for Children Health and Development Study of Early Child Care and Youth Development to evaluate features of wage and childcare price changes that are associated with positive effects on children's early cognitive skills. Identifying beneficial characteristics of changes in market variables is especially relevant in a policy environment where the main priority of tax incentives related to the use of childcare is not facilitating the formation of children's cognitive skills, but reducing reliance on the welfare system through increase in employment among poor households.

We estimate jointly the discrete household choices related to the employment status of the mother and the use of a paid care mode, the demand functions for quantity and quality of childcare, the production function for cognitive outcomes, the wage process for the mother, and childcare price equations based on the hedonic pricing method, while at the same time introducing unobserved heterogeneity in the disturbance terms of the estimated outcomes. Our strategy for handling selection problems also utilizes the exogenous variation in childcare prices across the 10 geographical markets defined by the study sites in the NICHD SECCYD dataset, which in our model influence choices, but do not affect cognitive outcomes directly.

Our results show that failing to account for common unobserved characteristics would lead to underestimating the impact of all analyzed wage and price changes. We find that prices and wages do not have a statistically significant impact on the quality of paid care, while the marginal product of that attribute of care is positive for almost all input combinations in the production of cognitive attainment. Therefore, a policy utilizing changes in wages and prices can be effective in improving early cognitive skill only through the impact of those changes on the intensity of paid care use.

The comparison of the effects of wage and price changes on early cognitive skills for three sets of values of the observable household characteristics representing low, middle and high income households lead to the following conclusions: (1) a tax credit for working mothers and childcare subsidies for center-based care can bring disproportionate gains for children in low and middle income groups; (2) subsidizing paid home care for children less than three and a half years old can be more effective than subsidizing center-based care for the same age group in terms of improving cognitive outcomes at the age of five; (3) conditioning childcare assistance for paid care on the employment status of the mother does not seem to have a strong negative effect on early skill formation; and (4) tax incentives affecting wage rates and childcare prices prove to be beneficial for the formation of early cognitive skills only when they are implemented while the child is less than three and a half years old.

Naturally-occurring cell death is a fundamental developmental mechanism for regulating cell numbers and sculpting developing organs. This is particularly true in the central nervous system, where large numbers of neurons and oligodendrocytes are eliminated via apoptosis during normal development. Given the profound impact of death upon these two major cell populations, it is surprising that developmental death of another major cell type – the astrocyte – has rarely been studied. It is presently unclear whether astrocytes are subject to significant amounts of developmental death, or how it occurs. Here we address these questions using mouse retinal astrocytes as our model system. We show that the total number of retinal astrocytes declines by over 3-fold during a death period spanning postnatal days 5-14. Surprisingly, these astrocytes do not die by apoptosis, the canonical mechanism underlying the vast majority of developmental cell death. Instead, we find that microglia kill and engulf astrocytes to mediate their developmental removal. Genetic ablation of microglia inhibits astrocyte death, leading to a larger astrocyte population size at the end of the death period. However, astrocyte death is not completely blocked in the absence of microglia, apparently due to the ability of astrocytes to engulf each other. Nevertheless, mice lacking microglia showed significant anatomical changes to the retinal astrocyte network, with functional consequences for the astrocyte-associated vasculature leading to retinal hemorrhage. These results establish a novel modality for naturally-occurring cell death, and demonstrate its importance for formation and integrity of the retinal gliovascular network.

Public health data show that many everyday reckless behaviors reach a developmental peak in adolescence, with adolescents engaging in more reckless behaviors than both children and adults. In contrast, most studies of decision-making across development do not find laboratory risk-taking to peak in adolescence. Here, I focus on two factors that contribute to the discrepancy between public health and laboratory findings: ambiguity and social context. Everyday decisions tend to involve ambiguous decisions (choices with unknown probabilities), while previous laboratory studies have largely focused on risky decisions (choices with known probabilities). Consequently, little is known about the ambiguity preferences of young children. Across three behavioral studies, I show that ambiguity aversion is absent in 5-year-old children (Chapter 2) and 8- and 9-year-old children (Chapter 3) but present in 15- to 18-year-old adolescents (Chapter 4) and adults (Chapters 2 to 4). The results of Chapters 2 through 4 indicate that the willingness to take ambiguous gambles, like the willingness to take risky gambles, does not peak in adolescence. Everyday decisions also often occur in social contexts when friends are present and outcomes can be shared, whereas most laboratory studies occur in social isolation. In Chapter 5, I use functional magnetic resonance imaging to show that neural response to reward for self and for friend are similar in a sample of young adults (ages 18 to 28), and that neural response to reward linearly decreases with age when participants are watched by their friends but not when they are alone. In Chapter 6, I use behavioral modeling to show that adults value rewards similarly for themselves and for their friend. Adolescents, in contrast, value their own rewards more than those of their friend, but the presence of their friend reduces this valuation difference. The results of Chapters 5 and 6 indicate that the presence of friends prompts adolescents and young adults to engage in behavior that benefits both themselves and their friends. Collectively, the results in this dissertation demonstrate the need to consider contextual influences on decision-making in order to better capture everyday decision behavior in the laboratory.

A major goal of biological studies is to understand how complex forms develop and evolve. Each form is the result of molecular developmental patterning, growth, and the accumulation of changes in these processes from internal and external perturbations in ancestral forms. This dissertation uses each of these lenses to investigate the complex forms in the insect family Membracidae, which arises from the pronotum. In most insects, the pronotum is a simple, domed structure just behind the head, but in membracids it has enlarged and elaborated to look like thorns, plant stipules, fungi, and ants, among other shapes. To investigate this diversity, I rely on landmark based geometric morphometrics to quantify pronotal shapes. The specimens I used included those from a laboratory colony, those collected in and around San Jose, Costa Rica, and those from the Smithsonian National Museum of Natural History collection. In Chapter 1, I examined 5th instar morphogenesis to elucidate the timing of developmental events during the transition from juvenile to adult. These findings informed Chapter 2, which revealed developmental mechanisms related to growth led to transcriptional similarity between the pronotum and wings. In Chapter 3, I identified ontogenetic changes in the patterning of membracid pronotal shape compared to that of a closely related outgroup. Finally, in Chapter 4, I used a phylogenetic framework to investigate developmental modules and the co-occurrence of pronotal shape with two life history characteristics.

Developmental physiology is very sensitive to nutrient availability. For instance, in the nematode C. elegans, newly hatched L1-stage larvae require food to initiate postembryonic development. Despite the essential role of food in C. elegans development, the contribution of food perception versus ingestion on physiology has not been delineated. We used a pharmacological approach to uncouple the effects of food (bacteria) perception and ingestion in C. elegans. Perception was not sufficient to promote postembryonic development in L1-stage larvae. However, L1 larvae exposed to food without ingestion failed to develop upon return to normal culture conditions, instead displaying an irreversible arrest phenotype. Inhibition of gene expression during perception rescued subsequent development, demonstrating that the response to perception without feeding is deleterious. Perception altered DAF-16/FOXO subcellular localization, reflecting activation of insulin/IGF signaling (IIS). However, genetic manipulation of IIS did not modify the irreversible arrest phenotype caused by food perception, revealing that wild-type function of the IIS pathway is not required to produce this phenotype and that other pathways affected by perception of food in the absence of its ingestion are likely to be involved. Gene expression and Nile red staining showed that food perception could alter lipid metabolism and storage. We found that starved larvae sense environmental polypeptides, with similar molecular and developmental effects as perception of bacteria. We conclude that actual ingestion of food is required to initiate postembryonic development in C. elegans. We also conclude that polypeptides are perceived as a food-associated cue in this and likely other animals, initiating a signaling and gene regulatory cascade that alters metabolism in anticipation of feeding and development, but that this response is detrimental if feeding does not occur.

The C. elegans insulin-like signaling network supports homeostasis and developmental plasticity. The genome encodes 40 insulin-like peptides and one known receptor. Feedback regulation has been reported, but the extent of feedback and its effect on signaling dynamics in response to changes in nutrient availability has not been determined. We measured mRNA expression for each insulin-like peptide, the receptor daf-2, components of the PI3K pathway, and its transcriptional effectors daf-16/FOXO and skn-1/Nrf at high temporal resolution during transition from a starved, quiescent state to a fed, growing state in wild type and mutants affecting daf-2/InsR and daf-16/FOXO. We also analyzed the effect of temperature on insulin-like gene expression. We found that most PI3K pathway components and insulin-like peptides are affected by signaling activity, revealing pervasive positive and negative feedback regulation at intra- and inter-cellular levels. Reporter gene analysis demonstrated that the daf-2/InsR agonist daf-28 positively regulates its own transcription and that the putative agonist ins-6 cross-regulates DAF-28 protein expression through feedback. Our results show that positive and negative feedback regulation of insulin-like signaling is widespread, giving rise to an organismal FOXO-to-FOXO signaling network that supports homeostasis during fluctuations in nutrient availability.

L1 arrest (or "L1 diapause") is associated with increased stress resistance, supporting starvation survival. Loss of the transcription factor daf-16/FOXO results in arrest-defective and starvation-sensitive phenotypes. We show that daf-16/FOXO regulates L1 arrest cell-nonautonomously, suggesting that insulin/IGF signaling regulates at least one additional signaling pathway. We used mRNA-seq to identify candidate signaling molecules affected by daf-16/FOXO during L1 arrest. dbl-1/TGF-β, a ligand for the Sma/Mab pathway, daf-12/NHR, and daf-36/oxygenase, an upstream component of the daf-12 steroid hormone signaling pathway, were up-regulated during L1 arrest in a daf-16/FOXO mutant. Using genetic epistasis analysis, we show that dbl-1/TGF-β and daf-12/NHR steroid hormone signaling pathways are required for the daf-16/FOXO arrest-defective phenotype, suggesting that daf-16/FOXO represses dbl-1/TGF-β, daf-12/NHR and daf-36/oxygenase. The dbl-1/TGF-β and daf-12/NHR pathways have not previously been shown to affect L1 development, but we found that disruption of these pathways delayed L1 development in fed larvae, consistent with these pathways promoting development in starved daf-16/FOXO mutants. Though the dbl-1/TGF-β and daf-12/NHR pathways are epistatic to daf-16/FOXO for the arrest-defective phenotype, disruption of these pathways does not suppress starvation sensitivity of daf-16/FOXO mutants. This observation uncouples starvation survival from developmental arrest, indicating that DAF-16/FOXO targets distinct effectors for each phenotype and revealing that inappropriate development during starvation does not cause the early demise of daf-16/FOXO mutants. We show that daf-16/FOXO promotes developmental arrest cell-nonautonomously by repressing pathways that promote larval development.

The cholinergic system is intricately linked with hippocampal memory. As well, choline is anti-inflammatory in the brain and periphery (Terrando et al., 2011; Rivera et al., 1998). However, few have analyzed the anti-inflammatory properties of choline as an alternate means by which cholinergic manipulations affect hippocampal memory throughout the lifespan. The first aim of this dissertation work sought to determine if dietary choline supplementation protects against the deleterious effects of air pollution in the developing brain. Pregnant mice were given a high-choline diet (approximately 4.5x the choline chloride in the control diet) or a synthetic control diet. As well, dams were exposed to a series of diesel particulate (DEP) or saline vehicle sessions throughout pregnancy. Mice were sacrificed and tissues were collected on embryonic day 18. The activation state of microglia, identified by quantifying morphology using Iba1+ immunohistochemical staining, was examined in the dentate gyrus of the hippocampus (DG), the paraventricular nucleus (PVN) of the hypothalamus, the basolateral amygdala (AMY), and the parietal cortex (PCX). As expected, we found that DEP led to increased microglial activation in the fetal DG in males. Choline supplementation partially prevented this increase in activation. Interestingly, these effects were region-specific: the opposite pattern is seen in the PVN, and no significant diesel effect was seen in the AMY and PCX. These findings suggest that prenatal choline supplementation throughout pregnancy may protect the fetal hippocampus against the neuroinflammation associated with air pollution. To analyze whether the acute effects of dietary choline seen prenatally also occur in adulthood, adult dietary choline supplementation alongside the tibial fracture model of post-operative cognitive dysfunction (POCD) was used. POCD occurs when increased neuroinflammation due to peripheral surgery leads to impairments in cognition. Differences were found in almost hippocampal-dependent behavior, astrocytic activation, and cell proliferation. Differences were time point-specific. In the hippocampus, astrocytic activation, cell proliferation, and hilar granule cells all increased 1 day after surgery, and these increases were blunted by dietary choline. An increase in hippocampal young neurons was found 2 weeks after surgery. However, both were blunted by choline supplementation. At both time points assessed, tibial fracture impaired novel object recognition performance, and dietary choline rescued these impairments. As well, dietary choline supplementation did not mitigate the increase in anxiety-related behavior – specifically implicating hippocampal actions of the nutrient. Because the hippocampal-dependent memory impairment and rescue is not time point-specific, but the neural effects of tibial fracture are each specific to a certain timepoint, the mechanisms of behavior are likely different at each time point. Building upon aim 2, aim 3 explores if perinatal choline supplementation can act via “programming” of the neuroimmune system in development to prevent POCD in adulthood. Perinatal choline supplementation prevented POCD and neuroinflammation due to peripheral surgery, but did not protect against increases in young neurons or hilar neurons. Perinatal choline nutrition, in addition to its already-known neuroprotection, is additionally protective against POCD and its associated neuroinflammation in adulthood. Taken together, this body of work concludes that dietary choline supplementation at various administration dates is protective in neuroinflammatory models in behavior and brain.