Thioredoxin and Jab1 control estrogen- and antiestrogen-mediated progression of the cell cycle through p27 interactions

A major problem with breast cancer treatment is the prevalence of antiestrogen resistance, be it de novo or acquired after continued use. Many of the underlying mechanisms of antiestrogen resistance are not clear, although estrogen receptor-mediated actions have been identified as a pathway that is blocked by antiestrogens. Selective estrogen receptor modulators (SERMs), such as tamoxifen, are capable of producing reactive oxygen species (ROS) through metabolic activation, and these ROS, at high levels, can induce irreversible growth arrest that is similar to the growth arrest incurred by SERMs. This suggests that SERM-mediated growth arrest may also be through ROS accumulation. Breast cancer receiving long-term antiestrogen treatment appears to adapt to this increased, persistent level of ROS. This, in turn, leads to the disruption of reversible redox signaling that involves redox-sensitive phosphatases and protein kinases and transcription factors. This has downstream consequences for apoptosis, cell cycle progression, and cell metabolism. For this dissertation, we explored if altering the ROS formed by tamoxifen also alters sensitivity of the drug in resistant cells. We explored an association with a thioredoxin/Jab1/p27 pathway, and a possible role of dysregulation of thioredoxin-mediated redox regulation contributing to the development of antiestrogen resistance in breast cancer. We used standard laboratory techniques to perform proteomic assays that showed cell proliferation, protein concentrations, redox states, and protein-protein interactions. We found that increasing thioredoxin reductase levels, and thus increasing the amount of reduced thioredoxin, increased tamoxifen sensitivity in previously resistant cells, as well as altered estrogen and tamoxifen-induced ROS. We also found that decreasing levels of Jab1 protein also increased tamoxifen sensitivity, and that the downstream effects showed a decrease p27 phosphorylation in both cases. We conclude that the chronic use of tamoxifen can lead to an increase in ROS that alters cell signaling and causing cell growth in the presence of tamoxifen, and that this resistant cell growth can be reversed with an alteration to the thioredoxin/Jab1 pathway.

Trait Contributions to Fish Community Assembly Emerge From Trophic Interactions in an Individual-Based Model

Community ecology seeks to understand and predict the characteristics of communities that can develop under different environmental conditions, but most theory has been built on analytical models that are limited in the diversity of species traits that can be considered simultaneously. We address that limitation with an individual-based model to simulate assembly of fish communities characterized by life history and trophic interactions with multiple physiological tradeoffs as constraints on species performance. Simulation experiments were carried out to evaluate the distribution of 6 life history and 4 feeding traits along gradients of resource productivity and prey accessibility. These experiments revealed that traits differ greatly in importance for species sorting along the gradients. Body growth rate emerged as a key factor distinguishing community types and defining patterns of community stability and coexistence, followed by egg size and maximum body size. Dominance by fast-growing, relatively large, and fecund species occurred more frequently in cases where functional responses were saturated (i.e. high productivity and/or prey accessibility). Such dominance was associated with large biomass fluctuations and priority effects, which prevented richness from increasing with productivity and may have limited selection on secondary traits, such as spawning strategies and relative size at maturation. Our results illustrate that the distribution of species traits and the consequences for community dynamics are intimately linked and strictly dependent on how the benefits and costs of these traits are balanced across different conditions.

Does variation in movement tactics and trophic interactions among American alligators create habitat linkages?

1. Highly mobile top predators are hypothesized to spatially and/or temporally link disparate habitats through the combination of their movement and feeding patterns, but recent studies suggest that individual specialization in habitat use and feeding could keep habitats compartmentalized. 2.  We used passive acoustic telemetry and stable isotope analysis to investigate whether specialization in movement and feeding patterns of American alligators (Alligator mississippiensis) in an oligotrophic subtropical estuary created habitat linkages between marine and estuarine/freshwater food webs. 3.  Individual alligators adopted one of the three relatively distinct movement tactics that were linked to variation in diets. Fifty-six per cent of alligators regularly travelled from the upstream (freshwater/mid-estuary) areas into the downstream (marine-influenced) areas where salinities exceed those typically tolerated by alligators. Thirty-one per cent of the alligators made regular trips from the mid-estuarine habitat into the upstream habitat; 13% remained in the mid-estuary zone year-round. 4.  Stable isotopic analysis indicated that, unlike individuals remaining in the mid-estuary and upstream zones, alligators that used the downstream zone fed at least partially from marine food webs and likely moved to access higher prey abundance at the expense of salt stress. Therefore, ‘commuting’ alligators may link marine food webs with those of the estuary and marshes in the coastal Everglades and create an upstream vector for allochthonous nutrient inputs into the estuary. 5.  This study lends further support to the hypothesis that large-bodied highly mobile predators faced with trade-offs are likely to exhibit individual specialization leading to habitat linkages, rather than compartmentalization. However, the conditions under which this scenario occurs require further investigation.

Indirect and direct controls of macroinvertebrates and small fish by abiotic factors and trophic interactions in the Florida Everglades

1. The roles of nutrients, disturbance and predation in regulating consumer densities have long been of interest, but their indirect effects have rarely been quantified in wetland ecosystems. The Florida Everglades contains gradients of hydrological disturbance (marsh drying) and nutrient enrichment (phosphorus), often correlated with densities of macroinvertebrate infauna (macroinvertebrates inhabiting periphyton), small fish and larger invertebrates, such as snails, grass shrimp, insects and crayfish. However, most causal relationships have yet to be quantified. 2.  We sampled periphyton (content and community structure) and consumer (small omnivores, carnivores and herbivores, and infaunal macroinvertebrates inhabiting periphyton) density at 28 sites spanning a range of hydrological and nutrient conditions and compared our data to seven a priori structural equation models. 3.  The best model included bottom-up and top-down effects among trophic groups and supported top-down control of infauna by omnivores and predators that cascaded to periphyton biomass. The next best model included bottom-up paths only and allowed direct effects of periphyton on omnivore density. Both models suggested a positive relationship between small herbivores and small omnivores, indicating that predation was unable to limit herbivore numbers. Total effects of time following flooding were negative for all three consumer groups even when both preferred models suggested positive direct effects for some groups. Total effects of nutrient levels (phosphorus) were positive for consumers and generally larger than those of hydrological disturbance and were mediated by changes in periphyton content. 4.  Our findings provide quantitative support for indirect effects of nutrient enrichment on consumers, and the importance of both algal community structure and periphyton biomass to Everglades food webs. Evidence for top-down control of infauna by omnivores was noted, though without substantially greater support than a competing bottom-up-only model.

A study of the relationship between employee virtuality and technology deviance as mediated by leadership and employee perceptions

Recent studies found that organizations have been investing significant capital in developing teams and employees in geographic areas where labor and resources are considerably cheaper. Furthermore, organizations are moving core operational activities such as research and development and back-office processes to globally distributed teams. ^ However, several factors that are inherent to these virtual teams can have a negative impact on employee perceptions and engagement; specifically, the physical and temporal differences between employees and their supervisors, the lack of meaningful social interaction intrinsic to working relationships, and cultural biases that can be fostered when close, daily interactions is not there to help bridge the dissimilarity. ^ When strategies are not in place to mitigate these deficiencies, it can cause virtual employees to disengage emotionally and intellectually from the organization, or lead them to feel justified in working against the best interest of the company. ^ Past research indicates that although deviant behavior in the workplace is not new, transgressions committed by employees have been increasing significantly every year. Beyond the focus of why employees are motivated to act against the organization, to what extent do the recent changes to the organization’s structure influence this type of behavior through their actions at the macro (organizational) and micro level (leadership). ^ In addition, there is a related phenomenon that has aided the transformation of the workplace—namely, the ubiquity of technology. In the context of workplace deviance, established research has documented an increasing trend of employees utilizing company technology as a medium and amplifier when harming the organization. It is important to understand whether technology has facilitated or hindered workplace deviance by virtue of the technology itself (as a means), and as part of the new employee roles created by the evolving technology (i.e., virtual employees). Therefore, it is important to identify how individual attitudes and behaviors can be affected by an employee’s degree of virtuality. ^ This study will add to the understanding of how social interaction and physical proximity, leadership and other perception factors contribute to the changes organizations are experiencing as their structure evolves and adapts to compete in the new global environment. ^

A Study of the Relationship between Employee Virtuality and Technology Deviance as Mediated by Leadership and Employee Perceptions

Recent studies found that organizations have been investing significant capital in developing teams and employees in geographic areas where labor and resources are considerably cheaper. Furthermore, organizations are moving core operational activities such as research and development and back-office processes to globally distributed teams. However, several factors that are inherent to these virtual teams can have a negative impact on employee perceptions and engagement; specifically, the physical and temporal differences between employees and their supervisors, the lack of meaningful social interaction intrinsic to working relationships, and cultural biases that can be fostered when close, daily interactions is not there to help bridge the dissimilarity. When strategies are not in place to mitigate these deficiencies, it can cause virtual employees to disengage emotionally and intellectually from the organization, or lead them to feel justified in working against the best interest of the company. Past research indicates that although deviant behavior in the workplace is not new, transgressions committed by employees have been increasing significantly every year. Beyond the focus of why employees are motivated to act against the organization, to what extent do the recent changes to the organization’s structure influence this type of behavior through their actions at the macro (organizational) and micro level (leadership). In addition, there is a related phenomenon that has aided the transformation of the workplace – namely, the ubiquity of technology. In the context of workplace deviance, established research has documented an increasing trend of employees utilizing company technology as a medium and amplifier when harming the organization. It is important to understand whether technology has facilitated or hindered workplace deviance by virtue of the technology itself (as a means), and as part of the new employee roles created by the evolving technology (i.e, virtual employees). Therefore, it is important to identify how individual attitudes and behaviors can be affected by an employee’s degree of virtuality. This study will add to the understanding of how social interaction and physical proximity, leadership and other perception factors contribute to the changes organizations are experiencing as their structure evolves and adapts to compete in the new global environment.