Dual modulation of cell survival and cell death by beta(2)-adrenergic signaling in adult mouse cardiac myocytes.

The goal of this study was to determine whether beta(1)-adrenergic receptor (AR) and beta(2)-AR differ in regulating cardiomyocyte survival and apoptosis and, if so, to explore underlying mechanisms. One potential mechanism is that cardiac beta(2)-AR can activate both G(s) and G(i) proteins, whereas cardiac beta(1)-AR couples only to G(s). To avoid complicated crosstalk between beta-AR subtypes, we expressed beta(1)-AR or beta(2)-AR individually in adult beta(1)/beta(2)-AR double knockout mouse cardiac myocytes by using adenoviral gene transfer. Stimulation of beta(1)-AR, but not beta(2)-AR, markedly induced myocyte apoptosis, as indicated by increased terminal deoxynucleotidyltransferase-mediated UTP end labeling or Hoechst staining positive cells and DNA fragmentation. In contrast, beta(2)-AR (but not beta(1)-AR) stimulation elevated the activity of Akt, a powerful survival signal; this effect was fully abolished by inhibiting G(i), G(beta gamma), or phosphoinositide 3 kinase (PI3K) with pertussis toxin, beta ARK-ct (a peptide inhibitor of G(beta gamma)), or LY294002, respectively. This indicates that beta(2)-AR activates Akt via a G(i)-G(beta gamma)-PI3K pathway. More importantly, inhibition of the G(i)-G(beta gamma)-PI3K-Akt pathway converts beta(2)-AR signaling from survival to apoptotic. Thus, stimulation of a single class of receptors, beta(2)-ARs, elicits concurrent apoptotic and survival signals in cardiac myocytes. The survival effect appears to predominate and is mediated by the G(i)-G(beta gamma)-PI3K-Akt signaling pathway.

Brands, Close Relationships, and Consumer Well-Being

Consumers have relationships with other people, and they have relationships with brands similar to the ones they have with other people. Yet, very little is known about how brand and interpersonal relationships relate to one another. Even less is known about how they jointly affect consumer well-being. The goal of this research, therefore, is to examine how brand and interpersonal relationships influence and are influenced by consumer well-being. Essay 1 uses both empirical methods and surveys from individuals and couples to investigate how consumer preferences in romantic couples, namely brand compatibility, influences life satisfaction. Using traditional statistical techniques and multilevel modeling, I find that the effect of brand compatibility, or the extent to which individuals have similar brand preferences, on life satisfaction depends upon power in the relationship. For high power partners, brand compatibility has no effect on life satisfaction. On the other hand, for low power partners, low brand compatibility is associated with decreased life satisfaction. I find that conflict mediates the link between brand compatibility and power on life satisfaction. In Essay 2 I again use empirical methods and surveys to investigate how resources, which can be considered a form of consumer well-being, influence brand and interpersonal relations. Although social connections have long been considered a fundamental human motivation and deemed necessary for well-being (Baumeister and Leary 1995), recent research has demonstrated that having greater resources is associated with weaker social connections. In the current research I posit that individuals with greater resources still have a need to connect and are using other sources for connection, namely brands. Across several studies I test and find support for my theory that resource level shifts the preference of social connection from people to brands. Specifically, I find that individuals with greater resources have stronger brand relationships, as measured by self-brand connection, brand satisfaction, purchase intentions and willingness to pay with both existing brand relationships and with new brands. This suggests that individuals with greater resources place more emphasis on these relationships. Furthermore, I find that resource level influences the stated importance of brand and interpersonal relationships, and that having or perceiving greater resources is associated with an increased preference to engage with brands over people. This research demonstrates that there are times when people prefer and seek out connections with brands over other people, and highlights the ways in which our brand and interpersonal relationships influence one another.

Men's knowledge and attitudes about cervical cancer screening in Kenya.

BACKGROUND: A number of studies have identified male involvement as an important factor affecting reproductive health outcomes, particularly in the areas of family planning, antenatal care, and HIV care. As access to cervical cancer screening programs improves in resource-poor settings, particularly through the integration of HIV and cervical cancer services, it is important to understand the role of male partner support in women's utilization of screening and treatment. METHODS: We administered an oral survey to 110 men in Western Kenya about their knowledge and attitudes regarding cervical cancer and cervical cancer screening. Men who had female partners eligible for cervical cancer screening were recruited from government health facilities where screening was offered free of charge. RESULTS: Specific knowledge about cervical cancer risk factors, prevention, and treatment was low. Only half of the men perceived their partners to be at risk for cervical cancer, and many reported that a positive screen would be emotionally upsetting. Nevertheless, all participants said they would encourage their partners to get screened. CONCLUSIONS: Future interventions should tailor cervical cancer educational opportunities towards men. Further research is needed among both men and couples to better understand barriers to male support for screening and treatment and to determine how to best involve men in cervical cancer prevention efforts.

Metabolism Regulates the Fate and Function of T Lymphocytes

Proper balancing of the activities of metabolic pathways to meet the challenge of providing necessary products for biosynthetic and energy demands of the cell is a key requirement for maintaining cell viability and allowing for cell proliferation. Cell metabolism has been found to play a crucial role in numerous cell settings, including in the cells of the immune system, where a successful immune response requires rapid proliferation and successful clearance of dangerous pathogens followed by resolution of the immune response. Additionally, it is now well known that cell metabolism is markedly altered from normal cells in the setting of cancer, where tumor cells rapidly and persistently proliferate. In both settings, alterations to the metabolic profile of the cells play important roles in promoting cell proliferation and survival.

It has long been known that many types of tumor cells and actively proliferating immune cells adopt a metabolic phenotype of aerobic glycolysis, whereby the cell, even under normoxic conditions, imports large amounts of glucose and fluxes it through the glycolytic pathway and produces lactate. However, the metabolic programs utilized by various immune cell subsets have only recently begun to be explored in detail, and the metabolic features and pathways influencing cell metabolism in tumor cells in vivo have not been studied in detail. The work presented here examines the role of metabolism in regulating the function of an important subset of the immune system, the regulatory T cell (Treg) and the role and regulation of metabolism in the context of malignant T cell acute lymphoblastic leukemia (T-ALL). We show that Treg cells, in order to properly function to suppress auto-inflammatory disease, adopt a metabolic program that is characterized by oxidative metabolism and active suppression of anabolic signaling and metabolic pathways. We found that the transcription factor FoxP3, which is highly expressed in Treg cells, drives this phenotype. Perturbing the metabolic phenotype of Treg cells by enforcing increased glycolysis or driving proliferation and anabolic signaling through inflammatory signaling pathways results in a reduction in suppressive function of Tregs.

In our studies focused on the metabolism of T-ALL, we observed that while T-ALL cells use and require aerobic glycolysis, the glycolytic metabolism of T-ALL is restrained compared to that of an antigen activated T cell. The metabolism of T-ALL is instead balanced, with mitochondrial metabolism also being increased. We observed that the pro-anabolic growth mTORC1 signaling pathway was limited in primary T-ALL cells as a result of AMPK pathway activity. AMPK pathway signaling was elevated as a result of oncogene induced metabolic stress. AMPK played a key role in the regulation of T-ALL cell metabolism, as genetic deletion of AMPK in an in vivo murine model of T-ALL resulted in increased glycolysis and anabolic metabolism, yet paradoxically increased cell death and increased mouse survival time. AMPK acts to promote mitochondrial oxidative metabolism in T-ALL through the regulation of Complex I activity, and loss of AMPK reduced mitochondrial oxidative metabolism and resulted in increased metabolic stress. Confirming a role for mitochondrial metabolism in T-ALL, we observed that the direct pharmacological inhibition of Complex I also resulted in a rapid loss of T-ALL cell viability in vitro and in vivo. Taken together, this work establishes an important role for AMPK to both balance the metabolic pathways utilized by T-ALL to allow for cell proliferation and to also promote tumor cell viability by controlling metabolic stress.

Overall, this work demonstrates the importance of the proper coupling of metabolic pathway activity with the function needs of particular types of immune cells. We show that Treg cells, which mainly act to keep immune responses well regulated, adopt a metabolic program where glycolytic metabolism is actively repressed, while oxidative metabolism is promoted. In the setting of malignant T-ALL cells, metabolic activity is surprisingly balanced, with both glycolysis and mitochondrial oxidative metabolism being utilized. In both cases, altering the metabolic balance towards glycolytic metabolism results in negative outcomes for the cell, with decreased Treg functionality and increased metabolic stress in T-ALL. In both cases, this work has generated a new understanding of how metabolism couples to immune cell function, and may allow for selective targeting of immune cell subsets by the specific targeting of metabolic pathways.