B cell memory and idiotype network regulation

This investigation examined the clonal dynamics of B-cell expression and evaluated the role of idiotype network interactions in shaping the expressed secondary B-cell repertoire. Three interrelated experimental approaches were applied. The first approach was designed to distinguish between regulatory influences controlled by the major histocompatibility complex (MHC) and regulatory influences controlled by non-MHC factors including the idiotype network. This approach consisted of studies on the clonal dynamics and heterogeneity of the expressed IgG antibody repertoire of BALB/c mice. The second approach involved the analysis of the clonal dynamics of antibody responses of outbred rabbits. This analysis was coupled with studies to detect the occurrence and activity of constituents of the idiotype network. In the third approach the transfer of rabbit lymphocytes from immunized donors to MHC matched naive recipients was used to examine the effects of recipient non-MHC immunoregulatory influences on the expression of donor memory B-cells. Although many memory B cells were unaffected by non-MHC influences, these data show that non-MHC immunoregulatory influences can affect the expression of B-cells in the secondary response of inbred mice and outbred rabbits. The results also indicate that most IgG antibody responses are heterogeneous and are characterized by a stable group of dominant clonotypes. Clonal dominance and B-cell memory were found to be established early in an immune response. The expression of B memory clones appeared to be favored over the expression of virgin B cells. The injection of anti-tetanus antibody induced the antigen independent production of anti-tetanus antibody, probably through idiotypic mechanisms. These results demonstrate that both antibody and antigen can affect the expressed B-ceIl repertoire. Thus, idiotypic interactions are capable of influencing the expression of B-cells and these findings support the existence and function of an idiotype network with strong immunoregulatory potential. ^

Social network size and perceived network sufficiency as predictors of perceived health status

This study focused on the relationship between social network size (number of friends and relatives), perceived sufficiency of the network and self-rated health utilizing data from the National Survey of Personal Health Practices and Consequences, 1979. For men neither perceived sufficiency nor number of relatives were associated with self-rated health status. The number of friends was positively associated with health status. For women perceived network sufficiency was positively and significantly related to health status, independent of network size. The number of friends and relatives was not associated with self-rated health status. The sociodemographic variables accounted for most of the explained variance in health status for both males and females. Social networks may hold different meanings for women and men, and may require qualitative as well as quantitative analysis. There may have been insufficient variance in the major variables to produce meaningful results. ^

Bifurcation and singularity analysis of a molecular network for the induction of long-term memory.

Withdrawal reflexes of the mollusk Aplysia exhibit sensitization, a simple form of long-term memory (LTM). Sensitization is due, in part, to long-term facilitation (LTF) of sensorimotor neuron synapses. LTF is induced by the modulatory actions of serotonin (5-HT). Pettigrew et al. developed a computational model of the nonlinear intracellular signaling and gene network that underlies the induction of 5-HT-induced LTF. The model simulated empirical observations that repeated applications of 5-HT induce persistent activation of protein kinase A (PKA) and that this persistent activation requires a suprathreshold exposure of 5-HT. This study extends the analysis of the Pettigrew model by applying bifurcation analysis, singularity theory, and numerical simulation. Using singularity theory, classification diagrams of parameter space were constructed, identifying regions with qualitatively different steady-state behaviors. The graphical representation of these regions illustrates the robustness of these regions to changes in model parameters. Because persistent protein kinase A (PKA) activity correlates with Aplysia LTM, the analysis focuses on a positive feedback loop in the model that tends to maintain PKA activity. In this loop, PKA phosphorylates a transcription factor (TF-1), thereby increasing the expression of an ubiquitin hydrolase (Ap-Uch). Ap-Uch then acts to increase PKA activity, closing the loop. This positive feedback loop manifests multiple, coexisting steady states, or multiplicity, which provides a mechanism for a bistable switch in PKA activity. After the removal of 5-HT, the PKA activity either returns to its basal level (reversible switch) or remains at a high level (irreversible switch). Such an irreversible switch might be a mechanism that contributes to the persistence of LTM. The classification diagrams also identify parameters and processes that might be manipulated, perhaps pharmacologically, to enhance the induction of memory. Rational drug design, to affect complex processes such as memory formation, can benefit from this type of analysis.

Signalling ballet in space and time.

Although we have amassed extensive catalogues of signalling network components, our understanding of the spatiotemporal control of emergent network structures has lagged behind. Dynamic behaviour is starting to be explored throughout the genome, but analysis of spatial behaviours is still confined to individual proteins. The challenge is to reveal how cells integrate temporal and spatial information to determine specific biological functions. Key findings are the discovery of molecular signalling machines such as Ras nanoclusters, spatial activity gradients and flexible network circuitries that involve transcriptional feedback. They reveal design principles of spatiotemporal organization that are crucial for network function and cell fate decisions.

Spatial and temporal aspects of synaptic plasticity

The notion that changes in synaptic efficacy underlie learning and memory processes is now widely accepted even if definitive proof of the synaptic plasticity and memory hypothesis is still lacking. When learning occurs, patterns of neural activity representing the occurrence of events cause changes in the strength of synaptic connections within the brain. Reactivation of these altered connections constitutes the experience of memory for these events and for other events with which they may be associated. These statements summarize a long-standing theory of memory formation that we refer to as the synaptic plasticity and memory hypothesis. Since activity-dependent synaptic plasticity is induced at appropriate synapses during memory formation, and is both necessary and sufficient for the information storage, we can speculate that a methodological study of the synapse will help us understand the mechanism of learning. Random events underlie a wide range of biological processes as diverse as genetic drift and molecular diffusion, regulation of gene expression and neural network function. Additionally spatial variability may be important especially in systems with nonlinear behavior. Since synapse is a complex biological system we expect that stochasticity as well as spatial gradients of different enzymes may be significant for induction of plasticity. ^ In that study we address the question "how important spatial and temporal aspects of synaptic plasticity may be". We developed methods to justify our basic assumptions and examined the main sources of variability of calcium dynamics. Among them, a physiological method to estimate the number of postsynaptic receptors as well as a hybrid algorithm for simulating postsynaptic calcium dynamics. Additionally we studied how synaptic geometry may enhance any possible spatial gradient of calcium dynamics and how that spatial variability affect plasticity curves. Finally, we explored the potential of structural synaptic plasticity to provide a metaplasticity mechanism specific for the synapse. ^

The interorganizational implementation of state health policy: A network approach

This is an implementation analysis of three consecutive state health policies whose goal was to improve access to maternal and child health services in Texas from 1983 to 1986. Of particular interest is the choice of the unit of analysis, the policy subsystem, and the network approach to analysis. The network approach analyzes and compares the structure and decision process of six policy subsystems in order to explain program performance. Both changes in state health policy as well as differences in implementation contexts explain evolution of the program administrative and service unit, the policy subsystem. And, in turn, the evolution of the policy subsystem explains changes in program performance. ^

LIFE SATISFACTION: A COMPARISON OF RETIRED AND EMPLOYED WOMEN

This research addressed the question of life satisfaction for retired and employed women with long-term employment in a typically female occupational setting. Questions of how women's retirement is related to life satisfaction have been largely neglected because of cultural assumptions about the relative unimportance of the work role in women's lives. It is generally believed that the major source of satisfaction for women is in traditional family roles. Therefore, it follows that retirement from work is not experienced as a loss for women.^ The actual consequences of women's retirement have not been examined systematically. Descriptive data about their lives are inadequate. It is not known what patterns and resources result from a lifetime of work for women.^ The objectives of the study were to test assumptions from role and continuity theory regarding life satisfaction for retired women and women employed late in life and to describe the retirement and work experiences of the women.^ Life satisfaction was measured by the Neugarten, Havighurst and Tobin Life Satisfaction Index. Perceptions of appropriate roles for females and males were assessed through an attitudinal sex-role instrument. A composite index, derived from perceptions of health, social participation, and income at two time periods, measured level of continuity. These indices and demographic information, attitudinal items about work and retirement, and social network data comprised the mailed, self-administered survey and the personal interviews.^ The study population included 91 retired and 53 employed women, 55 years or older with a minimum of 20 years continuous employment, who were enrolled in the pension program of a large retail store.^ The retired women's perceptions of their health and social participation were more positive than the employed women's. Traditional retired women demonstrated higher life satisfaction than nontraditional retired women. Both retired and employed women who perceived continuity in life patterns scored statistically higher on life satisfaction than women who perceived discontinuity. Financial planning was the area of greatest retirement concern for retired and employed women.^

Assessing the relationship between board composition and nonprofit hospital financial performance from a multi-theoretic perspective

This dissertation assesses the relationship between board composition and financial performance for the top 71 major nonprofit hospitals in the United States during the period 2004-2009. The underlying data were collected from copies of IRS Form 990 available at http://www.guidestar.org . The dissertation investigates five factors: board size, board independence (percentage of outsiders), number of MDs, CEO succession and CEO compensation. And it evaluates the results within a multi-theoretic framework drawing on agency theory, resource dependence theory, institutional theory and social network theory. Corporate governance literature suggests that board composition has an important impact on firm financial performance. This dissertation examines whether the same may be true for nonprofit hospitals. The results should help hospital executives make better governance decisions during trying economic times.^