Poisson's equation for discrete-time quasi-birth-and-death processes

We consider Poisson's equation for quasi-birth-and-death processes (QBDs) and we exploit the special transition structure of QBDs to obtain its solutions in two different forms. One is based on a decomposition through first passage times to lower levels, the other is based on a recursive expression for the deviation matrix. We revisit the link between a solution of Poisson's equation and perturbation analysis and we show that it applies to QBDs. We conclude with the PH/M/1 queue as an illustrative example, and we measure the sensitivity of the expected queue size to the initial value

SBE13, a newly identified inhibitor of inactive polo-like kinase 1

Poster presentation at 5th German Conference on Cheminformatics: 23. CIC-Workshop Goslar, Germany. 8-10 November 2009 Protein kinases are important targets for drug development. The almost identical protein folding of kinases and the common co-substrate ATP leads to the problem of inhibitor selectivity. Type II inhibitors, targeting the inactive conformation of kinases, occupy a hydrophobic pocket with less conserved surrounding amino acids. Human polo-like kinase 1 (Plk1) represents a promising target for approaches to identify new therapeutic agents. Plk1 belongs to a family of highly conserved serine/threonine kinases, and is a key player in mitosis, where it modulates the spindle checkpoint at metaphase/anaphase transition. Plk1 is over-expressed in all today analyzed human tumors of different origin and serves as a negative prognostic marker in cancer patients. The newly identified inhibitor, SBE13, a vanillin derivative, targets Plk1 in its inactive conformation. This leads to selectivity within the Plk family and towards Aurora A. This selectivity can be explained by docking studies of SBE13 into the binding pocket of homology models of Plk1, Plk2 and Plk3 in their inactive conformation. SBE13 showed anti-proliferative effects in cancer cell lines of different origins with EC50 values between 5 microM and 39 microM and induced apoptosis. Increasing concentrations of SBE13 result in increasing amounts of cells in G2/M phase 13 hours after double thymidin block of HeLa cells. The kinase activity of Plk1 was inhibited with an IC50 of 200 pM. Taken together, we could show that carefully designed structure-based virtual screening is well-suited to identify selective type II kinase inhibitors targeting Plk1 as potential anti-cancer therapeutics

Changes in Personality and Well-Being Across Adulthood: Riding the Self-Esteem Rollercoaster

Personality factors have long been implicated in how individuals manage and cope with circumstances to maintain well-being and health across the lifespan (Lazarus & Folkman, 1984; Mroczek & Spiro, 2007; Wrosch & Scheier, 2003). However, personality factors have also been shown to change over time in both situational and normative contexts (Caspi & Roberts, 1999; Crocker & Wolfe, 2006; Robins et al., 2002; Roberts, Walton & Virchtbauer, 2006). These changes in personality can provide important information about how individuals adapt to and navigate life events and challenges. We investigate self-esteem as a personality factor that changes across the lifespan and identify age-related differences in the impact of self-esteem levels and changes on indices of well-being. This line of research combines personality and lifespan developmental literature to address the question whether levels of and changes in self-esteem can predict well-being and whether there are age-related effects as self-esteem changes across the lifespan. The present dissertation had three main goals: 1) To examine the impact of self-esteem changes and levels across the adult lifespan; 2) to examine changes in self-esteem in different ways – intraindividual changes in self-esteem, normative changes in self-esteem and experimental changes in self-esteem; 3) to investigate the moderating role of self-esteem changes. In order to address these goals, data was collected to examine within-person changes in self-esteem among older adults, data from Statistics Canada was analyzed to examine normative changes in self-esteem, and finally an intervention study was developed to examine experimental changes in self-esteem among young and older adults, and data on psychological and emotional well-being were collected. Three manuscripts were then written based on this data and are included as part of this dissertation. The first manuscript examined the potential moderating role of self-esteem on older adults’ perceived stress and regret intensity, over 10 years in a sample of 167 community dwelling older adults. This study examined the within-person associations between older adults’ perceived stress and regret intensity, and the moderating role of levels of, and within-person changes in, self-esteem. Within-person results indicated that older adults reported higher levels of regret intensity when they reported higher than their average levels of perceived stress, and that within-person increases of self-esteem, but not between-person levels, moderated this association. The results suggest that within-person changes in self-esteem may be more important than individual differences of self-esteem in protecting older adults from experiencing greater regret intensity under stressful circumstances. The second manuscript, revised and re-submitted for publication in Social Science and Medicine, examines normative changes in self-esteem across the adult lifespan in a 16-year longitudinal sample of 14,117 adults from the National Population Health Survey (NPHS). The study examines whether changes in self-esteem and chronic disease exert reciprocal effects on subsequent changes in self-esteem and chronic disease, and whether individuals’ age would moderate these associations. The findings from this paper suggest that there are reciprocal age-related associations between changes in self-esteem and chronic disease. Only among young adults, but not middle-aged or older adults, initial decline in self-esteem predicted subsequent increases in chronic disease, and initial increases in chronic disease predicted subsequent declines in self-esteem. The results from this study highlight that adverse changes in both self-esteem and physical health may be particularly problematic for young adults, and have comparably less impact among middle-aged and older adults. The third and final manuscript included in this dissertation attempted to improve young and older adults’ self-esteem through a brief writing intervention. The study examines whether self-esteem can be improved, whether baseline levels of self-esteem and naturally occurring changes in self-esteem play an adaptive role in mitigating consequences of stress, and predict psychological and emotional well-being, and whether these associations are moderated by age. The study examines 106 young and older adults, randomized into control and intervention groups, who were asked to engage in three consecutive days of writing. All participants completed an in-lab stress task, and cortisol data were also examined. The results of the study suggest that our writing intervention did not work. In addition, the results suggest that high levels of self-esteem and naturally occurring increases in self-esteem (and not experimental changes), predicted positive outcomes, only for older, but not younger, adults. Consistent with previous research, our results highlight age differences in the association between self-esteem and psychological and emotional well-being, which may also suggest that future self-esteem interventions could be more tailored to each specific age group