Apoptosis and cell survival are two seemingly opposing fate-determining processes that are regulated by distinct and complex signaling pathways. Caspase-8, an apical caspase, plays a pivotal regulatory role in initiating apoptosis. c-Src, a prototypical member of the Src family kinases (SFKs), regulates a myriad of cellular processes including cell mitogenesis, proliferation, growth and migration. Although the regulation of caspase-8 by c-Src has been suggested, the reciprocal regulation of these two seemingly opposing signaling molecules, caspase-8 and c-Src, has never been explored. To study this reciprocal regulation, we asked three questions. (1) Can active caspase-8 negatively regulate c-Src activity to allow the propagation of apoptosis? (2) Can c-Src negatively regulate caspase-8 activity to prevent the propagation of apoptosis? (3) Can caspase-8, when its enzymatic activity is inhibited, further promote c-Src activity to allow the propagation of cell survival? To address these questions, we first investigated the effect of active caspase-8 on the activation and activity of c-Src. We discovered that active caspase-8 inhibited c-Src activation and some of its downstream effectors. Next, we investigated whether c-Src could tyrosine phosphorylate caspase-8. We discovered that c-Src could phosphorylate caspase-8 at multiple tyrosine sites. We then examined whether tyrosine phosphorylated caspase-8 prevents apoptosis. We found that phosphorylation of caspase-8 at Y465 prevented its cleavage, and activity towards activating caspase-3 and towards causing cell morphological changes associated with apoptosis. Finally, we studied whether tyrosine phosphorylation of caspase-8 could further promote the activation of c-Src. We showed that phosphorylation of caspase-8 at both Y465 and Y397 resulted in the activation of c-Src and extracellular signal-regulated kinase 1/2 (Erk1/2). In conclusion, this work demonstrated the reciprocal regulation of two opposing signaling molecules, caspase-8 and c-Src. These results also suggest an elegant mechanism for a cell to commit efficiently and rapidly to a fate-determining process, either apoptosis or survival, by further suppression of the opposing signaling pathway.

<p>Changes in gene transcription driven by the activation of intracellular calcium signaling pathways play an important role in neural development and plasticity. A growing body of evidence suggests that stimulus-driven modulation of histone modifications play an important role in the regulation of neuronal activity-regulated gene transcription. However, the histone modifying enzymes that are targets of activity-regulated signaling cascades in neurons remain to be identified. The histone demethylases (HDMs) are a large family of enzymes that have selective catalytic activity against specific sites of histone methylation. To identify HDMs that may be important for activity-regulated gene transcription in neurons, we induced seizures in mice and screened for HDMs whose expression is induced in the hippocampus. Among the few HDMs that changed expression, Kdm6b showed the highest induction. Kdm6B is a histone H3K27-specific HDM whose enzymatic activity leads to transcriptionally permissive chromatin environments. In situ hybridization analysis revealed that Kdm6b is highly induced in post-mitotic neurons of the dentate gyrus region of the hippocampus. We can recapitulate the activity-dependent induction of Kdm6b expression in cultured hippocampal neurons by application of Bicuculline, a GABAA receptor antagonist that leads to synaptic NMDA receptor activation and calcium influx. Kdm6b expression is also induced following application of BDNF, a neurotrophic factor that is upregulated in the seized hippocampus. To investigate possible functions of Kdm6b in neuronal development, we performed in situ hybridization analysis that allows for the identification of regions with high Kdm6b expression that could be sites of potential function in the developing mouse brain. We found high levels of Kdm6b expression in the inner layer of the external granule layer of the cerebellum, a region where pre-migratory immature neurons reside and a site of significant apoptosis. On the basis of this data and the fact that intracellular calcium signaling arising from synaptic firing supports neuronal survival, we explored the necessity for Kdm6b in the survival of cultured cerebellar granule cells. Knock down of Kdm6b by RNAi increases cell death, demonstrating that Kdm6b contributes to neuronal survival. Ongoing experiments are addressing the role of Kdm6b in neuronal differentiation. Overall these data raise the possibility that stimulus-dependent regulation of Kdm6b, and perhaps regulation of H3K27 methylation mediated by Kdm6b, may contribute to the regulation of gene expression in neurons and thus to their proper development and plasticity.</p> / Dissertation

This thesis interrogates the social/political stakes in three nonfiction narratives of life and death: Jon Krakauer's Into the Wild, Peter Gzowski's The Sacrament and John and Jean Silverwood's Black Wave. An analysis of Nietzsche's concept of "freedom as responsibility," as developed by contemporary theorists of freedom and the body, especially Wendy Brown and Judith Butler, provides the ground for this theoretical examination. Additionally, Fred Alford's consideration of "freedom with" and Laurence Gonzales's interrogation of the conditions of survival help delimit this site of contest. Each of the texts is critiqued in terms of its engagement with freedom as a practice of responsibility grounded in recognition of mutual vulnerability and enacted through a contest for meaning. / Graduate

No description available.

Many studies have reported deficient or intermittent patterns of natural regeneration in temperate deciduous woodland. The present study aimed to assess the relative impact of herbivore-mediated plant mortality on the natural regeneration dynamics of representative tree species (Acer pseudoplatanus, Betula pendula, Fraxinus excelsior, Ilex aquifolium, Sorbus aucuparia, Taxus baccata and Ulmus glabra) in representative temperate deciduous woodland (Shipley Wood and Derwent Gorge, County Durham). Sapling density and the density, spatial association and size distribution of adult tree populations varied significantly between tree species and study sites, reflecting contrasting patterns of current and historical regeneration. Rates of post-dispersal seed predation and seedling herbivory were quantified using field-based 'cafeteria' trials. Rodents were the principal agents responsible for seed predation, whereas seedling herbivory was attributable to a mixed suite of herbivores including invertebrates, rodents and larger mammals. Rates of seed predation and seedling herbivory varied significantly between tree species, most likely reflecting individualistic, trade-off responses to chemical and physical attributes. Fine-scale spatial variation most likely reflected the preferential foraging of rodents beneath protective vegetation cover. There was no consistent evidence to support the hypothesis that dispersed seeds may escape disproportionately high offspring mortality beneath parent plants resulting from increased herbivore activity. Natural seedling density varied significantly between years and between tree species, according to the abundance of viable seeds produced by conspecific adult trees. Although seedling survivorship varied significantly between species, the survivorship of each species was similar between years and between cohorts of the same year. Canopy cover, field layer cover or correlated factors were significant determinants of seed germination and seedling emergence, establishment and survival, according to age- and species-specific tolerances. In relative terms, patterns of natural regeneration were primarily herbivore- limited (Acer and Taxus), microsite-limited (Betula, Fraxinus, Ilex and Ulmus) or limited by herbivores and microsites (Sorbus). The availability of viable seeds may have also limited the recruitment of Ilex, Sorbus, Taxus and Ulmus. Vegetative expansion, mast seeding, seed bank regeneration and repeated, prolonged reproduction may have reduced the actual impact of herbivory on natural regeneration, such that long-lived iteroparous tree species were unlikely to have been critically dependent on current recruitment.

When subjects are recruited through a cross-sectional survey they have already experienced the initiation of the event of interest, say the onset of a disease. This method of recruitment results in the fact that subjects with longer duration of the disease have a higher chance of being selected. It follows that censoring in such a case is not non-informative. The application of standard techniques for right-censored data thus introduces a bias to the analysis; this is referred to as length-bias. This paper examines the case where the subjects are assumed to enter the study at a uniform rate, allowing for the analysis in a more efficient unconditional manner. In particular, a new method for unconditional analysis is developed based on the framework of a conditional estimator. This new method is then applied to the several data sets and compared with the conditional technique of Tsai [23].

Standard survival analysis focuses on population-based studies. The objective of our work, survival prediction, is different: to find the most accurate model for predicting the survival times for each individual patient. We view this as a regression problem, where we try to map the features for each patient to his/her survival time. This is challenging in medical data due to the presence of irrelevant features, outliers, and missing class labels. Our approach consists of two major steps: (1) apply various grouping methods to segregate patients, and (2) apply different regression to each sub-group we obtained from the first step. We focus our experiments on a data set of 2402 patients (1260 censored). Our final predictor can obtain an average relative absolute error < 0.54. The experimental results verify that we can effectively predict survival times with a combination of statistical and machine learning approaches.

Resting metabolic rate (RMR) is the minimum energy expenditure necessary for survival. RMR varies widely both among and within species and a central question in evolutionary physiology concerns the functional basis for this variation. Juvenile North American red squirrels were used to investigate fitness consequences of variation in RMR by considering how expenditure relates to differences in food availability and to overwinter survival. Additionally, this thesis examines whether red squirrels exhibit phenotypic plasticity in RMR in response to varying levels of food availability. Results indicate that heavier juveniles with relatively low RMRs were more likely to survive overwinter. Moreover, these juveniles were capable of allocating more energy towards mechanical work and possessed larger food stores. Food supplemented yearlings exhibited higher RMRs than unsupplemented controls at the onset of the breeding season, while no difference in RMR was detected following termination of supplementation. / Wildlife Ecology

No description available.

Thesis (M.S.)--Georgia State University, 2007. / Title from file title page. Yichuan Zhao, committee chair; Yu-Sheng Hsu , Xu Zhang, Yuanhui Xiao , committee members. Electronic text (54 p.) : digital, PDF file. Description based on contents viewed Feb. 25, 2008. Includes bibliographical references (p. 30-32).