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T lymphocyte acute lymphoblastic leukemia (T-ALL) is frequently associated with increased expression of the E protein transcription factor inhibitors TAL1 and LYL1. In mouse models, ectopic expression of Tal1 or Lyl1 in T cell progenitors or inactivation of E2a, is sufficient to predispose mice to develop T-ALL. How E2a suppresses thymocyte transformation is currently unknown. Here, we show that early deletion ofE2a, prior to the DN3 stage, was required for robust leukemogenesis and was associated with alterations in thymus cellularity, T cell differentiation, and gene expression in immature CD4+CD8+ thymocytes. Introduction of wild-type thymocytes into mice with early deletion ofE2aprevented leukemogenesis, or delayed disease onset, and impacted the expression of multiple genes associated with transformation and genome instability. Our data indicate that E2a suppresses leukemogenesis by promoting T cell development and enforcing inter-thymocyte competition, a mechanism that is emerging as a safeguard against thymocyte transformation. These studies have implications for understanding how multiple essential regulators of T cell development suppress T-ALL and support the hypothesis that thymus cellularity is a determinant of leukemogenesis.

Interferon-γ producing invariant natural killer T (iNKT1) cells are lipid reactive innate-like lymphocytes that are resident in the thymus and peripheral tissues where they protect against pathogenic infection. The thymic functions of iNKT1 cells are not fully elucidated but subsets of thymic iNKT cells modulate CD8 T cell, dendritic cell, B cell and thymic epithelial cell numbers or function. Here we show that a subset of thymic iNKT1 cells require transforming growth factor (TGF)-β induced signals for their development and for expression of residency associated adhesion receptors. Liver and spleen iNKT1 cells do not share this TGF-β gene signature but nonetheless TGF-β is required for optimal liver iNKT1 cell function. Our findings provide insight into the heterogeneity of mechanisms guiding iNKT1 cell development in different tissues and suggest a close association between a subset of iNKT1 cells and TGF-β producing cells in the thymus.

To complement the sequencing of the three kinetoplastid genomes reported in this issue, we have undertaken a whole-organism, proteomic analysis of the four life-cycle stages of Trypanosoma cruzi . Peptides mapping to 2784 proteins in 1168 protein groups from the annotated T. cruzi genome were identified across the four life-cycle stages. Protein products were identified from >1000 genes annotated as “hypothetical” in the sequenced genome, including members of a newly defined gene family annotated as mucin-associated surface proteins. The four parasite stages appear to use distinct energy sources, including histidine for stages present in the insect vectors and fatty acids by intracellular amastigotes.

This doctoral dissertation is a study of Nietzsche's views on morality in order to assess his contribution to moral philosophy. Towards this end, it examines Nietzsche's understanding of morality as well as the scope of his attack. I then offer a reading of Nietzsche's critique of morality, arguing that he rejects morality insofar as it functions within society to preserve the 'herd' at the expense of 'higher types' whose flourishing resides elsewhere. In short, I claim that Nietzsche rejects morality insofar as it proves inimical to the flourishing of these 'higher types'. I also claim that Nietzsche is more than a mere critic of morality, and that his fundamental 'ethical' preoccupation with exemplary individuals is what motives his critique, and forms the basis of his affirmative ethic of human flourishing. Moreover, I contend that Nietzsche defends his positive morality by presenting the character of Zarathustra (Thus Spoke Zarathustra), and later himself (Ecce Homo) as exemplars of human excellence who must rely on their ability to convince others performatively, rather than by means of discourse, or argumentation. Ultimately, I conclude that Nietzsche's ethics does not fit comfortably within the moral tradition as he is an opponent of deontological ethics, utilitarianism, and virtue ethics despite certain affinities with the latter. This fact does not detract from the rich contribution that Nietzsche makes to moral philosophy as bode critic and champion of an affirmative ethic.

The aim was to compare digital and conventional panoramic imaging techniques for identifying high-risk radiographic markers associated with mandibular nerve (MN) injury after mandibular third molar (M3) removal.The study used a retrospective cohort model. The predictor variable was the presence or absence of radiographic signs associated with MN exposure during M3 removal. The outcome variable was MN exposure. Intraexaminer variability was estimated using a kappa statistic. Logistic regression modeling was used to measure the association between radiographic signs and MN exposure and determine if imaging technique modified that association. The level of statistical significance was set at P.05.The sample was composed of 571 patients having 1,017 mandibular M3s removed. The MN was visualized in 66 extraction sites (6.5%). In the adjusted logistic model, radiographic signs were statistically associated with MN exposure (P.001) and imaging technique was a statistically insignificant effect modifying variable (P = .4).The results of this study suggest that imaging technique does not modify the relationship between high-risk panoramic radiographic signs and MN exposure.

MS/MS and database searching has emerged as a valuable technology for rapidly analyzing protein expression, localization, and post-translational modifications. The probability-based search engine Mascot has found widespread use as a tool to correlate tandem mass spectra with peptides in a sequence database. Although the Mascot scoring algorithm provides a probability-based model for peptide identification, the independent peptide scores do not correlate with the significance of the proteins to which they match. Herein, we describe a heuristic method for organizing proteins identified at a specified false-discovery rate using Mascot-matched peptides. We call this method PROVALT, and it uses peptide matches from a random database to calculate false-discovery rates for protein identifications and reduces a complex list of peptide matches to a nonredundant list of homologous protein groups. This method was evaluated using Mascot-identified peptides from a Trypanosoma cruzi epimastigote whole-cell lysate, which was separated by multidimensional LC and analyzed by MS/MS. PROVALT was then compared with the two traditional methods of protein identification when using Mascot, the single peptide score and cumulative protein score methods, and was shown to be superior to both in regards to the number of proteins identified and the inclusion of lower scoring nonrandom peptide matches.