The Grizzly, December 2, 2004

UC Students Opposed to Drunk Driving • Post-election Blues Give Rise to New Interest Group on Campus • Behind Closed Doors: Secret Places on Campus • Wheelchair Basketball Rolls in the Money • Upcoming Choir Concert • Interview with the President: Strassburger Shares Plans for Ursinus • Dance Company Concert a Success • Holly Singh Presents Mistaken Identity: Sikhs in America at Unity House • Major Highlight: Gender and Women\u27s Studies • Opinions: Enjoy Your Carbs this Holiday Season; Freedom on the Line • Pro Athletes Brawling with Fans • Men\u27s Basketball Season Heating Uphttps://digitalcommons.ursinus.edu/grizzlynews/1573/thumbnail.jp

The Grizzly, November 3, 1992

Senior Party Success • Keith Strunk Rallies Student Support • Vote: Our Future Depends on Us • Smoking Danger Update • Blue Eyes, Brown Eyes • Phi Psi Clothes Drive • Truth About Tomatoes • Coffee House: Good to the Last Drop! • Coffee Talk • Singles Review • Fresh Brewed, Mountain Grown, 70\u27s Rock • New Berman Endowment to Preserve Outdoor Art • Another Dark Hit Brewed by Waters • Choir Percolates a Performance • In Search of Purpose • Letters to the Editor • Intramural Football Culminates in Thriller • Field Hockey Struggles; Season Ends This Week • Volleyball Finished Season with Split • Football Battles Ranked W.P.I.https://digitalcommons.ursinus.edu/grizzlynews/1303/thumbnail.jp

A Novel Statistical Algorithm for Gene Expression Analysis Helps Differentiate Pregnane X Receptor-Dependent and Independent Mechanisms of Toxicity

Genome-wide gene expression profiling has become standard for assessing potential liabilities as well as for elucidating mechanisms of toxicity of drug candidates under development. Analysis of microarray data is often challenging due to the lack of a statistical model that is amenable to biological variation in a small number of samples. Here we present a novel non-parametric algorithm that requires minimal assumptions about the data distribution. Our method for determining differential expression consists of two steps: 1) We apply a nominal threshold on fold change and platform p-value to designate whether a gene is differentially expressed in each treated and control sample relative to the averaged control pool, and 2) We compared the number of samples satisfying criteria in step 1 between the treated and control groups to estimate the statistical significance based on a null distribution established by sample permutations. The method captures group effect without being too sensitive to anomalies as it allows tolerance for potential non-responders in the treatment group and outliers in the control group. Performance and results of this method were compared with the Significant Analysis of Microarrays (SAM) method. These two methods were applied to investigate hepatic transcriptional responses of wild-type (PXR+/+) and pregnane X receptor-knockout (PXR−/−) mice after 96 h exposure to CMP013, an inhibitor of β-secretase (β-site of amyloid precursor protein cleaving enzyme 1 or BACE1). Our results showed that CMP013 led to transcriptional changes in hallmark PXR-regulated genes and induced a cascade of gene expression changes that explained the hepatomegaly observed only in PXR+/+ animals. Comparison of concordant expression changes between PXR+/+ and PXR−/− mice also suggested a PXR-independent association between CMP013 and perturbations to cellular stress, lipid metabolism, and biliary transport

Predictive Power Estimation Algorithm (PPEA) - A New Algorithm to Reduce Overfitting for Genomic Biomarker Discovery

Toxicogenomics promises to aid in predicting adverse effects, understanding the mechanisms of drug action or toxicity, and uncovering unexpected or secondary pharmacology. However, modeling adverse effects using high dimensional and high noise genomic data is prone to over-fitting. Models constructed from such data sets often consist of a large number of genes with no obvious functional relevance to the biological effect the model intends to predict that can make it challenging to interpret the modeling results. To address these issues, we developed a novel algorithm, Predictive Power Estimation Algorithm (PPEA), which estimates the predictive power of each individual transcript through an iterative two-way bootstrapping procedure. By repeatedly enforcing that the sample number is larger than the transcript number, in each iteration of modeling and testing, PPEA reduces the potential risk of overfitting. We show with three different cases studies that: (1) PPEA can quickly derive a reliable rank order of predictive power of individual transcripts in a relatively small number of iterations, (2) the top ranked transcripts tend to be functionally related to the phenotype they are intended to predict, (3) using only the most predictive top ranked transcripts greatly facilitates development of multiplex assay such as qRT-PCR as a biomarker, and (4) more importantly, we were able to demonstrate that a small number of genes identified from the top-ranked transcripts are highly predictive of phenotype as their expression changes distinguished adverse from nonadverse effects of compounds in completely independent tests. Thus, we believe that the PPEA model effectively addresses the over-fitting problem and can be used to facilitate genomic biomarker discovery for predictive toxicology and drug responses

Atonal homolog 1 Is a Tumor Suppressor Gene

Colon cancer accounts for more than 10% of all cancer deaths annually. Our genetic evidence from Drosophila and previous in vitro studies of mammalian Atonal homolog 1 (Atoh1, also called Math1 or Hath1) suggest an anti-oncogenic function for the Atonal group of proneural basic helix-loop-helix transcription factors. We asked whether mouse Atoh1 and human ATOH1 act as tumor suppressor genes in vivo. Genetic knockouts in mouse and molecular analyses in the mouse and in human cancer cell lines support a tumor suppressor function for ATOH1. ATOH1 antagonizes tumor formation and growth by regulating proliferation and apoptosis, likely via activation of the Jun N-terminal kinase signaling pathway. Furthermore, colorectal cancer and Merkel cell carcinoma patients show genetic and epigenetic ATOH1 loss-of-function mutations. Our data indicate that ATOH1 may be an early target for oncogenic mutations in tissues where it instructs cellular differentiation

Dynamic changes in eIF4F-mRNA interactions revealed by global analyses of environmental stress responses

BACKGROUND: Translation factors eIF4E and eIF4G form eIF4F, which interacts with the messenger RNA (mRNA) 5' cap to promote ribosome recruitment and translation initiation. Variations in the association of eIF4F with individual mRNAs likely contribute to differences in translation initiation frequencies between mRNAs. As translation initiation is globally reprogrammed by environmental stresses, we were interested in determining whether eIF4F interactions with individual mRNAs are reprogrammed and how this may contribute to global environmental stress responses. RESULTS: Using a tagged-factor protein capture and RNA-sequencing (RNA-seq) approach, we have assessed how mRNA associations with eIF4E, eIF4G1 and eIF4G2 change globally in response to three defined stresses that each cause a rapid attenuation of protein synthesis: oxidative stress induced by hydrogen peroxide and nutrient stresses caused by amino acid or glucose withdrawal. We find that acute stress leads to dynamic and unexpected changes in eIF4F-mRNA interactions that are shared among each factor and across the stresses imposed. eIF4F-mRNA interactions stabilised by stress are predominantly associated with translational repression, while more actively initiating mRNAs become relatively depleted for eIF4F. Simultaneously, other mRNAs are insulated from these stress-induced changes in eIF4F association. CONCLUSION: Dynamic eIF4F-mRNA interaction changes are part of a coordinated early translational control response shared across environmental stresses. Our data are compatible with a model where multiple mRNA closed-loop complexes form with differing stability. Hence, unexpectedly, in the absence of other stabilising factors, rapid translation initiation on mRNAs correlates with less stable eIF4F interactions

The structure and function of Alzheimer's gamma secretase enzyme complex

The production and accumulation of the beta amyloid protein (Aβ) is a key event in the cascade of oxidative and inflammatory processes that characterizes Alzheimer’s disease (AD). A multi-subunit enzyme complex, referred to as gamma (γ) secretase, plays a pivotal role in the generation of Aβ from its parent molecule, the amyloid precursor protein (APP). Four core components (presenilin, nicastrin, aph-1, and pen-2) interact in a high-molecular-weight complex to perform intramembrane proteolysis on a number of membrane-bound proteins, including APP and Notch. Inhibitors and modulators of this enzyme have been assessed for their therapeutic benefit in AD. However, although these agents reduce Aβ levels, the majority have been shown to have severe side effects in pre-clinical animal studies, most likely due to the enzymes role in processing other proteins involved in normal cellular function. Current research is directed at understanding this enzyme and, in particular, at elucidating the roles that each of the core proteins plays in its function. In addition, a number of interacting proteins that are not components of γ-secretase also appear to play important roles in modulating enzyme activity. This review will discuss the structural and functional complexity of the γ-secretase enzyme and the effects of inhibiting its activity

Coordinates of liminality: Emerson, Fuller, and the landscape of empire

This project examines the rhetorical construction of place and self in the writing of Ralph Waldo Emerson and Margaret Fuller and argues that it must be understood as revealing the contradictions of a nation poised between settler colonialism and imperialism. Written against a backdrop of disparaging European texts like those produced by Frances Trollope and Charles Dickens, and in part addressed to European readers, these works of self-enculturation display postcolonial ambivalence as they simultaneously declare independence from and maintain connection with their colonial past. At the same time, Emerson\u27s continual emphasis on the acquisition of individual power inevitably colludes with the competitive ideology at the heart of empire-building while Fuller often glosses over the politics of domination and even celebrates westward expansion as a sign of progress. Chapter One provides a brief introduction to theories of settler postcolonial nationalism and their relevance for understanding the literature of the antebellum United States. Chapters Two and Three examine Emerson\u27s and Fuller\u27s investigations into the importance of aesthetic perception as foundational to individual and social health. Chapter Four discusses the significance of journalism as a form of travel writing crucial to the development of national identity. Chapter Five foregrounds Emerson\u27s analysis of the conditions of national and imperial power. Key texts examined in this project include Emerson\u27s Nature and English Traits and Fuller\u27s Summer on the Lakes and selected articles from the New York Tribune as well as Dickens\u27s American Notes , Alexis de Tocqueville\u27s Democracy in America, and Frances Trollope\u27s Domestic Manners of the Americans

Intermediate accounting

*** *** Bibliografi hlm.xvii, 890 hlm. ; il. ; 24 cm