Joint Sophomore Composition Recital:Roy Magnuson & Brian Bromberg

Kemp Recital Hall Monday Evening March 31, 2003 6:00p.m

The Promise of a Cooperative and Proportional Discovery Process in North Carolina: House Bill 380 and the New State Electronic Discovery Rules

Using the experience of the federal courts under the 2006 Amendments as a guide, this Article examines H.B. 380 and the effect it will have on the discovery process in the state courts. Part I of this Article describes the litigation challenges created by the proliferation of ESI. Part II describes the history, structure and substance of the 2006 Amendments, and discusses their impact in the areas of cooperation and the use of proportionality principles in the federal courts. Part III describes the substance and structure of the rules changes encompassed by H.B. 380, and analyzes the effect that they will have on the discovery process in the State. Part IV discusses specific procedural tools that practitioners and courts can use under the new e-discovery rules in North Carolina to manage the exchange of ESI more efficiently

The Promise of a Cooperative and Proportional Discovery Process in North Carolina: House Bill 380 and the New State Electronic Discovery Rules

Using the experience of the federal courts under the 2006 Amendments as a guide, this Article examines H.B. 380 and the effect it will have on the discovery process in the state courts. Part I of this Article describes the litigation challenges created by the proliferation of ESI. Part II describes the history, structure and substance of the 2006 Amendments, and discusses their impact in the areas of cooperation and the use of proportionality principles in the federal courts. Part III describes the substance and structure of the rules changes encompassed by H.B. 380, and analyzes the effect that they will have on the discovery process in the State. Part IV discusses specific procedural tools that practitioners and courts can use under the new e-discovery rules in North Carolina to manage the exchange of ESI more efficiently

Regulation of the Mechanistic Target of Rapamycin by Cellular Stress.

In complex eukaryotes, cell, tissue, and organismal homeostasis requires proper sensing of growth factors and nutrients. The mechanistic target of rapamycin (mTOR) functions as a central integrator of diverse cellular stimuli to regulate fundamental cellular processes. mTOR, a serine/threonine protein kinase, forms the catalytic core of at least two distinct signaling complexes, the raptor-associated mTOR complex 1 (mTORC1) and the rictor-associated mTOR complex 2 (mTORC2). Growth factors and nutrients activate mTORC1 to promote anabolic processes including protein and lipid biosynthesis, cell growth, and cell proliferation. mTORC1 dysregulation contributes to insulin resistance, type 2 diabetes, tumorigenesis, and neurodegenerative disorders. mTORC2 responds to insulin signaling and is important for glucose homeostasis and cell survival. The regulation and function of mTORC2 is not well understood. We have found that mTORC1 is regulated by phosphorylation of mTOR, yet the upstream pathways that control this phosphorylation and the role of mTOR phosphorylation in mTORC2 are unclear. My research has uncovered a novel mTOR regulatory mechanism whereby cellular stress promotes mTOR phosphorylation and regulates both mTORC1 and mTORC2 signaling. I expect these results to shed light on the regulation of mTOR and provide the rationale for targeting mTOR and stress pathways upstream of mTOR in the treatment of metabolic disorders.PhDCell and Developmental BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/97910/1/bmagnuso_1.pd

ERp29 triggers a conformational change in polyomavirus to stimulate membrane binding

Funding Information: We thank Tom Rapoport and Kristen Verhey for critically reading the manuscript. B.T. is a Biological Scholar at the University of Michigan Medical School. E.K.R. is supported by a training grant from the National Science Foundation. S.M. was supported by the Swedish Medical Research Council and the Swedish Society of Medicine. M.B. received a scholarship from the Royal Swedish Academy. The work was supported in part by a grant to T.B. from the National Cancer Institute (CA 082395). Copyright: Copyright 2008 Elsevier B.V., All rights reserved.Membrane penetration of nonenveloped viruses is a poorly understood process. We have investigated early stages of this process by studying the conformational change experienced by polyomavirus (Py) in the lumen of the endoplasmic reticulum (ER), a step that precedes its transport into the cytosol. We show that a PDI-like protein, ERp29, exposes the C-terminal arm of Py's VP1 protein, leading to formation of a hydrophobic particle that binds to a lipid bilayer; this reaction likely mimics initiation of Py penetration across the ER membrane. Expression of a dominant-negative ERp29 decreases Py infection, indicating ERp29 facilitates viral infection. Interestingly, cholera toxin, another toxic agent that crosses the ER membrane into the cytosol, is unfolded by PDI in the ER. Our data thus identify an ER factor that mediates membrane penetration of a nonenveloped virus and suggest that PDI family members are generally involved in ER remodeling reactions.publishersversionPeer reviewe

Mutant p53R270H drives altered metabolism and increased invasion in pancreatic ductal adenocarcinoma

Pancreatic cancer is characterized by nearly universal activating mutations in KRAS. Among other somatic mutations, TP53 is mutated in more than 75% of human pancreatic tumors. Genetically engineered mice have proven instrumental in studies of the contribution of individual genes to carcinogenesis. Oncogenic Kras mutations occur early during pancreatic carcinogenesis and are considered an initiating event. In contrast, mutations in p53 occur later during tumor progression. In our model, we recapitulated the order of mutations of the human disease, with p53 mutation following expression of oncogenic Kras. Further, using an inducible and reversible expression allele for mutant p53, we inactivated its expression at different stages of carcinogenesis. Notably, the function of mutant p53 changes at different stages of carcinogenesis. Our work establishes a requirement for mutant p53 for the formation and maintenance of pancreatic cancer precursor lesions. In tumors, mutant p53 becomes dispensable for growth. However, it maintains the altered metabolism that characterizes pancreatic cancer and mediates its malignant potential. Further, mutant p53 promotes epithelial-mesenchymal transition (EMT) and cancer cell invasion. This work generates new mouse models that mimic human pancreatic cancer and expands our understanding of the role of p53 mutation, common in the majority of human malignancies

Targeting DNA Repair and Survival Signaling in Diffuse Intrinsic Pontine Gliomas to Prevent Tumor Recurrence

Therapeutic resistance remains a major obstacle to successful clinical management of diffuse intrinsic pontine glioma (DIPG), a high-grade pediatric tumor of the brain stem. In nearly all patients, available therapies fail to prevent progression. Innovative combinatorial therapies that penetrate the blood-brain barrier and lead to long-term control of tumor growth are desperately needed. We identified mechanisms of resistance to radiotherapy, the standard of care for DIPG. On the basis of these findings, we rationally designed a brain-penetrant small molecule, MTX-241F, that is a highly selective inhibitor of EGFR and PI3 kinase family members, including the DNA repair protein DNA-PK. Preliminary studies demonstrated that micromolar levels of this inhibitor can be achieved in murine brain tissue and that MTX-241F exhibits promising single-agent efficacy and radiosensitizing activity in patient-derived DIPG neurospheres. Its physiochemical properties include high exposure in the brain, indicating excellent brain penetrance. Because radiotherapy results in double-strand breaks that are repaired by homologous recombination (HR) and non-homologous DNA end joining (NHEJ), we have tested the combination of MTX-241F with an inhibitor of Ataxia Telangiectasia Mutated to achieve blockade of HR and NHEJ, respectively, with or without radiotherapy. When HR blockers were combined with MTX-241F and radiotherapy, synthetic lethality was observed, providing impetus to explore this combination in clinically relevant models of DIPG. Our data provide proof-of-concept evidence to support advanced development of MTX-241F for the treatment of DIPG. Future studies will be designed to inform rapid clinical translation to ultimately impact patients diagnosed with this devastating disease

Oxphos Promotes Apoptotic Resistance and Cellular Persistence in TH17 Cells in the Periphery and Tumor Microenvironment

T cell proliferation and cytokine production are bioenergetically and biosynthetically costly. The inability to meet these metabolic demands results in altered differentiation, accompanied by impaired effector function, and attrition of the immune response. Interleukin-17-producing CD4 T cells (TH17s) are mediators of host defense, autoimmunity, and antitumor immunity in the setting of adoptive T cell therapy. TH17s are long-lived cells that require mitochondrial oxidative phosphorylation (OXPHOS) for effector function in vivo. Considering that TH17s polarized under standardized culture conditions are predominately glycolytic, little is known about how OXPHOS regulates TH17 processes, such as their ability to persist and thus contribute to protracted immune responses. Here, we modified standardized culture medium and identified a culture system that reliably induces OXPHOS dependence in TH17s. We found that TH17s cultured under OXPHOS conditions metabolically resembled their in vivo counterparts, whereas glycolytic cultures were dissimilar. OXPHOS TH17s exhibited increased mitochondrial fitness, glutamine anaplerosis, and an antiapoptotic phenotype marked by high BCL-XL and low BIM. Limited mitophagy, mediated by mitochondrial fusion regulator OPA-1, was critical to apoptotic resistance in OXPHOS TH17s. By contrast, glycolytic TH17s exhibited more mitophagy and an imbalance in BCL-XL to BIM, thereby priming them for apoptosis. In addition, through adoptive transfer experiments, we demonstrated that OXPHOS protected TH17s from apoptosis while enhancing their persistence in the periphery and tumor microenvironment in a murine model of melanoma. Together, our work demonstrates how metabolism regulates TH17 cell fate and highlights the potential for therapies that target OXPHOS in TH17-driven diseases

BigMouth : development and maintenance of a successful dental data repository

DATA AVAILABILITY : The data underlying this article will be shared on reasonable request to the corresponding author.Few clinical datasets exist in dentistry to conduct secondary research. Hence, a novel dental data repository called BigMouth was developed, which has grown to include 11 academic institutions contributing Electronic Health Record data on over 4.5 million patients. The primary purpose for BigMouth is to serve as a high-quality resource for rapidly conducting oral health-related research. BigMouth allows for assessing the oral health status of a diverse US patient population; provides rationale and evidence for new oral health care delivery modes; and embraces the specific oral health research education mission. A data governance framework that encouraged data sharing while controlling contributed data was initially developed. This transformed over time into a mature framework, including a fee schedule for data requests and allowing access to researchers from noncontributing institutions. Adoption of BigMouth helps to foster new collaborations between clinical, epidemiological, statistical, and informatics experts and provides an additional venue for professional development.The National Library of Medicine.https://academic.oup.com/jamiaam2023Dental Management Science

An Interactive Database for the Assessment of Histone Antibody Specificity

Access to high quality antibodies is a necessity for the study of histones and their posttranslational modifications (PTMs). Here we debut The Histone Antibody Specificity Database (http://www.histoneantibodies.com), an online and expanding resource cataloguing the behavior of widely used commercially available histone antibodies by peptide microarray. This interactive web portal provides a critical resource to the biological research community who routinely use these antibodies as detection reagents for a wide range of applications