ScholarWorks is an archive that shares over 50,000 articles, working papers, chapters, presentations, posters, theses, historical documents and other items submitted by members of the IU Indianapolis campus community.
Get started! Login with your IU credentials to share freely with 2 million readers per year.
Communities in ScholarWorks
Select a community to browse its collections.
Recent Submissions
Nf1+/− mast cells induce neurofibroma like phenotypes through secreted TGF-β signaling
(Oxford University Press, 2006) Yang, Feng-Chun; Chen, Shi; Clegg, Travis; Li, Xiaohong; Morgan, Trent; Estwick, Selina A.; Yuan, Jin; Khalaf, Waleed; Burgin, Sarah; Travers, Jeff; Parada, Luis F.; Ingram, David A.; Clapp, D. Wade; Pediatrics, School of Medicine
Neurofibromas are common tumors found in neurofibromatosis type 1 (NF1) patients. These complex tumors are composed of Schwann cells, mast cells, fibroblasts and perineurial cells embedded in collagen that provide a lattice for tumor invasion. Genetic studies demonstrate that in neurofibromas, nullizygous loss of Nf1 in Schwann cells and haploinsufficiency of Nf1 in non-neuronal cells are required for tumorigenesis. Fibroblasts are a major cellular constituent in neurofibromas and are a source of collagen that constitutes approximately 50% of the dry weight of the tumor. Here, we show that two of the prevalent heterozygous cells found in neurofibromas, mast cells and fibroblasts interact directly to contribute to tumor phenotype. Nf1+/- mast cells secrete elevated concentrations of the profibrotic transforming growth factor-beta (TGF-beta). In response to TGF-beta, both murine Nf1+/- fibroblasts and fibroblasts from human neurofibromas proliferate and synthesize excessive collagen, a hallmark of neurofibromas. We also establish that the TGF-beta response occurs via hyperactivation of a novel Ras-c-abl signaling pathway. Genetic or pharmacological inhibition of c-abl reverses fibroblast proliferation and collagen synthesis to wild-type levels. These studies identify a novel molecular target to inhibit neurofibroma formation.
Role of Cellular FKBP52 Protein in Intracellular Trafficking of Recombinant Adeno-associated Virus 2 Vectors
(Elsevier, 2006) Zhao, Weihong; Zhong, Li; Wu, Jianqing; Chen, Linyuan; Qing, Keyun; Weigel-Kelley, Kirsten A.; Larsen, Steven H.; Shou, Weinian; Warrington, Kenneth H., Jr.; Srivastava, Arun; Microbiology and Immunology, School of Medicine
We have reported that tyrosine-phosphorylated forms of a cellular protein, FKBP52, inhibit the second-strand DNA synthesis of adeno-associated virus 2 (AAV), leading to inefficient transgene expression from recombinant AAV vectors. To further explore the role of FKBP52 in AAV-mediated transduction, we established murine embryo fibroblasts (MEFs) cultures from FKBP52 wild-type (WT), heterozygous (HE), and knockout (KO) mice. Conventional AAV vectors failed to transduce WT MEFs efficiently, and the transduction efficiency was not significantly increased in HE or KO MEFs. AAV vectors failed to traffic efficiently to the nucleus in these cells. Treatment with hydroxyurea (HU) increased the transduction efficiency of conventional AAV vectors by approximately 25-fold in WT MEFs, but only by approximately 4-fold in KO MEFs. The use of self-complementary AAV (scAAV) vectors, which bypass the requirement of viral second-strand DNA synthesis, revealed that HU treatment increased the transduction efficiency approximately 23-fold in WT MEFs, but only approximately 4-fold in KO MEFs, indicating that the lack of HU treatment-mediated increase in KO MEFs was not due to failure of AAV to undergo viral second-strand DNA synthesis. Following HU treatment, approximately 59% of AAV genomes were present in the nuclear fraction from WT MEFs, but only approximately 28% in KO MEFs, indicating that the pathway by which HU treatment mediates nuclear transport of AAV was impaired in KO MEFs. When KO MEFs were stably transfected with an FKBP52 expression plasmid, HU treatment-mediated increase in the transduction efficiency was restored in these cells, which correlated directly with improved intracellular trafficking. Intact AAV particles were also shown to interact with FKBP52 as well as with dynein, a known cellular protein involved in AAV trafficking. These studies suggest that FKBP52, being a cellular chaperone protein, facilitates intracellular trafficking of AAV, which has implications in the optimal use of recombinant AAV vectors in human gene therapy.
Automated Mapping of Local Radiology Terms to LOINC
(American Medical Informatics Association, 2005) Vreeman, Daniel J.; McDonald, Clement J.; Medicine, School of Medicine
We developed an automated tool, called the Intelligent Mapper (IM), to improve the efficiency and consistency of mapping local terms to LOINC. We evaluated IM's performance in mapping diagnostic radiology report terms from two hospitals to LOINC by comparing IM's term rankings to a manually established gold standard. Using a CPT-based restriction, for terms with a LOINC code match, IM ranked the correct LOINC code first in 90% of our development set terms, and in 87% of our test set terms. The CPT-based restriction significantly improved IM's ability to identify correct LOINC codes. We have made IM freely available, with the aim of reducing the effort required to integrate disparate systems and helping move us towards the goal of interoperable health information exchange.
Overexpression of bone morphogenetic protein 10 in myocardium disrupts cardiac postnatal hypertrophic growth
(Elsevier, 2006) Chen, Hanying; Yong, Weidong; Ren, Shuxun; Shen, Weihua; He, Yongzheng; Cox, Karen A.; Zhu, Wuqiang; Li, Wei; Soonpaa, Mark; Payne, R. Mark; Franco, Diego; Field, Loren J.; Rosen, Vicki; Wang, Yibin; Shou, Weinian; Pediatrics, School of Medicine
Postnatal cardiac hypertrophies have traditionally been classified into physiological or pathological hypertrophies. Both of them are induced by hemodynamic load. Cardiac postnatal hypertrophic growth is regarded as a part of the cardiac maturation process that is independent of the cardiac working load. However, the functional significance of this biological event has not been determined, mainly because of the difficulty in creating an experimental condition for testing the growth potential of functioning heart in the absence of hemodynamic load. Recently, we generated a novel transgenic mouse model (alphaMHC-BMP10) in which the cardiac-specific growth factor bone morphogenetic protein 10 (BMP10) is overexpressed in postnatal myocardium. These alphaMHC-BMP10 mice appear to have normal cardiogenesis throughout embryogenesis, but develop to smaller hearts within 6 weeks after birth. alphaMHC-BMP10 hearts are about half the normal size with 100% penetrance. Detailed morphometric analysis of cardiomyocytes clearly indicated that the compromised cardiac growth in alphaMHC-BMP10 mice was solely because of defect in cardiomyocyte postnatal hypertrophic growth. Physiological analysis further demonstrated that the responses of these hearts to both physiological (e.g. exercise-induced hypertrophy) and pathological hypertrophic stimuli remain normal. In addition, the alphaMHC-BMP10 mice develop subaortic narrowing and concentric myocardial thickening without obstruction by four weeks of age. Systematic analysis of potential intracellular pathways further suggested a novel genetic pathway regulating this previously undefined cardiac postnatal hypertrophic growth event. This is the first demonstration that cardiac postnatal hypertrophic growth can be specifically modified genetically and dissected out from physiological and pathological hypertrophies.
Validation analysis of informant's ratings of cognitive function in African Americans and Nigerians
(Wiley, 2006) Shen, Jianzhao; Gao, Sujuan; Unverzagt, Frederick W.; Ogunniyi, Adesola; Baiyewu, Olusegun; Gureje, Oye; Hendrie, Hugh C.; Hall, Kathleen S.; Medicine, School of Medicine
Objectives: To examine informant validity using the Community Screening Interview for Dementia (CSI 'D') both cross-sectionally and longitudinally in two very different cultures and to explore the effects of informants and study participants' characteristics on the validity of informants' reports.
Methods: Elderly African Americans age 65 years and older residing in Indianapolis, USA and elderly Yoruba Nigerians age 65 years and older residing in Ibadan, Nigeria were assessed on cognitive functioning using the CSI 'D' at baseline (1992-1993) and five-year follow-up (1997-1998). At baseline, the informant validity in both samples was evaluated against participants' cognitive tests using Pearson correlation and regular regression models. At follow-up, informants ratings on cognitive decline were assessed against participants' cognitive decline scores from baseline to follow-up using biserial correlation and logistic regressions.
Results: At baseline, informants' reports on cognitive functioning significantly correlated with cognitive scores in both samples (Indianapolis:r = -0.43, p < 0.001; Ibadan:r = -0.47, p < 0.001). The participant-informant relationships significantly affected the informants' reports in the two samples with different patterns (p = 0.005 for Indianapolis and p < 0.001 for Ibadan) at a given level of cognitive functioning. African Americans spouses reported more cognitive problems, while siblings reported more problems for the Yoruba Nigerians. At follow-up, informants' ratings on cognitive decline significantly correlated with the cognitive decline scores (Indianapolis r = 0.38, p < 0.001; Ibadan r = 0.32, p < 0.001). The characteristics of study participants and informants had little impact on the informants' ratings on cognitive decline.
Conclusions: Informant reports are valid in assessing the cognitive functioning of study participants both cross-sectionally and longitudinally in two very different cultures, languages and environments.