Open Access Policy Articles

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The IUPUI Faculty Council adopted an open access policy on October 7th, 2014 (available from: https://openaccess.indianapolis.iu.edu/). This policy shows IUPUI's commitment to disseminating the fruits of research and scholarship as widely as possible. Open access policies increase authors’ rights, readership and citation rates for scholarly articles. The opt out provision ensures that all faculty authors have the freedom to publish in the journal of their choice.

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Behavioral Symptoms in Community-dwelling Elderly Nigerians with Dementia, Mild Cognitive Impairment, and Normal Cognition
(Wiley, 2012) Baiyewu, O.; Unverzagt, F. W.; Ogunniyi, A.; Smith-Gamble, V.; Gureje, O.; Lane, K. A.; Gao, S.; Hall, K. S.; Hendrie, H. C.; Psychiatry, School of Medicine
Background: Few studies have examined the neuropsychiatric status of patients with dementia and cognitive impairment in the developing world despite the fact that current demographic trends suggest an urgent need for such studies. Objective: To assess the level of neuropsychiatric symptoms in community-dwelling individuals with dementia, cognitive impairment no dementia and normal cognition. Methods: Subjects were from the Ibadan site of Indianapolis-Ibadan Dementia Project with stable diagnoses of normal cognition, cognitive impairment, no dementia/mild cognitive impairment (CIND/MCI), and dementia. Informants of subjects made ratings on the neuropsychiatric inventory and blessed dementia scale; subjects were tested with the mini mental state examination. Results: One hundred and eight subjects were included in the analytic sample, 21 were cognitively normal, 34 were demented, and 53 were CIND/MCI. The diagnostic groups did not differ in age, per cent female, or per cent with any formal education. The most frequent symptoms among subjects with CIND/MCI were depression (45.3%), apathy (37.7%), night time behavior (28.3%), appetite change (24.5%), irritability (22.6%), delusions (22.6%), anxiety (18.9%), and agitation (17.0%). Depression was significantly more frequent among the CIND/MCI and dementia (44.1%) groups compared with the normal cognition group (9.5%). Distress scores were highest for the dementia group, lowest for the normal cognition group, and intermediate for the CIND/MCI group. Conclusion: Significant neuropsychiatric symptomatology and distress are present among cognitively impaired persons in this community-based study of older adults in this sub-Saharan African country. Programs to assist family members of cognitively impaired and demented persons should be created or adapted for use in developing countries.
Gene Profile of Myeloid-Derived Suppressive Cells from the Bone Marrow of Lysosomal Acid Lipase Knock-Out Mice
(Public Library of Science, 2012) Yan, Cong; Ding, Xinchun; Dasgupta, Nupur; Wu, Lingyan; Du, Hong; Pathology and Laboratory Medicine, School of Medicine
Background: Lysosomal acid lipase (LAL) controls development and homeostasis of myeloid lineage cells. Loss of the lysosomal acid lipase (LAL) function leads to expansion of myeloid-derived suppressive cells (MDSCs) that cause myeloproliferative neoplasm. Methodology/principal findings: Affymetrix GeneChip microarray analysis identified detailed intrinsic defects in Ly6G(+) myeloid lineage cells of LAL knock-out (lal-/-) mice. Ingenuity Pathway Analysis revealed activation of the mammalian target of rapamycin (mTOR) signaling, which functions as a nutrient/energy/redox sensor, and controls cell growth, cell cycle entry, cell survival, and cell motility. Loss of the LAL function led to major alteration of large GTPase and small GTPase signal transduction pathways. lal-/- Ly6G(+) myeloid cells in the bone marrow showed substantial increase of cell proliferation in association with up-regulation of cyclin and cyclin-dependent kinase (cdk) genes. The epigenetic microenvironment was significantly changed due to the increased expression of multiple histone cluster genes, centromere protein genes and chromosome modification genes. Gene expression of bioenergetic pathways, including glycolysis, aerobic glycolysis, mitochondrial oxidative phosphorylation, and respiratory chain proteins, was also increased, while the mitochondrial function was impaired in lal-/- Ly6G(+) myeloid cells. The concentration of reactive oxygen species (ROS) was significantly increased accompanied by up-regulation of nitric oxide/ROS production genes in these cells. Conclusions/significance: This comprehensive gene profile study for the first time identifies and defines important gene pathways involved in the myeloid lineage cells towards MDSCs using lal-/- mouse model.
Changes in predicted protein disorder tendency may contribute to disease risk
(Springer Nature, 2011) Hu, Yang; Liu, Yunlong; Jung, Jeesun; Dunker, A. Keith; Wang, Yadong; Medical and Molecular Genetics, School of Medicine
Background: Recent studies suggest that many proteins or regions of proteins lack 3D structure. Defined as intrinsically disordered proteins, these proteins/peptides are functionally important. Recent advances in next generation sequencing technologies enable genome-wide identification of novel nucleotide variations in a specific population or cohort. Results: Using the exonic single nucleotide variations (SNVs) identified in the 1,000 Genomes Project and distributed by the Genetic Analysis Workshop 17, we systematically analysed the genetic and predicted disorder potential features of the non-synonymous variations. The result of experiments suggests that a significant change in the tendency of a protein region to be structured or disordered caused by SNVs may lead to malfunction of such a protein and contribute to disease risk. Conclusions: After validation with functional SNVs on the traits distributed by GAW17, we conclude that it is valuable to consider structure/disorder tendencies while prioritizing and predicting mechanistic effects arising from novel genetic variations.
Safety of Tenofovir Use During Pregnancy: Early Growth Outcomes in HIV-Exposed Uninfected Infants
(Wolters Kluwer, 2012) Siberry, George K.; Williams, Paige L.; Mendez, Hermann; Seage, George R., III; Jacobson, Denise L.; Hazra, Rohan; Rich, Kenneth C.; Griner, Raymond; Tassiopoulos, Katherine; Kacanek, Deborah; Mofenson, Lynne M.; Miller, Tracie; DiMeglio, Linda A.; Watts, D. Heather; Pediatric HIV/AIDS Cohort Study (PHACS); Pediatrics, School of Medicine
Objective: To evaluate the association of tenofovir disoproxil fumarate (TDF) use during pregnancy with early growth parameters in HIV-exposed, uninfected (HEU) infants. Design: US-based prospective cohort study of HEU children to examine potential adverse effects of prenatal TDF exposure. Methods: We evaluated the association of maternal TDF use during pregnancy with small for gestational age (SGA); low birth weight (LBW, <2.5 kg); weight-for-age z-scores (WAZ), length-for-age z-scores (LAZ), and head circumference-for-age (HCAZ) z-scores at newborn visit; and LAZ, HCAZ, and WAZ at age 1 year. Logistic regression models for LBW and SGA were fit, adjusting for maternal and sociodemographic factors. Adjusted linear regression models were used to evaluate LAZ, WAZ, and HCAZ by TDF exposure. Results: Of 2029 enrolled children with maternal antiretroviral information, TDF was used by 449 (21%) HIV-infected mothers, increasing from 14% in 2003 to 43% in 2010. There was no difference between those exposed to combination regimens with vs. without TDF for SGA, LBW, and newborn LAZ and HCAZ. However, at age 1 year, infants exposed to combination regimens with TDF had significantly lower adjusted mean LAZ and HCAZ than those without TDF (LAZ: -0.17 vs. -0.03, P=0.04; HCAZ: 0.17 vs. 0.42, P=0.02). Conclusion: TDF use during pregnancy was not associated with increased risk for LBW or SGA. The slightly lower mean LAZ and HCAZ observed at age 1 year in TDF-exposed infants are of uncertain significance but underscore the need for additional studies of growth outcomes after TDF use during pregnancy.
Electroanatomic Remodeling of the Left Stellate Ganglion After Myocardial Infarction
(Elsevier, 2012) Han, Seongwook; Kobayashi, Kenzaburo; Joung, Boyoung; Piccirillo, Gianfranco; Maruyama, Mitsunori; Vinters, Harry V.; March, Keith; Lin, Shien-Fong; Shen, Changyu; Fishbein, Michael C.; Chen, Peng-Sheng; Chen, Lan S.; Medicine, School of Medicine
Objectives: The purpose of this study was to evaluate the changes of left stellate ganglionic nerve activity (SGNA) and left thoracic vagal nerve activity (VNA) after acute myocardial infarction (MI). Background: Whether MI results in remodeling of extracardiac nerve activity remains unclear. Methods: We implanted radiotransmitters to record the SGNA, VNA, and electrocardiogram in 9 ambulatory dogs. After baseline monitoring, MI was created by 1-h balloon occlusion of the coronary arteries. The dogs were then continuously monitored for 2 months. Both stellate ganglia were stained for growth-associated protein 43 and synaptophysin. The stellate ganglia from 5 normal dogs were used as control. Results: MI increased 24-h integrated SGNA from 7.44 ± 7.19 Ln(Vs)/day at baseline to 8.09 ± 7.75 Ln(Vs)/day after the MI (p < 0.05). The 24-h integrated VNA before and after the MI was 5.29 ± 5.04 Ln(Vs)/day and 5.58 ± 5.15 Ln(Vs)/day, respectively (p < 0.05). A significant 24-h circadian variation was noted for the SGNA (p < 0.05) but not the VNA. The SGNA/VNA ratio also showed significant circadian variation. The nerve densities from the left SG were 63,218 ± 34,719 μm(2)/mm(2) and 20,623 ± 4,926 μm(2)/mm(2) for growth-associated protein 43 (p < 0.05) and were 32,116 ± 8,190 μm(2)/mm(2)and 16,326 ± 4,679 μm(2)/mm(2) for synaptophysin (p < 0.05) in MI and control groups, respectively. The right SG also showed increased nerve density after MI (p < 0.05). Conclusions: MI results in persistent increase in the synaptic density of bilateral stellate ganglia and is associated with increased SGNA and VNA. There is a circadian variation of the SGNA/VNA ratio. These data indicate significant remodeling of the extracardiac autonomic nerve activity and structures after MI.
TGF-β1 enhances contractility in engineered skeletal muscle
(Wiley, 2013) Weist, Michael R.; Wellington, Michael S.; Bermudez, Jacob E.; Kostrominova, Tatiana Y.; Mendias, Christopher L.; Arruda, Ellen M.; Larkin, Lisa M.; Anatomy, Cell Biology and Physiology, School of Medicine
Scaffoldless engineered 3D skeletal muscle tissue created from satellite cells offers the potential to replace muscle tissue that is lost due to severe trauma or disease. Transforming growth factor-beta 1 (TGF-β1) plays a vital role in mediating migration and differentiation of satellite cells during the early stages of muscle development. Additionally, TGF-β1 promotes collagen type I synthesis in the extracellular matrix (ECM) of skeletal muscle, which provides a passive elastic substrate to support myofibres and facilitate the transmission of force. To determine the role of TGF-β1 in skeletal muscle construct formation and contractile function in vitro, we created tissue-engineered 3D skeletal muscle constructs with varying levels of recombinant TGF-β1 added to the cell culture medium. Prior to the addition of TGF-β1, the primary cell population was composed of 75% Pax7-positive cells. The peak force for twitch, tetanus and spontaneous force were significantly increased in the presence of 2.0 ng/ml TGF-β1 when compared to 0, 0.5 and 1.0 ng/ml TGF-β1. Visualization of the cellular structure with H&E and with immunofluorescence staining for sarcomeric myosin heavy chains and collagen type I showed denser regions of better organized myofibres in the presence of 2.0 ng/ml TGF-β1 versus 0, 0.5 and 1.0 ng/ml. The addition of 2.0 ng/ml TGF-β1 to the culture medium of engineered 3D skeletal muscle constructs enhanced contractility and extracellular matrix organization.
Prioritizing single-nucleotide variations that potentially regulate alternative splicing
(Springer Nature, 2011-11-29) Teng, Mingxiang; Wang, Yadong; Wang, Guohua; Jung, Jeesun; Edenberg, Howard J.; Sanford, Jeremy R.; Liu, Yunlong; Medical and Molecular Genetics, School of Medicine
Recent evidence suggests that many complex diseases are caused by genetic variations that play regulatory roles in controlling gene expression. Most genetic studies focus on nonsynonymous variations that can alter the amino acid composition of a protein and are therefore believed to have the highest impact on phenotype. Synonymous variations, however, can also play important roles in disease pathogenesis by regulating pre-mRNA processing and translational control. In this study, we systematically survey the effects of single-nucleotide variations (SNVs) on binding affinity of RNA-binding proteins (RBPs). Among the 10,113 synonymous SNVs identified in 697 individuals in the 1,000 Genomes Project and distributed by Genetic Analysis Workshop 17 (GAW17), we identified 182 variations located in alternatively spliced exons that can significantly change the binding affinity of nine RBPs whose binding preferences on 7-mer RNA sequences were previously reported. We found that the minor allele frequencies of these variations are similar to those of nonsynonymous SNVs, suggesting that they are in fact functional. We propose a workflow to identify phenotype-associated regulatory SNVs that might affect alternative splicing from exome-sequencing-derived genetic variations. Based on the affecting SNVs on the quantitative traits simulated in GAW17, we further identified two and four functional SNVs that are predicted to be involved in alternative splicing regulation in traits Q1 and Q2, respectively.
Quantitative RT-PCR Analyses of Five Evolutionary Conserved Genes in Alligator Brains During Development
(De Gruyter, 2011) Wilson, Sarah M.; Zhu, Tianli; Khanna, Rajesh; Pritz, Michael B.; Pharmacology and Toxicology, School of Medicine
Gene expression was investigated in the major brain subdivisions (telencephalon, diencephalon, midbrain and hindbrain) in a representative reptile, Alligator mississipiensis, during the later stages of embryonic development. The following genes were examined: voltage-gated sodium channel isoforms: NaV1.1 and NaV1.2; synaptic vesicle 2a (SV2a); synaptophysin; and calbindin 2. With the exception of synaptophysin, which was only expressed in the telencephalon, all genes were expressed in all brain regions sampled at the time periods examined. For NaV1.1, gene expression varied according to brain area sampled. When compared with NaV1.1, the pattern of NaV1.2 gene expression differed appreciably. The gene expression of SV2a was the most robust of any of the genes examined. Of the other genes examined, although differences were noted, no statistically significant changes were found either between brain part or time interval. Although limited, the present analysis is the first quantitative mRNA gene expression study in any reptile during development. Together with future experiments of a similar nature, the present gene expression results should determine which genes are expressed in major brain areas at which times during development in Alligator. When compared with other amniotes, these results will prove useful for determining how gene expression during development influences adult brain structure.
Fractionated laser resurfacing corrects the inappropriate UVB response in geriatric skin
(Elsevier, 2012) Spandau, Dan F.; Lewis, Davina A.; Somani, Ally-Khan; Travers, Jeffrey B.; Dermatology, School of Medicine
Non-melanoma skin cancer is a disease primarily afflicting geriatric patients as evidenced by the fact that 80% of all non-melanoma skin cancers are diagnosed in patients over the age of 60 years. As such, geriatric skin responds to cancer-inducing UVB irradiation in a manner that allows the establishment of tumor cells. Currently, the only effective treatment for non-melanoma skin cancer is the removal of the tumors after they appear, indicating the need for a more cost-effective prophylactic therapy. Geriatric volunteers were treated with fractionated laser resurfacing therapy on either sun-protected (upper buttocks) or chronically sun-exposed (dorsal forearm) skin. Fractionated laser resurfacing therapy was shown to decrease the occurrence of senescent fibroblasts in geriatric dermis, increase the dermal expression of IGF-1, and correct the inappropriate UVB response observed in untreated geriatric skin. These responses to fractionated laser resurfacing were equal to the effects seen previously using the more aggressive wounding following dermabrasion. Furthermore, fractionated laser resurfacing was equally effective in both sun-protected and sun-exposed skin. The ability of fractionated laser resurfacing treatment to protect against the occurrence of UVB-damaged proliferating keratinocytes indicates the potential of fractionated laser resurfacing to reduce or prevent aging-associated non-melanoma skin cancer.
Identification of multiple rare variants associated with a disease
(Springer Nature, 2011-11-29) Jung, Jeesun; Dantzer, Jessica; Liu, Yunlong; Medical and Molecular Genetics, School of Medicine
Identifying rare variants that are responsible for complex disease has been promoted by advances in sequencing technologies. However, statistical methods that can handle the vast amount of data generated and that can interpret the complicated relationship between disease and these variants have lagged. We apply a zero-inflated Poisson regression model to take into account the excess of zeros caused by the extremely low frequency of the 24,487 exonic variants in the Genetic Analysis Workshop 17 data. We grouped the 697 subjects in the data set as Europeans, Asians, and Africans based on principal components analysis and found the total number of rare variants per gene for each individual. We then analyzed these collapsed variants based on the assumption that rare variants are enriched in a group of people affected by a disease compared to a group of unaffected people. We also tested the hypothesis with quantitative traits Q1, Q2, and Q4. Analyses performed on the combined 697 individuals and on each ethnic group yielded different results. For the combined population analysis, we found that UGT1A1, which was not part of the simulation model, was associated with disease liability and that FLT1, which was a causal locus in the simulation model, was associated with Q1. Of the causal loci in the simulation models, FLT1 and KDR were associated with Q1 and VNN1 was correlated with Q2. No significant genes were associated with Q4. These results show the feasibility and capability of our new statistical model to detect multiple rare variants influencing disease risk.

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