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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Now showing 1 - 10 of 30283

Visual contrast sensitivity in Alzheimer's disease, mild cognitive impairment, and older adults with cognitive complaints
(Elsevier, 2013) Risacher, Shannon L.; WuDunn, Darrell; Pepin, Susan M.; MaGee, Tamiko R.; McDonald, Brenna C.; Flashman, Laura A.; Wishart, Heather A.; Pixley, Heather S.; Rabin, Laura A.; Paré, Nadia; Englert, Jessica J.; Schwartz, Eben; Curtain, Joshua R.; West, John D.; O’Neill, Darren P.; Santulli, Robert B.; Newman, Richard W.; Saykin, Andrew J.; Radiology and Imaging Sciences, School of Medicine
Deficits in contrast sensitivity (CS) have been reported in Alzheimer's disease (AD). However, the extent of these deficits in prodromal AD stages, including mild cognitive impairment (MCI) or even earlier, has not been investigated. In this study, CS was assessed using frequency doubling technology in older adults with AD (n = 10), amnestic MCI (n = 28), cognitive complaints without performance deficits (CC; n = 20), and healthy controls (HC; n = 29). The association between CS and cognition was also evaluated. Finally, the accuracy of CS measures for classifying MCI versus HC was evaluated. CS deficits were found in AD and MCI, while CC showed intermediate performance between MCI and HC. Upper right visual field CS showed the most significant difference among groups. CS was also associated with cognitive performance. Finally, CS measures accurately classified MCI versus HC. The CS deficits in AD and MCI, and intermediate performance in CC, indicate that these measures are sensitive to early AD-associated changes. Therefore, frequency doubling technology-based measures of CS may have promise as a novel AD biomarker.
A genome wide association study of alcohol dependence symptom counts in extended pedigrees identifies C15orf53
(Springer Nature, 2013) Wang, Jen-Chyong; Foroud, Tatiana; Hinrichs, Anthony L.; Le, Nhung X. H.; Bertelsen, Sarah; Budde, John P.; Harari, Oscar; Koller, Daniel L.; Wetherill, Leah; Agrawal, Arpana; Almasy, Laura; Brooks, Andrew I.; Bucholz, Kathleen; Dick, Danielle; Hesselbrock, Victor; Johnson, Eric O.; Kang, Sun; Kapoor, Manav; Kramer, John; Kuperman, Samuel; Madden, Pamela A. F.; Manz, Niklas; Martin, Nicholas G.; McClintick, Jeanette N.; Montgomery, Grant W.; Nurnberger, John I., Jr.; Rangaswamy, Madhavi; Rice, John; Schuckit, Marc; Tischfield, Jay A.; Whitfield, John B.; Xuei, Xiaoling; Porjesz, Bernice; Heath, Andrew C.; Edenberg, Howard J.; Bierut, Laura J.; Goate, Alison M.; Medical and Molecular Genetics, School of Medicine
Several studies have identified genes associated with alcohol-use disorders (AUDs), but the variation in each of these genes explains only a small portion of the genetic vulnerability. The goal of the present study was to perform a genome-wide association study (GWAS) in extended families from the Collaborative Study on the Genetics of Alcoholism to identify novel genes affecting risk for alcohol dependence (AD). To maximize the power of the extended family design, we used a quantitative endophenotype, measured in all individuals: number of alcohol-dependence symptoms endorsed (symptom count (SC)). Secondary analyses were performed to determine if the single nucleotide polymorphisms (SNPs) associated with SC were also associated with the dichotomous phenotype, DSM-IV AD. This family-based GWAS identified SNPs in C15orf53 that are strongly associated with DSM-IV alcohol-dependence symptom counts (P=4.5 × 10(-8), inflation-corrected P=9.4 × 10(-7)). Results with DSM-IV AD in the regions of interest support our findings with SC, although the associations were less significant. Attempted replications of the most promising association results were conducted in two independent samples: nonoverlapping subjects from the Study of Addiction: Genes and Environment (SAGE) and the Australian Twin Family Study of AUDs (OZALC). Nominal association of C15orf53 with SC was observed in SAGE. The variant that showed strongest association with SC, rs12912251 and its highly correlated variants (D'=1, r(2) 0.95), have previously been associated with risk for bipolar disorder.
Akt Phosphorylates the Transcriptional Repressor Bmi1 to Block Its Effects on the Tumor-Suppressing Ink4a-Arf Locus
(American Association for the Advancement of Science, 2012-10-23) Liu, Yan; Liu, Fan; Yu, Hao; Zhao, Xinyang; Sashida, Goro; Deblasio, Anthony; Harr, Michael; She, Qing-Bai; Chen, Zhenbang; Lin, Hui-Kuan; Di Giandomenico, Silvana; Elf, Shannon E.; Yang, Youyang; Miyata, Yasuhiko; Huang, Gang; Menendez, Silvia; Mellinghoff, Ingo K.; Rosen, Neal; Pandolfi, Pier Paolo; Hedvat, Cyrus V.; Nimer, Stephen D.; Pediatrics, School of Medicine
The Polycomb group protein Bmi1 is a transcriptional silencer of the Ink4a-Arf locus, which encodes the cell cycle regulator p16(Ink4a) and the tumor suppressor p19(Arf). Bmi1 plays a key role in oncogenesis and stem cell self-renewal. We report that phosphorylation of human Bmi1 at Ser³¹⁶ by Akt impaired its function by triggering its dissociation from the Ink4a-Arf locus, which resulted in decreased ubiquitylation of histone H2A and the inability of Bmi1 to promote cellular proliferation and tumor growth. Moreover, Akt-mediated phosphorylation of Bmi1 also inhibited its ability to promote self-renewal of hematopoietic stem and progenitor cells. Our study provides a mechanism for the increased abundance of p16(Ink4a) and p19(Arf) seen in cancer cells with an activated phosphoinositide 3-kinase to Akt signaling pathway and identifies crosstalk between phosphorylation events and chromatin structure.
Comparative effects of non-steroidal anti-inflammatory drugs (NSAIDs) on blood pressure in patients with hypertension
(Springer Nature, 2012-10-24) Aljadhey, Hisham; Tu, Wanzhu; Hansen, Richard A.; Blalock, Susan J.; Brater, D. Craig; Murray, Michael D.; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) may disrupt control of blood pressure in hypertensive patients and increase their risk of morbidity, mortality, and the costs of care. The objective of this study was to examine the association between incident use of NSAIDs and blood pressure in patients with hypertension. Methods: We conducted a retrospective cohort study of adult hypertensive patients to determine the effects of their first prescription for NSAID on systolic blood pressure and antihypertensive drug intensification. Data were collected from an electronic medical record serving an academic general medicine practice in Indianapolis, Indiana, USA. Using propensity scores to minimize bias, we matched a cohort of 1,340 users of NSAIDs with 1,340 users of acetaminophen. Propensity score models included covariates likely to affect blood pressure or the use of NSAIDs. The study outcomes were the mean systolic blood pressure measurement after starting NSAIDs and changes in antihypertensive therapy. Results: Compared to patients using acetaminophen, NSAID users had a 2 mmHg increase in systolic blood pressure (95% CI, 0.7 to 3.3). Ibuprofen was associated with a 3 mmHg increase in systolic blood pressure compared to naproxen (95% CI, 0.5 to 4.6), and a 5 mmHg increase compared to celecoxib (95% CI, 0.4 to 10). The systolic blood pressure increase was 3 mmHg in a subgroup of patients concomitantly prescribed angiotensin converting enzyme inhibitors or calcium channel blockers and 6 mmHg among those prescribed a beta-adrenergic blocker. Blood pressure changes in patients prescribed diuretics or multiple antihypertensives were not statistically significant. Conclusion: Compared to acetaminophen, incident use of NSAIDs, particularly ibuprofen, is associated with a small increase in systolic blood pressure in hypertensive patients. Effects in patients prescribed diuretics or multiple antihypertensives are negligible.
The Association between Metabolic Syndrome and Colorectal Neoplasm: Systemic review and Meta-analysis
(Wolters Kluwer, 2013) Jinjuvadia, Raxitkumar; Lohia, Prateek; Jinjuvadia, Chetna; Montoya, Sergio; Liangpunsakul, Suthat; Medicine, School of Medicine
Background: There has been constant speculation about the association between metabolic syndrome (MetS) and colorectal neoplasia (CN); however, the published results are conflicting. The aims of this study are to conduct a systematic search, and assess the literature to determine the available evidence on the association between these two conditions. Methods: Meta-analysis was conducted based on relevant studies identified through a systematic literature review from PubMed, OvidSP, and Cochrane database during January 1980 to July 2011. A combined analysis was performed, followed by a subgroup analyses stratified by the study design, type of colorectal lesions, and sex. Publication bias was assessed using the Begg and Egger tests and visual inspection of funnel plot. Results: Eighteen studies were included in the final analysis. Overall, MetS was associated with 34% increase in the risk of CN [summary relative risk (RR), 1.34; 95% confidence interval (CI), 1.24-1.44]. The association between MetS and CN was found to be statistically significant in separate analysis for both case-control studies (summary RR, 1.58; 95% CI, 1.44-1.73) and cohort studies (summary RR, 1.21; 95% CI, 1.13-1.29). The association remained significant when analyses were restricted by type of colorectal lesions (colorectal cancer: RR, 1.30; 95% CI, 1.18-1.43; colorectal adenoma: RR, 1.37; 95% CI, 1.26-1.49). Further subgroup analysis by sex showed significant association between MetS and CN in both male and female population. Conclusions: Our meta-analysis showed significant association between presence of MetS and CN. These results may help in identifying high-risk individuals at early stage, who might benefit from targeted colorectal cancer screening intervention.
Meta-analysis of genome-wide studies identifies WNT16 and ESR1 SNPs associated with bone mineral density in premenopausal women
(Oxford University Press, 2013) Koller, Daniel L.; Zheng, Hou-Feng; Karasik, David; Yerges-Armstrong, Laura; Liu, Ching-Ti; McGuigan, Fiona; Kemp, John P.; Giroux, Sylvie; Lai, Dongbing; Edenberg, Howard J.; Peacock, Munro; Czerwinski, Stefan A.; Choh, Audrey C.; McMahon, George; St. Pourcain, Beate; Timpson, Nicholas J.; Lawlor, Debbie A.; Evans, David M.; Towne, Bradford; Blangero, John; Carless, Melanie A.; Kammerer, Candace; Goltzman, David; Kovacs, Christopher S.; Prior, Jerilynn C.; Spector, Tim D.; Rousseau, Francois; Tobias, Jon H.; Akesson, Kristina; Econs, Michael J.; Mitchell, Braxton D.; Richards, J. Brent; Kiel, Douglas P.; Foroud, Tatiana; Medical and Molecular Genetics, School of Medicine
Previous genome-wide association studies (GWAS) have identified common variants in genes associated with variation in bone mineral density (BMD), although most have been carried out in combined samples of older women and men. Meta-analyses of these results have identified numerous single-nucleotide polymorphisms (SNPs) of modest effect at genome-wide significance levels in genes involved in both bone formation and resorption, as well as other pathways. We performed a meta-analysis restricted to premenopausal white women from four cohorts (n = 4061 women, aged 20 to 45 years) to identify genes influencing peak bone mass at the lumbar spine and femoral neck. After imputation, age- and weight-adjusted bone-mineral density (BMD) values were tested for association with each SNP. Association of an SNP in the WNT16 gene (rs3801387; p = 1.7 × 10(-9) ) and multiple SNPs in the ESR1/C6orf97 region (rs4870044; p = 1.3 × 10(-8) ) achieved genome-wide significance levels for lumbar spine BMD. These SNPs, along with others demonstrating suggestive evidence of association, were then tested for association in seven replication cohorts that included premenopausal women of European, Hispanic-American, and African-American descent (combined n = 5597 for femoral neck; n = 4744 for lumbar spine). When the data from the discovery and replication cohorts were analyzed jointly, the evidence was more significant (WNT16 joint p = 1.3 × 10(-11) ; ESR1/C6orf97 joint p = 1.4 × 10(-10) ). Multiple independent association signals were observed with spine BMD at the ESR1 region after conditioning on the primary signal. Analyses of femoral neck BMD also supported association with SNPs in WNT16 and ESR1/C6orf97 (p < 1 × 10(-5) ). Our results confirm that several of the genes contributing to BMD variation across a broad age range in both sexes have effects of similar magnitude on BMD of the spine in premenopausal women. These data support the hypothesis that variants in these genes of known skeletal function also affect BMD during the premenopausal period.
Brain injury following trial of hypothermia for neonatal hypoxic–ischaemic encephalopathy
(BMJ, 2012) Shankaran, Seetha; Barnes, Patrick D.; Hintz, Susan R.; Laptook, Abbott R.; Zaterka-Baxter, Kristin M.; McDonald, Scott A.; Ehrenkranz, Richard A.; Walsh, Michele C.; Tyson, Jon E.; Donovan, Edward F.; Goldberg, Ronald N.; Bara, Rebecca; Das, Abhik; Finer, Neil N.; Sanchez, Pablo J.; Poindexter, Brenda B.; Van Meurs, Krisa P.; Carlo, Waldemar A.; Stoll, Barbara J.; Duara, Shahnaz; Guillet, Ronnie; Higgins, Rosemary D.; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network; Pediatrics, School of Medicine
Objective: The objective of our study was to examine the relationship between brain injury and outcome following neonatal hypoxic-ischaemic encephalopathy treated with hypothermia. Design and patients: Neonatal MRI scans were evaluated in the National Institute of Child Health and Human Development (NICHD) randomised controlled trial of whole-body hypothermia and each infant was categorised based upon the pattern of brain injury on the MRI findings. Brain injury patterns were assessed as a marker of death or disability at 18-22 months of age. Results: Scans were obtained on 136 of 208 trial participants (65%); 73 in the hypothermia and 63 in the control group. Normal scans were noted in 38 of 73 infants (52%) in the hypothermia group and 22 of 63 infants (35%) in the control group. Infants in the hypothermia group had fewer areas of infarction (12%) compared to infants in the control group (22%). Fifty-one of the 136 infants died or had moderate or severe disability at 18 months. The brain injury pattern correlated with outcome of death or disability and with disability among survivors. Each point increase in the severity of the pattern of brain injury was independently associated with a twofold increase in the odds of death or disability. Conclusions: Fewer areas of infarction and a trend towards more normal scans were noted in brain MRI following whole-body hypothermia. Presence of the NICHD pattern of brain injury is a marker of death or moderate or severe disability at 18-22 months following hypothermia for neonatal encephalopathy.
Voxel and Surface-Based Topography of Memory and Executive Deficits in Mild Cognitive Impairment and Alzheimer’s Disease
(Springer, 2012) Nho, Kwangsik; Risacher, Shannon L.; Crane, Paul K.; DeCarli, Charles; Glymour, M. Maria; Habeck, Christian; Kim, Sungeun; Lee, Grace J.; Mormino, Elizabeth; Mukherjee, Shubhabrata; Shen, Li; West, John D.; Saykin, Andrew J.; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Radiology and Imaging Sciences, School of Medicine
Mild cognitive impairment (MCI) and Alzheimer's disease (AD) are associated with a progressive loss of cognitive abilities. In the present report, we assessed the relationship of memory and executive function with brain structure in a sample of 810 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, including 188 AD, 396 MCI, and 226 healthy older adults (HC). Composite scores of memory (ADNI-Mem) and executive function (ADNI-Exec) were generated by applying modern psychometric theory to item-level data from ADNI's neuropsychological battery. We performed voxel-based morphometry (VBM) and surface-based association (SurfStat) analyses to evaluate relationships of ADNI-Mem and ADNI-Exec with grey matter (GM) density and cortical thickness across the whole brain in the combined sample and within diagnostic groups. We observed strong associations between ADNI-Mem and medial and lateral temporal lobe atrophy. Lower ADNI-Exec scores were associated with advanced GM and cortical atrophy across broadly distributed regions, most impressively in the bilateral parietal and temporal lobes. We also evaluated ADNI-Exec adjusted for ADNI-Mem, and found associations with GM density and cortical thickness primarily in the bilateral parietal, temporal, and frontal lobes. Within-group analyses suggest these associations are strongest in patients with MCI and AD. The present study provides insight into the spatially unbiased associations between brain atrophy and memory and executive function, and underscores the importance of structural brain changes in early cognitive decline.
Lead Discovery, Chemistry Optimization, and Biological Evaluation Studies of Novel Biamide Derivatives as CB2 Receptor Inverse Agonists and Osteoclast Inhibitors
(ACS, 2012) Yang, Peng; Myint, Kyaw-Zeyar; Tong, Qin; Feng, Rentian; Cao, Haiping; Almehizia, Abdulrahman A.; Alqarni, Mohammed Hamed; Wang, Lirong; Bartlow, Patrick; Gao, Yingdai; Gertsch, Jürg; Teramachi, Jumpei; Kurihara, Noriyoshi; Roodman, Garson David; Cheng, Tao; Xie, Xiang-Qun; Medicine, School of Medicine
N,N'-((4-(Dimethylamino)phenyl)methylene)bis(2-phenylacetamide) was discovered by using 3D pharmacophore database searches and was biologically confirmed as a new class of CB(2) inverse agonists. Subsequently, 52 derivatives were designed and synthesized through lead chemistry optimization by modifying the rings A-C and the core structure in further SAR studies. Five compounds were developed and also confirmed as CB(2) inverse agonists with the highest CB(2) binding affinity (CB(2)K(i) of 22-85 nM, EC(50) of 4-28 nM) and best selectivity (CB(1)/CB(2) of 235- to 909-fold). Furthermore, osteoclastogenesis bioassay indicated that PAM compounds showed great inhibition of osteoclast formation. Especially, compound 26 showed 72% inhibition activity even at the low concentration of 0.1 μM. The cytotoxicity assay suggested that the inhibition of PAM compounds on osteoclastogenesis did not result from its cytotoxicity. Therefore, these PAM derivatives could be used as potential leads for the development of a new type of antiosteoporosis agent.
A Highly Selective and Potent PTP-MEG2 Inhibitor with Therapeutic Potential for Type 2 Diabetes
(ACS, 2012) Zhang, Sheng; Liu, Sijiu; Tao, Rongya; Wei, Dan; Chen, Lan; Shen, Weihua; Yu, Zhi-Hong; Wang, Lina; Jones, David R.; Dong, Xiaocheng C.; Zhang, Zhong-Yin; Biochemistry and Molecular Biology, School of Medicine
Protein tyrosine phosphatases (PTPs) constitute a large family of signaling enzymes that control the cellular levels of protein tyrosine phosphorylation. A detailed understanding of PTP functions in normal physiology and in pathogenic conditions has been hampered by the absence of PTP-specific, cell-permeable small-molecule agents. We present a stepwise focused library approach that transforms a weak and general non-hydrolyzable pTyr mimetic (F(2)Pmp, phosphonodifluoromethyl phenylalanine) into a highly potent and selective inhibitor of PTP-MEG2, an antagonist of hepatic insulin signaling. The crystal structures of the PTP-MEG2-inhibitor complexes provide direct evidence that potent and selective PTP inhibitors can be obtained by introducing molecular diversity into the F(2)Pmp scaffold to engage both the active site and unique nearby peripheral binding pockets. Importantly, the PTP-MEG2 inhibitor possesses highly efficacious cellular activity and is capable of augmenting insulin signaling and improving insulin sensitivity and glucose homeostasis in diet-induced obese mice. The results indicate that F(2)Pmp can be converted into highly potent and selective PTP inhibitory agents with excellent in vivo efficacy. Given the general nature of the approach, this strategy should be applicable to other members of the PTP superfamily.

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