Posted by: kelsijo97 | February 16, 2012

February 2012

Bao, Ying, Vigderman, L., Zubarev, E. R., and Jiang, Chaoyang Y. “Robust Multi Layer Thin Films Containing Cationic Thiol-Functionalized Gold Nanorods for Tunable Plasmonic Properties.” Langmuir 28, no. 1 (2012): 923-30.

Gold nanorods have great potential in a variety of applications because of their unique physical properties. In this article, we present the layer-by-layer (LbL) assembly of thin films containing positively charged gold nanorods that are covalently functionalized by cationic thiol molecules. The cationic gold nanorods are uniformly distributed in ultrathin nanocomposite LbL thin films. We studied the collective surface plasmon resonance coupling in the LbL films via UV-visible spectroscopy and evaluated their application in the surface-enhanced Raman scattering detection of rhodarnine 6G probe molecules. Furthermore, we successfully manufactured freestanding nanoscale thin films containing multilayers of gold nanorods with a total thickness of less than 50 nrn. The surface morphology and their optical and mechanical properties were systematically investigated, and the polycationic gold nanorods were found to play an important role in manipulating the properties of the nanocomposite thin films. Our findings reveal that such nanorods are excellent building blocks for constructing functional LbL films with tunable plasmonic behavior and robust mechanical properties.

Chemistry Department.

Chauhan, Subash C., Ebeling, Mara C., Maher, Diane M., Koch, Michael D., Watanabe, Akira, Aburatani, Hiroyuki, Lio, Yuhlong L., and Jaggi, Meena. “Muc13 Mucin Augments Pancreatic Tumorigenesis.” Molecular Cancer Therapeutics 11, no. 1 (2012): 24-33.

The high death rate of pancreatic cancer is attributed to the lack of reliable methods for early detection and underlying molecular mechanisms of its aggressive pathogenesis. Although MUC13, a newly identified transmembrane mucin, is known to be aberrantly expressed in ovarian and gastro-intestinal cancers, its role in pancreatic cancer is unknown. Herein, we investigated the expression profile and functions of MUC13 in pancreatic cancer progression. The expression profile of MUC13 in pancreatic cancer was investigated using a recently generated monoclonal antibody (clone PPZ0020) and pancreatic tissue microarrays. The expression of MUC13 was significantly (P < 0.005) higher in cancer samples compared with normal/nonneoplastic pancreatic tissues. For functional analyses, full-length MUC13 was expressed in MUC13 null pancreatic cancer cell lines, MiaPaca and Panc1. MUC13 overexpression caused a significant (P < 0.05) increase in cell motility, invasion, proliferation, and anchorage-dependent or -independent clonogenicity while decreasing cell-cell and cell-substratum adhesion. Exogenous MUC13 expression significantly (P < 0.05) enhanced pancreatic tumor growth and reduced animal survival in a xenograft mouse model. These tumorigenic characteristics correlated with the upregulation/phosphorylation of HER2, p21-activated kinase 1 (PAK1), extracellular signal-regulated kinase (ERK), Akt, and metastasin (S100A4), and the suppression of p53. Conversely, suppression of MUC13 in HPAFII pancreatic cancer cells by short hairpin RNA resulted in suppression of tumorigenic characteristics, repression of HER2, PAK1, ERK, and S100A4, and upregulation of p53. MUC13 suppression also significantly (P < 0.05) reduced tumor growth and increased animal survival. These results imply a role of MUC13 in pancreatic cancer and suggest its potential use as a diagnostic and therapeutic target. Mol Cancer Ther; 11(1); 24-33. (C) 2011 AACR.

Sanford School of Medicine, Sioux Falls Campus.

Dement-Brown, J., Newton, C. S., Ise, T., Damdinsuren, B., Nagata, Satoshi, and Tolnay, M. “Fc Receptor-Like 5 Promotes B Cell Proliferation and Drives the Development of Cells Displaying Switched Isotypes.” Journal of Leukocyte Biology 91, no. 1 (2012): 59-67.

The biological roles of B cell membrane proteins in the FCRL family are enigmatic. FCRL proteins, including FCRL5, were shown to modulate early BCR signaling, although the subsequent, functional consequences of receptor engagement are poorly understood. We found that FCRL5 surface protein itself was induced temporarily upon BCR stimulation of human, naive B cells, indicating precise control over timing of FCRL5 engagement. Cross-linking of FCRL5 on cells induced to express FCRL5 enhanced B cell proliferation significantly. This enhancement required costimulation of the BCR and TLR9, two signals required for optimal proliferation of naive B cells, whereas T cell help in the form of anti-CD40 and IL-2 was dispensable. In addition, we found that FCRL5 stimulation generated a high proportion of cells displaying surface IgG and IgA. Optimal development of cells expressing switched isotypes required T cell help, in addition to stimuli found necessary for enhanced proliferation. Surprisingly, cells that developed upon FCRL5 stimulation simultaneously displayed surface IgM, IgG, and IgA. Cells expressing multiple Ig isotypes were described in hairy cell leukemia, a disease in which FCRL5 is overexpressed. Enhanced proliferation and downstream isotype expression upon FCRL5 stimulation could reflect a physiological role for FCRL5 in the expansion and development of antigen-primed B cells. In addition, FCRL5 may promote growth of malignant cells in hairy cell leukemia and other FCRL5-expressing tumors. J. Leukoc. Biol. 91: 59-67; 2012.

Sanford School of Medicine, Sioux Falls Campus.

Ehli, Erik A., Hu, Y., Lengyel-Nelson, T., Hudziak, J. J., and Davies, Garreth E. “Identification and Functional Characterization of Three Novel Alleles for the Serotonin Transporter-Linked Polymorphic Region.” Molecular psychiatry 17, no. 2 (2012): 185-92.

A promoter polymorphism in the serotonin transporter gene (5-HTTLPR) has been reported to confer relative risk for phenotypes (depression/anxiety) and endophenotypes (amygdala reactivity). In this report, we identify and characterize three rare 5-HTTLPR alleles not previously described in the human literature. The three novel alleles were identified while genotyping 5-HTTLPR in a family-based attention deficit hyperactivity disorder clinical population. Two of the novel alleles are longer than the common 16-repeat long (L) allele (17 and 18 repeats) and the third is significantly smaller than the 14-repeat short (S) allele (11 repeats). The sequence and genetic architecture of each novel allele is described in detail. We report a significant decrease in the expression between the XL(17) (17r) allele and the L(A) (16r) allele. The XS(11) (11r) allele showed similar expression with the S (14r) allele. A 1.8-fold increase in expression was observed with the L(A)(16r) allele compared with the L(G) (16r) allele, which replicates results from earlier 5-HTTLPR expression experiments. In addition, transcription factor binding site (TFBS) analysis was performed using MatInspector (Genomatix) that showed the presence or absence of different putative TFBSs between the novel alleles and the common L (16r) and S (14r) alleles. The identification of rare variants and elucidation of their functional impact could potentially lead to understanding the contribution that the rare variant may have on the inheritance/susceptibility of multifactorial common diseases.

Sanford School of Medicine, Sioux Falls Campus.

Gillies, P. J., Harris, William S., and Kris-Etherton, P. M. “Omega-3 Fatty Acids in Food and Pharma: The Enabling Role of Biotechnology.” Current Atherosclerosis Reports 13, no. 6 (2011): 467-73.

Omega-3 fatty acid research, which began as an epidemiologic curiosity, has generated perhaps the strongest dataset for any nutrient in regard to cardiovascular disease risk reduction. Although once a relatively descriptive field, advances in analytic techniques have opened up the biochemistry of omega-3 fatty acids and nutritional genomics in plants and man and have taken the field into the “omic” era. Despite this progress, fundamental questions remain unanswered, such as which fatty acid or metabolite thereof drives a given health benefit, how much of a given fatty acid should we consume, and how do we best source the requisite fatty acids? Of these questions, the ability to source omega-3 fatty acids in order to meet dietary guidelines has become a practical concern. The advent of novel oils from plants and single cell organisms as enabled by biotechnology may provide a solution to this problem and in the process open up new uses for omega-3 fatty acids in dietary supplements and drugs.

Snford School of Medicine, Sioux Falls Campus.

Gustafson, J. D., Fox, J. P., Ouellette, J. R., Hellan, M., Termuhlen, P., McCarthy, M. C., and Thambi-Pillai, Thavam. “Open Versus Laparoscopic Liver Resection: Looking Beyond the Immediate Postoperative Period.” Surgical Endoscopy and Other Interventional Techniques 26, no. 2 (2012): 468-72.

Laparoscopic liver resection for malignant disease has shown short-term benefit. This study aimed to compare in-house, 30-day, and 1-year morbidity between laparoscopic and open liver resections. The charts for all patients who underwent liver resection for malignant disease between April 2006 and October 2009 were reviewed. Patient, operative, and outcomes data at 30 days and 1 year were collected. For 76 patients, 49 open and 27 laparoscopic resections were performed. The two groups were similar in terms of age, gender, body mass index (BMI), extent of liver resection, use of ablation therapy, and tumor pathology (P > 0.05). The laparoscopic group had less blood loss (P = 0.004) and shorter hospital stays (P = 0.002). During their hospital stay, patients treated laparoscopically had fewer complications, but the difference was not significant. Home disposition was similar in the laparoscopic (96%) and open (90%) groups. More patients were readmitted at 30 days (2 vs. 9; P = 0.31) and 1 year (4 vs. 19; P = 0.04) in the open group. The all-cause 1-year mortality rates were similar between the laparoscopic and open groups (14.8% vs. 10.2%). The benefits of laparoscopic liver resection may extend beyond the initial postoperative period, with fewer readmissions despite shorter hospital stays. This also may suggest lower long-term hospital costs.

Sanford School of Medicine, Sioux Falls Campus.

Hanson, Jessica D. “Understanding Prenatal Health Care for American Indian Women in a Northern Plains Tribe.” Journal of Transcultural Nursing 23, no. 1 (2012): 29-37.

Early and regular prenatal care appointments are imperative for the health of both the mother and baby to help prevent complications associated with pregnancy and birth. American Indian women are especially at risk for health disparities related to pregnancy and lack of prenatal health care. Previous research has outlined a basic understanding of the reasons for lack of prenatal care for women in general; however, little is known about care received by pregnant women at Indian Health Service hospitals. Qualitative interviews were carried out with 58 women to better understand the prenatal health experiences of American Indian women from one tribe in the Northern Plains. Several themes related to American Indian women’s prenatal health care experiences were noted, including communication barriers with physicians, institutional barriers such as lack of continuity of care, and sociodemographic barriers. Solutions to these barriers, such as a nurse midwife program, are discussed.

Sanford School of Medicine, Sioux Falls Campus.

Harris, Wiliiam S. “Stearidonic Acid as a ‘Pro-Eicosapentaenoic Acid’.” Current Opinion in Lipidology 23, no. 1 (2012): 30-34.

Purpose of review omega-3 Fatty acids continue to be promoted as cardioprotective, generating an increased demand for these nutrients. Ocean-based supplies are limited, and so land-based sources are being sought. Stearidonic acid-fortified soybean oil may help to meet this demand. Recent findings Stearidonic acid has been shown in animal and human studies to be more effective than its precursor, alpha-linolenic acid, in enriching membranes with eicosapentaenoic acid. Hence, stearidonic acid can serve as a ‘pro-eicosapentaenoic acid’. Summary Stearidonic acid-fortified soybean oil may be able to help close the gap between actual and recommended intakes of omega-3 fatty acids in an environmentally friendly manner.

Sanford School of Medicine, Sioux Falls Campus.

Kerby, Jacob L., Hart, A. J., and Storfer, A. “Combined Effects of Virus, Pesticide, and Predator Cue on the Larval Tiger Salamander (Ambystoma Tigrinum).” Ecohealth 8, no. 1 (2012): 46-54.

Emerging diseases and environmental contamination are two of the leading hypotheses for global amphibian declines. Yet few studies have examined the influence of contaminants on disease susceptibility, and even fewer have incorporated the role of natural stressors such as predation. We performed a factorial study investigating the interaction of the insecticide carbaryl, dragonfly predator cue, and the emerging pathogen Ambystoma tigrinum virus (ATV) on fitness correlates and disease susceptibility in tiger salamander larvae. Four week old larvae were exposed for 22 days in a 2 (0, 500 mu g/l carbaryl) x 2 (control, predator cue water) x 2 (0, 1 x 10(4) pfu ATV) factorial designed laboratory study. Results show significant impacts to survival of larvae for both virus and predator cue treatments, as well as an interactive effect between the two, in which predator cue strongly exacerbated disease-driven mortality. There was a clear pattern of reduced survival with the addition of stressors, with those where all three stressors were present exhibiting the worst effects (a decrease in survival from 93 to 60%). On those that survived, we also detected several sub-lethal impacts in mass, SVL, and development. Predator cue and pesticide treatments significantly reduced both SVL and mass. Virus and predator treatments significantly slowed development. Stressors also exhibited opposing effects on activity. Predator cue caused a significant reduction in activity, whereas virus caused a significant increase in activity over time. These results highlight the importance of examining combined natural and introduced stressors to understand potential impacts on amphibian species. Such stressors may contribute to the emergence of ATV in particular regions, raising concerns about the influence of pesticides on disease emergence in general.

Biology Department.

Li, W., and Keifer, Joyce. “Rapid Enrichment of Presynaptic Protein in Boutons Undergoing Classical Conditioning Is Mediated by Brain-Derived Neurotrophic Factor.” Neuroscience 203 (2012): 50-8.

Presynaptic structural modifications are thought to accompany activity-dependent synaptic plasticity and learning. This may involve the conversion of nonfunctional synapses into active ones or the generation of entirely new synapses. Here, using an in vitro neural analog of classical conditioning, we investigated presynaptic structural changes restricted to auditory nerve synapses that convey the conditioned stimulus (CS) by tract tracing using fluorescent tracers combined with immunostaining for the synaptic vesicle-associated protein synaptophysin. The results show that the size of presynaptic auditory boutons increased and the area and fluorescence intensity of punctate staining for synaptophysin were enhanced after conditioning. This occurred only for auditory nerve boutons apposed to the dendrites but not the somata of abducens motor neurons. Conditioning increased the percentage of boutons that were immunopositive for synaptophysin and enhanced the number of synaptophysin puncta they contained. Pretreatment with antibodies against brain-derived neurotrophic factor (BDNF) inhibited these conditioning-induced structural changes. There was also a net increase in the number of boutons apposed to abducens motor neurons after conditioning or BDNF treatment. These data indicate that the rapid enrichment of presynaptic boutons with proteins required for neurotransmitter recycling and release occurs during classical conditioning and that these processes are mediated by BDNF. Copyright 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Basic Biomedical Sciences, Vermillion Campus.

Martin, Douglas S., Klinkova, Olga, and Eyster, Kathleen M. “Regional Differences in Sexually Dimorphic Protein Expression in the Spontaneously Hypertensive Rat (Shr).” Molecular and cellular biochemistry 362, no. 1-2 (2012): 103-14.

Hypertension is sexually dimorphic and modified by removal of endogenous sex steroids. This study tested the hypothesis that endogenous gonadal hormones exert differential effects on protein expression in the kidney and mesentery of SHR. At ~5weeks of age male and female SHR underwent sham operation, orchidectomy, or ovariectomy (OVX). At 20-23weeks of age, mean arterial pressure (MAP) was measured in conscious rats. The mesenteric arterial tree and kidneys were collected, processed for Western blots, and probed for Cu Zn superoxide dismutase (SOD1), soluble epoxide hydrolase (sEH), and Alpha 2A adrenergic receptor (A2AR) expression. MAP was unaffected by ovariectomy (Sham 1644: Ovariecttomy 1593mm Hg). MAP was reduced by orchidectomy (Sham 1895:Orchidectomy 1672mm Hg). In mesenteric artery, SOD1 expression was greater in male versus female SHR. Orchidectomy increased while ovariectomy decreased SOD1 expression. The kidney exhibited a different pattern of response. SOD1 expression was reduced in male compared to female SHR but gonadectomy had no effect. sEH expression was not significantly different among the groups in mesenteric artery. In kidney, sEH expression was greater in males compared to females. Ovariectomy but not orchidectomy increased sEH expression. A2AR expression was greater in female than male SHR in mesentery artery and kidney. Gonadectomy had no effect in either tissue. We conclude that sexually dimorphic hypertension is associated with regionally specific changes in expression of three key proteins involved in blood pressure control. These data suggest that broad spectrum inhibition or stimulation of these systems may not be the best approach for hypertension treatment. Instead regionally targeted manipulation of these systems should be investigated.

Basic Biomedical Sciences, Vermillion Campus.

Mize, Erica L., Tsao, J. I., and Maurer, B. A. “Habitat Correlates with the Spatial Distribution of Ectoparasites on Peromyscus Leucopus in Southern Michigan.” Journal of Vector Ecology 36, no. 2 (2011): 308-20.

The goal of this study was to evaluate the role of habitat in determining ectoparasite distribution of Peromyscus leucopus. We tested the hypothesis that ectoparasite occurrence is associated with particular host environments and this association is stronger for ectoparasites with limited interactions (i.e., ticks) than those with frequent interactions (i.e., lice). Ectoparasites from three different groups (Acari, Siphonaptera, and Phthiraptera) were collected from P. leucopus inhabiting a number of forested habitats in southern Michigan. Measurements of plant species structure and composition were collected and models were developed using quadratic discriminant function analysis to determine if habitats associated with ectoparasite presence were different from those associated with their absence. Mice parasitized by ticks were more likely to be found in areas having undergone a recent disturbance. Mice parasitized by ticks, fleas, and lice were more likely to be found in areas having tree species associated with dry soils. Our results show there is a distinct difference in habitats associated with the presence of ectoparasites, though we did not observe a stronger association of host habitat for ticks than for fleas or lice. This implies habitat should be included as an important component of assessments of the spatial distribution of ectoparasites.

Biology Department.

Mroch, Amelia R., Laudenschlager, Mark, and Flanagan, Jason D. “Detection of a Novel Fh Whole Gene Deletion in the Propositus Leading to Subsequent Prenatal Diagnosis in a Sibship with Fumarase Deficiency.” American Journal of Medical Genetics Part A 158A, no. 1 (2012): 155-58.

Fumarase deficiency is a rare autosomal recessive metabolic condition. We report on a sibship with molecularly confirmed fumarase deficiency. Prenatal findings included agenesis of the corpus callosum, ventriculomegaly, and ventriculoseptal defect. The postnatal course was significant for metabolic acidosis ultimately leading to death around 3 weeks of age. Postmortem findings were noted including swollen mitochondria with abnormal cristae on electron microscopy within the liver. Molecular testing revealed a novel whole gene deletion in conjunction with a point mutation. While the point mutation has been previously reported, the detection of a whole gene deletion has not been described to date in an individual with fumarase deficiency. (C) 2011 Wiley Periodicals, Inc.

Sanford School of Medicine, Sioux Falls Campus.

Patacsil, D., Osayi, S., Tran, A. T., Saenz, F., Yimer, L., Shajahan, A. N., Gokhale, P. C., Verma, M., Clarke, R., Chauhan, Subhash C., and Kumar, D. “Vitamin E Succinate Inhibits Survivin and Induces Apoptosis in Pancreatic Cancer Cells.” Genes and Nutrition 7, no. 1 (2012): 83-89.

Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States. Identifying novel chemotherapeutic and chemopreventive approaches is critical in the prevention and treatment of cancers such as pancreatic cancer. Vitamin E succinate (VES) is a redox-silent analog of the fat-soluble vitamin alpha-tocopherol. In the present study, we explored the antiproliferative action of VES and its effects on inhibitor of apoptosis proteins in pancreatic cancer cells. We show that VES inhibits cell proliferation and induces apoptosis in pancreatic cancer cells. Further, we demonstrate that VES downregulates the expression of survivin and X-linked inhibitor of apoptosis proteins. The apoptosis induced by VES was augmented by siRNA-mediated inhibition of survivin in PANC-1 cells. In summary, our results suggest that VES targets survivin signaling and induces apoptosis in pancreatic cancer cells.

Sanford School of Medicine, Sioux Falls Campus.

Randall, Brad, Donelan, Kent, Koponen, Mark, Sens, Mary Ann, and Krous, Henry F. “Application of a Classification System Focusing on Potential Asphyxia for Cases of Sudden Unexpected Infant Death.” Forensic science, medicine, and pathology 8, no. 1 (2012): 34-9.

Current classification schemes for sudden unexpected infant death (SUID) may not be optimal for capturing scene events that potentially predispose to asphyxia. (1) To compare causes of death in a group of SUID cases assigned by multiple reviewers using our recently published classification scheme for SUID that is based on asphyxial risk at the death scene, and (2) To compare these newly assigned causes of death to that originally assigned by the medical examiners of record who performed the autopsies. Five reviewers independently assigned causes of death for 117 cases of SUID, including 83 originally diagnosed as sudden infant death syndrome (SIDS), accessioned into the San Diego SIDS/SUDC Research Project from the San Diego County Medical Examiner’s Office. The diagnostic categories are: A: SIDS; B: Unexplained-Potentially Asphyxia; C: Unexplained-Other Potential Causes of Death; D: Unclassified-Other; E: Unclassified; and F: Known Cause of Death. The reviewers collectively opined that conditions at the death scene contributed to or caused death in 32-50% of all of the 117 cases as well as in 40-59% of the 83 originally diagnosed SIDS cases. Another cause of death was considered plausible in 2-12% of the SIDS cases. Application of this new classification system resulted in 55-69% decrease in SIDS diagnoses. Asphyxia as a potential contributor to, or as the specific cause of death, appears to exist in a large percentage of cases designated as SIDS using other classification schemes. When certifiers use a classification system that focuses upon potential asphyxia in determining the cause of death the incidence of SIDS dramatically declines.

Sanford School of Medicine, Sioux Falls Campus.

Shinozaki, Gen, Jowsey, S., Amer, H., Biernacka, J. M., Colby, C., Walker, D., Black, J., Rundell, J., Stegall, M., and Mrazek, D. A. “Relationship between Fkbp5 Polymorphisms and Depression Symptoms among Kidney Transplant Recipients.” Depression and Anxiety 28, no. 12 (2011): 1111-18.

Background: Several polymorphisms in FK506 Binding Protein gene (FKBP5) and a history of child abuse have been shown to be associated with an increased risk for posttraumatic stress disorder (PTSD). It has also been demonstrated that the same polymorphisms of FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. However, there are only limited numbers of studies replicating the polymorphisms as vulnerability factors for the development of mental illnesses, such as PTSD and depression after stressful life event, especially with a specific incidence, such as kidney transplant surgery. Methods: A retrospective analysis was conducted using the electronic medical records of 131 adult kidney transplant recipients. Depression severity after kidney transplantation was measured by PHQ-9, and stored blood was genotyped for variants in the Serotonin Transporter (SLC6A4), Brain-Derived Neurotrophic Factor, Catecholamine-O-Methyltransferase, Corticotropin-Releasing Hormone Receptor, and FKBP5 genes. Spearman correlations were used to test for association between genetic variants and depression severity. Results: The rare alleles at three out of four SNPs in FKBP5 (rs1360780, rs9296158, and rs9470080) were associated with increased PHQ-9 scores (P<.05), whereas the last FKBP5 SNP (rs3800373) showed a trend of association (P<.10). All four FKBP5 SNPs are in strong linkage disequilibrium. Although in a subgroup of Caucasian non-Hispanic subjects the association was not statistically significant, the direction of association was consistent with that observed in the entire sample as well as in previous studies. Polymorphisms in genes other than FKBP5 were not associated with PHQ-9 scores. Conclusions: Polymorphisms in FKBP5 may be associated with higher depression scores in kidney transplant recipients. Depression and Anxiety, 2011. (C) 2011 Wiley Periodicals, Inc.

Sanford School of Medicine, Sioux Falls Campus.

Suen, Chen S., and Burn, Paul. “The Potential of Incretin-Based Therapies in Type 1 Diabetes.” Drug discovery today 17, no. 1-2 (2012): 89-95.

Finding a cure for type 1 diabetes (T1D) has been elusive. Incretin-based therapies, since their approval, have demonstrated their clinical utilities in type 2 diabetes (T2D). Yet, their potential clinical benefits in T1D remain to be appraised. GLP-1, in addition to its insulinotropic action in alleviating hyperglycemia, possesses beneficial effects in protecting progressive impairment of pancreatic beta-cell function, preservation of beta-cell mass and suppression of glucagon secretion, gastric emptying and appetite. Preclinical data using incretin-based therapies in diabetic NOD mice demonstrated additional effects including immuno-modulation, anti-inflammation and beta-cell regeneration. Thus, data accumulated hold the promise that incretin-based therapies may be effective in delaying the new-onset, halting the further progression, or reversing T1D in subjects with newly diagnosed or long-standing, established disease. Copyright 2011 Elsevier Ltd. All rights reserved.

Sanford School of Medicine, Sioux Falls Campus.

Vaags, A. K., Lionel, A. C., Sato, D., Goodenberger, M., Stein, Quinn P., Curran, S., Ogilvie, C., Ahn, J. W., Drmic, I., Senman, L., Chrysler, C., Thompson, A., Russell, C., Prasad, A., Walker, S., Pinto, D., Marshall, C. R., Stavropoulos, D. J., Zwaigenbaum, L., Fernandez, B. A., Fombonne, E., Bolton, P. F., Collier, D. A., Hodge, J. C., Roberts, W., Szatmari, P., and Scherer, S. W. “Rare Deletions at the Neurexin 3 Locus in Autism Spectrum Disorder.” American Journal of Human Genetics 90, no. 1 (2012): 133-41.

The three members of the human neurexin gene family, neurexin 1 (NRXN1), neurexin 2 (NRXN2), and neurexin 3 (NRXN3), encode neuronal adhesion proteins that have important roles in synapse development and function. In autism spectrum disorder (ASD), as well as in other neurodevelopmental conditions, rare exonic copy-number variants and/or point mutations have been identified in the NRXN1 and NRXN2 loci. We present clinical characterization of four index cases who have been diagnosed with ASD and who possess rare inherited or de novo microdeletions at 14q24.3-31.1, a region that overlaps exons of the alpha and/or beta isoforms of NRXN3. NRXN3 deletions were found in one father with subclinical autism and in a carrier mother and father without formal ASD diagnoses, indicating issues of penetrance and expressivity at this locus. Notwithstanding these clinical complexities, this report on ASD-affected individuals who harbor NRXN3 exonic deletions advances the understanding of the genetic etiology of autism, further enabling molecular diagnoses.

Sanford School of Medicine, Sioux Falls Campus.

Vermeer, Paola D., Bell, Megan, Lee, Kimberly, Vermeer, Daniel W., Wieking, Byrant G., Bilal, Erhan, Bhanot, Gyan, Drapkin, Ronny I., Ganesan, Shridar, Klingelhutz, Aloysius J., Hendriks, Wiljan J., and Lee, John H. “Erbb2, Ephrinb1, Src Kinase and Ptpn13 Signaling Complex Regulates Map Kinase Signaling in Human Cancers.” PloS one 7, no. 1 (2012): e30447.

In non-cancerous cells, phosphorylated proteins exist transiently, becoming de-phosphorylated by specific phosphatases that terminate propagation of signaling pathways. In cancers, compromised phosphatase activity and/or expression occur and contribute to tumor phenotype. The non-receptor phosphatase, PTPN13, has recently been dubbed a putative tumor suppressor. It decreased expression in breast cancer correlates with decreased overall survival. Here we show that PTPN13 regulates a new signaling complex in breast cancer consisting of ErbB2, Src, and EphrinB1. To our knowledge, this signaling complex has not been previously described. Co-immunoprecipitation and localization studies demonstrate that EphrinB1, a PTPN13 substrate, interacts with ErbB2. In addition, the oncogenic V660E ErbB2 mutation enhances this interaction, while Src kinase mediates EphrinB1 phosphorylation and subsequent MAP Kinase signaling. Decreased PTPN13 function further enhances signaling. The association of oncogene kinases (ErbB2, Src), a signaling transmembrane ligand (EphrinB1) and a phosphatase tumor suppressor (PTPN13) suggest that EphrinB1 may be a relevant therapeutic target in breast cancers harboring ErbB2-activating mutations and decreased PTPN13 expression.

Sanford School of Medicine, Sioux Falls Campus.

Wang, Xuejun J., Li, Jie, Zheng, Hanqiao Q., Su, Huabo, and Powell, S. R. “Proteasome Functional Insufficiency in Cardiac Pathogenesis.” American Journal of Physiology-Heart and Circulatory Physiology 301, no. 6 (2011): H2207-H19.

Wang X, Li J, Zheng H, Su H, Powell SR. Proteasome functional insufficiency in cardiac pathogenesis. Am J Physiol Heart Circ Physiol 301: H2207-H2219, 2011. First published September 23, 2011; doi:10.1152/ajpheart.00714.2011.-The ubiquitin-proteasome system (UPS) is responsible for the degradation of most cellular proteins. Alterations in cardiac UPS, including changes in the degradation of regulatory proteins and proteasome functional insufficiency, are observed in many forms of heart disease and have been shown to play an important role in cardiac pathogenesis. In the past several years, remarkable progress in understanding the mechanisms that regulate UPS-mediated protein degradation has been achieved. A transgenic mouse model of benign enhancement of cardiac proteasome proteolytic function has been created. This has led to the first demonstration of the necessity of proteasome functional insufficiency in the genesis of important pathological processes. Cardiomyocyte-restricted enhancement of proteasome proteolytic function by overexpression of proteasome activator 28 alpha protects against cardiac proteinopathy and myocardial ischemia-reperfusion injury. Additionally, exciting advances have recently been achieved in the search for a pharmacological agent to activate the proteasome. These breakthroughs are expected to serve as an impetus to further investigation into the involvement of UPS dysfunction in molecular pathogenesis and to the development of new therapeutic strategies for combating heart disease. An interplay between the UPS and macroautophagy is increasingly suggested in noncardiac systems but is not well understood in the cardiac system. Further investigations into the interplay are expected to provide a more comprehensive picture of cardiac protein quality control and degradation.

Basic Biomedical Sciences, Vermillion Campus.

Watson, Kendra D., Arendt, K. W., Watson, W. J., and Volcheck, G. W. “Systemic Mastocytosis Complicating Pregnancy.” Obstetrics and Gynecology 119, no. 2 (2012): 486-89.

BACKGROUND: Systemic mastocytosis is a rare medical disorder in which an increased number of mast cells can precipitate immediate hypersensitivity reactions, leading to hypotension, shock, and death. It is characterized by persistent elevated serum tryptase levels. The few published reports on pregnancy complicated by systemic mastocytosis indicate favorable maternal and fetal outcomes in gravidas known to have systemic mastocytosis. CASE: A pregnant woman treated with terbutaline at 31 weeks of gestation developed severe hypotension which resulted in fetal demise; this was initially diagnosed to be an anaphylactic reaction. The finding of persistently high maternal tryptase levels led to the diagnosis of systemic mastocytosis. In her subsequent pregnancy she was treated with an H1 blocker. Hypotension during her cesarean delivery was managed with steroid and epinephrine therapy. CONCLUSION: Exacerbations of systemic mastocytosis during pregnancy can lead to significant maternal and fetal complications. Treatment with H1 blockers, and when indicated, steroids and epinephrine, can reduce these complications. (Obstet Gynecol 2012;119:486-9) DOI: 10.1097/AOG.0b013e318242d3c5

Basic Biomedical Sciences, Vermillion Campus.

Wolf, S. L., Thompson, Paul A., Estes, E., Lonergan, T., Merchant, R., and Richardson, N. “The Excite Trial: Analysis of “Noncompleted” Wolf Motor Function Test Items.” Neurorehabilitation and Neural Repair 26, no. 2 (2012): 178-87.

Objective. This is the first study to examine Wolf Motor Function Test (WMFT) tasks among EXCITE Trial participants that could not be completed at baseline or 2 weeks later. Methods. Data were collected from participants who received constraint-induced movement therapy (CIMT) immediately at the time of randomization (CIMT-I, n = 106) and from those for whom there was a delay of 1 year in receiving this intervention (CIMT-D, n = 116). Data were collected at baseline and at a 2-week time point, during which the CIMT-I group received the CIMT intervention and the CIMT-D group did not. Generalized estimating equation (GEE) analyses were used to examine repeated binary data and count values. Group and visit interactions were assessed, adjusting for functional level, affected side, dominant side, age, and gender covariates. Results. In CIMT-I participants, there was an increase in the proportion of completed tasks at posttest compared with CIMT-D participants, particularly with respect to those tasks requiring dexterity with small objects and total incompletes (P < .0033). Compared with baseline, 120 tasks governing distal limb use for CIMT-I and 58 tasks dispersed across the WMFT for CIMT-D could be completed after 2 weeks. Common movement components that may have contributed to incomplete tasks include shoulder stabilization and flexion, elbow flexion and extension, wrist pronation, supination and ulnar deviation, and pincer grip. Conclusion. CIMT training should emphasize therapy for those specific movement components in patients who meet the EXCITE criteria for baseline motor control.

Sanford School of Medicine, Sioux Falls Campus.

Xie, K. Q., Ge, S. C., Collins, Victoria E., Haynes, C. L., Renner, Kenneth J., Meisel, R. L., Lujan, R., and Martemyanov, K. A. “G Beta 5-Rgs Complexes Are Gatekeepers of Hyperactivity Involved in Control of Multiple Neurotransmitter Systems.” Psychopharmacology 219, no. 3 (2012): 823-34.

Our knowledge about genes involved in the control of basal motor activity that may contribute to the pathology of the hyperactivity disorders, e.g., attention deficit hyperactivity disorder (ADHD), is limited. Disruption of monoamine neurotransmitter signaling through G protein-coupled receptors (GPCR) is considered to be a major contributing factor to the etiology of the ADHD. Genetic association evidence and functional data suggest that regulators of G protein signaling proteins of the R7 family (R7 RGS) that form obligatory complexes with type 5 G protein beta subunit (G beta 5) and negatively regulate signaling downstream from monoamine GPCRs may play a role in controlling hyperactivity. To test this hypothesis, we conducted behavioral, pharmacological, and neurochemical studies using a genetic mouse model that lacked G beta 5, a subunit essential for the expression of the entire R7 RGS family. Elimination of G beta 5-RGS complexes led to a striking level of hyperactivity that far exceeds activity levels previously observed in animal models. This hyperactivity was accompanied by motor learning deficits and paradoxical behavioral sensitization to a novel environment. Neurochemical studies indicated that G beta 5-RGS-deficient mice had higher sensitivity of inhibitory GPCR signaling and deficits in basal levels, release, and reuptake of dopamine. Surprisingly, pharmacological treatment with monoamine reuptake inhibitors failed to alter hyperactivity. In contrast, blockade of NMDA receptors reversed the expression of hyperactivity in G beta 5-RGS-deficient mice. These findings establish that G beta 5-RGS complexes are critical regulators of monoamine-NMDA receptor signaling cross-talk and link these complexes to disorders that manifest as hyperactivity, impaired learning, and motor dysfunctions.

Biology Department

Xu, T. T., Yan, M., Hoefelmeyer, James D., and Qiao, Q. Q. “Exciton Migration and Charge Transfer in Chemically Linked P3ht-Tio(2) Nanorod Composite.” Rsc Advances 2, no. 3 (2012): 854-62.

Exciton migration and charge transfer in the chemically linked P3HT-TiO(2) nanorod composite (P3HT-Si-nr-TiO(2)) solution were investigated in comparison with pristine P3HT and physically mixed P3HT/LA-nr-TiO(2) solutions. The chemically linked P3HT-Si-nr-TiO(2) was made by covalently linking in situ polymerized P3HT onto nr-TiO(2) using triethoxy-2-thienylsilane as a linker to replace the initial linoleic acid (LA) capping agent on nr-TiO(2). The physically mixed P3HT/LA-nr-TiO(2) was prepared by adding ex situ synthesized P3HT into the LA-capped nr-TiO(2) solution. In the chemically linked sample, charge transfer from P3HT to TiO(2) nanorods was found to occur evidenced by photoluminescence (PL) quenching and ultrafast decay dynamics with a timescale of 0.75 ps. However, both the emission spectra and femtosecond dynamics in physically mixed sample overlapped very well with those from pristine P3HT solution, indicating no PL quenching or charge transfer from P3HT to nr-TiO(2). In addition, blue shift in absorbance and PL spectra, larger Stokes shift, and structureless PL spectra found in the chemically linked sample indicated that P3HT formed a more coil-like conformation with more twisted torsion disorders than those in pristine P3HT and physically mixed samples. This is consistent with the femtosecond measurement result that torsional relaxation occurred with a longer decay time and higher amplitude. Moreover, intersystem crossings (ISC) from singlet state (S(1)) to triplet state (T(1)) in P3HT of the three samples were all found to occur in a comparable timescale of similar to 1 ns and showed no dependence on conformational disorders such as torsional defects.

Chemisty Department.

Yallapu, Murali M., Jaggi, Meena, and Chauhan, Subhash C. “Curcumin Nanoformulations: A Future Nanomedicine for Cancer.” Drug discovery today 17, no. 1-2 (2012): 71-80.

Curcumin, a natural diphenolic compound derived from turmeric Curcuma longa, has proven to be a modulator of intracellular signaling pathways that control cancer cell growth, inflammation, invasion and apoptosis, revealing its anticancer potential. In this review, we focus on the design and development of nanoparticles, self-assemblies, nanogels, liposomes and complex fabrication for sustained and efficient curcumin delivery. We also discuss the anticancer applications and clinical benefits of nanocurcumin formulations. Only a few novel multifunctional and composite nanosystem strategies offer simultaneous therapy as well as imaging characteristics. We also summarize the challenges to developing curcumin delivery platforms and up-to-date solutions for improving curcumin bioavailability and anticancer potential for therapy. Copyright 2011 Elsevier Ltd. All rights reserved.

Sanford School of Medicine, Sioux Falls Campus.

Epping, Lori L., and Mark Wilder, W. “U.S.-Listed Foreign Firms’ Non-GAAP Financial Performance Disclosure Behavior.” Journal of International Accounting Research 10, no. 2 (2011): 77-96.

The purpose of this study is to observe the extent to which U.S.-listed foreign firms report non-GAAP financial performance measures and to compare the characteristics of these disclosures to those of U.S. firms. Using a matched-sample design, this research compares U.S.-listed foreign firm and U.S. firm non-GAAP disclosure frequency, non-GAAP disclosure adjustment characteristics, and reconciliation quality. Tests of the hypotheses indicate similar disclosure frequencies for U.S. firms and U.S.-listed foreign firms. Analyses of non-GAAP disclosure and adjustment characteristics provide evidence consistent with the interpretation that U.S. firms engage in aggressive non-GAAP reporting behaviors (reporting income-increasing adjustments and adjusting GAAP numbers with a greater magnitude and with a higher number of adjustments) equally or more so than U.S.-listed foreign firms. However, the quality of U.S. firm reconciliations to U.S. GAAP is equal to or greater than that of U.S.- listed foreign firms.

 Beacom School of Business.


Erford, Bradley T., Schein, Hallie, and Duncan, Kelly. “Technical Analysis of Scores on the Self-Efficacy Self-Report Scale.” Assessment for Effective Intervention 37, no. 1 (2011): 58-64.

The purpose of this study was to provide preliminary analysis of reliability and validity of scores on the Self-Efficacy Self-Report Scale, which was designed to assess general self-efficacy in students aged 10 to 17 years. Confirmatory factor analysis on cross-validated samples was conducted revealing a marginal fit of the data to the 19-item unidimensional scale. Studies of internal consistency and test–retest reliability revealed adequate levels of total scale consistency. Criterion-related validity estimates were moderate to strong. Norms and a test protocol are provided to encourage free use of the scale for student assessment and research purposes. (PsycINFO Database Record (c) 2012 APA, all rights reserved) (journal abstract)

 School of Education.


Hovland, Michelle R., Gapp, Susan C., and Theis, Becky L. “Look: Examining the Concept of Learning to Look at Print.” Reading Improvement 48, no. 3 (2011): 128-38.

The purpose of this observation case study was to understand pre-school and kindergarten teachers’ perceptions of what “distinguishing the characteristics of print” means and to identify strategies pre-school and kindergarten teachers employ to assist young children in learning to distinguish the characteristics. This study used questionnaires, analysis of children’s writing samples, and classroom observations from pre-school and kindergarten teachers in rural locations in the Midwest. Data was separated into three categories: (a) questionnaire data, (b) writing sample analysis data, and (c) observational notes. A multistep analysis was conducted to identify patterns among participant responses. The distinguishing characteristics of print perceived by pre-school and kindergarten teachers included print has a purpose, pictures correspond to words, letters/words convey a message, sounds can be represented by letters, recognition and formation of letters, letters make words, letter sequence, directionality, spacing, capital and lowercase letters, letter order within words, writing is used for various purposes. The teaching strategies pre-school and kindergarten teachers used to assist young children distinguish the characteristics of print included promoting a safe risk free environment, reading aloud, emphasizing reading for meaning by discussing stories, making predictions, and making connection, providing opportunities for shared writing and shared reading activities, emphasizing letters, providing writing opportunities, practice writing letters, handwriting program, literacy centers, word work, emphasizing letter-sound associations by teaching students how to say words slowly. The teachers in this study showed evidence of providing effective instruction in general in learning to look at print. However, the majority of instructional decisions revolved around reading and overlooked the inclusion of writing to support learning to look at print.

 School of Education.


Li, Xiaolin, and Ghosh, Suvankar. “Power-Dependence and Reseller Influence on Smes’ Continued Use of Online Direct Sales Channels: An Empirical Study.” Journal of Organizational Computing & Electronic Commerce 22, no. 1 (2012): 87-106.

A dual-channel model with a physical sales channel and an online direct sales channel (ODSC) frequently causes channel conflicts. Small- and medium-sized enterprises (SMEs) using such a model may be forced to suspend ODSC to ease conflicts and maintain traditional resellers. From a channel conflict perspective, this study investigates a few critical factors underlying SMEs’ intention to continue with an existing ODSC. We develop a research model by integrating power-dependence theory and the technology acceptance model. Then we construct and administer a survey to a sample of US SMEs currently using the dual-channel model. Partial least squares regression is employed to analyze the data and evaluate the impact of four key factors on SMEs’ continuance of ODSCs: perceived business value of ODSCs, perceived ease of continuance with ODSCs, reseller dependence, and reseller forceful actions. Findings of the study contribute to the understanding of supplier-reseller relationships and continued use of information technologies among SMEs.

Beacom School of Business.


Olagundoye, Stacy Shwartz, and Lawler, Michael J. “Building Effective Program Strategies for Youth-Adult Partnerships: Reflections and Guidance on Promising Practices.” Relational Child & Youth Care Practice 24, no. 4 (2011): 63-73.

Youth-serving organizations today often employ youth-adult partnerships (YAPs) to strengthen the overall effectiveness of their mission and to provide more enriching leadership experiences for young people. This study explores YAPs — a mutually beneficial relationship in which both parties have shared voice and decision- making power — across six nominated California county 4-H Youth Development Programs. The adults and youth interviewed provided reflections on promising practices of youth-adult partnerships, and their reflections were shared with a focus group of local youth development experts in a small study. Taken together, both groups’ reflections suggested a five step strategy for creating youth- friendly environments for YAPs. This study reveals the critical conditions that the interviewees described, as well as explores the varied ways by which young people can achieve richer forms of youth participation through YAPs.

 School of Health Sciences.


Sørensen, Christina, Nilsson, Göran E., Summers, Cliff H., and Øverli, Øyvind. “Social Stress Reduces Forebrain Cell Proliferation in Rainbow Trout (Oncorhynchus Mykiss).” Behavioural Brain Research 227, no. 2 (2012): 311-18.

Abstract: Compared to mammals, teleost fish have a very high rate of adult brain cell proliferation. Still little is known about how this process is regulated in comparative models, and what its functional implications are. We investigated the effect of stressful social interaction on brain cell proliferation in size matched rainbow trout pairs after the formation of stable social hierarchies. After 4 days of interaction, socially subordinate fish displayed common signs of chronic stress including reduced feeding behaviour, elevated plasma cortisol levels, and up-regulated brain stem 5-HT activity. The number of newborn cells in the telencephalon was quantified using immunohistochemistry for the exogenously administered S-phase marker BrdU. Subordinate fish had 40% fewer BrdU-positive telencephalic cells compared to isolated controls, while dominant individuals showed a non-significant tendency towards reduced cell proliferation. Cell proliferation in subordinate animals correlated negatively with aggression received immediately after hierarchy formation, indicating that the level of cell division suppression is related to the severity of the social stressor. These findings are comparable to findings in mammalian models of psychosocial stress, indicating that the suppressive effect of social stress on brain cell proliferation is conserved, and thus likely confers adaptive benefits throughout the vertebrate subphylum.

 Biology Department.


Stoltenberg, Scott F., Lehmann, Melissa K., Christ, Christa C., Hersrud, Samantha L., and Davies, Gareth E. “Associations among Types of Impulsivity, Substance Use Problems and Neurexin-3 Polymorphisms.” Drug and Alcohol Dependence 119, no. 3 (2011): e31-e38.

Background: Some of the genetic vulnerability for addiction may be mediated by impulsivity. This study investigated relationships among impulsivity, substance use problems and six neurexin-3 (NRXN3) polymorphisms. Neurexins (NRXNs) are presynaptic transmembrane proteins that play a role in the development and function of synapses. Methods: Impulsivity was assessed with the Barratt Impulsiveness Scale Version 11 (BIS-11), the Boredom Proneness Scale (BPS) and the TIME paradigm; alcohol problems with the Michigan Alcoholism Screening Test (MAST); drug problems with the Drug Abuse Screening Test (DAST-20); and regular tobacco use with a single question. Participants (n = 439 Caucasians, 64.7% female) donated buccal cells for genotyping. Six NRXN3 polymorphisms were genotyped: rs983795, rs11624704, rs917906, rs1004212, rs10146997 and rs8019381. A dual luciferase assay was conducted to determine whether allelic variation at rs917906 regulated gene expression. Results: In general, impulsivity was significantly higher in those who regularly used tobacco and/or had alcohol or drug problems. In men, there were modest associations between rs11624704 and attentional impulsivity (p = 0.005) and between rs1004212 and alcohol problems (p = 0.009). In women, there were weak associations between rs10146997 and TIME estimation (p = 0.03); and between rs1004212 and drug problems (p = 0.03). The dual luciferase assay indicated that C and T alleles of rs917906 did not differentially regulate gene expression in vitro. Conclusions: Associations between impulsivity, substance use problems and polymorphisms in NRXN3 may be gender specific. Impulsivity is associated with substance use problems and may provide a useful intermediate phenotype for addiction. (PsycINFO Database Record (c) 2012 APA, all rights reserved) (journal abstract)

 Basic Biomedical Sciences, Vermillion Campus.


Suen, Chen S., and Burn, Paul. “The Potential of Incretin-Based Therapies in Type 1 Diabetes.” Drug Discovery Today 17, no. 1/2 (2012): 89-95.

Finding a cure for type 1 diabetes (T1D) has been elusive. Incretin-based therapies, since their approval, have demonstrated their clinical utilities in type 2 diabetes (T2D). Yet, their potential clinical benefits in T1D remain to be appraised. GLP-1, in addition to its insulinotropic action in alleviating hyperglycemia, possesses beneficial effects in protecting progressive impairment of pancreatic β-cell function, preservation of β-cell mass and suppression of glucagon secretion, gastric emptying and appetite. Preclinical data using incretin-based therapies in diabetic NOD mice demonstrated additional effects including immuno-modulation, anti-inflammation and β-cell regeneration. Thus, data accumulated hold the promise that incretin-based therapies may be effective in delaying the new-onset, halting the further progression, or reversing T1D in subjects with newly diagnosed or long-standing, established disease.

Sanford School of Medicine, Sioux Falls Campus.


Vaags, Andrea K, Lionel, Anath C, Sato, Daisuke, Goodenberger, McKinsey, and Stein, Quinn P. “Rare Deletions at the Neurexin 3 Locus in Autism Spectrum Disorder.” American Journal of Human Genetics 90, no. 1 (2012): 133-41.

The three members of the human neurexin gene family, neurexin 1 (NRXN1), neurexin 2 (NRXN2), and neurexin 3 (NRXN3), encode neuronal adhesion proteins that have important roles in synapse development and function. In autism spectrum disorder (ASD), as well as in other neurodevelopmental conditions, rare exonic copy-number variants and/or point mutations have been identified in the NRXN1 and NRXN2 loci. We present clinical characterization of four index cases who have been diagnosed with ASD and who possess rare inherited or de novo microdeletions at 14q24.3–31.1, a region that overlaps exons of the alpha and/or beta isoforms of NRXN3. NRXN3 deletions were found in one father with subclinical autism and in a carrier mother and father without formal ASD diagnoses, indicating issues of penetrance and expressivity at this locus. Notwithstanding these clinical complexities, this report on ASD-affected individuals who harbor NRXN3 exonic deletions advances the understanding of the genetic etiology of autism, further enabling molecular diagnoses.

Sanford School of Medicine, Sioux Falls Campus.


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